TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms

Abstract

Revised 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 (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms

“…While the 25% TP53 VAF cutoff in our study was admittedly data-driven, it was nevertheless in line with the 23% cutoff proposed by Bahaj and coworkers [ 22 ] as well as the 25% cutoff used by Grob and coworkers [ 5 ] although this latter study was an exclusively chemotherapy-treated, and slightly younger cohort. In comparing the impact of VAF by treatment subgroups, we note as well that TP53 VAF is relevant only within the intensive chemotherapy treated subgroups, in line with prior studies [ 17 , 23 ]. We were however surprised by the higher CR rates in females possibly attributable to less frequent TP53 MH in females.…”

Real World Predictors of Response and 24-month survival in high-grade TP53-mutated Myeloid Neoplasms

“…In comparing the impact of VAF by treatment subgroups, we note as well that TP53 VAF is relevant only within the intensive chemotherapy treated subgroups, in line with prior studies. 17,23 We were however surprised by the higher CR rates in females possibly attributable to less frequent TP53 MH in females. Whether additional fitness-related factors or better compliance in females play a role remains to be seen.…”

Envita’s Precision Cancer Care: 35-Fold Improvement in Response Rates

“…The overall and progression free survival for patients with a MAF > 6% for a TP53 mutation at the time of diagnosis was significantly shorter compared to patients with a MAF < 6% at the time of diagnosis or patients without the mutation [52]. Similarly, a MAF ≥ 10% in patients with TP53-mutated myeloid neoplasms had significantly shorter survival compared to patients with wild type TP53 and patients with MAF < 10% [53].…”