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. 2025 Apr;100(4):552-560.
doi: 10.1002/ajh.27609. Epub 2025 Jan 28.

TP53 Mutations in Myeloproliferative Neoplasms: Context-Dependent Evaluation of Prognostic Relevance

Ayalew Tefferi  1 , Maymona Abdelmagid  1 , Giuseppe G Loscocco  1   2 , Saubia Fathima  1 , Kebede H Begna  1 , Aref Al-Kali  1 , James Foran  3 , Jeanne Palmer  4 , Talha Badar  3 , Mrinal M Patnaik  1 , Kaaren K Reichard  1 , Rong He  1 , Cinthya J Zepeda Mendoza  1 , Mithun Shah  1 , Attilio Orazi  5 , Daniel A Arber  6 , Animesh Pardanani  1 , Alessandro M Vannucchi  2 , Devendra Hiwase  7 , Naseema Gangat  1 , Paola Guglielmelli  2
Affiliations

TP53 Mutations in Myeloproliferative Neoplasms: Context-Dependent Evaluation of Prognostic Relevance

Ayalew Tefferi et al. Am J Hematol. 2025 Apr.

Abstract

The clinical relevance of TP53 mutations (TP53 MUT ) in myeloproliferative neoplasms (MPN) and their prognostic interaction with MPN subtype designation has not been systematically studied. In the current study, 114 patients with MPN harboring TP53 MUT (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of TP53 MUT detection: chronic phase myelofibrosis (MF-CP; N = 61); blast-phase (MPN-BP; N = 31) or accelerated-phase (MPN-AP; N = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; N = 6). Sixty-five (57%) patients harbored International Consensus Classification (ICC)-defined multihit TP53 MUT and 56 (49%) monosomal/complex karyotype (MK/CK). Majority of MPN-BP (90%) and MPN-AP (81%) while 39% of MF-CP and none of PV/ET patients harbored multihit TP53 MUT . OS in MPN-BP and MPN-AP was equally dismal (median 6 vs. 4.5 months, respectively; p = 1.0), regardless of multihit configuration (p = 0.44), while OS in TP53 MUT MPN-BP/AP (N = 47; median 4 months) was inferior to that of a separate cohort (N = 49) with TP53 wild-type MPN-BP/AP (median 11 months; p < 0.01). OS in MF-CP was significantly shorter with multihit versus non-multihit TP53 MUT (median 10 vs. 35 months; HR 2.9; p < 0.01), independent of other MF-relevant genetic risk factors, including ASXL1/SRSF2/U2AF1 mutations. Multihit TP53 MUT was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus "not reached" in patients with (N = 9) versus without (N = 8) multihit TP53 MUT (p < 0.01). The presence of multihit or non-multihit TP53 MUT in MPN-BP/AP or multihit TP53 MUT in MF-CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of "myeloid neoplasms with mutated TP53." By contrast, detection of non-multihit TP53 MUT, by itself, might not endanger short-term survival in MF-CP, PV, or ET.

Keywords: ICC; WHO; karyotype; prognosis; survival.

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Conflict of interest statement

A.T. nothing to disclose; M.A. nothing to disclose; G.G.L. nothing to disclose; S.F. nothing to disclose; K.H.B. nothing to disclose; A.A.K. research support to institution: Novartis, Onconova, ALX Oncology, BMS, Celgene, H3Biomedicine/Hemavant, Aprea, Astex, MedImmune. Consultancy: Novartis; J.F. nothing to disclose; J.P. nothing to disclose; T.B. advisory board for Takeda, Pfizer, Morphosys, and Syndex; M.M.P. received research funding from Kura Oncology, Stemline therapeutics, Epigenetix, Solutherapeutics, Polaris and has served on the advisory board for AstraZeneca and SOBI pharmaceuticals; K.K.R. nothing to disclose; R.H. nothing to disclose; C.J.Z.M. nothing to disclose; M.S.: research funding to the institution from Astellas, AbbVie, Celgene, KURA Oncology, and Marker Therapeutics; A.O. nothing to disclose; D.A.A. nothing to disclose; A.P. nothing to disclose; A.M.V. advisory Board of Novartis, Incyte, BMS, Italfarmaco and received fees for lectures from BMS, Novartis, Blueprint, Abbvie, Italfarmaco; D.H. member of the board of directors or advisory committees of AbbVie and Novartis; N.G. advisory board to DISC Medicine and Agios; P.G. advisory Board of Novartis, Incyte, GSK and received fees for lectures from GSK, Novartis and abbvie.

Figures

FIGURE 1
FIGURE 1
Transplant‐censored survival data in patients with myeloproliferative neoplasms (MPN) variously stratified by TP53 mutation and allelic state and calculated from the time of TP53 mutation detection; (a) 114 TP53‐mutated patients stratified by MPN morphologic subtypes; (b) a subset of 61 TP53‐mutated patients with chronic phase myelofibrosis (MF‐CP) stratified by TP53 mutation allelic state; (c) a subset of 47 TP53‐mutated patients with accelerated (MPN‐AP) or blast (MPN‐BP) phase MPN, stratified by TP53 mutation allelic state; (d) overall survival comparisons between TP53‐mutated (N = 47) and TP53 wild‐type (N = 49) patients with MPN‐BP/AP. ET, essential thrombocythemia; PV, polycythemia vera. [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 2
FIGURE 2
Transplant‐censored survival data in patients with myeloproliferative neoplasms (MPN); (a) 61 patients with chronic phase myelofibrosis (MF‐CP), stratified by the presence or absence of monosomal/complex karyotype (MK/CK) and/or the presence or absence of multihit TP53 MUT; (b) 108 patients with TP53‐mutated myeloproliferative neoplasms (MPN) stratified by MPN subtype and the presence of multihit TP53 mutation or MK/CK. CK, complex karyotype; ICC, international consensus classification; MK, monosomal karyotype. [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 3
FIGURE 3
Overall survival data in patients with myeloproliferative neoplasms (MPN) stratified by MPN subtype, TP53 mutation allelic state and variant allele frequency (VAF), and allogeneic stem cell transplant (ASCT); (a) 163 patients with MPN stratified by MPN subtype, presence, or absence of TP53 mutation, and its allelic state; (b) 38 patients with chronic phase myelofibrosis (MF‐CP) without multihit TP53 mutation, stratified by TP53 variant allele frequency (VAF); (c) a subset of 17 TP53‐mutated patients who received ASCT, stratified by TP53 mutation allelic state. [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 4
FIGURE 4
Overall survival data among 108 TP53‐mutated patients with chronic phase myelofibrosis (MF‐CP) or blast or accelerated phase myeloproliferative neoplasm (MPN‐BP/AP) stratified by an operational risk model based on allogeneic stem cell transplant, presence of multihit configuration, disease stage, and gender (survival is calculated from time of TP53 mutation detection and not censored for transplant). [Color figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

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