AbstractRevised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53^mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53^mut. We analyzed 488 t-MN patients for TP53^mut. At least one TP53^mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53^mut t-MN had a VAF ≥10%. TP53^mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53^mut VAF < 10% and wild-type TP53 (TP53^wt) cases. Notably, TP53^mut VAF ≥ 10% had a significantly shorter survival compared to TP53^wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53^mut VAF < 10% was comparable to TP53^wt. Within TP53^mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53^mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53^mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.