Midostaurin + chemo improves OS in patients with AML and FLT3 mutation
Adding midostaurin to standard chemotherapy appeared to improve overall survival (OS) in patients recently diagnosed with acute myeloid leukaemia (AML) with a FLT3 mutation, according to a recent study.
“[We] determined that midostaurin, a multitargeted kinase inhibitor, 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,” said the researchers.
Seven hundred and seventeen patients (median age 47.9 years) with newly diagnosed AML (non-therapy-related) and a FLT3 mutation (either TKD* or ITD** subtype) received oral midostaurin (50 mg twice daily on days 8–21, n=360, 51.7 percent female) or placebo (n=357, 59.4 percent female) in addition to standard chemotherapy (induction therapy with intravenous daunorubicin [60 mg/m2/day on days 1, 2, and 3] and cytarabine [200 mg/m2 on days 1–7] and consolidation therapy [four 28-day cycles of cytarabine 3,000 mg/m2 over 3 hours every 12 hours on days 1, 3, and 5 after complete remission following induction therapy]).
Patients who remained in remission following consolidation therapy were continued on midostaurin or placebo for twelve 28-day cycles. Median follow-up time was 59 months.
Patients assigned to midostaurin had significantly longer OS compared with those on standard chemotherapy only (median 74.7 vs 25.6 months, hazard ratio [HR], 0.78, 95 percent confidence interval [CI], 0.63–0.96; one-sided p=0.009). At 4 years, the OS was 51.4 and 44.3 percent in the midostaurin and standard chemotherapy only groups, respectively. [N Engl J Med 2017;doi:10.1056/NEJMoa1614359]
There was no significant difference in OS rates between FLT3 subtypes, and rate of complete remission was also comparable between patients on midostaurin and standard chemotherapy only (58.9 percent vs 53.5 percent; p=0.15).
Event-free survival was longer in patients receiving midostaurin compared with those receiving standard chemotherapy only (median 8.2 vs 3.0 months, HR, 0.78, 95 percent CI, 0.66–0.93; one-sided p=0.002), as was disease-free survival (median 26.7 vs 15.5 months; p=0.01).
Incidence of grade 3, 4, or 5 (combined) adverse events was comparable between the two groups, though there was a higher incidence of grade 3, 4, or 5 anaemia and rash in the midostaurin compared with the standard chemotherapy only group (92.7 percent vs 87.8 percent; p=0.03 and 14.1 percent vs 7.6 percent; p=0.008, respectively), while the incidence of nausea was higher in the standard chemotherapy only group (9.6 percent vs 5.6 percent; p=0.05).
Fifty-seven percent of patients underwent transplantation at which point trial treatment was discontinued. After censoring data at time of transplantation, 4-year OS was longer in patients on midostaurin compared with those on standard chemotherapy only (63.7 percent vs 55.7 percent; p=0.08).
“Since exposure to the FLT3 inhibitor was relatively brief ... it is probable that the major effect ... was the early reduction of disease burden,” said the researchers, though they did not discount other potential actions. “It is possible that the benefit of midostaurin ... might lie beyond its ability to inhibit FLT3,” they said.