Impact of clonal hematopoiesis on clinical outcomes in patients undergoing CAR T-cell therapy: A systematic review and meta-analysis.

Abstract

e19011 Background: Clonal hematopoiesis (CH) is characterized by the expansion of hematopoietic cell clones harboring somatic mutations in genes associated with hematologic malignancies and has been linked to immune dysregulation and pro-inflammatory signaling. Given the immune-dependent mechanisms of chimeric antigen receptor (CAR) T-cell therapy, CH has emerged as a potential modifier of treatment response and toxicity; however, available evidence remains heterogeneous and inconclusive. Methods: We conducted a systematic review and meta-analysis of observational studies evaluating the impact of CH on outcomes following CAR T-cell therapy. PubMed, Embase, and the Cochrane Library were searched from inception through June 2025 (PROSPERO: CRD420251105655). Outcomes included overall response rate (ORR), complete response (CR), overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and post-treatment cytopenias. Random-effects models were used to pool risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (CI). Subgroup analyses were conducted for lymphoma and multiple myeloma (MM). Results: Nine observational studies comprising 702 patients were included; 291 patients (41.5%) had CH. Predominant underlying malignancies were lymphoma (n = 511) and MM (n = 186). Compared to patients without CH, those with CH demonstrated higher ORR (RR 1.20; 95% CI 1.07–1.35) and CR (RR 1.24; 95% CI 1.01–1.51) following CAR T-cell therapy, without corresponding improvements in OS (HR 0.94; 95% CI 0.66–1.34) or PFS (HR 0.86; 95% CI 0.66–1.12). Overall, CH was not associated with increased incidence or severity of CRS (RR 1.09; 95% CI 0.95–1.24) or ICANS (RR 1.12; 95% CI 0.89–1.43), although an exploratory lymphoma-restricted analysis suggested a higher incidence of grade III–IV ICANS (RR 1.66; 95% CI 1.03–2.65). Post-treatment cytopenias were heterogeneously reported and synthesized narratively, with greater hematopoietic support requirements observed in MM cohorts. Conclusions: These findings support the safe use of CAR T-cell therapy in patients with CH and highlight the need for prospective studies to clarify mutation-specific effects and long-term outcomes.