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The NCCN Guidelines for B-Cell Lymphomas, Version 3.2025, provide updated recommendations for the diagnosis and treatment of various types of B-cell lymphomas, emphasizing the importance of clinical trials. Key updates include revised treatment regimens for Follicular Lymphoma, Mantle Cell Lymphoma, and Diffuse Large B-Cell Lymphoma, along with changes in diagnostic procedures and supportive care recommendations. The guidelines encourage the use of independent medical judgment in patient care and are governed by a strict End-User License Agreement.

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B Cell

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

B-Cell Lymphomas
Version 3.2025 — August 18, 2025

NCCN.org

NCCN recognizes the importance of clinical trials and encourages participation when applicable and available.
Trials should be designed to maximize inclusiveness and broad representative enrollment.

NCCN Guidelines for Patients® available at www.nccn.org/patients

Continue

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

*Andrew D. Zelenetz, MD, PhD/Chair † Þ Luis E. Fayad, MD ‡ † Þ *Megan Lim, MD, PhD ≠
Memorial Sloan Kettering Cancer Center The University of Texas Memorial Sloan Kettering Cancer Center
MD Anderson Cancer Center
*Leo I. Gordon, MD/Vice Chair ‡ ξ Marcus Messmer, MD † ‡
Robert H. Lurie Comprehensive Cancer *Thomas M. Habermann, MD ‡ ξ Fox Chase Cancer Center
Center of Northwestern University Mayo Clinic Comprehensive Cancer Center Rachel Rabinovitch, MD §
*Jeremy S. Abramson, MD, MMSc † ‡ Muhammad Saad Hamid, MD ‡ University of Colorado Cancer Center
Mass General Cancer Center St. Jude Children's Research Hospital/The Praveen Ramakrishnan, MD, MS ‡
University of Tennessee Health Science Center UT Southwestern Simmons
Ranjana H. Advani, MD †
Stanford Cancer Institute Francisco Hernandez-Ilizaliturri, MD † Comprehensive Cancer Center
Roswell Park Comprehensive Cancer Center *Erin Reid, MD ‡
Babis Andreadis, MD, MSCE † ‡
UCSF Helen Diller Family *Boyu Hu, MD † ‡ Þ UC San Diego Moores Cancer Center
Comprehensive Cancer Center Huntsman Cancer Institute Kenneth B. Roberts, MD §
Nancy L. Bartlett, MD † at the University of Utah Yale Cancer Center/Smilow Cancer Hospital
Siteman Cancer Center at Barnes- Yasmin Karimi, MD ‡ Hayder Saeed, MD † ‡ Þ
Jewish Hospital and Washington University of Michigan Moffitt Cancer Center
University School of Medicine Rogel Cancer Center
Naoyuki G. Saito, MD, PhD §
L. Elizabeth Budde, MD, PhD † ξ Christopher R. Kelsey, MD § Indiana University Melvin and Bren Simon
City of Hope National Medical Center Duke Cancer Institute Comprehensive Cancer Center
Paolo F. Caimi, MD ‡ † ξ *Rebecca King, MD ≠ *Stephen D. Smith, MD ‡
Case Comprehensive Cancer Center/ Mayo Clinic Comprehensive Cancer Center Fred Hutchinson Cancer Center
University Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute Justin Kline, MD † Lode J. Swinnen, MBChB, MD † ‡ ξ
The UChicago Medicine Johns Hopkins Kimmel Cancer Center
*Julie E. Chang, MD ‡ Comprehensive Cancer Center
University of Wisconsin Joseph Tuscano, MD ‡
Susan Krivacic, MPAff ¥ UC Davis Comprehensive Cancer Center
Carbone Cancer Center Consultant
*Beth Christian, MD † Julie M. Vose, MD, MBA ‡ ξ
*Ann S. LaCasce, MD, MMSc † Fred & Pamela Buffett Cancer Center
The Ohio State University Comprehensive Dana-Farber/Brigham and
Cancer Center - James Cancer Hospital Women’s Cancer Center
and Solove Research Institute NCCN
Daniel Landsburg, MD †
Sven DeVos, MD, PhD ‡ † Þ Abramson Cancer Center Mary Dwyer, MS
UCLA Jonsson Comprehensive Cancer Center at the University of Pennsylvania Hema Sundar, PhD
Bhagirathbhai Dholaria, MD ‡ † ξ
ξ Bone marrow ≠ Pathology
Vanderbilt-Ingram Cancer Center
Continue transplantation ¥ Patient advocacy
‡ Hematology/ § Radiotherapy/
Hematology oncology Radiation oncology
Þ Internal medicine * Discussion Writing
NCCN Guidelines Panel Disclosures † Medical oncology Committee Member
Version 3.2025, 08/18/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Chetan V on 10/25/2025 1:39:09 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

NCCN B-Cell Lymphomas Panel Members

Summary of the Guidelines Updates Find an NCCN Member Institution:
https://www.nccn.org/home/member-
institutions.
• Diagnosis (DIAG-1)
• Follicular Lymphoma (FOLL-1) NCCN Categories of Evidence and
• Marginal Zone Lymphomas (MZL-1) Consensus: All recommendations are
• Mantle Cell Lymphoma (MANT-1) category 2A unless otherwise indicated.
• Diffuse Large B-Cell Lymphoma (BCEL-1) See NCCN Categories of Evidence and
• Primary Mediastinal Large B-Cell Lymphoma (PMBL-1) Consensus.
• Histologic Transformation of Indolent Lymphomas to DLBCL (HTBCEL-1) NCCN Categories of Preference:
• High-Grade B-Cell Lymphomas (HGBL-1) All recommendations are considered
• Burkitt Lymphoma (BURK-1) appropriate.
• HIV-Related B-Cell Lymphomas (HIVLYM-1)
See NCCN Categories of Preference.
• Lymphoblastic Lymphoma (BLAST-1)
• Post-Transplant Lymphoproliferative Disorders (PTLD-1)

• Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature

B-Cell Neoplasms (NHODG-A)
• Supportive Care for B-Cell Lymphomas (NHODG-B)
• Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C)
• Principles of Radiation Therapy (NHODG-D)
• Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell
Therapy (NHODG-E) NCCN Guidelines for Castleman Disease
Classification and Staging (ST-1) Primary CNS Lymphoma (NCCN Guidelines for CNS)
Abbreviations (ABBR-1)
Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma
(NCCN Guidelines for WM/LPL)

The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2025.
Version 3.2025, 08/18/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Chetan V on 10/25/2025 1:39:09 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 3.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2025 include:
Global changes
• References for suggested treatment regimens were updated throughout the guidelines.
MS-1
• The following sections of the Discussion were updated to reflect changes in the algorithm: Follicular lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma,
Primary mediastinal lymphoma, and High-grade B-cell lymphomas.
Updates in Version 2.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 1.2025 include:
Global changes
• References for suggested treatment regimens were updated throughout the guidelines.
Follicular Lymphoma
FOLL-B 2 of 6
• Second-Line Therapy,
Preferred regimens, added: Tafasitamab-cxix + lenalidomide + rituximab (≥1 prior systemic therapy including an anti-CD20 mAb) (category 2A) with corresponding
footnote k: It is unclear if tafasitamab-cxix or loncastuximab tesirine-lpyl or if any other CD19–directed therapy would have a negative impact on the efficacy of
subsequent anti-CD19 CAR T-cell therapy.
• Third-Line and Subsequent Therapy,
Other recommended regimens, added: Loncastuximab tesirine-lpyl + rituximab (category 2B) with corresponding footnote k: It is unclear if tafasitamab-cxix or
loncastuximab tesirine-lpyl or if any other CD19–directed therapy would have a negative impact on the efficacy of subsequent anti-CD19 CAR T-cell therapy.
Mantle Cell Lymphoma
MANT-A 1 of 5
• First-Line Therapy,
Less aggressive induction therapy, preferred regimens, added: Acalabrutinib (continuous) + bendamustine + rituximab (category 2A).
Diffuse Large B-Cell Lymphoma
BCEL-A 1 of 3
• Clinical utility of genetic alterations in DLBCL
1st row, removed: COL6A5
BCEL-C 2 of 7
• Second-Line Therapy
Relapsed disease <12 mo or primary refractory disease), Non-Candidates for CAR T-Cell Therapy,
◊ Preferred regimens, added: Epcoritamab-bysp + GemOx.
◊ Other recommended, revised: GemOx (gemcitabine, oxaliplatin) ± rituximab (if unable to receive epcoritamab-bysp or glofitamab-gxbm). (Also for BCEL-C 3 of 7)
BCEL-C 3 of 7
• Second-Line Therapy
Relapsed disease >12 mo, No Intention to Proceed to Transplant,
◊ Preferred regimens: Glofitamab-gxbm + GemOx changed from a category 2A to a category 1.
Discussion
MS-1
• The following sections of the Discussion were updated to reflect changes in the algorithm: HIV-related B-cell lymphomas and Post-transplant lymphoproliferative
disorders.

Continued
Version 3.2025, 08/18/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Chetan V on 10/25/2025 1:39:09 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:
Global changes
• References for suggested treatment regimens were updated throughout the guidelines.
• Statement, "An FDA-approved biosimilar is an appropriate substitute for rituximab" replaced by the general footnote: An FDA-approved biosimilar is an appropriate
substitute for any recommended systemic biologic therapy in the NCCN Guidelines.
• Diagnosis, under Adequate immunophenotyping:
Bullet revised: Cell surface marker analysis by Flow cytometry with...
• "Observe" was changed to "active surveillance" throughout.
• Footnote regarding the use of bendamustine in patients receiving T-cell engager therapy was revised as follows: In patients intended to receive CAR T-cell therapy or
CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until after CAR-T leukapheresis unless after leukapheresis
prior to CAR T-cell therapy, since it could impact the success of the patient's T-cell collection.
• New footnote was added to clarify the use bispecific antibody therapy in patients with CD20-negative lymphomas: In the setting of CD20-negative lymphomas, the
activity of CD3 x CD20 bispecific antibody therapy is unclear. Rebiopsy to confirm CD20 positivity is recommended prior to initiating CD3 x CD20 bispecific antibody
therapy.

Diagnosis
DIAG-1
• 1st bullet revised: Excisional or incisional biopsy is preferred for the definitive diagnosis or histologic grading of lymphoma.
• 2nd bullet revised: 2nd bullet revised: A fine-needle aspiration (FNA) biopsy is insufficient alone is not generally suitable for the initial diagnosis or histologic grading
of lymphoma. A core needle biopsy is not optimal but can be used under certain circumstances. Core needle biopsy (multiple biopsies preferred) is an appropriate
alternative to excisional or incisional biopsy especially in certain circumstances (when a lymph node is not easily accessible for excisional or incisional biopsy or if
surgical biopsy would cause significant morbidity or substantial treatment delays); a combination of core needle biopsy...
• 3rd bullet revised: Hematopathology review of all slides with at least one paraffin block representative of the tumor lesion. Rebiopsy if consult material is nondiagnostic,
preferably the most FDG-avid, accessible lymph node.
• Bullet removed: Histologic grading cannot be performed on an FNA.

Follicular Lymphoma
FOLL-1
• Additional diagnostic testing
Useful, 4th bullet revised by adding: CREBBP and MAP2K1
• Footnote c revised by removing: Consider NGS for TNFRSF14 and MAP2K1 mutations. (Also for FOLL-6)
FOLL-2
• Workup, Useful, bullet revised: Echocardiogram or multigated acquisition (MUGA) scan if anthracycline or anthracenedione-based regimen is indicated. (Also for
EMZLG-1, EMZLNG-1, NMZL-1, MANT-1, BURK-1, PTLD-1)
FOLL-3
• Footnote p, last sentence revised: If transformation is histologically confirmed, treat with anthracycline-based therapy treatment options should be directed towards the
large cell transformation, see HTBCEL-1. (Also for FOLL-4 and 5; footnote l on NMZL-2, 3, and 4)
FOLL-5
• NR or progressive disease, after rebiopsy, 1st bullet added: No histologic transformation (Also for NMZL-4)
FOLL-6
• Footnote v revised: If patients have an excellent prognosis, no surveillance imaging is necessary Patients typically have an excellent prognosis and therefore, the
majority of patients will not require surveillance imaging...
Continued
Version 3.2025, 08/18/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Chetan V on 10/25/2025 1:39:09 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:

EMZL of the Stomach

EMZLG-1
• Additional diagnostic testing
Essential, 3rd bullet revised: Helicobacter pylori stain (gastric), if positive, then polymerase chain reaction (PCR) or FISH for t(11;18) MALT1 rearrangements
Useful, 2nd bullet: t(14;18) added to FISH or Karyotype. The use of PCR to detect t(14;18) was removed. (Also for EMZLNG-1, SMZl-1)
Footnote c revised: Typical immunophenotype: CD10-, CD5-, CD20+, cyclin D1-, with BCL2- follicles. (Also for EMZLNG-1, NMZL-1, SMZl-1)
EMZLG-5
• After ISRT or rituximab
H. pylori positive, Lymphoma negative and H. pylori positive, Lymphoma positive, added: Second-line antibiotic treatment and reassess

Extranodal MZL of Nongastric Sites (Noncutaneous)

EMZLNG-1
• Additional diagnostic testing
Useful, 1st bullet revised: ...PCR for t(11;18) FISH for MALT1 rearrangements. (Also for NMZL-1, SMZL-1)

Nodal Marginal Zone Lymphoma

NMZL-1
• Footnote b revised: ...and cyclin D1-, may have BCL2- follicles.

Splenic Marginal Zone Lymphoma

SMZL-1
• Workup,"PET/CT scan" was moved from Useful to Essential and added to 7th bullet.
• Footnote a revised by adding: ...In patients with lymphocytosis (>3), evaluation of peripheral blood with flow cytometry and NGS panel including MYD88 mutation may
be adequate to confirm the diagnosis.

Marginal Zone Lymphomas

MZL-A 1 of 4
• First-line therapy
Other recommended regimens, rituximab revised: Rituximab (375 mg/m2 weekly for 4 doses) for EMZL (multifocal) and nodal MZL (preferred for low burden disease)

Continued

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:

Mantle Cell Lymphoma

MANT-3
• Classical TP53 mutated,
3rd bullet, options moved to MANT-A
◊ Zanubrutinib/obinutuzumab/venetoclax (suitable for all patients)
◊ Not suitable for aggressive induction therapy: Less aggressive induction therapy is recommended
◊ Suitable for aggressive induction therapy: TRIANGLE regimen with covalent BTKi + rituximab maintenance is recommended
MANT-5
• Additional therapy
After PR, revised from "Consider second-line therapy" to "Chemoimmunotherapy (MANT-A) to achieve CR or If covalent BTKi naive, then covalent BTKi (preferred)
(MANT-A)"
After "If covalent BTKi naive, then covalent BTKi (preferred) (MANT-A)" added: Continue covalent BTKi until progression
• Footnote r revised: Patients Active surveillance is recommended for patients who have achieved a very good PR or better can be observed or consider rituximab
maintenance.
MANT-6
• Relapsed/Refractory Disease, Second-line therapy with fixed-duration regimens
After PR, added: Active surveillance
Footnote t added: Patients with a very good PR are potentially candidates for active surveillance. Patients with a minimal PR are considered as having refractory
disease and go on to additional treatment.
MANT-A 1 of 5
• Regimens reorganized by stage and TP53 mutation status.
MANT-A 2 of 5
• Second-Line and Subsequent Therapy
Added: Progressive disease after CAR T-cell therapy and pirtobrutinib or ineligible for CAR T-cell therapy
◊ Added: Glofitamab-gxbm (category 2B)
MANT-A 3 of 5
• Footnote c added: In selected cases, relapsed disease may be managed with induction therapy recommended for newly diagnosed advanced stage MCL.
• Footnote k revised: Patients with ibrutinib intolerance have been successfully treated with acalabrutinib or zanubrutinib without recurrence of symptoms. Pirotbrutinib
is effective for the management of resistance to covalent BTKi, including in patients with BTK C481 mutations (which is uncommon in MCL). Patients with
intolerance to a BTKi will often be successfully treated with an alternate BTKi (covalent or non-covalent).
• Footnote m added: Pirtobrutinib can be given as second-line therapy for disease progression during induction or maintenance therapy with covalent BTKi-based
regimens.

Continued

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:

Diffuse Large B-Cell Lymphoma

BCEL-1
• Additional diagnostic testing
Essential, IHC panel: CD5, CD45 and Ki-67 moved from Essential to Useful.
Useful, 4th bullet added: NGS lymphoma panel. Corresponding footnote b added: See BCEL-A 1 of 3 for a minimal list of accepted genes that should be included in
the NGS lymphoma panel for DLBCL.
BCEL-3
• Stage I, II (excluding stage II with extensive mesenteric disease)
Non-bulky, "smIPI 0" clarified as "smIPI 0–1."
BCEL-4
• Header revised: STAGE I (smIPI 0 smIPI 0–1; Non-bulky; <7.5 cm)
• After restage with PET/CT scan, "No response" was added to "Progressive disease"
After follow-up, relapse was clarified with "relapse <12 mo" and "relapse >12 mo". (Also for BCEL-5 and BCEL-6)
• Footnote v revised by adding: If end-of treatment PET is positive, consider repeat biopsy or if biopsy not feasible, consider circulating tumor DNA (ctDNA) for minimal
residual disease (MRD) (ctDNA-MRD) assessment (category 2B), using a test with a detection limit of <1 part per million, prior to additional therapy. If biopsy and/or
ctDNA-MRD–negative, follow PET-negative pathway. (Also for BCEL-5 and footnote aa on BCEL-6)
• Footnote w revised by adding: Surveillance imaging at 12 mo has treatment implications. (Also for BCEL-5 and BCEL-6)
BCEL-7
• Relapsed disease <12 mo or Primary refractory disease, after complete response, added: Consolidation with HDT/ ASCR ± ISRT (optional)
• Footnote ff added: If patient's clinical situation improves markedly and patient becomes eligible for HDT/ASCR. This may include patients who do not have access to
CAR T-cell therapy. Additional RT can be given before or after transplant to sites of previous positive disease.
BCEL-10
• Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
Second-line therapy, manage as relapsed/refractory DLBCL clarified with "<12 mo (BCEL-7)" and ">12 mo (BCEL-8)."
BCEL-A 1 of 3
• New table added: Clinical Utility of Genetic Alterations in DLBCL.
BCEL-C 1 of 7
• Concurrent presentation with CNS disease
1st bullet revised: ... Different schedules have been used for the integration of high-dose methotrexate with RCHOP early- or mid-cycle or; however, the Panel prefers
day 15 of a 21-day cycle)

Continued
Version 3.2025, 08/18/25 © 2025 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
UPDATES
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
Printed by Chetan V on 10/25/2025 1:39:09 AM. Copyright © 2025 National Comprehensive Cancer Network, Inc. All Rights Reserved.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:

Diffuse Large B-Cell Lymphoma (continued)

BCEL-C 2 of 7 and BCEL-C 3 of 7
• Second-line therapy regimens reorganized by duration of relapse and/or primary refractory disease
Relapsed disease <12 mo or primary refractory disease
◊ Candidates for CAR T-Cell Therapy
◊ Non-Candidates for CAR T-Cell Therapy
Relapsed disease >12 mo
◊ Intention to Proceed to Transplant
◊ No Intention to Proceed to Transplant
BCEL-C 2 of 7
• Second-line therapy regimens, Relapsed disease <12 mo or primary refractory disease
Non-Candidates for CAR T-Cell Therapy,
◊ Preferred regimens,
– Added: Glofitamab-gxbm + GemOx (category 2A)
– Added: Polatuzumab vedotin-piiq + mosunetuzumab-axgb (category 2A)
– Revised: Tafasitamab-cxix + lenalidomide (excluding primary refractory disease)
◊ Other recommended regimens
– 3rd bullet revised: GemOx (gemcitabine, oxaliplatin) ± rituximab (if unable to receive glofitamab-gxbm) (Also for BCEL-C 3 of 7)
– Removed: DA-EPOCH ± rituximab
BCEL-C 3 of 7
• Second-line therapy regimens, Relapsed disease >12 mo
No Intention to Proceed to Transplant
◊ Preferred regimens
– Revised: CAR T-cell therapy (CD19-directed) (with bridging therapy as needed; BCEL-C 2 of 7) (if eligible)
– Added: Glofitamab-gxbm + GemOx (category 2A)
– Added: Polatuzumab vedotin-piiq + mosunetuzumab-axgb (category 2A)
◊ Other recommended regimens
– Removed: DA-EPOCH ± rituximab
BCEL-C 4 of 7
• Third-line and subsequent therapy
Added: Brentuximab vedotin + lenalidomide + rituximab (for CD30+ disease) (category 2A)
BCEL-C 5 of 7
• Footnotes
Footnote d added: Patients with a known history of histologic transformation of indolent lymphoma were not included in the POLARIX study.
Footnote q added: Responses with BV have been seen in patients with a low level of CD30 positivity and any level of CD30 positivity is acceptable for the use of BV-
based regimens.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:

Primary Mediastinal Large B-Cell Lymphoma

PMBL-1
• Footnote j added: Responses with BV have been seen in patients with a low level of CD30 positivity and any level of CD30 positivity is acceptable for the use of BV-
based regimens.
Histologic Transformation of Indolent Lymphomas to DLBCL
HTBCEL-1
• Revised: Histologic transformation of FL to DLBCL after minimal or no prior therapy
• Removed: Histologic transformation of MZL to DLBCL after minimal or no prior therapy
• Revised: Histologic transformation of FL or MZL to DLBCL after multiple lines of prior therapies
• Footnote d revised: This includes ≥2 of chemoimmunotherapy regimens for indolent or transformed disease lymphomas prior to histologic transformation. (Also for
HTBCEL-3)
HTBCEL-2
• PR or NR or progressive disease revised: Second-line therapy CAR T-cell therapy (HTBCEL-A) with or without bridging therapy (if eligible). If not eligible, see....

High-Grade B-Cell Lymphomas (HGBL)

HGBL-1
• Treatment options
HGBL with MYC and BCL2 rearrangements with or without BCL6 rearrangements DLBCL/HGBL with MYC and BCL2 rearrangements
◊ Removed: Pola-R-CHP (polatuzumab vedotin-piiq, rituximab, cyclophosphamide, doxorubicin, prednisone)
HGBL-NOS
◊ Added: Pola-R-CHP (polatuzumab vedotin-piiq, rituximab, cyclophosphamide, doxorubicin, prednisone) (category 2B)

Burkitt Lymphoma
BURK-1
• Workup
8th bullet combined with C/AP CT and revised: PET/CT scan (preferred; initiation of therapy should not be delayed for PET/CT scan) or C/A/P CT with contrast of
diagnostic quality; pretreatment imaging is essential. Corresponding footnote f added: If obtaining PET scan is delayed due to logistics, a C/A/P CT scan should be
obtained.
"Unilateral or bilateral bone marrow biopsy ± aspirate" moved from Essential to Useful.
• Footnote removed: Most common karyotype is MYC rearrangement as a sole abnormality. There is an uncommon variant of BL without MYC rearrangement but with
11q aberration (LBCL with 11q aberration [ICC]; HGBL with 11q aberrations [WHO5]). Optimum management of this rare subtype is undefined, though it is most often
treated like typical BL.
BURK-2
• Risk assessment, low risk revised: Normal LDH or and Stage I (Single extraabdominal mass <10 cm) and or Completely resected abdominal lesion or Single
extraabdominal mass <10 cm
• Follow-up, revised: C/A/P CT scan with contrast no more often than every 6 mo for 2 1 y after completion of treatment, then only as clinically indicated.
• Footnote k revised: Relapse after 2 y 1 y is rare uncommon; therefore, follow-up should be individualized according to patient characteristics.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:
Burkitt Lymphoma (continued)
BURK-A 1 of 3
• Induction therapy
Dose-adjusted EPOCH + rituximab regimen for low-risk disease clarified as "DA-EPOCH-RR (rituximab day 1 and 5) x 2 cycles followed by PET scan..."
BURK-A 2 of 3
• Second-line therapy, Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab for 6 cycles (if not previously given) + IT
methotrexate. Removed low-risk and high-risk bullets.
• Added bullet: For patients presenting with symptomatic CNS disease; initiate treatment with the portion of the systemic therapy that contains CNS-penetrating drugs).

HIV-Related B-Cell Lymphomas

HIVLYM-2
• Workup, "Lumbar puncture, except for PEL" moved from Essential to Useful
HIVLYM-4
• DLBCL..., after "For relapse" was clarified with "<12 mo (BCEL-7)" and ">12 mo (BCEL-8)"
• Plasmablastic lymphoma, for relapse, added: brentuximab vedotin (category 2A)
HIVLYM-A
• DLBCL, HHV8-POSITIVE DLBCL, NOS, PEL - First-line therapy
Added: If CD20-, rituximab is not indicated
Post-Transplant Lymphoproliferative Disorders
PTLD-1
• Additional diagnostic testing extensively updated.
• Workup, Useful, added: Hepatitis C testing
• Footnote f revised: In the WHO5, hyperplasia includes follicular hyperplasia, infectious mononucleosis-like hyperplasia (IMH), and plasmacytic hyperplasia (PCH); in
the ICC these three types are considered non-destructive.
• Footnote removed: Non-destructive lesions in the ICC Classification are of B-cell type and include PCH, infectious mononucleosis, and florid follicular hyperplasia.
PTLD-A
• Sequential chemoimmunotherapy
Rituximab, 1st sub-bullet revised: Restage with PET/CT scan (in 2 to 4 weeks)
• Concurrent chemoimmunotherapy
Added: Pola-R-CHP (polatuzumab vedotin-piiq, rituximab, cyclophosphamide, doxorubicin, prednisone) (≥ IPI 2) (category 2A)

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B-Cell Lymphomas Discussion

Updates in Version 1.2025 of the NCCN Guidelines for B-Cell Lymphomas from Version 3.2024 include:

Supportive Care for B-Cell Lymphomas

NHODG-B 4 of 5
• Anti-Infective Prophylaxis, 2nd bullet added: Pemivibart for pre-exposure prophylaxis of COVID-19 for individuals with moderate to severe immunocompromise.

Principles of Radiation Therapy

NHODG-D 3 of 4
• General dose guidelines, Definitive RT
• Revised: Marginal zone lymphoma (MZL): 24 Gy
EMZL of the stomach: can be treated with 24–30 Gy in 20 fractions 24 Gy in 16 fractions (1.5 Gy/fractions) to minimize acute GI toxicity.
◊ 4 Gy in 2 fractions has been used. However, additional 20 Gy is needed for some patients and careful follow-up is needed.
• Revised: MCL: 24–36 Gy
Primary treatment (without chemoimmunotherapy) - 36 Gy
Consolidation after chemoimmunotherapy
◊ CR - 24–30 Gy
◊ PR - 36 Gy
• DLBCL/HGBL/PMBL/MGZL
Primary treatment (without chemoimmunotherapy) revised from "40–55 Gy" to "40 Gy"
4th sub-bullet revised by adding: In combination with HCT: 20–36 Gy, depending on sites of disease and prior RT exposure; hypofractionate as appropriate to
expedite HCT procedure)
• Added: Bridging RT with CAR T-cell Therapy
Localized disease - 20–40 Gy (higher doses and comprehensive coverage preferred if feasible; hypofractionate as appropriate to expedite CAR T-cell procedure)
Extensive disease - 20–30 Gy (hypofractionate as outlined above)

Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy
NHODG-E 1 of 4
• Last bullet added: Secondary malignancies may develop. Monitor life-long for secondary malignancies. (Also for NHODG-E 3 of 4 and NHODG-E 4 of 4)

Discussion
MS-1
• The following sections of the Discussion were updated to reflect changes in the algorithm: Marginal zone lymphomas, Histologic Transformation of
Indolent Lymphomas to DLBCL and Burkitt Lymphoma.

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B-Cell Lymphomas Discussion

DIAGNOSIS ADDITIONAL
DIAGNOSTIC TESTINGb

• Follicular lymphoma (FL) FOLL-1

• Excisional or incisional biopsy is preferred for • Extranodal marginal zone lymphoma (EMZL) EMZLG-1
the definitive diagnosis or histologic grading of
lymphoma. of the stomach
• A fine-needle aspiration (FNA) biopsy is insufficient
• EMZL of nongastric sites (noncutaneous) EMZLNG-1
for the initial diagnosis or histologic grading
of lymphoma. Core needle biopsy (multiple
biopsies preferred) is an appropriate alternative to • Nodal marginal zone lymphoma (NMZL) NMZL-1
excisional or incisional biopsy especially in certain
circumstances (when a lymph node is not easily • Splenic marginal zone lymphoma (SMZL) SMZL-1
accessible for excisional or incisional biopsy or if
surgical biopsy would cause significant morbidity
or substantial treatment delays); a combination of • Mantle cell lymphoma (MCL) MANT-1
core needle biopsy (multiple biopsies preferred)
and FNA biopsy in conjunction with appropriate • Diffuse large B-cell lymphoma (DLBCL) BCEL-1
ancillary techniques for the differential diagnosis
(immunohistochemistry [IHC], flow cytometry, • High-grade B-cell lymphomas (HGBL) HGBL-1
molecular analysis to detect immunoglobulin [Ig]
gene rearrangements, karyotype or fluorescence in
situ hybridization [FISH] for major translocationsa) • Burkitt lymphoma (BL) BURK-1
may be sufficient for diagnosis.
• Hematopathology review of all slides with at least • HIV-related B-cell lymphomas HIVLYM-1
one paraffin block representative of the lesion.
Rebiopsy if consult material is nondiagnostic, • Lymphoblastic lymphoma (LL) BLAST-1
preferably the most FDG-avid, accessible lymph
node.
• Post-transplant
lymphoproliferative disorders (PTLD) PTLD-1

a Ifa high suspicion of a clonal process remains and other techniques have not resulted in a clear identification of a clonal process, then next-generation
sequencing (NGS) can be used.
b Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell Neoplasms (NHODG-A).

Note: All recommendations are category 2A unless otherwise indicated.

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Follicular Lymphoma Discussion

ADDITIONAL DIAGNOSTIC TESTINGa

In the 2022 WHO classification (WHO5), follicular lymphoma (FL) grades 1, 2, and 3A are termed as classic FL (cFL). International Consensus classification (ICC) has
retained the grading for FL (1–2, 3A, and 3B). FL1–2 (ICC) are managed according to the treatment recommendations for cFL (WHO5). FL3B (ICC)/follicular large
B-cell lymphoma (FLBCL; WHO5) is commonly treated as DLBCL (BCEL-1). Any area of DLBCL in FL of any grade should be diagnosed and treated as a DLBCL
(BCEL-1). The management of FL3A (ICC) is controversial and treatment should be individualized.

ESSENTIAL:
• Adequate immunophenotyping to establish diagnosisb Workup
Classic FL (cFL; WHO5)
IHC panel: CD20, CD3, CD5, CD10, BCL2,c BCL6, CD21, or CD23, (FOLL-2)
with or without BCL2-R negative, CD23-positive
Flow cytometry with peripheral blood and/or biopsy specimen: kappa/ follicle center lymphoma (ICC)/ Manage as cFL
lambda, CD19, CD20, CD5, CD23, CD10 FL with predominantly diffuse (FOLL-2)
growth pattern (dFL) (WHO5)d
USEFUL UNDER CERTAIN CIRCUMSTANCES:
• Molecular analysis to detect: Ig gene rearrangements; BCL2 Large B-cell lymphoma
rearrangements (LBCL) with IRF4/MUM1 BCEL-2
• Karyotype or FISH: t(14;18)c; BCL6, 1p36,d IRF4/MUM1 rearrangementse rearrangemente
• IHC panel: Ki-67f; IRF4/MUM1 for FL grade 3, cyclin D1
• Next-generation sequencing (NGS) panel including CREBBP, EZH2, Pediatric-type FL
MAP2K1, TNFRSF14, and STAT6 mutation FOLL-6
(PTFL) (in adults)c

d BCL2-R negative, CD23-positive follicle center lymphoma (ICC)/dFL (WHO5)

has a predominantly diffuse pattern, pelvis/inguinal location, and common STAT6
mutations along with 1p36 deletion or TNFRSF14 mutation.
e LBCL with IRF4/MUM1 rearrangement are usually DLBCL but occasionally are
a Germinal center (GC) or follicular center cell phenotype is not equivalent to FL purely FL3B (ICC/FLBCL [WHO5]) and often DLBCL with FL3B. Patients typically
and occurs in BL and some DLBCL. present with Waldeyer’s ring involvement and are often children/young adults.
b Typical immunophenotype: CD10+, BCL2+, CD23+/-, CD43-, CD5-, CD20+, These lymphomas are locally aggressive but respond well to chemotherapy ±
BCL6+. Rare cases of FL may be CD10- or BCL2-. radiation therapy (RT). They do not have a BCL2 rearrangement and should not
c In young patients with localized disease that lacks BCL2 expression or t(14;18), be treated as low-grade FL.
differential diagnosis should include PTFL in adult; BCL2-R negative, CD23- f There are reports showing that FL1–2 with a Ki-67 proliferation fraction of >30%
positive follicle center lymphoma (ICC)/dFL (WHO5) and LBCL with IRF4/MUM1 may be associated with a more aggressive clinical behavior, but there is no
rearrangement. evidence that this should guide treatment decisions.

Note: All recommendations are category 2A unless otherwise indicated.

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Classic Follicular Lymphoma Discussion

WORKUP
ESSENTIAL:
• Physical exam: attention to node-bearing areas, including Waldeyer’s ring, and
to size of liver and spleen
• Performance status
• B symptoms
• Complete blood count (CBC) with differential Stage Initial Therapy
• Lactate dehydrogenase (LDH) I, II (FOLL-3)
• Comprehensive metabolic panel
• Hepatitis B testingg
• PET/CT scan (preferred) or chest/abdomen/pelvis (C/A/P) CT with contrast of
diagnostic quality if systemic therapy is planned
• Bone marrow biopsy + aspirate (to document clinical stage I–II disease if
involved-site radiation therapy [ISRT] planned, or to evaluate unexplained
cytopenias)h
• Pregnancy testing in patients of childbearing age (if chemotherapy or radiation
therapy [RT] planned)

USEFUL IN SELECTED CASES:

• Echocardiogram or multigated acquisition (MUGA) scan if anthracycline-based
regimen is indicated
• Neck CT with contrast Stage Initial Therapy
• PET/CT scan if RT planned for stage I, II disease III, IV (FOLL-4)
• Beta-2-microglobulin (necessary for calculation of FLIPI-2)
• Uric acid
• Serum protein electrophoresis (SPEP) and/or quantitative Ig levels
• Hepatitis C testing
• Discuss fertility preservationi

g Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen (HBsAg) and core
antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and
consider consult with gastroenterologist.
h Bilateral or unilateral provided core biopsy is >2 cm. If active surveillance is initial therapy, bone marrow biopsy may be deferred.
i Fertility preservation options include: sperm banking, semen cryopreservation, in vitro fertilization (IVF), or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

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Classic Follicular Lymphoma Discussion

STAGE INITIAL THERAPY RESPONSE TO THERAPYo,p FOLLOW-UPq

CR or
j,k
ISRT (preferred) PR See Stage III, IV (FOLL-4)
Stage I or
or NR
or If histologic transformation,
Contiguous j
ISRT + anti-CD20 monoclonal see HTBCEL-1
stage II l
antibody (mAb) ± chemotherapy CR or Clinical
(FOLL-B) m PR • H&P and labs every
or See NR or progressive 3–6 mo for 5 y and
Progressive
Anti-CD20 mAbl ± chemotherapy then annually or as
disease (FOLL-5) disease,o,p see
(FOLL-B) m in certain NR or clinically indicated
Stage III, IV
Stage circumstancesn If histologic transformation, Surveillance imagingr
(FOLL-4)
I, II see HTBCEL-1 • Up to 2 y post
or
completion of
Anti-CD20 mAb ± l CR If histologic
treatment: C/A/P CT
chemotherapy transformation,
CR or scan with contrast no
(FOLL-B) m ± ISRT Consider see HTBCEL-1
PR more than every 6 mo
Non- for local palliationj PR or ISRTj if not See NR or • >2 y: No more than
contiguous NR previously progressive disease annually
stage II or given NR (FOLL-5) or
If histologic
transformation,
see HTBCEL-1
Active surveillancek
p Consider
possibility of histologic transformation in patients with progressive disease,
especially if LDH levels are rising, single site is growing disproportionately, extranodal
disease develops, or there are new B symptoms. If clinical suspicion of transformation,
j Principles of Radiation Therapy (NHODG-D). FDG-PET may help identify areas suspicious for transformation. FDG-PET scan
k Active surveillance may be appropriate in circumstances where potential demonstrating marked heterogeneity or sites of intense FDG avidity may indicate
toxicity of ISRT or systemic therapy outweighs potential clinical benefit in transformation, and biopsy should be directed biopsy at the most FDG-avid area.
consultation with a radiation oncologist. Functional imaging does not replace biopsy to diagnose transformation. If transformation
l Anti-CD20 mAbs include rituximab or obinutuzumab. Obinutuzumab is not is histologically confirmed, treatment options should be directed towards the large cell
indicated as single-agent therapy. transformation, see HTBCEL-1.
q Follow-up includes diagnostic tests and imaging using the same modalities performed
m Initiation of systemic therapy can improve failure-free survival (FFS), but
during workup as clinically indicated. Imaging should be performed whenever there are
has not been shown to improve overall survival. These are options for clinical indications. For surveillance imaging, see Discussion for consensus imaging
initial therapy. recommendations.
n Eg, for patients with bulky intra-abdominal or mesenteric stage I disease. r Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease
o Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT
PET/CT scan should be interpreted via the PET Five-Point Scale (5-PS). scans for surveillance.

Note: All recommendations are category 2A unless otherwise indicated.

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Classic Follicular Lymphoma Discussion

STAGE MANAGEMENT AND FOLLOW-UPq

Clinical
Progressive
• H&P and labs every 3–6 mo for 5 y and
diseaseo,p
Active then annually or as clinically indicated
Evaluate for indications No or
surveillance Surveillance imagingr
for treatments: indication If histologic
(category 1) • Up to 2 y: C/A/P CT scan with contrast
• Candidate for clinical trial transformation,
no more than every 6 mo
• Symptoms see HTBCEL-1
• >2 y: CT scan no more than annually
• Threatened end-organ
Stage function
III, IV • Clinically significant or
progressive cytopenia
secondary to lymphoma
• Clinically significant
See Suggested Regimens (FOLL-B)
bulky diseases Response
or
• Steady or rapid Indication PET/CT Assessment
Clinical trial
progressionp present scanp and Additional
and/or
Therapy (FOLL-5)
Palliative ISRTj

j Principles of Radiation Therapy (NHODG-D).

o Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.
p Consider possibility of histologic transformation in patients with progressive disease, especially if LDH levels are rising, single site
is growing disproportionately,
extranodal disease develops, or there are new B symptoms. If clinical suspicion of transformation, FDG-PET may help identify areas suspicious for transformation. FDG-
PET scan demonstrating marked heterogeneity or sites of intense FDG avidity may indicate transformation, and biopsy should be directed biopsy at the most FDG-avid
area. Functional imaging does not replace biopsy to diagnose transformation. If transformation is histologically confirmed, options should be directed towards the large
cell transformation, see HTBCEL-1.
q Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever
there are clinical indications. For surveillance imaging, see Discussion for consensus imaging recommendations.
r Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to
proceed with PET/CT scans for surveillance.
s GELF criteria (FOLL-A).

