Midostaurin Prolongs Survival in Newly Diagnosed Acute Myeloid Leukaemia Patients With FLT3 Mutations

The results of RATIFY, an international prospective randomised placebo-controlled double-blind study presented at ASH 2015

The CALGB 10603/RATIFY (Alliance) trial demonstrated that a prospective trial in a pre-therapy genetically defined subgroup of patients with acute myeloid leukaemia (AML) was feasible and that the addition of the multi-kinase inhibitor midostaurin to standard chemotherapy and for one year of maintenance therapy significantly improved event-free survival (EFS) and overall survival (OS) in patients whose blasts had a tyrosine kinase domain (TKD) or internal tandem duplication (ITD) low or high FLT3 mutation burden. The results were presented at the Plenary session of the 57th ASH Annual Meeting (5-8 December 2015, Orlando, USA).

Midostaurin is a multi-targeted small molecule FLT3 inhibitor which has single agent activity in both ITD and TKD mutant FLT3 AML.

The objective of this global randomised phase III trial was to determine if the addition of midostaurin to induction and consolidation therapy followed by one year of maintenance would improve OS compared to standard chemotherapy in younger adults with activating FLT3 mutations.

Between May 2008 and October 2011, 3279 previously untreated AML patients age 18-60 (exclusive of acute promyelocytic leukaemia) in 225 sites across 17 countries were screened for FLT3 mutations at one of 7 academic laboratories.

Hydroxyurea was allowed for up to 5 days prior to beginning of induction therapy while awaiting results of mutation testing.

Patients were randomised for the duration of therapy to midostaurin or placebo stratified by FLT3 mutation subtype.

Induction therapy consisted of daunorubicin and cytarabine plus midostaurin or placebo. Re-treatment with a second blinded course was allowed if residual AML was noted on a day 21 marrow exam. Patients achieving complete remission (CR) received 4 cycles of high-dose cytarabine consolidation plus midostaurin or placebo followed by a year of maintenance therapy with misostaurin or placebo. Stem cell transplantation was allowed.

With a sample size of 717 patients, the trial was powered to detect an improvement from 16.3 to 20.9 months in median OS (HR = 0.78). The final analysis was to occur after 509 deaths, but given the slow rate of events (359 deaths by April 2015), the trial was amended to change the timing of the OS analysis, and promote EFS, defined as the earliest of death, relapse, or no CR within 61 days of the start of induction as a key secondary endpoint.

In this study 341 FLT3 ITD-low, 214 FLT3 ITD-high, and 162 FLT3 TKD patients were randomised to either midostaurin (360 patients) or placebo (357 patients). There were no significant differences between the arms in age (median 48 years), race, FLT3 subtype, or baseline CBC except for gender (midostaurin, 48.2% male; placebo, 40.6% male; p=0.04). All patients are off active treatment, with a median follow-up of 57 months for surviving patients.

The HRs comparing midostaurin to placebo for OS is 0.77 (one-sided p = 0.007), and for EFS is 0.80 (one-sided p = 0.004). The CR rate is 59% (midostaurin) and 54% (placebo) (p=0.18).

In total 57% patients received an allogeneic stem cell transplantation (midostaurin 58%; placebo, 54%) at any time; 25% in CR1 (midostaurin, 27%; placebo, 22%). Median time to allogeneic stem cell transplantation was similar in each arm (midostaurin, 5.0 months; placebo, 4.6).

Secondary analyses for OS and EFS censoring at the time of stem cell transplantation provided similar results.

The benefit of midostaurin was consistent across all FLT3 subgroups for both EFS and OS.

No statistically significant differences were observed in the overall rate of grade 3 or higher haematologic or non-haematologic adverse events between midostaurin and placebo. A total of 37 grade 5 adverse events were reported (midostaurin, 5.3%; placebo, 5.0%). No differences in treatment-related grade 5 adverse events were observed (midostaurin, 3.1%; placebo, 2.5%).

The authors concluded that their findings may lead to improved outcomes through the use of midostaurin for therapy in younger adults with mutant FLT3 AML.

The study was supported by U10CA180821, U10CA180882, CA31946 grants and Novartis.