Epidemiological, clinical and therapeutic profiles of mantle cell lymphoma cared for in a Moroccan center: a review of 14 cases.

Mantle cell lymphoma (MCL) accounts for 3-10% of non-Hodgkin's lymphomas (NHL). We identified 14 patients with mantle cell lymphoma, with an average number of 3.5 new cases/year. A male predominance was observed with a sex ratio equal to 6. The average age of our patients was 64.4±14.1 years, with an average diagnostic delay of 6.57 months. Regarding the clinical presentation, adenopathy was the most reported physical sign (78.6%) followed by B symptoms (57.1%). Disseminated stages were the most frequent in our series: stages IV (78.5%) and III (7.1%) versus stages I (0%) and II (7.1%). The extra-ganglionic localizations observed were hepatic 5 cases (31.1%), pulmonary 04 cases (25%), medullary 4 cases (25%), pleural 2 cases (12.5%) and prostate 1 case (6.2%). All diagnosed cases are mantle cell lymphomas, of which 12 cases (85.7%) are classical and 2 cases (14.3%) indolent. The high-risk group is, according to international prognostic index (MIPI) MCL prognostic score, the most represented in our series: 0-3 = 6 cases (42.9%), 6-11 = 8 cases (57.1%). The therapeutic protocol chosen 1st line: 9 patients treated with R-DHAP, three with R-CHOP, one with DHAOX and one with R-CVP. Second line: two patients treated with R-DHAP, one after R-CHOP and the other after R-CVP. Two patients received autologous hematopoietic stem cell transplant at the end of the treatment. The evolution was marked by the death of 7 patients, 3 lost to follow-up and 4 still followed. Additionally, the study highlights characteristics and treatment patterns of mantle cell lymphoma, emphasizing its predominance in males, delayed diagnosis, frequent dissemination, and high-risk classification, with chemotherapy as the primary treatment modality and a challenging prognosis contributing to a comprehensive understanding of mantle cell lymphoma presentation and management.

Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network.

BACKGROUND: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. METHODS: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. FINDINGS: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). INTERPRETATION: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. FUNDING: Janssen and Leukemia & Lymphoma Society.

Patient perspectives on treatment for mantle cell lymphoma and chronic lymphocytic leukemia in Japan.

The increasing number of treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Japan underscores the critical need to comprehend their treatment preferences. In this study, individual semi-structured interviews with 20 Japanese patients with diagnosis of MCL or CLL/SLL were conducted and qualitatively analyzed to elicit concepts important for patients regarding treatment selection. Although effectiveness and safety were imperative for treatment selection, convenience and quality of life were also reported as important attributes. Over the course of their disease journey, patients reported diverse and changing preferences in terms of treatment characteristics. Additionally, there was a discrepancy between their desired and actual levels of involvement in shared decision-making with physicians about treatment choices. Optimal personalized care for better outcomes of patients with MCL and CLL/SLL hinges on healthcare professionals acknowledging individual patient needs and preferences within their cultural, societal and personal context.

Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma.

ABSTRACT: Mantle cell lymphoma (MCL) is an uncommon mature B-cell lymphoma that presents a clinical spectrum ranging from indolent to aggressive disease, with challenges in disease management and prognostication. MCL is characterized by significant genomic instability, affecting various cellular processes, including cell cycle regulation, cell survival, DNA damage response and telomere maintenance, NOTCH and NF-κB/ B-cell receptor pathways, and chromatin modification. Recent molecular and next-generation sequencing studies unveiled a broad genetic diversity among the 2 molecular subsets, conventional MCL (cMCL) and leukemic nonnodal MCL (nnMCL), which may partially explain their clinical heterogeneity. Some asymptomatic and genetically stable nnMCL not requiring treatment at diagnosis may eventually progress clinically. Overall, the high proliferation of tumor cells, blastoid morphology, TP53 and/or CDKN2A/B inactivation, and high genetic complexity influence treatment outcome in cases treated with standard regimens. Emerging targeted and immunotherapeutic strategies are promising for refractory or relapsed cases and a few genetic and nongenetic determinants of refractoriness have been reported. This review summarizes the recent advances in MCL biology, focusing on molecular insights, prognostic markers, and novel therapeutic approaches.

Mantle Cell Lymphoma Under the Scope of Personalized Medicine: Perspective and Directions.