Note: All recommendations are category 2A unless otherwise indicated.

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Classic Follicular Lymphoma Discussion

RESPONSE ASSESSMENTo AND FOLLOW-UPq SECOND-

ADDITIONAL THERAPY LINE AND
Consolidation or
SUBSEQUENT
Clinical THERAPY
extended therapy • H&P and labs every
(optional) 3–6 mo for 5 y and Evaluate for
(FOLL-B) Relapsed or indications for
CRo then annually or as
or clinically indicated Progressive treatments:
Active Surveillance imagingr diseaseo,p • Candidate for
surveillance or clinical trial No
• Up to 2 y post Active surveillance
If histologic • Symptoms indication
completion of
Consolidation or transformation, • Threatened end-
treatment: C/A/P CT organ function
extended therapy scan with contrast see HTBCEL-1
PET/CT (optional) • Clinically
no more than every significant or See
(preferred) (FOLL-B) Suggested
or
6 mo progressive
or C/A/P • >2 y: CT scan no cytopenia Regimens
CT scan Active surveillance (FOLL-B)
PRo,t or more than annually secondary to
or
with lymphoma
contrast In third-line
• Clinically Clinical trial
systemic therapy significant bulky or
or later: T-cell– Indication PET/CT Palliative
diseases scanp
engager therapy • Steady or rapid
present ISRTj
(FOLL-B) progressionp
• No histologic transformation
NR or progressive • If histologic transformation, see HTBCEL-1
Rebiopsy
diseaseo,p • In third-line systemic therapy or later:
T-cell–engager therapy (FOLL-B)
j Principles of Radiation Therapy (NHODG-D).
o Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan q Follow-up includes diagnostic tests and imaging using the same modalities
should be interpreted via the PET 5-PS.
p Consider possibility of histologic transformation in patients with progressive disease, performed during workup as clinically indicated. Imaging should be performed
especially if LDH levels are rising, single site is growing disproportionately, extranodal whenever there are clinical indications. For surveillance imaging, see
disease develops, or there are new B symptoms. If clinical suspicion of transformation, Discussion for consensus imaging recommendations.
r Surveillance imaging is used for monitoring asymptomatic patients. When
FDG-PET may help identify areas suspicious for transformation. FDG-PET scan
a site of disease can only be visualized on PET/CT scan (eg, bone), it is
demonstrating marked heterogeneity or sites of intense FDG avidity may indicate appropriate to proceed with PET/CT scans for surveillance.
transformation, and biopsy should be directed biopsy at the most FDG-avid area. s GELF criteria (FOLL-A).
Functional imaging does not replace biopsy to diagnose transformation. If transformation t A PET-positive PR is associated with a shortened progression-free survival
is histologically confirmed,treatment options should be directed towards the large cell (PFS) (Discussion); however, additional treatment at this juncture has not
transformation, see HTBCEL-1. been shown to change outcome.

Note: All recommendations are category 2A unless otherwise indicated.

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Pediatric-Type Follicular Lymphoma Discussion

PEDIATRIC-TYPE FOLLICULAR LYMPHOMA IN ADULTS

PATHOLOGIC AND CLINICAL STAGING WORKUP TREATMENT
PRESENTATIONc,u

• Pathologic
Morphology: expansile follicles,
effacement of architecture, absence
of diffuse area
Expresses: BCL6, CD10, ± IRF4/
MUM1 (~20%) Active
Excision (preferred) surveillancev Active
Proliferation index (Ki-67/MIB-1) >30% or CRo
No rearrangement of BCL2, BCL6, surveillancev
• PET/CT scan ISRTj
IRF4/MUM1 or
• Bone marrow Stage
• Clinical RCHOP for patients
biopsy I, IIu Restage with
Localized disease (stage I, II) with extensive local
(optional) PET/CT
Head and neck (tonsillar, cervical, disease who are
submandibular, submental, not candidates for
postauricular, or periparotid lymph excision or ISRT NR or
nodes) or less common inguinal Progressive
<CR disease
lymph nodes
Male sex predominant (FOLL-5)
Younger age than typical FL (though
can occur in adults >60 years)

c In young patients with localized disease that lacks BCL2 expression or t(14;18), differential diagnosis should include PTFL in adults, BCL2-R negative, CD23-positive
follicle center lymphoma (ICC)/dFL (WHO5) and LBCL with IRF4/MUM1 rearrangement.
j Principles of Radiation Therapy (NHODG-D).
o Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.
u Localized disease (stage I, II) is the most common presentation. If the patient has disease >stage II, it is by definition not PTFL.
v Patients typically have an excellent prognosis and therefore, the majority of patients will not require surveillance imaging. There are no data to support maintenance
therapy.

Note: All recommendations are category 2A unless otherwise indicated.

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Classic Follicular Lymphoma Discussion

Nodal Areas
GELF CRITERIAa,b
• Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm Right Cervical Left Cervical
• Any nodal or extranodal tumor mass with a diameter of ≥7 cm Preauricular
Upper Cervical
Preauricular
Upper Cervical
• B symptoms Median or Lower Median or Lower
• Splenomegaly Postcervical
Supraclavicular
Postcervical
Supraclavicular
• Pleural effusions or peritoneal ascites
Mediastinal
• Cytopenias (leukocytes <1.0 x 109/L and/or platelets <100 x 109/L) Paratracheal
• Leukemia (>5.0 x 109/L malignant cells) Mediastinal
Hilar
Right Axillary Left Axillary

Right Epitrochlear Left Epitrochlear

FLIPI - 1 CRITERIAa,c,d
Para-Aortic Mesenteric
RISK FACTORS RISK GROUPS Para-Aortic Mesenteric
Common Iliac Splenic Hilar
• Age ≥60 y Number of factors External Iliac Portal
Celiac
• Ann Arbor Stage III–IV Low 0–1
Right Inguinal Left Inguinal
• Hemoglobin level <12 g/dL Intermediate 2 Inguinal Inguinal
Femoral
• Serum LDH level >ULN High ≥3 Femoral

• Number of nodal sitesd ≥5 Right Popliteal Left Popliteal

Legend for labels

ULN = upper limit of normal Blue = Bilateral
Black = Midline

Mannequin used for counting the number of involved areas.e

© 2007 Dana-Farber Cancer Institute, Inc.
All rights reserved. Permission is hereby granted for copying this image by photocopy or similar process
for use in the practice of medicine or for research purposes. No other use is permitted which will infringe
the copyright without the express written consent of Dana-Farber Cancer Institute, Inc.
a These criteria may be clinically useful to guide initiation of treatment.
b Solal-Celigny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen d FLIPI-2 (Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma
with or without interferon alfa 2b for advanced follicular lymphomas: final international prognostic index 2: a new prognostic index for follicular lymphoma
analysis of survival and toxicity in the Groupe d'Etude des Lymphomes developed by the international follicular lymphoma prognostic factor project. J
Folliculaire 86 trial. J Clin Oncol 1998;16:2332-2338. Clin Oncol 2009;27:4555-4562) predicts for outcomes after active therapy; see
c This research was originally published in Blood. Solal-Celigny P, Roy P, Colombat P, Discussion.
et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258- e The map is used to determine the number of nodal sites in FLIPI-1 criteria and is
1265. © the American Society of Hematology. different than the conventional Ann Arbor site map.

Note: All recommendations are category 2A unless otherwise indicated.

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Classic Follicular Lymphoma Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

FIRST-LINE THERAPY FIRST-LINE EXTENDED THERAPY (optional)

Preferred regimens, high tumor burden (in alphabetical order) Preferred regimens following chemoimmunotherapy
• Bendamustined + obinutuzumabe or rituximab • Rituximab maintenance 375 mg/m2 one dose every 8–12 weeks for 2
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + years for patients initially presenting with high tumor burden (category 1)g
obinutuzumabe or rituximab • Obinutuzumab maintenance (1 g every 8 weeks for 12 doses)
• CVP (cyclophosphamide, vincristine, prednisone) + obinutuzumabe or
rituximab Other recommended regimens
• Lenalidomide + rituximab • If initially treated with single-agent rituximab, rituximab maintenance 375
mg/m2 one dose every 8 weeks for 4 doses
Preferred regimen, low tumor burden
• Rituximab (375 mg/m2 weekly for 4 doses)f

Other recommended regimen Footnotes on FOLL-B 4 of 6

• Lenalidomide + obinutuzumab (category 2B)
Second-line Therapy on FOLL-B 2 of 6

FIRST-LINE THERAPY FOR OLDER OR INFIRM Third-line and Subsequent Therapy on FOLL-B 3 of 6
(if none of the above are expected to be tolerable
in the opinion of treating physician)
Preferred regimen
• Rituximab (375 mg/m2 weekly for 4 doses)

Other recommended regimens

• Chlorambucil ± rituximab
• Cyclophosphamide ± rituximab

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B
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SUGGESTED TREATMENT REGIMENSa,b,c

SECOND-LINE THERAPYh
Preferred regimens (in alphabetical order)
• Bendamustined,i + obinutuzumabj or rituximab (not recommended if treated with prior bendamustine)
• CHOP + obinutuzumabj or rituximab
• CVP + obinutuzumabj or rituximab
• Lenalidomide + rituximab
• Tafasitamab-cxixk + lenalidomide + rituximab (≥1 prior systemic therapy including an anti-CD20 mAb)
Other recommended regimens (in alphabetical order)
• Lenalidomide (if not a candidate for anti-CD20 mAb therapy)
• Lenalidomide + obinutuzumab
• Obinutuzumab
• Rituximab

SECOND-LINE THERAPY FOR OLDER OR INFIRM

(if none of the therapies are expected to be tolerable in the opinion of treating physician)
Preferred regimens
• Rituximab (375 mg/m2 weekly for 4 doses)
• Tazemetostatl (irrespective of EZH2 mutation status)
Other recommended regimen
• Cyclophosphamide ± rituximab

SECOND-LINE EXTENDED THERAPY (optional)

Preferred regimens
• Rituximab maintenance 375 mg/m2 one dose every 12 weeks for 2 years (category 1)
• Obinutuzumab maintenance for rituximab-refractory disease (1 g every 8 weeks for total of 12 doses)

SECOND-LINE CONSOLIDATION THERAPY (optional)

• High-dose therapy with autologous stem cell rescue (HDT/ASCR)

Consider prophylaxis for tumor lysis syndrome (NHODG-B) Footnotes on FOLL-B 4 of 6

See monoclonal antibody and viral reactivation (NHODG-B) See Third-Line and Subsequent Therapy on FOLL-B 3 of 6

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B
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SUGGESTED TREATMENT REGIMENSa,b,c

THIRD-LINE AND SUBSEQUENT THERAPY

Subsequent systemic therapy options include second-line therapy regimens (FOLL-B 2 of 6) that were not previously given.
Preferred regimens (in alphabetical order) Other recommended regimens
• T-cell engager therapy • EZH2 inhibitor
Bispecific antibody therapyl,m Tazemetostatl (irrespective of EZH2 mutation status)
◊ Epcoritamab-bysp • BTK inhibitor (BTKi)
◊ Mosunetuzumab-axgb Zanubrutinibl + obinutuzumab
Chimeric antigen receptor (CAR) T-cell therapy n • Loncastuximab tesirine-lpyl + rituximab (category 2B)k
◊ Axicabtagene ciloleucel (CD19-directed)
◊ Lisocabtagene maraleucel (CD19-directed)
◊ Tisagenlecleucel (CD19-directed)

THIRD-LINE CONSOLIDATION THERAPY

Useful in Certain Circumstances
• Allogeneic hematopoietic cell transplantation (HCT) in selected caseso

Footnotes on FOLL-B 4 of 6

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B
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Table of Contents
Classic Follicular Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

FOOTNOTES
a See references for regimens on FOLL-B 5 of 6 and FOLL-B 6 of 6.
b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human
injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
c The choice of therapy requires consideration of many factors, including age, comorbidities, and future treatment possibilities (eg, HDT with ASCR). Therefore, treatment
selection is highly individualized.
d In the GALLIUM study, there was an increased risk of mortality from opportunistic infections and secondary malignancies in patients receiving bendamustine. Increased
risk of mortality occurred over the entire treatment program and extending beyond maintenance. Prophylaxis for pneumocystis jirovecii pneumonia (PJP) and varicella
zoster virus (VZV) should be administered; see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
e The clinical trial evaluating this regimen included obinutuzumab maintenance. The use without maintenance was an extrapolation of the data.
f Rituximab may be appropriate if active surveillance was initial therapy and for patients with progression of low tumor burden disease not meeting GELF criteria
(FOLL-A). Immediate initial therapy with rituximab in patients not meeting GELF criteria has not improved overall survival (Ardeshna K, et al. Lancet Oncol 2014;15:424-
435).
g This is based on the PRIMA study for patients with high tumor burden following treatment with RCVP and RCHOP. There are no data for rituximab maintenance
following other regimens.
h Generally, a first-line regimen is not repeated.
i In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until
after CAR-T leukapheresis.
j The clinical trial evaluating this regimen included obinutuzumab maintenance. The use without maintenance was an extrapolation of the data. Obinutuzumab is preferred
in patients with rituximab refractory disease, which includes disease progressing on or within 6 months of prior rituximab therapy.
k It is unclear if tafasitamab-cxix or loncastuximab tesirine-lpyl or if any other CD19–directed therapy would have a negative impact on the efficacy of subsequent anti-
CD19 CAR T-cell therapy.
l Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/index.
cfm.
m In the setting of CD20-negative lymphomas, the activity of CD3 x CD20 bispecific antibody therapy is unclear. Rebiopsy to confirm CD20 positivity is recommended
prior to initiating CD3 x CD20 bispecific antibody therapy.
n Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy (NHODG-E).
o Selected cases include mobilization failures and persistent bone marrow involvement.

Note: All recommendations are category 2A unless otherwise indicated.

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Table of Contents
Classic Follicular Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
First-line Therapy
Kahl BS, Jegede OA, Peterson C, et al. Long-Term Follow-Up of the RESORT Study (E4402): A
Bendamustine + rituximab
Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus
Burden Follicular Lymphoma. J Clin Oncol 2024;42:774-778.
rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label,
Northend M, Wilson W, Clifton-Hadley L, et al. Long term follow-up of international randomised phase
multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-1210.
3 study of rituximab versus a watch and wait approach for patients with asymptomatic, low tumour
Flinn IW, van der Jagt R, Kahl BS, et al. Open-label, randomized, noninferiority study of bendamustine-
burden follicular lymphoma shows rituximab is highly effective at delaying time to new treatment
rituximab or R-CHOP/R-CVP in first-line treatment of advanced indolent NHL or MCL: the BRIGHT
without detrimental impact following next line of therapy [abstract]. Blood 2022;140:1456-1458.
study. Blood 2014;123:2944-2952.
Lenalidomide + rituximab
Bendamustine + obinutuzumab
Martin P, Jung SH, Pitcher B, et al. A phase II trial of lenalidomide plus rituximab in previously
Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N
untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol
Engl J Med 2017;377:1331-1344.
2017;28:2806-2812.
RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
Fowler N, Davis R, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated
Czuczman MS, Weaver R, Alkuzweny B, et al. Prolonged clinical and molecular remission in patients
indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol 2014;15:1311-1318.
with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy:
Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated
9-year follow-up. J Clin Oncol 2004;22:4711-4716.
follicular lymphoma. N Engl J Med 2018;379:934-947.
Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination
Lenalidomide + obinutuzumab
of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the
Bachy E, Houot R, Feugier P, et al. Obinutuzumab plus lenalidomide (GALEN) in advanced, previously
outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone:
untreated follicular lymphoma in need of systemic therapy: a LYSA study. Blood 2022;139:2338-2346.
results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood
2005;106:3725-3732.
First-line Consolidation or Extended Dosing
CHOP + obinutuzumab
Chemoimmunotherapy followed by rituximab maintenance
Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N
Bachy E, Seymour JF, Feugier P, et al. Sustained progression-free survival benefit of rituximab
Engl J Med 2017;377:1331-1344.
maintenance in patients with follicular lymphoma: Long-term results of the PRIMA Study. J Clin Oncol
RCVP (rituximab, cyclophosphamide, vincristine, prednisone)
2019;37:2815-2824.
Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide,
Extended dosing with rituximab
vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J
Ghielmini M, Schmitz SH, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with
Clin Oncol 2008;26:4579-4586.
follicular lymphoma significantly increases event-free survival and response duration compared with
CVP + obinutuzumab
the standard weekly x 4 schedule. Blood 2004;103:4416-4423.
Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N
Obinutuzimab-based chemoimmunotherapy followed by obinutuzumab maintenance
Engl J Med 2017;377:1331-1344.
Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N
Rituximab
Engl J Med 2017;377:1331-1344.
Witzig TE, Vukov AM, Habermann TM, et al. Rituximab therapy for patients with newly diagnosed,
advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer
Treatment Group. J Clin Oncol 2005;23:1103-1108.
Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma
receiving single-agent rituximab at two different schedules in trial SAKK 35/98.
J Clin Oncol 2010;28:4480-4484.
Northend M, Wilson W, Ediriwickrema K, et al. Early rituximab monotherapy versus watchful waiting
for advanced stage, asymptomatic, low tumour burden follicular lymphoma: long-term results of a
randomised, phase 3 trial. Lancet Haematol 2025;12:e335–e345. Continued

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B
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Table of Contents
Classic Follicular Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
Second-line and Subsequent Therapy Third-line and Subsequent Therapy
Bendamustine + obinutuzumab Loncastuximab tesirine-lpyl + rituximab
Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine Alderuccio JP, Alencar AJ, Schatz JH, et al. Loncastuximab tesirine with rituximab in patients with
monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a relapsed or refractory follicular lymphoma: A single-centre, single-arm, phase 2 trial. Lancet Haematol
randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016;17:1081-1093. 2025;12:e23-e34.
Lenalidomide ± rituximab Zanubrutinib + obinutuzumab
Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus
plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma.
2015;33:3635-3640. J Clin Oncol 2023;41:5107-5117.
Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: A phase III study of lenalidomide plus
T-Cell–Engager Therapy
rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol
CAR T-Cell Therapy
2019;37:1188‑1199.
Axicabtagene ciloleucel
Lenalidomide + obinutuzumab
Neelapu SS, Chavez JC, Sehgal AR, et al. Three-year follow-up analysis of axicabtagene ciloleucel in
Morschhauser F, Le Gouill S, Feugier P, et al. Obinutuzumab combined with lenalidomide for
relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 2024;143:496-506.
relapsed or refractory follicular B-cell lymphoma (GALEN): a multicentre, single-arm, phase 2 study.
Lisocabtagene maraleucel
Lancet Haematol 2019;6:e429-e437.
Morschhauser F, Dahiya S, Palomba ML, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase
Rituximab
2 TRANSCEND FL study. Nat Med 2024;30:2199–2207.
McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody
Tisagenlecleucel
therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program.
Dreyling M, Fowler NH, Dickinson M, et al. Durable response after tisagenlecleucel in adults with relapsed/
J Clin Oncol 1998;16:2825-2833.
refractory follicular lymphoma: ELARA trial update. Blood 2024;143:1713-1725.
Ghielmini M, Schmitz SH, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with
Bispecific Antibody Therapy
follicular lymphoma significantly increases event-free survival and response duration compared with
Epcoritamab-bysp
the standard weekly x 4 schedule. Blood 2004;103:4416-4423.
Linton KM, Vitolo U, Jurczak W, et al. Epcoritamab monotherapy in patients with relapsed or refractory
Tafasitamab-cxix + lenalidomide + rituximab
follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol
Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma:
2024;11:e593–e605.
Results from a Phase 3 Study (inMIND) [abstract]. Blood 2024:Abstract LBA-1.
Mosunetuzumab-axgb
Tazemetostat
Sehn LH, Bartlett NL, Matasar MJ, et al. Long-term 3-year follow-up of mosunetuzumab in relapsed or
Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory
refractory follicular lymphoma after >/=2 prior therapies. Blood 2025;145:708–719.
follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol
2020;21:1433-1442.

Second-line Consolidation or Extended Dosing

Rituximab maintenance
van Oers MHJ, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/
resistant follicular non-hodgkin’s lymphoma: Long-term outcome of the EORTC 20981 Phase III
randomized Intergroup Study. J Clin Oncol 2010;28:2853-2858.
Obinutuzumab maintenance for rituximab refractory disease
Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine
monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a
randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016;17:1081-1093.

Note: All recommendations are category 2A unless otherwise indicated.

FOLL-B
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Table of Contents
Marginal Zone Lymphomas Discussion

EMZL of the Diagnosis and Workup (EMZLG-1)

stomach

Extranodal EMZL of
marginal zone nongastric sites Diagnosis and Workup (EMZLNG-1)
lymphoma (EMZL) (noncutaneous)

Primary Cutaneous Marginal Zone Lymphoma in NCCN

Cutaneous
Guidelines for Primary Cutaneous Lymphomas

Nodal marginal zone lymphoma (NMZL) Diagnosis and Workup (NMZL-1)

Splenic marginal zone lymphoma (SMZL) Diagnosis and Workup (SMZL-1)

Histologic transformation to DLBCL HTBCEL-1

Note: All recommendations are category 2A unless otherwise indicated.

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NCCN Guidelines Index
Extranodal Marginal Zone B-Cell Lymphoma Table of Contents
Discussion
Extranodal MZL of the Stomach
ADDITIONAL DIAGNOSTIC TESTINGa,b WORKUP
ESSENTIAL:
• Physical exam
ESSENTIAL: • Performance status
• Diagnosis of EMZL of the stomach requires an • CBC with differential
endoscopic biopsy. An FNA is never adequate. • Comprehensive metabolic panel
• Adequate immunophenotyping to establish diagnosisc • LDH
IHC panel: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, • If H. pylori negative by histopathology, then use noninvasive
CD21 or CD23, cyclin D1,d BCL6 H. pylori testing (stool antigen test or urea breath test)
with or without • Hepatitis B testingf
Flow cytometry with peripheral blood and/or biopsy • Hepatitis C testing
specimen: • C/A/P CT with contrast of diagnostic quality or PET/CT scan Initial
kappa/lambda, CD19, CD20, CD5, CD23, CD10 (especially if ISRT anticipated) Therapy
• Helicobacter pylori stain (gastric), if positive, then FISH • Pregnancy testing in patients of childbearing age (if (EMZLG-2)
for MALT1 rearrangementse chemotherapy or RT planned)

USEFUL UNDER CERTAIN CIRCUMSTANCES: USEFUL IN SELECTED CASES:

• Molecular analysis to detect: Ig gene rearrangements; • Bone marrow biopsy ± aspirate
MYD88 mutation status to help differentiate Waldenström • Echocardiogram or MUGA scan if anthracycline-based regimen
macroglobulinemia (WM) (90%) versus MZL (10%) if is indicated
plasmacytic differentiation present • Endoscopy with ultrasound (if available) with multiple biopsies
• Karyotype or FISH: t(1;14); t(3;14); t(11;14)d; t(14;18) of anatomical sitesg
• Discuss fertility preservationh
• SPEP

a Nondiagnostic atypical lymphoid infiltrates that are H. pylori positive should be

rebiopsied to confirm or exclude lymphoma prior to treatment of H. pylori.
b Any area of DLBCL should be treated as DLBCL (BCEL-1).
c Typical immunophenotype: CD10-, CD5-, CD20+, cyclin D1-, with BCL2- f Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy
follicles. + chemotherapy. Tests include HBsAg and core antibody for a patient with no risk
d In CD5+ cases, concurrent IHC positivity for cyclin D1 is more compatible with factors. For patients with risk factors or previous history of hepatitis B, add e-antigen
the diagnosis of MCL. FISH for t(11;14) is helpful to exclude the diagnosis of (NHODG-B). If positive, check viral load and consider consult with gastroenterologist.
MCL; see MANT-1. g This is particularly useful for H. pylori-positive cases because the likelihood of tumor
e Locally advanced disease is more likely in patients with EMZL of the stomach response is related to depth of tumor invasion.
with t(11;18), and is a predictor for lack of tumor response (<5%) to antibiotic h Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or
therapy. ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

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NCCN Guidelines Index
Extranodal Marginal Zone B-Cell Lymphoma Table of Contents
Discussion
Extranodal MZL of the Stomach
LUGANO LUGANO INITIAL THERAPY
STAGE/ MODIFICATION
GI OF ANN ARBOR H. pylori
LYMPHOMASi STAGINGi positive, t(11;18) Currently accepted antibiotic
Evaluate with endoscopyn (EMZLG-4)
negative, or therapy for H. pylori
t(11;18) unknown
Stage IE Currently accepted antibiotic
j H. pylori therapy for H. pylori and
Stage I1, or I2 (T1–3,N0,M0)
positive, • ISRTl (preferred)
or or t(11;18) or
Stage II1j Stage IIE positivek • Rituximab (if ISRT is
(T1–3,N1,M0) contraindicated)
Evaluate with endoscopyn (EMZLG-5)

H. pylori ISRTl,m (preferred)

or
negative Rituximab (if ISRT is contraindicated)
Stage IIE
Stage II2
(T1–3,N2,M0)
or
or
Stage IIE
Stage IIE
or
(T4,N0,M0) EMZLG-3
Stage IV
or
(distant nodal,
Stage IV
advanced
(T1–4,N3,M0;
stage)
T1–4,N0–3,M1)
EMZL of the stomach
Manage as Diffuse Large
with concurrent large cell
B-Cell Lymphoma (BCEL-1)
transformation

i Staging of EMZL of the Stomach: Comparison of Different Systems (EMZLG-A).

j Involvement of submucosa or regional lymph nodes are much less likely to respond l Principles of Radiation Therapy (NHODG-D).
to antibiotic therapy. If there is persistent disease after evaluation, RT may be m If H. pylori negative by both histology and serumantibodies, ISRT is
considered earlier in the course. recommended.
k t(11;18) is a predictor for lack of tumor response (<5%) to antibiotic therapy. n If re-evaluation suggests slowly responding disease or asymptomatic
Antibiotic therapy is used in these patients to eradicate the H. pylori infection. These nonprogression, continued active surveillance may be warranted. Complete
patients should be considered for alternative therapy for lymphoma. Liu H, et al. responses may be acheived as early as 3 months after initial therapy, but can
Gastroenterology 2002;122:1286-1294. take longer to achieve (up to 18 months) (category 2B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

Evaluate for indications for

treatment: No Active
• Candidate for clinical trialo indication surveillance
• Symptoms
• Gastrointestinal (GI) bleeding
• Threatened end-organ function • Evaluate with endoscopy, if evidence
• Clinically significant bulky First-line Therapy for Marginal of recurrence (MZL), Second-line and
disease Indication Zone Lymphomas (MZL-A 1 of 4) Subsequent Therapy for Marginal Zone
• Steady or rapid progression present p or Lymphomas (MZL-A 2 of 4)
Palliative ISRTl • If histologic transformation,
see HTBCEL-1

l Principles of Radiation Therapy (NHODG-D).

o Given incurability with conventional therapy, consider investigational therapy as first line of treatment.
p Surgical resection is generally limited to specific clinical situations (ie, life-threatening hemorrhage).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

H. pylori negative,
Lymphoma negative

Repeat endoscopy
and biopsy after 3
Asymptomatic mon
H. pylori negative, or
Lymphoma positive ISRTl
Restage at 6 moq with
endoscopy/biopsyn,r Symptomatic ISRTl
for H. pylori/lymphoma
after antibiotics EMZLG-6

H. pylori positive,
Second-line
Lymphoma negative
antibiotic
treatment
and
Stable reassess
disease
H. pylori positive, ISRTl and
Lymphoma positive second-line
Progressive or antibiotic
symptomatic treatment
disease and
reassess

l Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

H. pylori negative
Lymphoma negative

H. pylori positive Second-line antibiotic

Lymphoma negative treatment and reassess
Restage at 6 moq
with endoscopy and
biopsyn,r after ISRT EMZLG-6
or rituximab

H. pylori negative
Lymphoma positive

H. pylori positive Second-line antibiotic

Lymphoma positive treatment and reassess

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

Recurrence
post ISRT EMZLG-3
or rituximab
Clinical follow-up
H. pylori every 3–6 mo for Systemic
negative, 5 y and then Recurrence recurrence
Lymphoma annually or as post antibiotics
negative clinically indicateds Local
Locoregional ISRTl
If histologic recurrence
Response transformation,
after see HTBCEL-1
completion H. pylori Consult with an
of antibiotic positive, infectious disease
treatment, Lymphoma specialist for additional
ISRT, or negative antibiotic treatment
rituximabn,r

H. pylori
negative, Previous ISRT
EMZLG-3
Lymphoma or rituximab
positive
or
H. pylori Recurrence
positive, Locoregional
or
Lymphoma Previous antibiotic ISRT (if not
If histologic
positive treatment previously
transformation,
given)l
see HTBCEL-1

l Principles of Radiation Therapy (NHODG-D).

n If re-evaluation suggests slowly responding disease or asymptomatic nonprogression, continued active surveillance may be warranted. Complete responses may be
acheived as early as 3 months after initial therapy, but can take longer to achieve (up to 18 months) (category 2B).
r Reassessment to rule out H. pylori by institutional standards. Biopsy to rule out large cell lymphoma. Any area of DLBCL should be treated as DLBCL (BCEL-1).
s Optimal interval for follow-up endoscopy and imaging is not known. Follow-up endoscopy and imaging using the modalities performed during workup is driven by
symptoms. Relapse rates are higher after treatment with rituximab and may warrant serial endoscopy.
Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025

Lugano TNM Staging System

Lugano Staging System for Modification of
Adapted for Gastric Tumor Extension
Gastrointestinal Lymphomas Ann Arbor Staging
System Lymphoma

Stage I Confined to GI tracta

I1 = mucosa, submucosa IE T1 N0 M0 Mucosa, submucosa

IE T2 N0 M0 Muscularis propria
I2 = muscularis
propria, serosa IE T3 N0 M0 Serosa

Stage II Extending into abdomen

II1 = local nodal
involvement IIE T1-3 N1 M0 Perigastric lymph nodes

II2 = distant nodal More distant regional lymph

IIE T1-3 N2 M0
involvement nodes
Stage IIE Penetration of serosa to
Invasion of adjacent
involve adjacent organs IIE T4 N0 M0
structures
or tissues
Stage IVb Disseminated Lymph nodes on both
extranodal involvement T1-4 N3 M0 sides of the diaphragm/
or concomitant distant metastases (eg,
supradiaphragmatic IV T1-4 N0-3 M1 bone marrow or additional
nodal involvement extranodal sites)
Zucca E, Bertoni F, Yahalom J, Isaacson P. Extranodal Marginal Zone B-cell Lymphoma of Mucosa-Associated Lymphoid Tissue
(MALT lymphoma) in Armitage et al eds. Non-Hodgkin's Lymphomas. Philadelphia: Lippincott, 2010:242. (http://lww.com)

a Single primary or multiple, noncontiguous.

b Involvement of multiple extranodal sites in MALT
lymphoma appears to be biologically distinct from multiple extranodal involvement in other lymphomas, and these
patients may be managed by treating each site separately with excision or RT. In contrast, cases with disseminated nodal involvement appear to behave more like
nodal marginal zone lymphoma or like disseminated follicular lymphoma.

Note: All recommendations are category 2A unless otherwise indicated.

Version 3.2025, 08/18/25 © 2025 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
EMZLG-A
NCCN Guidelines Version 3.2025
PLEASE NOTE that use of this NCCN Content is governed by the End-User License Agreement, and you MAY NOT distribute this Content or use it with any artificial intelligence model or tool.
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NCCN Guidelines Index
Extranodal Marginal Zone B-Cell Lymphoma Table of Contents
Discussion
Extranodal MZL of Nongastric Sites (Noncutaneous)
ADDITIONAL DIAGNOSTIC TESTINGa,b WORKUP
ESSENTIAL:
• Physical exam with attention to nongastric sitesa
• Performance status
ESSENTIAL: • CBC with differential
• Adequate immunophenotyping to establish • Comprehensive metabolic panel
diagnosisc • LDH
• Hepatitis B testingd
IHC panel: CD20, CD3, CD5, CD10, BCL2, • Hepatitis C testing
kappa/ lambda, CD21 or CD23, cyclin D1 • PET/CT scan or C/A/P CT with contrast of diagnostic quality if
with or without systemic therapy is planned
Flow cytometry with peripheral blood and/or • Pregnancy testing in patients of childbearing age (if chemotherapy
biopsy specimen: kappa/lambda, CD19, CD20, or RT planned) Initial
CD5, CD23, CD10
USEFUL IN SELECTED CASES: Therapy
• Echocardiogram or MUGA scan if anthracycline-based regimen is (EMZLNG-2)
USEFUL UNDER CERTAIN CIRCUMSTANCES:
• Molecular analysis to detect: Ig gene indicated
rearrangements; MYD88 mutation status to • Bone marrow biopsy ± aspirate
help differentiate WM (90%) versus MZL (10%) • Endoscopy with multiple biopsies of anatomical sitese
• MRI with contrast for neurologic evaluation or if CT with contrast is
if plasmacytic differentiation present; FISH for contraindicated
MALT1 rearrangements • MRI of head/neck, cranial, and ocular adnexa
• Karyotype or FISH: t(11;18), t(11;14), t(3;14); • Neck CT scan with contrast particularly if RT planned for stage I, II
t(14;18) disease
• Evaluation for autoimmune disease (eg, Sjogren's)
• SPEP
• Discuss fertility preservationf

a Typical nongastric sites include the following: bowel (small and large), breast, head and neck, lung, dural, ocular adnexa, ovary, parotid, prostate, and
salivary gland. Infectious agents have been reported to be associated with many nongastric sites, but testing for these infectious organisms is not required for
management in the United States.
b This guideline pertains to EMZL of nongastric sites (noncutaneous); for primary cutaneous marginal zone lymphoma (PCMZL), see NCCN Guidelines for Primary
Cutaneous Lymphomas.
c Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, cyclin D1-, with BCL2- follicles.
d Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with
no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with
gastroenterologist.
e In cases where primary site is thought to be in head/neck or lungs, upper GI endoscopy should be considered.
f Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

ISRT h (preferred)
or Consider
Surgery may be considered Positive
locoregional
for certain sitesi (lung, breast margins
Stage IE or ISRTh
[lumpectomy], thyroid, colon/small
contiguous Negative Active
bowel) Follow-up
stage IIE margins surveillance
or (EMZLNG-3)
Rituximab in selected cases
or
Active surveillance in selected casesj

ISRTh,k
or
Active surveillance in selected
Stage IV casesj
or
Manage per advanced-stage NMZL
(NMZL-3)

EMZL of nongastric
sites with Manage as Diffuse Large
concurrent large cell B-Cell Lymphoma (BCEL-1)
transformation

g Based on anecdotal responses to antibiotics in ocular and cutaneous marginal zone lymphomas, some physicians will give an empiric course of doxycycline
prior to initiating other therapy.
h Principles of Radiation Therapy (NHODG-D).
i Surgical excision for adequate diagnosis may be appropriate treatment for disease.
j Active surveillance may be considered for patients whose diagnostic biopsy was excisional, or where RT could result in significant morbidity.
k Definitive treatment of multiple sites may be indicated (eg, bilateral orbital disease without evidence of disease elsewhere) or palliative treatment of symptomatic sites.

Note: All recommendations are category 2A unless otherwise indicated.

ISRT if not previously givenh

Local
or
recurrence
Manage per advanced-stage NMZL (NMZL-3)

No
Active surveillance
Evaluate for indications for indication
Clinical follow-up treatment:
every 3–6 mo for • Candidate for clinical trial
5 y and then Systemic • Symptoms Treatment naive, see First-line
annually or as recurrence • GI bleeding Therapy for Marginal Zone
clinically indicatedl • Threatened end-organ function Lymphomas (MZL-A 1 of 4)
• Clinically significant bulky Indication or
disease present Prior treatment with rituximab,
• Steady or rapid progression see Second-line and Subsequent
Therapy for Marginal Zone
Lymphomas (MZL-A 2 of 4)
If histologic
HTBCEL-1
transformation

h Principles of Radiation Therapy (NHODG-D).

l Follow-up includes diagnostic tests and imaging previously used as clinically indicated.

Note: All recommendations are category 2A unless otherwise indicated.

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Nodal Marginal Zone Lymphoma Discussion

ADDITIONAL DIAGNOSTIC TESTINGa WORKUP

a NMZL is rare and occurs most commonly as spread from extranodal sites; must also be distinguished from nodal FL, MCL, lymphoplasmacytic lymphoma (LPL), and
chronic lymphocytic leukemia (CLL), all of which are more common.
b Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and cyclin D1-, may have BCL2- follicles.
c Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with
no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with
gastroenterologist.
d In NMZL, extranodal involvement is common: Neck nodes: ocular, parotid, thyroid, and salivary gland; axillary nodes: lung, breast, and skin; mediastinal/hilar nodes:
lung; abdominal nodes: splenic and GI; inguinal/iliac nodes: GI and skin.
e Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

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Nodal Marginal Zone Lymphoma Discussion

STAGE INITIAL THERAPY RESPONSE TO THERAPYk,l FOLLOW-UPm

CR or
PR
ISRTf,g (preferred) See Stage III, IV (NMZL-3)
or
Stage I or NR
If histologic transformation,
or see HTBCEL-1
Contiguous ISRTf + anti-CD20 mAbh ± Clinical
CR or • H&P and labs every
stage II chemotherapy (MZL-A) i
or PR 3–6 mo for 5 y and then
See NR or progressive
Anti-CD20 mAbh ± disease (NMZL-4) annually or as clinically Progressive
chemotherapy (MZL-Ai in NR or indicated disease,k,l see
certain circumstances)j If histologic transformation, Surveillance imagingn Stage III, IV
Stage see HTBCEL-1 • Up to 2 y post (NMZL-3)
I, II completion of or
Anti-CD20 mAbh ± treatment: C/A/P CT If histologic
CR
chemotherapy scan with contrast no transformation,
CR or more than every 6 mo see HTBCEL-1
(MZL-A) ± ISRT for Consider PR
Non- local palliationf PR or ISRTf if not See NR or • >2 y: No more than
NR previously progressive annually
contiguous
given NR disease (NMZL-4)
stage II or or
If histologic
transformation,
see HTBCEL-1
Active surveillance g
l Consider
possibility of histologic transformation in patients with progressive disease,
especially if LDH levels are rising, single site is growing disproportionately, extranodal
disease develops, or there are new B symptoms. If clinical suspicion of transformation,
FDG-PET may help identify areas suspicious for transformation. FDG-PET scan
demonstrating marked heterogeneity or sites of intense FDG avidity may indicate
f Principles of Radiation Therapy (NHODG-D).
transformation, and biopsy should be directed biopsy at the most FDG-avid area.
g Active surveillance may be appropriate in circumstances where potential
Functional imaging does not replace biopsy to diagnose transformation. If transformation
toxicity of ISRT or systemic therapy outweighs potential clinical benefit in is histologically confirmed, treatment options should be directed towards the large cell
consultation with a radiation oncologist. transformation. See HTBCEL-1.
h Anti-CD20 mAbs include rituximab or obinutuzumab. Obinutuzumab is not m Follow-up includes diagnostic tests and imaging using the same modalities performed
indicated as single-agent therapy. during workup as clinically indicated. Imaging should be performed whenever there are
i Initiation of systemic therapy can improve FFS, but has not been shown to
clinical indications. For surveillance imaging, see Discussion for consensus imaging
improve overall survival. These are options for initial therapy. recommendations.
j Eg, for patients with bulky intra-abdominal or mesenteric stage I disease. n Surveillance imaging is used for monitoring asymptomatic patients. When a site of
k Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT
disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to proceed
scan should be interpreted via the PET 5-PS. with PET/CT scans for surveillance.

