Abstract
Acute myeloid leukemia (AML) with NPM1 gene mutations is currently recognized as a distinct entity, due to its unique biological and clinical features. We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated AML, receiving either intensive chemotherapy or hematopoietic stem cell transplantation. Several clinical trials have so far demonstrated a significant independent prognostic impact of molecular MRD monitoring in NPM1-mutated AML and, accordingly, the Consensus Document from the European Leukemia Net MRD Working Party has recently recommended that NPM1-mutated AML patients have MRD assessment at informative clinical timepoints during treatment and follow-up. However, several controversies remain, mainly with regard to the most clinically significant timepoints and the MRD thresholds to be considered, but also with respect to the optimal source to be analyzed, namely bone marrow or peripheral blood samples, and the correlation of MRD with other known prognostic indicators. Moreover, we discuss potential advantages, as well as drawbacks, of newer molecular technologies such as digital droplet PCR and next-generation sequencing in comparison to conventional RQ-PCR to quantify NPM1-mutated MRD. In conclusion, further prospective clinical trials are warranted to standardize MRD monitoring strategies and to optimize MRD-guided therapeutic interventions in NPM1-mutated AML patients.
Highlights
The results of cytogenetic and molecular examinations at diagnosis of non-promyelocytic acute myeloid leukemia (AML), combined with the achievement of morphologic complete remission (CR) after remission induction chemotherapy, have significant prognostic impact on clinical outcome and usually serve to guide post-remission therapeutic strategies in younger adult patients [1–3]
We summarize here the results of published studies investigating the clinical application of minimal/measurable residual disease (MRD) in patients with NPM1-mutated Acute myeloid leukemia (AML), receiving either intensive chemotherapy or hematopoietic stem cell transplantation
Recent studies have suggested that patients with NPM1 mutation and FLT3-ITD with a low (
Summary
The results of cytogenetic and molecular examinations at diagnosis of non-promyelocytic acute myeloid leukemia (AML), combined with the achievement of morphologic complete remission (CR) after remission induction chemotherapy, have significant prognostic impact on clinical outcome and usually serve to guide post-remission therapeutic strategies in younger adult patients [1–3]. The risk stratification in AML patients remains inadequate, and there is growing interest in the use of more sensitive laboratory tools, such as multiparametric flow cytometry (MFC) or molecular techniques, to detect low levels of residual disease in either BM or peripheral blood (PB) at different treatment timepoints [1]. Even within homogeneous genetic subgroups, the long-term outcome of AML patients depends on the clearance of the molecular lesion, as clearly demonstrated in other myeloid neoplasms, namely chronic myeloid leukemia and acute promyelocytic leukemia [1,4]. Beyond MFC, several molecular techniques are currently available for MRD determination in AML patients, including real-time quantitative polymerase chain reaction (RQ-PCR), which is highly sensitive, reliable, rapid and reproducible between different laboratories, as well as newer but less standardized tools such as next-generation sequencing (NGS) and digital droplet PCR (ddPCR) [2,4]. While MFC, despite its limitations, could enable MRD assessment in the vast majority of AML patients, a major drawback of RQ-PCR is its applicability only to those cases, accounting for approximately 50–60% of younger AML patients, who bear at least one molecular lesion, specific and stable over the treatment course, which could reliably be monitored using this molecular technique [2,4,10]
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