Mutations that persist after initial chemotherapy may confer an increased risk of relapse and poor survival in patients with acute myeloid leukemia (AML), according to research published in JAMA.
Investigators found that patients who still had leukemia-specific mutations 30 days after they began chemotherapy had significantly shorter event-free and overall survival than patients whose bone marrow was free of these mutations.
These findings suggest genetic profiling of AML and other cancers may be more effective if it is focused 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.
“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 study author Jeffery M. Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“This approach to genetic profiling, which focuses on performing genome sequencing after a patient’s initial treatment, also may be useful for other cancers.”
To investigate the utility of this approach, Dr Klco and his colleagues conducted a retrospective study of AML patients. The team began with bone marrow samples from 71 AML patients treated with standard induction chemotherapy.
The investigators first sequenced these samples, which were obtained at the time of diagnosis, to see if the presence of mutations correlated with the outcome of chemotherapy. They found that mutations were no more informative than standard methods used to predict patient outcomes.
So the team sequenced samples obtained from 50 AML patients at the time of diagnosis and again 30 days after the initiation of chemotherapy, when the patients were in remission. Twenty-five of the 50 patients were from the first cohort of 71 patients, and 25 were new cases.
Analyzing these samples, the investigators found that 24 patients (48%) had persistent mutations in at least 5% of bone marrow cells after chemotherapy, even though, by standard clinical measures, they were in remission.
These patients had inferior event-free and overall survival when compared to the patients whose mutations had been cleared by initial chemotherapy.
The median event-free survival was 6 months and 17.9 months in patients with and without mutations, respectively (P<0.001). And the median overall survival was 10.5 months and 42 months, respectively (P=0.004).
The investigators noted that only a subset of the persistent mutations were in recurrently mutated AML genes (NPM1, FLT3, DNMT3A, etc.).
“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 study author Timothy J. Ley, MD, of the Washington University School of Medicine in St. Louis, Missouri.
“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.”
