Multikinase Inhibitor Midostaurin in Newly Diagnosed AML Patients with FLT3 Mutations: Results of the CALGB 10603/RATIFY Trial

Conference Correspondent - ASH 2015 - Leukemia


Midostaurin, a multitargeted small-molecule FMS-like tyrosine kinase 3 receptor (FLT3) inhibitor, has demonstrated single-agent activity in patients with acute myeloid leukemia (AML) harboring activating both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) FLT3 mutations.1 The randomized phase 3 CALGB 10603/RATIFY trial evaluated the benefit of midostaurin addition to induction and consolidation therapy followed by maintenance therapy in improving efficacy and survival outcomes compared with standard chemotherapy in younger adults with activating FLT3 mutation; the results were reported by Stone and colleagues.2

A total of 717 previously untreated FLT3 mutant patients with AML (not including acute promyelocytic leukemia) aged 18 to 60 years were randomized to receive midostaurin (n = 360) or placebo (n = 357). Stratification was based on FLT3 mutation subtype: FLT3 ITD-Low (n = 341), FLT3 ITD-High (n = 214), and FLT3 TKD-High (n = 162). Of the 717 patients, 408 (57%) patients underwent allogeneic stem-cell transplantation (SCT). The treatment regimen consisted of induction therapy with standard daunorubicin/cytarabine plus midostaurin or placebo (50 mg orally twice daily, days 8-22), followed by consolidation therapy with 4 cycles of cytarabine (3 g/m2 every 12 hours on days 1, 3, and 5) plus midostaurin or placebo (50 mg orally twice daily, days 8-22) in patients who achieved complete remission (CR), and followed by maintenance therapy for a year with midostaurin or placebo (50 mg orally twice daily). Midostaurin treatment resulted in a significant prolongation of event-free survival (EFS; 8.0 vs 3.0 months; hazard ratio [HR], 0.80; P = .004), which translated to a significant improvement in the primary end point of overall survival (OS; median OS, 74.7 vs 26.0 months; HR, 0.77; P = .007); the 4-year OS rate was 51.4% in the midostaurin arm versus 44.2% in the placebo arm. The benefit of midostaurin was consistent across all FLT3 mutation subgroups for both EFS and OS. Censoring at the time of SCT also provided similar EFS (median EFS, 8.2 vs 3.0 months; HR, 0.84; P = .025) and OS (median OS, NR vs NR months; HR, 0.77; P = .047) results as the primary analysis. The rate of CR by day 60 was similar between the 2 treatment arms; however, patients treated with midostaurin achieved a significantly higher rate of CR in induction/consolidation (66% vs 59%; P = .045). There were no statistically significant differences between treatment arms in grade ?3 hematologic or nonhematologic adverse events (AEs) except for a higher incidence of rash with midostaurin versus placebo therapy (13% vs 8%; P = .02); incidence of grade 5 AEs were similar (5% vs 5.3%). Based on the results of the RATIFY trial, the authors concluded that including midostaurin as a component of standard therapy significantly improved survival outcomes in younger adults with mutant FLT3, and represents a new standard of care in this setting.

  1. Fischer T, et al. J Clin Oncol. 2010;28(28):4339-4345.
  2. Stone RM, et al. ASH 2015. Abstract 6.