ASH 2017 | Maintenance therapy with midostaurin in FLT3 mutated AML patients: sub analysis of the phase III RATIFY study 

Maintenance therapy with midostaurin was well tolerated but its value could not be established in patients with Fms Like Tyrosine Kinase 3 (FLT3) mutated Acute Myeloid Leukemia (AML) according to results from a sub-analysis of the phase III randomized RATIFY study which was presented during an oral abstract session at the 59th American Society of Hematology (ASH) Annual Meeting, Atlanta, GA on Saturday 9^th December 2017.

Published results from this phase III Cancer and Leukemia Group B (CALGB) RATIFY study (NCT00651261) have demonstrated that the addition of the multi-targeted kinase inhibitor, midostaurin, to induction and consolidation chemotherapy can prolong the Overall Survival (OS) of younger adult patients with Fms Like Tyrosine Kinase 3 (FLT3) mutated AML compared to standard chemotherapy alone.¹

Richard A. Larson, MD, from the University of Chicago Comprehensive Cancer Center, Chicago, IL. presented results at ASH 2017 from a subset analysis of the phase III RATIFY study, which aimed to evaluate the contribution of maintenance therapy with midostaurin to the overall outcomes of FLT3 mutated AML patients treated in this trial.²

In this study, 717 newly diagnosed FLT3+ AML patients were randomly assigned to receive induction and consolidation chemotherapy with intravenous daunorubicin and cytarabine plus either placebo (n = 357) or midostaurin (n = 360) 50 mg orally twice daily on Days 8–21 of each cycle of induction and consolidation chemotherapy. The median follow-up was 59 months from enrollment for surviving patients. Data was frozen in March 2016.

Four-hundred and three patients achieved Complete Remission (CR) within the protocol specified 60 Days (CR60) wth no signficant difference between the midostaurin and placebo arm. After consolidation, patients remained on their orginally assigned double-blind treatment arm and were not re-randomized. 

Of the 403 patients in CR60, 174 patients in First CR (CR1) received four cycles of high-dose cytarabine plus 12 4-week cycles of maintenance with 50 mg orally twice daily of midostaurin (n = 105, median age = 49 years) or placebo (n = 69, median age = 52 years). The key results of the study were: 

• During the 12 cycles of maintenance
  • Landmark Disease Free Survival (DFS) was not significantly different between the midostaurin and placebo arms; HR = 0.83, P = 0.49
  • Safety
    • Adverse events (AEs) occurred in patients in the midostaurin arm including relapse (n = 30) and death (n = 1)
    • AEs occurred in the placebo arm mostly due relapse (22%)
    • Discontinuation due to adverse events was infrequent in both the midostaurin (8%) and placebo (6%) arm
  • At the end of maintenance
    • Sixty and 44 patients remained on the midostaurin and placebo arm respectively
    • Landmark Disease Free Survival (DFS) was not significantly different between the midostaurin and placebo arms; HR = 1.4, P = 0.38
    • Safety
      • AEs occurred in patients in the midostaurin arm including relapse (n = 16)
      • AEs occurred in the placebo arm including relapse (n = 7) and death (n = 2)

The speaker highlighted some key limitations of their study including the fact that this was an “unplanned post-hoc subset analysis”. Additionally, only newly diagnosed patients were enrolled in this RATIFY study, only the patients who achieved CR60 were analyzed for maintenance outcomes, minimal residual disease assesment were not made prior to starting maintenance and patients were not re-randomized at the start of the maintenance treatment.

Richard A Larson concluded by noting that the clinical benefit of midostaurin for maintenance therapy could not be ascertained from their sub analysis. However, midostaurin was well tolerated. He concluded by suggesting that a prospective randomization study would be required to determine the definite impact of maintenance strategies with midostaurin in AML.