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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, K.S.* ; Müller, F.* ; Bücklein, V.* ; Rejeski, K.* ; Subklewe, M.*

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

Leukemia, DOI: 10.1038/s41375-026-03083-1 (2026)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Haematopoiesis ; Myeloid ; Hematology ; Phenotype ; Clinical Significance ; Genotype ; Adverse Effect ; Clinical Trial; Clonal Hematopoiesis; Impact

ISSN (print) / ISBN 0887-6924

e-ISSN 1476-5551

Journal Leukemia

Publisher Springer

Publishing Place The Campus, 4 Crinan St, London, N1 9xw, England

Reviewing status Peer reviewed

Institute(s) Core Facility Metabolomics and Proteomics (CF-MPC)

Grants Elite Network of Bavaria (I-Target: immunotargeting of cancer.
Bruno and Helene Jster Foundation (360degrees CAR).
Frderprogramm fr Forschung und Lehre - Grant reference number: FFoLe-1048
German Cancer Consortium (DKTK)
Bavarian Cancer Research Center (BZKF).
Bavarian Cancer Research Center (BZKF) - Grant Reference Number: BZKF-#TLG-22
Deutsche Jos Carreras Leukmie Stiftung - Grant Reference Number: DJCLS 05 R/2025
Bruno and Helene Jster Foundation
Marie Sklstrok
odowska-Curie doctoral n
Bavarian Cancer Research Center (BZKF)