Post-transplant lymphoproliferative disorders (PTLDs) are iatrogenic immune deficiencyassociated ... more Post-transplant lymphoproliferative disorders (PTLDs) are iatrogenic immune deficiencyassociated lymphoid/plasmacytic proliferations developing due to immunosuppression in solid organ or hematopoietic stem cell allograft patients. PTLDs are characterized by abnormal proliferation of lymphoid cells and have a heterogeneous clinical behavior. We profiled expression of >700 tumor microenvironment (TME)-related genes in 75 post-transplant aggressive B-cell lymphomas (PT-ABCLs). EBV-positive PT-ABCLs clustered together and were enriched for type I interferon pathway and antiviral response genes. Additionally, a cytotoxicity gene signature associated with EBV-positivity and favorable overall survival (OS; HR 0.61, P=0.019). In silico immunophenotyping revealed two subgroups with distinct immune cell compositions. The inflamed subgroup with higher proportions of immune cells had better outcome compared to non-inflamed subgroup (median OS >200.0 vs. 15.2 months, P=0.006). In multivariable analysis with EBV status, International Prognostic Index, and rituximab-containing treatment, the inflamed TME remained as an independent predictor for favorable outcome. We also compared the TME between posttransplant and immunocompetent host diffuse large B-cell lymphomas (DLBCLs) (n=75) and discovered that the proportions of T cells were lower in PT-DLBCL. In conclusion, we provide a comprehensive phenotypic characterization of PT-ABCLs, highlighting the importance of immune cell composition of TME in determining the clinical behavior and prognosis of PT-ABCL.
lenalidomide and rituximab are highly active in both frontline and relapsed disease. Obinutuzumab... more lenalidomide and rituximab are highly active in both frontline and relapsed disease. Obinutuzumab has increased antibody dependent cellular cytotoxicity (ADCC) compared to rituximab in preclinical models and is approved for FL. We hypothesized that the immunologic properties of obinutuzumab and lenalidomide would be synergistic in relapsed FL. The study's objectives were to determine the MTD of lenalidomide with obinutuzumab and describe the efficacy of the combination. Methods: This open label phase I/II study enrolled relapsed/refractory Gr 1-3a FL. Exclusions included transformation, prior malignancy, and infection. Lenalidomide was given on D 2-22 with 1000 mg obinutuzumab on D1, 8, 15, and 22 of cycle 1 and monthly on D 1 for up to 12 cycles. Extended dosing with obinutuzumab was given every 2 months thereafter for up to 30 months total in patients (pts) who responded following doublet therapy. During phase I, three escalating dose levels were planned with 10, 15, and 20 mg of lenalidomide. Phase II planned to enroll 30 pts at MTD with efficacy and safety as primary endpoints. Results: All 36 pts with FL enrolled (6 in dose escalation and 30 at MTD), and all are eligible for efficacy and safety analysis. The median age was 65 with a median of 2 prior therapies. No DLTs were observed in phase I, and 20 mg of lenalidomide was used for the phase II dose. To date, the most common all grade non-hematologic toxicities included fatigue (83%), diarrhea (67%), and rash (53%). Grade 3+ toxicities included neutropenia (23%), infection (11%), and fatigue (8%). The overall response rate was 100% with 78% (95% CI: 60.85-89.88%), of pts attaining complete remission (CR/Cru). At a median follow up of 14 months, 10 pts progressed. The estimated 24 month PFS is 61% (95% CI: 43-87%). Conclusions: Lenalidomide and obinutuzumab is highly active with durable remissions in relapsed FL, with all pts responding and 78% achieving CR. The majority of pts remain on therapy and the combination appeared safe. Correlatives are ongoing to identify biomarkers of response and frontline studies of the combination are currently enrolling.
proportion of patients achieving complete response or VGPR, as determined by an independent revie... more proportion of patients achieving complete response or VGPR, as determined by an independent review committee by modified Owens criteria (Br J Haematol. 2013;160:171 and National Comprehensive Cancer Network Guidelines). Key secondary end points include major response rate, duration of response, progression free survival, and safety. Study recruitment is ongoing, with the first patient enrolled in January 2017 and participating sites in Europe, Asia-Pacific, and North America (NCT03053440).
Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy reg... more Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy regimens. The majority of adult patients with Burkitt lymphoma in the United States are over age 40. Older patients have historically been underrepresented in published clinical trials of modern intensive therapy, and the outcome of these patients has not been systematically reported. We therefore obtained and analyzed primary data from 14 Burkitt lymphoma treatment series and confirmed that older patients (age > 40) are underrepresented in the literature. Historically inferior outcomes of this age subgroup have improved substantially over time. We conclude that 1) modern intensive chemotherapy regimens should remain the standard of care for patients > age 40 with Burkitt lymphoma, 2) selected patients > age 40 now have highly favorable outcomes, and 3) future studies should include formal analysis of this subgroup of patients.
enriched for 'double hit' FISH status. This molecular high grade (MHG) subset of patients was ide... more enriched for 'double hit' FISH status. This molecular high grade (MHG) subset of patients was identified from the REMoDL-B trial using Illumina WG-DASL data and showed an inferior response to R-CHOP, 1 confirmed in our population based cohort. 2 The MaPLe trial (Molecular Profiling for Lymphoma) is a multicentre prospective observational cohort study for the collection of tumour samples from patients with DLBCL, with almost 3000 samples now collated. The aim of this analysis was to characterise lymphomas that progressed early according to gene expression profiling (GEP) status, including MHG and cell of origin (COO), as well as double hit FISH status and targeted sequencing. Patients who progressed within 6 months of MaPLe study baseline visit were identified. To allow assessment of biological variables which may contribute to treatment failure, each case was matched to another patient who had not progressed within 6 months based on age and IPI score at diagnosis. Samples with sufficient material were interrogated using the HTG EdgeSeq Pan B-Cell Lymphoma Panel and classified according to MHG and COO status. Targeted sequencing of 191 gene/ region targets using TWIST library prep, sequenced on an Illumina HiSeq was also performed and FISH for double hit status is underway. Thirty nine eligible patients were identified as 'early progressors' and matched to 39 controls. HTG data was available and passed QC metrics in 64 patients (32 from each group). In total, 18/64 (28%) were classified as MHG, with 12/18 of these (67%) represented within the early progressor group. This is significantly higher than the prevelance of MHG previously demonstrated in REMoDL-B and population based datasets, reflecting the case selection within this study. ABCs were evenly distributed between groups (11/21 vs 10/ 21) while GCBs and unclassifiable samples were slightly more prevalent in the control group (7/18 vs 11/18 and 2/7 vs 5/7 respectively). Relevant mutations, previously described to be associated with ABC, GCB and MHG, were demonstrated within the GEP subgroups, however there was no significant association between individual or subtype-specific mutations and progression. The results of this study confirm that the MHG gene expression profile can be reproduced using HTG EdgeSeq Pan B-Cell Lymphoma Panel data. MHG was more frequently identified in the early progressor cohort, suggesting that MHG GEP contributes to poor response to conventional R-CHOP treatment for DLBCL. Prospective identification of this group for testing more effective treatment strategies is a priority.
The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with r... more The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the...
Tumor microenvironment (TME) and limited immune surveillance play important roles in lymphoma pat... more Tumor microenvironment (TME) and limited immune surveillance play important roles in lymphoma pathogenesis. Here, we aimed to characterize immunological profiles of diffuse large B-cell lymphoma (DLBCL), and predict the outcome in response to immunochemotherapy. We profiled the expression of 730 immune-related genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize T-cell phenotypes, including cytotoxic T-cells (CD8, Granzyme B, OX40, Ki67), T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188 patients. We observed a high degree of heterogeneity at the transcriptome level. Correlation matrix analysis identified gene expression signatures with highly correlating genes - the main cluster containing genes for cytolytic factors, immune checkpoint molecules, T-cells and macrophages, together entitled as a TME immune ...
Background Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and p... more Background Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. Methods This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7•5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and vincristine (1•4 mg/m², with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m² of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5•5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. Findings Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the noninferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. Interpretation In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. Funding Deutsche Krebshilfe.
Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or ... more Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient require...
Introduction: High dose therapy with autologous stem cell transplantation (HD-ASCT) is associated... more Introduction: High dose therapy with autologous stem cell transplantation (HD-ASCT) is associated with increased risk of late effects. Our aim was to assess lifestyle behavior and factors associated with unhealthy lifestyle among HD-ASCT-treated lymphoma survivors (HD-ASCT-LS). We conducted a national cross-sectional study of HD-ASCT-LS treated during 1987-2008. Among 399 eligible participants, 312 (78%) completed patientreported outcomes measures (PROMs) on lifestyle behavior (physical activity, overweight, smoking and alcohol consumption), chronic fatigue (CF) and somatic and mental illness. We assessed lifestyle according to WHO recommendations. Multivariable logistic regression models were used to study associations between variables. A comparison to the general population was performed. Results: Mean age at survey was 54.6 years, 60% were men, 55% sedentary, 55% overweight, 18% smokers and 5% had unhealthy alcohol consumption. Being sedentary was positively associated with older age, low household income, CF and higher somatic burden (≥4 self-reported somatic conditions). Overweight was positively associated with male gender and negatively associated with increased number of chemotherapy regimens prior to HD-ASCT. Current smoking was positively associated with living alone and CF, and negatively associated with older age. Male gender, CF and higher somatic burden increased the risk of an unhealthier lifestyle whereas increased number of chemotherapy regimens prior to HD-ASCT decreased the risk. HD-ASCT-LS were significantly less sedentary, less overweight, and had a lower likelihood of smoking than the controls. Discussion: Assessed by PROMs, unhealthy habits was frequent among HD-ASCT-LS and associated with comorbidity. Nevertheless, compared with controls significantly more HD-ASCT-LS met lifestyle recommendations. These results indicate that the HD-ASCT-LS may consist of two groups, the adhering group with less comorbidity and the non-adhering group with more comorbidity. Our findings illustrate the necessity of recommendations and support for improving health-related behavior in cancer survivorship and the need for personalized follow-up.
