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CAR T: A Novel Approach for Mantle Cell Lymphoma

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New treatment options expand management of relapsed or refractory disease.

This content originally appeared on our sister site, Targeted Oncology.

Mantle cell lymphoma MCL) is a non-Hodgkin lymphoma (NHL) subtype with relapse expected in almost all patients at some point. Thus management of relapsed or refractory (R/R) disease is a highly relevant topic for patients and the clinicians who treat them. The treatment landscape for relapsed MCL has changed rapidly over the past decade, with the development and approval of Bruton tyrosine kinase (BTK) inhibitors at the forefront of the changing treatment paradigm.

“Novel Treatment Approaches in Relapsed/ Refractory Mantle Cell Lymphoma,” presented by Kami Maddocks, MD, at the Society of Hematologic Oncology 2021 Annual Meeting, provided an overview of recent developments in the treatment of R/R MCL with updates outlined by class of therapies. With the approval of chimeric antigen receptor (CAR) T-cell therapy for R/R MCL, referral to an authorized CAR T-cell treatment center is critical when considering options for patients seen in clinical practice. Despite the plethora of emerging treatment options, clinical trial participation should be strongly encouraged for patients with R/R MCL. Results of a number of ongoing clinical trials are expected to lead to new approvals and changes in clinical practice in the near future.

Chimeric Antigen Receptor T-Cells

Brexucabtagene autoleucel (Tecartus) is a CD19-directed CAR T-cell therapy that is FDA-approved for the treatment of R/R MCL. The approval was based upon results of the pivotal phase 2 ZUMA-2 study (NCT02601313) in which 74 patients with R/R MCL, all previously treated with BTK inhibitors, were enrolled and 68 patients successfully received CAR T-cell infusion following lymphodepletion.1 In addition to prior BTK inhibitor treatment, the study population had other high-risk features, including high Ki67 index of 30% or greater in 40 patients and blastoid morphology in 31% of patients. The ORR among the 60 infused patients was 93% with 67% achieving a CR. Even when assessing the entire study population, including patients who did not receive CAR T-cell infusion, the ORR remained 85% with 59% CR. The 1-year estimated PFS among evaluable patients was 61%, with similar response rates and PFS seen among patients with high-risk features, including TP53 mutation or blastoid morphology. Cytokine release syndrome (CRS) and neurotoxicity of any grade were frequently observed (91% and 63% of patients, respectively), with grade 3 or higher neurotoxicity occurring in 31% of patients. The anti-CD19 CAR T-cell therapy lisocabtagene maraleucel (Breyanzi) also is under investigation for treatment of MCL in the TRANSCEND NHL-001 study (NCT02631044).2 The observed ORR was 84% with 59% CR, with follow-up not yet mature for PFS estimate. CRS of any grade occurred in 59% of patients, whereas neurotoxicity of any grade was observed in 34%, rates that are lower in comparison than those observed with brexucabtagene autoleucel. It also is notable that patients with central nervous system involvement by MCL were eligible for TRANSCEND NHL- 001. Final results will provide further data regarding the efficacy of CAR T-cell therapy in this difficult-to-treat scenario.

Bright Future

The future today is brighter for patients with previously treated MCL, with the approval of both BTK inhibitor and CAR T-cell therapies providing 2 highly effective classes of treatment for patients with R/R disease. Randomized studies are looking at combination treatment options as well as comparing noncovalent reversible BTK inhibitors with the currently approved covalent BTK inhibitors in patients with R/R disease. Despite this progress, further treatment options are needed, but multiple new therapies are on the horizon, including noncovalent BTK inhibitors as well as ADCs.

REFERENCES:
1. 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
2. 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.
 Blood. 2020;136(suppl 1):10-11. doi:10.1182/blood-2020-136158