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

Rappa G, Ziemann F, White K, Kruk L, Shamas S, Muth A, Shi K, Zucchinetti C, Süß S, Rothenberg-Thurley M, Holzem A, Tix T, Petrera A, Ksienzyk B, Bentenrieder C, Götze KS, Müller F, Bücklein V, Rejeski K, Subklewe M (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Leukemia Springer Nature

DOI: 10.1038/s41375-026-03083-1

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.

Authors with CRIS profile

Fabian Müller Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Klinikum der Universität München (LMU Klinikum) DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Bayerisches Zentrum für Krebsforschung (BZKF) DE Germany (DE)

How to cite

APA:

Rappa, G., Ziemann, F., White, K., Kruk, L., Shamas, S., Muth, A.,... Subklewe, M. (2026). TP53-mutant CHIP defines a pro-inflammatory phenotype and predicts adverse outcomes after CAR T-cell therapy. Leukemia. https://doi.org/10.1038/s41375-026-03083-1

MLA:

Rappa, Giulia, et al. "TP53-mutant CHIP defines a pro-inflammatory phenotype and predicts adverse outcomes after CAR T-cell therapy." Leukemia (2026).

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