Mantle cell lymphoma has multiple treatment options, yet the disease is difficult to cure. Relapses are common, treatments can cause severe side-effects, and current recommendations are still largely based on age rather than biology. Although suitability for intensive treatment was previously the decisive parameter, increasing knowledge on the biology of mantle cell lymphoma and less toxic targeted therapies has made non-risk adapted treatments outdated. TP53 mutations or deletions, blastoid histology, and a high Ki-67 proliferation index consistently identify patients at high risk of relapse. Additionally, positive measurable residual disease serves as a powerful surrogate endpoint to identify patients with an inadequate treatment response who might benefit from treatment modification. Similarly, markers of indolent mantle cell lymphoma, toxicity, and tolerability need to be further refined and might permit chemotherapy-free approaches. We outline future initiatives aimed at refining risk stratification, harmonising treatment, and integrating multiparameter biomarkers to improve prognosis and provide the biological rational for combination strategies. These efforts are essential to accelerate the translation of biological insights into clinical practice.
Real-world data are essential for understanding treatment-related toxicities in haematology, but traditional analyses are limited by data access, sharing constraints, and reduced data granularity. Emerging digital health technologies (DHTs), such as electronic patient-reported outcomes and wearable devices, can be used to capture continuous, patient-generated data not reliably captured by current post-marketing toxicity assessments. Artificial intelligence, synthetic data, and digital twins can be used to predict and simulate toxicity at a much larger scale beyond the capacity of traditional methodologies. These emerging DHTs could overcome barriers, such as data fragmentation and lack of harmonisation, between existing real-world toxicity data sources. However, they also come with new challenges, including data quality and interpretability, integration into existing clinical workflows, privacy protection, and data governance. Developing and implementing them in partnership with patients, clinicians, payers, and regulators is necessary to maximise their impact in both individual patient and population-level clinical care.
With more potent and novel treatment options, the number of survivors of haematological malignancies is increasing steadily, which in turn leads to the need for parallel improvements in survivorship monitoring and care. The present paper forms part of The Lancet Haematology Series on adverse event reporting, dedicated to improving adverse event assessment in haematological malignancies. Here, we review current survivorship care practice from a global perspective and conclude that access to long-term care plans is highly heterogeneous, with insufficient adaptation to the specific needs of haematological malignancy survivors treated curatively or non-curatively. To advance the field, we propose that clinical trials should include extended follow-up, direct patient reporting, and innovative designs that promote evaluation of survivorship care. Furthermore, we emphasise the importance of observational studies of long-term toxicities using prospective cohorts and national registers leveraged by automated data extraction and advanced statistical modelling. International collaboration and knowledge sharing will be vital to optimise survivorship care for current and future patients.
BACKGROUND:Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell non-Hodgkin lymphoma, but centralised manufacturing-with its complex logistics and long vein-to-vein times-drives up costs and restricts access. We aimed to evaluate the safety of GLPG5101, a fresh, CD19 CAR T-cell product manufactured through a decentralised process, and determine the recommended phase 2 dose. METHODS:This phase 1 dose-escalation part of the ATALANTA-1 phase 1/2, single-arm study, was executed in five hospitals in the Netherlands and Belgium. Patients aged 18 years or older, with histologically confirmed diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL) after two or more lines of therapy, measurable disease according to the Lugano classification, Eastern Cooperative Oncology Group Performance Status 0-2, and adequate organ function were enrolled. Patients were treated with a single intravenous