The role of CHIP and pre-treatment neutropenia in patients treated with chimeric antigen receptor T cells for hematological malignancies

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapies are effective in relapsed and refractory Bcell neoplasia but can cause immune-effector cell (IEC)-related toxicities, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), hematologic toxicity (ICAHT), and hemophagocytic lymphohistiocytosis-like syndrome (IECHS). We hypothesized that clonal hematopoiesis of indeterminate potential (CHIP) may influence outcomes by modulating inflammatory responses. We retrospectively analyzed 113 patients treated with CAR-T-cells for B-cell neoplasia, evaluating the impact of CHIP and pretreatment neutropenia on patient outcomes. CHIP was detected in 30.8% of patients with multiple myeloma (MM); 13.7% of patients with large B-cell lymphoma (LBCL) and 28.6% in follicular and mantle cell lymphoma, with DNMT3A being the most frequently detected CHIPassociated mutation among 62 sequenced patients. CHIP remained stable after CAR T-cell therapy, with comparable variant allele frequencies (VAFs) and mutational burden in paired pre- and post-treatment samples (n=33). Pre-treatment neutropenia was present in approximately 30%. Neither CHIP nor pre-treatment neutropenia influenced overall survival (OS), progression-free survival (PFS), or the incidence of CRS and ICANS. However, CHIP was associated with increased IEC-HS and higher ferritin levels in MM, while pre-treatment neutropenia was associated with severe ICAHT in the overall cohort and CD19-directed cohort. These findings suggest that CHIP and pre-treatment neutropenia are not major determinants of outcome after CAR-T cell therapy but may identify patients at increased risk for specific toxicities. This study is limited by its small sample size, heterogeneous cohort, and retrospective design. Prospective studies in larger cohorts are warranted to further investigate these effects.