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
The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53<sup>mut</sup>) 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<sup>mut</sup> (variant allele frequency, VAF ≥ 2%). WHO-5 and ICC would not classify 64% and 20% of these cases as TP53<sup>mut</sup> MN, respectively. Moreover, of those classified, 67.5% would be classified discrepantly. Primary drivers of discrepancies included: (i) prognostic importance of TP53<sup>mut</sup> 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<sup>mut</sup> VAF threshold, we analyzed survival outcomes of each of these groups with an aim to provide clarity. TP53<sup>mut</sup> AML was associated with significantly poor survival compared to TP53-wild type TP53<sup>wt</sup> AML, myelodysplasia-related (AML, MR 4.7 vs. 18.3 months; P < 0.0001), supporting its inclusion within TP53<sup>mut</sup> MN as a distinct subentity. Secondly, the survival of TP53<sup>mut</sup> with blast 10-19% was poor regardless of the allelic status. Thirdly, for cases with a single TP53<sup>mut</sup> 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<sup>mut</sup> AML, MDS multi-hit/multi-hit equivalent with VAF < 10% had significantly poorer survival compared to TP53<sup>mut</sup> 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.
Authors
- David T Yeung (ORCID: https://orcid.org/0000-0002-7558-9927)
- Naseema Gangat (ORCID: https://orcid.org/0000-0002-9104-6172)
- Antoine N. Saliba (ORCID: https://orcid.org/0000-0001-5134-7336)
- Cecilia Y. Arana Yi (ORCID: https://orcid.org/0000-0002-7441-5140)
- Aref Al‐Kali (ORCID: https://orcid.org/0000-0002-0824-3715)
- Abhishek Avinash Mangaonkar (ORCID: https://orcid.org/0000-0003-2458-9887)
- C. R. Toop
- Ayalew Tefferi (ORCID: https://orcid.org/0000-0003-4605-3821)
- Sharad Kumar (ORCID: https://orcid.org/0000-0001-7126-9814)
- Mithun Vinod Shah (ORCID: https://orcid.org/0000-0002-5359-336X)
- Monika Kutyna (ORCID: https://orcid.org/0000-0003-2315-091X)
- James M. Foran (ORCID: https://orcid.org/0000-0003-1673-1708)
- Attilio Orazi (ORCID: https://orcid.org/0000-0002-1660-7013)
- Hamish S. Scott (ORCID: https://orcid.org/0000-0002-5813-631X)
- Aasiya Matin (ORCID: https://orcid.org/0000-0001-6807-0871)
- Anmol Baranwal (ORCID: https://orcid.org/0000-0002-3432-0489)
- Dariusz Ladon
- Kevin Hung (ORCID: https://orcid.org/0009-0001-9354-5864)
- Devendra Hiwase (ORCID: https://orcid.org/0000-0002-6666-3056)
- Christopher N Hahn (ORCID: https://orcid.org/0000-0001-5105-2554)
- Chung Hoow Kok (ORCID: https://orcid.org/0000-0002-3181-7852)
- Hassan B. Alkhateeb (ORCID: https://orcid.org/0000-0002-3609-8404)
- Mehrdad Hefazi (ORCID: https://orcid.org/0000-0001-8860-3380)
- Anna Brown (ORCID: https://orcid.org/0000-0002-9023-0138)
- Daniel A. Arber (ORCID: https://orcid.org/0000-0002-2160-9689)
- Mrinal M. Patnaik (ORCID: https://orcid.org/0000-0001-6998-662X)
- Patricia T. Greipp (ORCID: https://orcid.org/0000-0002-5536-9011)
- Talha Badar (ORCID: https://orcid.org/0000-0003-1548-918X)
- Rong Lucy He (ORCID: https://orcid.org/0000-0001-6116-8163)
- Kebede H. Begna (ORCID: https://orcid.org/0000-0003-2730-8593)
- William J. Hogan (ORCID: https://orcid.org/0000-0002-5841-4105)
- Danièl Thomas (ORCID: https://orcid.org/0000-0002-0837-1231)
- Danielle Rud
- Gauri Wechalekar
- Dong Chen (ORCID: https://orcid.org/0000-0001-7627-9560)
- Mark R. Litzow
- Peter Bardy
Institutions
- South Australia Pathology (AU)
- Texas Tech University (US)
- Royal Adelaide Hospital (AU)
- Mayo Clinic (US)
- University of South Australia (AU)
- University of Illinois Chicago (US)
- University of Chicago (US)
- Mayo Clinic in Arizona (US)
- South Australian Health and Medical Research Institute (AU)
- Centre for Cancer Biology (AU)
- Mayo Clinic in Florida (US)
- The University of Adelaide (AU)
- Texas Tech University Health Sciences Center (US)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1038/s41408-025-01290-0
- Citations
- 5
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 8.85
Funders
- Leukemia and Lymphoma Society
- Leukaemia Foundation
- Cancer Australia
- Medical Research Council
- National Health and Medical Research Council