*1.1.1.1.1 Midostaurin*

Midostaurin (Rydapt®, Novartis Pharmaceuticals, Inc. (PKC412)) is a multikinase inhibitor, targets wild type FLT3 and mutated FLT3 (ITD and tyrosine kinase domain (TKD)) [10]. Midostaurin also inhibits c-kit, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and protein kinase C [11]. A phase III international prospective, multinational, randomized, placebo-controlled, double-blind RATIFY study confirmed that, addition of midostaurin to standard induction chemotherapy could significantly increase OS vs. placebo among AML adults with FLT3 mutation (median OS of 74.7 m vs. 25.6 m, HR = 0.78, n = 717). RATIFY enrolled adults aged 18–59 years with newly diagnosed FLT3-mutated (ITD or TKD) AML. Patients were stratified according to FLT3 mutation type (TKD, ITD with a high AR [>0.7], and ITD with a low AR [0.05–0.7]) The addition of midostaurin demonstrated a significant survival benefit in patients with FLT3-mutated AML compared with placebo, with a 22% reduction in the rate of death compared with placebo (hazard ratio [HR], 0.78 [95% CI, 0.63–0.96]; P = 0.009). Although not specifically mandated, allogeneic stem cell transplantation (allo-SCT) was performed in 25% of patients in first complete remission (CR) and 57% of patients overall. Furthermore, patients receiving an allo-SCT in first CR had better outcome if they were treated with midostaurin during induction therapy (P = 0.08), suggesting that the optimal treatment strategy in FLT3-mutated AML would be to move on to allo-SCT early in first CR [12]. Adverse events (AEs) occurring during treatment with midostaurin were common in patients receiving intensive chemotherapy for AML. The most common nonhematologic grade ≥ 3 AEs were febrile neutropenia, infection, lymphopenia, diarrhea, and rash/desquamation. The rates of grade ≥ 3 AEs were largely similar between the midostaurin and placebo groups, with the exceptions of rash/desquamation and anemia (higher in the midostaurin group) and nausea (nearly twice as common in the placebo group) [12, 13]. Other, less common AEs reported with midostaurin included pulmonary AEs (i.e., pneumonitis or pulmonary infiltrate), cardiac AEs (e.g., prolonged corrected QT interval) and hepatic or renal dysfunction [12–14].
