Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis.
Highlights
Acute myeloid leukemia (AML) is a highly heterogeneous malignancy, especially in terms of the molecular and phenotypic characteristics
DNA methyltransferase 3A (DNMT3A) mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis
Which of the potential molecular and/or cellular markers should be assessed? Second, what type of biological sample should be analyzed? Third, where should the sensitivity threshold be set, and what are the relevant time-points to consider for minimal residual disease (MRD) assessment? One study found that IDH1/2 gene mutations persisted in patients who were in complete remission (CR), other molecular markers were not analyzed at the time of AML diagnosis [10]
Summary
Acute myeloid leukemia (AML) is a highly heterogeneous malignancy, especially in terms of the molecular and phenotypic characteristics. Recent studies have shown that minimal residual disease (MRD) in AML patients, during or after treatment, has prognostic value [4,5,6,7,8,9]. One study found that IDH1/2 gene mutations persisted in patients who were in complete remission (CR), other molecular markers were not analyzed at the time of AML diagnosis [10]. These mutations may be attributed to a preleukemic clone that acquires additional mutations promoting proliferation and differentiation block, which eventually results in leukemia. The prognostic impact of DNMT3A mutations seems to be unfavorable [12, 13], but their applicability MRD monitoring remains unclear [14]
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