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Next generation sequencing for risk assessment in acute myeloid leukemia

Klco J, Miller C, et al. (2015) Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 314(8): 811–822.

Citation summary: Read how these researchers use next generation sequencing (NGS) techniques with patients diagnosed with AML to identify associations between specific mutations and disease outcome. These techniques were also used to track the elimination of leukemia-specific mutations in AML patients following chemotherapy. The xGen AML Cancer Panel v1.0 was used to target and capture 264 commonly mutated genes in AML.

Sep 30, 2015

Background

Acute myeloid leukemia (AML) is a cancer of the blood and/or bone marrow. The disease is initially treated with chemotherapy, and recent evidence has shown that aggressive stem cell transplantation can be effective in preventing disease relapse. Transplantation therapies are expensive and not always needed, however, and can have profound side effects. Therefore, a method for determining risk of relapse after chemotherapy would help clinicians in providing this costly treatment only to patients who will benefit from it.

In this paper, the authors use next generation sequencing (NGS) techniques on patients diagnosed with AML to identify associations between specific mutations and disease outcome. They also use these techniques to track the elimination of leukemia-specific mutations in AML patients following chemotherapy.

Experiment

Klco and colleagues first collected bone marrow samples from 71 subjects at the time of their AML diagnosis. The scientists tracked the outcomes of these patients and split them into 3 groups: those who relapsed within 6 months, those who relapsed between 6 and 12 months, and those who remained in remission for over 12 months. They performed whole-genome or whole-exome sequencing on the 71 samples, and compared the number of common AML mutations between the 3 groups, as well as the amount of total genomic mutation. The IDT xGen® AML Cancer Panel v1.0 was used to target and capture 264 commonly mutated genes in AML. Using this panel, the researchers were able to increase depth of coverage from 119X to 215X.

The researchers then sequenced bone marrow samples from 50 patients, including 25 subjects from the previous 71, and 25 new subjects, using the xGen AML Cancer Panel or an exome capture panel supplemented with the xGen AML Cancer Panel. In these 50 patients, they identified leukemia-associated mutations at diagnosis and monitored the mutations’ elimination or persistence 30 days after induction chemotherapy.

Results

In the first study, the researchers did not observe a significant association between specific AML mutations or total genomic coding mutations and the probability of AML relapse. While the results do not provide a method to improve the assessment of patient outcome, they do shed light on the genetic complexity of the disease.

In the second study, the researchers found that 24 of 50 patients had persistent leukemia-associated mutations in their bone marrow cells after chemotherapy. These patients had a significantly increased likelihood of relapse and reduced overall survival (median 10.5 months) compared to those with successful mutation elimination (median 42.2 months). The results of this second study demonstrate the important role that genetic mutation plays in AML and also suggest that targeted NGS techniques can improve risk assessment of patients with AML.

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