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However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring\n TP53<\/jats:italic>\n mut<\/jats:sup>\n (variant allele frequency, VAF\u2009\u2265\u20092%). WHO-5 and ICC would not classify 64% and 20% of these cases as\n TP53<\/jats:italic>\n mut<\/jats:sup>\n MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of\n TP53<\/jats:italic>\n mut<\/jats:sup>\n acute myeloid leukemia (AML), (ii) interaction of the blast percentage and allelic status, (iii) 17p.13.1 deletion detected by cytogenetics, (iv) complex karyotype (CK) as multi-hit equivalent, and (v)\n TP53<\/jats:italic>\n mut<\/jats:sup>\n VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity.\n TP53<\/jats:italic>\n mut<\/jats:sup>\n AML was associated with significantly poor survival compared to\n TP53<\/jats:italic>\n -wild type\n TP53<\/jats:italic>\n wt<\/jats:sup>\n AML, myelodysplasia-related (AML, MR 4.7\n vs<\/jats:italic>\n . 18.3 months;\n P<\/jats:italic>\n \u2009<\u20090.0001), supporting its inclusion within\n TP53<\/jats:italic>\n mut<\/jats:sup>\n MN as a distinct subentity. Secondly, the survival of\n TP53<\/jats:italic>\n mut<\/jats:sup>\n with blast 10\u201319% was poor regardless of the allelic status. Thirdly, for cases with a single\n TP53<\/jats:italic>\n mut<\/jats:sup>\n with VAF\u2009<\u200950%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally,\n TP53<\/jats:italic>\n mut<\/jats:sup>\n AML, MDS multi-hit\/multi-hit equivalent with VAF\u2009<\u200910% had significantly poorer survival compared to\n TP53<\/jats:italic>\n mut<\/jats:sup>\n MDS VAF\u2009<\u200910% without CK and 17p del, and were comparable to those with VAF\u2009\u2265\u200910% (14.1\n vs<\/jats:italic>\n . 48.8\n vs<\/jats:italic>\n .7.8 months,\n P<\/jats:italic>\n \u2009<\u20090.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.\n <\/jats:p>","DOI":"10.1038\/s41408-025-01290-0","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T08:26:15Z","timestamp":1746606375000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5359-336X","authenticated-orcid":false,"given":"Mithun 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D.H. is a member of the board of directors or advisory committees of AbbVie and Novartis. A.A.K. provides research support to Novartis and Astex. M.P. is a member of the board of directors or advisory committees of Stemline Therapeutics and receives research funding from Kura Oncology. P.G. is a member of the advisory board of AbbVie. N.G. has served on the Advisory Board for Agio and DISC Medicine. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"88"}}