Challenges and unmet needs in MCL exist for both high-risk and low-risk disease. For patients with high-risk disease, treatment approaches that either limit or avoid the use of dose-intensive therapy are needed to improve outcomes. High-intensity therapy for us today still means dose-intensive chemotherapy, which is largely associated with high toxicity. It would be nice to have aggressive approaches for high-risk patients that do not have the toxicities of dose-intensive therapy. As noted by Dr Leonard and colleagues in their publication in Blood, nonchemotherapy agents, when thoughtfully directed, might address certain aspects of the pathobiology that underlie a poor prognosis, such as TP53 aberration, and might resolve some of the challenges related to the toxicity and deliverability of standard chemotherapy regimens.

Another significant challenge today relates to the use of risk stratification to identify low-risk patients who may benefit from less intensive therapies that can be delivered in a time-limited fashion. We currently have novel approaches, such as Bruton tyrosine kinase (BTK) inhibitor–based therapy, and other active therapies that may be useful in low-risk individuals. However, none of these approaches are currently time limited. We must develop strategies that utilize these novel therapies—perhaps alone but more likely in combination with other treatments—to provide time-limited options for low-risk patients.

The management of relapsed/refractory MCL is one of the greatest challenges, as the duration of remission after second and subsequent lines of therapy is typically shorter than with initial therapy. A better understanding of how to optimally treat patients with relapsed/refractory MCL to provide disease control over longer periods of time, potentially resulting in cure or more durable responses, is one area of unmet need. Patients with TP53 aberration, as well as those with blastic, blastoid, or pleomorphic morphologies, are at exceptionally high risk, and we know that they have inferior survival with the chemoimmunotherapy approaches that are US Food and Drug Administration approved in the frontline setting. There may be opportunities in the future to treat these patients with either novel biologically targeted therapies earlier in their treatment course, as has been shown to be effective in chronic lymphocytic leukemia, or to potentially incorporate some newer therapies (eg, chimeric antigen receptor T-cell therapy, bispecific antibody therapies) that may allow for improvements in overall survival for these highest-risk patients. 

Another unmet need is an incomplete understanding of mechanisms for resistance to BTK inhibition and other biologically targeted therapies in patients with MCL. We lack an understanding of the process of clonal evolution and the emergence of resistance mutations or other molecular alterations associated with therapy resistance. Novel insights into those areas will allow us to refine our understanding of how to select and sequence rational biologically based treatment approaches for different molecular subsets of patients with MCL.

Another unmet need relates to our ability to tailor therapy based on posttreatment prognostic findings. Thus, there has been growing interest in minimal residual disease (MRD) and its significance in MCL. As with many other non-Hodgkin lymphomas, most patients with MCL have advanced-stage disease at diagnosis. And, although the stage does have some influence on outcomes in MCL, it is not as dominant of a factor as it may be with other malignancies such as breast, colorectal, prostate, and skin cancers, where there have been efforts to improve outcomes through early detection. The presence of MRD after treatment, however, appears to be very central to the challenges associated with MCL. Patients who are MRD negative after treatment do better as a group than those who are MRD positive after treatment. Clinical trials evaluating posttransplant consolidation or maintenance approaches have found that survival (both progression-free survival and overall survival) is significantly better among patients who had achieved MRD-negative status post induction.

Ongoing clinical trials may give us answers to important related clinical questions. Can you reduce treatment intensity in patients who are MRD negative? Or should you intensify treatment in those who are MRD positive? Determining how to use MRD to improve outcomes is a subject of major interest at this point. It is one of several ways in which we might tailor subsequent therapies based on posttreatment prognostic findings.