Papers by Geir Tjønnfjord
Tidsskrift for Den Norske Laegeforening, Mar 18, 2004
T-prolymfocy leukemi er en sjelden pos ymisk T-celleneoplasi med et svaert aggressivt forløp og m... more T-prolymfocy leukemi er en sjelden pos ymisk T-celleneoplasi med et svaert aggressivt forløp og med resistens overfor alkylerende kjemoterapeutika. Behandling med purinanalogen 2-deoksykoformisin har gi dokumentert partiell eller komple respons i opptil 45 % av tilfellene. Behandling med monoklonalt antistoff mot CD52, alemtuzumab, representerer et ny og lovende behandlingsprinsipp for denne pasientgruppen.
Cancer Genomics & Proteomics, 2019
Background/Aim: The aim of the study was to determine the genetic and molecular consequences of t... more Background/Aim: The aim of the study was to determine the genetic and molecular consequences of trisomy 4, a recurrent but rare chromosomal abnormality in acute myeloid leukemia (AML). Materials and Methods: Interphase fluorescence in situ hybridization, reverse transcriptasequantitative polymerase chain reaction for 28 chromosomal gene translocations/fusion genes, and targeted sequencing analyses were performed on five AMLs with trisomy 4 as the sole chromosomal anomaly. Results: An NPM1 frameshift mutation was found in all leukemic bone marrows, DNMT3A, FLT3, and IDH1 mutations were found in three, KIT and NRAS mutations in two, whereas IDH2 (R140Q), RUNX1, and WT1 mutations were found in only one patient each. The three patients with a DNMT3A (R882H) mutation have died. In contrast, the two patients whose leukemic cells were without this mutation, are alive 55 and 31 months after diagnosis, respectively. Conclusion: The results suggest a possible association between trisomy 4 and additional mutations that may influence prognosis. Acute myeloid leukemia (AML) is a heterogenous group of malignancies with different clinical phenotypes and responses to therapy (1, 2). AMLs can be classified according to distinct cytogenetic and genetic abnormalities of leukemic cells at diagnosis, but also by phenotypic and epigenetic differences that act as a guide to risk assessment and choice of treatment (1, 2). AML cases with a single trisomy constitute a heterogenous subgroup with regard to clinical, morphological, and immunophenotypic features, as well as the mutational profiles (3). Trisomy 4 is a recurrent, but rare chromosomal abnormality in AML. It may be the sole aberration or one of several chromosomal changes (4). Trisomy 4 was first described by Mecucci et al. in 1986, and a year later by Sandberg et al. (5), as the sole chromosomal abnormality in AML (6). In the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, 83 (48 female and 35 male patients) out of 18029 AML-cases had trisomy 4 as the sole chromosomal abnormality (http://cgap.nci.nih.gov/Chromosomes/Mitelman, database last updated on February 20, 2017). Most cases are morphologically classified as M1, M2, or M4 using the French-American-British (FAB) classification. Because trisomy 4 is rare, few studies have addressed its clinical impact. As a consequence, the prognosis of AML with solitary trisomy 4 remains unclear (7, 8). However, a recent study based on 87 AML cases with trisomy 4 concluded that the prognostic significance of the aberration depended on the patient's age, and despite an initial good response to treatment, patients with trisomy 4 were prone to relapse (4). Recently, we reported the genetic, molecular and clinical features of a pediatric AML case with trisomy 4 and an FLT3-ITD mutation (9). Fluorescence in situ hybridization assay demonstrated that part of the RUNX1 probe had moved to chromosome band 6q25 indicating a cryptic t(6;21)(q25;q22) translocation. Molecular analysis of the translocation showed fusion of RUNX1 with an intergenic sequence from 6q25, resulting in a putative RUNX1 truncated protein that would contain the Runt homology domain responsible for both heterodimerization with CBFB and DNA binding (9). The findings prompted us to investigate additional cases of myeloid 175 This article is freely accessible online.
BioMed Research International, 2015
Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous ... more Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found. Whole genome microarray showed increased expression of immunoglobulin genes, Killer Immunoglobulin Receptor (KIR) genes, and HLA genes in the Agaricus group. Furthermore, AndoSan displayed a concentration dependent antiproliferative effect on mouse myeloma cells in vitro. There were no statistically significant differences in treatment response, overall survival, and time to new treatment. The study was registered with Clinicaltrials.gov NCT00970021.