Patients with diffuse large B-cell lymphoma that is refractory to primary and secondline therapie... more Patients with diffuse large B-cell lymphoma that is refractory to primary and secondline therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248.
SummaryIn this phase II, multicentre, single‐arm study, 52 patients with relapsed/refractory diff... more SummaryIn this phase II, multicentre, single‐arm study, 52 patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) received the anti‐CD19 antibody–drug conjugate coltuximab ravtansine (55 mg/m2) and rituximab (375 mg/m2) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0–41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2–78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0–72·1%]) or first‐line therapy (15·4% [80% CI: 6·9–28·4%]). Median progression‐free survival, overall survival and duration of response were 3·9 [80% CI: 3·22–3·98], 9·0 [80% CI: 6·47–13·67] and 8·6 (range: 0–18) months, respectively. The pharmacokinetics of both...
This national population-based study aimed to investigate conditional survival and standardized m... more This national population-based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) for non-Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT-ASCT for NHL in Norway between 1987 and 2008 were included (n = 578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5-, 10- and 20-year overall survival was 61% (95% confidence interval [CI] 56-64%), 52% (95%CI 48-56%) and 45% (95%CI 40-50%), respectively. The 5-year survival conditional on having survived 2, 5 and 10 years after HDT-ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0-13·9), 4·9 (95%CI 4·1-5·9), 2·4 (95%CI 1·8-3·2) and 1·0 (95%CI 0·6-1·8) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT-ASCT respectively. Of the 281 deaths observed, 77% wer...
To investigate outcome for patients with follicular lymphoma (FL) stage I-II treated at a populat... more To investigate outcome for patients with follicular lymphoma (FL) stage I-II treated at a population-based referral institution with a median follow-up of 15 years. Overall and causespecific survival was compared to that of a sex, age and residency matched individuals from normal population. 404 patients with early stage FL treated between 1980 and 2005 were retrospectively analyzed. Two of three patients had stage I disease. Based on clinical characteristics, first line treatments were radiotherapy (RT) (48% of patients), chemotherapy (CT) (16%), combined chemo-and radiotherapy (CRT) (16%) or observation (OBS) (15%). Survival was modeled with Kaplan-Meier methodology. Multivariate analyses were performed with the Cox model. Fifteen years overall survival (OS), progression free survival (PFS) and time to next treatment (TNT) were 50% (95% confidence interval [CI]: 45-55), 42% (95% CI: 36-47) and 48% (95% CI, 42-54), respectively. For patients treated with RT 97% achieved a complete remission, and 15 year OS, PFS and TNT were 57% (95% CI, 50-64), 46% (95% CI, 39-54) and 49% (95% CI, 42-57), respectively. Relapse rate after RT and CRT was 49% and 36%, respectively. Only 2% of patients who received RT or CRT relapsed inside the radiation field and 5% had isolated near-field relapse. No statistical differences were found
Kreft-, kirurgi-og transplantasjonsklinikken Oslo universitetssykehus og Institutt for klinisk me... more Kreft-, kirurgi-og transplantasjonsklinikken Oslo universitetssykehus og Institutt for klinisk medisin Det medisinske fakultet Universitetet i Oslo Engelsk oversettelse på www.tidsskriftet.no Høydosebehandling med autolog stamcellestøtte (HMAS) har vaert et terapialternativ ved lymfomer i Norge helt siden 1987. Ved å gjenopprette beinmargsfunksjonen via tilbakeføring av pasientens egne stamceller kan man gi kreftbehandling i høyere og ellers dødelige doser og dermed oppnå bedre behandlingsresultater. Opprinnelig ble stamcellene høstet fra beinmarg og høydosebehandlingen inkluderte helkroppsbestråling, men fra midten av 1990årene har man høstet stamceller venøst og høydosebehandlingen har bestått i kjemoterapi alene (BEAM-kur). I 1995 ble behandlingen regionalisert og er siden blitt gjennomført i alle helseregioner. HMAS-prosedyren ble innført som utprøvende behandling i kliniske studier med internasjonalt samarbeid. Indikasjonene har endret seg over tid, og dette er nå etablert behandling ved en rekke lymfomtyper.
