*1.1.1.1.3 Sunitinib*

*Acute Leukemias*

with FLT3-ITD-mutated AML.

*1.1.1.1.1 Midostaurin*

*1.1.1.1 First-generation FLT3 inhibitors*

through various signaling pathways, including PI3K, RAS, and STAT5 [5]. It is present in approximately 20–30% of adult AML patients and 5–15% of pediatric AML patients [6, 7]. FLT3-ITD mutations are associated with higher relapse rate and poorer overall survival, particularly with a high ratio of mutant allelic burden [8, 9]. Several first- and next generation FLT3 inhibitors have been investigated in patients

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].

Sorafenib is a potent first-generation multikinase inhibitor with activity against FLT3/ITD receptor but resistance emerges as FLT3-TKD point mutations [15]. It has been evaluated as either single agent or in combination with chemotherapies in numerous phase I and phase II clinical trials [16–20]. In an early phase clinical trial, sorafenib combined with idarubicin and high dose cytarabine in younger de novo AML patients provided a CR rate of 93% and a 1-year survival rate of 74% in FLT3-ITD positive AML patients [18]. In SORAML study, a placebocontrolled randomized study from Germany in 267 newly diagnosed patients aged 18–60 years. Sorafenib was added to daunorubicin and cytarabine (7 + 3) which resulted in a significantly prolonged 3-year EFS (40 vs. 22%, P = 0.013) and RFS

**242**

*1.1.1.1.2 Sorafenib*

Sunitinib is an oral multitargeted kinase inhibitor with selectivity for FLT3, PDGFa/b, VEGF receptor, and Kit receptor tyrosine kinases [24]. Sunitinib induces G1 phase arrest, increases pro-apoptotic molecule expression, and decreases anti-apoptotic molecule expression in AML cells [25]. In a study by O'Farrell and colleagues in 29 AML patients each received a single dose of sunitinib, inhibition of FLT3 phosphorylation was observed in 50% of FLT3 wild-type patients and 100% of FLT3 mutated patients [26]. In another phase I study of sunitinib in 15 patients with refractory AML partial responses were achieved in all 4 patients with FLT3 mutations compared with 2 of 10 in patients with wild-type FLT3. All responses were of short duration and the most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations occurring with a regimen of 50 mg/week [27]. In another phase I/II clinical trial, sunitinib combined with intensive chemotherapy included 22 patients older than 60 years with FLT3/ITD-mutated. Thirteen patients, including 8 patients with FLT3/ITD mutation, achieved CR/CRi. The median overall, relapse-free, and event-free survival of the 17 patients were 1.6, 1.0, and 0.4years, respectively [28].
