TP53-mutant CHIP defines a pro-inflammatory phenotype and predicts adverse outcomes after CAR T-cell therapy.

Authors

Giulia Rappa, Frank Ziemann, Kieron White, Linus Kruk, Samar Shamas, Amelie Muth, Kayleen Shi, Cristina Zucchinetti, Savanna Süß, Maja Rothenberg-Thurley, Alessandra Holzem, Tobias Tix, Agnese Petrera, Bianka Ksienzyk, Charlotte Bentenrieder, Katharina S Götze, Fabian Müller, Veit Bücklein, Kai Rejeski, Marion Subklewe

Published in

Leukemia. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

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.

PMID:
42637877
Bibliographic data and abstract were imported from PubMed on 25 Aug 2026.

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