Note: All recommendations are category 2A unless otherwise indicated.

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Nodal Marginal Zone Lymphoma Discussion

STAGE MANAGEMENT AND FOLLOW-UPm

Clinical
Progressive
• H&P and labs every 3–6 mo for 5 y and
Active diseasek,l
Evaluate for indications then annually or as clinically indicated
No or
for treatmento: surveillance Surveillance imagingn
indication (category 1) If histologic
• Candidate for clinical trial • Up to 2 y: C/A/P CT scan with contrast
transformation,
• Symptoms no more than every 6 mo
see HTBCEL-1
• Threatened end-organ • >2 y: CT scan no more than annually
function
Stage
• Clinically significant or
III, IV
progressive cytopenia
secondary to lymphoma
• Clinically significant See Suggested Regimens (MZL-A)
bulky diseaseo or
Response
• Steady or rapid Indication PET/CT Assessment and
Clinical trial
progressionl present scanl Additional Therapy
and/or
(NMZL-4)
Palliative ISRTf

f Principles of Radiation Therapy (NHODG-D).

k Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.
l Consider possibility of histologic transformation in patients with progressive disease, especially if LDH levels are rising, single
site is growing disproportionately,
extranodal disease develops, or there are new B symptoms. If clinical suspicion of transformation, FDG-PET may help identify areas suspicious for transformation.
FDG-PET scan demonstrating marked heterogeneity or sites of intense FDG avidity may indicate transformation, and biopsy should be directed biopsy at the most
FDG-avid area. Functional imaging does not replace biopsy to diagnose transformation. If transformation is histologically confirmed, treatment options should be
directed towards the large cell transformation. See HTBCEL-1.
m Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever
there are clinical indications. For surveillance imaging, see Discussion for consensus imaging recommendations.
n Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT scan (eg, bone), it is appropriate to
proceed with PET/CT scans for surveillance.
o GELF criteria (FOLL-A).

Note: All recommendations are category 2A unless otherwise indicated.

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Nodal Marginal Zone Lymphoma Discussion

RESPONSE Consolidation or FOLLOW-UPm SECOND-

ASSESSMENTk extended therapy LINE AND
AND (optional) for SUBSEQUENT
Clinical
ADDITIONAL patients treated Evaluate for THERAPY
• H&P and labs every
THERAPY with single-agent indications for
3–6 mo for 5 y and
CRk rituximab
then annually or as Relapsed or treatmento:
(MZL-A) • Candidate for
or clinically indicated Progressive clinical trial
Active Surveillance diseasek,l • Symptoms No Active
surveillance imagingn or • Threatened end- indication surveillance
Consolidation or
• Up to 2 y post If histologic organ function
extended therapy completion of transformation, • Clinically
(optional) for treatment: C/A/P see HTBCEL-1 significant or
patients treated CT scan with progressive
C/A/P CT with single-agent contrast no more cytopenia
scan with PRk,p rituximab than every 6 mo secondary to
contrast (MZL-A) lymphoma Suggested
or • >2 y: CT scan no Regimens
more than annually • Clinically
Active surveillance significant bulky Indication PET/CT (MZL-A)
or scanl
In third-line systemic diseaseo present or
therapy or later: • Steady or rapid Clinical trial
CAR T-cell therapy progression or
(MZL-A 3 of 4) Palliative
• No histologic transformation ISRTf
• If histologic transformation, see HTBCEL-1
NR or progressive diseasek,l Rebiopsy
• In third-line systemic therapy or later:
T-cell–engager therapy (MZL-A 3 of 4)

f Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

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Splenic Marginal Zone Lymphoma Discussion

ADDITIONAL DIAGNOSTIC TESTINGa WORKUP

ESSENTIAL:
• Physical exam with performance status
ESSENTIAL: • CBC with differential
• Adequate immunophenotyping to establish diagnosisb • Comprehensive metabolic panel
IHC panel: CD20, CD3, CD5, CD10, BCL2, kappa/lambda, • LDH
CD21 or CD23, cyclin D1, IgD, CD43, annexin A1; • Hepatitis B testingd
with or without • Hepatitis C testing
Flow cytometry with peripheral blood and/or biopsy • PET/CT scan or C/A/P CT or other suspected
specimen: kappa/lambda, CD19, CD20, CD5, CD23, sites with contrast of diagnostic quality
CD10, CD43, CD103 • SPEP and/or quantitative Ig levels
• Pregnancy testing in patients of childbearing Management
USEFUL UNDER CERTAIN CIRCUMSTANCES: age (if chemotherapy or RT planned) (SMZL-2)
• Molecular analysis to detect: Ig gene rearrangements;
MYD88 mutation status to help differentiate WM (90%) USEFUL IN SELECTED CASES:
versus MZL (10%) if plasmacytic differentiation presentc; • Bone marrow biopsy ± aspirate
BRAF mutation status (by IHC or sequencing) to • Additional imaging as needed based on clinical
differentiate MZL from hairy cell leukemia (HCL); FISH for presentation or symptoms
MALT1 rearrangements • Immunofixation of blood (for elevated Ig or
• Karyotype or FISH: chronic lymphocytic leukemia (CLL) positive SPEP)
panel; t(11;18), t(11;14), del(7q); t(14;18) • Cryoglobulins
• Direct Coombs testing
• Discuss fertility preservatione
a SMZL is most definitively diagnosed at splenectomy, since the
immunophenotype is nonspecific and morphologic features on the bone
marrow may not be diagnostic. However, the diagnosis of SMZL may be
made on the basis of bone marrow ± peripheral blood involvement by small b Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, and cyclin D1-, with
lymphoid cells with Ig light chain restriction that lack characteristic features BCL2- follicles, annexin A1, and CD103- (distinction from HCL) with expression of both
of other small B-cell neoplasms (ie, CD5, CD10, cyclin D1). In patients IgM and IgD.
with lymphocytosis (>3), evaluation of peripheral blood with flow cytometry c NOTCH2 and KLF2 mutation status may be helpful to differentiate SMZL from other B-cell
and NGS panel including MYD88, NOTCH2, and KLF2 mutations may lymphoma subtypes.
be adequate to confirm the diagnosis. Plasmacytoid differentiation with d Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy +
cytoplasmic Ig detectable on paraffin sections may occur. In such cases, the chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors.
differential diagnosis may include LPL. With a characteristic intrasinusoidal For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B).
lymphocytic infiltration of the bone marrow, the diagnosis can strongly If positive, check viral load and consider consult with gastroenterologist.
be suggested on bone marrow biopsy alone, if the immunophenotype is e Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or
consistent. ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

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Splenic Marginal Zone Lymphoma Discussion

CLINICAL PRESENTATION MANAGEMENT FOLLOW-UP

Asymptomatic,
without progressive Follow-up (SMZL-3)
cytopenia, no
splenomegaly
No
contraindications Appropriate CR/
for treatment of treatment PR
hepatitis
Hepatitis C Hepatology
positivef consult NR

Contraindications
for treatment of
hepatitis
Follow-up (SMZL-3)

Splenomegaly

Rituximabg (preferred)
• Cytopenias or
• Symptoms Splenectomyh
(category 2B)
Hepatitis C
Assess
negative

No symptoms Active surveillance

f If there is hepatic involvement and hepatitis C positive, treat with an appropriate regimen for hepatitis C.
g Tsimberidou AM, et al. Cancer 2006;107:125-135.
h Pneumococcal, meningococcal, haemophilus influenza, and hepatitis B vaccinations should be given at least 2 weeks before splenectomy.

Note: All recommendations are category 2A unless otherwise indicated.

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Splenic Marginal Zone Lymphoma Discussion

FOLLOW-UP

Evaluate for indications for No

Active surveillance
treatment: indication
Clinical follow- • Candidate for clinical trial
up every 3–6 Recurrence • Symptoms
• Treatment naive, then see First-
mo for 5 y and • If histologic • Threatened end-organ function
line Therapy for Marginal Zone
then annually transformation, • Cytopenias including
Lymphomas (MZL-A 1 of 4)
or as clinically see HTBCEL-1 autoimmune cytopenia
or
indicatedi • Clinically significant bulky
• Prior treatment with rituximab,
disease
Indication then see Second-line and
• Steady or rapid progression
present Subsequent Therapy for Marginal
Zone Lymphomas (MZL-A 2 of 4)
or
Splenectomyh
or
Palliative ISRTj

h Pneumococcal, meningococcal, haemophilus influenza, and hepatitis B vaccinations should be given at least 2 weeks before splenectomy.
i Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.
j Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

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Marginal Zone Lymphomas Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

FIRST-LINE THERAPY FIRST-LINE THERAPY FOR OLDER OR INFIRM

Preferred regimens (in alphabetical order) (if none of the above are expected to be tolerable
in the opinion of treating physician)
• Bendamustine + rituximab
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + Preferred regimen
rituximab • Rituximab (375 mg/m2 weekly for 4 doses)
• CVP (cyclophosphamide, vincristine, prednisone) + rituximab Other recommended regimens
• Rituximab (375 mg/m2 weekly for 4 doses) for SMZL • Chlorambucil ± rituximab
• Cyclophosphamide ± rituximab
Other recommended regimens
• Lenalidomide + rituximab (category 2B) FIRST-LINE EXTENDED THERAPY (optional)
• Rituximab (375 mg/m2 weekly for 4 doses) for EMZL (multifocal) and
nodal MZL (preferred for low burden disease) • Rituximab maintenance 375 mg/m2 one dose every 8–12 weeks for up to
2 years

Footnotes on MZL-A 3 of 4
Second-line and Subsequent Therapy on MZL-A 2 of 4

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

Note: All recommendations are category 2A unless otherwise indicated.

MZL-A
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Marginal Zone Lymphomas Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

SECOND-LINE AND SUBSEQUENT THERAPY SECOND-LINE AND SUBSEQUENT THERAPY FOR OLDER OR INFIRM
Preferred regimens (in alphabetical order) (if combination chemoimmunotherapy is not expected to be tolerable
in the opinion of treating physician)
• Bendamustined + obinutuzumab (not recommended if treated with
prior bendamustine) Preferred regimens (in alphabetical order)
• Bendamustined + rituximab (not recommended if treated with prior • BTKis
bendamustine) Covalent BTKi
• BTKis ◊ Acalabrutinibe,f
Covalent BTKi ◊ Zanubrutinibe (after at least one prior anti-CD20 mAb-based regimen)
◊ Acalabrutinibe,f Non-covalent BTKi
◊ Zanubrutinibe (after at least one prior anti-CD20 mAb-based ◊ Pirtobrutinib (after prior covalent BTKi)e
regimen) • Lenalidomide + rituximab
Non-covalent BTKi • Rituximab (375 mg/m2 weekly for 4 doses)
◊ Pirtobrutinib (after prior covalent BTKi)e Other recommended regimens (in alphabetical order)
• CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + • Chlorambucil ± rituximab
rituximab • Cyclophosphamide ± rituximab
• CVP (cyclophosphamide, vincristine, prednisone) + rituximab • Ibrutinibe,g
• Lenalidomide + rituximab
Other recommended regimens (in alphabetical order)
• Ibrutinibe,g SECOND-LINE EXTENDED THERAPY (optional)
• Lenalidomide + obinutuzumab Preferred regimen
• Rituximab (if longer duration of remission) • If treated with bendamustine + obinutuzumab for recurrent disease then
obinutuzumab maintenance for rituximab-refractory disease
(1 g every 8 weeks for total of 12 doses)

SECOND-LINE CONSOLIDATION THERAPY (optional)

• HDT/ASCR

Consider prophylaxis for tumor lysis syndrome (NHODG-B) Footnotes on MZL-A 3 of 4

See monoclonal antibody and viral reactivation (NHODG-B) Third-line and Subsequent Therapy on MZL-A 3 of 4

Note: All recommendations are category 2A unless otherwise indicated.

MZL-A
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Marginal Zone Lymphomas Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

THIRD-LINE AND SUBSEQUENT THERAPY

Subsequent systemic therapy options include
second-line therapy regimens (MZL-A 2 of 4) that were not previously given.
Preferred regimen
• CAR T-cell therapy
Axicabtagene ciloleucelh (CD19-directed) (if not previously given)

THIRD-LINE CONSOLIDATION THERAPY (optional)

• Allogeneic HCT in highly selected casesi

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

a See references for regimens (MZL-A 4 of 4).

b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
c The choice of therapy requires consideration of many factors, including age, comorbidities, and future treatment possibilities (eg, HDT/ASCR). Therefore, treatment
selection is highly individualized.
d In patients intended to receive CAR T-cell therapy, bendamustine should be used with caution. Delay bendamustine until after CAR-T leukapheresis.
e Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/
index.cfm.
f Studies of acalabrutinib excluded concomitant use of warfarin or equivalent vitamin K antagonists.
g Head-to-head clinical trials in other B-cell malignancies have demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib compared to ibrutinib
without compromising efficacy.
h Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy (NHODG-E).
i Selected cases include mobilization failures and persistent bone marrow involvement.

Note: All recommendations are category 2A unless otherwise indicated.

MZL-A
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SUGGESTED TREATMENT REGIMENS

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First-line Therapy Second-line and Subsequent Therapy
Chlorambucil ± rituximab Acalabrutinib
Zucca E, Conconi A, Martinelli G, et al. Final results of the IELSG-19 randomized Strati P, Coleman M, Champion R, et al. A phase 2, multicentre, open-label trial (ACE-LY-003)
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Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a
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Kiesewetter B, Willenbacher E, Willenbacher W, et al. A phase 2 study of the Fondazione Italiana Linfomi. Haematologica 2016;101:e196.
rituximab plus lenalidomide for mucosa-associated lymphoid tissue lymphoma. Pirtobrutinib
Blood 2017;129:383-385. Patel K, Vose JM, Nasta SD, et al. Pirtobrutinib, a highly selective, non-covalent (Reversible) BTK
Rituximab (preferred for SMZL) inhibitor in relapsed/refractory marginal zone lymphoma: Results from phase 1/2 BRUIN study
Tsimberidou AM, Catovsky D, Schlette E, et al. Outcomes in patients with splenic [abstract]. Blood 2023;142:Abstract 1660.
marginal zone lymphoma and marginal zone lymphoma treated with rituximab Zanubrutinib
with or without chemotherapy or chemotherapy alone. Cancer 2006;107:125-135. Opat S, Tedeschi A, Hu B, et al. Safety and efficacy of zanubrutinib in relapsed/refractory marginal
Else M, Marin-Niebla A, de la Cruz F, et al. Rituximab, used alone or in zone lymphoma: final analysis of the MAGNOLIA study. Blood Adv 2023;7:6801-6811.
combination, is superior to other treatment modalities in splenic marginal zone
lymphoma. Br J Haematol 2012;159:322-328. Second-line Consolidation or Extended Dosing (optional)
Kalpadakis C, Pangalis GA, Angelopoulou MK, et al. Treatment of splenic Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine
marginal zone lymphoma with rituximab monotherapy: progress report and monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a
comparison with splenectomy. Oncologist 2013;18:190-197. randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol 2016;17:1081-1093.
First-line Extended Therapy (optional)
Extended dosing with rituximab Third-line and Subsequent Therapy
Williams ME, Hong F, Gascoyne RD, et al. Rituximab extended schedule or CAR T-cell therapy
retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin Axicabtagene ciloleucel
lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Neelapu SS, Chavez JC, Sehgal AR, et al. Three-year follow-up analysis of axicabtagene ciloleucel
Haematol 2016;173:867-875. in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 2024;143:496-506.

Note: All recommendations are category 2A unless otherwise indicated.

MZL-A
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ADDITIONAL DIAGNOSTIC TESTING WORKUP

ESSENTIAL:
• Physical exam: Attention to node-bearing areas,
including Waldeyer’s ring, and to size of liver and
ESSENTIAL: spleen
• Adequate immunophenotyping to establish diagnosisa • Performance status
IHC panel: CD20, CD3, CD5, cyclin D1, CD10, CD21, • B symptoms
• CBC with differential Initial
CD23, BCL2, BCL6, SOX11, Ki-67b Stage I, II Therapy
• Comprehensive metabolic panel
with or without • LDH (MANT-2)
Flow cytometry with peripheral blood and/or biopsy • PET/CT scan (preferred) or C/A/P CT with contrast
specimen: of diagnostic quality if systemic therapy is planned
kappa/lambda, CD19, CD20, CD5, CD23, CD10, • Hepatitis B testinge
CD200 • Echocardiogram or MUGA scan if anthracycline-
• TP53 sequencingc based regimen is indicated
• Pregnancy testing in patients of childbearing age
USEFUL UNDER CERTAIN CIRCUMSTANCES: (if chemotherapy or RT planned)
• IHC: LEF1 may help distinguish from variant CLL;
SOX11 or IGHV sequencing may be useful for USEFUL UNDER CERTAIN CIRCUMSTANCES:
determination of clinically indolent MCL;d may also • Endoscopy/colonoscopyf
• Bone marrow biopsy ± aspirate Stage
help in diagnosis of CCND1- MCL • Neck CT with contrast Initial
• Karyotype or FISH: t(11;14), FISH for CCND2 and II bulky
• Uric acid noncontiguous; Therapy
CCND3 rearrangements may also help in diagnosis of • Beta-2-microglobulin (MANT-3)
CCND1- MCL • Hepatitis C testing Stage III, IV
• Lumbar puncture (for blastic variant or
central nervous system [CNS] symptoms)
• Discuss fertility preservationg
a Typical immunophenotype: CD5+, CD20+, CD43+, CD23-/+, cyclin
D1+, CD10-/+. Note: Some cases of MCL may be CD5- or CD23+. If the
diagnosis is suspected, cyclin D1 staining or FISH for t(11;14) should be d Most common biomarker for indolent disease: SOX11- [IGHV mutated]. Typical clinical
done. There are rare cases of CCND1- MCL (<5%) with an otherwise presentation: leukemic non-nodal CLL-like with splenomegaly, low tumor burden, Ki-67
typical immunophenotype. proliferation fraction <10%.
b Ki-67 proliferation fraction of <30% in lymph nodes is associated with a e Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy +
more favorable prognosis. chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors.
c TP53 mutation has been associated with poor prognosis in patients For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B).
treated with conventional therapy, including transplant. Clinical trial is If positive, check viral load and consider consult with gastroenterologist.
strongly recommended for these patients. TP53 sequencing is preferred; f Essential for confirmation of stage I–II disease. See Discussion for details.
however, in the front-line setting, TP53 by IHC can be used as a g Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or
surrogate but should be confirmed with sequencing. ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

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Mantle Cell Lymphoma Discussion

STAGEh INDUCTION INITIAL FOLLOW-UPm/ADDITIONAL THERAPY SECOND-LINE

THERAPYi RESPONSE THERAPY

Prior treatment
MANT-3
Partial with ISRT alone
response or
Progressionl
Prior treatment with
chemoimmunotherapy ± ISRT • Relapsed or
Stage I ISRTj,k Clinical Refractory
or or • H&P and labs every Prior treatment Disease
Stage II, Less aggressive 3–6 mo for 5 y and with ISRT (MANT-6)
nonbulky induction therapy then annually or as alone for stage MANT-3 • In selected
contiguous (MANT-A) ± ISRTj clinically indicated I or contiguous cases,
Surveillance imaging stage II relapsed
Complete
• Up to 2 y post Relapse disease may
responsel completion of be managed
Stage treatment: C/A/P CT Prior treatment with
as newly
I,II Less aggressive scan with contrast no chemoimmunotherapy
diagnosed
induction therapy more than every 6 mo ± ISRT
• >2 y: No more than advanced-
(MANT-A) stage MCL
annually
(MANT-3)
Stage II, Partial
nonbulky or response or
noncontiguous Progressionl

Active surveillance Symptomatic or

in highly selected other indication for MANT-3
cases treatment

h Localized presentation is extremely rare.

i In the treatment plan, early referral for HDT/ASCR is advisable.
j Principles of Radiation Therapy (NHODG-D).
k Leitch HA, et al. Ann Oncol 2003;14:1555-1561.
l Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
m Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.

Note: All recommendations are category 2A unless otherwise indicated.

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Mantle Cell Lymphoma Discussion

MANAGEMENT AND FOLLOW-UPm

Classical TP53
MANT-4
wild type

• TP53 mutation has been associated with poor prognosis in patients treated with conventional
Classical TP53 therapy including transplant
Stage mutated • Clinical trial is strongly recommended
II bulky • In absence of clinical trial, consider the induction therapy options listed on MANT-A.
noncontiguous;
Stage III, IVi

• Common • Evaluate for

presentations Symptomatic or clinical concern of Treat as described
include: other indication transformation above based on the
Leukemic non- for treatment Rebiopsy and TP53 mutation status
nodal CLL-like with TP53 sequencing
splenomegaly
Indolentn
GI or blood/
bone marrow
involvement only
Low tumor burden, Asymptomatic, no
Ki-67 proliferation Active
other indication
fraction <10% surveillance
for treatment

i In the treatment plan, early referral for HDT/ASCR is advisable.

m Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.
n Most common biomarker for indolent disease: SOX11- (IGHV mutated).

Note: All recommendations are category 2A unless otherwise indicated.

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Mantle Cell Lymphoma Discussion

INDUCTION ADDITIONAL THERAPY FOLLOW-UPm SECOND-LINE

THERAPYi THERAPY
Clinical follow-
up every
Covalent BTKi + rituximab 3–6 mo for
5 y and then Relapse
maintenancep (MANT-A)
annually or
CRl as clinically
indicated
HDT/ASCRq
Clinical Relapsed or
trial Refractory
Suitable for Disease
or
aggressive (MANT-6)
Aggressive
induction
Induction Chemoimmunotherapy
therapy
Therapy (MANT-A) to achieve CR
(MANT-A) PRl,o or
Classical TP53 If covalent BTKi naive,
wild type then covalent BTKi Continue covalent
Stage II bulky (preferred) (MANT-A) BTKi until progression
noncontiguous;
Stage III, IVi No response
or progressive
Not suitable diseasel
for
aggressive MANT-5
induction
therapy

i In the treatment plan, early referral for HDT/ASCR is advisable.

l Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
m Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.
o Patients who have achieved near CR can proceed to HDT/ASCR. Patients who have achieved minimal PR with substantial disease should be treated as having
refractory or progressive disease. Patients who have achieved a very good PR may be treated with additional therapy to achieve CR with the goal of proceeding to
HDT/ASCR.
p Benefit of 2 years of ibrutinib maintenance after alternating RCHOP + ibrutinib/RDHAP was shown in the TRIANGLE study (Dreyling M, et al. Blood 2022;140:1-
3). The value of ibrutinib maintenance after other aggressive induction therapy regimens has not been established. Alternate covalent BTKi (acalabrutinib and
zanubrutinib) were not evaluated in the TRIANGLE study.
q HDT/ASCR is considered as an appropriate option for consolidation therapy in some NCCN Member Institutions.

Note: All recommendations are category 2A unless otherwise indicated.

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Mantle Cell Lymphoma Discussion

INDUCTION ADDITIONAL THERAPY FOLLOW-UPm SECOND-LINE

THERAPY THERAPY
Clinical follow-
up every
Consider rituximab 3–6 mo for 5 y
maintenance and then
CRl Relapse
(category 1 following annually or
RCHOP) (MANT-A) as clinically
indicated
Clinical
Not trial
Classical TP53 Chemoimmunotherapy
suitable or Relapsed or
wild type (MANT-A) to achieve CR
for Less Refractory
Stage II bulky
aggressive aggressive Disease
noncontiguous; or
Stage III, IVi
induction induction PRl,r (MANT-6)
therapy therapy If covalent BTKi naive,
(MANT-A) then covalent BTKi Continue covalent
(preferred) (MANT-A) BTKi until progression

No response
or progressive
diseasel

i In the treatment plan, early referral for HDT/ASCR is advisable.

l Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
m Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated.
r Active surveillance is recommended for patients who have achieved a very good PR or consider rituximab maintenance. Patients who have achieved minimal PR with
substantial disease should be treated as having refractory or progressive disease.

Note: All recommendations are category 2A unless otherwise indicated.

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Mantle Cell Lymphoma Discussion

RELAPSED/ CONSOLIDATION/ FOLLOW-UPm RELAPSE #2 OR

REFRACTORY DISEASE ADDITIONAL THERAPY GREATER
Second-line Continue treatment
therapy with Responsel with covalent BTKi Progression
covalent BTKi- until progression
containing or
other continuous
treatment CAR T-cell therapy (MANT-A)
regimens or
[Suggested Non-covalent BTKi (MANT-A)
or
Regimens NR or Clinical trial
(MANT-A)] progressive or Clinical follow-up
every 3–6 mo for 5 y Relapse or
or diseasel Alternative second-line therapy Progressive
ISRTj followed by allogeneic HCT in and then annually or
as clinically indicated Disease
selected cases if CR or PR is
NR or achieveds ± ISRTj
Relapsed/ progressive CAR T-cell therapy (if not
refractory diseasel If covalent BTKi naive, then covalent previously given; MANT-A)
disease Second-line BTKi (preferred) (MANT-A) or
therapy with Non-covalent BTKi (if not
Active surveillance previously given; MANT-A)
fixed-duration or
regimens or
If covalent BTKi naive, then covalent
[Suggested PRl,t Alternative systemic
BTKi (preferred) (MANT-A)
Regimens or therapy for relapsed/
(MANT-A)] CAR T-cell therapy (MANT-A) refractory disease (not
or or previously given; MANT-A)
ISRTj Non-covalent BTKi (MANT-A) or
Clinical trial
Allogeneic HCT in selected casess or
± ISRTj Palliative ISRTj
CRl
j Principles of Radiation Therapy (NHODG-D). or or
l Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). HDT/ASCR (in selected cases, if Best supportive care
m Follow-up includes diagnostic tests and imaging using the same not previously received) (NCCN Guidelines for
modalities performed during workup as clinically indicated. or Palliative Care)
s Selected cases include mobilization failures and persistent bone Active surveillance
marrow involvement.
t Patients with a very good PR are potentially candidates for active
surveillance. Patients with a minimal PR are considered as having
refractory disease and go on to additional treatment.

Note: All recommendations are category 2A unless otherwise indicated.

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Mantle Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENSa,b

INDUCTION THERAPY
Stage I or Stage II nonbulky Classical TP53 wildtype: Classical TP53 mutated:
(contiguous or noncontiguous)c Stage II bulky noncontiguous; Stage II bulky noncontiguous;
or Stage III, IV Stage III, IV
Classical TP53 wildtype:
Stage II bulky noncontiguous;
Stage III, IV
Less Aggressive Induction Therapy Aggressive Induction Therapy Suitable for all patients
Preferred regimens Preferred regimens (in alphabetical order) • Zanubrutinib/obinutuzumab/venetoclax
• Acalabrutinibf,g (continuous) + • LyMA regimen: RDHA (rituximab, dexamethasone, cytarabine)
bendamustine + rituximab + platinum (carboplatin, cisplatin, or oxaliplatin) x 4 cycles Suitable for aggressive induction
• Bendamustine + rituximabd followed by RCHOP (rituximab, cyclophosphamide, doxorubicin, therapy:
• VR-CAP (bortezomib, rituximab, vincristine, prednisone) for non-PET CR • TRIANGLE regimen (fixed duration):
cyclophosphamide, doxorubicin, and • NORDIC regimen: Dose-intensified induction Alternating RCHOP + covalent BTKif/
prednisone) immunochemotherapy with rituximab + cyclophosphamide, RDHA (rituximab, dexamethasone,
• RCHOPe vincristine, doxorubicin, prednisone (maxi-CHOP) alternating with cytarabine) + platinum (carboplatin,
• Lenalidomide (continuous) + rituximab + high-dose cytarabine cisplatin, or oxaliplatin) (category 2A for
rituximab • Rituximab, bendamustineh followed by rituximab, high-dose ibrutinib; category 2B for acalabrutinib
cytarabine or zanubrutinib)
Other recommended regimen • TRIANGLE regimen (fixed duration): Alternating RCHOP +
• Acalabrutinibf,g (continuous) + covalent BTKif/RDHA (rituximab, dexamethasone, cytarabine) Not suitable for aggressive induction
rituximab + platinum (carboplatin, cisplatin, or oxaliplatin) (category 2A for therapy:
ibrutinib; category 2B for acalabrutinib or zanubrutinib) • Less aggressive induction therapy
regimens (as recommended for
Other recommended regimen classical TP53 wildtype)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and
dexamethasone alternating with high-dose methotrexate and
cytarabine) + rituximabi (NOTE: There are conflicting data
regarding the need for consolidation with HDT/ASCR)
• RBAC500 (rituximab, bendamustine,h cytarabine)

Footnotes on MANT-A 3 of 5
Maintenance Therapy on MANT-A 2 of 5
Consider prophylaxis for tumor lysis syndrome (NHODG-B) Second-line Therapy on MANT-A 2 of 5
See monoclonal antibody and viral reactivation (NHODG-B)

Note: All recommendations are category 2A unless otherwise indicated.

MANT-A
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Mantle Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENSa,b

MAINTENANCE AFTER HDT/ASCR OR AGGRESSIVE INDUCTION THERAPY

• Covalent BTKi (fixed duration)f x 2 yearsj (category 2A for ibrutinib; category 2B for acalabrutinib or zanubrutinib) + rituximab every 8
weeks x 3 years
MAINTENANCE AFTER LESS AGGRESSIVE INDUCTION THERAPY
• Rituximab every 8 weeks for 2–3 years following RCHOP (category 1) or Bendamustine + rituximab
Maintenance rituximab following VR-CAP or RBAC500 has not been evaluated

SECOND-LINE AND SUBSEQUENT THERAPY

Preferred regimens (in alphabetical order) Useful in Certain Circumstances (in alphabetical order)
• Covalent BTKi (continuous)f,k • Bendamustineh + rituximab (not recommended if treated with prior
Acalabrutinib g bendamustine)
Zanubrutinib • Bortezomib ± rituximab
• Lenalidomide (continuous) + rituximab • DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or
oxaliplatin) + rituximab (if not previously given)
Other recommended regimen • GemOx (gemcitabine, oxaliplatin) + rituximab
• Covalent BTKi (continuous)f • Ibrutinibf (continuous) + venetoclax
• RBAC500 (rituximab, bendamustine,h cytarabine) (not recommended if
Ibrutinibl ± rituximab
treated with prior bendamustine)
• Venetoclaxf (continuous) ± rituximab

• Progressive disease after prior covalent BTKi

Non-covalent BTKi (continuous)
◊ Pirtobrutinibf,m
CAR T-cell therapyn
◊ Brexucabtagene autoleucel (CD19-directed)
◊ Lisocabtagene maraleucel (CD19-directed)

• Progressive disease after CAR T-cell therapy and pirtobrutinib or ineligible

for CAR T-cell therapy
Glofitamab-gxbmf,o (category 2B)

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B) Footnotes on MANT-A 3 of 5

Note: All recommendations are category 2A unless otherwise indicated.

MANT-A
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SUGGESTED TREATMENT REGIMENS

FOOTNOTES
a See references for regimens MANT-A 4 of 5 and MANT-A 5 of 5.
b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
Obinutuzumab can optionally be substituted for rituximab at the discretion of the treating physician.
c In selected cases, relapsed disease may be managed with induction therapy recommended for newly diagnosed advanced stage MCL.
d Addition of ibrutinib to BR followed by continuous ibrutinib maintenance was shown in the SHINE study to have a superior PFS but overall survival was
compromised by excess non-lymphoma deaths (Wang ML, et al. N Engl J Med 2022;386:2482-2494).
e There is a randomized trial that demonstrated that RCHOP was not superior to CHOP.
f Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/
index.cfm.
g Studies of acalabrutinib excluded concomitant use of warfarin or equivalent vitamin K antagonists.
h In patients intended to receive HDT/ASCR, bendamustine should be used with caution as there are conflicting data regarding ability to collect peripheral progenitor
cell collection. In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay
bendamustine until after CAR-T leukapheresis.
i Rituximab + covalent BTKi (acalabrutinib, ibrutinib, zanubrutinib) can be used as a pre-treatment to limit the number of cycles of R-HyperCVAD/rituximab
maintenance. Wang ML et al. Lancet Oncol 2022;23:406-415.
j Benefit of 2 years of ibrutinib maintenance after alternating RCHOP + ibrutinib/RDHAP was shown in the TRIANGLE study (Dreyling M, et al. Blood 2022;140:1-
3). The value of ibrutinib maintenance after other aggressive induction therapy regimens has not been established. Alternate covalent BTKi (acalabrutinib and
zanubrutinib) were not evaluated in the TRIANGLE study.
k Acalabrutinib and zanubrutinib have not been shown to be effective for ibrutinib-refractory MCL with BTK C481S mutations. Pirtobrutinib is effective for the
management of resistance to covalent BTKi, including in patients with BTK C481 mutations (which are uncommon in MCL). Patients with intolerance to a BTKi will
often be successfully treated with an alternate BTKi (covalent or non-covalent).
l Head-to-head clinical trials in other B-cell malignancies have demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib compared to ibrutinib
without compromising efficacy.
m Pirtobrutinib can be given as second-line therapy for disease progression during induction or maintenance therapy with covalent BTKi-based regimens.
n Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy (NHODG-E).
o In the setting of CD20-negative lymphomas, the activity of CD3 x CD20 bispecific antibody therapy is unclear. Rebiopsy to confirm CD20 positivity is recommended
prior to initiating CD3 x CD20 bispecific antibody therapy.

Note: All recommendations are category 2A unless otherwise indicated.

