Evolving therapeutic strategies in mantle cell lymphoma: advancements and future directions

Leukemia REVIEW ARTICLE www.nature.com/leu OPEN Evolving therapeutic strategies in mantle cell lymphoma: advancements and future directions ✉ Rita Tavarozzi 1,2 , Nawar Maher 1,2, Gioacchino Catania2, Giulia Zacchi2, Francesca D’Andrea2, Antonella Sofia2, 2 Manuela Zanni and Marco Ladetto1,2 1234567890();,: © The Author(s) 2026 Mantle cell lymphoma (MCL) is a biologically and clinically heterogeneous B-cell malignancy with a historically poor prognosis. Recent advances have substantially expanded treatment options, particularly through the integration of targeted therapies, chemotherapy-free regimens, and cellular approaches. Frontline treatment now incorporates Bruton’s tyrosine kinase inhibitors (BTKi) in combination with chemotherapy and in chemotherapy-free regimens. For patients with relapsed or refractory disease, particularly those previously exposed to BTKi, chimeric antigen receptor T-cell (CAR T) therapies and third-generation BTKi like pirtobrutinib provide highly effective options while several novel agents, including bispecific antibodies (bsAbs), are under investigation. Nevertheless, achieving long-lasting remissions is still a major challenge, especially among high-risk patients. Future directions include optimizing sequencing, refining rational combination therapies, expanding the application of bsAbs, and integrating small molecules and novel immunoconjugates to enhance therapeutic efficacy and long-term outcomes. This review provides an overview of the current and emerging therapies for MCL, highlighting how the integration of biological agents, strategic combinations, and patient-centered approaches are driving the next phase of MCL treatment. Leukemia; https://doi.org/10.1038/s41375-026-02942-1 INTRODUCTION Mantle cell lymphoma (MCL) is an uncommon and aggressive subtype of B-cell non-Hodgkin lymphoma (B-NHL), first recognized as a distinct clinicopathological entity in the 1980s and formally classified by the World Health Organization (WHO) in 1994 [1, 2]. It is mainly characterized by the t(11;14) translocation, which leads to cyclin D1 overexpression and uncontrolled cell proliferation [3, 4]. MCL presents with a broad clinical spectrum, ranging from indolent, slow-progressing to highly aggressive forms [3, 4]. While in the past MCL was associated with poor outcomes, with a median survival of just 3–5 years [2], advancements in risk stratification, and treatment have significantly improved the outcomes of MCL patients [5]. This review examines the recent therapeutic progress in MCL, with a particular focus on targeted therapies and emerging immunotherapeutic approaches. Ultimately, it aims to provide clinicians with an updated framework to understand the ongoing therapeutic advances and guide informed, patient-centered decision-making. PROGNOSTIC FEATURES IN MCL As the therapeutic landscape continues to evolve, a deeper understanding of the prognostic factors influencing MCL outcome has become increasingly important. Prognostic models now integrate histopathologic characteristics [3, 4, 6], clinical indices [7–10], genomic alterations [11–13], relapse timing [14], and measurable residual disease (MRD) [15–19] status. While a comprehensive description of these factors goes beyond the scope of this review, we herein summarize the key clinical predictors currently identified (Table 1), along with a critical evaluation of their limitations (Table 2). FIRST-LINE TREATMENT OF MCL The historical backbone in MCL For many years, chemoimmunotherapy (CI) represented the standard first-line approach for patients with previously untreated MCL [20–25], although its role was increasingly being challenged by emerging biologic and targeted strategies [26, 27]. In younger, fit patients, Ara-C-containing induction followed by autologous stem-cell transplantation (ASCT) was historically considered the conventional standard [20–22]; however, accumulating evidence showed that the clinical benefit of ASCT was substantially diminished [28, 29]. For patients who are ineligible for intensive therapy, there was no universally accepted front-line treatment [24, 25, 30]. Bendamustine-based regimens were widely used due to their favorable balance of efficacy and tolerability. R-bendamustine (RB) achieved higher response rates and longer PFS compared with R-CHOP, and in day-to-day practice many clinicians preferred R-B because of its superior tolerability profile, especially regarding neuropathy and alopecia [23, 24]. The low-dose 1 Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy. 2SCDU of Hematology, Azienda Ospedaliera Universitaria SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. ✉email: Received: 24 July 2025 Revised: 23 February 2026 Accepted: 17 March 2026 R. Tavarozzi et al. 2 Table 1. Selected clinical prognostic scores in MCL. Scoring system Components Calculation Risk group PFS OS MIPI [7] Age, ECOG PS, LDH, WCC 0.03535 × age (years) + 0.6978 (if ECOG PS > 1) + 1.367 × log10 (LDH/ULN) + 0.9393 × log10 (WCC per 10-6) LR < 5.70 IR ≥ 5.70 HR ≥ 6.20 s-MIPI [8] Age, ECOG PS, LDH, WCC - Age: 1 point for 50–59, 2 for 60–69, 3 for ≥ 70 years - ECOG: 2 points for ECOG 2-4 - LDH/ULN ratio: 1 point for 0.67–0.99, 2 points for 1.0–1.49, 3 points for ≥ 1.50 - WCC 109/L: 1 point 6.7–9.99, 2 points 1.00–14.99, 3 points ≥ 15.0 LR: 0–3 IR: 4–5 HR: 6–11 LR: not reached IR: 58 months HR: 37 months LR 60% IR 35% HR 20% MIPI-b [9] Age, ECOG PS, LDH, WCC, Ki67% CBS: 0.03535 × age (years) 1 0.6978 (if ECOG > 1) + 1.367 × log10(LDH/ULN) + 0.9393 x log10(WCC) + 0.02142 × Ki67%. LR: CBS < 5.7 IR: CBS 5.7–6.5 HR: CBS ≥ 6.5 3-year PFS LR 74.9% IR 43.4% HR 16.1% 3-year OS LR84.4%, IR62.2%, HR 27.6% MIPI-c [10] Age, ECOG PS, LDH, WCC, Ki67% - MIPI calculation - Ki67% ( < 30% or ≥ 30%) LR: LR MIPI + Ki67 < 30% LI: either LR MIPI + Ki67 ≥ 30% or IR MIPI + Ki67 < 30% HI: either IR MIPI + Ki67 ≥ 30% or HR MIPI + Ki67 < 30% HR: HR MIPI and Ki67 ≥ 30% 5-year OS LR 83% IR 63% HR 34% 5-year OS LR 85% LI 72% HI 43% HR 17% Age Patient age (years), CBS Continuous Biological Score, ECOG PS Eastern Cooperative Oncology Group Performance Status, HI High-Intermediate Risk, HR High Risk, IR Intermediate Risk, Ki67% Ki-67 proliferation index (percentage of tumor cells staining positive), LDH Lactate Dehydrogenase, LI Low-Intermediate Risk, LR Low Risk, MIPI Mantle Cell Lymphoma International Prognostic Index, MIPI-b Biologic Mantle Cell Lymphoma International Prognostic Index, MIPI-c Combined Mantle Cell Lymphoma International Prognostic Index, OS Overall Survival, PFS Progression-Free Survival, s-MIPI Simplified Mantle Cell Lymphoma International Prognostic Index, ULN Upper Limit of Normal, WCC White Cell Count (white blood cell count). cytarabine–containing R-BAC regimen produced deep and durable responses in older patients, and in experienced centers it was often considered for fit elderly individuals able to tolerate the added myelosup (...truncated)