Midostaurin Improves Survival in FLT3-Mutant AML

Adding midostaurin to chemotherapy prolonged survival in younger adult patients with acute myeloid leukemia (AML) and a FLT3 mutation, according to a randomized trial.

“Mutations in the fms-related tyrosine kinase 3 gene (FLT3) are present in 30% of adults with newly diagnosed AML,” wrote study authors led by Richard M. Stone, MD, of the Dana-Farber Cancer Institute in Boston. Mutations of FLT3 fall into several categories, some of which are known to worsen prognosis of the disease.

The new study tested whether midostaurin, a multitargeted kinase inhibitor, could improve outcomes when added to standard chemotherapy in AML. It included 717 patients with a median age of 47.9 years randomized to either standard chemotherapy plus midostaurin (360 patients) or chemotherapy plus placebo (357 patients). Of the full cohort, 22.6% had a point mutation in the tyrosine kinase domain (TKD), 29.8% had an internal tandem duplication with a high ratio (> 0.7) of mutant to wild-type alleles (ITD high), and 47.6% had the same type of duplication with a low ratio (0.05 to 0.7; ITD low). Results of the study were published online today in the New England Journal of Medicine.

The median overall survival with midostaurin was 74.7 months, compared with 25.6 months with placebo, yielding a hazard ratio (HR) for death of 0.78 (95% CI, 0.63–0.96; P = .009). The HR for overall survival favored midostaurin in each of the FLT3 mutation subtypes, but each individual HR did not reach significance. The 4-year overall survival rate was 51.4% with midostaurin, and 44.3% with placebo.

Complete remission was achieved in 58.9% of midostaurin patients and in 53.5% of placebo patients (P = .15). The median event-free survival was also better with the study drug, at 8.2 months compared with 3 months with placebo, for an HR of 0.78 (95% CI, 0.66–0.93; P = .002).

In total, 57% of patients underwent transplantation at some point during their disease course. Because this was an important alternative therapy, the investigators conducted a sensitivity analysis that censored transplantation patients; the risk of death was still 24.3% lower with midostaurin in this analysis.

There was no unexpected toxicity observed in the study, and the rates of grade 3 or higher adverse events were similar between the groups. Grade 3 or higher anemia was more common in the midostaurin group (92.7% vs 87.8%; P = .03), as was grade 3 or higher rash (14.1% vs 7.6%; P = .008). Nausea was more common in the placebo group.

“In this large collaborative effort, we determined that midostaurin … led to improved outcomes among younger adults with AML and a FLT3 mutation, a population with a poor prognosis that represents approximately one fourth of all patients with AML,” the authors wrote. They added that open questions included whether more specific FLT3 inhibitors might further improve outcomes in these patients, and whether midostaurin may be effective in an older AML population as well.