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.  For patients with an often-deadly form of leukemia, this research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.

Using genetic profiling to study bone marrow samples from patients with acute myeloid leukemia (AML), researchers found that those whose cells still carried mutations 30 days after the initiation of chemotherapy were about three times more likely to relapse and die than patients whose bone marrow was cleared of these mutations.

While the genetic profiling of cancer is not yet routine, such testing typically is performed only at the time of diagnosis to try to pinpoint how aggressive a tumor is and whether it will respond to a particular treatment. The new findings suggest a different approach, one that focuses less on the specific set of mutations present in a patient's tumor at the time of diagnosis and more on whether those mutations are cleared by initial treatment with chemotherapy.

"Most patients diagnosed with AML fall into a gray area when it comes to being able to predict their risk of relapse," said senior author Timothy J. Ley, M.D., the Lewis T. and Rosalind B. Apple Professor of Oncology in the Department of Medicine, Washington University School of Medicine in St. Louis. "About 80 percent of AML patients go into remission with chemotherapy, but most of them eventually will relapse. Unfortunately, we still don't have a definitive test that tells us early on which patients will relapse.

"Such information is important to know because high-risk patients need aggressive, potentially curative therapy with a stem-cell transplant when they are in remission, early in the course of the disease. However, we don't want to transplant patients who are unlikely to relapse following conventional chemotherapy because the transplant procedure is expensive and carries a significant risk of severe side effects and even death."

In this retrospective study, investigators studied leukemic bone marrow samples obtained at diagnosis from 71 AML patients treated at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. Genome sequencing and analysis were performed at the university's McDonnell Genome Institute.

The researchers first sequenced the 71 bone marrow samples obtained at the time of diagnosis to see if specific leukemia-related mutations found in each patient's AML cells correlated with relapse after initial treatment with chemotherapy. But they found that such mutations were no more informative than standard methods for assessing risk of relapse.

The researchers then conducted genome sequencing on bone marrow samples that had been obtained from 50 patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when they were in remission. Analyzing these samples, the researchers found that 24 patients had persistent mutations in bone marrow cells after chemotherapy, even though by standard clinical measures they were in remission. This suggested that at least some leukemia cells had survived the initial therapy. In several cases, these same cells were shown to expand and contribute to relapse.

Those with persistent mutations had a median survival of only 10.5 months, compared with 42 months for the 26 patients whose leukemia mutations had been cleared by initial chemotherapy.

"If our results are confirmed in larger, prospective studies, genetic profiling after initial chemotherapy could help oncologists predict prognosis early in the course of a patient's leukemia and determine whether that patient has responded to the chemotherapy - without having to wait for the cancer to recur," said first author Jeffery M. Klco, M.D., Ph.D., now at St. Jude Children's Research Hospital. "This approach to genetic profiling, which focuses on performing genome sequencing after a patient's initial treatment, also may be useful for other cancers."

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."

The research is supported by grants from the National Institutes of Health (NIH) and The Foundation for Barnes-Jewish Hospital, grant numbers KO8 HL116605, PO1 CA101937 and U54 HG003079.