Background: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL)... more Background: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. Conclusion: COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL.
Epigenetic alterations of gene expression are important in the development of cancer. In this stu... more Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n = 480) when compared to normal B cells (n = 5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt `s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n = 42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n = 25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.
Genes with altered DNa methylation can be used as biomarkers for cancer detection and assessment ... more Genes with altered DNa methylation can be used as biomarkers for cancer detection and assessment of prognosis. here we analyzed the methylation status of a colorectal cancer biomarker panel (CNRIP1, FBN1, INA, MAL, SNCA, and SPG20) in 97 cancer cell lines, derived from 17 different cancer types. Interestingly, the genes were frequently methylated also in hematological cancer types and were therefore subjected to analyses in primary tumor samples from the major types of non-hodgkin lymphomas (NhL) and in healthy controls. In total, the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 were methylated in 53%, 23%, 52%, 69%, 97%, and 92% of the tumor samples, respectively, and were unmethylated in all healthy controls. With the exception of a single tumor sample, a correct prediction of lymphoma or normal sample was made in a blinded analysis of the validation series using a combination of SNCA and SPG20. The combined ROc-curve analysis of these genes resulted in an area under the curve of 0.999 (P = 4.2 × 10 -18 ), and a sensitivity and specificity of 98% and 100%, respectively, across the test and validation series. Interestingly, the promoter methylation of CNRIP1 was associated with decreased overall survival in diffuse large B-cell lymphoma (DLBcL) (P = 0.03). In conclusion, our results demonstrate that SNCA and SPG20 methylation might be suitable for early detection and monitoring of NhL. Furthermore, CNRIP1 could potentially be used as a prognostic factor in DLBcL.
Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy reg... more Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy regimens. The majority of adult patients with Burkitt lymphoma in the United States are over age 40. Older patients have historically been underrepresented in published clinical trials of modern intensive therapy, and the outcome of these patients has not been systematically reported. We therefore obtained and analyzed primary data from 14 Burkitt lymphoma treatment series and confirmed that older patients (age > 40) are underrepresented in the literature. Historically inferior outcomes of this age subgroup have improved substantially over time. We conclude that 1) modern intensive chemotherapy regimens should remain the standard of care for patients > age 40 with Burkitt lymphoma, 2) selected patients > age 40 now have highly favorable outcomes, and 3) future studies should include formal analysis of this subgroup of patients.
Post-transplant lymphoproliferative disorders (PTLDs) are iatrogenic immune deficiencyassociated ... more Post-transplant lymphoproliferative disorders (PTLDs) are iatrogenic immune deficiencyassociated lymphoid/plasmacytic proliferations developing due to immunosuppression in solid organ or hematopoietic stem cell allograft patients. PTLDs are characterized by abnormal proliferation of lymphoid cells and have a heterogeneous clinical behavior. We profiled expression of >700 tumor microenvironment (TME)-related genes in 75 post-transplant aggressive B-cell lymphomas (PT-ABCLs). EBV-positive PT-ABCLs clustered together and were enriched for type I interferon pathway and antiviral response genes. Additionally, a cytotoxicity gene signature associated with EBV-positivity and favorable overall survival (OS; HR 0.61, P=0.019). In silico immunophenotyping revealed two subgroups with distinct immune cell compositions. The inflamed subgroup with higher proportions of immune cells had better outcome compared to non-inflamed subgroup (median OS >200.0 vs. 15.2 months, P=0.006). In multivariable analysis with EBV status, International Prognostic Index, and rituximab-containing treatment, the inflamed TME remained as an independent predictor for favorable outcome. We also compared the TME between posttransplant and immunocompetent host diffuse large B-cell lymphomas (DLBCLs) (n=75) and discovered that the proportions of T cells were lower in PT-DLBCL. In conclusion, we provide a comprehensive phenotypic characterization of PT-ABCLs, highlighting the importance of immune cell composition of TME in determining the clinical behavior and prognosis of PT-ABCL.
