(PA-016) Delayed Hematologic Recovery After BCMA CAR-T Is Associated with Progressive Loss of Endogenous T Cell Diversity After CAR-T Infusion

BCMA-directed CAR-T can induce deep and durable remissions in myeloma patients, but a significant subset develop prolonged cytopenias. We previously reported (Avigan et al, ASH 2024 abstract 3329) that patients with prolonged cytopenias beyond day 100 have decreased survival and persistently increased inflammatory markers after CAR-T. The endogenous T cell repertoire, as reflected by native T cell recovery after lymphodepletion and CAR-T, is similarly associated with outcomes and may be both a reflection and important mediator of inflammatory dysregulation. We therefore hypothesized that patients with delayed hematologic recovery after CAR-T would show a distinct endogenous T cell recovery pattern, which may contribute to ongoing hematotoxicity.

Methods: We reviewed patients treated with cilta-cel with available NGS of their T cell receptor (TCR) repertoire within 2 years and prior to relapse. Patients were divided by hematologic recovery before or after 100 days post-CAR-T, with recovery defined as the first of a consecutive 30-day period without grade 3 toxicity or growth-factor support. T cell clones present at more than 3x the upper limit of the polyclonal background were considered clonally expanded, in accordance with our center’s validated protocol, and Fisher’s exact test compared clonality distributions between groups. TCR diversity within top 10 clones was calculated by the Shannon equitability index and compared by Wilcoxon rank-sum test, as well as by multivariate linear regression analysis modeling diversity over time and adjusting for age and prior lines of therapy.

Results:

A total of 32 TCR samples across 21 patients were included. Patients had a median age of 63.5 and median 5 prior lines of therapy; 11 (52%) had sustained hematologic recovery prior to day 100, and 10 (48%) had prolonged cytopenias beyond 100 days. Patients with delayed hematologic recovery had a trend toward increased prevalence of expanded monoclonal TCR populations compared to those with early myeloid recovery (60% vs 27%, p=0.08), including both at timepoints before 6 months (50% vs 17%) and beyond 6 months post-CAR-T (57% vs 22%). While both groups showed similar TCR diversity at early timepoints, patients with delayed hematologic recovery had significantly lower T cell diversity after 6 months (p=0.029). Similarly, a multivariate linear regression of native TCR diversity showed stable diversity in those with early hematologic recovery but highlighted progressive loss of endogenous TCR clonal diversity over time after CAR-T in the patients with delayed myeloid recovery (p=0.032).

Conclusions:

Patients with delayed hematologic recovery after CAR-T showed increased TCR clonal dominance and decreased diversity in endogenous T cell populations, with a marked disruption in diversity after 6 months. Our current efforts are aimed at understanding and characterizing the role of native T cell diversity in driving inflammatory dysregulation, hematologic toxicity, and disease response after CAR-T.