*1.5.1 Volasertib*

*Acute Leukemias*

chemotherapy [84, 85].

(≥50% patients) were diarrhea and nausea [90].

terminated by the sponsor because of lack of efficacy [93].

*1.4.1.1 Glasdegib*

*1.4.1.2 Sonidegib*

leukopenia [92].

*1.4.1.3 Vismodegib*

cancer [81–83]. Aberrant activation of the HhP has been implicated in the maintenance of leukaemia stem cells in several model systems. Overexpression of various HH/GLI components have been found in chemotherapy resistant myeloid blasts and subsequent inhibition of the HH/GLI pathway revised the sensitivity to

Glasdegib (PF-913) is an oral, potent, selective, small molecule inhibitor of HH/GLI signalling, which binds to the smoothened (SMO) receptor [86]. In vitro treatment with Glasdegib induced a decrease in the quiescent cell population and in vivo treatment attenuated the leukemia-initiation potential of AML cells in a serial transplantation mouse model [87]. An open-label, dose-finding, phase 1 study of glasdegib in 47 adult patients with myeloid malignancies (AML, n = 28) found 400 mg once daily as the MTD and a minor response was achieved (over 25% decrease from baseline in BM blasts) or better in more than 30% of AML patients. The most common treatment-related adverse events included dysgeusia, decreased appetite, and alopecia [88]. Based on this study a phase II, randomized, open-label, multicenter study evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with AML or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg was administered orally in 28-day cycles. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC. Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05) [89]. Based on this study the FDA approved glasdegib in combination with low dose cytarabine for AML patients unfit for IC. Another phase-II study to evaluate glasdegib from day 3 plus standard-induction chemotherapy for untreated and fit AML or high-risk MDS patients revealed that 46.4% of patients achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4–19.3) months, with 12-month survival probability 66.6%. The most common treatment-related adverse events

Sonidegib (LDE225) is a specific SMO inhibitor and in refractory AML cells increased cell apoptosis and the efficacy of Adriamycin against tumor cells and lowered the expression of the targeted protein [91]. In a phase I/Ib study of azacitidine and sonidegib in myeloid malignancies the best response outcome for untreated AML/MDS patients was 23.1% and for rel/ref 7.1%. However, the rate of SD was remarkably high particularly in the rel/ref AML population at 76%. The most common Gr 3/4 AEs were: thrombocytopenia, neutropenia, anemia and

Vismodegib (GDC-0449) safety and efficacy were evaluated in a phase Ib trial in patients with relapsed/refractory acute myeloid leukaemia. All enrolled patients had received prior cancer therapy; most had received more than one therapy, including hypomethylating agents, immunomodulators and targeted signalling pathway inhibitors. 38 received at least one dose of vismodegib but the study was

**250**

Volasertib (BI 6727) is a low-molecular-weight, adenosine triphosphate–competitive kinase inhibitor that potently inhibits Plk1 [97]. In a randomized, phase 1/2, open-label, multicenter trial of low-dose cytarabine with or without volasertib in patients with AML ineligible for intensive induction therapy eighty-seven patients (median age 75 years) received LDAC or LDAC + volasertib. The result confirmed greater clinical efficacy in the combination arm, statistically significant in CR (30 vs. 13.3%, P = 0.052). Median overall survival was 8.0 vs. 5.2 months, respectively. LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events [98].