lenalidomide and rituximab are highly active in both frontline and relapsed disease. Obinutuzumab... more lenalidomide and rituximab are highly active in both frontline and relapsed disease. Obinutuzumab has increased antibody dependent cellular cytotoxicity (ADCC) compared to rituximab in preclinical models and is approved for FL. We hypothesized that the immunologic properties of obinutuzumab and lenalidomide would be synergistic in relapsed FL. The study's objectives were to determine the MTD of lenalidomide with obinutuzumab and describe the efficacy of the combination. Methods: This open label phase I/II study enrolled relapsed/refractory Gr 1-3a FL. Exclusions included transformation, prior malignancy, and infection. Lenalidomide was given on D 2-22 with 1000 mg obinutuzumab on D1, 8, 15, and 22 of cycle 1 and monthly on D 1 for up to 12 cycles. Extended dosing with obinutuzumab was given every 2 months thereafter for up to 30 months total in patients (pts) who responded following doublet therapy. During phase I, three escalating dose levels were planned with 10, 15, and 20 mg of lenalidomide. Phase II planned to enroll 30 pts at MTD with efficacy and safety as primary endpoints. Results: All 36 pts with FL enrolled (6 in dose escalation and 30 at MTD), and all are eligible for efficacy and safety analysis. The median age was 65 with a median of 2 prior therapies. No DLTs were observed in phase I, and 20 mg of lenalidomide was used for the phase II dose. To date, the most common all grade non-hematologic toxicities included fatigue (83%), diarrhea (67%), and rash (53%). Grade 3+ toxicities included neutropenia (23%), infection (11%), and fatigue (8%). The overall response rate was 100% with 78% (95% CI: 60.85-89.88%), of pts attaining complete remission (CR/Cru). At a median follow up of 14 months, 10 pts progressed. The estimated 24 month PFS is 61% (95% CI: 43-87%). Conclusions: Lenalidomide and obinutuzumab is highly active with durable remissions in relapsed FL, with all pts responding and 78% achieving CR. The majority of pts remain on therapy and the combination appeared safe. Correlatives are ongoing to identify biomarkers of response and frontline studies of the combination are currently enrolling.
proportion of patients achieving complete response or VGPR, as determined by an independent revie... more proportion of patients achieving complete response or VGPR, as determined by an independent review committee by modified Owens criteria (Br J Haematol. 2013;160:171 and National Comprehensive Cancer Network Guidelines). Key secondary end points include major response rate, duration of response, progression free survival, and safety. Study recruitment is ongoing, with the first patient enrolled in January 2017 and participating sites in Europe, Asia-Pacific, and North America (NCT03053440).
Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy reg... more Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy regimens. The majority of adult patients with Burkitt lymphoma in the United States are over age 40. Older patients have historically been underrepresented in published clinical trials of modern intensive therapy, and the outcome of these patients has not been systematically reported. We therefore obtained and analyzed primary data from 14 Burkitt lymphoma treatment series and confirmed that older patients (age > 40) are underrepresented in the literature. Historically inferior outcomes of this age subgroup have improved substantially over time. We conclude that 1) modern intensive chemotherapy regimens should remain the standard of care for patients > age 40 with Burkitt lymphoma, 2) selected patients > age 40 now have highly favorable outcomes, and 3) future studies should include formal analysis of this subgroup of patients.
enriched for 'double hit' FISH status. This molecular high grade (MHG) subset of patients was ide... more enriched for 'double hit' FISH status. This molecular high grade (MHG) subset of patients was identified from the REMoDL-B trial using Illumina WG-DASL data and showed an inferior response to R-CHOP, 1 confirmed in our population based cohort. 2 The MaPLe trial (Molecular Profiling for Lymphoma) is a multicentre prospective observational cohort study for the collection of tumour samples from patients with DLBCL, with almost 3000 samples now collated. The aim of this analysis was to characterise lymphomas that progressed early according to gene expression profiling (GEP) status, including MHG and cell of origin (COO), as well as double hit FISH status and targeted sequencing. Patients who progressed within 6 months of MaPLe study baseline visit were identified. To allow assessment of biological variables which may contribute to treatment failure, each case was matched to another patient who had not progressed within 6 months based on age and IPI score at diagnosis. Samples with sufficient material were interrogated using the HTG EdgeSeq Pan B-Cell Lymphoma Panel and classified according to MHG and COO status. Targeted sequencing of 191 gene/ region targets using TWIST library prep, sequenced on an Illumina HiSeq was also performed and FISH for double hit status is underway. Thirty nine eligible patients were identified as 'early progressors' and matched to 39 controls. HTG data was available and passed QC metrics in 64 patients (32 from each group). In total, 18/64 (28%) were classified as MHG, with 12/18 of these (67%) represented within the early progressor group. This is significantly higher than the prevelance of MHG previously demonstrated in REMoDL-B and population based datasets, reflecting the case selection within this study. ABCs were evenly distributed between groups (11/21 vs 10/ 21) while GCBs and unclassifiable samples were slightly more prevalent in the control group (7/18 vs 11/18 and 2/7 vs 5/7 respectively). Relevant mutations, previously described to be associated with ABC, GCB and MHG, were demonstrated within the GEP subgroups, however there was no significant association between individual or subtype-specific mutations and progression. The results of this study confirm that the MHG gene expression profile can be reproduced using HTG EdgeSeq Pan B-Cell Lymphoma Panel data. MHG was more frequently identified in the early progressor cohort, suggesting that MHG GEP contributes to poor response to conventional R-CHOP treatment for DLBCL. Prospective identification of this group for testing more effective treatment strategies is a priority.
