Introduction to a review series on mantle cell lymphoma: sands shifting in the darkness

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that has historically been as easy to diagnose as it has been challenging to treat. Survival in this disease was woeful as recently as 15 years ago, with median overall survival (OS) under 5 years, even after the introduction of rituximab.¹ Since then, there has been remarkable improvement, at least in younger patients. This appeared to result from the more aggressive use of cytotoxic agents, including cytarabine in induction and autologous stem cell transplantation (ASCT), as well as rituximab maintenance, yielding median frontline progression-free survival rates close to double the prior median OS rates.^2-4 In parallel, new treatments have become available for patients with relapsed/refractory (R/R) disease, in particular Bruton tyrosine kinase inhibitors (BTKis) and chimeric antigen receptor (CAR) T cells, although the median duration of benefit for both is still limited, such that their impact on OS may be attenuated compared with that of advances in frontline therapy.

Enter the 2020s, with randomized studies upending our previous beliefs. The TRIANGLE study demonstrated not only a benefit (at least in failure-free survival) with the addition of a BTKi with induction and maintenance in front line but also a lack of benefit for ASCT with this combination.⁵ Furthermore, the phase 3 EA4151 showed no benefit of ASCT even after standard induction, at least in patients who were in deep remission at the end of induction.⁶ The EA4181 trial showed no increase in minimal residual disease (MRD)–negative complete response (CR) rate with the addition of a BTKi to a modern induction chemoimmunotherapy (CIT) regimen.⁷ Finally, long-term analysis of the LyMA study showed that maintenance rituximab after induction and ASCT did not, in fact, prolong OS.⁸ Together, these landmark studies are fundamentally challenging our treatment paradigms for younger patients. With no apparent benefit to ASCT (when studied in TRIANGLE and EA4181), no apparent benefit to BTKi addition to induction CIT (for MRD-negative CR rate at least), and no OS benefit to rituximab maintenance, and considering our still limited success in R/R disease, it is now less clear what standard frontline therapy should be, and what might then explain the dramatic improvement in OS in the last 15 years.

In parallel, the last decade has brought significant improvement in risk stratification in MCL, in particular with the recognition that patients with TP53-mutated MCL have much poorer outcomes with most available therapies, as well as a better understanding of which patients are at high risk of treatment failure beyond TP53 status (see the review by Jain and Wang in this series). Yet despite this understanding, we have absolutely no standard of care for high-risk patients, nor even a uniform way of categorizing who they are. Chemotherapy-free regimens are a tempting alternative for those patients,⁹ but there are no comparative data to prove the superiority of this approach.

Our review series seeks to frame those questions for readers in a modern context with the following articles:

• Christine E. Ryan, Philippe Armand, and Ann S. LaCasce, “Frontline management of mantle cell lymphoma”

• Elisabeth Silkenstedt and Martin Dreyling, “Treatment of relapsed/refractory MCL”

• Preetesh Jain and Michael Wang, “High-risk MCL: recognition and treatment”

• Clémentine Sarkozy, Benoit Tessoulin, and David Chiron, “Unraveling MCL biology to understand resistance and identify vulnerabilities”

Ryan et al review some of the key questions in the choice and design of frontline treatments. Silkenstedt and Dreyling review the many advances in the treatment of patients with R/R disease, addressing the complexity of accounting for disease risk and prior therapy in the rapidly shifting landscape. Jain and Wang provide extensive details and recommendations on how to recognize patients with high- and very high-risk disease and how to select their treatment. These 3 reviews propose expert treatment recommendations, but upcoming trial results will doubtlessly affect these; perhaps more importantly, they frame the questions that clinicians need to be mindful of in selecting treatments for individual patients, and the questions that researchers need to tackle in order to improve these treatments. This latter part will certainly require a deepening of our biological understanding of MCL and its molecular subtypes, which will be critical to target its specific vulnerabilities. Sarkozy et al address this, summarizing the current state of our understanding and how it might inform future research.

We hope that this review series helps readers understand some of the key current questions in MCL, how to manage patients, what to expect from ongoing trials, and how future research might lead, in the next decade, to improvements in OS as large as what the last 2 decades have brought; in short, we hope that they help to illuminate what our approach to MCL treatment might look like as the sands shift.