Molecular characterization of AML‐MRC reveals TP53 mutation as an adverse prognostic factor irrespective of MRC‐defining criteria, TP53 allelic state, or TP53 variant allele frequency

Abstract

Background Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) generally confers poor prognosis, however, patient outcomes are heterogeneous. The impact of TP53 allelic state and variant allele frequency (VAF) in AML‐MRC remains poorly defined. Methods We retrospectively evaluated 266 AML‐MRC patients who had NGS testing at our institution from 2014 to 2020 and analyzed their clinical outcomes based on clinicopathological features. Results TP53 mutations were associated with cytogenetic abnormalities in 5q, 7q, 17p, and complex karyotype. Prognostic evaluation of TP53 MUT AML‐MRC revealed no difference in outcome between TP53 double/multi‐hit state and single‐hit state. Patients with high TP53 MUT variant allele frequency (VAF) had inferior outcomes compared to patients with low TP53 MUT VAF. When compared to TP53 WT patients, TP53 MUT patients had inferior outcomes regardless of MRC‐defining criteria, TP53 allelic state, or VAF. TP53 mutations and elevated serum LDH were independent predictors for inferior OS and EFS, while PHF6 mutations and transplantation were independent predictors for favorable OS and EFS. NRAS mutation was an independent predictor for favorable EFS. Conclusions Our study suggests that TP53 MUT AML‐MRC defines a very‐high‐risk subentity of AML in which novel therapies should be explored.

A real-world analysis of clinical outcomes in AML with myelodysplasia-related changes: a comparison of ICC and WHO-HAEM5 criteria

“…Previously, we had shown that TP53 mutations were associated with inferior outcomes in patients with AML with myelodysplasia-related changes (AML-MRC) regardless of TP53 allelic state. 15 We sought to evaluate whether this holds true in the AML-MR cohort. A workflow to allocate TP53 allelic state in our cohort is presented in supplemental Figure 4 A.…”

“…TP53 mutations are frequently associated with complex karyotype, negative correlation with other gene mutations, and dismal outcomes regardless of therapy. 2 , 4 , 15 , 21 , 22 , 23 , 24 The divergences in 2 classifications regarding TP53 are (1) WHO-HAEM5 does not have a TP53 -AML category and (2) ICC includes pure erythroid leukemia in the AML- TP53 but WHO-HAEM5 includes it in the AML-DIFF. Our results show that TP53 mutations are associated with distinct pathological features and extremely dismal outcomes.…”

“… 28 , 29 , 30 , 31 As we previously reported, TP53 mutated AML showed extremely poor outcomes, irrespective of prior history of MDS or MDS/MPN, cytogenetic lesions used to define AML-MRC, TP53 allelic state or VAF, thus should be considered a distinct entity and warrant novel therapies urgently. 15 Based on these results, TP53 mutated AML should be viewed as a separate entity, and likely requires a unique therapeutic approach.…”

“… 14 NGS was conducted in patients diagnosed after 2018 using a custom hybrid-capture–based myeloid panel consisting of 49 genes implicated in myeloid malignancies as previously reported. 15 , 16 , 17 The limit of detection for variant calling was 2%. Variants were annotated and then classified as oncogenic mutations or variants of unknown significance, as previously described.…”

Tp53-Mutated Myelodysplasia and Acute Myeloid Leukemia

“…Particularly, in the context of AML-MRC, the AML-MRC-C subtype is particularly enriched in TP53 mutations (40–55%), while the AML-MRC-H and AML-MRC-M subtypes more rarely display TP53 mutations. 102 , 103 It is of interest to note that AML-MRC-C subgroup is heterogeneous in that it can be subdivided into TP53 -mutant and TP53 -WT cases: the TP53 -mutant cases have a lower rate of mutations of RNA splicing genes and of ASXL1, BCOR and EZH2 genes compared to those TP53 -WT. 102 , 103 TP53 -mutant AML-MRC-C are associated with cytogenetic abnormalities in 5q, 7q, 17p and complex karyotype and are associated with poor outcome, independently of their multi-hit or single-hit TP53 mutational status.…”