FROM THE EHA CONGRESS
Adding the multitargeted kinase inhibitor midostaurin to standard chemotherapy led to significantly longer overall and event-free survival compared to placebo and standard chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients with FLT3 gene mutations, according to phase III trial results presented at the annual congress of the European Hematology Association that were published simultaneously in the New England Journal of Medicine.
About 30% of AML patients have mutations to the FLT3 gene – with three-quarters of those internal tandem duplication (ITD) mutations, which involves duplication of between 3 and 100 amino acids in the juxtamembrane region. These mutations are linked with a high relapse rate and poor prognosis, especially when there is a high ratio of these mutations to wild-type FLT3. About 8% of patients with newly diagnosed AML have an FLT3 point mutation in the tyrosine kinase domain (TKD), but the effect of these on prognosis isn’t clear.
In the trial, called RATIFY and conducted at 225 sites in 17 countries, 360 patients were randomized to the midostaurin group and 360 to placebo, and they were treated from 2008 to 2013. In all, 29.8% of patients were “ITD high,” meaning their ITD FLT3 mutation to wild-type FLT3 ratio was higher than 0.7, and 47.6% were “ITD low,” with a mutation-to-wild-type FLT3 ratio of 0.5 to 0.7. A total of 22.6% of patients had TKD mutations.
Patients received standard induction chemotherapy, with daunorubicine and cytarabine, and on days 8 through 21 either 50 mg of midostaurin or placebo orally twice a day. Patients were given an identical second cycle of induction therapy, with midostaurin or placebo, if they showed definitive clinically significant residual leukemia after the first induction treatment.
Those who achieved complete remission after induction were given 4, 28-day cycles of consolidation treatment, with midostaurin or placebo on days 8 through 21. If they stayed in remission after that, they were given maintenance of 12, 28-day cycles of midostaurin or placebo.
They were not required to receive hematopoetic stem cell transplantation (HSCT), but it was performed at investigator discretion.
Midostaurin improved survival but not rates of complete remission as defined in the trial protocol, researchers reported.
The hazard ratio for death in the midostaurin group was 0.78 (95% CI, 0.63 to 0.96; one-sided P = .0009). The 4-year overall survival rate was 51.4% for the midostaurin group and 44.3% for the placebo group. Midostaurin was shown to benefit all mutation subgroups, but with no greater benefit in one group than another.
Patients in the midostaurin group had a 21.6% lower likelihood of having an event, defined as failure to achieve protocol-defined complete remission, relapse or death without relapse.
There was no significant difference between the groups in complete remission, which under protocol had to occur by day 60.
HSCT was performed in 57% of patients – during the first complete remission in 28.1% of the midostaurin group and in 22.7% during the first complete remission in the placebo group. For those who were transplanted after the first complete remission, no treatment effect was seen.
Researchers noted that there was a therapeutic benefit even among patients with ITD mutations but with a low allelic burden, in whom the disease might be due largely 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,” possibly through inhibition of KIT, researchers said.
They also noted that as the trial went on, more and more investigators decided to treat patients with hematopoietic stem cell transplantation, based on newly reported data elsewhere. Since midostaurin was discontinued at the time of transplant, that could have limited exposure to the drug and limited its effect.