Cancer Genomics & Proteomics, Nov 3, 2017
Background/Aim: Given the diagnostic, prognostic, biologic, and even therapeutic impact of leukem... more Background/Aim: Given the diagnostic, prognostic, biologic, and even therapeutic impact of leukemia-associated translocations and fusion genes, it is important to detect cryptic genomic rearrangements that may exist in hematological malignancies. Case Report: RNAsequencing was performed on an acute myeloid leukemia case with the bone marrow karyotype 45,X,-Y,t(9;12) (q34;q15) . Results: The DEK-NUP214 and PRRC2B-DEK fusion genes were found. Reverse transcriptase polymerase chain reaction together with direct sequencing verified the presence of both. Fluorescence in situ hybridization showed that the DEK-NUP214 fusion gene was located on the 6p22 band of a seemingly normal chromosome 6. Conclusion: RNA-sequencing proved to be a valuable tool for the detection of a fusion of genes DEK and NUP214 in a leukemia that showed cryptic cytogenetic rearrangement of chromosome band 9q34.
American Journal of Clinical Pathology, Mar 1, 2013
Hematology-oncology Clinics of North America, Jun 1, 2015
Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold a... more Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold agglutinin disease (CAD) is characterized by a clonal lymphoproliferative disorder. Secondary cold agglutinin syndrome (CAS) complicates specific infections and malignancies. Hemolysis in CAD and CAS is mediated by the classical complement pathway and is predominantly extravascular. Not all patients require treatment. Successful CAD therapy targets the pathogenic B-cell clone. Complement modulation seems promising in both CAD and CAS. Further development and documentation are necessary before clinical use. We review options for possible complement-directed therapy.
Hematology-oncology Clinics of North America, Jun 1, 2015
Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold a... more Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold agglutinin disease (CAD) is characterized by a clonal lymphoproliferative disorder. Secondary cold agglutinin syndrome (CAS) complicates specific infections and malignancies. Hemolysis in CAD and CAS is mediated by the classical complement pathway and is predominantly extravascular. Not all patients require treatment. Successful CAD therapy targets the pathogenic B-cell clone. Complement modulation seems promising in both CAD and CAS. Further development and documentation are necessary before clinical use. We review options for possible complement-directed therapy.
Tidsskrift for Den norske lægeforening, 2012
Tidsskrift for Den norske lægeforening, 2012
Journal of Blood Medicine, Apr 1, 2019
Cold agglutinin disease (CAD) is a complement-dependent, classical pathwaymediated immune hemolyt... more Cold agglutinin disease (CAD) is a complement-dependent, classical pathwaymediated immune hemolytic disease, accounting for 15-25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.
Journal of Blood Medicine, Apr 1, 2019
Cold agglutinin disease (CAD) is a complement-dependent, classical pathwaymediated immune hemolyt... more Cold agglutinin disease (CAD) is a complement-dependent, classical pathwaymediated immune hemolytic disease, accounting for 15-25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.
Bone Marrow Transplantation, Jun 30, 2008
Bone Marrow Transplantation, Jun 30, 2008
Clinical advances in hematology & oncology, 2020
Primary cold agglutinin disease (CAD) is characterized by a very indolent bone marrow clonal B-ce... more Primary cold agglutinin disease (CAD) is characterized by a very indolent bone marrow clonal B-cell lymphoproliferative disorder that initiates an autoimmune hemolytic anemia. The clonal B cells produce a monoclonal autoantibody termed cold agglutinin, most often of the immunoglobulin (Ig) Mκ class. After binding to its antigen, the IgM initiates a complement classical pathway-driven erythrocyte destruction, predominantly mediated by opsonization with complement protein C3b and extravascular hemolysis in the liver. We review the molecular biology, histopathology, clinical features, and diagnostic procedures in CAD. Some patients are only slightly anemic and do not require treatment, but moderate or severe anemia frequently occurs, and the disease burden has been underestimated. CAD should not be treated with corticosteroids. Several B-cell-directed treatment options are available, and complement-directed approaches are being rapidly developed. Current and possible future therapies are reviewed.
