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

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dc.contributor.authorShah, M.V.
dc.contributor.authorHung, K.
dc.contributor.authorBaranwal, A.
dc.contributor.authorWechalekar, G.
dc.contributor.authorAl-Kali, A.
dc.contributor.authorToop, C.R.
dc.contributor.authorGreipp, P.
dc.contributor.authorKutyna, M.M.
dc.contributor.authorMatin, A.
dc.contributor.authorLadon, D.
dc.contributor.authorSaliba, A.
dc.contributor.authorChen, D.
dc.contributor.authorBegna, K.
dc.contributor.authorBrown, A.
dc.contributor.authorRud, D.
dc.contributor.authorLitzow, M.R.
dc.contributor.authorHogan, W.J.
dc.contributor.authorBardy, P.
dc.contributor.authorBadar, T.
dc.contributor.authorKumar, S.
dc.contributor.authoret al.
dc.date.issued2025
dc.description.abstractThe 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.
dc.description.statementofresponsibilityMithun Vinod Shah, Kevin Hung, Anmol Baranwal, Gauri Wechalekar, Aref Al-Kali, Carla R. Toop, Patricia Greipp, Monika M. Kutyna, Aasiya Matin, Dariusz Ladon, Antoine Saliba, Dong Chen, Kebede Begna, Anna Brown, Danielle Rud, Mark R. Litzow, William J. Hogan, Peter Bardy, Talha Badar, Sharad Kumar, David T. Yeung, Mrinal M. Patnaik, James M. Foran, Rong He, Naseema Gangat, Mehrdad Hefazi, Hamish S. Scott, Cecilia Y. Arana Yi, Hassan Alkhateeb, Abhishek A. Mangaonkar, Daniel Thomas, Christopher N. Hahn, Attilio Orazi, Daniel A. Arber, Chung Hoow Kok, Ayalew Tefferi, and Devendra Hiwase
dc.identifier.citationBlood Cancer Journal, 2025; 15(1):88-1-88-11
dc.identifier.doi10.1038/s41408-025-01290-0
dc.identifier.issn2044-5385
dc.identifier.issn2044-5385
dc.identifier.orcidKutyna, M.M. [0000-0003-2315-091X]
dc.identifier.orcidBrown, A. [0000-0002-9023-0138]
dc.identifier.orcidKumar, S. [0000-0001-7126-9814]
dc.identifier.orcidYeung, D.T. [0000-0002-7558-9927]
dc.identifier.orcidScott, H.S. [0000-0002-5813-631X]
dc.identifier.orcidHahn, C.N. [0000-0001-5105-2554]
dc.identifier.orcidKok, C.H. [0000-0002-3181-7852]
dc.identifier.orcidHiwase, D. [0000-0002-6666-3056]
dc.identifier.urihttps://hdl.handle.net/2440/147245
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© 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/.
dc.source.urihttps://doi.org/10.1038/s41408-025-01290-0
dc.subjectAcute myeloid leukaemia; Cancer genomics; Myelodysplastic syndrome
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshConsensus
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshLeukemia, Myeloid, Acute
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshMutation
dc.subject.meshPrognosis
dc.subject.meshRetrospective Studies
dc.subject.meshTumor Suppressor Protein p53
dc.subject.meshWorld Health Organization
dc.titleValidation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort
dc.typeJournal article
pubs.publication-statusPublished

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