We assessed stage-specific trends in primary therapy and relative survival among adult follicular lymphoma (FL) patients diagnosed in the Netherlands between 1989-2016 (N = 12,372; median age, 62 ...years; and 21% stage I disease). Patients were stratified by disease stage and subsequently categorized into four calendar periods (1989-1995, 1996-2002, 2003-2008, and 2009-2016) and three age groups (18-60, 61-70, and >70 years). The use of radiotherapy in stage I FL remained relatively stable over time and across the three age groups (i.e., 66%, 54%, and 49% in 2009-2016, respectively). In stage II-IV FL, the start of chemotherapy within 12 months post-diagnosis decreased over time, indicating a broader application of a watch-and-wait approach. Relative survival improved considerably over time, especially since 2003 when rituximab was introduced in the Netherlands, and for stage III-IV FL patients and older age groups. Five-year relative survival for patients with stage I-II versus stage III-IV FL in the period 2009-2016 was 96% versus 90%, 93% versus 83%, and 92% versus 68% across the three age groups, respectively. Collectively, the improvement in survival since 2003 is accounted for by advances in FL management, particularly the implementation of rituximab. There remains, however, room for improvement among elderly stage III-IV FL patients.
Patients aged <65 years with peripheral T-cell lymphoma (PTCL) are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Although the addition of etoposide (CHOEP) and ...consolidation with autologous stem cell transplantation (ASCT) are preferred in some countries, randomized trials are lacking. This nationwide population-based study assessed the impact of etoposide and ASCT on overall survival (OS) among patients aged 18 to 64 years with stage II to IV anaplastic large-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (NOS) diagnosed between 1989 and 2018 using the Netherlands Cancer Registry. Patients were categorized into 2 calendar periods, representing pre- and post-eras of etoposide and ASCT, respectively. A total of 1427 patients were identified (ALCL, 35%; AITL, 21%; and PTCL NOS, 44%). OS increased from 39% in the period from 1989 to 2009 to 49% in the period of 2009 to 2018 (P < .01). Five-year OS was superior for patients treated with CHOEP vs CHOP (64% and 44%, respectively; P < .01). When adjusted for subtype, International Prognostic Index score, and ASCT, the risk of mortality was similar between the 2 groups, except for patients with ALK+ ALCL, for whom the risk of mortality was 6.3 times higher when treated with CHOP vs CHOEP. Patients undergoing consolidation with ASCT had superior 5-year OS of 81% compared with 39% for patients not undergoing ASCT (P < .01), regardless of whether complete remission was achieved. In patients aged <65 years with advanced-stage ALK− ALCL, AITL, or PTCL, the use of ASCT consolidation, but not the addition of etoposide, was associated with improved OS.
•In advanced-stage T-cell lymphoma, the addition of etoposide to CHOP improved OS in ALK+ ALCL but not in ALK− ALCL, AITL, or PTCL NOS.•Consolidation with ASCT in the first-line setting significantly increased OS in ALK− ALCL, AITL, and PTCL NOS.
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Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large ...B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment.
Patients with angioimmunoblastic T-cell lymphoma (AITL) are treated with cyclophosphamide, doxorubicin, vincristine and prednisone with or without etoposide (CHO(E)P). In the majority of cases, ...Epstein–Barr virus (EBV)-positive B-cells are present in the tumour. There is paucity of research examining the effect of rituximab when added to CHO(E)P. In this nationwide, population-based study, we analysed the impact of rituximab on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) of patients with AITL.
Patients with AITL diagnosed between 2014 and 2020 treated with ≥one cycle of CHO(E)P with or without rituximab were identified in the Netherlands Cancer Registry. Survival follow-up was up to 1st February 2022. Baseline characteristics, best response during first-line treatment and survival were collected. PFS was defined as the time from diagnosis to relapse or to all-cause-death. OS was defined as the time from diagnosis to all-cause-death. Multivariable analysis for the risk of mortality was performed using Cox regression.
Out of 335 patients, 146 patients (44%) received R–CHO(E)P. Rituximab was more frequently used in patients with a B-cell infiltrate (71% versus 89%, p < 0·01). The proportion of patients who received autologous stem cell transplantation (ASCT) was similar between CHO(E)P and R–CHO(E)P (27% versus 30%, respectively). The ORR and 2-year PFS for patients who received CHO(E)P and R–CHO(E)P were 71% and 78% (p = 0·01), and 40% and 45% (p = 0·12), respectively. The 5-year OS was 47% and 40% (p = 0·99), respectively. In multivariable analysis, IPI-score 3–5, no B-cell infiltrate and no ASCT were independent prognostic factors for risk of mortality, whereas the use of rituximab was not.
