FLT3

Midostaurin in combination with chemotherapy prolongs survival in FLT3 mutated AML patients – RATIFY study

Addition of the multi-targeted kinase inhibitor, midostaurin, to standard chemotherapy can prolong the survival of younger adult patients with Fms Like Tyrosine Kinase 3 (FLT3) mutated Acute Myeloid Leukemia (AML) according to results from the phase III Cancer and Leukemia Group B (CALGB) RATIFY study (NCT00651261), published in the New England Journal of Medicine by Richard M. Stone, M.D. from the Dana-Farber Cancer Institute, Boston, and colleagues.

Mutations in the FLT3 gene represent one of the most commonly encountered, and clinically challenging, classes of AML mutations and it is expressed in approximately 30% of patients. Stone et al., aimed to determine the effect of the addition of midostaurin (FLT3 inhibitor) to standard chemotherapy in newly diagnosed young adult patients with FLT3 mutated AML, hence they conducted a phase III randomized, double-blind, placebo-controlled study.

In this study, 717 newly diagnosed FLT3+ AML patients (median age = 47.9 years, range 18–59 years) 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 primary endpoint of the study was Overall Survival (OS).

The key results of the study were:
  • Median OS in patients assigned to the midostaurin and placebo group; 74.7 vs 25.6 months; Hazard Ratio (HR) for death = 0.78, P = 0.009
  • Median Event Free Survival (EFS) in patients assigned to the midostaurin and placebo group; 8.3 vs 3.0 months, HR for death = 0.78, P = 0.002
  • 4-year OS in patients who underwent transplantation in the midostaurin and placebo group; 63.7% vs 55.7%, P = 0.08
  • Adverse Events (AEs) were similar between the midostaurin and placebo groups, however patients in the midostaurin group experienced more grade 3–5 anemia (92.7% vs 87.8%, P = 0.03) and rash (14.1% vs 7.6%, P = 0.008)

The authors concluded their study by stating that “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,”. Furthermore, they added that questions still remain on whether “more specific FLT3 inhibitors, would also improve outcomes if they were added to usual therapy for younger adults with AML and a FLT3 mutation and whether chemotherapy plus midostaurin might be beneficial” for older AML patients.  

The data from this pivotal phase III RATIFY trial led to the recent approval of midostaurin by the U.S Food and Drug Administration (FDA) for treatment of AML patients with FLT3 mutation in combination with standard cytarabine and daunorubicin and cytarabine consolidation.

Abstract

Background Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. Methods We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. Results A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. Conclusions The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261).

References
  1. Stone R.M. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Jun 23. DOI: 10.1056/NEJMoa1614359. [Epub ahead of print].