The MCL treatment landscape has changed in recent years with the introduction of novel targeted therapies. In the relapsed setting, chemotherapy-free treatment strategies are now preferred for nearly all patients with MCL, particularly those with TP53 mutation. Data from the Nordic Lymphoma Group suggest that these patients are not well served by intensive immunochemotherapy in the frontline and relapsed settings. Eskelund et al examined the prognostic value of genetic aberrations in diagnostic bone marrow specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 studies. The authors concluded that those with TP53 mutations appear to have a phenotypically distinct and highly aggressive form of MCL, with poor or no response to regimens that include cytarabine, rituximab, and autologous stem cell transplantation. 

In general, we would favor novel therapeutic approaches for patients with MCL in the relapsed setting. BTK inhibition has emerged as a standard treatment approach for relapsed MCL. Many clinical trials are actively studying BTK inhibition in combination with other biologically targeted agents, such as BCL2 inhibitors, PI3K inhibitors, and CDK4/6 inhibitors. These combinations may increase the depth and durability of response in the relapsed setting. Patients with relapsed/refractory MCL and TP53 mutation can have responses to BTK inhibition; however, the depth and duration of response are quite limited. In addition to combinatorial approaches, there are also emerging novel immunotherapies, such as chimeric antigen receptor (CAR) T cells or bispecific antibody therapies, that may be associated with more durable responses, even in the highest-risk patients with MCL. 

We have moved into a new era of chemotherapy-free approaches to the treatment of patients with MCL who relapse or become refractory to treatment. In the past, we would have thought of giving chemotherapy for induction and then chemotherapy again in relapse, but that is no longer the case in most instances. Thus, we really have moved to a chemotherapy-free era in the relapsed setting. BTK inhibitors have become the most commonly used and most appropriate second-line therapy in the relapsed setting for patients with MCL. These include the first-generation BTK inhibitor ibrutinib, as well as the second-generation BTK inhibitors acalabrutinib and zanubrutinib. Other options, including bortezomib, lenalidomide, and other small molecules, are used less frequently. Chemotherapy is still a potential option for this patient population, but nonchemotherapy approaches are now being used with increased frequency for MCL in the relapsed setting. CAR T-cell therapy and other novel approaches are currently under evaluation and may be available in the near future, but these are still investigational approaches as of now. The US Food and Drug Administration and the European Medicines Agency have not yet approved these treatments for MCL.

Chemotherapy-free approaches may have a role in some upfront settings as well as in relapsed settings. Whether these approaches are better than chemotherapy in terms of response rates and toxicities, and better for certain patients, is the focus of ongoing investigation. We now have several BTK inhibitors approved for the treatment of patients with MCL. At this point, I do not believe that we have strong evidence that the BTK inhibitors differ meaningfully in efficacy in the treatment of MCL. Although there are theoretical reasons for potential differences that we might see in efficacy, these are not well established. The toxicity profiles are a bit variable in some ways, and that may influence how specific BTK inhibitors are chosen for a specific individual patient.

Another consideration is that, at this point, chemotherapy-free approaches are primarily BTK inhibitor based or lenalidomide based, and some of the important questions relate to risk-benefit considerations and trade-offs at the patient level. For example, how is quality of life impacted in those receiving these regimens on a chronic basis? We have to consider whether the patient is better served by a chemotherapy-free approach that may be long-term or a chemotherapy-based approach that has a finite treatment duration. With respect to the investigational agents and combinations, these are considered most frequently for patients with multiple relapses, but there are no firm guidelines that would steer us toward any specific trial at this time.