Background: The prognosis for patients (pts) with AML is variable and dependent on the presence of mutations in the FLT3 tyrosine kinase. Internal tandem duplications (ITD) in the juxtamembrane region and mutations in the tyrosine kinase domain (TKD) cause constitutive activation of FLT3 and lead to blast proliferation. Preclinical data suggested that chemotherapy combined with FLT3 inhibitors, including midostaurin, could synergistically kill leukemic cells. In a phase Ib study of midostaurin 50 mg BID with chemotherapy, 92% of FLT3mut pts and 74% of FLT3WT pts achieved a CR. OS of FLT3mut pts was similar to FLT3WT pts (Stone, ASH 2009), supporting the rationale for the ongoing study (NCT00651261). Methods: This is a CALGB-led intergroup, international, randomized, double-blind, PBO controlled trial of adult (age 18-59), untreated FLT3mut AML pts treated with induction chemotherapy and 4 post-remission cycles of high dose ara-C with PBO or midostaurin 50 mg BID on d8-21 of each cycle, followed by 1 yr of midostaurin or PBO. This is the first large study to use molecular screening of FLT3 mutation and ITD allelic ratio at baseline to stratify pts. The primary endpoint is OS (not censored for stem cell transplantation [SCT]). Secondary objectives include EFS and CR. Prognostic impact of FLT3 autophosphorylation and comparison of mutation status at baseline and at relapse are being investigated. A review of blinded rates of SCT and FLT3 TKD mutations demonstrated that both are higher than assumptions used in initial trial design. Since SCT and FLT3 TKD both lead to better prognosis, OS estimates are impacted. Thus, sample size was increased by 200 pts (N=714) to maintain 90% power for the original treatment effect. An OS analysis with censoring at the time of SCT has been added as a secondary endpoint. Over 2470 pts have been preregistered. Reporting of FLT3 mutation status has been rapid at all global diagnostic laboratories (approximately 26 hrs in the North American reference lab at OSU). 564 pts have been enrolled to date; expected accrual completion is 2011.