Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome.

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.

Molecular Minimal Residual Disease Detection in Acute Myeloid Leukemia.

Initial induction chemotherapy to eradicate the bulk of acute myeloid leukemia (AML) cells results in complete remission (CR) in the majority of patients. However, leukemic cells persisting in the bone marrow below the morphologic threshold remain unaffected and have the potential to proliferate and re-emerge as AML relapse. Detection of minimal/measurable residual disease (MRD) is a promising prognostic marker for AML relapse as it can assess an individual patients' risk profile and evaluate their response to treatment. With the emergence of molecular techniques, such as next generation sequencing (NGS), a more sensitive assessment of molecular MRD markers is available. In recent years, the detection of MRD by molecular assays and its association with AML relapse and survival has been explored and verified in multiple studies. Although most studies show that the presence of MRD leads to a worse clinical outcome, molecular-based methods face several challenges including limited sensitivity/specificity, and a difficult distinction between mutations that are representative of AML rather than clonal hematopoiesis. This review describes the studies that have been performed using molecular-based assays for MRD detection in the context of other MRD detection approaches in AML, and discusses limitations, challenges and opportunities.