The utility of next‐generation sequencing in diagnosis and monitoring of acute myeloid leukemia and myelodysplastic syndromes

Abstract

Summary 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.

The evolving role of next generation sequencing in myelodysplastic syndromes

“…In terms of practical considerations, it can take one to three weeks to receive a finalized data report, which may be too long to affect an initial treatment decision for a patient with more aggressive disease. Likewise, the costs for a myeloid gene panel have ranged anywhere from $200 to $1000 dollars (Duncavage & Tandon, ), and insurance coverage of these tests is not guaranteed – though admittedly, this is a moving target. Still, while NGS testing is now widely accessible, tests are not standardized.…”

Molecular therapy for acute myeloid leukaemia

“…The addition of targeted agents to induction therapy in a small set of AML trials demonstrates that rapid testing for alterations in a single gene is possible, but needs to be coordinated across cooperative sites in order to allow for adequate accrual of patients with rare mutations. Thus, future directions for research should include the continued development of faster DNA-sequencing platforms to allow for a reasonable turnaround time from sample receipt to reporting of results, enabling integration of these data to inform decisions on induction therapy 57–60 . To obtain statistically meaningful results from clinical trials, multicentre studies with upfront application of mutational data, acquired through a central lab or via a platform that can be performed at the different centres, will be required to investigate which molecularly targeted therapies are most effective in newly diagnosed patients with AML.…”

Hybridization capture-based next generation sequencing reliably detects FLT3 mutations and classifies FLT3-internal tandem duplication allelic ratio in acute myeloid leukemia: a comparative study to standard fragment analysis

“…The US Food and Drug Administration also approved a companion diagnostic test for midostaurin and gilteritinib using fragment analysis. At the same time, with the advent of next generation sequencing, clinical laboratories have increasingly adopted next generation sequencing as a more comprehensive acute myeloid leukemia genetic testing method, given its ability to simultaneously evaluate multiple clinically informative markers, such as NPM1, CEBPA, KIT, TP53, AXSL1, RUNX1, IDH1, and IDH2 [20]. However, FLT3-internal tandem duplication is a difficult-to-detect entity by next generation sequencing given its heterogeneity in size (3-400 bp), insertion site and perfect/near-perfect duplication of wild-type sequence, posing challenges for informatics processing and analysis [21][22][23].…”