BTKi in the peri-infusion period in lymphoma patients receiving CD19 CAR T cell therapy

Abstract

Abstract Introduction With evidence for beneficial effects on CAR T cell phenotype and the potential for mitigation of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), Bruton's tyrosine kinase inhibitor (BTKi) use in the peri-infusion period is under investigation in several ongoing clinical trials. However, our understanding of outcomes in patients is limited to small studies lacking non-BTKi-exposed comparators. Here, we present on clinical outcomes, CAR T-related, and BTKi-related adverse events in patients receiving BTKi in the peri-CAR T infusional period. Methods In this single-center, retrospective study, we analyzed the association between BTKi exposure and survival/toxicity outcomes in lymphoma patients after CD19 CAR T cells. Patients were included who received cells for a commercial indication or investigational liso-cel (TRANSCEND study) at Memorial Sloan Kettering Cancer Center. We excluded patients who did not receive bridging therapy and those who received multiple CAR T cell infusions. BTKi-exposure was defined as at least 7 days of drug within 7 days of apheresis through infusion. Timing of BTKi exposure was classified as pre-apheresis, bridging, post-infusion, or a combination of these timeframes. Survival outcomes were analyzed from the date of infusion. CRS and ICANS were graded according to ASTCT criteria. OS and PFS were estimated using the Kaplan-Meier method, and log-rank tests were used to compare groups. Cox Proportional Hazards regression was used to examine associations with OS and PFS; models were stratified by diagnosis. Fisher's exact tests were used to test for differences in best overall response rate (ORR), complete response rate (CRR), and toxicities. Results We included 359 patients with a median age of 67 (IQR 58 – 73) at CAR T infusion (40% liso-cel, 36% axi-cel, 16% tisa-cel, and 8% brexu-cel) between 2016 and 2025. Among 63 (14%) who received BTKi in the peri-infusion period before CAR T, exposure intervals included 51 (81%) pre-apheresis, 53 (84%) bridging, and 16 (25%) post-infusion. Indications for cell therapy included large B cell lymphoma (LBCL; 78%), mantle cell lymphoma (MCL; 14%), and other (8%; including 7% follicular lymphoma and 1% CLL). Among LBCL with classified cell of origin (n = 270), there were 124 (46%) germinal center and 146 (54%) non-germinal center cases. BTKi administered included ibrutinib (59%), zanubrutinib (21%), pirtobrutinib (14%), or acalabrutinib (6%). Comparing BTKi-exposed and non-exposed patients, central nervous system involvement pre-apheresis (23% vs 11%), MCL (41% vs 8%), and non-germinal center LBCL (49% vs 39%) were more common whereas LBCL overall (52% vs 82%) and germinal center LBCL (3% vs 41%) were less common. Best ORR and CRR by one year were similar (82% vs. 83%; 69% vs. 69%), among BTKi-exposed and non-exposed, respectively. PFS and OS were not significantly different between groups. On multivariable assessment (stratified by disease) for PFS and OS, CNS involvement (HR 1.67 (1.11 – 2.52), p = 0.014; HR 1.73 (1.09 – 2.76), p = 0.02), but not BTKi exposure (HR 0.90 (0.57 – 1.42), p = 0.65; HR 0.85 (0.51 – 1.41), p = 0.53), was significant. On assessment of safety outcomes, univariable analysis of BTKi-exposure versus non-exposure was associated with grade 3+ ICANS (23% vs 11%, p=0.044), however, in a multivariable model adjusting for CNS involvement and CAR T cell product, BTKi-exposure was not significant. BTKi exposure was not significantly associated with grade 3+ CRS, neutropenia, thrombocytopenia, bacteremia, fungal infections, cardiac arrhythmias, or bleeding events after CAR T. Conclusions In the largest retrospective analysis to date studying CAR T cell patients receiving peri-infusional BTKi, we observed similar disease outcomes between the BTKi-exposed and non-exposed cohorts. CNS involvement was associated with inferior PFS and OS in both cohorts. ICANS was more frequent in BTKi-exposed patients possibly due to higher incidence of secondary CNS involvement and disproportionate use of brexu-cel and axi-cel. Relative to CAR T cell therapy alone, the toxicity of combination treatment was comparable including grade 3+ CRS, heme toxicity, infections, bleeding, and arrhythmias. Our data largely support the safety of bridging BTKi, though prospective validation is needed to substantiate our findings and to determine whether adding BTKi to CAR T is therapeutically advantageous.