Two major treatment advances that have occurred in recent years are Bruton tyrosine kinase (BTK)–based therapy and rituximab maintenance after autologous stem cell transplantation. Still, the treatment of patients with high-risk MCL remains an unmet need. BTK-based therapy is a major advance that has clearly become standard treatment for almost every patient with MCL at some point in their disease course. Ibrutinib has proven to be an effective agent for patients with relapsed/refractory MCL; however, although it is usually well tolerated, ibrutinib can be associated with unique toxicities that require discontinuation in some patients. Novel BTK inhibitors such as acalabrutinib and zanubrutinib were designed to improve on the safety and efficacy of first-generation BTK inhibitors, but we lack head-to-head data. Further, zanubrutinib was only recently introduced, so the bulk of the data that we have right now on toxicities with these agents relate to ibrutinib. The use of rituximab maintenance after autologous stem cell transplantation has improved overall survival and is another major advance. As relates to prognostic indices and their interpretation in the current treatment era, the Mantle Cell Lymphoma International Prognostic Index score has held up in most studies, just as the International Prognostic Index score has held up in just about every study for large cell lymphoma. I think that it is likely that many of the clinical MCL prognostic factors will maintain their utility going forward and that the biologic prognostic factors will evolve with the emergence of newer therapies.

We also have a greater ability to identify patients at the highest risk, whether using morphology, such as blastoid or pleomorphic morphology, the presence of a TP53 mutation, or the proliferation signature. Unfortunately, even though we can identify these very high-risk patients, we have not yet defined tailored treatment approaches that we can offer these patients as an alternative (ie, to optimally match their phenotype). I believe that the identification of these high-risk patients will lead to unique clinical trial approaches, such as the early use of biologically targeted therapies or immunotherapy strategies (eg, chimeric antigen receptor T-cell therapy, bispecific antibody therapy). These novel therapeutic strategies may significantly improve the survival outcomes of the highest-risk patients in the future.

The progress that has been made in our understanding of MCL over the past 10 years is really quite amazing. Although the concept of MCL existed as early as the 1980s, its classification and diagnostic criteria were unsettled for some time. Prior to the 2008 World Health Organization classification, patients with what is now recognized as MCL may have been classified as having an aggressive small B-cell lymphoma, or perhaps chronic lymphocytic leukemia. The classification system has evolved; today, MCL is an entity that we can distinguish and understand clinically. We have prognostic factors that predict which patients are likely to have a shortened progression-free survival and overall survival and which may have a longer life expectancy. 

Still, one of the major challenges with this disease is that chronological age remains a prominent part of the prognostic system. That is, while older age does successfully predict worse survival, age as a prognostic factor is not tremendously helpful to us in terms of identifying the best ways to manage this disease. The broader challenge is that, while we have prognostic factors that indicate how a patient might do generally, we still lack predictive biomarkers that tell us how to treat individual patients, to optimize outcomes based on those particular factors or biomarkers.