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Ohio State team finds gene mutation improves leukemia drug effect
COLUMBUS, Ohio—A study led by Ohio State University researchers shows that a gene mutation present in some cases of leukemia could improve the performance of the anti-cancer drug cytarbine.
The study, published online in the June 16 issue of the Journal of Clinical Oncology, shows that people with acute myeloid leukemia (AML) whose leukemia cells have mutations in the RAS gene are more likely to be cured when treated after remission with high doses of the drug cytarabine. It also suggests that testing for RAS mutations might help doctors identify which AML patients should receive high-dose cytarabine as their post-remission therapy.
According to the research team, led by internationally known leukemia specialist Dr. Clara D. Bloomfield of OSU's Comprehensive Cancer Center, the findings could change how doctors manage patients with AML.
"This appears to be the first example in AML of a mutation in an oncogene that favorably modifies a patient's response to the dose of a routinely used chemotherapeutic drug," Bloomfield says. "These data strongly suggest that mutations in RAS influence the response of AML patients to high-dose cytarabine, and they support the use of these mutations as biomarkers for this therapy."
Newly diagnosed AML patients are treated with drugs intended to drive the disease into total remission before they are given additional chemotherapy, such as high-dose cytarabine consolidation (HDAC), or more aggressive therapy such as a stem cell transplant, to prevent relapse and to cure the malignancy.
After analyzing 185 AML patients under the age of 60 who achieved complete remission following initial therapy, the researchers found HDAC is the better therapy for some patients. Thirty-four of the patients had mutations in the RAS gene, and of these, 22 received high-dose cytarabine and 12 received the drug at low dose. The high-dose patients with RAS mutations had the lower relapse rate—45 percent experienced disease recurrence after an average 10-year follow-up compared with 68 percent for those with normal RAS genes.
"That means fifty-five percent of patients with RAS mutations were cured compared with 32 percent of high-dose patients with normal RAS," Bloomfield says.
Of patients who received low doses of the drug, all those with the mutations relapsed, as did 80 percent of those with normal RAS genes.
"This seems to be the ﬁrst example of an activating oncogene mutation favorably modifying response to higher drug doses in AML," the researchers wrote in their study. "Mutations in the RAS gene constitute a novel molecular marker potentially useful in the clinic to identify patients who would optimally beneﬁt from consolidation with HDAC. Because RAS mutations seem to be the ﬁrst example of activating oncogene mutations that sensitize AML blasts to higher doses of cell-cycle phase-speciﬁc chemotherapeutic agent, further studies are needed to elucidate the molecular mechanisms of this phenomenon.
Bloomfield says if the study's findings are confirmed, future patients will likely be screened for RAS mutations, and those who have one may get HDAC for post-remission therapy rather than a stem-cell transplant.
The study, Beneﬁt Most From Postremission High-Dose Cytarabine: A Cancer and Leukemia Group B Study, was co-authored by OSU researchers Kati Maharry, Krzysztof Mrozek, Guido Marcucci and Peter Paschka. The research was funded by the National Cancer Institute, the Coleman Leukemia Research Foundation and the Deutsche Forschungsgemeinschaft, a German organization that promotes research at universities and other publicly financed research institutions.