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Acute Myeloid Leukemia
Monitoring of clonal evolution of acute myeloid leukemia identifies the leukemia subtype, clinical outcome and potential new drug targets for post-remission strategies or relapse
Esther Onecha,1,2,3 Inmaculada Rapado,1,2,3,4 María Luz Morales,1,2,3 Gonzalo Carreño-Tarragona,1,2 Pilar Martinez-Sanchez,1,2,3 Xabier Gutierrez,1 José María Sánchez Pina,1 María Linares,1,2,3 Miguel Gallardo,1,2,3
Joaquín Martinez-López,1,2,3,4,5 and Rosa Ayala1,2,3,4,5
1Hematology Department, Hospital Universitario 12 de Octubre; 2Instituto de Investigacion Hospital 12 de Octubre, Imas12; 3Hematological Malignancies Clinical Research Unit, CNIO; 4CIBERONC, Instituto Carlos III and 5Complutense University of Madrid, Madrid, Spain
ABSTRACT
In cases of treatment failure in acute myeloid leukemia (AML), the util- ity of mutational profiling in primary refractoriness and relapse is not established. We undertook a perspective study using next-generation sequencing (NGS) of clinical follow-up samples (n=91) from 23 patients with AML with therapeutic failure to cytarabine plus idarubicin or flu- darabine. Cases of primary refractoriness to treatment were associated with a lower number of DNA variants at diagnosis than cases of relapse (median 1.67 and 3.21, respectively, P=0.029). The most frequently affected pathways in patients with primary refractoriness were signal- ing, transcription and tumor suppression, whereas methylation and splicing pathways were mainly implicated in relapsed patients. New therapeutic targets, either by an approved drug or within clinical trials, were not identified in any of the cases of refractoriness (zero of ten); however, eight potential new targets were found in five relapsed patients (five of 13, P=0.027): one IDH2, three SF3B1, two KRAS, one KIT and one JAK2. Sixty-five percent of all variants detected at diagnosis were not detected at complete response. Specifically, 100% of variants in EZH2, RUNX1, VHL, FLT3, ETV6, U2AF1, PHF6 and SF3B1 disappeared at complete response, indicating their potential use as markers to evalu- ate minimal residual disease for follow-up of AML. Molecular follow-up using a custom NGS myeloid panel of 32 genes in the post-treatment evaluation of AML can help in the stratification of prognostic risk, the selection of minimal residual disease markers to monitor the response to treatment and guide post-remission strategies targeting AML, and the selection of new drugs for leukemia relapse.
Introduction
Approximately 20–30% of all patients with acute myeloid leukemia (AML) show primary refractoriness to induction therapy without achieving complete remission (CR) and approximately 50% will relapse.1 Both primary refractoriness and relapse are therapeutic failures associated with adverse prognosis, with cure rates no higher than 10%.2-5
AML is often an oligoclonal disease at its origin, because tumor clones with diverse genetic identity are present within the same patient in greater or lesser representation. In the last decade, much progress has been made in our understanding of tumor purity and the representation of clonal and sub-clonal mutations, particularly in the role played by sub-clones in the clonal architecture in AML.6 In this context, the clonal architecture can be driven not only by a single predominant clone, but also in some
Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2325-2333
Correspondence:
ROSA AYALA
rosam.ayala@salud.madrid.org/rayala@ucm.es
Received: April 4, 2020. Accepted: July 20, 2020. Pre-published: July 30, 2020.
https://doi.org/10.3324/haematol.2020.254623 ©2021 Ferrata Storti Foundation
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