infusion at one of three dose levels of GLPG5101 (dose level 1 [35-50 × 106 viable CAR+ T-cells], dose level 2 [85-110 × 106 viable CAR+ T-cells], and dose level 3 [200-250 × 106 viable CAR+ T-cells]). The phase 1 part of the study applied a Bayesian Optimal Interval design and the primary endpoints were safety (incidence of adverse events and serious adverse events until end of treatment [week 14], and dose-limiting toxicities [DLTs] until day 28) in patients who received fresh GLPG5101 at any dose (excluding recipients of non-conforming product [not meeting prespecified release criteria other than dose]) and determination of the recommended phase 2 dose. The study was registered with ClinicalTrials.gov (NCT06561425) and is closed for recruitment. FINDINGS:From March 15, 2022, to Sept 10, 2024, 27 patients were screened for eligibility, 24 of whom were enrolled, underwent leukapheresis and lymphodepleting chemotherapy and received GLPG5101. Data cutoff was June 1, 2025. In the intention-to-treat population (n=24), the median age was 66·5 years (IQR 59·0-71·5), 15 (63%) patients were male, nine (38%) were female, and 21 (88%) were White. One of the 24 patients received a non-conforming product and was excluded from the safety analysis population. Median follow-up was 24·0 months (IQR 20·7-24·9). Five DLTs were reported: grade 3 thrombocytopenia (n=1, dose level 1), death from intra-abdominal haemorrhage (n=1, dose level 2), and grade 4 prolonged neutropenia not resolving to grade 2 or lower within 28 days (n=1 at dose level 1 and n=2 at dose level 2). All 23 patients in the safety analysis population had grade 3 or higher treatment-emergent adverse events; the most common were neutropenia (22 [96%]), leukopenia (nine [39%]), lymphopenia (seven [30%]), anaemia (six [26%]), and thrombocytopenia (five [22%]). Treatment-related deaths occurred in four patients: one during the 14-week treatment period due to intra-abdominal haemorrhage, and three after the treatment period due to Escherichia coli sepsis (n=1), immune-effector cell-associated haemophagocytic lymphohistiocytic syndrome (n=1), and COVID-19 (n=1). The safety review committee selected 110 × 106 (range 50-110 × 106) viable CAR T-cells as the recommended phase 2 dose. INTERPRETATION:The results of this study showed the feasibility of rapid multicentre decentralised manufacturing and delivery of fresh CAR T-cell therapy in heavily pretreated B-cell non-Hodgkin lymphoma. The phase 2 part of ATALANTA-1 will provide further information on clinical activity and safety. FUNDING:CellPoint, Lakefront Biotherapeutics.
BACKGROUND:High-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, known as double-hit lymphoma, is a highly aggressive malignancy with poor outcomes after standard chemoimmunotherapy. We aimed to study whether the addition of the BCL2-inhibitor venetoclax to chemoimmunotherapy in patients with double-hit lymphoma resulted in superior efficacy compared with chemotherapy alone. METHODS:ALLIANCE A051701 is an open-label, randomised, controlled, phase 2-3 trial in separate cohorts of patients with double-hit lymphoma and patients with double-expressor lymphoma. In this analysis, we report phase 2 results from the double-hit lymphoma cohort. Patients aged 18-80 years with newly diagnosed double-hit lymphoma and Eastern Cooperative Oncology Group (ECOG) performance status 0-2 were recruited from 41 hospitals and outpatient clinics in the USA. Patients were randomly assigned (1:1) to receive DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) either alone (DA-EPOCH-R group) or with venetoclax (DA-EPOCH-R plus venetoclax group) using permuted block randomisation schedule. All patients and investigators were aware of group assignment. DA-EPOCH-R was administered on a 21-day schedule for up to six total cycles. Venetoclax was given as 600 mg by mouth daily on days 4-8 of cycle 1 and on days 1-5 of cycles 2-6. The primary endpoint was progression-free survival in the modified intent-to-treat population inclusive of all eligible patients with centrally confirmed double-hit lymphoma. The safety analysis population consisted of all evaluable patients who received at least one dose of protocol treatment. This trial is registered with ClinicalTrials.gov (NCT03984448) and is closed to enrolment. FINDINGS:36 patients were randomly assigned to the DA-EPOCH-R group and 37 to the DA-EPOCH-R plus venetoclax group between Oct 22, 2019, and Sept 18, 2020. Median age was 65 years (IQR 56-73) and baseline demographic factors were well balanced between groups, with 30 (45%) female and 36 (55%) male patients. Most patients (59 [89%]) were white, two (3%) were Asian, one (2%) was Black or African American, and four (6%) had unknown or unreported ethnicity. The majority of patients had MYC-BCL2 double-hit lymphoma (59 [89%] patients), advanced stage disease (57 [86%] patients), and high-intermediate/high-risk IPI score (42 [64%] patients). Median follow-up was 34·7 months (IQR 30·1-36·8). Median progression-free survival was 28·4 months (95% CI 5·2-not estimable) in the DA-EPOCH-R group (n=30) and 7·7 months (95% CI 4·7-NE) in the DA-EPOCH-R plus venetoclax group (n=36; hazard ratio [HR] 1·13, 95% CI 0·53-2·37; p=0·75). Deaths on treatment occurred in one (3%) patient in the DA-EPOCH-R group (due to dyspnoea; possibly related to treatment) and six (17%) patients in the DA-EPOCH-R plus venetoclax group (four due to sepsis [three at least possible related and one unrelated], two due to cardiac arrest [at least possibly related]), prompting early closure of the double-hit lymphoma cohort. The most common grade 3-4 non-haematological adverse event was febrile neutropenia, occurring in 15 (43%) of 35 patients in the DA-EPOCH-R plus venetoclax group and 11 (37%) of 30 patients in the DA-EPOCH-R group. The median overall survival has not been reached in either group. The 24-month overall survival estimates were 72% (95% CI 52-85) in the DA-EPOCH-R group compared with 52% (95% CI 33-68) in the DA-EPOCH-R plus venetoclax group (HR 2·49, 95% CI 1·03-6·04; p=0·038). INTERPRETATION:The addition of venetoclax to DA-EPOCH-R resulted in excess mortality, prompting early study closure. Robust accrual shows that prospective multicentre trials are feasible in double-hit lymphoma, and the outcomes in the DA-EPOCH-R group serve as a benchmark for future studies. FUNDING:National Cancer Institute of the National Institutes of Health.
The therapeutic landscape of haematological malignancies has evolved rapidly with the introduction of targeted therapies, immunotherapies, and cell-based and gene-based interventions, leading to improved survival and, in some cases, long-term remission or cure. These advances have exposed limitations in traditional approaches to adverse event assessment and reporting. Building on the 2025 Lancet Haematology Series on adverse event reporting, this Series paper examines how proposed improvements in toxicity reporting can be operationalised and integrated into regulatory decision making across clinical trials and real-world settings. We focus on key challenges and opportunities related to measuring cumulative and long-term toxicity burden, incorporating patient-reported outcomes, improving adverse event reporting quality and efficiency in clinical trials, and leveraging real-world data, registries, and emerging technologies, such as artificial intelligence and natural language processing. We also discuss regulatory perspectives from international agencies, including the European Medicines Agency, the Japanese Pharmaceuticals and Medical Devices Agency, and the Australian Therapeutic Goods Administration.
Plasma cell leukaemia is an aggressive plasma cell malignancy characterised by the presence of a high percentage of circulating clonal plasma cells on conventional peripheral blood smear examination. We argue that plasma cell leukaemia must no longer be considered as a separate disease entity but as a type of high-risk multiple myeloma. With the adoption of more strict criteria for defining high-risk multiple myeloma and the relaxation of criteria in defining plasma cell leukaemia, the clinical implications of the terms have converged. Circulating plasma cells-the defining feature of plasma cell leukaemia-are present in almost all patients with multiple myeloma. Thus, the term plasma cell leukaemia merely reflects the high end of a continuum, with the main difference being a quantitative arbitrary threshold based on the percentage of circulating plasma cells. One of the key drivers of our proposal is to make progress against this aggressive malignancy, and to include such patients in clinical trials for multiple myeloma. The term plasma cell leukaemia creates substantial confusion and concern to patients, and it is time for a change. Finally, we provide counterarguments to our proposal and highlight the need to harmonise these proposed changes in disease definitions used by health organisations.
