*1.1.1.1.2 Sorafenib*

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

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*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

skin reaction and rash [21].

*1.1.1.1.3 Sunitinib*

respectively [28].

*1.1.1.1.4 Lestaurtinib*

(56 vs. 38%, P = 0.017) without improvement in OS and CR [21]. Another randomized placebo-controlled trial in 201 older patients aged 61–80 years did not demonstrated improvement in EFS, CR, and OS. The results showed higher early mortality (17 versus 7%, P = 0.052) compared with placebo [22]. In multivariate analysis of retrospective study analysing the effect of sorafenib as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML) in 26 sorafenib patients and 55 controls, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). Also there was no difference in 2-year non-relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1-year chronic graft-versus-host disease (55·5% vs. 37·2%, P = 0·28) [23]. The most common adverse events occurring during treatment with sorafenib in SORAML study were fever, infections, pneumonia and pain. Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever, diarrhea, bleeding, cardiac events, hand-foot-

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,

Lestaurtinib (CEP-701) is an orally bioavailable first generation FLT3 inhibitor. It is derived from the bacterial fermentation product K-252a as indolocarbazole alkaloid compound. Except inhibition of FLT3 Lestaurtinib also inhibits JAK2, tropomyosin receptor kinases and neurotrophin receptors [29–33]. In a phase 2 trial lestaurtinib was administered as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy, irrespective of FLT3 mutation status. This study involved 29 patients with median age of 73 years. Lestaurtinib was administered orally at doses of 60 mg and 80 mg twice daily for 8 weeks. Clinical activity was evident in 8 (30%) patients, including 3 (60%) of 5 FLT3 mutant patients and 5 (23%) of 22 evaluable FLT3 WT patients, the difference in response rates between mutation groups not reaching statistical significance. Lestaurtinib was generally well tolerated. Commonly observed toxicities included mild nausea (8 patients), emesis (5 patients), constipation (5 patients), diarrhea (6 patients), and elevations in alkaline phosphatase concentration (13 patients) [34]. Another phase 1/2 trial in 14 heavily pretreated AML patients treated with CEP-701 at an initial dose of 60 mg orally twice daily, showed clinical evidence of biologic

#### *Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

(56 vs. 38%, P = 0.017) without improvement in OS and CR [21]. Another randomized placebo-controlled trial in 201 older patients aged 61–80 years did not demonstrated improvement in EFS, CR, and OS. The results showed higher early mortality (17 versus 7%, P = 0.052) compared with placebo [22]. In multivariate analysis of retrospective study analysing the effect of sorafenib as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML) in 26 sorafenib patients and 55 controls, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). Also there was no difference in 2-year non-relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1-year chronic graft-versus-host disease (55·5% vs. 37·2%, P = 0·28) [23]. The most common adverse events occurring during treatment with sorafenib in SORAML study were fever, infections, pneumonia and pain. Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever, diarrhea, bleeding, cardiac events, hand-footskin reaction and rash [21].