Mantle cell lymphoma (MCL) is a rare, incurable non-Hodgkin's lymphoma characterized by naive B cells infiltrating the lymphoid follicle's mantle zone. A key feature of MCL is the cytogenetic abnormality t(11;14) (q13:q14), found in 95% of cases, leading to Cyclin D1 overexpression resulting in uncontrolled cell cycle progression and genetic instability. Occasionally, Cyclin D2 or D3 overexpression can substitute for Cyclin D1, causing similar effects. The transcription factor SOX11 is a hallmark of classical Cyclin D1-positive MCL and also in cases without the typical t(11;14) abnormality, making it an important diagnostic marker. MCL's development necessitates secondary genetic changes, including mutations in the ATM, TP53, and NOTCH1 genes, with the TP53 mutation being the only genetic biomarker with established clinical prognostic value. The Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which considers age, performance status, serum LDH levels, and leukocyte count, stratifies patients into risk groups. Histologic variants of MCL, such as classic, blastoid, and pleomorphic, offer additional prognostic information. Recent research highlights new mutations potentially tied to specific populations among MCL patients, suggesting the benefit of personalized management for better predicting outcomes like progression-free survival. This approach could lead to more effective, risk-adapted treatment strategies. However, challenges remain in patient stratification and in developing new therapeutic targets for MCL. This review synthesizes current knowledge on genetic mutations in MCL and their impact on prognosis. It aims to explore the prognostic value of genetic markers related to population traits, emphasizing the importance of tailored molecular medicine in MCL.

Obinutuzumab vs rituximab for transplant-eligible patients with mantle cell lymphoma.

ABSTRACT: Obinutuzumab (O) and rituximab (R) are 2 CD antibodies that have never been compared in a prospective randomized trial of mantle cell lymphoma (MCL). Herein, we report the long-term outcome of the LyMa-101 trial, in which newly diagnosed patients with MCL were treated with chemotherapy plus O before transplantation, followed by O maintenance (O group). We then compared these patients with those treated with the same treatment design with R instead of O (R group). A propensity score matching (PSM) was used to compare the 2 populations (O vs R groups) in terms of measurable residual disease (MRD) at the end of induction (EOI), progression-free survival (PFS), and overall survival (OS). In LyMa-101, the estimated 5-year PFS and OS after inclusion (n = 85) were 83.4% (95% confidence interval [CI], 73.5-89.8) and 86.9% (95% CI, 77.6-92.5), respectively. At EOI, patients treated in the O group had more frequent bone marrow MRD negativity than those treated in the R group (83.1% vs 63.4%; χ2, P = .007). PSM resulted in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, the O group had a longer estimated 5-year PFS (P = .029; 82.8% vs 66.6%; hazard ratio [HR], 1.99; 95% confidence interval (CI), 1.05-3.76) and OS (P = .039; 86.4% vs 71.4%; HR, 2.08; 95% CI, 1.01-4.16) compared with the R group. Causes of death were comparable in the 2 groups, the most common cause being lymphoma. O before transplantation and in maintenance provides better disease control and enhances PFS and OS compared with R in transplant-eligible patients with MCL. These trials were registered at www.clinicaltrials.gov as #NCT00921414 and NCT02896582.

Empowering macrophages: the cancer fighters within the tumour microenvironment in mantle cell lymphoma.

In Mantle Cell Lymphoma (MCL), the role of macrophages within the tumour microenvironment (TME) has recently gained attention due to their impact on prognosis and response to therapy. Despite their low absolute number in MCL tumour tissue, recent findings reveal an association between the levels of macrophages and prognosis, consistent with trends observed in other lymphoma subtypes. M2-like macrophages, identified by markers such as CD163, contribute to angiogenesis and suppression of the immune response. Clinical trials with MCL patients treated with chemoimmunotherapy and targeted treatments underscore the adverse impact of high levels of M2-like macrophages. Immunomodulatory drugs like lenalidomide reduce the levels of MCL-associated CD163+ macrophages and enhance macrophage phagocytic activity. Similarly, clinical approaches targeting the CD47 "don't eat me" signalling, in combination with the anti-CD20-antibody rituximab, demonstrate increased macrophage activity and phagocytosis of MCL tumour cells. Cell-based therapies such as chimeric antigen receptor (CAR) T-cell have shown promise but various challenges persist, leading to a potential interest in CAR-macrophages (CAR-M). When macrophages are recruited to the TME, they offer advantages including phagocytic function and responsiveness to microenvironment alterations, suggesting their potential as a manipulable and inducible alternative when CAR T-cell therapies fails in the complex landscape of MCL treatment.

Twenty Years of Advancing Discoveries and Treatment of Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14) chromosomal translocation, which leads to the dysregulation of the cell cycle through overexpression of cyclin D1. Although advances in treatment have improved outcomes, in particular the introduction of Bruton tyrosine kinase inhibitors to the treatment armamentarium and more recently chimeric antigen receptor T-cell therapy, MCL often rapidly develops resistance and has a high rate of relapse. In addition, MCL is clinically heterogeneous. Response to treatment can vary, making it difficult to establish a standard treatment approach. Thus, there remains a significant need for more research on MCL biology, including those molecular mechanisms underpinning treatment response or lack thereof, so that novel agents may be identified and/or the use of existing agents may be optimized. At the Lymphoma Research Foundation's 20th MCL Scientific Consortium and Workshop, researchers gathered to discuss recent developments in both basic scientific and clinical research to continue to develop an understanding of MCL and improve outcomes for patients. This report, which includes a summary of each presentation, reviews the findings presented at the workshop and highlights opportunities, open questions, and areas for future study that would pave the way for a cure for this disease in the coming decades.

