BTK Inhibitors and CAR T-Cell Therapy in Treating Mantle Cell Lymphoma-Finding a Dancing Partner

Abstract

Purpose of review: This review focuses on the feasibility of combining Bruton's tyrosine kinase (BTK) inhibitors (BTKis) with chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL). Potential scenarios for combination treatment with these agents are presented.

Recent findings: BTKis and CAR T-cell therapy have revolutionized the treatment paradigm for R/R MCL. Ibrutinib, acalabrutinib, and zanubrutinib are covalent irreversible BTKis approved for R/R MCL. Brexucabtagene autoleucel was the first CAR T-cell therapy approved for R/R MCL based on findings from the ZUMA-2 trial. There is evidence to suggest that combination treatment with BTKis and CAR T-cell therapy may improve CAR T-cell efficacy. As BTKis and CAR T-cell therapy become mainstays in R/R MCL therapy, combination treatment strategies should be evaluated for their potential benefit in R/R MCL.

Keywords: Bruton’s tyrosine kinase; Chimeric antigen receptor T-cell therapy; Combination therapy; Relapsed/refractory mantle cell lymphoma.

Fig. 1

Implementation of BTK inhibitors in CAR T-cell therapy strategies for R/R MCL. (A) Potential benefit of BTK inhibitors on CAR T-cell efficacy. (B) CAR T-cell therapy in BTKi-exposed R/R MCL. (C) CAR T-cell therapy in BTKi-naïve R/R MCL. (D) BTKi therapy after failure of CAR T-cell therapy. (E) Concomitant CAR T-cell and BTKi therapy. ^aNon-covalent BTKis have not yet been approved for treatment of MCL. ^bBridging therapies in ZUMA-2 were restricted to ibrutinib, acalabrutinib, or corticosteroids; lenalidomide or venetoclax were not permitted but were implemented in a US-based real-world study of brexu-cel in patients with R/R MCL [53]. ^cCorticosteroids or radiation may be administered alone or in combination with chemoimmunotherapy, radiation, BTKi, or other listed bridging therapy options. ^dHigh-risk features include blastoid/pleomorphic phenotype, CNS involvement; TP53 mutations, or high Ki67 index. ^eUse of BTK inhibitors in the peri-infusion period has not been established. BTKi, Bruton’s tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CNS, central nervous system; CR, complete response; CRS, cytokine release syndrome; MCL, mantle cell lymphoma; NR, no response; PR, partial response; R, rituximab; R/R, relapsed or refractory