Although the addition of rituximab to CHO(E)P improved ORR for patients with AITL, the PFS and OS did not improve.
•Epstein–Barr virus-positive B-cells are present in most angioimmunoblastic T-cell lymphomas.•The effect of rituximab when added to CHO(E)P remains unknown.•Nearly half of patients with angioimmunoblastic T-cell lymphoma (44%) at population level received rituximab.•There is no progression-free survival and overall survival difference between patients treated with or without rituximab.
Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics ...of isatuximab (Isa, anti‐CD38 antibody) in combination with cemiplimab (Cemi, anti‐programmed death‐1 PD‐1 receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B‐cell lymphoma (DLBCL), and peripheral T‐cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de‐escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti‐PD‐1/programmed death‐ligand 1 PD‐L1 naïve), and objective response rate in Cohorts A2 (cHL anti‐PD‐1/PD‐L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose‐limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti‐PD‐1/PD‐L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations.
Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of mature T-cell neoplasms with an unfavorable prognosis; presentation with stage I(E) disease is uncommon. In clinical practice, an ...abbreviated chemotherapy treatment regimen combined with radiotherapy (combined modality treatment CMT) is commonly used, although evidence from clinical trials is lacking. The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL. All newly diagnosed patients ≥18 years with stage I(E) anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma NOS (PTCL not otherise specified NOS) in 1989-2020 were identified in the Netherlands Cancer Registry. Patients were categorized according to treatment regimen, i.e., chemotherapy (CT), radiotherapy (RT), CMT, other therapy and no treatment. The primary endpoint was overall survival (OS). Patients with stage I(E) ALCL, AITL and PTCL NOS (n=576) were most commonly treated with CMT (28%) or CT (29%), 2% underwent SCT. RT only was given in 18%, and 8% received other therapy and 16% no treatment. Overall, the 5-year OS was 59%. According to subtype, 5-year OS was superior for ALCL as compared to PTCL NOS and AITL (68% vs. 55% and 52%, respectively; P=0.03). For patients treated with CMT, 5-year OS was significantly higher (72%) as compared to patients treated with either CT or RT alone (55% and 55%, respectively; P<0.01). In multivariable analysis, age per year increment (hazard ratio HR =1.06, 95% confidence interval CI: 1.05-1.07), male sex (HR=1.53, 95% CI: 1.23-1.90), and CT, or no treatment (HR=1.64, 95% CI: 1.21-2.21, and HR=1.55, 95% CI: 1.10-2.17, respectively) were associated with a higher risk of mortality. For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 59%, comparing favorably to historical outcome in advanced-stage disease. Superior outcome estimates were observed in patients treated with CMT.
Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose ...methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months.
One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively.
For event-free survival, the hazard ratio was 0.85, 95% CI 0.61-1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term.
Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.
The MOSA study (Maastricht Observational study of late effects after Stem cell trAnsplantation) aims to study the prevalence of adverse health effects in hematopoietic stem cell transplantation (HCT) ...survivors compared to a matched cohort, representing the general population.
The MOSA study is a matched cohort study, nested within a large prospective cohort, The Maastricht Study. Participants of The Maastricht Study serve as a reference group matched on age, gender, and education to compare MOSA participants to the general population. In both studies, the same study protocol and extensive phenotyping measurements are used.
HCT Survivors: Five hundred and thirty nine survivors were invited of which, so far, 123 (23%) participants completed the study assessments. Data will be analyzed and published separately. Reference Group: For each MOSA participant, four reference cases were matched. After matching, both groups are comparable with respect to age, gender, and education.
To our knowledge, this is the first study conducting such detailed phenotyping in HCT survivors. Comparison with a large reference group provides essential information about late effects of HCT and associated risk factors. This may improve screening and prevention strategies, potentially leading to a positive impact on morbidity, mortality, and quality of life.
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•A cohort study with a large reference group matched on age, gender, and education representing the general population to study long-term adverse effects in hematopoietic stem cell transplantation (HCT) survivors.•The first study conducting extensive in-depth phenotyping in HCT survivors including assessment of relevant outcomes of cardiovascular, neurological, respiratory, and musculoskeletal diseases.•HCT survivors and the reference group undergo the same measurements. The reference group enables detection of somatic diseases, mental disorders, and functional limitations that occur earlier or more frequently than expected.
The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the ...Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.
