Clonal hematopoiesis as a predictor of immune toxicity and efficacy after chimeric antigen receptor T-cell therapy: A systematic review and meta-analysis.

Abstract

7039 Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with age-related inflammation and may influence immune toxicity and efficacy after CAR T-cell therapy, although reported associations are inconsistent. We performed a systematic review and meta-analysis to quantify CHIP associations with CAR-T toxicities and response. Methods: We conducted a systematic review and meta-analysis of comparative studies reporting CAR-T outcomes by sequencing-defined CHIP status. PubMed, Embase, Cochrane Central, and Web of Science were searched through 2025; nine observational studies were included from 3,529 records. The evidence comprised nine retrospective cohorts (n=869) of adults receiving commercial CD19 CAR-T for B-cell malignancies (mainly aggressive lymphoma/LBCL, B-ALL) or BCMA CAR-T for multiple myeloma. CHIP was identified from pre-infusion blood-derived samples using targeted myeloid sequencing, typically at VAF ≥2% (range >0.3%–≥2%; one study ≥1%), with prevalence 16–56%. Primary endpoints were ASTCT grade ≥3 CRS and ICANS; secondary endpoints included CRS ≥2, any-grade ICANS, ORR, and CR. Risk ratios were pooled using random-effects Mantel–Haenszel models with prespecified subgroup and sensitivity analyses by CAR target/disease; risk of bias was assessed with ROBINS-I. Results: Four cohorts (n=360; 2 CD19, 1 BCMA, 1 mixed) contributed to primary toxicity analyses. CHIP was not associated with severe CRS (ASTCT ≥3; 8/172 vs 14/188; RR 0.72, 95% CI 0.24–2.13; I²=31%) or severe ICANS (RR 1.16, 95% CI 0.48–2.81; I²=39%), with wide confidence intervals reflecting low event counts. A CD19-restricted sensitivity analysis demonstrated higher risk of severe ICANS among CHIP-positive patients (RR 1.66, 95% CI 1.03–2.65; I²=0%). For moderate-to-severe CRS (ASTCT ≥2), five cohorts (n=456) showed no association (RR 1.04, 95% CI 0.73–1.48; I²=59%); exclusion of a mixed cohort reduced heterogeneity and remained null (RR 1.02, 95% CI 0.79–1.32; I²=18%). Any-grade ICANS was not increased (six cohorts, n=440; RR 1.10, 95% CI 0.85–1.41; I²=1%). Efficacy was preserved: ORR was modestly higher in CHIP-positive patients in full-text cohorts (n=347; RR 1.14, 95% CI 1.02–1.27; I²=0%), with similar estimates when including abstract-only data (RR 1.10, 95% CI 1.01–1.21). CR showed a small overall increase (n=385; RR 1.24, 95% CI 1.01–1.52; I²=15%) that was not robust on sensitivity analysis (RR 1.23, 95% CI 0.90–1.67). Conclusions: CHIP was not consistently associated with CRS severity or overall ICANS incidence after CAR-T therapy, although severe ICANS may be higher in CD19 CAR-T lymphoma. Efficacy was preserved in CHIP-positive patients, with no evidence of impaired ORR or CR, and observed response differences should be interpreted cautiously given observational design and heterogeneous definitions.