MANT-A
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SUGGESTED TREATMENT REGIMENS

REFERENCES
Induction Therapy
Aggressive therapy Less aggressive therapy
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high-dose methotrexate and cytarabine. J Clin Oncol 2005;23:7013-7023. 2016;174:899-910.
Merli F, Luminari S, Ilariucci F, et al. Rituximab plus HyperCVAD alternating with high dose cytarabine and Rodríguez J, Gutierrez A, Palacios A, et al. Rituximab, gemcitabine and oxaliplatin: an effective
methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo regimen in patients with refractory and relapsing mantle cell lymphoma. Leuk Lymphoma
Italiano Studio Linfomi. Br J Haematol 2012;156:346-353. 2007;48:2172-2178.
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rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP] alternating with Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin,
and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and
rituximab + high-dose cytarabine)
prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell
Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma
lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol
following intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: A non-randomized 2018;19:1449-1458.
phase-II multicenter study by the Nordic Lymphoma Group. Blood 2008;112:2687-2693. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab
Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide,
trial (MCL2): prolonged remissions without survival plateau. Br J Haematol 2016;175:410-418. doxorubicin, vincristine, and prednisone significantly improves response and time to treatment
LyMA regimen: RDHA (rituximab, dexamethasone, cytarabine) + platinum (cisplatin, oxaliplatin or failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma:
carboplatin) x 4 cycles followed by RCHOP for non- PET CR results of a prospective randomized trial of the German Low Grade Lymphoma Study Group
Sarkozy C, Thieblemont C, Oberic L, et al. Long-term follow-up of rituximab maintenance in young patients (GLSG). J Clin Oncol 2005;23:1984-1992.
with mantle-cell lymphoma included in the LYMA trial: A LYSA study. J Clin Oncol 2024;42:769-773. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell
Tessoulin B, Chiron D, Thieblemont C, et al. Oxaliplatin before autologous transplantation in combination lymphoma. N Eng J Med 2012;367:520-531.
with high-dose cytarabine and rituximab provides longer disease control than cisplatin or carboplatin in Lenalidomide + rituximab
patients with mantle-cell lymphoma: results from the LyMA prospective trial. Bone Marrow Transplant Yamshon S, Chen GZ, Gribbin C, et al. Nine-year follow-up of lenalidomide plus rituximab as initial
2021;56:1700-1709. treatment for mantle cell lymphoma. Blood Adv 2023;7:6579–6588.
Rituximab, bendamustine followed by rituximab, high-dose cytarabine
Merryman R, Edwin N, Redd R, et al. Rituximab/bendamustine and rituximab/cytarabine induction therapy Induction Therapy for classical TP53 mutated MCL
for transplant-eligible mantle cell lymphoma. Blood Adv 2020;45:858-867. Zanubrutinib, obinutuzumab, and venetoclax
RBAC500 (rituximab, bendamustine, cytarabine) Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line
Tisi MC, Moia R, Patti C, et al. Long-term follow-up of rituximab plus bendamustine and cytarabine in older treatment of mantle cell lymphoma with a TP53 mutation. Blood 2025;145:497-507.
patients with newly diagnosed MCL. Blood Adv 2023;7:3916–3924.
Bega G, Olivieri J, Riva M, et al. Rituximab and Bendamustine (BR) Compared with Rituximab,
Bendamustine, and Cytarabine (R-BAC) in Previously Untreated Elderly Patients with Mantle Cell
Lymphoma. Cancers (Basel) 2021;13.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
MANT-A
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Mantle Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
First-line Consolidation DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) + rituximab
High-dose therapy with autologous stem cell rescue Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with
Zoellner AK, Unterhalt M, Stilgenbauer S, et al. Long-term survival of patients with mantle rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.
cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a Cancer Invest 2006;24:593-600.
post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol Lignon J, Sibon D, Madelaine I, et al. Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) is
2021;8:e648-e657. an effective and safe salvage regimen in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Lymphoma
Thieblemont C, Antal D, Lacotte-Thierry L, et al. Chemotherapy with rituximab followed by high- Myeloma Leuk 2010;10:262-269.
dose therapy and autologous stem cell transplantation in patients with mantle cell lymphoma. Rigacci L, Fabbri A, Puccini B, et al. Oxaliplatin-based chemotherapy (dexamethasone, high-dose cytarabine,
Cancer 2005;104:1434-1441. and oxaliplatin) +/- rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma.
Ritchie D, Seymour J, Grigg A, et al. The hyper-CVAD–rituximab chemotherapy programme Cancer 2010;116:4573-4579.
followed by high-dose busulfan, melphalan and autologous stem cell transplantation produces Ibrutinib ± rituximab
excellent event-free survival in patients with previously untreated mantle cell lymphoma. Ann Wang ML, Blum KA, Martin P, et al. Long-term follow-up of MCL patients treated with single-agent ibrutinib:
Hematol 2007;86:101-105. updated safety and efficacy results. Blood 2015;126:739-745.
van 't Veer MB, de Jong D, MacKenzie M, et al. High-dose Ara-C and beam with autograft rescue Rule S, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously
in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol 2009;144:524-530. treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia
Ibrutinib + rituximab maintenance 2018;32:1799-1803.
Dreyling M, Doorduijn J, Gine E, et al. Ibrutinib combined with immunochemotherapy with or Wang ML, Lee H, Chuang H, et al. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell
without autologous stem-cell transplantation versus immunochemotherapy and autologous stem- lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol 2016;7:48-56.
cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): Ibrutinib + venetoclax
a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Wang M, Jurczak W, Trneny M, et al. Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma
Lymphoma Network. Lancet 2024;403:2293-2306. (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol
Rituximab maintenance 2025;26:200–213.
Sarkozy C, Thieblemont C, Oberic L, et al. Long-term follow-up of rituximab maintenance in Lenalidomide + rituximab
young patients with mantle-cell lymphoma included in the LYMA trial: A LYSA study. J Clin Oncol Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with
2024;42:769-773. relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 2012;13:716-723.
Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle cell RBAC500 (rituximab, bendamustine, cytarabine)
lymphoma (MCL): Long-term follow-up of the randomized European MCL Elderly Trial. J Clin McCulloch R, Lewis D, Crosbie N, et al. Ibrutinib for mantle cell lymphoma at first relapse: a United Kingdom
Oncol 2020;38:248-256. real-world analysis of outcomes in 211 patients. Br J Haematol 2021;193:290-298.
Rummel MJ, Lerchenmüller C, Hensel M, et al. Two years rituximab maintenance vs. observation Venetoclax
after first line treatment with bendamustine plus rituximab (B-R) in patients with waldenström's Davids MS, Roberts AW, Kenkre VP, et al. Long-term follow-up of patients with relapsed or refractory non-Hodgkin
macroglobulinemia (MW): Results of a prospective, randomized, multicenter phase 3 study (the lymphoma treated with venetoclax in a phase I, first-in-human study. Clin Cancer Res 2021;27:4690-4695.
StiL NHL7-2008 MAINTAIN trial) [abstract]. Blood 2019;134:Abstract 343. Davids, M, von Keudell G, Portell G, et al. Revised dose ramp-up to mitigate the risk of tumor lysis syndrome
Second-line and Subsequent Therapy when initiating venetoclax in patients with mantle cell lymphoma. J Clin Oncol 2018;36:3525-3527.
Acalabrutinib Zanubrutinib
Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients Song Y, Zhou K, Zou D, et al. Treatment of patients with relapsed or refractory mantle-cell lymphoma with
with relapsed or refractory mantle cell lymphoma. Leukemia 2019;33:2762-2766. zanubrutinib, a selective inhibitor of Bruton's tyrosine kinase. Clin Cancer Res 2020;26:4216-4224.
Bendamustine Tam CS, Opat S, Simpson D, et al. Zanubrutinib for the treatment of relapsed or refractory mantle cell
Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine lymphoma. Blood Adv 2021;5:2577-2585.
plus rituximab in patients with relapsed indolent B-cell and mantle cell Non-Hodgkin’s Lymphoma.
J Clin Oncol 2008;26:4473-4479. Brexucabtagene autoleucel
Rummel M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine plus Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell
rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol 2023;41:555-567.
randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol 2016;17:57-66. Lisocabtagene maraleucel
Bortezomib ± rituximab Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma:
Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients with relapsed or refractory mantle primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter
cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann seamless design study. J Clin Oncol 2024;42:1146-1157.
Oncol 2009;20:520-525.
Baiocchi RA, Alinari L, Lustberg ME, et al. Phase 2 trial of rituximab and bortezomib in patients Pirtobrutinib
with relapsed or refractory mantle cell and follicular lymphoma. Cancer 2011;117:2442-2451. Wang ML, Jurczak W, Zinzani PL, et al. Pirtobrutinib in covalent Bruton tyrosine kinase inhibitor pretreated
mantle-cell lymphoma. J Clin Oncol 2023;41:3988-3997.
Glofitamab
Phillips T, Carlo-Stella C, Morschhauser F, et al. Glofitamab monotherapy in patients with heavily pretreated
relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study [abstract]. J
Clin Oncol 2024;42:Abtract 7008.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

ADDITIONAL DIAGNOSTIC TESTINGa,b SUBTYPES

ESSENTIAL:
• Adequate immunophenotyping to establish • DLBCL, not otherwise specified (DLBCL-NOS)e
diagnosis and germinal center B-cell (GCB) (includes germinal center [GC] and non-GC)
versus non-GCB originc • FL3B (ICC)/FLBCL (WHO5)
IHC panel: CD3, CD20, CD10, CD21, BCL2, • Intravascular LBCL
BCL6, IRF4/MUM1, MYC • DLBCL associated with chronic inflammation Workup
with or without • Fibrin-associated LBCL (BCEL-2)
Flow cytometry with peripheral blood and/or • EBV-positive DLBCL, NOS
biopsy specimen: kappa/lambda, CD3, CD5, • T-cell/histiocyte-rich LBCL
CD19, CD10, CD20, CD45, • LBCL with IRF4/MUM1 rearrangement
• Karyotype or FISH for MYC; FISH for BCL2, • HGBL with MYC and BCL6 rearrangements (ICC)
BCL6 rearrangements if MYC positive
• Primary cutaneous DLBCL, leg type BCEL-10
USEFUL UNDER CERTAIN CIRCUMSTANCES: • ALK-positive LBCL BCEL-B 1 of 2
• Additional immunohistochemical studies to • Mediastinal gray zone lymphoma (MGZL) BCEL-B 2 of 2
establish lymphoma subtype • Primary mediastinal large B-cell lymphoma (PMBL) PMBL-1
IHC panel: cyclin D1, kappa/lambda, CD5, • HGBL
HGBL-1
CD30, CD45, CD138, anaplastic lymphoma • HGBL, NOS
kinase (ALK), human herpesvirus-8 (HHV8), • LBCL with 11q aberration [ICC]/HGBL with 11q aberrations [WHO5] BURK-1
SOX11, Ki-67 • DLBCL arising from FL or MZL HTBCEL-1
• Epstein-Barr virus (EBV)-encoded RNA (EBER) • Primary DLBCL of the CNS (See NCCN Guidelines for CNS)
in situ hybridization (EBER-ISH) • DLBCL arising from CLL (Richter transformation) (See NCCN Guidelines for CLL/SLL)
• Karyotype or FISH for IRF4/MUM1
rearrangementsd
• NGS lymphoma panelb

a Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).
b See BCEL-A 1 of 3 for a minimal list of accepted genes that should be included in the NGS lymphoma panel for DLBCL.
c Typical immunophenotype: CD20+, CD45+, CD3-; additional markers are used for subclassification.
d LBCL with IRF4/MUM1 rearrangement are usually DLBCL but occasionally are purely FL grade 3b (ICC/FLBCL [WHO5])
and often DLBCL with FL grade 3b. Patients
typically present with Waldeyer’s ring involvement and are often children/young adults. These lymphomas are locally aggressive but respond well to chemotherapy ±
RT. They do not have a BCL2 rearrangement and should not be treated as low-grade FL.
e GC (or follicle center) phenotype is not equivalent to FL and can occur in DLBCL and BL. Morphology is required to establish diagnosis.

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Diffuse Large B-Cell Lymphoma Discussion

WORKUP
ESSENTIAL:
• Physical exam: attention to node-bearing areas, including Waldeyer’s ring, and to
size of liver and spleen
• Performance status
• B symptoms
• CBC with differential
• LDH
• Comprehensive metabolic panel
• Uric acid
• PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality
• Calculation of International Prognostic Index (IPI) (BCEL-A 2 of 3)
• Hepatitis B testingf
• Echocardiogram or MUGA scan if anthracycline or anthracenedione-based First-LIne Therapy
regimen is indicated (BCEL-3)
• Pregnancy testing in patients of childbearing age (if chemotherapy or RT planned)

USEFUL IN SELECTED CASES:

• Head CT/MRI with contrast or neck CT/MRI with contrast
• HIV testing
• Hepatitis C testing
• Beta-2-microglobulin
• Lumbar puncture for patients at risk for CNS involvement; see BCEL-A 3 of 3
• Adequate bone marrow biopsy (>1.6 cm) ± aspirate; bone marrow biopsy is not
necessary if PET/CT scan demonstrates bone disease. Bone marrow biopsy with
a negative PET/CT scan may reveal discordant lymphoma
• Discuss fertility preservationg

f Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with
no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with
gastroenterologist.
g Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.

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Diffuse Large B-Cell Lymphoma Discussion

STAGE FIRST-LINE THERAPY p

Interim restaging with

smIPI 0–1 RCHOP x 3 cycles BCEL-4
PET/CT
Nonbulky
Stage I, II (<7.5 cm)l
(excluding stage Follow pathway below for Stage
II with extensive smIPI >1 II with extensive mesenteric
mesenteric disease or Stage III, IV
diseaseh)i,j,k,l Bulky
(≥7.5 cm)l
Interim restaging with
smIPI 0–1 RCHOP x 3–4 cycles BCEL-5
PET/CTo

Stage II with extensive

First-line therapy
mesenteric diseaseh Interim restaging with PET/
See Suggested BCEL-6
or CTq or CT after 2–4 cycles
Regimens (BCEL-C)
Stage III, IV i,k,m,n,o

h Includes multifocal disease and bulky disease that is not amenable to RT.
i In testicular lymphoma, after completion of chemoimmunotherapy, scrotal RT m Prognostic Model to Assess the Risk of CNS Disease (BCEL-A 3 of 3).
should be given. See Principles of Radiation Therapy (NHODG-D). n Patients with systemic disease with concurrent CNS disease; see BCEL-C.
j In patients who are not candidates for chemoimmunotherapy, ISRT is o In selected cases, RT to initially bulky sites of disease may be beneficial
recommended. (category 2B).
k See BCEL-C for regimens used in patients with poor left ventricular function, p Recommendations are for HIV-negative lymphoma only. For HIV-positive DLBCL,
patients who are very frail, and patients >80 years of age with comorbidities. see HIVLYM-2.
There are limited data for treatment of early-stage disease with these regimens; q PET/CT scan at interim restaging can lead to increased false positives and should
however, short-course chemoimmunotherapy + RT for stage I–II disease is be carefully considered in select cases. If PET/CT scan performed and positive,
practiced at NCCN Member Institutions. rebiopsy before changing course of treatment. In selected cases, PET is necessary
l Some studies have used 10 cm as the cutoff for bulky disease. when disease is occult on CT scan (eg, bone only disease).

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Diffuse Large B-Cell Lymphoma Discussion

STAGE I (smIPI 0–1; Non-bulky; <7.5 cm) END-OF- FOLLOW-UP

TREATMENT
RESPONSE Clinical
• H&P and labs, every
3–6 mo for 5 y and Relapse
Complete RCHOP x 1 cycle then annually or as BCEL-7
responser (total of 4 cycles)k <12 mo
clinically indicated
(PET negative or Imagingw
[5-PS 1–3])s ISRTt Complete • C/A/P CT scan
responser with contrast no
(PET more often than
negative [5- every 6 mo for 2 y Relapse
>12 mo BCEL-8
RCHOP x 1–3 PS 1–3])s after completion of
End-of-
Restage with Partial cycles (total of treatment, then only
treatment
PET/CT after responser Repeat 4–6 cycles)k ± as clinically indicated
restaging
3 cycles of (PET positive biopsyu ISRTt with PET/
RCHOPk [5-PS 4])s or CTu,v
ISRTt PRr or
Progressive
No disease (PET Repeat biopsyu,v
response or positive [5-PS
Progressive 4 or 5])s BCEL-7
diseaser Repeat biopsyu
(PET positive
[5-PS 5])s
k See BCEL-C for regimens used in patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities. There are
limited data for treatment of early-stage disease with these regimens; however, short-course chemoimmunotherapy + RT for stage I–II disease is practiced at NCCN
Member Institutions.
r Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
s PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3).
t Principles of Radiation Therapy (NHODG-D).
u Repeat biopsy should be strongly considered if PET-positive prior to additional therapy. If biopsy negative, follow PET-negative pathway. In cases where biopsy
cannot be done or is unsafe, clinical judgment should be used.
v The optimum timing of end-of-treatment PET/CT is unknown; however, waiting a minimum of 8 weeks after RT to repeat PET/CT scan is suggested. False positives
may occur due to post-treatment changes. If end-of treatment PET is positive, consider repeat biopsy or if biopsy not feasible, consider circulating tumor DNA (ctDNA)
for minimal residual disease (MRD) (ctDNA-MRD) assessment (category 2B), using a test with a detection limit of <1 part per million, prior to additional therapy. If
biopsy and/or ctDNA-MRD–negative, follow PET-negative pathway.
w Surveillance imaging at 12 mo has treatment implications. Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be
visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

STAGE I–II (smIPI 0–1; BULKY; ≥7.5 CM) FOLLOW-UP

(EXCLUDING STAGE II WITH EXTENSIVE MESENTERIC DISEASEh)
RESTAGING AND ADDITIONAL THERAPY
Clinical
• H&P and labs, every
3–6 mo for 5 y and
Complete then annually or as Relapse
responser,x RCHOP x 2–3 cycles (total of clinically indicated BCEL-7
<12 mo
(PET negative 6 cycles)k ± ISRT (initial dose)t Imagingw
[5-PS 1–3])s • C/A/P CT scan with
Complete
contrast no more
responser,x
often than every 6
(PET
mo for
negative Relapse
2 y after completion BCEL-8
[5-PS 1–3])s >12 mo
of treatment, then
RCHOP x 2–3 End-of- only as clinically
Restage with Partial
cycles (total treatment indicated
PET/CT after responser Repeat
biopsyu of 6 cycles)k restaging
3–4 cycles of (PET positive
± ISRT with PET/
RCHOPk [5-PS 4])s
(higher dose)t CTu,v
PRr or
Progressive
Repeat
disease (PET
biopsyu,v BCEL-7
positive
No response or
[5-PS 4 or 5])s
Progressive diseaser Repeat
(PET positive biopsyu
[5-PS 5])s
h Includes u Repeat biopsy should be strongly considered if PET-positive prior to additional therapy. If
multifocal disease and bulky disease that is not amenable
to RT. biopsy negative, follow PET-negative pathway. In cases where biopsy cannot be done or is
k See unsafe, clinical judgment should be used.
BCEL-C for regimens used in patients with poor left ventricular v The optimum timing of end-of-treatment PET/CT is unknown; however, waiting a minimum of 8
function, patients who are very frail, and patients >80 years of weeks after RT to repeat PET/CT scan is suggested. False positives may occur due to post-
age with comorbidities. There are limited data for treatment of treatment changes. If end-of treatment PET is positive, consider repeat biopsy or if biopsy not
early-stage disease with these regimens; however, short-course feasible, consider ctDNA-MRD assessment (category 2B), using a test with a detection limit
chemoimmunotherapy + RT for stage I–II disease is practiced at of <1 part per million, prior to additional therapy. If biopsy and/or ctDNA-MRD–negative, follow
NCCN Member Institutions. PET-negative pathway.
r Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). w Surveillance imaging at 12 mo has treatment implications. Surveillance imaging is used for
s PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3
monitoring asymptomatic patients. When a site of disease can only be visualized on PET/CT
of 3). scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.
t Principles of Radiation Therapy (NHODG-D). x Patients in first remission may be candidates for consolidation trials including HDT/ASCR.

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Diffuse Large B-Cell Lymphoma Discussion

STAGE I–II WITH FOLLOW-UP END-OF- END-OF-TREATMENT FOLLOW-UP

EXTENSIVE MESENTERIC THERAPY TREATMENT RESPONSE
DISEASEh OR STAGE III–IV RESTAGING Clinical
DISEASE RESTAGING AND • H&P and labs,
ADDITIONAL THERAPY every 3–6 mo
Active for 5 y and
surveillance then annually Relapse
<12 mo BCEL-7
Complete or or as clinically
responser Consider indicated
Complete Imagingw
(PET ISRTt to
responser (PET negative initially bulky
• C/A/P CT scan
negative [5-PS At end of with contrast no
Continue first- [5-PS 1–3])s disease or more often than
1–3])s or line therapyy treatment, isolated Relapse
partial repeat all every 6 mo for 2 y
to a total skeletal sites after completion >12 mo BCEL-8
responser (PET of 6 cycles positive of treatment, then
Restage positive [5-PS (category 1) studiesu,aa only as clinically
with PET/ 4aa/5])s indicated
Partial
CT or CT responser
after 2–4 (PET positive Repeat biopsyu,aa
cycles of [5-PS 4bb/5])s
first-line
therapyy,z BCEL-7
Progressive
Repeat biopsyu,aa
No diseaser
responser or
Repeat biopsyu
progressive
diseaser
y See
BCEL-C for regimens used in patients with poor left ventricular function,
patients who are very frail, and patients >80 years of age with comorbidities.
z In selected cases, PET is necessary when disease is occult on CT scan (eg,
h Includes multifocal disease and bulky disease that is not amenable to RT. bone only disease). PET/CT scan at interim restaging can lead to increased false
r Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). positives and should be carefully considered in select cases. If PET/CT scan
s PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3). performed and positive, rebiopsy before changing course of treatment.
t Principles of Radiation Therapy (NHODG-D). aa If end-of treatment PET is positive, consider repeat biopsy or if biopsy not
u Repeat biopsy should be strongly considered if PET-positive prior to additional feasible, consider ctDNA-MRD assessment (category 2B), using a test with a
therapy. If biopsy negative, follow CR or PR pathway. In cases where biopsy detection limit of <1 part per million, prior to additional therapy. If biopsy and/or
cannot be done or is unsafe, clinical judgment should be used. ctDNA-MRD–negative, follow PET-negative pathway.
w Surveillance imaging at 12 mo has treatment implications. Surveillance imaging bb In cases where PET/CT needs to be used, a 5-PS = 4 response can reflect post-
is used for monitoring asymptomatic patients. When a site of disease can only be treatment inflammation as well as active disease. If there is uncertainty regarding
visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT interpretation of the response, consider brief interval restaging to clarify post-
scans for surveillance. treatment inflammation response.

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Diffuse Large B-Cell Lymphoma Discussion

RELAPSE/ ADDITIONAL RESPONSE

REFRACTORY DISEASE THERAPY ASSESSMENT

Candidates CAR T-cell therapy with

Follow-up
for CAR bridging therapy (BCEL-C 2
(BCEL-9)
T-cell therapy of 7) as clinically indicateddd
Relapsed disease
<12 mo Consolidation
or Clinical trial Complete with HDT/
Primary refractory Follow-up (BCEL-9)
or responser ASCR ± ISRTt,ff
diseasecc Second-line therapy; see (optional)
Non- Suggested Regimens (BCEL-C
Partial
candidates 2 of 7)
responser,ee Relapse #2 or
for CAR or
T-cell therapy Palliative ISRTt Greater (BCEL-9)
No response or
or progressive diseaser
Best supportive care (NCCN
Guidelines for Palliative Care)

r Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

t Principles of Radiation Therapy (NHODG-D).
cc Management of localized refractory disease is uncertain. RT ± chemoimmunotherapy followed by HDT/ASCR may be an option for some patients.
dd If bridging therapy results in CR or very good PR, proceeding with HDT/ASCR is an appropriate alternative.
ee Repeat biopsy should be strongly considered if PET-positive prior to additional therapy, because PET positivity may represent post-treatment inflammation.If biopsy
negative, follow CR pathway.
ff If patient's clinical situation improves markedly and patient becomes eligible for HDT/ASCR. This may include patients who do not have access to CAR T-cell therapy.
Additional RT can be given before or after transplant to sites of previous positive disease.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

RELAPSE/ ADDITIONAL RESPONSE CONSOLIDATION/ADDITIONAL THERAPY

REFRACTORY DISEASE THERAPY ASSESSMENT
HDT/ASCR (category 1) ± ISRTt,hh
or
Complete
Clinical trial
responser
or
Allogeneic HCT in selected casesii ± ISRTt,hh

CAR T-cell therapy (BCEL-C 2 of 7) Follow-up

Second-line or (BCEL-9)
Intention therapy; see HDT/ASCR ± ISRTt,hh
Partial
Suggested or
to proceed to responser,gg
transplant Regimens Clinical trial
(BCEL-C 3 of 7) or
Allogeneic HCT in selected casesii ± ISRTt,hh
Treatment for
No response or
Relapse #2 or
Relapsed progressive diseaser
Greater (BCEL-9)
disease >12 mo Clinical trial
or Complete
Follow-up (BCEL-9)
Second-line therapy; responser
see Suggested Partial
Regimens responser,jj Treatment for
No intention
(BCEL-C 3 of 7) Relapse #2 or
to proceed to
or Greater (BCEL-9)
transplant No response or
Palliative ISRTt
progressive diseaser
or
Best supportive
care (See NCCN
Guidelines for
Palliative Care)
r Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
t Principles of Radiation Therapy (NHODG-D).
gg Some NCCN Member Institutions require a complete metabolic response in order to proceed to HDT/ASCR.
hh Additional RT can be given before or after transplant to sites of previous positive disease.
ii Selected cases include mobilization failures and persistent bone marrow involvement.
jj Repeat biopsy should be strongly considered if PET-positive prior to additional therapy, because PET positivity may represent post-treatment inflammation. If biopsy
negative, follow CR pathway.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

FOLLOW-UP TREATMENT FOR RELAPSE

#2 OR GREATER
Third-line therapy (BCEL-C 4 of 7)
or
• Clinical If CR/PR, consider
Alternative systemic therapy for
H&P and labs, every 3–6 mo allogeneic HCT in
relapsed/refractory disease (not
for 5 y and then annually or selected casesii,nn
previously given)ll (BCEL-C 2 of
as clinically indicated ± ISRTt,hh
Follow-up after Partial 7 and BCEL-C 3 of 7)
• Imagingw
treatment for responser,kk or
C/A/P CT scan with contrast
relapsed/refractory or Clinical trialmm
no more often than every
disease Relapse or
6 mo for 2 y after
Palliative ISRTt,mm
completion of treatment,
or
then only as clinically
Best supportive caremm
indicated
(See NCCN Guidelines for
Palliative Care)

r Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).

t Principles of Radiation Therapy (NHODG-D).
w Surveillance imaging at 12 mo has treatment implications. Surveillance imaging is used for monitoring asymptomatic patients. When a site of disease can only be
visualized on PET/CT scan (eg, bone), it is appropriate to proceed with PET/CT scans for surveillance.
hh Additional RT can be given before or after transplant to sites of previous positive disease.
ii Selected cases include mobilization failures and persistent bone marrow involvement.
kk Repeat biopsy should be strongly considered if PET-positive prior to additional therapy, because PET positivity may represent post-treatment inflammation.
ll Patients who progress after three successive regimens are unlikely to derive additional benefit from currently utilized combination chemotherapy regimens, except for
patients with a long disease-free interval.
mm If not a candidate for T-cell engager therapy.
nn Patients achieving high-quality CR/PR following alternative second-line therapy may benefit from an allogeneic HCT.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG TYPEoo

STAGEpp INITIAL THERAPYqq,rr,ss Clinical SECOND-LINE THERAPYrr
• H&P and labs, every 3–6 mo
for 5 y and then annually or
as clinically indicated RCHOPtt (if not
Imaging previously received)
CRvv Relapsevv or
RCHOPtt+ local ISRTt • C/A/P CT scan with contrast
or no more often than every Manage as relapsed/
Solitary regional, T1–2 6 mo for 2 y after completion refractory DLBCL
Local ISRTt,uu
(Ann Arbor Stage IE) of treatment, then only as • <12 mo (BCEL-7)
or
Clinical trial clinically indicated • >12 mo (BCEL-8)
or
PR or NR or Local ISRT to
Progressive disease previously unirradiated
Clinical tumort
• H&P and labs, every 3–6 mo
for 5 y and then annually or
as clinically indicated
Imaging Manage as relapsed/
CRvv Relapsevv refractory DLBCL
• C/A/P CT scan with contrast
RCHOPtt ± local ISRTt no more often than every • <12 mo (BCEL-7)
Generalized disease 6 mo for 2 y after completion • >12 mo (BCEL-8)
or
(skin only), T3 of treatment, then only as
Clinical trial
clinically indicated or
PR or NR or
Extracutaneous Manage as DLBCL Progressive disease Palliative ISRTt
disease (BCEL-3)
t Principles of Radiation Therapy (NHODG-D).
oo Expert hematopathologist review is essential to confirm the diagnosis of primary cutaneous DLBCL, leg type.
pp For TNM Classification of Cutaneous Lymphoma other than MF/SS, see NCCN Guidelines for Primary Cutaneous Lymphoma.
qq Consider prophylaxis for tumor lysis syndrome (NHODG-B) and see monoclonal antibody and viral reactivation (NHODG-B).
rr An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human
injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
ss These patients are at higher risk for CNS involvement (BCEL-A 3 of 3); consider CNS prophylaxis according to institutional standards.
tt For patients who cannot tolerate anthracyclines, see BCEL-C for regimens for patients with poor left ventricular function.
uu For patients not able to tolerate chemoimmunotherapy.
vv PET/CT (strongly preferred) or C/A/P CT with contrast at the end of treatment to assess response. It can be repeated if there is clinical suspicion of progressive
disease.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

CLINICAL UTILITY OF GENETIC ALTERATIONS IN DLBCLa

GENE CLINICAL ASSOCIATION

ACTB, BCL2,b
BCL6, CARD11, CD79B,
CREBBP, EZH2, KMT2D, MYC,c MYD88, Diagnostic significance
MEF2B, SOCS1
BTK, CARD11, CD79B, MYD88 Associated with non-GCB DLBCL
NOTCH2 BN2 molecular subclassification
EZH2, SMARCB1 Treatment significance (EZH2 inhibitors)
PLCG2 Richter transformation; DLBCL arising from BTKi treated CLL/SLL
Mutations are frequent in DLBCL associated with chronic inflammation; TP53 mutations
TP53c
in conjunction with MYC rearrangement are associated with worse prognosis
ID3, TCF3, SMARCA4, CCND3 Mutations are more frequent in BL
B2M, CREBBP, EZH2, MYD88 L265P, SOCS1,
Mutations favor other aggressive B-cell lymphoma subtypes other than BL
TNFRSF14
Mutations are more frequent in dark zone gene expression signature + LBCL with MYC
KMT2D,TP53
and BCL2 or BCL6 rearrangements (double-hit lymphomas)
JAK/STAT, MAPK/ERK, NOTCH1 or NOTCH2 Mutations are frequent in plasmablastic lymphoma
Mutations are frequent in intravascular LBCL, primary cutaneous DLBCL, leg type,
MYD88, CD79B, PDL1, PDL2
primary LBCL of immune-privileged sites
IL4R, ITPKB, NFKBIE, SOCS1, STAT6, XPO1 Mutations are characteristic of PMBL
CD79B, CREBBP, KMT2D, MYD88, PIM1 Often mutated in DLBCL, NOS, but not altered in PMBL
ATM, BIRC3, NSD2, UBR5 Mutations support the diagnosis of MCL

a This table provides a minimal list of accepted genes that should be included in the NGS lymphoma panel for DLBCL.
b BCL2 mutations imply the presence of IGH::BCL2, thereby favoring entities other than BL.
c Blastoid MCL may harbor secondary MYC rearrangement or TP53 mutations.

Note: All recommendations are category 2A unless otherwise indicated.

BCEL-A
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INTERNATIONAL PROGNOSTIC INDEXa

ALL PATIENTS: INTERNATIONAL INDEX, ALL PATIENTS:
• Age >60 years • Low 0 or 1
• Serum LDH > normal • Low-intermediate 2
• Performance status 2–4 • High-intermediate 3
• Stage III or IV • High 4 or 5
• Extranodal involvement >1 site
AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEXa STAGE-MODIFIED INTERNATIONAL PROGNOSTIC INDEX (smIPI)b
PATIENTS ≤60 YEARS: INTERNATIONAL INDEX, STAGE I OR II PATIENTS: INTERNATIONAL INDEX, STAGE I OR
PATIENTS ≤60 YEARS: II PATIENTS:
• Stage III or IV • Low 0 • Age >60 years • Low 0 or 1
• Serum LDH > normal • Low-intermediate 1 • Serum LDH > normal • High 2–4
• Performance status 2–4 • High-intermediate 2 • Performance status 2–4
• High 3 • Stage II or IIE
NCCN-IPIc
RISK GROUP
Age, years
>40 to ≤60 1 • Low 0–1
>60 to <75 2 • Low-intermediate 2–3
≥75 3 • High-intermediate 4–5
LDH, normalized • High ≥6
>1 to ≤3 1
>3 2
Ann Arbor stage III–IV 1
Extranodal disease* 1 *Disease in bone marrow, CNS, liver/GI
tract, or lung.
Performance status ≥2 1
a The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993;329:987-994.
b Miller TP, Dahlberg S, Cassady JR. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J
Med 1998;339:21-26.
c This research was originally published in Blood. Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell
lymphoma treated in the rituximab era. Blood 2014;123:837-842. © The American Society of Hematology Back to Workup
(BCEL-2)
Note: All recommendations are category 2A unless otherwise indicated.
BCEL-A
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PROGNOSTIC MODEL TO ASSESS THE RISK OF CNS DISEASEd

RISK FACTORS RISK GROUPS
• Age >60 years • Low risk 0–1
• Serum LDH > normal • Intermediate-risk 2–3
• Performance status >1 • High-risk 4–6 or kidney or adrenal gland involvement
• Stage III or IV
• Extranodal involvement >1 site
• Kidney or adrenal gland involvement

• Additional indications for CNS prophylaxis independent of CNS risk score

Testicular lymphoma
Primary cutaneous DLBCL, leg type
Stage IE DLBCL of the breast
Kidney or adrenal gland involvement

• Role of CNS prophylaxis remains controversial but can be considered in patients with high-risk
factors based on the aforementioned criteria. If CNS prophylaxis is used, options include:
Systemic high-dose methotrexate (3–3.5 g/m2 for 2–4 cycles) during or after the course of treatmente
and/or
IT methotrexate and/or cytarabine (4–8 doses) during or after the course of treatment

d Schmitz N, Zeynalova S, Nickelsen M, et al. CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-cell lymphoma
treated with R-CHOP. J Clin Oncol 2016;34:3150-3156.
e Wilson M, Eyre T, Kirkwood A, et al. Timing of high-dose methotrexate CNS prophylaxis in DLBCL: A multicenter international analysis of 1384 patients.
Blood 2022;139:2499–2511. Back to Workup
(BCEL-2)
Note: All recommendations are category 2A unless otherwise indicated.
BCEL-A
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ALK-POSITIVE LARGE B-CELL LYMPHOMAS (ALK+ LBCL)a

Definition • ALK-positive LBCL is a mature aggressive B-cell lymphoma characterized by large cells with plasmablastic differentiation and
cytoplasmic expression of ALK, and lacking CD20 expression.
• Cytoplasmic ALK expression helps differentiate this entity from other aggressive CD20-negative LBCL with plasmacytic differentiation
such as plasmablastic lymphoma, primary effusion lymphoma (PEL), and HHV8-positive DLBCL.
• EBV and HHV8 are negative in ALK-positive LBCL, and there is no association with immune deficiency.
• Cytogenetic/FISH analysis most commonly demonstrates the t(2;17)(p23;q23), denoting the CLTC (clathrin heavy chain)/ALK fusion.

Clinical • The median age at diagnosis is approximately 40 years and there is a strong male predominance.
presentation • Most patients present with rapidly progressive disease at advanced stage, and both nodal and extranodal involvement are common.

Treatment Initial therapy Relapsed/refractory disease

• Clinical trial is recommended, if available • Clinical trial is recommended, if available
• Consolidative ISRT is preferred for localized diseaseb • Second-line platinum-based chemotherapy (without rituximab)
• These are most often CD20 negative and rituximab is not followed by HDT/ASCR for chemosensitive disease should be
necessary. considered in transplant-eligible patients.
• While the optimal systemic treatment approach is not established, • Responses have been observed to next-generation ALK
the following induction regimens have been used: inhibitors such as alectinib and lorlatinib, which should be
DA-EPOCH favored over the first-generation inhibitor crizotinib. Patients
CHOEP with CR to a next-generation ALK inhibitor should be
CHOP may be associated with a suboptimal outcome. CHOP considered for allogeneic HCT.
can be considered for patients with early-stage disease receiving
combined modality therapy.
Mini-CHOP may be considered for patients who are frail or older
Potentially toxic regimens; performance status and comorbidities
should be considered:
◊ HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and
dexamethasone alternating with high-dose methotrexate and
cytarabine)
◊ CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin,
and methotrexate alternating with ifosfamide, etoposide, and
cytarabine)

a Castillo JJ, et al. Leuk Lymphoma 2021;62:2845-2853; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of
tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024; Campo E, et al. Blood 2022;140:1229-1253; Soumerai JD, et
al. N Blood 2022;140:1822-1826.
b Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

BCEL-B
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MEDIASTINAL GRAY ZONE LYMPHOMA (MGZL)a

(overlapping features between PMBL and CHL)
Clinical • Present with large anterior mediastinal mass with or without supraclavicular lymph nodes.
presentationb More common in males, presenting between 20–40 y
Morphology • Expert hematopathology review is essential.
• Diagnosis should not be made on a core needle biopsy.
• Large pleomorphic cells in a diffusely fibrous stroma.
• Typically larger and more pleomorphic than in PMBL, sometimes resembling lacunar or Hodgkin-like cells.
• Necrosis without neutrophilic infiltrate is frequent.
Immunophenotype • Atypical immunophenotype, often showing transitional features between PMBL and CHL.
• Typical immunophenotype: CD45+, PAX5+, BOB.1+, OCT-2+, CD15+, CD20+, CD30+, and CD79a+; CD10- and ALK-; BCL6
is variably expressed and EBV is usually negative.
• If the morphology more closely resembles PMBL:
CD20 dim/-; CD30+ and CD15+ would be suggestive of gray zone lymphoma.
• If the morphology more closely resembles CHL:
Strong uniform CD20+ (and/or other B-cell markers) and CD15- would be suggestive of MGZL.
Prognosis and • A worse prognosis than either CHL or PMBL has been suggested.
Treatment • While there is no consensus on the treatment, aggressive LBCL regimens are preferred.
• If the tumor cells are CD20+, the addition of rituximab to chemotherapy should be considered.c
• Data suggest that the use of anthracycline-based chemoimmunotherapy as recommended for DLBCL (BCEL-C)d is helpful. If
localized disease, then consolidative ISRT is preferred.

a Pilichowska M, et al. Blood Adv 2017;1:2600-2609; Wilson WH, et al. Blood 2014;124:1563-1569; WHO Classification of Tumours Editorial Board. Haematolymphoid
tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024; Campo E, et al. Blood
2022;140:1229-1253; Quintanilla-Martinez L, et al. J Hematop 2009;2:211-236.
b Clinical and genomic data indicate that most non-mediastinal gray-zone lymphomas are distinct from MGZL; thus, patients with extra-mediastinal disease should be
diagnosed as having DLBCL-NOS.
c An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
d Polatuzumab-R-CHP is not recommended for mediastinal gray zone lymphoma.

Note: All recommendations are category 2A unless otherwise indicated.

BCEL-B
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SUGGESTED TREATMENT REGIMENSa,b

FIRST-LINE THERAPY
Stage I–II Stage II (with extensive mesenteric Patients with Poor Left Very Frail Patients and Patients
(excluding stage II with disease) Ventricular Functione,f,g >80 Years of Age with
extensive mesenteric or (all stages) Comorbiditiesf,g
disease) Stage III–IV (all stages)
• RCHOP (rituximab,c Preferred regimens Other recommended regimens Other recommended regimens
cyclophosphamide, • RCHOP (rituximab,c (in alphabetical order by category) (in alphabetical order by category)
doxorubicin, vincristine, cyclophosphamide, doxorubicin, • DA-EPOCHh (etoposide, prednisone, • RCDOP
prednisone) vincristine, prednisone) (category 1) vincristine, cyclophosphamide, • R-mini-CHOP
• Pola-R-CHP (polatuzumab • Pola-R-CHP (polatuzumab vedotin- doxorubicin) + rituximab • RGCVP
vedotin-piiq, rituximab, piiq, rituximab, cyclophosphamide, • RCDOP (rituximab, cyclophosphamide, • RCEPP (category 2B)
cyclophosphamide, doxorubicin, prednisone) (IPI ≥2)d liposomal doxorubicin, vincristine,
doxorubicin, prednisone) (category 1) prednisone)
(smIPI >1)d (category 1) • RCEOP (rituximab, cyclophosphamide,
Other recommended regimens etoposide, vincristine, prednisone)
• Dose-adjusted EPOCH • RGCVP (rituximab, gemcitabine,
(etoposide, prednisone, vincristine, cyclophosphamide, vincristine,
cyclophosphamide, doxorubicin) + prednisone)
rituximab • RCEPP (rituximab, cyclophosphamide,
etoposide, prednisone, procarbazine)
(category 2B)

CONCURRENT PRESENTATION WITH CNS DISEASEi

• Parenchymal: systemic high-dose methotrexate (≥3 g/m2 given with RCHOP cycle that has been supported by growth factors). Different schedules have
been used for the integration of high-dose methotrexate with RCHOP; however, the Panel prefers day 15 of a 21-day cycle.
• Leptomeningeal: IT methotrexate/cytarabine, consider Ommaya reservoir placement. Systemic high-dose methotrexate (3–3.5 g/m2) can be given in
combination with RCHOP or as consolidation after RCHOP + IT methotrexate/cytarabine

Footnotes on BCEL-C 5 of 7
Consider prophylaxis for tumor lysis syndrome (NHODG-B) Second-line Therapy on BCEL-C 2 of 7 and
See monoclonal antibody and viral reactivation (NHODG-B) BCEL-C 3 of 7

Note: All recommendations are category 2A unless otherwise indicated.

