It can be challenging to choose between chemoimmunotherapy and chemotherapy-free induction regimens for older patients with mantle cell lymphoma (MCL) who are ineligible for autologous stem cell transplant (ASCT). While chemoimmunotherapy has been evaluated in a greater number of clinical trials, there are now effective chemotherapy-free induction regimens available and additional promising regimens currently under evaluation.

A critical question that we face with older patients and their caregivers is: What induction therapy do we choose for patients who are not suited for ASCT? The good news is that there are a lot of options available for the first-line treatment of MCL, regardless of age, comorbidities, TP53 mutation status, and other disease features, and our options are expanding. There are some patients with limited options for whom one treatment is clearly preferred, but, for many patients, there is no clear right or wrong choice between chemoimmunotherapy and chemotherapy-free induction regimens.

Although there are broad treatment paradigms, treatment selection is very individualized. We consider patients’ functional status, extent and localization of disease, chronological age, disease indolence, and goals/preferences. We also consider how often patients would need to come in to receive each therapy, whether they travel, and whether they have any other quality-of-life concerns that would impact our decision. Patients might prefer a more or less aggressive treatment approach or be more or less averse to potential side effects.

Disease factors that we assess and consider as we make decisions regarding treatment include histology, the Mantle Cell Lymphoma International Prognostic Index (MIPI; ideally, the biologic MIPI [MIPIb]) score, and TP53 status. Blastoid or pleomorphic histology suggests more aggressive disease. The MIPIb incorporates Ki-67 and improves its prognostication; a higher Ki-67 percentage often corresponds to more disease activity or aggressiveness. TP53 deletions and mutations are the most established genetic biomarkers in MCL and are associated with an inferior prognosis. If a patient’s MCL displays more adverse risk features, that makes me more worried and suggests that we may need to act more urgently and/or consider a more intensive treatment approach. Additionally, especially for TP53 mutations and blastoid or pleomorphic MCL, these are scenarios in which we often favor novel targeted therapy, ideally administered in a clinical trial, over chemoimmunotherapy such as bendamustine plus rituximab (BR) or cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We encourage patients with MCL to enroll in clinical trials whenever possible because that is how we move the field forward.

The most established frontline chemotherapy-free regimen combines the IMiD lenalidomide with rituximab, and one of the most common chemoimmunotherapy regimens is BR. Regarding other novel targeted therapies, the ongoing BOVen trial, led by our center, is combining the BTK inhibitor zanubrutinib, the anti-CD20 monoclonal antibody obinutuzumab, and the Bcl-2 inhibitor venetoclax in (a) patients with TP53-mutated MCL or (b) ASCT-ineligible patients. There are also supportive data for the combination of acalabrutinib plus rituximab, and the ongoing MANGROVE study is evaluating zanubrutinib plus rituximab vs BR specifically in ASCT-ineligible patients. We eagerly anticipate the results from this study to inform our future practice.

Overall, there is a fair degree of optimism right now within in the MCL field about the recent advances that have been made. The toolbelt of treatments is expanding, much of it borrowed from other B-cell non-Hodgkin lymphomas, and hopefully this pattern continues with CAR T-cell therapy and bispecific antibodies. I think that, over the next 10 years, the field will really continue ahead in a very positive way for patients, and we will continue to expand that toolbelt over time.