Ayalew Tefferi, Maymona Abdelmagid, Giuseppe G. Loscocco, Saubia Fathima, Kebede H. Begna, Aref Al-Kali, James Foran, Jeanne Palmer, Talha Badar, Mrinal M. Patnaik, Kaaren K. Reichard, Rong He, Cinthya J. Zepeda Mendoza, Mithun Shah, Attilio Orazi, Daniel A. Arber, Animesh Pardanani, Alessandro M. Vannucchi, Devendra Hiwase, Naseema Gangat, Paola Guglielmelli
{"title":"TP53 Mutations in Myeloproliferative Neoplasms: Context-Dependent Evaluation of Prognostic Relevance","authors":"Ayalew Tefferi, Maymona Abdelmagid, Giuseppe G. Loscocco, Saubia Fathima, Kebede H. Begna, Aref Al-Kali, James Foran, Jeanne Palmer, Talha Badar, Mrinal M. Patnaik, Kaaren K. Reichard, Rong He, Cinthya J. Zepeda Mendoza, Mithun Shah, Attilio Orazi, Daniel A. Arber, Animesh Pardanani, Alessandro M. Vannucchi, Devendra Hiwase, Naseema Gangat, Paola Guglielmelli","doi":"10.1002/ajh.27609","DOIUrl":null,"url":null,"abstract":"<p>The clinical relevance of <i>TP53</i> mutations (<i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup>) 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 <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup> (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup> detection: chronic phase myelofibrosis (MF-CP; <i>N</i> = 61); blast-phase (MPN-BP; <i>N</i> = 31) or accelerated-phase (MPN-AP; <i>N</i> = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; <i>N</i> = 6). Sixty-five (57%) patients harbored International Consensus Classification (ICC)-defined multihit <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup> 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 <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup>. OS in MPN-BP and MPN-AP was equally dismal (median 6 vs. 4.5 months, respectively; <i>p</i> = 1.0), regardless of multihit configuration (<i>p</i> = 0.44), while OS in <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup> MPN-BP/AP (<i>N</i> = 47; median 4 months) was inferior to that of a separate cohort (<i>N</i> = 49) with <i>TP53</i> wild-type MPN-BP/AP (median 11 months; <i>p</i> < 0.01). OS in MF-CP was significantly shorter with multihit versus non-multihit <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup> (median 10 vs. 35 months; HR 2.9; <i>p</i> < 0.01), independent of other MF-relevant genetic risk factors, including <i>ASXL1/SRSF2/U2AF1</i> mutations. Multihit <i>TP53</i>\n <sup>\n <i>MUT</i>\n </sup> was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus “not reached” in patients with (<i>N</i> = 9) versus without (<i>N</i> = 8) multihit <i>TP53</i>\n <sup>MUT</sup> (<i>p</i> < 0.01). The presence of multihit or non-multihit <i>TP53</i>\n <sup>MUT</sup> in MPN-BP/AP or multihit <i>TP53</i>\n <sup>MUT</sup> in MF-CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of “myeloid neoplasms with mutated <i>TP53</i>.” By contrast, detection of non-multihit <i>TP53</i>\n <sup>MUT</sup>, by itself, might not endanger short-term survival in MF-CP, PV, or ET.</p>","PeriodicalId":7724,"journal":{"name":"American Journal of Hematology","volume":"100 4","pages":"552-560"},"PeriodicalIF":10.1000,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajh.27609","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Hematology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ajh.27609","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The clinical relevance of TP53 mutations (TP53MUT) 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 TP53MUT (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of TP53MUT 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 TP53MUT 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 TP53MUT. 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 TP53MUT 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 TP53MUT (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 TP53MUT 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 TP53MUT (p < 0.01). The presence of multihit or non-multihit TP53MUT in MPN-BP/AP or multihit TP53MUT 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 TP53MUT, by itself, might not endanger short-term survival in MF-CP, PV, or ET.
期刊介绍:
The American Journal of Hematology offers extensive coverage of experimental and clinical aspects of blood diseases in humans and animal models. The journal publishes original contributions in both non-malignant and malignant hematological diseases, encompassing clinical and basic studies in areas such as hemostasis, thrombosis, immunology, blood banking, and stem cell biology. Clinical translational reports highlighting innovative therapeutic approaches for the diagnosis and treatment of hematological diseases are actively encouraged.The American Journal of Hematology features regular original laboratory and clinical research articles, brief research reports, critical reviews, images in hematology, as well as letters and correspondence.