Shah, M.V.Hung, K.Baranwal, A.Wechalekar, G.Al-Kali, A.Toop, C.R.Greipp, P.Kutyna, M.M.Matin, A.Ladon, D.Saliba, A.Chen, D.Begna, K.Brown, A.Rud, D.Litzow, M.R.Hogan, W.J.Bardy, P.Badar, T.Kumar, S.et al.2025-09-102025-09-102025Blood Cancer Journal, 2025; 15(1):88-1-88-112044-53852044-5385https://hdl.handle.net/2440/147245The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53- mutated (TP53(mut)) myeloid neoplasm (MN). 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 TP53(mut) (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53(mut) MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53mut 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) TP53(mut) VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53mut AML was associated with significantly poor survival compared to TP53-wild type TP53(wt) AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53mut MN as a distinct subentity. Secondly, the survival of TP53(mut) with blast 10–19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53(mut) with VAF < 50%, 17p13.1 del or CK serve as practical surrogates of biallelic inactivation, obviating the need for an additional copy number analysis. Finally, TP53(mut) AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53mut MDS VAF < 10% without CK and 17p del, and were comparable to those with VAF ≥ 10% (14.1 vs. 48.8 vs.7.8 months, P < 0.0001). Collectively, these findings address key areas of contention and provide valuable insights that will guide future revisions of the WHO and ICC classifications.en© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Acute myeloid leukaemia; Cancer genomics; Myelodysplastic syndromeAdultAgedAged, 80 and overConsensusFemaleHumansLeukemia, Myeloid, AcuteMaleMiddle AgedMutationPrognosisRetrospective StudiesTumor Suppressor Protein p53World Health OrganizationJournal article10.1038/s41408-025-01290-0739159Kutyna, M.M. [0000-0003-2315-091X]Brown, A. [0000-0002-9023-0138]Kumar, S. [0000-0001-7126-9814]Yeung, D.T. [0000-0002-7558-9927]Scott, H.S. [0000-0002-5813-631X]Hahn, C.N. [0000-0001-5105-2554]Kok, C.H. [0000-0002-3181-7852]Hiwase, D. [0000-0002-6666-3056]