clinical topic updates

Chimeric Antigen Receptor T-cell Therapy in Relapsed Mantle Cell Lymphoma

by Caron A. Jacobson, MD, MMSc

Overview

Chimeric antigen receptor (CAR) T-cell therapy has been approved by the US Food and Drug Administration (FDA) for patients with relapsed/refractory mantle cell lymphoma (R/R MCL), expanding the population for whom aggressive cellular therapy may be considered.

Expert Commentary

Caron A. Jacobson, MD, MMSc

Medical Director, Immune Effector Cell Therapy Program
Dana-Farber Cancer Institute
Assistant Professor of Medicine
Harvard Medical School
Boston, MA

“ . . . the FDA was very prescient in approving brexu-cel for the treatment of R/R MCL without specifying a list of required prior therapies. This likely reflects the recognition that, in the future, not all patients will follow the same path to CAR T-cell therapy.”

Caron A. Jacobson, MD, MMSc

Two trials of CAR T-cell therapy have enrolled similar populations of patients with R/R MCL. The ZUMA-2 trial led to the FDA approval of brexucabtagene autoleucel (brexu-cel) in R/R MCL. The ongoing TRANSCEND NHL 001 study is the initial pivotal trial of lisocabtagene maraleucel (liso-cel) in large B-cell lymphoma, and it includes an MCL cohort. Both studies included patients with R/R MCL after chemoimmunotherapy and a Bruton tyrosine kinase (BTK) inhibitor. Relapses while on BTK inhibitor therapy or intolerance and discontinuation can lead to very rapid progression in MCL, and it is these high-risk patients who were enrolled in both trials.

The complete response (CR) rates in these studies were quite impressive. In the ZUMA-2 study, the objective response rate among the 60 patients in the primary efficacy analysis was 93%, with a CR rate of 67%. In the TRANSCEND NHL 001 study, among the 32 patients with MCL who received liso-cel, the objective response rate was 84% and the CR rate was 59%. 

In the SCHOLAR-2 analysis, a standard-of-care (SOC), real-world cohort was constructed to closely match the patients enrolled in ZUMA-2, aiming to estimate and compare effectiveness between existing SOC therapies and brexu-cel. The results of the analysis suggested that brexu-cel can improve survival over current active SOC for the treatment of R/R MCL in patients who have previously received BTK inhibitor therapy. 

In my view, the FDA was very prescient in approving brexu-cel for the treatment of R/R MCL without specifying a list of required prior therapies. This likely reflects the recognition that, in the future, not all patients will follow the same path to CAR T-cell therapy. The disease is very heterogeneous, and patients with high-risk features that predict chemoresistance might be candidates for any number of combinations that are now under investigation that incorporate BTK inhibitors and other drugs up front.

Patient eligibility for CAR T-cell therapy is different from transplant eligibility in that many more individuals can be treated with CAR T-cell therapy compared with autologous stem cell transplantation. Patients are eligible for CAR T cells well into their 80s, and you can be a bit more liberal with heart and kidney function than you would be with high-dose chemotherapy. At present, patients with MCL typically receive chemoimmunotherapy first line, BTK inhibitors second line, and CAR T-cell therapy third line, much like in the clinical trials. While most of the patients in ZUMA-2 actually received ibrutinib because the study started when ibrutinib was the only FDA-approved BTK inhibitor for MCL, we now have 2 additional BTK inhibitors with which we can treat our patients (ie, acalabrutinib and zanubrutinib). It is not clear whether one is better than another as a preceding therapy prior to CAR T cells; this is under investigation.

For MCL, which generally evades cure except in a subset of patients receiving an allogeneic stem cell transplant, CAR T-cell therapy represents a potentially natural history–changing intervention. We do not know whether it can cure patients because the follow-up has not been long enough, but even if we can get 5 to 10 years out of CAR T cells, that is far in excess of what we have been able to obtain thus far.

References

Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

Hess G, Dreyling M, Oberic L, et al. KTE-X19 versus standard of care for relapsed/refractory mantle cell lymphoma previously treated with Bruton tyrosine kinase inhibitors: real-world evidence from Europe [abstract EP786]. Abstract presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021.

Iacoboni G, Rejeski K, Villacampa G, et al. Real-world evidence of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2022 Mar 10;bloodadvances.2021006922. doi:10.1182/bloodadvances.2021006922

Marangon M, Visco C, Barbui AM, et al. Allogeneic stem cell transplantation in mantle cell lymphoma in the era of new drugs and CAR-T cell therapy. Cancers (Basel). 2021;13(2):291. doi:10.3390/cancers13020291

Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in TRANSCEND NHL 001 [abstract 118]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: real world experience from the US Lymphoma CAR T Consortium [abstract 744]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

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