The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with r... more The JULIET phase 2 trial evaluated a single infusion of tisagenlecleucel in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The objective of the current analysis was to evaluate patient-reported health-related quality of life (HRQoL) with a median follow-up of 19.3 months among patients infused with a single dose of tisagenlecleucel. Patients enrolled were ≥18 years of age with r/r DLBCL after ≥2 lines of therapy and had either undergone a failed autologous stem cell transplant or were ineligible for the procedure. Two validated HRQoL instruments, Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and Short Form-36 (SF-36) Health Survey, were used to measure HRQoL at baseline and months 3, 6, 12, and 18. At data cutoff (21 May 2018), 115 patients had received tisagenlecleucel infusion. Among the 99 patients evaluated, overall response rate was 54%, and 40% of patients achieved complete response (CR). Initially, 108 patients completed the...
Tumor microenvironment (TME) and limited immune surveillance play important roles in lymphoma pat... more Tumor microenvironment (TME) and limited immune surveillance play important roles in lymphoma pathogenesis. Here, we aimed to characterize immunological profiles of diffuse large B-cell lymphoma (DLBCL), and predict the outcome in response to immunochemotherapy. We profiled the expression of 730 immune-related genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize T-cell phenotypes, including cytotoxic T-cells (CD8, Granzyme B, OX40, Ki67), T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188 patients. We observed a high degree of heterogeneity at the transcriptome level. Correlation matrix analysis identified gene expression signatures with highly correlating genes - the main cluster containing genes for cytolytic factors, immune checkpoint molecules, T-cells and macrophages, together entitled as a TME immune ...
Background Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and p... more Background Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. Methods This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7•5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and vincristine (1•4 mg/m², with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m² of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5•5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. Findings Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the noninferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. Interpretation In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. Funding Deutsche Krebshilfe.
Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or ... more Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient require...
Introduction: High dose therapy with autologous stem cell transplantation (HD-ASCT) is associated... more Introduction: High dose therapy with autologous stem cell transplantation (HD-ASCT) is associated with increased risk of late effects. Our aim was to assess lifestyle behavior and factors associated with unhealthy lifestyle among HD-ASCT-treated lymphoma survivors (HD-ASCT-LS). We conducted a national cross-sectional study of HD-ASCT-LS treated during 1987-2008. Among 399 eligible participants, 312 (78%) completed patientreported outcomes measures (PROMs) on lifestyle behavior (physical activity, overweight, smoking and alcohol consumption), chronic fatigue (CF) and somatic and mental illness. We assessed lifestyle according to WHO recommendations. Multivariable logistic regression models were used to study associations between variables. A comparison to the general population was performed. Results: Mean age at survey was 54.6 years, 60% were men, 55% sedentary, 55% overweight, 18% smokers and 5% had unhealthy alcohol consumption. Being sedentary was positively associated with older age, low household income, CF and higher somatic burden (≥4 self-reported somatic conditions). Overweight was positively associated with male gender and negatively associated with increased number of chemotherapy regimens prior to HD-ASCT. Current smoking was positively associated with living alone and CF, and negatively associated with older age. Male gender, CF and higher somatic burden increased the risk of an unhealthier lifestyle whereas increased number of chemotherapy regimens prior to HD-ASCT decreased the risk. HD-ASCT-LS were significantly less sedentary, less overweight, and had a lower likelihood of smoking than the controls. Discussion: Assessed by PROMs, unhealthy habits was frequent among HD-ASCT-LS and associated with comorbidity. Nevertheless, compared with controls significantly more HD-ASCT-LS met lifestyle recommendations. These results indicate that the HD-ASCT-LS may consist of two groups, the adhering group with less comorbidity and the non-adhering group with more comorbidity. Our findings illustrate the necessity of recommendations and support for improving health-related behavior in cancer survivorship and the need for personalized follow-up.
Patients with diffuse large B-cell lymphoma that is refractory to primary and secondline therapie... more Patients with diffuse large B-cell lymphoma that is refractory to primary and secondline therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248.
