A study led by Memorial Sloan-Kettering researchers has identified a set of genetic abnormalities that can be used to make more-accurate prognoses in people with acute myelogenous leukemia (AML). This information could help clinicians determine which treatments are most likely to benefit patients with this type of leukemia.
“Our study shows that genetic profiling makes it possible to categorize leukemia patients more precisely in terms of whether their disease will return after treatment,” says medical oncologist Ross L. Levine, the lead author of the study reported in the March 22 issue of the New England Journal of Medicine. Dr. Levine is a member of Memorial Sloan-Kettering's Leukemia Service and the Human Oncology and Pathogenesis Program.
“We also want to use existing therapies more intelligently,” Dr. Levine adds. “It helps a great deal to know which subset of patients will actually benefit from intensive therapies, such as a higher chemotherapy dose or a bone marrow transplant.”
Calculating Risk Based on Genes
At present, clinicians rely on a handful of known genetic biomarkers (markers of disease) to predict outcome in leukemia patients, and these biomarkers provide useful information for only a subset of patients. For most people diagnosed with AML, it is difficult to predict the chance of a cure.
The method used in the study incorporates information from an array of genes and could enable nearly two-thirds of patients to be categorized into clearly defined prognostic groups. “Our goal was not to ask whether a certain gene or two raised or lowered risk, but to determine whether an amalgam of information from a set of genes made it possible to precisely stratify patients by risk,” Dr. Levine says.
Linking Gene Mutations to Treatment Response
In the study, the researchers analyzed blood or bone marrow samples from 502 patients with AML who were participating in a clinical trial. Such samples are routinely taken for research purposes during trials with patient consent. Led by Martin S. Tallman, Chief of Memorial Sloan-Kettering’s Leukemia Service, the clinical trial investigated whether increasing the standard dose of chemotherapy in AML patients under age 60 would improve survival.
The team that performed the genetic analysis, which included investigators from Memorial Sloan-Kettering, Weill Cornell Medical College, and other institutions, examined the samples for mutations within 18 genes known to have abnormalities in people with AML. The researchers noted the relationship between the mutations present in each patient and how that patient ultimately fared with the disease under either the standard or increased chemotherapy dose.
The analysis enabled the researchers to determine specific risk levels for a variety of gene-mutation combinations. They also were able to establish that the higher chemotherapy dose used in the trial benefited only some of the patients.
The researchers took into account variables such as patient age and gender, and validated the results in a separate group of patients — ensuring that the profiling approach could be generally applied beyond the current trial.
“We want to show this approach can be used not just at Memorial Sloan-Kettering but throughout the leukemia community,” Dr. Levine explains.
Dr. Levine and his Memorial Sloan-Kettering colleagues are working to translate the results from the study into clinical use. “We’ve already developed genetic tests for this set of mutations in patients, and we’re in the process of making sure they work well in practice,” he says.
“We have preliminary evidence that they do, and we’re hoping to have a pilot study soon as a step toward getting it into the clinic.”