Mutations after chemo signal deadly leukemia

"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," says Timothy J. Ley. (Credit: Airman Magazine/Flickr)

Mutations may explain why some people with leukemia are more likely to relapse or die after chemotherapy.

Using genetic profiling to study bone marrow samples from patients with acute myeloid leukemia (AML), researchers found 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 genetic profiling of cancer is not yet routine, such testing typically is performed only at the time of diagnosis to pinpoint how aggressive a tumor is and whether it will respond to a particular treatment.

Who will relapse?

The new findings suggest a different approach: focus 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,” says senior author Timothy J. Ley, professor of oncology at Washington University 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.”

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AML is a cancer of blood-forming cells in the bone marrow. An estimated 19,000 cases of AML will be diagnosed in the United States this year, and some 14,000 will die of the disease.

The current study, published in the Journal of the American Medical Association, is retrospective, meaning that researchers looked at bone marrow samples from patients whose outcomes were already known. The 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.

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.

Genetic profiling

They 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.

The samples showed that 24 patients had persistent mutations in bone marrow cells after chemotherapy, even though by standard clinical measures they were in remission, suggesting  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.

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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,” says first author Jeffery M. Klco, 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.”

The National Institutes of Health (NIH) and the Foundation for Barnes-Jewish Hospital supported the work.

Source: Washington University in St. Louis