Understanding What Causes Relapse in Patients with Acute Myeloid Leukemia

Genetic profiling after initial chemotherapy may help oncologists predict early prognosis.

Cancer-related mutations that arise as a result of chemotherapy could be responsible for a greater risk of relapse and poor survival rates among patients with acute myeloid leukemia (AML), a recent study found.

The study showed that patients with mutations after 30 days of the initiation of chemotherapy were 3 times more likely to relapse and die than patients whose bone marrow was cleared of the mutations.

Genetic profiling of cancer is the typical route doctors take when trying to pinpoint how aggressive a tumor is and whether it will respond to a particular treatment. However, this new research indicates an alternative to this approach which 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, MD. “About 80% 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.”

The researchers looked at bone marrow samples from patients whose outcomes were previously determined. They studied bone marrow samples from 71 AML patients treated at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. Genome sequencing was then performed at the university’s McDonnell Genome Institute.

Researchers found that this method did not reveal any more information than did standard methods for assessing the risk of relapse.

The researchers then performed the same test in 50 patients at the time of diagnosis and again 30 days after the initiation of chemotherapy when they were in remission. In analyzing the samples, scientists found that 24 patients had persistent mutations in the bone marrow after chemotherapy. This suggested that at least some leukemia cells had survived the initial therapy. In many cases, these cells expanded and contributed to relapse.

Those with the mutations post-chemotherapy had a survival rate of only 10.5 months, whereas patients without the mutations survived for 42 months on average.

“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, MD, PhD. “This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”