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^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 TP53^mut 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. TP53^mut 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 TP53^mut 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 TP53^mut 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.