SOHO State of the Art Updates and Next Questions: Treatment Evolution of Mantle Cell Lymphoma: Navigating the Different Entities and Biological Heterogeneity of Mantle Cell Lymphoma in 2024

Progress in mantle cell lymphoma (MCL) has led to significant improvement in outcomes of patients even in the real world (RW) setting albeit to a lesser degree. In parallel to the demonstration of benefit using combination therapy with rituximab plus high-dose cytarabine (R-AraC) as well as dose intensive therapy-autologous stem cell transplantation (DIT-ASCT) consolidation and maintenance, it became clear over the last 2 decades that MCL is a highly heterogenous disease at the molecular level, explaining differences observed in clinical behavior and response to therapy. While clinical prognostic factors and models have helped stratify patients with distinct outcomes, they failed to help guide therapy. The identification of molecular high-risk (HR) features, in particular, but not only, p53 aberrations (including mutations and deletions [del]), as well as complex karyotype (CK), has allowed to identify subsets of patients with poorer outcomes (median overall survival [OS] < 2 years) regardless of conventional therapies used. The constant pattern of relapse seen in MCL has fueled sustained and productive efforts, with 7 novel agents approved in the United States (US), showing high and durable efficacy even in HR and chemo-refractory patients and likely curing a subset of patients in the relapsed or refractory (R/R) setting. Progress in diagnostics, in particular next-generation sequencing (NGS), which is accessible in routine practice nowadays, can help recognize patients with HR features, well beyond MIPI or Ki-67 prognostication, although the impact on decision making is still unclear. The era of integrating novel agents into our prior standard of care (SOC) has begun with a confirmed benefit, for example, ibrutinib (Ib) in the TRIANGLE study, defining the first new potential SOC in younger patients in over 30 years. Expanding on novel agents, either in combination, sequentially or to replace chemotherapy altogether, using biological doublets or triplets has led to a median progression-free survival (PFS) in excess of 72 months, certainly competitive with prior SOC and will continue to reshape the management of MCL patients. Achieving minimal residual disease negative (MRD-ve) status is becoming a new endpoint in MCL, and customizing maintenance and/or de-escalation/consolidation strategies is within reach, although it will require prospective, built-in MRD-based approaches, with the goal of eliminating subclinical disease and not simply delaying time to relapse. Taking into account the biological diversity of MCL is now feasible in routine clinical practice and has already helped recognize what not to do for HR patients (i.e., avoid intensive induction chemotherapy and/or ASCT for p53 mutated patients) as well as identify promising novel options. Ongoing and future work will help expand on these dedicated approaches, to further improve the management and outcomes of all MCL patients.