Clinical advances in hematology & oncology, 2020
Primary cold agglutinin disease (CAD) is characterized by a very indolent bone marrow clonal B-ce... more Primary cold agglutinin disease (CAD) is characterized by a very indolent bone marrow clonal B-cell lymphoproliferative disorder that initiates an autoimmune hemolytic anemia. The clonal B cells produce a monoclonal autoantibody termed cold agglutinin, most often of the immunoglobulin (Ig) Mκ class. After binding to its antigen, the IgM initiates a complement classical pathway-driven erythrocyte destruction, predominantly mediated by opsonization with complement protein C3b and extravascular hemolysis in the liver. We review the molecular biology, histopathology, clinical features, and diagnostic procedures in CAD. Some patients are only slightly anemic and do not require treatment, but moderate or severe anemia frequently occurs, and the disease burden has been underestimated. CAD should not be treated with corticosteroids. Several B-cell-directed treatment options are available, and complement-directed approaches are being rapidly developed. Current and possible future therapies are reviewed.
Cancer Epidemiology, Jun 1, 2019
Background: Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial ... more Background: Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial subset of patients who must discontinue targeted therapy for chronic lymphocytic leukemia (CLL). RS has an extremely poor prognosis. Methods: Using the nationwide database of The Cancer Registry of Norway of 7664 CLL patients registered between 1953-2012, we identified 107 patients experiencing RS. Results: Seventy seven (72%) of RS patients were identified among 2631 CLL patients diagnosed between 2003-2012; diffuse large B-cell lymphoma (DLBCL) was identified in 65 (84%), Hodgkin lymphoma (HL) in 12 (16%) patients and the diagnosis was confirmed in 50 (65%) available biopsy specimens. The incidence rate in this period was 4.7/1000 person-years (95% CI: 3.8-5.9). The median survival from CLL diagnosis was 1.7 years (95% CI: 0.34-2.3) for RS patients while it was 10.3 years (95% CI: 9.5-10.9) for the remaining CLL patients. Male gender predominated among RS patients (69%) compared to CLL population (58%) and RS patients were diagnosed with CLL at a significantly younger age than the remaining patients (65 vs. 72 years). Median time from diagnosis of CLL to RS was 2 years (Range, 0-13 years). No CLL treatment was administered in 25 (33%) patients prior RS diagnosis; a median of 1 treatment line was administered to pretreated patients. The median duration of survival after RS diagnosis was 27 months (95% CI; 9-88). Conclusions: Collectively, RS was a rare complication of CLL in the chemoimmunotherapy era, occurred early in the CLL course in younger, and both treatment naïve and pretreated patients, and shortened survival substantially.
Cancer Epidemiology, Jun 1, 2019
Background: Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial ... more Background: Transformation to aggressive lymphoma (Richter syndrome, RS) occurs in a substantial subset of patients who must discontinue targeted therapy for chronic lymphocytic leukemia (CLL). RS has an extremely poor prognosis. Methods: Using the nationwide database of The Cancer Registry of Norway of 7664 CLL patients registered between 1953-2012, we identified 107 patients experiencing RS. Results: Seventy seven (72%) of RS patients were identified among 2631 CLL patients diagnosed between 2003-2012; diffuse large B-cell lymphoma (DLBCL) was identified in 65 (84%), Hodgkin lymphoma (HL) in 12 (16%) patients and the diagnosis was confirmed in 50 (65%) available biopsy specimens. The incidence rate in this period was 4.7/1000 person-years (95% CI: 3.8-5.9). The median survival from CLL diagnosis was 1.7 years (95% CI: 0.34-2.3) for RS patients while it was 10.3 years (95% CI: 9.5-10.9) for the remaining CLL patients. Male gender predominated among RS patients (69%) compared to CLL population (58%) and RS patients were diagnosed with CLL at a significantly younger age than the remaining patients (65 vs. 72 years). Median time from diagnosis of CLL to RS was 2 years (Range, 0-13 years). No CLL treatment was administered in 25 (33%) patients prior RS diagnosis; a median of 1 treatment line was administered to pretreated patients. The median duration of survival after RS diagnosis was 27 months (95% CI; 9-88). Conclusions: Collectively, RS was a rare complication of CLL in the chemoimmunotherapy era, occurred early in the CLL course in younger, and both treatment naïve and pretreated patients, and shortened survival substantially.
Bone Marrow Transplantation, Jan 22, 2018
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Papers by Geir Tjønnfjord