Persistent Mutations throughout Remission Linked with Poor Survival in Leukemia

August 26, 2015
Persistent Mutations throughout Remission Linked with Poor Survival in Leukemia
8 in 10 patients with acute myeloid leukemia relapse after remission, and for most of them there's no reliable way to predict relapse. But new research suggests that performing genetic profiling while a patient is in remission can help physicians assess response to treatment and determine whether aggressive, follow-up treatment is necessary. [Darryl Leja, NHGRI]

While the incidence of acute myeloid leukemia (AML) is still relatively rare, accounting for approximately 1% of cancer deaths in the U.S., rates of occurrence are expected to rise as the largest portion of the population continues to age. Moreover, there remains a significant level of disparity in clinical outcomes, as 50% of patients relapse and die from refractory disease after an initial response to chemotherapy.  

Now, researchers from the Washington University School of Medicine (WUSM) have published data that suggests lingering cancer-related mutations—detected after initial treatments—are associated with an increased risk of relapse and poor survival.

The investigators used next-generation sequencing techniques to profile bone marrow samples from patients with AML. They found that cells carrying mutations 30 days after the initial chemotherapy treatment were roughly three times more likely to relapse and die than patients who cleared the mutations.   

"Most patients diagnosed with AML fall into a gray area when it comes to being able to predict their risk of relapse," explained senior author Timothy Ley, M.D., professor of oncology in the Department of Medicine at WUSM. "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.”

Dr. Ley continued, stating that "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."

The findings from this study were published recently in JAMA through an article entitled “Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.”

The WUSM scientists utilized whole genome and exome sequencing on bone marrow samples obtained from 50 patients at the time of their diagnosis and 30 days after the initiation of chemotherapy. The researchers found that 24 of the patients had persistent mutations within their bone marrow cells—suggesting that at least some of the leukemia cells had survived the initial therapy. Additionally, 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," stated lead author Jeffery Klco, M.D,. Ph.D., assistant faculty member 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."

The researchers are now looking into developing assays to detect residual disease after AML treatment, as well as formulating new therapeutic regimens to target the residual disease.

"These findings build on studies performed more than a decade ago that suggested the failure to clear leukemia cells bearing chromosomal abnormalities was associated with increased risk of relapse,” said Dr. Ley. “But that technology was applicable only for the subset of patients with abnormal chromosomes, while genome sequencing can detect mutations in virtually all patients and is much more sensitive and specific. This new approach gives us a way to think about how to use genomics to evaluate the risk of relapse for nearly all AML patients."

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