SummaryIn this phase II, multicentre, single‐arm study, 52 patients with relapsed/refractory diff... more SummaryIn this phase II, multicentre, single‐arm study, 52 patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) received the anti‐CD19 antibody–drug conjugate coltuximab ravtansine (55 mg/m2) and rituximab (375 mg/m2) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0–41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2–78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0–72·1%]) or first‐line therapy (15·4% [80% CI: 6·9–28·4%]). Median progression‐free survival, overall survival and duration of response were 3·9 [80% CI: 3·22–3·98], 9·0 [80% CI: 6·47–13·67] and 8·6 (range: 0–18) months, respectively. The pharmacokinetics of both...
This national population-based study aimed to investigate conditional survival and standardized m... more This national population-based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with autologous stem-cell transplantation (HDT-ASCT) for non-Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT-ASCT for NHL in Norway between 1987 and 2008 were included (n = 578). Information from the Cause of Death Registry and Cancer Registry of Norway were linked with clinical data. The 5-, 10- and 20-year overall survival was 61% (95% confidence interval [CI] 56-64%), 52% (95%CI 48-56%) and 45% (95%CI 40-50%), respectively. The 5-year survival conditional on having survived 2, 5 and 10 years after HDT-ASCT was 81%, 86% and 93%. SMRs were 12·3 (95%CI 11·0-13·9), 4·9 (95%CI 4·1-5·9), 2·4 (95%CI 1·8-3·2) and 1·0 (95%CI 0·6-1·8) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT-ASCT respectively. Of the 281 deaths observed, 77% wer...
To investigate outcome for patients with follicular lymphoma (FL) stage I-II treated at a populat... more To investigate outcome for patients with follicular lymphoma (FL) stage I-II treated at a population-based referral institution with a median follow-up of 15 years. Overall and causespecific survival was compared to that of a sex, age and residency matched individuals from normal population. 404 patients with early stage FL treated between 1980 and 2005 were retrospectively analyzed. Two of three patients had stage I disease. Based on clinical characteristics, first line treatments were radiotherapy (RT) (48% of patients), chemotherapy (CT) (16%), combined chemo-and radiotherapy (CRT) (16%) or observation (OBS) (15%). Survival was modeled with Kaplan-Meier methodology. Multivariate analyses were performed with the Cox model. Fifteen years overall survival (OS), progression free survival (PFS) and time to next treatment (TNT) were 50% (95% confidence interval [CI]: 45-55), 42% (95% CI: 36-47) and 48% (95% CI, 42-54), respectively. For patients treated with RT 97% achieved a complete remission, and 15 year OS, PFS and TNT were 57% (95% CI, 50-64), 46% (95% CI, 39-54) and 49% (95% CI, 42-57), respectively. Relapse rate after RT and CRT was 49% and 36%, respectively. Only 2% of patients who received RT or CRT relapsed inside the radiation field and 5% had isolated near-field relapse. No statistical differences were found
Kreft-, kirurgi-og transplantasjonsklinikken Oslo universitetssykehus og Institutt for klinisk me... more Kreft-, kirurgi-og transplantasjonsklinikken Oslo universitetssykehus og Institutt for klinisk medisin Det medisinske fakultet Universitetet i Oslo Engelsk oversettelse på www.tidsskriftet.no Høydosebehandling med autolog stamcellestøtte (HMAS) har vaert et terapialternativ ved lymfomer i Norge helt siden 1987. Ved å gjenopprette beinmargsfunksjonen via tilbakeføring av pasientens egne stamceller kan man gi kreftbehandling i høyere og ellers dødelige doser og dermed oppnå bedre behandlingsresultater. Opprinnelig ble stamcellene høstet fra beinmarg og høydosebehandlingen inkluderte helkroppsbestråling, men fra midten av 1990årene har man høstet stamceller venøst og høydosebehandlingen har bestått i kjemoterapi alene (BEAM-kur). I 1995 ble behandlingen regionalisert og er siden blitt gjennomført i alle helseregioner. HMAS-prosedyren ble innført som utprøvende behandling i kliniske studier med internasjonalt samarbeid. Indikasjonene har endret seg over tid, og dette er nå etablert behandling ved en rekke lymfomtyper.