BCEL-C
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SUGGESTED TREATMENT REGIMENSa,b

SECOND-LINE THERAPYe,j,k
(relapsed disease <12 mo or primary refractory disease)
Candidates for CAR T-Cell Therapy Non-Candidates for CAR T-Cell Therapy
• CAR T-cell therapy l Preferred regimens (in alphabetical order)
Axicabtagene ciloleucel (CD19-directed) (category 1) • Epcoritamab-bysp + GemOxn,o
Lisocabtagene maraleucel (CD19-directed) (category 1) • Glofitamab-gxbm + GemOxn,o
• Polatuzumab vedotin-piiq ± bendamustinem ± rituximab
Bridging Therapy Options (≥1 cycles as needed until CAR T-cell • Polatuzumab vedotin-piiq + mosunetuzumab-axgbn,o
product is available) • Tafasitamab-cxixp + lenalidomide (excluding primary refractory disease)
• DHA + platinum (carboplatin, cisplatin, or oxaliplatin) ± rituximab
• GDP (gemcitabine, dexamethasone, carboplatin or cisplatin) ± Other recommended regimens (in alphabetical order)
rituximab • CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ± rituximab
• GemOx ± rituximab • DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or
• ICE ± rituximab oxaliplatin) ± rituximab
• Polatuzumab vedotin-piiq ± rituximab ± bendamustinem • ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± rituximab
• ISRT (can be used as monotherapy or sequentially with systemic • GDP (gemcitabine, dexamethasone, carboplatin or cisplatin) ± rituximab
therapy) (NHODG-D 3 of 4)
• GemOx (gemcitabine, oxaliplatin) ± rituximab (if unable to receive
epcoritamab-bysp or glofitamab-gxbm)
• ICE (ifosfamide, carboplatin, etoposide) ± rituximab
• MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab

Useful in certain circumstances

• Brentuximab vedotin for CD30+ diseaseq
• Ibrutinibn (non-GCB DLBCL)
• Lenalidomide ± rituximab (non-GCB DLBCL)

Footnotes on BCEL-C 5 of 7
First-line Therapy on BCEL-C 1 of 7
Second-line Therapy (relapsed disease >12 mo) on BCEL-C 3 of 7
Third-line Therapy on BCEL-C 4 of 7
Note: All recommendations are category 2A unless otherwise indicated.
BCEL-C
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SUGGESTED TREATMENT REGIMENSa,b

SECOND-LINE THERAPYe,j,k
(relapsed disease >12 mo)
Intention to Proceed to Transplant No Intention to Proceed to Transplant
Preferred regimens (in alphabetical order) Preferred regimens (in alphabetical order)
• DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, • CAR T-cell therapy (CD19-directed)l (with bridging therapy as needed;
or oxaliplatin) ± rituximab BCEL-C 2 of 7) (if eligible)
• GDP (gemcitabine, dexamethasone, carboplatin or cisplatin) ± Lisocabtagene maraleucel
rituximab • Epcoritamab-bysp + GemOxn,o
• ICE (ifosfamide, carboplatin, etoposide) ± rituximab • Glofitamab-gxbm + GemOxn,o (category 1)
• Polatuzumab vedotin-piiq ± bendamustinem ± rituximab
Other recommended regimens (in alphabetical order) • Polatuzumab vedotin-piiq + mosunetuzumab-axgbn,o
• ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± • Tafasitamab-cxixp + lenalidomide
rituximab Other recommended regimens (in alphabetical order)
• GemOx (gemcitabine, oxaliplatin) ± rituximab • CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ± rituximab
• MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab • GDP (gemcitabine, dexamethasone, carboplatin or cisplatin) ± rituximab
• GemOx ± rituximab (if unable to receive epcoritamab-bysp or glofitamab-
gxbm)
• Rituximab
Useful in certain circumstances
• Brentuximab vedotin for CD30+ diseaseq
• Ibrutinibn (non-GCB DLBCL)
• Lenalidomide ± rituximab (non-GCB DLBCL)

Footnotes on BCEL-C 5 of 7
First-line Therapy on BCEL-C 1 of 7
Second-line Therapy (relapsed disease <12 mo or
primary refractory disease) on BCEL-C 2 of 7
Third-line Therapy on BCEL-C 4 of 7

Note: All recommendations are category 2A unless otherwise indicated.

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Table of Contents
Diffuse Large B-Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENSa,b

THIRD-LINE AND SUBSEQUENT THERAPY

Subsequent systemic therapy options include second-line therapy regimens (BCEL-C 2 of 7 and BCEL-C 3 of 7)
that were not previously used.
Preferred regimens Other recommended regimens
• T-cell engager therapy • Brentuximab vedotin + lenalidomide + rituximab (for CD30+ disease)q
l
CAR T-cell therapy (preferred if not previously given) • Loncastuximab tesirine-lpylp
(in alphabetical order) • Selinexor (including patients with disease progression after transplant or
◊ Axicabtagene ciloleucel (CD19-directed) CAR T-cell therapy)
◊ Lisocabtagene maraleucel (CD19-directed)
◊ Tisagenlecleucel (CD19-directed)
Bispecific antibody therapy (only after at least two lines of systemic
therapy; including patients with disease progression after transplant
or CAR T-cell therapy) (in alphabetical order)
◊ Epcoritamab-byspn,o
◊ Glofitamab-gxbmn,o

Footnotes on BCEL-C 5 of 7
Consider prophylaxis for tumor lysis syndrome (NHODG-B) First-line Therapy on BCEL-C 1 of 7
See monoclonal antibody and viral reactivation (NHODG-B) Second-line Therapy on BCEL-C 2 of 7 and
BCEL-C 3 of 7

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

FOOTNOTES
a See references for regimens on BCEL-C 6 of 7 and BCEL-C 7 of 7.
b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
c In RCHOP-21, may consider increasing dose of rituximab to 500 mg/m2 in patients assigned male at birth >60 y.
d Patients with a known history of histologic transformation of indolent lymphoma were not included in the POLARIX study.
e Inclusion of any anthracycline or anthracenedione in patients with impaired cardiac functioning should have more frequent cardiac monitoring.
f There are limited published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the first-line treatment of DLBCL for
patients with poor left ventricular function, patients who are very frail, and patients >80 years of age with comorbidities.
g There are limited data for treatment of early-stage disease with these regimens; however, short-course chemoimmunotherapy + RT for stage I–II disease is practiced
at NCCN Member Institutions.
h If upward dose adjustment is necessary, doxorubicin should be maintained at base dose and not increased.
i Concurrent high-dose methotrexate with dose-adjusted EPOCH can result in unacceptable toxicities.
j If additional anthracycline is administered after a full course of therapy, careful cardiac monitoring is essential. Dexrazoxane may be added as a cardioprotectant.
k Rituximab should be included in second-line therapy if there is relapse after a reasonable remission (>6 mo); however; rituximab can be omitted in patients with
primary refractory disease.
l Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy (NHODG-E).
m In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until
after CAR-T leukapheresis.
n Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/
index.cfm.
o In the setting of CD20-negative lymphomas, the activity of CD3 x CD20 bispecific antibody therapy is unclear. Rebiopsy to confirm CD20 positivity is recommended
prior to initiating CD3 x CD20 bispecific antibody therapy.
p It is unclear if tafasitamab-cxix or loncastuximab tesirine-lpyl or if any other CD19–directed therapy would have a negative impact on the efficacy of subsequent anti-
CD19 CAR T-cell therapy.
q Responses with BV have been seen in patients with a low level of CD30 positivity and any level of CD30 positivity is acceptable for the use of BV-based regimens.

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
First-line Therapy First-line Therapy for Patients with Poor Left Ventricular Function
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab with RT CDOP (cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) + rituximab
Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus Martino R, Perea G, Caballero MD, et al. Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx),
radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med vincristine and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: Results from
a prospective phase II study. Haematologica 2002;87:822-827.
1998;339:21-26.
Zaja F, Tomadini V, Zaccaria A, et al. CHOP-rituximab with pegylated liposomal doxorubicin for the
Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 2006;47:2174-2180.
aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group Study 1484. J Clin Oncol RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone)
2004;22:3032-3038. Moccia AA, Schaff K, Freeman C, et al. Long-term outcomes of R-CEOP show curative potential in
Persky DO, Unger JM, Spier CM, et al. Phase II study of rituximab plus three cycles of CHOP and patients with DLBCL and a contraindication to anthracyclines. Blood Adv 2021;5:1483-1489.
involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone)
Oncology Group Study 0014. J Clin Oncol 2008;26:2258-2263. Fields PA, Townsend W, Webb A, et al. De novo treatment of diffuse large B-cell lymphoma with
CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, comorbidity: a United Kingdom National Cancer Research Institute trial. J Clin Oncol 2014;32:282-287.
First-line Therapy for Older Patients (aged >80 years)
the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL
R-mini-CHOP
patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010;116:2040-2045. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in
Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase
elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de 2 trial. Lancet Oncol 2011;12:460-468.
l'Adulte. J Clin Oncol 2005;23:4117-4126. Al-Sarayfi D, Brink M, Chamuleau MED, et al. R-miniCHOP versus R-CHOP in elderly patients
Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like with diffuse large B-cell lymphoma: A propensity matched population-based study. Am J Hematol
chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised 2024;99:216-222.
controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379-391.
Poeschel V, Held G, Ziepert M, et al. Four versus six cycles of CHOP chemotherapy in combination Second-line and Subsequent Therapy
Polatuzumab vedotin ± bendamustine ± rituximab
with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis
Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab
(FLYER): a randomised, phase 3, non-inferiority trial. Lancet 2019;394:2271-2281. in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised
Persky DO, Li H, Stephens DM, et al. Positron emission tomography-directed therapy for patients with study (ROMULUS). Lancet Haematol 2019;6:e254-e265.
limited-stage diffuse large B-cell lymphoma: Results of Intergroup National Clinical Trials Network Study Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large
S1001. J Clin Oncol 2020;38:3003-3011. B-cell lymphoma. J Clin Oncol 2020;38:155-165.
Pola-R-CHP (polatuzumab vedotin-piiq, rituximab, cyclophosphamide, doxorubicin, prednisone) Polatuzumab vedotin-piiq + mosunetuzumab-axgb
Tilly H, Morschhauser F, Sehn L, et al Polatuzumab vedotin in previously untreated diffuse large B-cell Budde LE, Olszewski AJ, Assouline S, et al. Mosunetuzumab with polatuzumab vedotin in relapsed
therapy. N Eng J Med 2022;386:351-363. orrefractory aggressive large B cell lymphoma: a phase 1b/2 trial. Nat Med 2024;30:229-239.
Brentuximab vedotin
Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) +
Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a
rituximab phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 2015;125:1394-1402.
Purroy N, Bergua J, Gallur L, et al. Long-term follow-up of dose-adjusted EPOCH plus rituximab CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ± rituximab
(DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study Chao NJ, Rosenberg SA, and Horning SJ. CEPP(B): An effective and well-tolerated regimen in poor-
conducted by the Spanish PETHEMA Group. Br J Haematol 2015;169:188-198. risk, aggressive non-Hodgkin's lymphoma. Blood 1990;76:1293-1298.
Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in DHAP (dexamethasone, cisplatin, cytarabine) ± rituximab
untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in
combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-
biomarkers. J Clin Oncol 2008;26:2717-2724. Hodgkin's lymphoma. Cancer Invest 2006;24:593-600.
Wilson WH, Jung SH, Porcu P, et al. A Cancer and Leukemia Group B multi-center study of DA- Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell
EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular transplantation in patients with relapsed CD20+ diffuse large B-cell lymphoma: Final analysis of the
subtype. Haematologica 2012;97:758-765. collaborative trial in relapsed aggressive lymphoma. J Clin Oncol 2012;30:4462-4469.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
Second-line and Subsequent Therapy (continued)
DHAX (dexamethasone, cytarabine, oxaliplatin) ± rituximab Loncastuximab tesirine
Lignon J, Sibon D, Madelaine I, et al. Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) Caimi PF, Ai WZ, Alderuccio JP, et al. Loncastuximab tesirine in relapsed/refractory diffuse large
is an effective and safe salvage regimen in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin B-cell lymphoma: long-term efficacy and safety from the phase II LOTIS-2 study. Haematologica
Lymphoma Myeloma Leuk 2010;10:262-269. 2024;109:1184-1193
Rigacci L, Fabbri A, Puccini B, et al. Oxaliplatin-based chemotherapy (dexamethasone, high-dose Selinexor
cytarabine, and oxaliplatin) +/-rituximab is an effective salvage regimen in patients with relapsed or Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse
refractory lymphoma. Cancer 2010;116:4573-4579. large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.
ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± rituximab Lancet Haematol 2020;7:e511-e522.
Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP - an effective chemotherapy regimen in refractory T-Cell Engager Therapy
and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994;12:1169-1176. CAR T-Cell Therapy
Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory Axicabtagene ciloleucel
diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative
study. Haematologica 2008;93:1829-1836. potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood 2023;141:2307-2315.
GDP (gemcitabine, dexamethasone, carboplatin or cisplatin) ± rituximab Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large
Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and B-cell lymphoma. N Engl J Med 2022;386:640-654.
cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell Lisocabtagene maraleucel
transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel as second-line therapy for
2014;32:3490-3496. large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood 2023;141:1675-1684.
Gopal AK, Press OW, Shustov AR, et al. Efficacy and safety of gemcitabine, carboplatin, Hoda D, Sehgal A, Riedell PA, et al. Lisocabtagene maraleucel (liso-cel) as second-line therapy for R/R
dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi- large B-cell lymphoma in patients not intended for hematopoietic stem cell transplantation (HSCT): Final
center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma 2010;51:1523-1529. analysis of the phase 2 PILOT study. Transplantation and Cellular Therapy 2024;30:S202.
GemOX (gemcitabine, oxaliplatin) ± rituximab Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed
Corazzelli G, Capobianco G, Arcamone M, et al. Long-term results of gemcitabine plus oxaliplatin with or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.
and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing Lancet 2020;396:839-852.
B-cell lymphoma. Cancer Chemother Pharmacol 2009;64:907-916. Tisagenlecleucel
Mounier N, El Gnaoui T, Tilly H, et al. Rituximab plus gemcitabine and oxaliplatin in patients with Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients
refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-
phase II Lymphoma Study Association trial. Haematologica 2013;98:1726-1731. arm, phase 2 study. Lancet Oncol 2021;22:1403-1415.
Ibrutinib Bispecific Antibody therapy
Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large Epcoritamab-bysp
B cell lymphoma. Nat Med 2015;21:922-926. Thieblemont C, Phillips T, Ghesquieres H, et al. Epcoritamab, a novel, subcutaneous CD3xCD20
ICE (ifosfamide, carboplatin, etoposide) ± rituximab bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: Dose expansion in
Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE (RICE) as second-line therapy prior a phase I/II trial. J Clin Oncol 2023;41:2238-2247.
to autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Vose JM, Cheah CY, Clausen MR, et al. 3-uear update from the Epcore NHL-1 trial: Epcoritamab
Blood 2004;103:3684-3688. leads to deep and durable responses in relapsed or refractory large B-cell lymphoma [abstract]. Blood
Lenalidomide ± rituximab 2024;144:Abstract 4480
Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory Epcoritamab-bysp + GemOx
diffuse large cell, follicular, and transformed lymphoma: a phase II clinical trial. Leukemia 2013;27:1902- Brody JD, Jørgensen J, Belada D, et al. Epcoritamab plus GemOx in transplant ineligible relapsed/
1909. refractory DLBCL: Results from the EPCORE NHL-2 trial. Blood 2025;145:1621-1631.
Czuczman MS, Trneny M, Davies A, et al. A phase 2/3 multicenter, randomized, open-label study to Glofitamab-gxbm
compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large
refractory diffuse large B-cell lymphoma. Clin Cancer Res 2017;23:4127-4137. B-cell lymphoma. N Engl J Med 2022;387:2220-2231.
Tafasitamab + lenalidomide Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Fixed-duration glofitamab monotherapy continues
Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large to demonstrate durable responses in patients with relapsed or refractory large B-cell lymphoma: 3-year
B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study.Haematologica follow-up from a pivotal phase II study [abstract]. Blood 2024;144:Abstract 865. Dickinson MJ, Carlo-
2024;109:553-566. Glofitamab-gxbm + GemOx
Third-line and Subsequent Therapy Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus
Brentuximab vedotin + lenalidomide + rituximab rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase
Bartlett NL, Hahn U, Kim WS, et al. Brentuximab vedotin combination for relapsed diffuse large B-cell 3, randomised, open-label trial. Lancet 2024;404:1940-1954.
lymphoma. J Clin Oncol 2025;43:1061–1072.

Note: All recommendations are category 2A unless otherwise indicated.

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Primary Mediastinal Large B-Cell Lymphoma Discussion

FIRST-LINE THERAPYa,b RESPONSE ASSESSMENT FOLLOW-UP

After DA-EPOCH-R x 6 cycles Active
or RCHOP-14 x 6 cycles surveillance
Clinical
Optimal first-line therapy for • H&P and labs, every
PMBLc is more controversial or 3–6 mo for 5 y and
than other subtypes. Most ISRTg then annually or as
Complete or Active
commonly used treatment responsed After R-CHOP-21 x 6 cycles clinically indicated
options are listed below. surveillance Imagingi
(PET negative Relapse
[5-PS 1–3])e or • C/A/P CT scan with
Dose-adjusted EPOCH + After R-CHOP-14 x 4 cycles contrast no more often
rituximab (DA-EPOCH-R) Followed by consolidation with ICE than every 6 mo for 2 y
x 6 cycles x 3 cycles ± rituximab (category 2B) after completion of
treatment, then only as
or clinically indicated
Restage
Negative
with PET/
RCHOP-14 x 4–6 cycles CT Partial responsed ISRTg followed
Repeat by restaging Relapsed/refractory therapy:
(PET positive
or biopsyh with PET/CT Pembrolizumab
[5-PS 4])e,f or
or
RCHOP-21 x 6 cycles Positive Relapsed/ Nivolumab ± brentuximab
refractory vedotinj (category 2B)
No response or therapy or
Progressive diseased
Repeat biopsyh Manage as relapsed/refractory
(PET positive
DLBCL
[5-PS 5])e
a Consider prophylaxis for tumor lysis syndrome (NHODG-B) and see monoclonal antibody • <12 mo (BCEL-7)
and viral reactivation (NHODG-B). • >12 mo (BCEL-8)
b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic f Persistent PET/CT positive masses at end of treatment after DA-
biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase human injection for EPOCH-R (5-PS 4 and on visual inspection demonstrate minimal uptake
subcutaneous use may be substituted for rituximab after patients have received the first full above liver) can be observed (with follow-up scans) without biopsy.
dose of rituximab by intravenous infusion. g Principles of Radiation Therapy (NHODG-D).
c PMBL can be defined as a clinical entity presenting with primary site of disease in the h Residual mediastinal masses are common. PET/CT scan is essential
anterior mediastinum with or without other sites and has histology of DLBCL. Clinical post-treatment. Biopsy of PET/CT scan positive mass is recommended if
pathologic correlation is required to establish diagnosis. PMBL overlaps with MGZL that have additional systemic treatment is contemplated.
intermediate features between Hodgkin lymphoma and PMBL and have unique diagnostic i Surveillance imaging is used for monitoring asymptomatic patients. When
characteristics. See Mediastinal Gray Zone Lymphoma (BCEL-B 2 of 2). See Special a site of disease can only be visualized on PET/CT scan (eg, bone), it is
Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas appropriate to proceed with PET/CT scans for surveillance.
(NHODG-B 4 of 5). j Responses with BV have been seen in patients with a low level of CD30
d Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). positivity and any level of CD30 positivity is acceptable for the use of BV-
e PET/CT scan should be interpreted via the PET 5-PS (NHODG-C 3 of 3). based regimens.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
Primary Mediastinal Large B-Cell Lymphoma Discussion

REFERENCES

Dose-adjusted EPOCH-rituximab
Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 2013;368:1408-1416.

RCHOP-14 x 6 cycles
Camus V, Rossi C, Sesques P, et al. Outcomes after first-line immunochemotherapy for primary mediastinal B-cell lymphoma: a LYSA study. Blood Adv 2021;5:3862-
3872.

RCHOP-14 followed by ICE

Bantilan KS, Luttwak E, Moskowitz CH, et al. Sequential R-CHOP/(R)-ICE and dose-adjusted EPOCH-R are both appropriate frontline treatments for newly diagnosed
primary mediastinal B-cell lymphoma: Results of a retrospective analysis [abstract]. Blood 2024;144: Abstract 4485.

Pembrolizumab
Armand P, Rodig S, Melnichenko V, et al. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma. J Clin Oncol 2019;37:3291-3299.

Nivolumab + brentuximab vedotin

Zinzani P, Santoro A, Gritti G, et al. Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large b-cell lymphoma: efficacy and safety
from the phase II Checkmate 436 study. J Clin Oncol 2019;37:3081-3089.

Note: All recommendations are category 2A unless otherwise indicated.

HGBL with
Treatment regimens as listed on
MYC and BCL2
HGBL-1
rearrangementsf
Histologic transformation
after minimal or no prior Response
therapya,b,c PET/CT to Therapy
Chemoimmunotherapy
DLBCL or (HTBCEL-2)
(anthracycline-based regimens
HGBL with
preferred unless contraindicated)
MYC and BCL6
(See BCEL-C, first-line therapy) ±
rearrangementsf
ISRTg,h

Histologic transformation
after multiple lines of prior HTBCEL-3
therapiesd,e

a Perform FISH for BCL2 rearrangement [t(14;18)], and MYC rearrangements [t(8;14) or variants, t(8;22), t(2;8)].
b ISRT alone or one course of single-agent therapy including rituximab.
c NGS may be useful for treatment selection.
d This includes ≥2 of chemoimmunotherapy regimens for indolent lymphomas prior to histologic transformation. For example, prior treatment with BR and RCHOP.
e Perform FISH for BCL6 and MYC rearrangements.
f Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee.
Blood 2022;140:1229-1253; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon
(France): International Agency for Research on Cancer; 2024.
g Principles of Radiation Therapy (NHODG-D).
h Consider ISRT for localized presentations, bulky disease, and/or limited osseous disease.

Note: All recommendations are category 2A unless otherwise indicated.

CR Active surveillancek Relapsed Repeat

Histologic Transformation
(PET negative or After Multiple Prior Therapies
diseasej biopsyl
[5-PS 1–3])i,j Clinical trial (HTBCEL-3)

PR (PET
positive
CAR T-cell therapy (HTBCEL-A) with or
[5-PS 4])i,j or
without bridging therapy (if eligible)
NR or Response Assessment and
progressive Additional Therapy (HTBCEL-3)
If not eligible, see HTBCEL-A for
disease (PET
suggested systemic therapy regimens
positive
[5-PS 5])i

i Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.
j If transformation is coexisting with extensive FL, consider maintenance (see FOLL-5, Optional Extended Therapy).
k Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever
there are clinical indications. For surveillance imaging, see Discussion for consensus imaging recommendations.
l Repeat biopsy should be strongly considered if PET-positive prior to additional therapy because PET positivity may represent post-treatment inflammation. If biopsy
negative, follow CR pathway. Patients with a durable response for transformed disease may recur with the original indolent lymphoma. In that case, the management
should be as per FOLL-5 or NMZL-4.

Note: All recommendations are category 2A unless otherwise indicated.

Active surveillancek
or
If transplant eligible,
CR HDT/ASCRn ± ISRT (if not
(PET previously given)g,h Relapsed or
negative or progressive Biopsyl
[5-PS Allogeneic HCT in selected diseasej
Clinical trial 1–3])i casesn,o ± ISRT (if not
or previously given)g,h Yes
See HTBCEL-A for
suggested systemic CAR T-cell therapy (preferred, if not Candidate
therapy regimens previously given) (HTBCEL-A)p for
(Selection of regimen or
Histologic must be highly additional
If transplant eligible, allogeneic HCT
transformation individualized taking into PR (PET therapy
in selected casesn,o ± ISRT (if not
after multiple account prior treatment positive
previously given)g,h
lines of prior history) ± ISRTg [5-PS 4])i,l,m or No
therapiesd or ISRTg for localized residual and/
ISRTg or residual FDG-avid disease not
or previously irradiated
Best supportive care or
Best supportive
(See NCCN Guidelines for Active surveillancek
Palliative Care) care (See NCCN
Guidelines for
NR or progressive disease Palliative Care)
(PET positive [5-PS 5])i
d This includes ≥2 of chemoimmunotherapy regimens for indolent lymphomas prior to histologic transformation. For example, prior treatment with BR and RCHOP.
g Principles of Radiation Therapy (NHODG-D).
h Consider ISRT for localized presentations, bulky disease, and/or limited osseous disease.
i Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C). PET/CT scan should be interpreted via the PET 5-PS.
k Follow-up includes diagnostic tests and imaging using the same modalities performed during workup as clinically indicated. Imaging should be performed whenever
there are clinical indications. For surveillance imaging, see Discussion for consensus imaging recommendations.
l Repeat biopsy should be strongly considered if PET-positive prior to additional therapy because PET positivity may represent post-treatment inflammation. If biopsy
negative, follow CR pathway. Patients with a durable response for transformed disease may recur with the original indolent lymphoma. In that case, the management
should be as per FOLL-5 or NMZL-4.
m If proceeding to transplant, consider additional systemic therapy not previously given ± ISRT to induce CR prior to transplant.
n Data on transplant after treatment with CAR T-cell (CD19-directed) therapy are not available. HDT/ASCR is not recommended CAR T-cell (CD19-directed) therapy.
Allogeneic HCT could be considered but remains investigational.
o Selected cases include mobilization failures and persistent bone marrow involvement.
p Patients should have received at least one anthracycline-based regimen, unless contraindicated.

Note: All recommendations are category 2A unless otherwise indicated.

SYSTEMIC THERAPY REGIMENSb

Intention to Preferred regimens
proceed to • RCHOP (if not previously given)
transplant • If previously treated with anthracycline-based regimen (in alphabetical order)
DHA (dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) ± rituximab
GDP (gemcitabine, dexamethasone, carboplatin or cisplatin)
ICE (ifosfamide, carboplatin, etoposide) ± rituximab
No intention Preferred regimens Other recommended regimens (in alphabetical order)
to proceed to • RCHOP (if not previously given) • CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ±
transplant • If previously treated with anthracycline-based regimen rituximab
(in alphabetical order) • GDP (gemcitabine, dexamethasone, carboplatin or cisplatin) ± rituximab
Polatuzumab vedotin-piiq ± bendamustinec ± rituximab • GemOx ± rituximab
Tafasitamab-cxixd + lenalidomide • Loncastuximab tesirine-lpyld
• Selinexor (transformed FL; only after at least two lines of systemic
therapy; including patients with disease progression after transplant or
CAR T-cell therapy)

T-CELL ENGAGER THERAPY

• CAR T-cell therapye,f (in
alphabetical order) • Bispecific antibody therapyg (only after at least two lines
Axicabtagene ciloleucel (CD-19 directed) of systemic therapy; including patients with disease
Lisocabtagene maraleucel (CD-19 directed) progression after transplant or CAR T-cell therapy)
Tisagenlecleucel (CD-19 directed) Epcoritamab-bysp
Glofitamab-gxbm

Consider prophylaxis for tumor lysis syndrome (NHODG-B) References on BCEL-C 5 of 7

See monoclonal antibody and viral reactivation (NHODG-B) Footnotes on HTBCEL-A 2 of 2

Note: All recommendations are category 2A unless otherwise indicated.

HTBCEL-A
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NCCN Guidelines Index
Histologic Transformation of Table of Contents
Discussion
Indolent Lymphomas to DLBCL
SUGGESTED TREATMENT REGIMENS
FOOTNOTES
a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
b Inclusion of any anthracycline in patients with impaired cardiac functioning should have more frequent cardiac monitoring.
c In patients intended to receive CAR T-cell therapy or CD3 x CD20 bispecific antibody therapy, bendamustine should be used with caution. Delay bendamustine until
after CAR-T leukapheresis.
d It is unclear if tafasitamab, loncastuximab tesirine, or any other CD19–directed therapy would have a negative impact on the efficacy of subsequent CAR T-cell (CD19-
directed) therapy.
e Guidance for Treatment of Patients with Chimeric Antigen Receptor (CAR) T-Cell Therapy (NHODG-E).
f Patients should have received at least one anthracycline-based regimen, unless contraindicated.
g Refer to package insert for full prescribing information, dose modifications, and monitoring for adverse reactions: https://www.accessdata.fda.gov/scripts/cder/daf/
index.cfm. In the setting of CD20-negative lymphomas, the activity of CD3 x CD20 bispecific antibody therapy is unclear. Rebiopsy to confirm CD20 positivity is
recommended prior to initiating CD3 x CD20 bispecific antibody therapy.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
High-Grade B-Cell Lymphomas (HGBL) Discussion

HGBL with MYC and BCL2 rearrangements

with or without BCL6 rearrangements (ICC) HGBL with MYC and BCL6
Classification HGBL-NOS (ICC and WHO5)b
DLBCL/HGBL with MYC and BCL2 rearrangements (ICC)a
rearrangements (WHO5)a
Treatment • Clinical trial is recommended. • Manage as DLBCL (BCEL-1). • Clinical trial is recommended.
optionsc,d • Consolidative ISRT is preferred for localized • HGBL with BCL6 and MYC • Consider consolidative ISRT for early-
disease.e While the optimal treatment rearrangements appear to have stage disease.e
approach is not established, the following outcomes equivalent to DLBCL NOS; • While the optimal treatment approach is
induction regimens have been used: however many of these patients not established, the following induction
DA-EPOCH-R were managed with DA-EPOCH-R. regimens have been used:
RCHOP may be associated with a Therefore, the optimal chemotherapy DA-EPOCH-R
suboptimal outcome. Could be considered regimen remains uncertain. Pola-R-CHP (polatuzumab vedotin-
for patients with low risk disease (IPI <2). piiq, rituximab, cyclophosphamide,
R-mini-CHOP may be considered for doxorubicin, prednisone) (category 2B)
patients who are frail or older RCHOP
Potentially toxic regimens; performance R-mini-CHOP may be considered for
status and comorbidities should be patients who are frail or older
considered: Potentially toxic regimens; performance
◊ R-HyperCVAD status and comorbidities should be
◊ R-CODOX-M/R-IVAC considered
• Relapsed/refractory disease, see <12 months ◊ R-HyperCVAD
(BCEL-7) or > 12 months (BCEL-8). ◊ R-CODOX-M/R-IVAC
• Relapsed/refractory disease, see
<12 months (BCEL-7) or > 12 months
(BCEL-8).

a LBCL with MYC and BCL2 or BCL6 rearrangements as detected by FISH or standard cytogenetics are known as "double-hit" lymphomas. If all three rearrangements
present, they are referred to as "triple-hit" lymphomas. The vast majority are GCB–like lymphomas. Patients often present with poor prognostic variables, such as
elevated LDH, bone marrow and CNS involvement, and a high IPI score.
b HGBL-NOS includes cases that appear blastoid or cases intermediate between DLBCL and BL, but which lack MYC and BCL2 with or without BCL6 rearrangement.
This category excludes HGBL with MYC and BCL2 with or without BCL6 rearrangement or clear DLBCL. Patients often present with poor prognostic parameters, such
as elevated LDH, bone marrow and CNS involvement, and a high IPI score
c An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
d Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).
e Principles of Radiation Therapy (NHODG-D).
References on
Note: All recommendations are category 2A unless otherwise indicated. HGBL-A

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
High-Grade B-Cell Lymphomas (HGBL) Discussion

REFERENCES
Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee. Blood
2022;140:1229-1253; WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon
(France): International Agency for Research on Cancer; 2024.
Petrich A, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective
analysis. Blood 2014;124:2354-2361.
Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated
aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol 2018;5:e609-e617.
Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide,
doxorubicin, vincristine, and prednisone. J Clin Oncol 2012;30:3452-3459.
Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with
rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012;30:3460-3467.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
Burkitt Lymphoma Discussion

ADDITIONAL DIAGNOSTIC TESTINGa,b,c WORKUP

ESSENTIAL:
• Physical exam: attention to node-bearing areas, including
Waldeyer’s ring, and to size of liver and spleen
• Performance status
ESSENTIAL: • B symptoms
• Adequate immunophenotyping to establish diagnosisd,e • CBC with differential
IHC panel: CD45, CD20, CD3, CD5, CD10, Ki-67, BCL2, • LDH
BCL6, TdT • Comprehensive metabolic panel
with or without • Uric acid
Flow cytometry with peripheral blood and/or biopsy • PET/CT scan (preferred; initiation of therapy should not
specimen: kappa/lambda, CD45, CD20, CD3, CD5, CD19, be delayed for PET/CT scan) or C/A/P CT with contrast of Risk
CD10, TdT diagnostic quality; pretreatment imaging is essentialf Assessment
• Karyotype ± FISH: t(8;14) or variants; MYC, BCL2; BCL6 • Lumbar puncture and
rearrangement • Flow cytometry of cerebrospinal fluid Induction
• HIV testing (if positive, see HIVLYM-1) Therapy
USEFUL UNDER CERTAIN CIRCUMSTANCES • Hepatitis B testingg (BURK-2)
• EBER-ISH • Echocardiogram or MUGA scan if anthracycline-based
• Consider chromosomal microarray to evaluate for 11q regimen is indicated
aberrations if otherwise resembles BL but FISH for • Pregnancy testing in patients of childbearing age (if
MYC, MYC::IGH, MYC::IGL, and MYC::IGK are negative chemotherapy or RT planned)
for LBCL with 11q aberration (ICC)/HGBL with 11q USEFUL IN SELECTED CASES:
aberrations (WHO5) • Unilateral or bilateral bone marrow biopsy ± aspirate
• Hepatitis C testing
• Neck CT with contrast
• Brain MRI with and without contrast
• Discuss fertility preservationh
a Special Considerations for Adolescent and Young Adult (AYA)
Patients with B-Cell Lymphomas (NHODG-B 4 of 5).
b For treatment of double- or triple-hit tumors, see HGBL-1. In other
cases where it is not possible to distinguish between BL and high-
grade lymphoma, therapy per this guideline may be appropriate. f If obtaining PET scan is delayed due to logistics, a C/A/P CT scan should be obtained.
c This disease is complex and curable; it is preferred that treatment g Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy +
occur at centers with expertise in the management of the disease. chemotherapy. Tests include HBsAg and core antibody for a patient with no risk factors. For
d Typical immunophenotype: sIg+, CD10+, CD20+, TdT-, Ki-67+ patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive,
(≥95%), BCL2-, BCL6+. check viral load and consider consult with gastroenterologist.
e If flow cytometry initially performed, IHC for selected markers h Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian
(BCL2 and Ki-67) can supplement the flow results. tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
Burkitt Lymphoma Discussion

RISK ASSESSMENT INDUCTION THERAPY INITIAL RESPONSE RELAPSE

Follow-up:
Low risk C/A/P CT scan with contrast no more
Complete
Normal LDH often than every 6 mo for 1 y after Relapse BURK-3
response j
and Clinical trial completion of treatment, then only as
Stage I (Single extra- or clinically indicatedk
abdominal mass See Suggested
<10 cm) or Regimensi (BURK-A)
Completely resected
abdominal lesion Clinical triall
< Complete
or
response j
Palliative ISRTm

Follow-up:
C/A/P CT scan with contrast no more
often than every 6 mo for 1 y after Relapse BURK-3
High risk completion of treatment, then only as
Complete
Stage I clinically indicatedk
response j
and or
Clinical trial
Abdominal mass
or
or Consolidation in clinical trial
See Suggested
Extra-abdominal mass
Regimensi (BURK-A)
>10 cm
or
Stage II–IV Clinical triall
< Complete
or
response j
Palliative ISRTm

i All regimens for BL include CNS prophylaxis/therapy.

j Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
k Relapse after 1 y is uncommon; therefore, follow-up should be individualized according to patient characteristics.
l If there is no clinical trial available, some NCCN Member Institutions use non–cross-resistant second-line therapy regimens listed on BURK-A in selected cases.
m Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
Burkitt Lymphoma Discussion

SECOND-LINE RESPONSE CONSOLIDATION/ADDITIONAL THERAPY

THERAPY ASSESSMENTj

Consider HDT/ASCR ± ISRTm

Complete or
response Consider allogeneic HCT in selected casesn ± ISRTm

Clinical trial
Additional second-line therapy (BURK-A)
or
or
Disease relapse See Second-line therapyi Partial
Consider HDT/ASCR ± ISRTm
>6 to 18 mo after (BURK-A) response
or
appropriate first- or
Consider allogeneic HCT in selected casesn ± ISRTm
line therapy Best supportive care
(NCCN Guidelines for
Palliative Care)
No response Clinical trial
or Progressive or
disease Best supportive care (See NCCN Guidelines for
Clinical triall Palliative Care) including palliative ISRTm
Disease relapse
or
<6 mo after
Best supportive care
appropriate first-
(See NCCN Guidelines
line therapy
for Palliative Care)

i All regimens for BL include CNS prophylaxis/therapy.

j Lugano Response Criteria for Non-Hodgkin Lymphoma (NHODG-C).
l If there is no clinical trial available, some NCCN Member Institutions use non–cross-resistant second-line therapy regimens listed on BURK-A in selected cases.
m Principles of Radiation Therapy (NHODG-D).
n Selected cases include mobilization failures and persistent bone marrow involvement.

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
Burkitt Lymphoma Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

CHOP is not an adequate therapy.
AGE RISK INDUCTION THERAPY
(Regimens are listed in alphabetical order)
• CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal [IT] methotrexate and cytarabine
followed by high-dose systemic methotrexate) + rituximab (3 cycles)
• DA-EPOCH-RR (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin + rituximab [day 1 and 5]) x 2 cycles
followed by PET scand:
Low Risk
CR (PET-negative) after 2 cycles: DA-EPOCH-RR (rituximab day 1 and 5) x 1 cycle (total of 3 cycles)
PR (PET-positive) after 2 cycles: DA-EPOCH-R (rituximab day 1 only) x 4 cycles (total of 6 cycles) + IT methotrexate
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and
cytarabine + rituximab (regimen includes IT therapy)
<60 y Patients presenting with symptomatic CNS disease:
High Risk • Initiate treatment with the portion of the systemic therapy that contains CNS-penetrating drugs
• CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with IT methotrexate and cytarabine followed by
high-dose systemic methotrexate) alternating with IVAC (ifosfamide, cytarabine, etoposide, IT methotrexate) + rituximab
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate and
cytarabine + rituximab (regimen includes IT therapy)
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximabd for 6 cycles + IT
methotrexate (for patients not able to tolerate aggressive therapy)
• DA-EPOCH-RR (rituximab day 1 and 5) x 2 cycles followed by PET scand:
Low Risk CR (PET-negative) after 2 cycles: DA-EPOCH-RR (rituximab day 1 and 5) x 1 cycle (total of 3 cycles)
PR (PET-positive) after 2 cycles: DA-EPOCH-R (rituximab day 1 only) x 4 cycles (total of 6 cycles) + IT methotrexate
≥60 y
• Initiate treatment with the portion of the systemic therapy that contains CNS-penetrating drugs
High Risk • Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximabd for 6 cycles + IT
methotrexate (for patients presenting with symptomatic CNS disease)

Prophylaxis for tumor lysis syndrome is mandatory (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

a See references for regimens on BURK-A 3 of 3.

Note: All recommendations are category 2A unless otherwise indicated.

