Midostaurin prolongs survival in FLT3-mutated AML
medwireNews: Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy prolongs survival among patients with acute myeloid leukemia (AML) and an fms-related tyrosine kinase 3 (FLT3) mutation, study findings indicate.
All participants in the CALGB 10603 (RATIFY) trial, conducted at 225 sites in 17 countries, received standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine). Those who also received oral midostaurin 50 mg twice daily on days 8 to 21 of a 28-day cycle (n=360) had a significant 22% lower risk for death than those who were randomly assigned to receive placebo (n=357).
Median overall survival was 74.7 months in the midostaurin group and 25.6 months in the placebo group, while the corresponding 4-year overall survival rates were 51.4% and 44.3%.
Patients in the midostaurin group, who were all aged 18 to 59 years with newly diagnosed AML, also had a significant 22% lower risk for relapse, death from any cause, or failure to achieve protocol-specified complete remission, during the 59-month median follow-up period, with 4-year event-free survival rates of 28.2% in the midostaurin group and 20.6% in the placebo group and median event-free survival times of 8.2 and 3.0 months respectively.
And the researchers note that, although the trial was not powered for subgroup analyses, the benefit of midostaurin was consistent among patients with the FLT3 internal tandem duplication (ITD) high (>0.7; n=214), ITD low (0.05–0.70; n=341), and tyrosine kinase domain (n=162) subtypes.
“Given that there was a benefit among patients with an ITD mutation with a low allelic burden and that the disease in such patients might be largely due to mutations other than FLT3, it is possible that the benefit of midostaurin, which is a multitargeted kinase inhibitor, might lie beyond its ability to inhibit FLT3,” Richard Stone (Dana–Farber Cancer Institute, Boston, Massachusetts, USA) and co-investigators remark.
The team also reports that there were no unexpected adverse events and those that did occur were at similar rates between the two groups, with the exceptions of grade 3, 4, or 5 anemia and rash or desquamation, which were both significantly more common in the midostaurin group than in the placebo group, at 92.7% versus 87.8% and 14.1% versus 7.6%, respectively.
Writing in The New England Journal of Medicine, Stone et al speculate that the major effect of midostaurin is likely in the early reduction of disease burden “[s]ince exposure to the FLT3 inhibitor was relatively brief (median duration of trial treatment, 3 months),” but other explanations are also possible, they add.
By Laura Cowen
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