The New England journal of medicine 2017-08-03
Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.
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 .).
Related Questions
Would you give GO and/or a FLT3 inhibitor for patients with AML with t(8;21) and FLT3-ITD low in addition to 7+3?
First, in terms of risk stratification, core binding factor (CBF) AML [whether inv16 or t(8;21)] is considered to be favorable risk by ELN22 even if a FLT3 mutation is present (Döhner et al., PMID 35797463). The incidence of FLT3-ITD in CBF-AML is 5-10% (Faber et al., PMID 27798625). There are some ...
For a patient who has core binding factor AML but also a small FLT3-ITD mutation detected, do you proceed with allo transplant or only HiDAC consolidation after achieving CR from induction chemotherapy?
My CBF patients with FLT3-ITD who have achieved CR1 following induction have done quite well with high dose cytarabine consolidation and I cannot recall any of them who have required transplant. Historically, I have managed my CBF-AML patients with FLT3-ITD the same as those without FLT3-ITD since t...
Would you include midostaurin in induction and consolidation for patients with good-risk AML with NPM1 mutation and FLT3-ITD (<0.5)?
Yes, in my practice I routinely include FLT3 inhibitor (midostaurin) in upfront 7 plus 3 chemotherapy for all younger fit patients with AML regardless of NPM1 status or FLT3 allelic ratio. The RATIFY trial validated the benefit of midostaurin in patients regardless of ITD allelic birder (both high a...
Would you consider adding midostaurin to azacitadine in elderly patients with newly diagnosed AML with FLT3-ITD mutations in the frontline setting?
Yes, would consider adding midostaurin to azacitidine in an elderly patient with newly diagnosed AML with FLT3 as long as if ITD allelic ratio is high where benefit outweighs risks of cytopenias and infections. Dose reductions can be considered based on tolerance. I would use the same regimen as stu...
For a patient with relapsed FLT3 positive AML on HMA and venetoclax, is there ever a role for the addition of midostaurin to the treatment regimen to improve response rate?
Short answer is no. The safety of the combination is unknown and there’s also not an indication for Midostaurin in relapsed AML. The trial that got Midostaurin approved was for combination with 7+3 in newly diagnosed patients. HMA+ venetoclax has better response frontline compared to relapsed/refrac...