BURK-A
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Table of Contents
Burkitt Lymphoma Discussion

SUGGESTED TREATMENT REGIMENSa,b,c

SECOND-LINE THERAPY
• Patients with disease relapse >6 to 18 mo after appropriate first-line therapy should be treated with alternate regimens. While no definitive second-
line therapies exist, there are limited data for the following regimens:
Other recommended regimens (in alphabetical order)
• Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximabd for 6 cycles (if not previously given) + IT
methotrexate
• RICE (rituximab, ifosfamide, carboplatin, etoposide); IT methotrexate if have not received previously
• RIVAC (rituximab, ifosfamide, cytarabine, etoposide); IT methotrexate if have not received previously

• For patients presenting with symptomatic CNS disease; initiate treatment with the portion of the systemic therapy that contains CNS-penetrating
drugs)

Useful in certain circumstances (in alphabetical order)

• High-dose cytarabine + rituximab
• RGDP (rituximab, gemcitabine, dexamethasone, cisplatin)

Prophylaxis for tumor lysis syndrome

is mandatory (NHODG-B)
See monoclonal antibody and viral
reactivation (NHODG-B)

a See references for regimens on BURK-A 3 of 3.

Note: All recommendations are category 2A unless otherwise indicated.

BURK-A
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Table of Contents
Burkitt Lymphoma Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
Induction Therapy Second-line Therapy
Low- and High-Risk Combination Regimens RICE (rituximab, ifosfamide, carboplatin, etoposide)
CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine Griffin TC, Weitzman S, Weinstein H, et al. A study of rituximab and ifosfamide,
with intrathecal methotrexate and cytarabine followed by high-dose systemic carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell
methotrexate) with (for high-risk) or without (for low-risk) alternating IVAC (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A
(ifosfamide, cytarabine, etoposide, and intrathecal methotrexate ± rituximab) report from the Children's Oncology Group. Pediatr Blood Cancer 2009;52:177-181.
LaCasce A, Howard O, Lib S, et al. Modified magrath regimens for adults with Burkitt
and Burkitt-like lymphoma: preserved efficacy with decreased toxicity. Leuk Lymphoma
2004;45:761-767.
Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and
CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom
Lymphoma Group LY06 study. Ann Oncol 2002;13:1264-1274.
Barnes JA, Lacasce AS, Feng Y, et al. Evaluation of the addition of rituximab
to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis. Ann Oncol
2011;22:1859-1864.
Evens AM, Carson KR, Kolesar J, et al. A multicenter phase II study incorporating high-
dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated
Burkitt's lymphoma. Ann Oncol 2013;24:3076-3081.
Phillips EH, Burton C, Kirkwood AA, et al. Favourable outcomes for high-risk Burkitt
lymphoma patients (IPI 3-5) treated with rituximab plus CODOX-M/IVAC: Results of a
phase 2 UK NCRI trial. EJHaem 2020;1:133-141.
Dose-adjusted EPOCH plus rituximab (regimen includes IT methotrexate)
Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with Burkitt's
lymphoma. N Engl J Med 2013;369:1915-1925.
Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted
therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma. J Clin
Oncol 2020;38:2519-2529.
HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone)
alternating with high-dose methotrexate and cytarabine + rituximab
Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD
plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute
lymphoblastic leukemia. Cancer 2006;106:1569-1580.
Samra B, Khoury JD, Morita K, et al. Long-term outcome of hyper-CVAD-R for Burkitt
leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse. Blood Adv
2021;5:3913-3918.

Note: All recommendations are category 2A unless otherwise indicated.

BURK-A
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Table of Contents
HIV-Related B-Cell Lymphomas Discussion

ADDITIONAL DIAGNOSTIC TESTING

ESSENTIAL:
• Adequate immunophenotyping to establish diagnosis and
subclassification (eg, DLBCL, BL, plasmablastic lymphoma, PEL)
IHC panel: CD45, CD20, CD3, CD10, BCL2, BCL6,
Ki-67, CD138, kappa/lambda, HHV8 latency-associated nuclear
antigen (LANA),a CD30 for PEL, Workup
with or without (HIVLYM-2)
Flow cytometry with peripheral blood and/or biopsy specimen:
kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20
• Karyotype or FISH for MYC; FISH for BCL2, BCL6 rearrangements if
MYC positive
• EBER-ISH

a HHV8 can also be detected by polymerase chain reaction (PCR).

Note: All recommendations are category 2A unless otherwise indicated.

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HIV-Related B-Cell Lymphomas Discussion

WORKUP
ESSENTIAL
• Physical exam: attention to node-bearing areas, including Waldeyer’s ring,
and to size of liver and spleen
• Performance status
• B symptoms Treatment
BL
• CBC with differential (HIVLYM-3)
• LDH
• Comprehensive metabolic panel
• Uric acid, phosphate
• PET/CT scan (preferred) or C/A/P CT with contrast of diagnostic quality
• CD4 count Treatment
Primary CNS lymphoma
• HIV viral load (HIVLYM-3)
• Hepatitis B testingb
• Hepatitis C testingc
• Echocardiogram or MUGA scan if anthracycline or anthracenedione-based
regimen is indicated
• Pregnancy testing in patients of childbearing age (if chemotherapy or RT
planned)

USEFUL IN SELECTED CASES: • DLBCL

• Upper GI/barium enema/endoscopy Treatment
• HHV8-positive DLBCL, NOS
• Adequate bone marrow biopsy (>1.6 cm) ± aspirate; bone marrow biopsy is (HIVLYM-4)
• PEL
not necessary if PET/CT scan demonstrates bone disease
• Lumbar puncture, except for PEL
• Neck CT with contrast
• Plain bone radiographs and bone scan Treatment
• Brain MRI with and without contrast, or head CT with contrast Plasmablastic lymphoma
(HIVLYM-4)
• Beta-2-microglobulin
• EBV polymerase chain reaction (PCR)
• Quantitative Ig
• Discuss fertility preservationd

b Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with
no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with
gastroenterologist.
c Hepatitis C antibody and if positive, viral load and consult with hepatologist.
d Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

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Table of Contents
HIV-Related B-Cell Lymphomas Discussion

TREATMENT
Antiretroviral therapy (ART) can be administered safely with chemotherapy, but consultation with an HIV specialist or pharmacist is important
to optimize compatibility. With continued development of new ARTs, effective alternatives are often available to patients when the existing
ARTs are expected to affect metabolism of or share toxicities with chemotherapy. In general, avoidance of zidovudine, cobicistat, and ritonavir
is strongly recommended. Concurrent ART is associated with higher CR rates (Barta S, et al. Blood 2013;122:3251-3262). Patients with HIV-
related DLBCL receiving ART are suitable candidates for CAR T-cell therapies with appropriate supportive care measures for HIV control. For
principles of concurrent HIV management and supportive care, see the NCCN Guidelines for Cancer in People with HIV.e

• First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)e For relapse, see
• If CD4 <50, maximize supportive care and monitor closely for cytopenias and infections Second-Line Therapy
BL
while administering lymphoma therapy (BURK-3)
• Granulocyte colony-stimulating factor (G-CSF) for all patients

• Initiate ART, if not already receiving

• Even with poorly controlled HIV and/or marginal performance status, consider high-dose For relapse,
methotrexatef see the NCCN
Primary CNS • For select patients with good performance status on ART, see the NCCN Guidelines for CNS - Guidelines for
lymphoma Primary CNS Lymphoma CNS - Primary CNS
• Consider RT alone as initial treatment for patients who are not candidates for systemic Lymphoma
therapy at presentation, then reassess eligibility for systemic therapy after RT
• Best supportive care (See NCCN Guidelines for Palliative Care)

Note: All recommendations are category 2A unless otherwise indicated.

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Table of Contents
HIV-Related B-Cell Lymphomas Discussion

TREATMENT
ART can be administered safely with chemotherapy, but consultation with an HIV specialist or pharmacist is important to optimize
compatibility. With continued development of new ARTs, effective alternatives are often available to patients when the existing ARTs are
expected to affect metabolism of or share toxicities with chemotherapy. In general, avoidance of zidovudine, cobicistat, and ritonavir is
strongly recommended. Concurrent ART is associated with higher CR rates (Barta S, et al. Blood 2013;122:3251-3262). Patients with HIV-
related DLBCL receiving ART are suitable candidates for CAR T-cell therapies with appropriate supportive care measures for HIV control. For
principles of concurrent HIV management and supportive care, see the NCCN Guidelines for Cancer in People with HIV.e
For relapse, see
• <12 mo (BCEL-7)
• First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)e • >12 mo (BCEL-8)
• DLBCL • G-CSF for all patients or
• HHV8-positive • IT therapy as per BCEL-A 3 of 3 Bortezomib-ICE ± rituximab
DLBCL, NOS • If CD20-, rituximab is not indicated (category 2B)
• PEL • If CD4 <50, maximize supportive care and monitor closely for
cytopenias and infections while administering lymphoma therapy

For relapse,
• Standard CHOP is not adequate therapy Brentuximab vedotin
• First-line therapy - See Suggested Treatment Regimens (HIVLYM-A)e or
Plasmablastic • Consider HDT/ASCR in first complete remission in select patients
lymphomag See BCEL-C second-line
with high-risk diseaseh therapy (without rituximab)
• IT therapy as per BCEL-A 3 of 3

e In the NCCN Guidelines for Cancer in People with HIV, see the Principles of HIV Management While Undergoing Cancer Therapy; Principles of Systemic Therapy and
Drug-Drug Interactions; and Principles of Supportive Care.
g Management can also apply to HIV-negative plasmablastic lymphoma.
h High-risk features include an age-adjusted IPI higher than 2, presence of MYC gene rearrangement, or TP53 gene deletion. Note that patients negative for HIV with
plasmablastic lymphoma are generally considered to have higher risk disease. Optimization of HIV control with ART is important.

Note: All recommendations are category 2A unless otherwise indicated.

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HIV-Related B-Cell Lymphomas Discussion

SUGGESTED TREATMENT REGIMENSa

BURKITT LYMPHOMA - FIRST-LINE THERAPYb
Preferred regimens
• CODOX-M/IVAC (modified): cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate
alternating with ifosfamide, etoposide, high-dose cytarabine + rituximabc
• DA-EPOCH-R: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin + rituximabd

Other recommended regimens

• R-HyperCVAD: rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating
with high-dose methotrexate and cytarabinec

DLBCL, HHV8-POSITIVE DLBCL, NOS, PEL - FIRST-LINE THERAPYb

• If CD20-, rituximab is not indicated
Preferred regimens
• R-EPOCHe

Other recommended regimens

• RCHOP
PLASMABLASTIC LYMPHOMA - FIRST-LINE THERAPY
Preferred regimens
• EPOCH (preferred)e

Other recommended regimens

• CODOX-M/IVAC (modified)
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone
alternating with high-dose methotrexate and cytarabine)
Prophylaxis for tumor lysis syndrome (NHODG-B)
Prophylaxis for tumor lysis syndrome is mandatory for BL
See monoclonal antibody and viral reactivation (NHODG-B)
a See references for regimens on HIVLYM-A 2 of 2.
b An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
c Patients presenting with high-risk and symptomatic CNS disease should be started with the portion of the systemic therapy that contains CNS-penetrating drugs.
d Dunleavy K, Pittaluga S, Shovlin M, et al. Engl J Med 2013;369:1915-1925. Roschewski M, Dunleavy K, Abramson JS, et al. J Clin Oncol 2020;38:2519-2529. For
dosing, see BURK-A 1 of 3.
e Recommendations for EPOCH ± Rituximab Dose Adjustments for Non-Burkitt Lymphomas (HIVLYM-B).

Note: All recommendations are category 2A unless otherwise indicated.

HIVLYM-A
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HIV-Related B-Cell Lymphomas Discussion

SUGGESTED TREATMENT REGIMENS

REFERENCES
CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and
methotrexate alternating with ifosfamide, etoposide, high-dose cytarabine) ± dexamethasone alternating with high-dose methotrexate and cytarabine) ±
rituximab rituximab
Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide,
cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral
and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus- therapy for patients with acquired immunodeficiency syndrome-related Burkitt
associated Burkitt lymphoma. Cancer 2003;98:1196-1205. lymphoma/leukemia. Cancer 2002;94:1492-1499.
Barnes JA, LaCasce AS, Feng Y, et al. Evaluation of the addition of rituximab Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD
to CODOX-M/IVAC for Burkitt's lymphoma: A retrospective analysis. Ann Oncol plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or
2011; 22:1859-1864. acute lymphoblastic leukemia. Cancer 2006;106:1569-1580.
Noy A, Lee JY, Cesarman E, et al. AMC 048: modified CODOX-M/IVAC-rituximab Samra B, Khoury JD, Morita K, et al. Long-term outcome of hyper-CVAD-R for
is safe and effective for HIV-associated Burkitt lymphoma. Blood 2015;126:160- Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS
166. relapse. Blood Advances 2021;5:3913-3918.
Dose-adjusted EPOCH (etoposide, prednisone, vincristine, CHOP + rituximab
cyclophosphamide, doxorubicin) Boue F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab
Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol
immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: 2006;24:4123-4128.
impact of antiretroviral therapy suspension and tumor biology. Blood Ribera JM, Oriol A, Morgades M, et al. Safety and efficacy of cyclophosphamide,
2003;101:4653-4659. adriamycin, vincristine, prednisone and rituximab in patients with human
Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a
therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma. phase II trial. Br J Haematol 2008;140:411-419.
J Clin Oncol 2020;38:2519-2529. Bortezomib/ICE (ifosfamide, carboplatin, etoposide) ± rituximab
EPOCH + rituximab Reid EG, Looney D, Maldarelli F, et al. Safety and efficacy of an oncolytic
Barta SK, Lee JY, Kaplan LD, et al. Pooled analysis of AIDS malignancy viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive
consortium trials evaluating rituximab plus CHOP or infusional EPOCH lymphomas. Blood Adv 2018;2:3618-3626.
chemotherapy in HIV-associated non-Hodgkin lymphoma. Cancer 2012;118:3977-
3983.
Bayraktar UD, Ramos JC, Petrich A, et al. Outcome of patients with relapsed/
refractory acquired immune deficiency syndrome-related lymphoma diagnosed
1999-2008 and treated with curative intent in the AIDS Malignancy Consortium.
Leuk Lymphoma 2012;53:2383-2389.
Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with
Burkitt's lymphoma. N Engl J Med 2013;369:1915-1925.
Ramos J, Sparano J, Rudek M, et al. Safety and preliminary efficacy of vorinostat
with R-EPOCH in high-risk HIV-associated non-Hodgkin’s lymphoma (AMC-075).
Clin Lymphoma Myeloma Leuk 2018;18:180-190.
Sparano JA, Lee JY, Kaplan LD et al. Rituximab plus concurrent infusional
EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin
lymphoma. Blood 2010;115:3008-3016.

Note: All recommendations are category 2A unless otherwise indicated.

HIVLYM-A
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HIV-Related B-Cell Lymphomas Discussion

RECOMMENDATIONS FOR EPOCH ± RITUXIMAB DOSE ADJUSTMENTS FOR NON-BURKITT LYMPHOMAS1

EPOCH ± rituximab dosing recommendations for cycle 1:
• Rituximab (if CD20-positive) 375 mg/m2 IV on Day 1
• Etoposide 50 mg/m2/day continuous IV infusion for 4 days (96 hours)
• Doxorubicin 10 mg/m2/day continuous IV infusion for 4 days (96 hours)
• Vincristine 0.4 mg/m2/day continuous IV infusion for 4 days (96 hours)
• Day 5 cyclophosphamide dosing
If baseline CD4 count is >200 cells/mm3, start cyclophosphamide at 750 mg/m2
If baseline CD4 count is 50–200 cells/mm3, start cyclophosphamide at 375 mg/m2
For baseline CD4 counts <50 cells/mm3, cycle 1 doses of cyclophosphamide above 187.5 mg/m2 have not been published
• Prednisone 60 mg/m2/day for 5 days

EPOCH Dose Modifications for Subsequent Cycles Based on Cytopenias (Non-Burkitt Lymphomas)1
Event Action
ANC nadir on any cycle <500/mm3 on 2 nonconsecutive Reduce cyclophosphamide dose by 187 mg/m2
days at least 3 days apart and/or platelet nadir <25,000/
mm3 in the previous cycle
ANC nadir <500/mm3 x ≥3 days or platelets <25,000/ Reduce doxorubicin and etoposide by 25% of the full dose
mm3 x ≥3 days, AND patient was receiving no
cyclophosphamide in the previous cycle
ANC nadir ≥500/mm3 AND platelet nadir ≥50,000/mm3 in Increase cyclophosphamide dose by 187 mg/m2 each cycle to a
the previous cycle maximum dose of 750 mg/m2

1 For R-EPOCH dosing for non-Burkitt lymphomas, see Ramos J, Sparano J, Rudek M, et al. Safety and preliminary efficacy of vorinostat with
R-EPOCH in high-risk HIV-associated non-Hodgkin’s lymphoma (AMC-075). Clin Lymphoma Myeloma Leuk 2018;18:180-190. This is an ongoing
clinical trial and the utility of adding vorinostat to R-EPOCH has not yet been established.

Note: All recommendations are category 2A unless otherwise indicated.

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Lymphoblastic Lymphoma Discussion

ADDITIONAL DIAGNOSTIC TESTINGa,b,c WORKUP

ESSENTIAL:
• Physical exam: attention to node-bearing areas, including
Waldeyer’s ring, and to size of liver and spleen
ESSENTIAL: • Performance status
• Adequate immunophenotyping to establish diagnosisd • B symptoms
IHC panel: CD45, CD19, CD20, CD79a, CD3, CD2, CD5, • CBC with differential
CD7, TdT, CD1a, CD10, cyclin D1, myeloperoxidase, • LDH
lysozyme, CD34, CD4, CD8 • Comprehensive metabolic panel
with or without • Uric acid, phosphate
Flow cytometry with peripheral blood and/or biopsy • C/A/P CT with contrast of diagnostic quality
specimen: kappa/lambda, CD45, CD3, CD5, CD4, CD7, • Lumbar puncture See NCCN
Guidelines for
CD8, CD19, CD20, CD10, TdT, CD13, CD33, CD34, • Flow cytometry of cerebrospinal fluid
Acute
CD1a, cytoplasmic CD3, CD22, myeloperoxidase • Bilateral or unilateral bone marrow biopsy ± aspirate with
Lymphoblastic
• Karyotype ± FISH: MYC; t(9;22); t(8;14); and variants or flow and cytogenetics Leukemia
PCR for BCR::ABL1 • Hepatitis B testinge
• Echocardiogram or MUGA scan if anthracycline or
USEFUL UNDER CERTAIN CIRCUMSTANCES: anthracenedione-based regimen is indicated
• Additional immunohistochemical studies to establish • Pregnancy testing in patients of childbearing age (if
lymphoma subtype chemotherapy or RT planned)
IHC panel: CD22, CD4, CD8, cyclin D1 USEFUL IN SELECTED CASES:
• Molecular analysis to detect: Ig gene rearrangements • Beta-2-microglobulin
• Brain MRI with and without contrast
• PET/CT scanf
• Discuss fertility preservationg
a The LL category comprises two diseases, T-cell LL (T-LL; 90%) and B-cell LL (B-LL; 10%), which corresponds to T-cell acute lymphoblastic leukemia (T-ALL) and
B-cell acute lymphoblastic leukemia (B-ALL), respectively, with presentations in extramedullary sites. See Cytogenetic and Molecular Prognostic Risk Stratification for
B-ALL in the NCCN Guidelines for Acute Lymphoblastic Leukemia.
b This disease is complex and curable; it is preferred that treatment occur at centers with expertise in the management of the disease.
c Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).
d Typical immunophenotype: B-LL: sIg-, CD10+/-, CD19+, CD20-/+, TdT+, CD34+, CD79a+.
T-LL: sIg-, CD10-, CD19/20-, CD3-/+, CD4/8+/+, CD1a+/-, TdT+, CD2+, CD7+ cytoplasmic CD3+, sCD3-/+.
e Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with
no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with
gastroenterologist.
f Initiation of therapy should not be delayed in order to obtain a PET/CT scan.
g Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.

Note: All recommendations are category 2A unless otherwise indicated.

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Post-Transplant Lymphoproliferative Disorders Discussion

ADDITIONAL DIAGNOSTIC TESTINGa WORKUP PTLD SUBTYPEe

ESSENTIAL:
ESSENTIAL: • Performance status
• Adequate immunophenotyping to establish • Albumin
diagnosis • History of therapy for transplant
IHC panel: CD3, B-cell markers (CD20, CD79a, • LDH, electrolytes, BUN, creatinine Non-destructive
PAX5), kappa, lambda • CBC with differential lesions (ICC)/
• EBV evaluation by EBER-ISH • Hepatitis B testingb Hyperplasia (WHO5)f
• EBV PCR for cell-free plasma EBV First-line
DNA markerc Therapy
• Additional immunophenotyping depending on Monomorphic PTLD (PTLD-2)
morphology and initial phenotyping: • PET/CT scan and/or C/A/P CT with (B-cell and T-cell/
IHC panel for cHL: CD15, CD30, CD45, PAX5 contrast NK-cell type) (ICC)/
IHC panel for DLBCL/BL: CD10, BCL6, MUM1/ • Pregnancy testing in patients of Lymphoma (WHO5)
IRF4, MYC, TdT, Ki67, BCL2 childbearing age (if chemotherapy or
IHC panel for plasmacytic/plasmablastic RT planned)
Polymorphic PTLD First-line
tumors: CD138, MUM1/IRF4, ALK, HHV8 (B-cell type) (ICC/ Therapy
IHC panel for T-cell lymphoma: CD2, CD5, USEFUL IN SELECTED CASES:
• Echocardiogram or MUGA scan WHO5) (PTLD-3)
CD7, CD4, CD8, ALK, TIA-1, granzyme B
IHC for EBV-LMP1 and EBV-EBNA2 to if anthracycline-based regimen is
See NCCN
determine latency status indicated Classic Hodgkin
Guidelines
Flow cytometry of biopsy specimen to • Bone marrow evaluation lymphoma (CHL)-
for Hodgkin
include B and T cell clonality assessment. • Brain MRI with and without contrast type PTLD
Lymphoma
FISH to detect MYC, BCL2, or BCL6 • Cytomegalovirus (CMV) PCR
rearrangements • EBV serology for primary versus Primary CNS
• Molecular analysis to detect: Ig gene reactivation PTLD PTLD-A
rearrangements • Hepatitis C testing (B-cell type)
• Discuss fertility preservationd

a Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas (NHODG-B 4 of 5).
b Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include HBsAg and core antibody for a patient with
no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen (NHODG-B). If positive, check viral load and consider consult with
gastroenterologist.
c If EBV-negative, should not be used as response marker.
d Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.
e Indolent small B-cell lymphomas arising in transplant recipients are not included among PTLDs, with the exception of EBV-positive marginal zone lymphomas in the
ICC. Indolent lymphomas arising in transplant recipients are included in the WHO5. EBV-positive mucocutaneous ulcer (WHO5) is an indolent lymphoma.
f In the WHO5, hyperplasia includes follicular hyperplasia, infectious mononucleosis-like hyperplasia (IMH), and plasmacytic hyperplasia (PCH); in the ICC these three
types are considered non-destructive.

Note: All recommendations are category 2A unless otherwise indicated.

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Post-Transplant Lymphoproliferative Disorders Discussion

PTLD SUBTYPE FIRST-LINE THERAPY INITIAL RESPONSEl FOLLOW-UP/SECOND-LINE THERAPY

Manage immunosuppressionm
Complete
and monitor EBV PCR, and
Non-destructive Reduction of response
graft organ function
lesions (ICC)/ immunosuppression (RI)i
Hyperplasia (WHO5)g Partial response,
persistent or Rituximab and monitor EBV PCR
progressive disease

Complete response See appropriate histologic subtype for follow-up

If RI was initial therapy, then rituximab or
• RI, if possiblei and/or: chemoimmunotherapyk
Monomorphic PTLD Rituximab alonej or
(B-cell type)h or If rituximab monotherapy was initial therapy, then
Chemoimmunotherapyk chemoimmunotherapyk or consider rituximab for
Partial response, patients with partial response and IPI 0–2n
persistent or or
progressive disease If chemoimmunotherapy was initial therapy, see BCEL-7
Monomorphic • Other than reduction of RI, there are no established or
PTLD (T-cell type) treatments. HDT/ASCR may not be appropriate. Clinical trial
(ICC)/Lymphoma • Consider chemotherapy (See NCCN Guidelines for or
(WHO5)h T-Cell Lymphomas) Immunotherapy with EBV-Specific Cytotoxic
T-lymphocytes (EBV-CTL) (if EBV-driven)

k For concurrent or sequential chemoimmunotherapy, see Suggested Treatment

g Non-destructive lesions in the ICC Classification are of B-cell type and include Regimens (PTLD-A).
PCH, infectious mononucleosis, and florid follicular hyperplasia. l Restage in 2 to 4 weeks.
h Treatment is based on the unique histology. m Re-escalation of immunosuppressive therapy should be individualized, taking
i Response to RI is variable and patients need to be closely monitored; RI should into account the extent of initial RI and the nature of the organ allograft. These
be coordinated with the transplant team. RI: Reduction in calcineurin inhibition decisions should be made in conjunction with the transplant team.
(cyclosporin and tacrolimus), discontinuation of antimetabolic agents (azathioprine n Zimmermann H, Koenecke C, Dreyling MH, et al. Modified risk-stratified
and mycophenolate mofetil), and for patients who are critically ill all non- sequential treatment (subcutaneous rituximab with or without chemotherapy)
glucocorticoid immunosuppression should be discontinued. in B-cell post-transplant lymphoproliferative disorder (PTLD) after solid organ
j As part of a step-wise approach in patients who are not highly symptomatic or transplantation (SOT): the prospective multicentre phase II PTLD-2 trial.
cannot tolerate chemotherapy secondary to comorbidity. Leukemia 2022;36:2468-2478.

Note: All recommendations are category 2A unless otherwise indicated.

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Post-Transplant Lymphoproliferative Disorders Discussion

PTLD SUBTYPE FIRST-LINE THERAPY INITIAL RESPONSEl FOLLOW-UP/SECOND-LINE THERAPY

• RI, if possiblei and: • Monitor EBV PCR and:

Rituximab alone Active surveillance
Systemic Complete response or
or
Chemoimmunotherapyk Continue RI, if possible ± maintenance
Polymorphic rituximab, and graft organ function monitoring
PTLD (B-cell
type) (ICC/
WHO5) • RI, if possiblei and:
ISRTo ± rituximab Chemoimmunotherapyk
or Partial response, or
Localized persistent or Clinical trial
Surgery ± rituximab
or progressive disease or
Rituximab alone EBV-CTL (if EBV driven)

i Response to RI is variable and patients need to be closely monitored; RI should be coordinated with the transplant team. RI: Reduction in calcineurin inhibition
(cyclosporin and tacrolimus), discontinuation of antimetabolic agents (azathioprine and mycophenolate mofetil), and for patients who are critically ill all non-
glucocorticoid immunosuppression should be discontinued.
k For concurrent or sequential chemoimmunotherapy, see Suggested Treatment Regimens (PTLD-A).
l Restage in 2 to 4 weeks.
o Principles of Radiation Therapy (NHODG-D).

Note: All recommendations are category 2A unless otherwise indicated.

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Post-Transplant Lymphoproliferative Disorders Discussion

SUGGESTED TREATMENT REGIMENSa

(in alphabetical order)

MONOMORPHIC PTLD (B-CELL TYPE) AND POLYMORPHIC PTLD (B-CELL TYPE)

Sequential chemoimmunotherapy
• Rituximab 375 mg/m2 weekly x 4 weeksb
Restage with PET/CT scan (in 2–4 weeks)
◊ If PET/CT scan negative (5-PS: 1–3), rituximab 375 mg/m2 every 3 weeks x 4 cycles
◊ If PET/CT scan positive (5-PS: 4–5), RCHOP-21 every 3 weeks + G-CSF x 4 cycles†
Concurrent chemoimmunotherapy
• Pola-R-CHP (polatuzumab vedotin-piiq, rituximab, cyclophosphamide, doxorubicin, prednisone) (≥ IPI 2)
• RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
• For patients who are frail who cannot tolerate anthracycline, no specific regimen has been identified but options may includec:
RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine)
RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone)
RCVP (rituximab, cyclophosphamide, vincristine, prednisone)
† If 5-PS: 5 because of new sites of disease or clear progression, treat as refractory disease.

PRIMARY CNS PTLD (B-CELL TYPE)a

• High-dose methotrexated + rituximab

Consider prophylaxis for tumor lysis syndrome (NHODG-B)

See monoclonal antibody and viral reactivation (NHODG-B)

a An FDA-approved biosimilar is an appropriate substitute for any recommended systemic biologic therapy in the NCCN Guidelines. Rituximab and hyaluronidase
human injection for subcutaneous use may be substituted for rituximab after patients have received the first full dose of rituximab by intravenous infusion.
b Trappe R, Dierickx D, Zimmermann H, et al. Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows
successful stratification into rituximab or R-CHOP consolidation in an international, prospective, multicenter phase II trial. J Clin Oncol 2017;35:536-543.
c There are no published data regarding the use of these regimens; however, they are used at NCCN Member Institutions for the treatment of PTLD.
d Patients with PTLD often have renal insufficiency. High-dose methotrexate should be used with caution. Alternate regimens (cytarabine-based) should be considered.

Note: All recommendations are category 2A unless otherwise indicated.

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Table of Contents
B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND NK/T-CELL NEOPLASMSa
(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

General Principles
• Morphology ± clinical features drive both the choice and the interpretation of special studies.
• Differential diagnosis is based on morphology ± clinical setting.
• Begin with a broad panel appropriate to morphologic diagnosis, limiting panel of antibodies based on the differential diagnosis.
Avoid “shotgun” panels of unnecessary antibodies unless a clinically urgent situation warrants.
• Add antigens in additional panels, based on initial results.
• Follow with genetic studies as needed.
• Return to clinical picture if immunophenotype + morphology are not specific.

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in
every case. Continued
Note: All recommendations are category 2A unless otherwise indicated.
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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
B-cell antigens positiveb,c (CD19, CD20, CD79a, PAX5)
• Morphology
Cytology
◊ Small cells
◊ Medium-sized cells
◊ Large cells
Pattern
◊ Diffuse
◊ Nodular, follicular, mantle, marginal
◊ Sinuses
• Clinical
Age (child, adult)
Location
◊ Nodal
◊ Extranodal, specific site
• Immunophenotype
Naïve B cells: CD5, CD23, IgD
GCB cells: CD10, BCL6
Follicular dendritic cells (FDC): CD21, CD23
Post-GCB cells: IRF4/MUM1, CD138
Ig heavy and light chains (surface, cytoplasmic, class switch, light chain type)
Oncogene products: BCL2, cyclin D1, MYC, BCL6, ALK
Viruses: EBV, HHV8
Other: CD43, Ki-67, LEF1, SOX11
• Genetic testing
BCL2, BCL6, CCND1, MYC, ALK, MYD88, BRAF, IRF4, 11q aberrations, Ig Initial Morphologic, Clinical, and Immunophenotypic Analysis
rearrangement (NHODG-A 3 of 8)

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every
case.
b Some lymphoid neoplasms may lack pan leukocyte (CD45), pan-B, and pan-T antigens. Selection of additional antibodies should be based on the differential diagnosis
generated by morphologic and clinical features (eg, plasma cell myeloma, ALK+ DLBCL, plasmablastic lymphoma, anaplastic large cell lymphoma [ALCL], NK-cell
lymphomas).
c Usually 1 pan-B (CD20) and 1 pan-T (CD3) markers are done unless a terminally differentiated B-cell or a specific peripheral T-cell lymphoma (PTCL) is suspected.

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-A
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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)

INITIAL MORPHOLOGIC, CLINICAL, AND IMMUNOPHENOTYPIC ANALYSIS

Small cells NHODG-A 4 of 8

Medium-sized cells NHODG-A 5 of 8

B-cell neoplasms
Large cells ± anaplastic
NHODG-A 6 of 8
morphology

Cutaneous localization NHODG-A 8 of 8

Lineage based on
immunophenotyped
(Pan-B and Pan-T antigens)
or
Suspected by morphology/
clinical features

T-cell neoplasms See NCCN Guidelines for T-Cell Lymphomas

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every
case.
d Initial panel will often include additional markers based on morphologic differential diagnosis and clinical features.

Note: All recommendations are category 2A unless otherwise indicated.

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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
Cyclin D1- del(11q)
B-CELL NEOPLASMS CD23+ CLL t(11;14)- del(13q)
trisomy 12 del(17p)
CD5+ Cyclin D1+
MCL
or t(11;14)+g
CD23- Cyclin D1-h
CLL
and t(11;14)-
Panel: CD5, CD10, BCL6- Consider HCL, LPL, other rare B-cell neoplasms
CD21, CD23, cyclin D1,
Small cells
BCL2, BCL6, Ki-67, CD10+f BCL2+i
FL • Confirm by Ki-67 >30%
CD11c, (CD25, CD103)e or t(14;18)+g,i
BCL6+ • Morphology: large, expansile follicles, grade 3
BCL2-i or blastoid cells, no diffuse component
PTFL
and t(14;18)-g,i • Clinical features: localized, nodal
CD103+e
CD5- CD123+ Confirmation with BRAF sequencing
CD25+ HCL
annexin A1+g or IHC for mutant protein
CD11c+
Small cells: • Morphology (MZL pattern)
• Chronic lymphocytic leukemia/small CD10- f • Clinical features MZL
lymphocytic lymphoma (CLL/SLL) Cytoplasmic (extranodal, splenic)
• Mantle cell lymphoma (MCL) Ig- j Pseudofollicular pattern, CD5- CLL or
• Splenic marginal zone lymphoma (SMZL) clinical features bone other splenic
• Hairy cell leukemia (HCL) CD103- marrow B-cell lymphomask
• Lymphoplasmacytic lymphoma (LPL) • Morphology (MZL pattern, MYD88
• Extranodal marginal zone lymphoma (EMZL) plasmacytoid features), LPL
mut+
• Nodal marginal zone lymphoma (NMZL) genetics [del(7q)]
• Follicular lymphoma (FL) Cytoplasmic • Clinical features
• Pediatric-type follicular lymphoma (PTFL) Ig+ j (splenomegaly, bone
marrow involvement, MYD88
MZL
paraprotein) mut-
a These are meant to be general guidelines. Interpretation of results should be based h Rare cases of cyclin D1- and t(11;14)-negative MCL have been reported.
on individual circumstances and may vary. Not all tests will be required in every case. Consider SOX11 (positive in cyclin D1-negative MCL) and LEF1 (positive in
e Flow cytometry on blood or bone marrow done only if HCL is in differential diagnosis
CLL/SLL) IHC. This diagnosis should be made with extreme caution and with
by morphology. expert consultation.
f Rare cases of HCL may be CD10+ or CD5+ and some cases of FL are CD10-. BCL6 i 85% of FL will be BCL2+ or t(14;18)+.
is a useful discriminate if needed (rarely). Rare cases of MCL are CD5-. j Kappa and lambda light chains; IgG, IgM, and IgA may be helpful.
g Can be done to confirm if necessary. k Splenic diffuse red pulp small B-cell lymphoma (SDRPL) or others.

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-A
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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
B-CELL NEOPLASMS
Cyclin D1+ MCL,n blastoid variant

CD5+ Increased
CLL
Cyclin D1- prolymphocytes
BCL6+/-
IRF4/MUM1+/- BCL6-
Consider cyclin D1- MCL
IRF4/MUM1-
Initial panel:
Diffuse pattern
CD5, CD10,
medium cells
cyclin D1, BCL2,
± starry sky
BCL6, IRF4/
patternl
MUM1, Ki-67m
See
• WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of
tumours series, 5th ed; vol 11). Lyon (France): International Agency for Research on Cancer; 2024.
• Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of
CD5-o Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood
2022;140:1229-1253.
• King RL, Hsi ED, Chan CC, et al. Diagnostic approaches and future directions in Burkitt
lymphoma and high-grade B-cell lymphoma Virchows Arch 2023;482:193-205.
Medium cells
• Burkitt lymphoma (BL)n
• MCL, blastoid variant
• High-grade B-cell lymphoma (HGBL), NOS
• HGBL with MYC and BCL2 rearrangements (ICC and WHO-5)
• HGBL with MYC and BCL6 rearrangements (ICC)
• LBCL with 11q aberration [ICC]; HGBL with 11q aberrations [WHO]

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.
l Starry sky pattern is typically present in BL and frequently in HGBL. If blastoid morphology, exclude LL (usually terminal deoxynucleotidyl transferase+ and often
CD34+).
m Ki-67 is a prognostic factor in some lymphomas (eg, mantle cell) and is typically >90% in BL. It is not useful in predicting the presence of MYC rearrangement or in
classification.
n Rare MCL may be cyclin D1-. Consider SOX11 IHC.
o Lymphomas resembling BL or HGBL without detectable MYC rearrangement may prompt consideration for LBCL with 11q aberration [ICC]; HGBL with 11q aberrations
[WHO]. Chromosomal microarray or FISH may be warranted. Correlation with morphology and clinical features is essential.

Note: All recommendations are category 2A unless otherwise indicated.

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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
B-CELL NEOPLASMS
Cyclin D1+ Pleomorphic MCL
CD5+
Cyclin D1- DLBCL, NOS CD5+q
Panelp: CD5, LBCL with IRF4 rearrangements
IRF4/MUM1+
CD10, BCL6, (Confirm by karyotype or FISH)
Large cells CD10+
IRF4/MUM1,
Ki-67m IRF4/MUM1- DLBCL, NOS GCB type (BCL6+)

CD5- DLBCL BCL6+

DLBCL, NOS GCB type
IRF4/MUM1-
BCL6+ Panel: CD20, PAX5,
Large cells: Non-GCB CD138, ALK, CD30,
IRF4/MUM1+
• Diffuse large B-cell lymphoma (DLBCL), NOS CD10- CD15, EBV-EBER,
GCB subtype BCL6- HHV8, Ig light and
Non-GCB
Non-GCB subtype IRF4/MUM1- heavy chains (If further
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) BCL6- characterization is
Primary DLBCL of the CNS Post-GCB warranted based on
IRF4/MUM1+
Primary cutaneous DLBCL, leg type clinical or morphologic
EBV-positive DLBCL (EBV + DLBCL), NOS features. The specific
• DLBCL associated with chronic inflammation panel will vary
• Lymphomatoid granulomatosis depending on the
• Primary mediastinal large B-cell lymphoma (PMBL) differential diagnosis.)
• Intravascular LBCL
Continued
• ALK-positive LBCL
• Plasmablastic lymphoma
• HHV8+ LBCL, NOS
• LBCL with IRF4 rearrangement a These are meant to be general guidelines. Interpretation of results should be based on
• Primary effusion lymphoma (PEL) individual circumstances and may vary. Not all tests will be required in every case.
m Ki-67 is a prognostic factor in some lymphomas (eg, mantle cell and is typically >90% in
• Mediastinal gray zone lymphoma (MGZL)
• MCL, pleomorphic variant BL). It is not useful in predicting the presence of : rearrangement or in classification.
p CD5 is included to identify pleomorphic MCL; if CD5 is positive, cyclin D1 staining is done
to confirm or exclude MCL.
q Consider SOX11 IHC to exclude cyclin D1-negative pleomorphic MCL.

