The FMS-related tyrosine kinase 3 (FLT3) gene mutation is present in 30% of adults with newly diagnosed acute myeloid leukaemia (AML). Of these patients, approximately 75% have a FLT3 internal tandem duplication mutation (ITD subtype), and approximately 8% have a FLT3 point mutation in the tyrosine kinase domain (TKD subtype).r
Midostaurin is a multitargeted kinase inhibitor that was initially developed as a protein kinase C inhibitor with the intent to treat patients with solid tumours. Preclinical studies which showed synergy between chemotherapy and midostaurin became the basis of a phase 1b study involving patients with newly diagnosed AML.r This study established that oral midostaurin at a dose of 50 mg twice daily for 14 days could be administered safely with an acceptable side-effect profile.r
This regimen was compared in an international phase 3 study to standard intensive chemotherapy (the RATIFY trial). A total of 3,277 patients, 18 to 59 years of age, who had newly diagnosed AML were screened for FLT3 mutations (mutant: wild-type allelic ratio ≥0.05). Patients were randomly assigned to receive induction therapy which consisted of daunorubicin and cytarabine, and consolidation therapy of high-dose cytarabine, in combination with either midostaurin or placebo. Patients in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Allogeneic transplantation was allowed. The primary endpoint was overall survival (OS).r
717 patients were randomised (555 with FLT3-ITD and 162 with FLT3-TKD), with 360 patients assigned to the midostaurin group and 357 to the placebo group. The patients in the midostaurin group had significantly longer OS (hazard ratio (HR) for death, 0.78; one-sided p=0.009), as well as event-free survival (EFS)(HR for event or death, 0.78; one-sided p=0.002) than patients in the placebo group. The benefit of midostaurin showed to be consistent across all FLT3 subtypes in both the primary analysis and an analysis where data for patients who underwent transplantation was censored. The incidence of severe adverse events was similar in the two groups.r
Efficacy
Stone et al.r reported the following:
|
Midostaurin
Group
(N = 360)
|
Placebo
Group
(N = 357)
|
p value
|
Complete remission (CR) within 60 days; no. (%)
|
212 (59)
|
191 (54)
|
0.15
|
Median survival
|
74.7 months
|
25.6 months
|
0.009
|
Overall survival at 4 years
|
51.4%
|
44.3%
|
-
|
Median event-free survival
|
8.2 months
|
3.0 months
|
0.002
|
Median disease-free survival
|
26.7 months
|
15.5 months
|
0.01
|
Toxicity
Stone et al.r reported the following toxicities:
© NEJM 2017