There are several unmet needs in MCL, including the need to improve outcomes for high-risk patients and for those with relapsed disease. We have made progress in characterizing indolent and aggressive subsets, but I think that we need to continue to characterize MCL biologically, utilizing genomic sequencing and other molecular and cytogenetic tools to help guide and optimize individualized treatment. That is really the holy grail of personalized medicine, which is critical in MCL, with its great clinical and biologic heterogeneity. 

Many studies have demonstrated that chemoimmunotherapy is associated with inferior outcomes in patients with TP53-mutant disease. With the US Food and Drug Administration approval of brexucabtagene autoleucel for relapsed or refractory MCL, there is now a chimeric antigen receptor (CAR) T-cell platform, and this is very exciting. There is excellent activity in patients who have high-risk features, so there is the suggestion that CAR T-cell therapy may be more agnostic to the patient’s underlying biologic features. And I think that all of us in the field are starting to think about how best to use these cellular therapies in high-risk patients at the appropriate point in time. Thus, trials to better inform the use of CAR T-cell therapies—not to mention bispecific antibodies—are needed.

Additionally, there is much interest in the use of combination approaches, and the next generation of clinical trials will likely provide us with answers to our ongoing questions. There are studies combining a BTK inhibitor with another biologically targeted agent to examine whether there may be improved depth and durability of response. Ongoing studies are also looking at the use of CAR T cells in combination with biologically targeted therapies such as BTK inhibitors in the frontline setting for the highest-risk patients with MCL. Although BTK inhibitors have excellent efficacy in individuals with MCL, we need to better understand which patients achieve the deepest and most durable responses. Other research is focused on the question of whether stem cell transplantation is truly required in patients with positron emission tomography–negative, minimal residual disease–negative MCL that is in first complete remission (eg, the TRIANGLE study in Europe and EA4151 in the United States).

While these studies are very exciting, outside of clinical trials, we are following the current evidence-based standards of care until we have more data to suggest that a different approach would be beneficial. In patients who are younger, cytarabine-containing induction followed by autotransplant should really be considered. The general paradigm is still chemoimmunotherapy, then BTK inhibitors in the second line, and then CAR T cells. That is the natural sequence in MCL right now, but we have to try to better understand and refine that sequence for different biologic subsets of the disease.