Background: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL)... more Background: Despite improved survival for the patients with diffuse large B-cell lymphoma (DLBCL), the prognosis after relapse is poor. The aim was to identify molecular events that contribute to relapse and treatment resistance in DLBCL. We analysed 51 prospectively collected pretreatment tumour samples from clinically high risk patients treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis with high resolution array comparative genomic hybridization (aCGH) and gene expression microarrays. Major finding was validated at the protein level immunohistochemically in a trial specific tissue microarray series of 70, and in an independent validation series of 146 patients. We identified 31 genes whose expression changes were strongly associated with copy number aberrations. In addition, gains of chromosomes 2p15 and 18q12.2 were associated with unfavourable survival. The 2p15 aberration harboured COMMD1 gene, whose expression had a significant adverse prognostic impact on survival. Immunohistochemical analysis of COMMD1 expression in two series confirmed the association of COMMD1 expression with poor prognosis. Conclusion: COMMD1 is a potential novel prognostic factor in DLBCLs. The results highlight the value of integrated comprehensive analysis to identify prognostic markers and genetic driver events not previously implicated in DLBCL.
Epigenetic alterations of gene expression are important in the development of cancer. In this stu... more Epigenetic alterations of gene expression are important in the development of cancer. In this study, we identified genes which are epigenetically altered in major lymphoma types. We used DNA microarray technology to assess changes in gene expression after treatment of 11 lymphoma cell lines with epigenetic drugs. We identified 233 genes with upregulated expression in treated cell lines and with downregulated expression in B-cell lymphoma patient samples (n = 480) when compared to normal B cells (n = 5). The top 30 genes were further analyzed by methylation specific PCR (MSP) in 18 lymphoma cell lines. Seven of the genes were methylated in more than 70% of the cell lines and were further subjected to quantitative MSP in 37 B-cell lymphoma patient samples (diffuse large B-cell lymphoma (activated B-cell like and germinal center B-cell like subtypes), follicular lymphoma and Burkitt `s lymphoma) and normal B lymphocytes from 10 healthy donors. The promoters of DSP, FZD8, KCNH2, and PPP1R14A were methylated in 28%, 67%, 22%, and 78% of the 36 tumor samples, respectively, but not in control samples. Validation using a second series of healthy donor controls (n = 42; normal B cells, peripheral blood mononuclear cells, bone marrow, tonsils and follicular hyperplasia) and fresh-frozen lymphoma biopsies (n = 25), confirmed the results. The DNA methylation biomarker panel consisting of DSP, FZD8, KCNH2, and PPP1R14A was positive in 89% (54/61) of all lymphomas. Receiver operating characteristic analysis to determine the discriminative power between lymphoma and healthy control samples showed a c-statistic of 0.96, indicating a possible role for the biomarker panel in monitoring of lymphoma patients.
Genes with altered DNa methylation can be used as biomarkers for cancer detection and assessment ... more Genes with altered DNa methylation can be used as biomarkers for cancer detection and assessment of prognosis. here we analyzed the methylation status of a colorectal cancer biomarker panel (CNRIP1, FBN1, INA, MAL, SNCA, and SPG20) in 97 cancer cell lines, derived from 17 different cancer types. Interestingly, the genes were frequently methylated also in hematological cancer types and were therefore subjected to analyses in primary tumor samples from the major types of non-hodgkin lymphomas (NhL) and in healthy controls. In total, the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 were methylated in 53%, 23%, 52%, 69%, 97%, and 92% of the tumor samples, respectively, and were unmethylated in all healthy controls. With the exception of a single tumor sample, a correct prediction of lymphoma or normal sample was made in a blinded analysis of the validation series using a combination of SNCA and SPG20. The combined ROc-curve analysis of these genes resulted in an area under the curve of 0.999 (P = 4.2 × 10 -18 ), and a sensitivity and specificity of 98% and 100%, respectively, across the test and validation series. Interestingly, the promoter methylation of CNRIP1 was associated with decreased overall survival in diffuse large B-cell lymphoma (DLBcL) (P = 0.03). In conclusion, our results demonstrate that SNCA and SPG20 methylation might be suitable for early detection and monitoring of NhL. Furthermore, CNRIP1 could potentially be used as a prognostic factor in DLBcL.
Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy reg... more Burkitt lymphoma is a highly curable disorder when treated with modern intensive chemotherapy regimens. The majority of adult patients with Burkitt lymphoma in the United States are over age 40. Older patients have historically been underrepresented in published clinical trials of modern intensive therapy, and the outcome of these patients has not been systematically reported. We therefore obtained and analyzed primary data from 14 Burkitt lymphoma treatment series and confirmed that older patients (age > 40) are underrepresented in the literature. Historically inferior outcomes of this age subgroup have improved substantially over time. We conclude that 1) modern intensive chemotherapy regimens should remain the standard of care for patients > age 40 with Burkitt lymphoma, 2) selected patients > age 40 now have highly favorable outcomes, and 3) future studies should include formal analysis of this subgroup of patients.
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Papers by Harald Holte