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-A
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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
LARGE CELLS T-cell-rich THRLBCL (May be BCL6+, IRF4/MUM1-)
(continued)
CD30 -
DLBCL, non-GCB
EBER-
Mediastinal PMBL (May be BCL6+, IRF4/MUM1-)
CD30 +
CD15- PMBL
Morphologically
borderline with CHL
CD15+ HGBL, NOS
Older or
EBV + DLBCL
CD20+ immunosuppressed
(PAX5+)
Extranodal, T-cell
EBER+ Lymphomatoid granulomatosis
rich, angiocentric

Chronic
DLBCL associated with chronic inflammation
inflammation

EBER- HHV8-positive DLBCL, NOS (ICC)/Kaposi sarcoma (KS)-associated herpes virus (KSHV)/
HHV8+ HHV8-positive DLBCL (WHO) (IgM lambda +) confirm by morphology
EBV+/-
Plasmablastic lymphoma MYC FISH +
HHV8-
EBV+/-
CD20- PEL (CD30+)
HHV8+
(PAX5-)
CD79a+ CD138+/-
IRF4/ EBV-
ALK + DLBCL IgA lambda + EMA +
MUM1+ ALK+

EBV-
Anaplastic/plasmablastic CD56 +/- cyclin D1 +/-
ALK-
myeloma/plasmacytoma IgG, IgA, kappa, or lambda
HHV8-

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.

Note: All recommendations are category 2A unless otherwise indicated.

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B-Cell Lymphomas Discussion

USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL NEOPLASMSa

(TO BE USED IN CONJUNCTION WITH CLINICAL AND MORPHOLOGIC CORRELATION)
B-CELL NEOPLASMS
CD10+ PCFCL
BCL6+
IRF4/MUM1-
(FDC+/-) PCFCL
Small/medium/large cells
Panel: CD3, CD5,
Many CD3+ cells
CD10,r BCL2, BCL6,r BCL2-
Cutaneous IRF4/MUM1, CD21/23
localization BCL6- (positive GC)
(FDC markers) IRF4/MUM1+/-
(FDC + follicular, disrupted) PCMZL
Small/medium cells
(Larger cells in GC)

BCL2 strongly +
CD10- BCL6+/-
IRF4/MUM1+
PC-DLBCL, leg type
(FDC-)
Large round cells
Few CD3+ T cells
BCL6- (positive GC)
IRF4/MUM1+/-
BCL2+ PCMZL
(FDC + follicular, disrupted)
Small/medium cells
BCL2 weakly +
BCL6+
IRF4/MUM1-
• Primary cutaneous marginal zone lymphoma (PCMZL) PCFCL
(FDC±, follicular)
• Primary cutaneous follicle center lymphoma (PCFCL) Small/medium/large cells
• Primary cutaneous DLBCL, leg type (PC-DLBCL, leg type) Many CD3+ T cells

a These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.
r These are assessed both in follicles (if present) and in intrafollicular/diffuse areas. CD10+ BCL6 + GCs are present in PCMZL, while both follicular and interfollicular/diffuse
areas (tumor cells) are positive for BCL6+/- CD10 in PCFCL.

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-A
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B-Cell Lymphomas Discussion

SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

Tumor Lysis Syndrome (TLS)
• Treatment of TLS:
• Laboratory hallmarks of TLS: TLS is best managed if anticipated and treatment is started prior to
High potassium chemotherapy.
High uric acid Centerpiece of treatment includes:
High phosphorous ◊ Rigorous hydration
Low calcium ◊ Management of hyperuricemia
◊ Frequent monitoring of electrolytes and aggressive correction
• Symptoms of TLS: (essential)
Nausea and vomiting, shortness of breath, irregular heartbeat, First-line and at retreatment for hyperuricemia.
clouding of urine, lethargy, and/or joint discomfort ◊ Glucose-6-phosphate dehydrogenase (G6PD) testing is required
prior to use of rasburicase. Rasburicase is contraindicated in
• TLS features: patients with a history consistent with G6PD. In these patients,
Consider TLS prophylaxis for patients with the following risk rasburicase should be substituted with allopurinol.
factors: ◊ Low-risk disease:
◊ Histologies of BL and LL; occasionally DLBCL Allopurinol or febuxostat beginning 2–3 days prior to
◊ Spontaneous TLS chemoimmunotherapy and continued for 10–14 days
◊ Elevated white blood cell (WBC) count ◊ Intermediate-risk disease: Stage I/II and LDH <2X ULN:
◊ Bone marrow involvement Allopurinol or febuxostat
◊ Pre-existing elevated uric acid OR
◊ Ineffectiveness/intolerance of allopurinol Rasburicase if renal dysfunction and uric acid, potassium,
◊ Renal disease or renal involvement by tumor and/or phosphate >ULN
◊ High-risk disease: Stage III/IV and/or LDH ≥2X ULN:
Rasburicase
Rasburicase (doses of 3–6 mg are usually effective).a One dose
of rasburicase is frequently adequate. Re-dosing should be
individualized and is indicated for patients with any of the following
risk factors:
◊ Urgent need to initiate therapy in a high-bulk patient
◊ Situations where adequate hydration may be difficult or impossible
◊ Acute renal failure
• If TLS is untreated, its progression may cause acute kidney failure,
cardiac arrhythmias, seizures, loss of muscle control, and death.

a There are data to support that fixed-dose rasburicase is very effective in adult patients. Continued

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-B
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B-Cell Lymphomas Discussion

SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

For other immunosuppressive situations, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
Viral Reactivation
Hepatitis B virus (HBV): Hepatitis C virus (HCV):
• Anti-CD20 mAb-based chemoimmunotherapy is associated with • New evidence from large epidemiologic studies, molecular biology
risk of HBV reactivation. Hepatitis B surface antigen (HBsAg) and research, and clinical observation supports an association between
hepatitis B core antibody (HBcAb) testing for all patients receiving HCV and B-cell non-Hodgkin lymphoma (NHL). Recently approved
anti-CD20 mAb therapy direct-acting antiviral (DAA) agents for chronic carriers of HCV with
Quantitative hepatitis B viral load by PCR and surface antibody genotype 1 demonstrated a high rate of sustained viral responses.
only if one of the screening tests is positive Low-grade B-cell NHL
• Note: Patients receiving IV immunoglobulin (IVIG) may be HBcAb- ◊ According to the American Association for the Study of Liver
positive as a consequence of IVIG therapy. Diseases, combined therapy with DAA agents should be
• Prophylactic antiviral therapy with entecavir is recommended for considered in asymptomatic patients with HCV genotype 1 since
any patient who is HBsAg-positive and receiving anti-lymphoma this therapy can result in regression of lymphoma.
therapy. If there is active disease (PCR+), it is considered treatment/ Aggressive B-cell NHL
management and not prophylactic therapy. In cases of HBcAb ◊ Patients should be initially treated with chemoimmunotherapy
positivity, prophylactic antiviral therapy is preferred; however, if regimens as outlined in these guidelines.
there is a concurrent high-level hepatitis B surface antibody, these ◊ Liver functional tests and serum HCV RNA levels should be
patients may be monitored with serial hepatitis B viral load. closely monitored during and after chemoimmunotherapy for
Entecavir is preferredb development of hepatotoxicity.
Avoid lamivudine due to risks of resistance development. ◊ Antiviral therapy should be considered in patients in complete
Other antivirals including adefovir, telbivudine, and tenofovir are remission after completion of lymphoma therapy.
proven active treatments and are acceptable alternatives.
Monitor hepatitis B viral load with PCR monthly through treatment John Cunningham virus (JCV) Reactivation:
and every 3 months thereafter. • Brentuximab vedotin (anti-CD30 antibody-drug conjugate) can cause
◊ If viral load is consistently undetectable, treatment is considered JCV reactivation and progressive multifocal leukoencephalopathy
prophylactic. (PML)
◊ If viral load fails to drop or previously undetectable PCR • PML is usually fatal. Clinical indications may include changes in
becomes positive, consult hepatologist and discontinue anti- behavior such as confusion, dizziness or loss of balance, difficulty
CD20 mAb therapy. talking or walking, and vision problems.
Maintain prophylaxis up to 12 months after oncologic treatment ends • Diagnosis made by PCR of cerebrospinal fluid and in some cases
◊ Consult with hepatologist for duration of therapy in patient with brain biopsy.
active HBV. • No known effective treatment.

b Huang YH, et al. J Clin Oncol 2013;31:2765-2772; Huang H, et al. JAMA 2014;312:2521-2530. Continued

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-B
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B-Cell Lymphomas Discussion

SUPPORTIVE CARE FOR B-CELL LYMPHOMASc

Additional Rare Complications of Monoclonal Antibody Therapy
• See NHODG-B 2 of 5 for Monoclonal Antibody Therapy and Viral Reactivation
• Rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur. Expert consultation with dermatology is recommended.
• Re-challenge with the same mAb is not recommended in patients experiencing rare complications to chosen anti-CD20 mAb (rituximab,
obinutuzumab, or ofatumumab). An alternative anti-CD20 mAb (eg, obinutuzumab) could be used for patients with intolerance to
rituximab, including those experiencing severe hypersensitivity reactions requiring discontinuation of chosen anti-CD20 mAb, regardless
of histology.d It is unclear that the use of alternative anti-CD20 mAb poses the same risk of recurrence.

Rituximab and Obinutuzumab Rapid Infusion

• If no infusion reactions were experienced with prior cycle of rituximab or obinutuzumab,e a rapid infusion over 90 minutes can be used.

Rituximab-Related Neutropenia Obinutuzumab-Related Neutropenia

• Late-onset neutropenia (weeks to months after last exposure) • Late-onset neutropenia can be seen in up to 20% of patients
occurs in up to 20% of patients • Early-onset neutropenia is a risk with obinutuzumab
• It can be severe, but patients usually do not present with monotherapy as well as with combination chemotherapy or
infections and can be initially observed for spontaneous recovery targeted agents
• A short course of G-CSF is indicated for prolonged neutropenia • Neutropenia is responsive to growth factors
• IVIG has been anecdotally successful in patients with
neutropenia that is refractory to G-CSF

Management of Methotrexate Toxicity

• If a patient receiving high-dose methotrexate experiences delayed elimination due to renal impairment, glucarpidase is strongly
recommended when:
plasma methotrexate concentrations are two standard deviations above the mean expected plasma concentration as determined
by MTXPK.org;
or
plasma methotrexate level is >30 μM at 36 hours, >10 μM at 42 hours, or >5 μM at 48 hours.
• Optimal administration of glucarpidase is within 48 to 60 hours from the start of methotrexate infusion. Leucovorin should be continued
for at least 2 days following glucarpidase administration and should be administered at least 2 hours before or 2 hours after the dose of
glucarpidase.

c Supportive care measures specific to rituximab include both rituximab as well as rituximab biosimilars.
d Castillo JJ, et al. Br J Haematol 2016;174:645-648; Ghione P, et al. J Clin Oncol 2020;38:Abstract 8062.
e Canales MA, et al. J Clin Oncol 2021;39:Abstract 7545; Ohmachi K, et al. Jpn J Clin Oncol 2018;48:736-742; Sharman JP, et al. Leuk Lymphoma 2019;60:894-
903. Zelenetz AD, et al. Blood 2019;133:1964-1976. Continued
Note: All recommendations are category 2A unless otherwise indicated.
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B-Cell Lymphomas Discussion

SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

Special Considerations for Adolescent and Young Adult (AYA) Patients with B-Cell Lymphomas
• See NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology for comprehensive initial evaluations and more details on fertility/
fertility preservation and psychosocial assessments in AYA patients.
• The use of dexrazoxane as a cardioprotectant in combination with first-line therapy is not recommended in AYA patients >18 y.
• Consider toxicity of RT, particularly in young females with mediastinal disease.
• Younger AYA patients may be eligible to participate in pediatric clinical trials. See NCCN Guidelines for Pediatric Aggressive Mature B-Cell
Lymphomas.

Immunizations
• See NCCN Guidelines for Survivorship - General Principles of Immunizations.
• COVID-19 vaccination: See CDC for Use of COVID-19 Vaccines in the US.

Anti-Infective Prophylaxis
• Prophylaxis for Pneumocystis Jiroveci Pneumonia (PJP) and Varicella-Zoster Virus (VZV): See NCCN Guidelines for Prevention and
Treatment of Cancer-Related Infections.
• Pemivibart for pre-exposure prophylaxis of COVID-19 for individuals with moderate to severe immunocompromise

Hypogammaglobulinemia
• Patients receiving anti-CD20 mAb and CAR T-cell (CD19–directed) therapy may experience hypogammaglobulinemia. Patients with
recurrent infections may benefit from IVIG replacement.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
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SUPPORTIVE CARE FOR B-CELL LYMPHOMAS

Bone Health: Recommendations for Patients Who Have Received Steroid-Containing Regimensf,g,h,i
(in addition to standard recommendations for screening)
• Evaluation • Therapy
Vitamin D, 25-OH level If vitamin D 25-OH is deficient, then replete.
Post-treatment bone mineral density (BMD) evaluation (1 year ◊ In patients with lymphoma with current elevations in 1,25-dihydroxyvitamin D,
following therapy) deficient 25(OH)D levels should not be aggressively replaced.
◊ Greatest risk in patients with chemotherapy-induced Calcium intake from food (plus supplements if necessary) should be
premature menopause commensurate with National Academy of Medicine recommendations except
– If osteopenic (T-score between -1.1 and -2.4): in cases of lymphoma-induced hypercalciuria/hypercalcemia due to excessive
◊ Use Fracture Risk Assessment Tool (FRAX) to determine 1,25-dihydroxyvitamin D production.
if drug therapy is necessary (https://www.sheffield.ac.uk/ ◊ In patients receiving corticosteroid-containing chemotherapy regimens,
FRAX/) adequate calcium intake is of paramount importance since corticosteroids
▪ 20% risk for any major osteoporotic fracture or 3% risk block calcium absorption and increase fracture risk.k
for hip fracture are the thresholds where drug therapy Patients with osteoporotic BMD, with a history of hip or vertebral fractures,
is recommended or with asymptomatic vertebral compression deformity (as seen on CT scan
– If T-score -2 to -2.4 (at any site) or ongoing or other imaging) should be started on therapy as per National Osteoporosis
glucocorticoid exposure repeat BMD every 1–2 years, as Foundation guidelines; referral to an endocrinologist with expertise in bone
long as risk factors persist.j health is recommended.
– If T-score -1.5 to -1.9 (at any site) with no risk factors, ◊ In appropriate patients with premature menopause, hormone replacement
repeat BMD in 5 yearsg therapy up until the expected time of natural menopause, or raloxifene could
• Consider diagnosis of avascular necrosis (AVN) in patients be considered.
who have received corticosteroids presenting with hip pain. ◊ Bisphosphonates should be used as first-line pharmacologic treatment for
See NCCN Guidelines for Survivorship. osteoporosis.
◊ In patients who cannot tolerate or whose symptoms do not improve with
bisphosphonate therapy, denosumab is an effective alternative medication to
prevent osteoporotic fractures.
– Teriparatide is contraindicated in patients with a history of RT; also,
f Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness theoretical concerns in patients with a recent history of cancer exist.
of pharmacologic treatments to prevent fractures: an updated systematic
review. Ann Intern Med 2014;161:711-723.
g MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative
effectiveness of treatments to prevent fractures in men and women with low i Paccou L, Merlusca I, Henry-Desailly A, et al. Alterations in bone mineral density
bone density or osteoporosis. Ann Intern Med 2008;148:197-213. and bone turnover markers in newly diagnosed adults with lymphoma receiving
h Cummings SR, San Martin J, McClung MR, et al. Denosumab for
chemotherapy: a 1-year prospective pilot study. Ann Oncol 2014;25:481-486.
prevention of fractures in postmenopausal women with osteoporosis. N Engl j https://www.uptodate.com/contents/screening-for-osteoporosis?source=see_link.
J Med 2009;361:756-765. [published correction appears in N Engl J Med k Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids and risk of
2009;361:1914]. fractures. J Bone Miner Res 2005;20:1487-1494.

Note: All recommendations are category 2A unless otherwise indicated.

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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA

PET should be done with contrast-enhanced diagnostic CT and can be done simultaneously or at separate procedures.
Response Site PET-CT (Metabolic response) CT (Radiologic response)d
All of the following:
Lymph nodes and Score 1, 2, 3a with or without a residual mass on 5-point scale Target nodes/nodal masses must regress to ≤1.5 cm in
extralymphatic (5-PS)b,c longest transverse diameter of a lesion (LDi)
sites No extralymphatic sites of disease
Non-measured Not applicable Absent
Complete lesion
response Organ Not applicable Regress to normal
enlargement
New lesions None None
Normal by morphology; if indeterminate and flow
Bone marrow No evidence of FDG-avid disease in marrow cytometry IHC negative
All of the following:
Score 4 or 5b ≥50% decrease in SPD of up to 6 target measurable
with reduced uptake compared with baseline.
Lymph nodes and nodes and extranodal sites
No new progressive lesions.
extralymphatic When a lesion is too small to measure on CT, assign 5
At interim these findings suggest responding disease.
sites mm x 5 mm as the default value.
At end of treatment these findings may indicate residual When no longer visible, 0x0 mm
disease. For a node >5 mm x 5 mm, but smaller than normal, use
actual measurement for calculation
Non-measured Not applicable Absent/normal, regressed, but no increase
Partial lesion
response
Organ Spleen must have regressed by >50% in length beyond
Not applicable
enlargement normal
New lesions None None
Residual uptake higher than update in normal marrow but
reduced compared with baseline (diffuse uptake compatible
with reactive changes from chemotherapy allowed). If there
Bone marrow Not applicable
are persistent focal changes in the marrow in the content of
a nodal response, consider further evaluation with biopsy, or
an interval scan.

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA

PET should be done with contrast-enhanced diagnostic CT and can be done simultaneously or at separate procedures.
Response Site PET-CT (Metabolic response) CT (Radiologic response)d
Target nodes/ Score 4 or 5b with no significant change in FDG uptake <50% decrease from baseline in SPD of up to 6 dominant,
nodal masses, from baseline at interim or end of treatment. No new or measurable nodes and extranodal sites; no criteria for
extranodal lesions progressive lesions. progressive disease are met
No Non-measured Not applicable No increase consistent with progression
response lesion
or stable Organ
disease enlargement Not applicable No increase consistent with progression

New lesions None None

Bone marrow No change from baseline Not applicable
Requires at least one of the following
PPD progression:
An individual node/lesion must be abnormal with:
LDi >1.5 cm and
Score 4 or 5b with an increase in intensity of uptake Increase by ≥50% from PPD nadir and
Individual
target nodes/ from baseline An increase in LDi or SDi from nadir
nodal masses, and/or 0.5 cm for lesions ≤2 cm
extranodal lesions New FDG-avid foci consistent with lymphoma at interim 1.0 cm for lesions >2 cm
or end-of-treatment assessmente In the setting of splenomegaly, the splenic length must
increase by >50% of the extent of its prior increase beyond
baseline. If no prior splenomegaly, must increase by at least 2
Progressive cm from baseline
disease New or recurrent splenomegaly
Non-measured None New or clear progression of preexisting nonmeasured lesions
lesion
Regrowth of previously resolved lesions
New FDG-avid foci consistent with lymphoma rather A new node >1.5 cm in any axis
than another etiology (eg, infection, inflammation). If A new extranodal site >1.0 cm in any axis; if <1 cm in
New lesions any axis, its presence must be unequivocal and must be
uncertain regarding etiology of new lesions, biopsy or
interval scan may be considerede attributable to lymphoma
Assessable disease of any size unequivocally attributable to
lymphoma
Bone marrow New or recurrent FDG-avid foci New or recurrent involvement
Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

Continued

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-C
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LUGANO RESPONSE CRITERIA FOR NON-HODGKIN LYMPHOMA

Footnotes
a Score 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where de-
escalation is investigated, it may be preferable to consider score 3 as an inadequate response (to avoid under-treatment).
b See PET Five-Point Scale (5-PS).
c It is recognized that in Waldeyer’s ring or extranodal sites with high physiological uptake or with activation within spleen or marrow, e.g. with chemotherapy or
myeloid colony stimulating factors, uptake may be greater than normal mediastinum and/or liver. In this circumstance, CMR may be inferred if uptake at sites of initial
involvement is no greater than surrounding normal tissue even if the tissue has high physiological uptake.
d FDG-avid lymphomas should have response assessed by PET-CT. Diseases that can typically be followed with CT alone include CLL/SLL and marginal zone
lymphomas.
e False-positive PET scans may be observed related to infectious or inflammatory conditions. Biopsy of affected sites remains the gold standard for confirming new or
persistent disease at end of therapy.

PET Five-Point Scale (5-PS)

1 No uptake above background
2 Uptake ≤ mediastinum
3 Uptake > mediastinum but ≤ liver
4 Uptake moderately > liver
5 Uptake markedly higher than liver and/or new lesions
X New areas of uptake unlikely to be related to lymphoma

SPD – Sum of the product of the perpendicular diameters for multiple lesions
LDi – Longest transverse diameter of a lesion
SDi – Shortest axis perpendicular to the LDi
PPD – Cross product of the LDi and perpendicular diameter

Measured dominant lesions – Up to 6 of the largest dominant nodes, nodal masses and extranodal lesions selected to be clearly measurable in 2 diameters.
Nodes should preferably be from disparate regions of the body, and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal
lesions include those in solid organs, e.g., liver, spleen, kidneys, lungs, etc, gastrointestinal involvement, cutaneous lesions of those noted on palpation.

Non-measured lesions – Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These
sites include any nodes, nodal masses, and extranodal sites not selected as dominant, measurable or which do not meet the requirements for measurability,
but are still considered abnormal. As well as truly assessable disease which is any site of suspected disease that would be difficult to follow quantitatively
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses and other lesions that cannot be
confirmed and followed by imaging.
Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

Note: All recommendations are category 2A unless otherwise indicated.

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B-Cell Lymphomas Discussion

PRINCIPLES OF RADIATION THERAPY

General Principlesa
• Treatment with photons, electrons, or protons is appropriate depending upon clinical scenario.
• Advanced RT technologies such as intensity-modulated RT (IMRT)/volumetric modulated arc therapy (VMAT),1-4 proton therapy,3,5-9 breath-
hold10-12 or respiratory gating,13 and/or image-guided therapy12 may offer significant and clinically relevant advantages in specific instances
to spare organs at risk (OARs) such as the heart (including coronary arteries and valves), lungs,14,15 kidneys, liver, spinal cord, esophagus,
bone marrow, breasts, stomach, muscle/soft tissue, and salivary glands to decrease the risk for late, normal tissue toxicity while still
achieving the primary goal of local tumor control.
• Reducing dose to normal tissues reduces the risk of late complications. Achieving highly conformal dose distributions is especially
important for patients who are being treated with curative intent or who have long life expectancies following therapy.
• For mediastinal and abdominal lymphoma, respiratory motion management such as gating or breath-hold techniques may be advantageous.
Breath-hold techniques have been shown to decrease incidental dose to the heart and lungs in many disease presentations.10-12 Similarly,
for abdominal lymphomas, reduction in radiation exposures to heart, liver, and kidneys may be achieved by motion management
techniques.16
• Since the advantages of these techniques include tightly conformal doses and steep gradients next to normal tissues, target definition and
treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in tumor
control. Image guidance may be required to provide this assurance.
• Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which take
10+ years to evolve. In light of that, the modalities and techniques that best reduce the doses to the OARs in a clinically meaningful way
without compromising target coverage should be considered.
• Radiation Dose Constraints - Recommendations for normal tissue dose constraints can be found in the Principles of Radiation Therapy
section of the NCCN Guidelines for Hodgkin Lymphoma.

a See references on NHODG-D 4 of 4. Continued

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RADIATION THERAPYa

Volumes
• ISRT for nodal disease17
ISRT is the recommended approach for volume definition and treatment planning for NHL. Planning for ISRT requires CT-based treatment
planning and incorporates volume determinations including gross tumor volume (GTV), clinical target volume (CTV), and planning target
volume (PTV). Incorporating other imaging tests such as PET and MRI often enhances treatment volume determination.
The pre-chemotherapy or pre-biopsy GTV provides the basis for determining the CTV. Concerns for questionable subclinical disease and
uncertainties in original imaging accuracy or localization may lead to expansion of the CTV and are determined individually using clinical
judgment. Further, adjacent uninvolved organs (eg, lungs, bone, muscle, kidney) are excluded from the CTV when disease regresses
following chemotherapy.
For early-stage indolent NHL treated with RT alone, larger treatment volumes should be considered to encompass potential microscopic
disease in adjacent lymph nodes or the immediate vicinity. For example, the CTV definition for treating FL with RT alone will be greater than
that used for DLBCL with similar disease distribution, as the latter is treated with combined modality therapy.
Motion of the target caused by respiration as determined by 4D-CT or fluoroscopy (internal target volume [ITV]) should also influence the
final CTV.
The PTV is an additional expansion of the CTV that accounts only for setup variations and potential target motion not previously accounted
for in the CTV (see International Commission on Radiation Units and Measurements [ICRU] definitions). Proton RT planning does not
generally use a PTV, but rather robustness evaluation to ensure coverage of the CTV.
OARs should be outlined for dose-volume analysis and optimizing treatment planning decisions.
The treatment plan can be designed with conventional, 3D conformal, IMRT/VMAT, or proton therapy techniques using clinical treatment
planning considerations of target coverage and normal tissue avoidance.

• ISRT for extranodal disease18

Similar principles as for ISRT nodal sites (see above).
For EMZL, the CTV generally consists of the entire affected organ (eg, stomach, salivary gland, thyroid). Partial organ ISRT may be
appropriate if the disease is well localized on imaging (eg, orbit and breast).
For most NHL subtypes, uninvolved lymph nodes should not be targeted.

a See references on NHODG-D 4 of 4. Continued

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF RADIATION THERAPYa

General Dose Guidelines:
• Definitive RT (1.5–2.0 Gy daily fractions)
FL: 24–30 Gy19,20
Marginal zone lymphoma (MZL): 24 Gy
◊ EMZL of the stomach: 24 Gy in 16 fractions (1.5 Gy/fractions) to minimize acute GI toxicity.19
– 4 Gy in 2 fractions has been used.21 However, additional 20 Gy is needed for some patients and careful follow-up is needed.
◊ Orbital and salivary gland MZL: 4 Gy in 2 fractions may be considered as an alternative to 24 Gy. Careful regular follow-up (physical
exam and imaging as appropriate) with radiation oncologist and ophthalmologist is essential when using this very-low-dose regimen.
Definitive doses are recommended for incomplete response or relapsed disease.22,23
MCL:
◊ Primary treatment (without chemoimmunotherapy) - 36 Gy
◊ Consolidation after chemoimmunotherapy
– CR - 24–30 Gy
– PR - 36 Gy
DLBCL/HGBL/PMBL/MGZL
◊ Primary treatment (without chemoimmunotherapy): 40 Gy
◊ Consolidation after chemoimmunotherapy
– CR (5-PS 1–3) - 30–36 Gy
– PR (5-PS 4) - 36–50 Gy
◊ Refractory disease (5-PS 4–5) - 40–55 Gy
◊ In combination with HCT: 20–36 Gy, depending on sites of disease and prior RT exposure24; hypofractionate as appropriate to expedite
HCT procedure)
◊ Prophylactic testicular irradiation (25–30 Gy)

• Palliative RT
FL/MZL/MCL/SLL: 2 Gy X 2 fractions or 4 Gy X 1 fraction (which may be repeated as needed); doses up to 30 Gy may be appropriate in
select circumstances
DLBCL/HGBL/PMBL/MGZL and BL: (higher doses/fraction typically appropriate)
◊ 20–30 Gy in 5–10 fractions. Standard hypofractionated palliative treatment schedules such as 20 Gy in 5 fractions and 30 Gy in 10
fractions are appropriate depending upon clinical scenario.
HIV-related B-cell lymphomas and PTLD: Treated based on underlying histologic subtype and treatment intent (curative vs. palliative)

• Bridging RT with CAR T-cell Therapy

Localized disease - 20–40 Gy (higher doses and comprehensive coverage preferred if feasible; hypofractionate as appropriate to
expedite CAR T-cell procedure)
Extensive disease - 20–30 Gy (hypofractionate as outlined above)
a See references on NHODG-D 4 of 4.

Note: All recommendations are category 2A unless otherwise indicated.

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18 Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J
Radiat Oncol Biol Phys 2015;92:11-31.
19 Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol
2014;15:457-463.
20 Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: A randomised phase III trial. Radiother Oncol 2011;100:86-92.
21 Gunther JR, Xu J, Bhutani MS, et al. Response-adapted ultra-low-dose 4 Gy radiation as definitive therapy of gastric MALT lymphoma: a single-centre, pilot trial. Lancet Haematol
2024;11:e521-e529.
22 Fasola CE, Jones JC, Huang DD, et al. Low-dose radiation therapy (2 Gy x 2) in the treatment of orbital lymphoma. Int J Radiat Oncol Biol Phys 2013;86:930-935.
23 Pinnix CC, Dabaja BS, Milgrom SA, et al. Ultra-low-dose radiotherapy for definitive management of ocular adnexal B-cell lymphoma. Head Neck 2017;39:1095-1100.
24 Ng AK, Yahalom J, Goda JS, et al. Role of radiation therapy in patients with relapsed/refractory diffuse large B-cell lymphoma: Guidelines from the International Lymphoma Radiation
Oncology Group. Int J Radiat Oncol Biol Phys 2018;100:652-669.

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-D
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GUIDANCE FOR TREATMENT OF PATIENTS WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY

Axicabtagene ciloleucel NHODG-E 1 of 4

Brexucabtagene autoleucel NHODG-E 2 of 4

Lisocabtagene maraleucel NHODG-E 3 of 4

Tisagenlecleucel NHODG-E 4 of 4

Note: All recommendations are category 2A unless otherwise indicated.

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Diffuse Large B-Cell Lymphoma Discussion

GUIDANCE FOR TREATMENT OF PATIENTS WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY
Axicabtagene ciloleucela
• Health care facilities that dispense and administer axicabtagene ciloleucel must be enrolled and comply with the Risk Evaluation and
Mitigation Strategies (REMS) requirements. See REMS for axicabtagene ciloleucel.
• Cytokine release syndrome (CRS) management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of
Immunotherapy-Related Toxicities
• Neurologic toxicity management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related
Toxicities
• Prolonged cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and axicabtagene ciloleucel infusion.
• Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with axicabtagene ciloleucel.
• Secondary malignancies may develop. Monitor life-long for secondary malignancies.

a Prescribing information for axicabtagene ciloleucel is available at: https://www.fda.gov/media/108377/download

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-E
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GUIDANCE FOR TREATMENT OF PATIENTS WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY
Brexucabtagene autoleucelb
• Health care facilities that dispense and administer brexucabtagene autoleucel must be enrolled and comply with the REMS requirements.
See REMS for brexucabtagene autoleucel.
• CRS management - See CAR T-Cell-Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities
• Neurologic toxicity management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related
Toxicities
• Hypersensitivity reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or
residual gentamicin in brexucabtagene autoleucel.
• Severe infections: Severe or life-threatening infections occurred in patients after brexucabtagene autoleucel infusion. Monitor patients for
signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local
guidelines.
• Prolonged cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and brexucabtagene autoleucel infusion.
• Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with brexucabtagene autoleucel.
• Secondary malignancies may develop. Monitor life-long for secondary malignancies.

b Prescribing information for brexucabtagene autoleucel is available at: https://www.fda.gov/media/140409/download

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-E
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Diffuse Large B-Cell Lymphoma Discussion

GUIDANCE FOR TREATMENT OF PATIENTS WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY
Lisocabtagene maraleucelc
• Health care facilities that dispense and administer lisocabtagene maraleucel must be enrolled and comply with the REMS requirements. See
REMS for lisocabtagene maraleucel.
• CRS management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities
• Neurologic toxicity management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related
Toxicities
• Prolonged cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and lisocabtagene maraleucel infusion.
• Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients with a complete remission after lisocabtagene maraleucel infusion.
• Secondary malignancies may develop. Monitor life-long for secondary malignancies.

c Prescribing information for lisocabtagene maraleucel is available at: https://www.fda.gov/media/145711/download

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-E
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Diffuse Large B-Cell Lymphoma Discussion

GUIDANCE FOR TREATMENT OF PATIENTS WITH CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY
Tisagenlecleuceld
• Health care facilities that dispense and administer tisagenlecleucel must be enrolled and comply with the REMS requirements. See REMS for
tisagenlecleucel.
• CRS management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related Toxicities
• Neurologic toxicity management - See CAR T-Cell–Related Toxicities in the NCCN Guidelines for Management of Immunotherapy-Related
Toxicities
• Prolonged cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and tisagenlecleucel infusion.
• Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients with a complete remission after tisagenlecleucel infusion.
• Secondary malignancies may develop. Monitor life-long for secondary malignancies.

d Prescribing information for tisagenlecleucel is available at: https://www.fda.gov/media/107296/download

Note: All recommendations are category 2A unless otherwise indicated.

NHODG-E
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B-Cell Lymphomas Discussion

Classification
Table 1
The International Consensus Classification (ICC) of WHO Classification of Hematolymphoid Tumors:
Mature Lymphoid Neoplasms (2022) Lymphoid Neoplasms (2024; 5th edition)
Mature B-cell lymphomas Mature B-cell lymphomas
Pre-neoplastic and neoplastic small lymphocytic proliferations
Monoclonal B-cell lymphocytosis
• Chronic lymphocytic leukemia type Monoclonal B-cell lymphocytosis
• Non-chronic lymphocytic leukemia type
Chronic lymphocytic leukemia/small lymphocytic lymphoma Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia Not included
Splenic B-cell lymphomas and leukemias
Hairy cell leukemia Hairy cell leukemia
Splenic marginal zone lymphoma Splenic marginal zone lymphoma
Splenic B-cell lymphoma/leukemia, unclassifiable Splenic diffuse red pulp small B-cell lymphoma
• Splenic diffuse red pulp small B-cell lymphoma
• Hairy cell leukemia-variant Splenic B-cell lymphoma/leukemia with prominent nucleoli
Lymphoplasmacytic lymphoma
Lymphoplasmacytic lymphoma
Lymphoplasmacytic lymphoma
• Waldenström macroglobulinemia
Marginal zone lymphoma
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue
(MALT lymphoma)
Primary cutaneous marginal zone lymphoproliferative disorder Primary cutaneous marginal zone lymphoma
Nodal marginal zone lymphoma Nodal marginal zone lymphoma
• Pediatric nodal marginal zone lymphoma Pediatric nodal marginal zone lymphoma

Continued

Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory
Committee. Blood 2022;140:1229-1253.
WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France):
International Agency for Research on Cancer; 2024.

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B-Cell Lymphomas Discussion

Classification
Table 1

The International Consensus Classification (ICC) of WHO Classification of Hematolymphoid Tumors:

Mature Lymphoid Neoplasms (2022) Lymphoid Neoplasms (2024; 5th edition)
Mature B-cell lymphomas Mature B-cell lymphomas
Follicular lymphoma
• Follicular Lymphoma (FL) grades 1, 2, 3A • Classic FL (cFL)
• FL grade 3B • Follicular large B-cell lymphoma (FLBCL)
• Not Included • Follicular lymphoma with unusual cytological features (ucFL)
• In situ follicular neoplasia • In situ follicular B-cell neoplasm
• Duodenal-type follicular lymphoma • Duodenal-type follicular lymphoma
Pediatric-type follicular lymphoma Pediatric-type follicular lymphoma
BCL2-R negative, CD23-positive follicle center lymphoma FL with predominantly diffuse growth pattern (dFL)
Testicular follicular lymphoma Not included
Mantle cell lymphoma
Mantle cell lymphoma Mantle cell lymphoma
• In situ mantle cell neoplasia In situ mantle cell neoplasm
• Leukemic non-nodal mantle cell lymphoma Leukaemic non-nodal mantle cell lymphoma
Transformations of indolent B-cell lymphomas
Not included Transformations of indolent B-cell lymphomas

Continued

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Table of Contents
B-Cell Lymphomas Discussion

Classification
Table 1
The International Consensus Classification (ICC) of WHO Classification of Hematolymphoid Tumors:
Mature Lymphoid Neoplasms (2022) Lymphoid Neoplasms (2024; 5th edition)
Mature B-cell lymphomas Mature B-cell lymphomas
Large B-cell lymphomas
Diffuse large B-cell lymphoma, NOS
• Germinal center B-cell Diffuse large B-cell lymphoma, NOS
• Activated B-cell
High-grade B-cell lymphoma with MYC and BCL6 rearrangements Not included
Diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2
High-grade B-cell lymphoma with MYC and BCL2 rearrangements
rearrangements
High-grade B-cell lymphoma, NOS High-grade B-cell lymphoma, NOS
T-cell/histiocyte-rich large B-cell lymphoma T-cell/histiocyte-rich large B-cell lymphoma
ALK-positive large B-cell lymphoma ALK-positive large B-cell lymphoma
Large B-cell lymphoma with IRF4 rearrangement Large B-cell lymphoma with IRF4 rearrangement
Large B-cell lymphoma with 11q aberration High-grade B-cell lymphoma with 11q aberrations
See Lymphoid proliferations and lymphomas associated with immune deficiency and
Epstein-Barr virus–positive mucocutaneous ulcer
dysregulation
EBV-positive diffuse large B-cell lymphoma, NOS EBV-positive diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma associated with chronic inflammation Diffuse large B-cell lymphoma associated with chronic inflammation
• Fibrin-associated diffuse large B-cell lymphoma Fibrin-associated large B-cell lymphoma
HHV8 and EBV-negative primary effusion-based lymphoma Fluid overload-associated large B-cell lymphoma
Lymphomatoid granulomatosis Lymphomatoid granulomatosis
Plasmablastic lymphoma Plasmablastic lymphoma

Primary DLBCL of the central nervous system Primary large B-cell lymphoma of immune-privileged sites
• Primary LBCL of the CNS
• Primary LBCL of the vitreoretina
Primary DLBCL of the testis • Primary LBCL of the testis
Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, leg type
Intravascular large B-cell lymphoma Intravascular large B-cell lymphoma
Primary mediastinal large B-cell lymphoma Primary mediastinal large B-cell lymphoma
Mediastinal grey zone lymphoma Mediastinal grey zone lymphoma
Continued ST-3
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B-Cell Lymphomas Discussion

Posttransplant lymphoproliferative disorders Hyperplasias arising in immune deficiency/dysregulation

• Nondestructive posttransplant lymphoproliferative disorders
Plasmacytic hyperplasia posttransplant lymphoproliferative disorder Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation
Infectious mononucleosis posttransplant lymphoproliferative disorder
Florid follicular hyperplasia posttransplant lymphoproliferative disorder
EBV-positive mucocutaneous ulcer
• Polymorphic posttransplant lymphoproliferative disorder
• Monomorphic posttransplant lymphoproliferative disorder (B-cell and T-cell/
NK-cell types) Lymphomas arising in immune deficiency / dysregulation
• Classic Hodgkin lymphoma posttransplant lymphoproliferative disorder
Other iatrogenic immunodeficiency-associated lymphoproliferative disorders Inborn error of immunity-associated lymphoid proliferations and lymphomas
Tumour-like lesions with B-cell predominance
Not included Reactive B-cell-rich lymphoid proliferations that can mimic lymphoma
Not included IgG4-related disease
Not included Unicentric Castleman disease
See HHV8-associated lymphoproliferative disorders Idiopathic multicentric Castleman disease
See HHV8-associated lymphoproliferative disorders KSHV/HHV8-associated multicentric Castleman disease
Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory
Committee. Blood 2022;140:1229-1253. Continued
WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. (WHO classification of tumours series, 5th ed; vol 11). Lyon (France):
International Agency for Research on Cancer; 2024.
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B-Cell Lymphomas Discussion

Staging
Lugano Modification of Ann Arbor Staging System*
(for primary nodal lymphomas)
Stage Involvement Extranodal (E) status
Limited
Stage I One node or a group of Single extranodal lesions
adjacent nodes without nodal involvement
Stage II Two or more nodal groups Stage I or II by nodal extent
on the same side of the with limited contiguous
diaphragm extranodal involvement
Stage II bulky** II as above with “bulky” Not applicable
disease
Advanced
Stage III Nodes on both sides of Not applicable
the diaphragm
Nodes above the diaphragm
with spleen involvement
Stage IV Additional non-contiguous Not applicable
extralymphatic involvement

*Extent of disease is determined by PET-CT for avid lymphomas, and CT for non-avid histologies.
Note: Tonsils, Waldeyer’s ring, and spleen are considered nodal tissue.
**Whether II bulky is treated as limited or advanced disease may be determined by histology and a number of prognostic factors.

