**6.4 Glasdegib**

Glasdegib is small molecule inhibitor of the hedgehog receptor smoothened. The hedgehog pathway is important during embryogenesis but repressed after birth. However, aberrant hedgehog signalling has been identified in AML, particularly in leukaemic stem cells, and has been associated with chemoresistance [64]. Inhibition of hedgehog signalling with glasdegib has shown promising results. A phase II study evaluating the combination of glasdegib and intensive chemotherapy in patients over 55 years of age with newly diagnosed AML reported a CR rate of 40% and median OS of 14.7 months [65]. Glasdegib was also evaluated in combination with LDAC in older patients unfit for intensive chemotherapy. Patients receiving glasdegib + LDAC had increased CR rates, 17.0% vs. 2.3%, and improved median OS 8.8 vs. 4.9 months, compared to patients receiving LDAC alone [66]. Based on these results, the FDA has approved glasdegib in combination with LDAC for AML patients ≥75 years or patients ineligible for intensive chemotherapy. In addition, glasdegib is being evaluated in combination with hypomethylating agents and a phase III trial of glasdegib in combination with intensive chemotherapy is ongoing (BRIGHT AML1019, NCT03416179).

#### **6.5 CPX-315**

CPX-315 is a liposomal formulation that delivers a 5:1 fixed-molar ratio of cytarabine and daunorubicine. With the liposomal encapsulation both drugs can be delivered in a fixed ratio with the highest proportion of synergy to enhance

treatment efficacy [67]. CPX-351 preferentially targets leukaemic cells to a greater degree than non-leukaemic cells in the bone marrow, leading to decreased cytotoxicity against normal haematopoietic cells [68]. A small study of CPX-351 as firstline therapy in 30 newly-diagnosed AML patients ≥65 years showed a promising remission rate of 53.2% with a median OS 14.5 months [68]. In a randomised phase II trial in older adults with untreated AML comparing CPX-351 and conventional '3 + 7' treatment a trend towards increased response rates was observed in the CPX-351 group, 66.7% vs. 51.2%. Survival was comparable between both treatment groups (14.7 vs. 12.9 for the CPX-351 and '3 + 7' group respectively). However, CPX-351 treatment was superior in the subset of secondary AML patients with a median OS of 12.1 months vs. 6.1 months in the '3 + 7' group [67]. Superiority of CPX-351 to conventional '3 + 7' chemotherapy in secondary AML, also including AML with MDS related changes, was confirmed in a phase III trial including 309 older AML patients. The observed remission rates were 47.7% vs. 33.3% and median OS was 9.6 vs. 6.0 months in favour of CPX-351 [69]. The safety profile of CPX-351 was similar to that of conventional chemotherapy.