Immunoglobulin High Throughput Sequencing (Ig-HTS) Minimal Residual Disease (MRD) Analysis is an Effective Surveillance Tool in Patients With Mantle Cell Lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) accounts for 4% to 6% of B-cell non-Hodgkin lymphoma with historically poor outcomes. With the advent of intensive first-line, targeted, and cellular therapies, outcomes have improved, and initial remission can be 8 to 10 years or longer. As patients experience longer remissions, this raises the question of the optimal surveillance modality. Peripheral blood minimal residual disease (MRD) analysis offers a potential alternative to surveillance imaging that is sensitive, less costly, and eliminates the risk of radiation exposure. MATERIALS AND METHODS: The clonoSEQ assay (Adaptive Biotechnologies) is an FDA-cleared commercially available Ig-HTS MRD assay with a sensitivity of 1 cell in 1,000,000. We performed a retrospective analysis of 34 patients from 2015 to 2021, who underwent MRD testing after achieving remission with first-line therapy. RESULTS: With a median follow-up of 6.5 years, 10-year progression free survival (PFS) was 60% and 10-year overall survival was 92% of the entire cohort. Among 12 patients who sustained a radiographic relapse, peripheral blood became MRD+ either at or prior to the time of relapse in 11 patients (92%). The first MRD+ test had a lead time of 0 to 24 months (median 34 days) prior to radiographic relapse. Only 1 patient had a MRD- result while being found to have progressive disease on imaging. Among 22 patients who sustained continuous clinical remission, 21 have remained MRD-. Several patients were able to enjoy 2 to 4-year intervals without surveillance imaging. CONCLUSIONS: Our data suggest that the clonoSEQ MRD assay is an effective surveillance tool for MCL patients following first-line therapy and is predictive of relapse prior to imaging.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Letting the mantle out of the bag.

Mantle cell lymphoma is a rare disease that attracts the curiosity of clinicians and scientists due to its heterogeneous clinical behaviour, that can vary from indolent forms to the most aggressive presentations among non-Hodgkin lymphomas. The report by Eyre and colleagues describes the current treatment strategies available in most countries, and offers insights to clinicians for several intriguing difficult-to-treat scenarios. Commentary on: Eyre et al. Diagnosis and management of mantle cell lymphoma: a British Society for Haematology Guideline. Br J Haematol 2024;204:108-126.

Predictive Value of Minimal Residual Disease for Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results From the European Mantle Cell Lymphoma Elderly Trial.

PURPOSE: The outcome of older patients with mantle cell lymphoma (MCL) has improved by the introduction of immunochemotherapy, followed by rituximab (R)-maintenance. Assessment of minimal residual disease (MRD) represents a promising tool for individualized treatment decisions and was a prospectively planned part of the European MCL Elderly trial. We investigated how MRD status influenced the efficacy of R-maintenance and how MRD can enable tailored consolidation strategies. PATIENTS AND METHODS: Previously untreated patients with MCL age 60 years or older have been randomly assigned to R versus interferon-alpha maintenance after response to rituximab, fludarabine, cyclophosphamide (R-FC) versus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). MRD monitoring was performed by real-time quantitative polymerase chain reaction (qPCR) following EuroMRD guidelines. RESULTS: A qPCR assay with a median sensitivity of 1 × 10-5 could be generated in 80% of 288 patients in an international, multicenter, multilaboratory setting. More extensive tumor dissemination facilitated the identification of a molecular marker. The efficacy of R-maintenance in clinical remission was confirmed for MRD-negative patients at the end of induction in terms of progression-free survival (PFS; hazard ratio [HR], 0.38 [95% CI, 0.21 to 0.63]) and overall survival (OS; HR, 0.37 [95% CI, 0.20 to 0.68]), particularly in R-CHOP-treated patients (PFS-HR, 0.23 [95% CI, 0.10 to 0.52]; OS-HR, 0.19 [95% CI, 0.07 to 0.52]). R-maintenance appeared less effective in MRD-positive patients (PFS-HR, 0.51 [95% CI, 0.26 to 1.02]) overall and after R-CHOP induction (PFS-HR, 0.59 [95% CI, 0.28 to 1.26]). R-FC achieved more frequent and faster MRD clearance compared with R-CHOP. MRD positivity in clinical remission after induction was associated with a short median time to clinical progression of approximately 1-1.7 years. CONCLUSION: The results confirm the strong efficacy of R-maintenance in patients who are MRD-negative after induction. Treatment de-escalation for MRD-negative patients is discouraged by our results. More effective consolidation strategies should be explored in MRD-positive patients to improve their long-term prognosis.