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Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy.

Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC.

The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004).

Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission ( P. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are clinically and genetically heterogeneous myeloid stem cell disorders with a median age at onset of about 67 years []. Older patients with AML or high-risk MDS have few treatment options and are often not eligible for intensive chemotherapy due to comorbidities and a higher incidence of high-risk biological features, which often lead to chemotherapy resistance. This population is thus treated with less-aggressive therapies, including low-dose cytarabine (LDAC) and hypomethylating agents.

However, studies with LDAC have demonstrated low response rates (7–18%), with median overall survival (OS) of 5 months in older patients [,,,,,]. With the hypomethylating agent decitabine, the response rate (18%) and median OS (7.7 months) were only slightly improved [].

Martina cole the take. Therefore, novel therapeutic strategies are needed to achieve higher response rates, more durable responses, and improved survival in this hard-to-treat population. The Hedgehog signaling pathway plays a key role in embryonic development and is typically silenced in adults []. Aberrant Hedgehog signaling has been implicated in hematologic malignancies and is critical for leukemia stem-cell survival and expansion [,,]. Overexpression of Hedgehog pathway components was observed in chemotherapy-resistant myeloid leukemia cells, and pharmacologic inhibition of the Hedgehog pathway substantially enhanced the sensitivity to chemotherapy []. These findings provide the rationale for combining an inhibitor of Hedgehog pathway with chemotherapy. Glasdegib is a potent and selective oral inhibitor of Hedgehog signaling through binding to Smoothened.