TP53 突变型 CHIP 定义促炎表型并预测 CAR-T 细胞治疗后的不良结局

Clonal hematopoiesis of indeterminate potential (CHIP) has been well-characterized in patients receiving chemotherapy and hematopoietic cell transplantation.

However, its immunologic relevance and potential role in modulating chimeric antigen receptor T-cell (CAR-T) therapy-related toxicities, inflammation, and clinical outcomes remains incompletely defined. In this exploratory study of 104 CAR-T recipients, we investigated the prognostic impact of pre-existing CHIP clones on toxicity and survival, and examined CHIP-associated inflammatory proteomic signatures leveraging longitudinal serum samples.

Overall CHIP status was not associated with inflammatory toxicities, outcomes, or systemic inflammatory profiles. Analysis of clonal dynamics revealed TP53- and ASXL1-mutated clones to be the dominant expanding CHIP clones post-infusion, whereas DNMT3A- and PPM1D-mutated clones showed reduced clonal abundance over time.

Notably, TP53-mutated CHIP was linked to lower platelet and hemoglobin levels, a higher baseline CAR-HEMATOTOX score, inferior clinical outcomes, and a distinct inflammatory signature.

These findings identify TP53-mutated CHIP in CAR-T-treated patients as a high-risk CHIP genotype compared with other CHIP mutations.

Importantly, patients who developed treatment-emergent myeloid neoplasms after CAR T-cell therapy exhibited distinct patterns of clonal expansion and inflammatory profiles.

Together, these findings support a risk-adapted approach prioritizing longitudinal monitoring of TP53-mutated CHIP, especially in patients with high CAR-HEMATOTOX scores who develop cytopenias.