What Is the Link Between Tumor Features, CAR-T Response in MCL?

Molecular features typically associated with inferior outcomes did not significantly affect survival or chimeric antigen receptor (CAR) T-cell therapy response in patients with relapsed or refractory mantle cell lymphoma (MCL), according to a study presented at the 66^th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

Using univariable logistic regression models, the researchers examined the link between tumor features and CAR-T response after collecting comprehensive patient-, disease-, and treatment-related data from 88 patients across five international centers. They also used Cox regression models to examine the relationship between predictive features and overall survival (OS) and progression-free survival (PFS), and Fisher’s exact test to examine the relationship between TP53 mutations and CAR-T response.

Patients had received either brexucabtagene autoleucel (n=57), lisocabtagene maraleucel (n=21), or a point-of-care CD19 CAR-T product (n=10) with a CD28 costimulatory domain. Before CAR-T infusion, 58% of patients had received up to three lines of therapy.

High-risk disease features were prevalent in this patient population, the researchers noted. Specifically, 46% of patients had blastoid or pleomorphic morphology, 68% had K67 ≥50%, and 54% had high-risk Mantle Cell Lymphoma International Prognostic Index with B symptom (MIBIb) at apheresis. Thirty percent of patients had del(17p) and 57% had P53. TP53 (54%) and ATM (26%) were the most frequent mutations among patients with available next generation sequencing (NGS) testing.

The overall response rate of 86% and the complete response (CR) rate of 82% were comparable to results in the pivotal CAR-T MCL clinical trials, the researchers noted. A low percentage of patients experienced grade 3 or more cytokine release syndrome (10%) or neurotoxicity (19%).

At a median follow-up of 18 months, the one-year overall survival (OS) was 64% (95% CI; 54-77%), and the one-year progression-free survival (PFS) was 59% (95% CI; 48-72%). Blastoid or pleomorphic morphology, Ki67 > median of 60%, P53 expression, SOX11 expression, del(17p), MIBIb group at apheresis, and lactate dehydrogenase levels before lymphodepletion were not associated with OS or PFS from time of infusion. In patients with NGS testing, TP53 and ATM mutations were not significantly associated with OS or PFS.

However, bridging therapy was associated with inferior PFS (HR 2.39, 95% CI; 1.12-5.03) and OS (HR 2.16, 95% CI; 1.01-4.63). TP53 mutations were associated with a lower CR rate (96% vs 74%), but this did not reach statistical significance (P=.053).

“Our findings, which warrant confirmation in larger genomically characterized cohorts, highlight the utility of CAR-T even in [patients] with high-risk MCL features,” the researchers concluded. These data also underscore the pressing need for identifying novel biomarkers to inform on resistance mechanisms and predict treatment success.”

Reference

Epstein-Peterson ZD, Ryan CE, Devlin SM, et al. “Tumor determinants of response to CAR-T therapy in relapsed or refractory mantle cell lymphoma” Abstract #4393. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.