Persistent leukemia-associated genetic mutations linked to increased risk of relapse, reduced overall survival

The JAMA Network JournalsAug 26 2015

In preliminary research, the detection of persistent leukemia-associated genetic mutations in at least 5 percent of bone marrow cells in day 30 remission samples among adult patients with acute myeloid leukemia was associated with an increased risk of relapse and reduced overall survival, according to a study in the August 25 issue of JAMA.

Approximately 20 percent of adult patients with acute myeloid leukemia (AML) fail to achieve remission with initial induction chemotherapy, and approximately 50 percent ultimately experience relapse after achieving complete remission. Even though potentially curative therapy (e.g., allogeneic hematopoietic stem cell transplantation) is now available for many patients, this therapy is expensive and is associated with significant side effects. Identifying patients at high risk for relapse would be helpful clinically, according to background information in the article.

Timothy J. Ley, M.D., of the Washington University School of Medicine, St. Louis, and colleagues sought to determine whether genomic approaches can provide prognostic information for adult patients with AML. Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (average age, 51 years) treated with standard induction chemotherapy at a single center starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing (next generation sequencing that permits sequencing of hundreds to thousands of individual molecules of DNA) was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.

Analysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48 percent) had persistent leukemia-associated mutations (mutations that are known to exist in a leukemia sample when the patient presents with the disease, but are not cleared after the initial chemotherapy is given, and the bone marrow recovers) in at least 5 percent of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free (6 vs. 17.9 months) and overall survival (10.5 vs. 42.2 months) vs the 26 who cleared all mutations (leukemia specific mutations that are found in the presentation sample that are completely eliminated after initial chemotherapy). These associations also were found among the 32 AML cases with intermediate risk cytogenetics (a risk classification category for AML based on looking at the tumor cell's chromosomes).

"The data presented in this report begin to define a genomic method for the risk stratification of patients with AML that places greater emphasis on the clearance of somatic mutations [mutations that are not inherited] after chemotherapy than the identification of specific mutations at the time of presentation," the authors write. "Although this study was not designed to determine the optimal clearance threshold for the association with outcomes, it represents a foundation for prospective trials focused on the role of digital sequencing to improve risk stratification for AML patients, and perhaps other cancer types as well."

Editorial: Next-Generation Sequencing and Detection of Minimal Residual Disease in Acute Myeloid Leukemia

Friederike Pastore, M.D., and Ross L. Levine, M.D., of the Memorial Sloan Kettering Cancer Center, New York City, comment on the findings of this study in an accompanying editorial.

"Although many important questions remain, the findings reported by Klco and colleagues provide critical insights into the role of molecular monitoring in AML and into the dynamics of genetic mutations during AML treatment. The next steps should involve development of assays that can be used to enumerate minimal residual disease (MRD) in the clinic, performance studies to enumerate how best to use MRD monitoring in clinical care, and formulation of therapeutic regimens to target MRD and eradicate mutant clones to improve outcomes for patients with AML."