Categorization of A versus B has been removed from the Lugano Modification of Ann Arbor Staging.

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved. Cheson B, Fisher R, Barrington S, et al. Recommendations for initial
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

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B-Cell Lymphomas Discussion

ABBREVIATIONS
3D-CRT 3-dimensional conformal radiation ctDNA circulating tumor DNA HBcAb hepatitis B core antibody
therapy CTV clinical target volume HBsAg hepatitis B surface antigen
4D-CT four-dimensional computed tomography HBV hepatitis B virus
5-PS five-point scale DAA direct-acting antiviral HCL hairy cell leukemia
dFL FL with predominantly diffuse growth HCT hematopoietic cell transplant
ABC activated B-cell pattern
HCV hepatitis C virus
ALCL anaplastic large cell lymphoma DLBCL diffuse large B-cell lymphoma
ANC absolute neutrophil count DMSO dimethyl sulfoxide HDT high-dose therapy
ART antiretroviral therapy HGBL high-grade B-cell lymphoma
ASCR autologous stem cell rescue EBER Epstein-Barr virus-encoded RNA HHV8 human herpesvirus 8
AVN avascular necrosis EBER- Epstein-Barr virus-encoded RNA in HIV human immunodeficiency virus
ISH situ hybridization H&P history and physical
AYA adoloescent and young adult
EBV Epstein-Barr virus
EMZL extranodal marginal zone lymphoma ICC International Consensus
B-ALL B-cell acute lymphoblastic leukemia
Classification
BL Burkitt lymphoma
FDC follicular dendritic cell ICRU International Commission on
BMD bone mineral density Radiation Units and Measurements
FFS failure-free survival
BPDC blastic plasmacytoid dendritic cell Ig immunoglobulin
FISH fluorescence in situ hybridization
BTKi BTK inhibitor IHC immunohistochemistry
FL follicular lymphoma
BUN blood urea nitrogen IMRT intensity-modulated radiation
FLBCL follicular large B-cell lymphoma therapy
FNA fine-needle aspiration IMH infectious mononucleosis-like
C/A/P chest/abdomen/pelvis
FRAX Fracture Risk Assessment Tool hyperplasia
CAR chimeric antigen receptor
IPI International Prognostic Index
CBC complete blood count
G6PD glucose-6-phosphate dehydrogenase ISRT involved-site radiation therapy
cFL classic follicular lymphoma
GC germinal center IT intrathecal
CHL classic Hodgkin lymphoma
GI gastrointestinal ITV internal target volume
CLL chronic lymphocytic leukemia
GCB germinal center B-cell IVF in vitro fertilization
CMV cytomegalovirus
G-CSF granulocyte colony-stimulating factor IVIG intravenous immunoglobulin
CNS central nervous system
CR complete response GTV gross tumor volume

CRS cytokine release syndrome

NCCN Guidelines Version 3.2025 NCCN Guidelines Index

Table of Contents
B-Cell Lymphomas Discussion

ABBREVIATIONS

JCV John Cunningham virus PC- primary cutaneous diffuse large B-cell SDi shortest axis perpendicular to the LDi
DLBCL lymphoma
SLL small lymphocytic lymphoma
PCFCL primary cutaneous follicle center
KS Kaposi sarcoma smIPI stage modified International
lymphoma
KSHV Kaposi sarcoma-associated herpesvirus Prognostic Index
PCH plasmacytic hyperplasia
SMZL splenic marginal zone lymphoma
PCMZL primary cutaneous marginal zone
LANA latency-associated nuclear antigen SPD sum of product of greatest
lymphoma perpendicular diameters
LBCL large B-cell lymphoma PCR polymerase chain reaction SPEP serum protein electrophoresis
LDH lactate dehydrogenase PEL primary effusion lymphoma
LDi longest transverse diameter of a lesion PFS progression-free survival
T-ALL T-cell acute lymphoblastic leukemia
PJP pneumocystis jirovecii pneumonia
LL lymphoblastic lymphoma T-LL T-cell lymphoblastic leukemia
PMBL primary mediastinal large B-cell
LPL lymphoplasmacytic lymphoma TLS tumor lysis syndrome
lymphoma
PML progressive multifocal
mAb monoclonal antibody leukoencephalopathy ULN upper limit of normal
PPD cross product of the LDi and
MCL mantle cell lymphoma
perpendicular diameter
MF mycosis fungoides VMAT volumetric modulated arc therapy
PR partial response
MGZL mediastinal gray zone lymphoma VZV varicella zoster virus
PTCL peripheral T-cell lymphoma
MRD minimal residual disease PTFL pediatric-type follicular lymphoma
MUGA multigated acquisition WBC white blood cell
PTLD posttransplant lymphoproliferative
MZL marginal zone lymphoma disorders WM Waldenström macroglobulinemia
PTV planning target volume
NGS next-generation sequencing
NHL non-Hodgkin lymphoma REMS risk evaluation and mitigation
NK natural killer strategy

NOS not otherwise specified RI reduction of immunosuppression

NMZL nodal marginal zone lymphoma

NR no response

OAR organ(s) at risk

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Table of Contents
B-Cell Lymphomas Discussion

NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is
uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the
intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but <85% support of the Panel) that the
intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

NCCN Guidelines Version 3.2025

B-Cell Lymphomas

Discussion This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. Last updated: August 18, 2025.

Overview .............................................................................................................................................................................................................. MS-2

Guidelines Update Methodology ........................................................................................................................................................................... MS-2
Sensitive/Inclusive Language Usage .................................................................................................................................................................... MS-3
Supportive Care ................................................................................................................................................................................................... MS-7
Follicular Lymphoma .......................................................................................................................................................................................... MS-22
Marginal Zone Lymphomas ................................................................................................................................................................................ MS-55
Mantle Cell Lymphoma ....................................................................................................................................................................................... MS-81
Diffuse Large B-Cell Lymphomas...................................................................................................................................................................... MS-110
ALK-Positive Large B-Cell Lymphomas............................................................................................................................................................. MS-130
Mediastinal Gray Zone Lymphomas .................................................................................................................................................................. MS-131
Primary Mediastinal Large B-Cell Lymphoma .................................................................................................................................................... MS-148
Histologic Transformation of Indolent Lymphomas to DLBCL .................................................................................. MS-156
High-Grade B-Cell Lymphomas ........................................................................................................................................................................ MS-165
Burkitt Lymphoma ............................................................................................................................................................................................ MS-173
HIV-Related B-Cell Lymphomas ....................................................................................................................................................................... MS-184
Post-Transplant Lymphoproliferative Disorders ................................................................................................................................................. MS-199

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NCCN Guidelines Version 3.2025

B-Cell Lymphomas
This discussion corresponds to the NCCN Guidelines for B-Cell Lymphomas. developed as a result of meetings convened by a multidisciplinary Panel of
Last updated: August 18, 2025.
experts, with the aim to provide recommendations for diagnostic workup,
Overview treatment, and surveillance strategies for the most common subtypes of B-
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of cell lymphomas, in addition to a general discussion on the classification
lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, systems and supportive care considerations.
or natural killer (NK) cells (NK/T-cell lymphomas are very rare). In 2025,
The most common subtypes that are covered in the NCCN Guidelines® for
an estimated 80,350 people will be diagnosed with NHL and there will be
B-Cell Lymphomas are listed below:
approximately 19,390 deaths due to the disease.1 Diffuse large B-cell
lymphoma (DLBCL; 32%), follicular lymphoma (FL; 17%), marginal zone • Follicular lymphoma (FL)
lymphoma (MZL; 8%) and mantle cell lymphoma (MCL; 4%), were the • Marginal zone lymphomas (MZLs)
major subtypes of B-cell lymphomas diagnosed in the United States ◊ Extranodal marginal zone lymphoma (EMZL) of the stomach
between 1998 and 2011.2 ◊ EMZL of non-gastric sites (noncutaneous)
◊ Nodal MZL
In 2020, an estimated 544,000 people were diagnosed with NHL
◊ Splenic MZL
worldwide, and approximately 260,000 people died from the disease.3 The
• Mantle cell lymphoma (MCL)
incidence of NHL has declined worldwide, and mortality rates have also
• Diffuse large B-cell lymphoma (DLBCL)
decreased since 2000 with the introduction of anti-CD20 monoclonal
antibody (mAb), rituximab.4 However, the mortality rates continue to be • ALK-positive large B-cell lymphomas
higher in regions with limited resources, mainly related to the prevalence • Mediastinal gray zone lymphomas (MGZL)
and distribution of underlying risk factors, and level of access to diagnostic • Primary mediastinal large B-cell lymphoma (PMBL)
techniques and treatment approaches.3 • Histologic transformation of indolent lymphomas to DLBCL
• High-grade B-cell lymphomas (HGBL)
NHL (along with Kaposi sarcoma [KS], and lung cancer) are the most • Burkitt lymphoma (BL)
common cancer types diagnosed in people with human • HIV-related B-cell lymphomas
immunodeficiency virus (HIV) in the United States, with the largest • Post-transplant lymphoproliferative disorders (PTLD)
declines in incidence rates are projected for NHL and KS through
2030.5,6 DLBCL, Burkitt lymphoma (BL), and primary central nervous Guidelines Update Methodology
system lymphoma (PCNSL) are the most common subtypes of B-cell The complete details of the Development and Update of the NCCN
lymphomas in people with HIV (PWH).7 Guidelines are available at www.NCCN.org.
The National Comprehensive Cancer Network (NCCN®) Clinical Practice
Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas were

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Sensitive/Inclusive Language Usage defining specific subtypes. In addition, detection of viruses, particularly
Epstein-Barr virus (EBV), HHV8, and HTLV1, is often necessary to
NCCN Guidelines strive to use language that advances the goals of
establish a specific diagnosis. The WHO Classification was revised in
equity, inclusion, and representation. NCCN Guidelines endeavor to use
2008, 2017, and 2022 to include new disease entities and better define
language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-
some of the heterogeneous and ambiguous subtypes, based on the
misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive
evolving genetic and molecular landscape of various subtypes of B-cell
of individuals of all sexual orientations and gender identities. NCCN
lymphomas.8-10
Guidelines incorporate non-gendered language, instead focusing on
organ-specific recommendations. This language is both more accurate In 2022, in addition to the newly revised WHO Classification of
and more inclusive and can help fully address the needs of individuals of Hematolymphoid Tumors (WHO5),10 another new classification system
all sexual orientations and gender identities. NCCN Guidelines will known as International Consensus Classification (ICC) was also
continue to use the terms men, women, female, and male when citing published.11 While both the ICC and WHO5 continue to classify the
statistics, recommendations, or data from organizations or sources that do lymphomas based on morphology, clinical features, cell lineage
not use inclusive terms. Most studies do not report how sex and gender (immunophenotype), and cytogenetic and molecular features, there are
data are collected and use these terms interchangeably or inconsistently. differences between the two classifications in terms of nomenclature and
If sources do not differentiate gender from sex assigned at birth or organs diagnostic criteria. These are discussed under the respective subtypes of
present, the information is presumed to predominantly represent cisgender B-cell lymphomas.
individuals. NCCN encourages researchers to collect more specific data in
future studies and organizations to use more inclusive and accurate Diagnosis
language in their future analyses. An accurate pathologic diagnosis of the subtype is the most important
first step in the management of B-cell lymphomas. The basic pathologic
Classification
evaluation is the same for each subtype, although some further
The 2001 World Health Organization (WHO) Classification of evaluation may be useful in certain circumstances to clarify a particular
Hematopoietic and Lymphoid Neoplasms represented the first diagnosis; these are outlined in the pathologic evaluation of the
international consensus on classification of hematologic malignancies. individual Guidelines.
After consideration of cell lineage (B, T, or NK), the classification
subdivided lymphoid neoplasms into precursor versus mature lymphomas. An excisional or incisional lymph node biopsy is preferred for the definitive
The classification was further refined based on clinical, cytogenetic, and diagnosis and histologic grading of B-cell lymphomas. Fine-needle
molecular features to aid in defining the diagnosis of specific subtypes of aspiration (FNA) biopsy alone is insufficient for the initial diagnosis or
lymphomas. histologic grading of lymphoma but can be a valuable method for the initial
screening of enlarged lymph nodes.12-15 Core needle biopsy (multiple
Cytogenetic features detected by karyotype or fluorescence in situ biopsies preferred) is an appropriate alternative to excisional or incisional
hybridization (FISH) and molecular analysis are increasingly important in

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biopsy especially when a clinical situation dictates that this is the only safe in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms in
means of obtaining diagnostic tissue (ie, when a lymph node is not easily the algorithm.
accessible for excisional or incisional biopsy or if surgical biopsy would
cause significant morbidity or substantial treatment delays). In such Workup
instances, a combination of core needle biopsy (multiple biopsies Essential workup procedures include a complete physical exam with
preferred) and FNA biopsies in conjunction with appropriate ancillary particular attention to node-bearing areas and the size of liver and
techniques (immunohistochemistry [IHC], flow cytometry, karyotype or spleen, symptoms present, performance status, and laboratory studies
fluorescence in-situ hybridization [FISH], and molecular studies) may be including complete blood count (CBC), serum lactate dehydrogenase
sufficient for the differential diagnosis.16-20 (LDH), hepatitis B virus (HBV) testing (see below), comprehensive
metabolic panel, and chest/abdomen/pelvis CT with oral and intravenous
Next-generation sequencing (NGS) can be used if a high suspicion of a contrast (unless coexistent renal insufficiency). Multigated acquisition
clonal process remains and other techniques have not resulted in a clear (MUGA) scan or echocardiograms are recommended when
identification of a clonal process. anthracyclines and anthracenedione-containing regimens are used.

Hematopathology review of all slides (with at least one paraffin block HBV reactivation (resulting in liver failure and death) has been reported
representative of the tumor) is recommended. Rebiopsy of lymph node with anti-CD20 mAb-based regimens.22 HBV carriers with lymphoid
(preferably the most fluorodeoxyglucose [FDG]-avid, accessible lymph malignancies have a high risk of HBV reactivation and disease, especially
node) should be done if consult material is nondiagnostic. those treated with anti-CD20 mAb-based regimens.23 The Panel has
included testing for hepatitis B surface antigen (HBsAg) and hepatitis B
Immunophenotyping is essential for the differentiation of various
core antibody (HBcAb) as part of essential workup prior to initiation of
subtypes of B-cell lymphomas to establish the proper diagnosis. It can be
treatment in all patients who will receive anti-CD20 mAb-based
performed by flow cytometry and/or IHC; the choice depends on the
regimens. See Hepatitis B Virus Reactivation in the Supportive Care
antigens as well as the expertise and resources available to the
section.
hematopathologist.21 Cytogenetic or molecular genetic analysis may be
necessary under certain circumstances to identify chromosomal Large population-based or multicenter case-control studies have
rearrangements or gene mutations that are characteristic of some demonstrated a strong association between seropositivity for hepatitis C
subtypes of B-cell lymphomas or to establish clonality. virus (HCV) and the development of B-cell lymphomas.24-31 The
prevalence of HCV seropositivity was consistently increased among
The NCCN Guidelines Panel developed a series of algorithms for the
patients with DLBCL and MZL.24,25,29,30 HCV testing is needed in patients
use of immunophenotyping and genetic testing to provide guidance for
with high-risk disease and in patients with splenic MZL. See Hepatitis C
surgical pathologists and clinicians in the interpretation of pathology
Virus-Associated B-Cell Lymphomas in the Supportive Care section.
reports. These algorithms should be used in conjunction with clinical and
pathologic correlation. See Use of Immunophenotyping/Genetic Testing

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Optional workup procedures (depending on specific lymphoma type) (FDG)-avid lymphomas.38,39 PET/CT is particularly important for staging
include beta-2-microglobulin, CT or PET/CT scans, endoscopic before consideration of radiation therapy (RT), and baseline PET/CT will
ultrasound, head CT, or brain MRI and lumbar puncture to analyze aid in the interpretation of post-treatment response evaluation based on
cerebrospinal fluid (CSF). Discussion of fertility issues and sperm the 5-point scale (5-PS) as described below.39
banking should be addressed in the appropriate circumstances.32
Response Assessment
Role of PET Scans The guidelines for response criteria for lymphoma, first published in 1999
Staging by the International Working Group (IWG), were revised in 2007 by the
PET has a high positivity and specificity when used for the staging and International Harmonization Project to incorporate IHC, flow cytometry,
restaging of lymphoma.33 PET is nearly universally positive at diagnosis and PET scans in the definition of response for lymphoma.40,41 In the
in DLBCL, FL, and nodal MZL, but less sensitive for extranodal MZL.34,35 revised guidelines, the response category of complete response uncertain
However, a number of benign conditions including sarcoid, infection, and (CRu) was essentially eliminated and response is categorized as complete
inflammation can result in false-positive PET scans, complicating the response (CR), partial response (PR), stable disease (SD), and relapsed
interpretation. Lesions <1 cm are not reliably visualized with PET scans. disease or progressive disease (PD) based on the result of a PET scan.
Although PET scans may detect additional disease sites at diagnosis,
In 2014, revised response criteria, known as the Lugano response
the clinical stage is modified only in 15% to 20% of patients and a
criteria, were introduced for response assessment using PET/CT scans
change in treatment in only 8% of patients.
according to the 5-PS.38,39 The 5-PS is based on the visual assessment
The combined PET/CT scans have distinct advantages in both staging of FDG uptake in the involved sites relative to that of the mediastinum
and restaging compared to full-dose diagnostic CT or PET alone.36,37 In a and the liver.42-44 A score of 1 denotes no abnormal FDG avidity, while a
retrospective study, PET/CT performed with low-dose non– score of 2 represents uptake less than the mediastinum. A score of 3
contrast-enhanced CT was found to be more sensitive and specific than denotes uptake greater than the mediastinum but less than the liver,
contrast-enhanced CT for the evaluation of lymph node and organ while scores of 4 and 5 denote uptake greater than the liver, and greater
involvement in patients with Hodgkin lymphoma or high-grade B-cell than the liver with new sites of disease, respectively. Different clinical
lymphomas.36 Preliminary results of a prospective study (47 patients; trials have considered scores of either 1 to 2 or 1 to 3 to be
patients who had undergone prior diagnostic CT were excluded) also PET-negative, but a score of 1 to 3 is now widely considered to be PET
showed a good correlation between low-dose non–contrast-enhanced negative. Scores of 4 to 5 are universally considered PET positive. A
PET/CT and full-dose contrast-enhanced PET/CT for the evaluation of score of 4 on an interim or end-of-treatment restaging scan may be
lymph nodes and extranodal disease in lymphomas.37 consistent with a PR if the FDG avidity has declined from initial staging,
while a score of 5 denotes PD.
PET/CT should be done with contrast-enhanced diagnostic CT and is
recommended for initial staging and restaging of all fluorodeoxyglucose However, the application of PET/CT to response assessment is limited to
FDG-avid lymphomas and the revised response criteria have thus far

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only been validated for DLBCL and Hodgkin lymphoma. The application This is especially important for patients being treated with curative intent
of the revised response criteria to other histologies requires validation or who have long life expectancies following therapy.
and the original IWG guidelines should be used.40,41 False-positive PET
scans may be observed related to infectious or inflammatory conditions. Randomized prospective studies to test these concepts are unlikely to be
Biopsy of affected sites remains the gold standard for confirming new or done since these techniques are designed to decrease late effects, which
persistent disease at end of treatment (EOT). usually develop ≥10 years after completion of treatment. Therefore, the
guidelines recommend that RT delivery techniques that are found to best
Principles of Radiation Therapy reduce RT dose to OAR in a clinically meaningful manner without
RT can be delivered with photons, electrons, or protons, depending upon compromising target coverage should be considered.
clinical circumstances.45 Advanced RT techniques emphasize tightly
Involved-site RT (ISRT) is recommended as the appropriate field for B-cell
conformal doses and steep gradients next to organs at risk (OAR).
lymphomas as it limits the radiation exposure to adjacent uninvolved
Therefore, accurate target delineation and careful monitoring of treatment
organs (such as lungs, bone, muscle, or kidney) when lymphadenopathy
delivery are critical to avoid the risk of underdosing the clinical target
regresses following chemotherapy, thus minimizing the potential long-term
volume (CTV) and subsequent decrease in tumor control. Image guidance
complications.59,60 ISRT targets the initially involved nodal and extranodal
may be required to facilitate accurate treatment delivery.
sites detectable at presentation.59,60 Larger RT fields utilizing elective
Preliminary results from single-institution studies have shown that nodal irradiation should be considered for limited-stage indolent B-cell
significant dose reduction to OAR (eg, lungs, heart, breasts, kidneys, lymphomas, often treated with RT alone.59
spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle,
Treatment planning for ISRT requires the use of CT-based simulation. The
soft tissue, and salivary glands) can be achieved with advanced RT
incorporation of additional imaging techniques such as PET and MRI often
planning and delivery techniques such as 4D-CT simulation, image-guided
improves the accuracy of treatment planning. The OAR should be outlined
RT, intensity-modulated RT (IMRT)/volumetric modulated arc therapy
for optimizing treatment plan decisions. The treatment plan is designed
(VMAT), and proton therapy.46-54 In mediastinal and abdominal lymphoma,
using conventional, 3D conformal, or IMRT/VMAT techniques using
the use of respiratory motion management techniques such as respiratory
clinical treatment planning considerations of coverage and dose
gating or breath-hold techniques, and image-guided RT have been shown
reductions for OAR.59
to decrease incidental dose to OAR such lung, heart, liver, and kidneys.55-
58
The principles of ISRT are similar for both nodal and extranodal disease.
The gross tumor volume (GTV) defined by radiologic imaging prior to
Thus, the use of advanced RT and motion management techniques offer
biopsy, chemotherapy, or surgery provides the basis for determining the
significant and clinically relevant advantages in specific instances to spare
CTV.61 Possible movement of the target by respiration as determined by
OAR and reduce the risk of late complications from normal tissue damage.
4D-CT or fluoroscopy should also influence the final CTV. Larger CTV
should be considered for the treatment of early-stage indolent B-cell

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lymphomas treated with RT alone to encompass potential microscopic cardiac arrhythmias, seizures, loss of muscle control, acute renal failure,
disease in adjacent lymph nodes or the immediate vicinity. The planning and even death.
treatment volume (PTV) is an additional expansion of the CTV that
accounts only for setup variations. In the case of extranodal disease, TLS is best managed if anticipated and when treatment is started prior to
particularly for MZL, the whole organ comprises the CTV in some chemoimmunotherapy. Histologies of BL, lymphoblastic lymphoma and
circumstances (eg, stomach, salivary gland, thyroid). Partial organ ISRT occasionally DLBCL, bone marrow involvement, bulky tumors that are
may be appropriate if the disease is well localized on imaging (eg, orbit chemosensitive, rapidly proliferative or aggressive hematologic
and breast). malignancies, an elevated leukocyte count or pretreatment LDH,
pre-existing elevated uric acid, renal disease, or renal involvement of
The general dose guidelines for individual subtypes of B-cell lymphomas tumor are considered as risk factors for developing TLS.64 TLS
are outlined in the Principles of Radiation Therapy section of the algorithm. prophylaxis should be considered for patients with any of these risk
Recommendations for normal tissue dose constraints can be found in the factors. Frequent monitoring of electrolytes and aggressive correction
Principles of Radiation Therapy section of the NCCN Guidelines for are essential.
Hodgkin Lymphoma.
The cornerstone of TLS management is hydration and the management
Supportive Care of hyperuricemia. Allopurinol, febuxostat, and rasburicase are highly
effective for the management of hyperuricemia.65-67 There are data to
Tumor Lysis Syndrome
suggest that single fixed dose (6 mg or 3 mg) or single weight-based
Tumor lysis syndrome (TLS) is a potentially serious complication of dose of rasburicase (0.05–0.15 mg/kg) are effective in adult patients with
anticancer therapy characterized by metabolic and electrolyte hyperuricemia or high-risk factors for TLS.68-73
abnormalities caused by the disintegration of malignant cells by
anticancer therapy and rapid release of intracellular contents into Allopurinol or febuxostat is recommended for patients with low-risk or
peripheral blood. It is usually observed within 12 to 72 hours after start of intermediate-risk disease. Allopurinol and febuxostat should be started 2
chemoimmunotherapy.62 to 3 days prior to the initiation of chemoimmunotherapy and continued for
10 to 14 days. Rasburicase is recommended for intermediate-risk
Laboratory TLS is defined as a 25% increase in the levels of serum uric disease (if renal dysfunction and uric acid, potassium, and/or phosphate
acid, potassium, or phosphorus or a 25% decrease in calcium levels.63 greater than upper limit of normal [ULN]) or high-risk disease. A single
Clinical TLS refers to laboratory TLS with clinical toxicity that requires dose of rasburicase (3 mg or 6 mg) is adequate in most circumstances
intervention. Hyperkalemia, hyperuricemia, hyperphosphatemia, and and repeat dosing should be individualized based on the presence of any
hypocalcemia are the primary electrolyte abnormalities associated with of the following risk factors: bulky disease requiring immediate therapy;
TLS. Clinical symptoms may include nausea and vomiting, diarrhea, adequate hydration is not possible; or acute renal failure. Rasburicase is
seizures, shortness of breath, renal insufficiency, or cardiac arrhythmias. contraindicated in patients with G6PD deficiency due to an increased risk
Untreated TLS can induce profound metabolic changes resulting in of methemoglobinemia or hemolysis.74 G6PD testing should be

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considered prior to the initiation of rasburicase. Rasburicase should be malignancies treated with immunosuppressive cytotoxic agents.23,89-91
substituted with allopurinol if there is G6PD deficiency. Entecavir has been shown to be more effective than lamivudine in
preventing rituximab-associated HBV reactivation.92-94 Pre-emptive therapy
Hepatitis B Virus Reactivation involves close surveillance with a highly sensitive quantitative assay for
Patients with malignancies and HBV infection (HBsAg-positive or HBcAb- HBV, combined with antiviral therapy given at the time of serological
positive) are at risk for HBV reactivation with cytotoxic chemotherapy.75-85 evidence of HBV reactivation based upon a rising HBV DNA load.82
A meta-analysis and evaluation of the U.S. Food and Drug Administration
(FDA) safety reports concerning HBV reactivation in patients with Testing for HBsAg and HBcAb can determine if an individual has HBV
lymphoproliferative disorders reported that HBcAb positivity was correlated infection. HBsAb positivity is of limited value because of the widespread
with increased incidence of rituximab-associated HBV reactivation.76 In use of the hepatitis B vaccine; however, in rare circumstances, HBsAb
patients with B-cell lymphomas treated with rituximab-containing levels can help to guide therapy. The Panel recommends HBsAg and
regimens, HBV reactivation was observed in patients with a positive test HBcAb testing for all patients with B-cell lymphomas planned for treatment
for HBcAb (with or without HBsAb positivity), even among patients with a with anti-CD20 mAb-containing regimens. In individuals who test positive
negative test for HBsAg prior to initiation of treatment.77,83,84 for HBsAg and/or HBcAb, baseline quantitative polymerase chain reaction
False-negative HBsAg results may occur in patients with chronic liver (PCR) for HBV DNA should be obtained to determine viral load. However,
disease; therefore, patients with a history of hepatitis in need of a negative baseline PCR does not preclude the possibility of reactivation.
chemoimmunotherapy should be assessed by viral load measurement.86 Patients receiving intravenous immunoglobulin (IVIG) may have a positive
HBsAb positivity is generally equated with protective immunity, although test for HBcAb as a consequence of IVIG therapy.95
reactivated HBV disease may occur in the setting of significant
Entecavir prophylaxis is recommended for patients with HBV infection
immunosuppression in individuals with HBV infection that is HBcAb
(HBsAg positive) receiving anti-lymphoma therapy.92,93 Entecavir
positive.82,87 Vaccination against HBV should be strongly considered in
prophylaxis is also the preferred approach for patients with HBV infection
patients without HBV infection (ie, negative for HBsAg, HBsAb, and
(HBsAg negative but HBcAb positive); however, in the presence of
HBcAb).82,88
concurrently high levels of HBsAb, appropriate supportive care
Antiviral prophylaxis or pre-emptive antiviral therapy are the recommended interventions (monitoring with serial measurements of HBV viral load and
strategies for the management of HBV reactivation in patients with treatment with pre-emptive antivirals upon increasing viral load) may be
hematologic malignancies undergoing immunosuppressive therapy. necessary. Lamivudine should be avoided due to the risks for the
Antiviral prophylaxis involves administration of antiviral therapy for patients development of resistance.96-98 Other antivirals such as adefovir,
with HBV infection (HBsAg positive or HBcAb positive), regardless of viral telbivudine, and tenofovir have also demonstrated antiviral efficacy in
load or presence of clinical manifestations of HBV reactivation. patients with chronic HBV infection and are acceptable alternatives.99-102
Lamivudine has been shown to reduce the risks for HBV reactivation in
The optimal choice of prophylactic antiviral therapy will be driven by
patients with HBV infection (HBsAg-positive) and hematologic
institutional standards or recommendation from hepatology or an

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infectious disease consultant. The appropriate duration of prophylaxis anti-lymphoma therapy, subsequent antiviral therapy may be associated
remains undefined, but the Panel recommended that surveillance and with lower risk of disease relapse.
antiviral prophylaxis should be continued for up to 12 months after the
completion of oncologic treatment.82 During the treatment period, viral load The optimal management of B-cell lymphomas in people with HCV
should be monitored monthly with PCR and then every 3 months after infection remains to be defined. Patients with indolent B-cell lymphomas
completion of treatment. If viral load is consistently undetectable, may benefit from initial antiviral therapy, as demonstrated in several
prophylaxis with antivirals should be continued. If viral load fails to drop or reports.103,105,107,109,110 In patients with aggressive B-cell lymphomas, an
a previously undetectable PCR becomes positive, consultation with a earlier analysis of pooled data from GELA clinical studies (prior to the
hepatologist and discontinuation of anti-CD20 mAb therapy is rituximab era) suggested that HCV seropositivity in patients with DLBCL
recommended. was associated with significantly decreased survival outcomes, due, in
part, to severe hepatotoxicity among those with HCV infection.111
Hepatitis C Virus-Associated B-Cell Lymphomas Subsequent studies in the rituximab era showed that HCV seropositivity
As noted earlier, large population-based or multicenter case-control was not predictive of outcomes in terms of PFS or OS in patients with
studies have demonstrated a strong association between seropositivity for DLBCL.112,113 However, the incidence of hepatotoxicity with
HCV and development of B-cell lymphomas.24-31 The prevalence of HCV chemoimmunotherapy was higher among people with HCV infection,
seropositivity was consistently increased among patients with DLBCL and confirming the observation made from the GELA studies.
MZL.24,25,29,30 In a retrospective study, based on multivariable analysis,
The treatment of chronic HCV infection has improved with the advent of
persistent HCV infection remained a significant independent factor
newer antiviral agents, especially those that target carriers of HCV
associated with development of malignant lymphomas and the
genotype 1. Direct-acting antiviral agents (DAA) administered in
achievement of sustained virologic response (SVR) with interferon-based
combination with standard antivirals (pegylated interferon and ribavirin)
therapy may reduce the incidence of malignant lymphoma in people with
have shown significantly higher rates of SVR compared with standard
HCV infection.27
therapy alone in chronic carriers of HCV genotype 1.114-117 Telaprevir and
Several published reports suggested that treatment with antivirals boceprevir are DAA that are approved by the FDA for the treatment (in
(typically interferon with or without ribavirin) led to regression of lymphoma combination with pegylated interferon and ribavirin) of patients with HCV
in people with HCV infection, which provides additional evidence for the genotype 1 infection. The updated guidelines for the management of HCV
involvement of HCV infection in the pathogenesis of lymphoproliferative infection from the American Association for the Study of Liver Diseases
diseases.103-109 Thus, in patients with HCV infection and indolent B-cell (AASLD) recommended that DAA be incorporated into standard antiviral
lymphomas not requiring immediate treatment with chemoimmunotherapy, therapy for patients infected with HCV genotype 1.118
initial treatment with interferon (with or without ribavirin) appeared to
The Panel recommends initial antiviral therapy in asymptomatic patients
induce lymphoma regression in a high proportion of patients. In patients
with HCV-positive low-grade B-cell lymphomas. For those with HCV
with HCV-infection and B-cell lymphomas in remission after
genotype 1, triple antiviral therapy with inclusion of DAAs should be

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considered as per AASLD guidelines. Patients with HCV-positive on the plasma concentrations of methotrexate) for patients receiving
aggressive B-cell lymphomas should initially be treated with appropriate high-dose methotrexate.123
chemoimmunotherapy regimens according to the NCCN Guidelines for B-
Cell Lymphomas. Liver function and serum HCV RNA levels should be Anti-CD20 Monoclonal Antibody Therapy Intolerance
closely monitored for the development of hepatotoxicity during and after Rare complications such as mucocutaneous reactions including
chemoimmunotherapy. Antiviral therapy should then be considered in paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid
patients who achieve a CR after completion of chemoimmunotherapy. dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can
occur in patients treated with anti-CD20 mAb. Expert consultation with a
Progressive Multifocal Leukoencephalopathy dermatologist is recommended.
Progressive multifocal leukoencephalopathy (PML) is a rare but serious
and usually fatal CNS infection caused by reactivation of the latent JC Re-challenge with the same anti-CD20 mAb is not recommended in
polyomavirus. PML generally occurs in individuals who are severely patients experiencing the aforementioned complications to chosen
immunocompromised, as in the case of people with HIV and in patients anti-CD20 mAb (rituximab or obinutuzumab). An alternative anti-CD20
with low CD4+ T-cells prior to or during anti-lymphoma treatment.119-121 mAb (obinutuzumab) could be used for patients with intolerance to
PML has been reported in patients with B-cell lymphomas treated with rituximab, including those experiencing severe hypersensitivity reactions
rituximab (usually in combination with chemotherapy) or brentuximab requiring discontinuation of chosen anti-CD20 mAb, regardless of
vedotin or chemotherapy with purine analogs or alkylating agents.119,122 histology.124-126 However, it is unclear if such a substitution poses the
same risk of recurrence.
PML is clinically suspected based on neurologic signs and symptoms
that may include confusion, motor weakness or poor motor coordination, An FDA-approved biosimilar is an appropriate substitute for rituximab in all
visual changes, and/or speech changes.119 PML is usually diagnosed subtypes of B-cell lymphomas. Rituximab and hyaluronidase injection for
with PCR of CSF or, in certain circumstances, by the analysis of brain subcutaneous use is approved by the FDA for the treatment of patients
biopsy material. There is no effective treatment for PML. Patients should with previously untreated and relapsed/refractory FL and previously
be carefully monitored for the development of any neurologic symptoms. untreated DLBCL, only for patients who have received at least one full
There is currently no consensus on pretreatment evaluations that can be dose of intravenous rituximab.127,128 The guidelines recommend that
undertaken to predict the subsequent development of PML. rituximab and hyaluronidase injection for subcutaneous use may be
substituted for intravenous rituximab after patients have received the first
Methotrexate Toxicity full dose of rituximab by intravenous infusion. Switching to subcutaneous
Glucarpidase should be used for patients with significant renal dysfunction rituximab is not recommended until a full intravenous dose of rituximab is
receiving high-dose methotrexate and the guidelines recommend the use successfully administered without experiencing severe adverse reactions.
of a web-based tool to optimize the administration of glucarpidase (based

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NCCN Guidelines Version 3.2025

B-Cell Lymphomas

Bone Health in Patients Receiving Steroid-Containing Regimens

Steroid-containing systemic therapy regimens have been associated with
increased risk of fractures and treatment-induced bone loss in patients
with B-cell lymphomas.129-131 The risk of treatment-induced bone loss is
higher among young females with chemotherapy-induced premature
menopause and older patients receiving chemotherapy.132,133 In addition,
patients with newly diagnosed B-cell lymphomas are also at risk of low
bone mineral density (BMD), which may worsen during treatment with
steroid-based systemic therapy.134 Referral to an endocrinologist with
expertise on bone health and initiation of treatment as per National
Osteoporosis Foundation guidelines is recommended for patients with
osteoporotic BMD, with a history of hip or vertebral fractures, or with
asymptomatic vertebral compression deformity (as seen on imaging
studies).135

Evaluation of vitamin D levels and post-treatment BMD evaluation using a

fracture risk assessment tool is recommended for patients receiving
steroid-based systemic therapy.136,137 Adequate calcium intake is essential
since corticosteroids block calcium absorption and increase the risk of
fracture. Raloxifene or hormone replacement therapy up until the expected
time of natural menopause could be considered in appropriate patients
with premature menopause. Bisphosphonates should be used as first-line
pharmacologic treatment for osteoporosis.138,139 Denosumab is an effective
alternative option to prevent osteoporotic fractures in patients who cannot
tolerate or whose symptoms do not improve with bisphosphonate
therapy.140

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B-Cell Lymphomas

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NCCN Guidelines Version 3.2025

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