Abstract
While TP53 mutations in myeloproliferative neoplasms (MPN) are associated with an increased risk of leukemic transformation, not all patients carrying a TP53 mutation progress. To better risk-stratify MPN patients with TP53 mutations, we analyzed data from 1540 patients treated at four specialized cancer centers. Among them, 1429 had wildtype TP53 and 111 had mutations in the TP53 gene. At first MPN diagnosis, 32% had polycythemia vera, 39% had essential thrombocythemia, and 25% had primary myelofibrosis. Among all MPN patients with TP53 mutations, presence of fibrosis in the bone marrow (hazard ratio (HR): 3.84, 95% CI: 1.98–7.43), multi-hit TP53 mutation status (HR: 2.74, 95% confidence interval (CI): 1.52–4.97), and higher PHANTM score (HR: 1.87, 95% CI: 1.02–3.42) were associated with worse OS in a multivariable analysis. Based on these variables, we developed a risk model to identify TP53-mutated MPN patients who are at high risk for inferior OS. Median OS from time of TP53 detection was 0.5 years in high-risk patients, compared to 2.3 years for patients with intermediate risk and 6.3 years for patients with low risk. This scoring system may help refine risk stratification for chronic phase MPN patients harboring TP53 aberrations.
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Acknowledgements
We thank all participating cancer centers for their outstanding collaboration. This study was supported by Dana-Farber Cancer Institute Hematologic Malignancy Data Repository (HMDR). We thank the HMDR team for assisting us with data extraction. We thank the MPN Research Foundation (MPNRF) for helping support MPN data entry in HMDR at Dana-Farber.
Funding
BR received funding from the German Cancer Aid (“Deutsche Krebshilfe”, Mildred-Scheel scholarship, No.70114570). JE received honoraria from GSK and Novartis. AM acknowledges funding from NIH NHLBI (R01HL131835, R01 HL167139), Department of Defense Congressionally Directed Medical Research Programs (W81XWH2110909) and the Starr Cancer Consortium (I15-0026).
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BR, MS, and AM conceptualized the project. BR, CMOF, MS, and AM wrote the original manuscript. AM provided clinical & scientific insights, edited the manuscript, obtained funding to support the research and provided supervision and oversight for the project. JK, YL, and MJA performed the major statistical analyses for the manuscript. BR, CMOF, NF, JB, CP, MSc, MRL, DJD, ShS, RMS, ACH, CK, LDW, LW, MW, JoH, AEM, RR, HKT, JG, VG, and MS provided clinical data, analyzed and interpreted the data. MF and HKT provided their genetic expertise, discussed the data with a focus on potential biological mechanisms and revised the manuscript. All authors provided scientific input and participated in the preparation of the manuscript. All authors agreed to the final version of the manuscript.
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MJA has financial interests in SeQure Dx. MS served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, Rigel, BMS, Sobi and Syndax, Kura; consulted for Boston Consulting, GLG and Dedham group and participated in CME activity for Novartis, Curis Oncology, Haymarket Media and Clinical Care Options and is a member of the Medical Safety Monitoring Board for Keros Pharmaceuticals. AM has received research funding from Morphic and Incyte and has consulted for Cellarity.
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Approval by the Institutional Review Board (IRB) at each participating center was obtained according to their local policies. All participating centers signed a data transfer and use agreement with DFCI.
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Rolles, B., Filho, C.M.d.O., Fergusson, N. et al. Risk stratification of patients with TP53-mutated myeloproliferative neoplasms. Leukemia (2026). https://doi.org/10.1038/s41375-026-02885-7
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DOI: https://doi.org/10.1038/s41375-026-02885-7
