RESUMO
Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal/genética , Epigênese Genética/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Exoma , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Resultado do Tratamento , Carga TumoralAssuntos
Crise Blástica/genética , Genômica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Cromossomo Filadélfia , Biópsia , Progressão da Doença , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide Aguda/diagnósticoRESUMO
Myeloid malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are a heterogeneous group of disorders that share a common biology and are a major source of morbidity and mortality. In the last several years, studies using next-generation sequencing (NGS) have identified a core set of recurrently mutated myeloid malignancy genes in the majority of patients with AML and MDS, including those with normal cytogenetics. DNA-level mutations in several of these genes including NPM1, FLT3, and CEBPA in AML and ASXL1, ETV6, EZH2, RUNX1, and TP53 in MDS are associated with changes in patient outcomes and are now tested for in clinical laboratories. In addition to providing prognostic information, these gene mutations can be used to monitor patient disease burden through the use of ultrasensitive detection techniques. In this review, we will focus on the clinical utility of various NGS-based methods including whole-genome sequencing, exome sequencing, and targeted panel-based sequencing in the initial diagnosis and management of AML and MDS and cover recent methodological advances for the molecular monitoring of AML and MDS.