CAR T-cell therapy is a game changer, particularly for patients with high-risk MCL. I am impressed by the overall response rates of higher than 90% and the complete response rates of 60% to 70%. These groundbreaking effector cell–based therapies have revealed novel toxicities that were not previously seen with other anticancer therapies, including potentially life-threatening events such as cytokine release syndrome (CRS) and neurological events, particularly immune effector cell–associated neurotoxicity syndrome. However, as practitioners have gained experience with these agents and as these therapies have evolved, the toxicities have become more manageable. Next-generation CAR T-cell therapies strive to reduce CRS-type toxicities and to improve outcomes by achieving durable responses in a wider swath of the R/R population.

We currently have 1 CAR T-cell therapy that is FDA approved for patients with MCL and 3 that are approved for patients with diffuse large B-cell lymphoma. I think that the primary reason for this is that diffuse large B-cell lymphoma is more common than MCL, so there is a greater unmet need; however, we may have additional FDA-approved CAR T-cell therapies for MCL in the future. These products have the potential to have a significant impact on the treatment of MCL. I cannot say that I would recommend CAR T cells in frontline consolidation, but I would certainly consider using CAR T-cell therapy earlier in the course of MCL relapse, in view of the fact that we have already defined the high-risk patient group.

I am very enthusiastic about the use of CAR T-cell therapy in patients with R/R MCL. As Dr Persky noted, in the phase 2 ZUMA-2 trial by Wang et al, overall response rates were higher than 90% and complete response rates occurred in a range of about 60% to 70%, depending on the population examined. Additionally, CAR T-cell therapy seems to be effective in patients with high-risk MCL, including those with elevated proliferation rates, TP53 mutations, and blastic morphologies. Long-term data are limited, however; and because of this, we do not know whether CAR T cells will be curative in patients with R/R MCL. We are all very interested in improving our understanding of the durability of remission in patients with MCL who are receiving CAR T-cell therapy. In the R/R setting, the preferential option for cellular therapy is CAR T-cell therapy, especially in patients who are failing or intolerant of 1 Bruton tyrosine kinase inhibitor, while allogeneic hematopoietic stem cell transplantation is recommended if CAR T-cell therapy fails or is infeasible. 

CAR T-cell therapy may have a promising role in an earlier phase of the MCL treatment paradigm for patients with high-risk features, and I think that this will be exciting to examine. Based on the published data and on our own experience over the course of the last year, I will say that this is a toxic therapy. The ZUMA-2 study reported that grade 3 or higher CRS occurred in 15% of patients and that grade 3 or higher neurologic events occurred in 31% of patients. When we look at the characteristics of patients who were included in this study, the median age was 65 years, which is lower than the median age at presentation for MCL. So, it will be important for us to better understand the tolerability of this treatment approach, particularly among older patients who have other comorbidities and who may not have met the eligibility criteria for study enrollment. And I think that it will be very important in the development of CAR T-cell products to focus on agents that have a more favorable toxicity profile that will allow this therapy to be used more broadly among patients with R/R MCL.

We are currently suffering from a lack of data other than that available from the ZUMA-2 trial. In an intention-to-treat analysis of the ZUMA-2 study, 85% of patients had an objective response and 59% had a complete response. At a median follow-up of 12.3 months, 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Notably, this trial has short follow-up, by definition, so we do not know what is going to eventually happen with these patients. Are they going to be in remission for a couple of years and then relapse? We hope not, but we do not really have that answer yet.

I do think, however, that CAR T-cell therapy provides an alternate mechanism of action for treating MCL and is worth considering early in the course of disease, especially for patients in whom we know that the standard therapies are not going to work. The toxicities of CAR-T-cell therapy are severe in some patients, but we are now more advanced in the care of these patients now than we were when CAR T-cell therapy was beginning to emerge. Many patients with MCL are older, which presents challenges when considering them for CAR T-cell therapy. Hopefully, as we gain more experience and perhaps make some modifications to these cellular products, we can apply this approach to a greater number of patients.