Jorge Cortes from MD Anderson Cancer Center, Houston, TX, and colleagues published data from a phase II study (NCT01546038) in the American Journal of Hematology. The main objectives were to evaluate the efficacy and safety of glasdegib, an oral smoothened (SMO) inhibitor, plus cytarabine and danorubicin in patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).
Seventy-one patients with AML (n = 66) and MDS (n = 5) were enrolled in this study. Of these, 69 (median age = 64 years; range, 17–75) patients received glasdegib (100 mg orally, once daily in continuous 28-day cycles from day -3) in combination with intravenous daunorubicin (60 mg/m2 on days 1–3) and continuous intravenous cytarabine (100 mg/m2 (on days 1–7). Patients in remission received consolidation therapy (2–4 cycles of cytarabine 1 g/m2 twice-daily on days 1, 3, 5 of each cycle), followed by maintenance with glasdegib (maximum 6 cycles). The primary endpoint of the study was complete remission rate in patients aged ³ 55 years old. Secondary endpoints include overall survival (OS), safety and mutational status.
- CR rate: 46.4% (80% CI, 38.7–54.1)
- CR rate in patients aged ≥ 55 years (n = 60): 40.0% (80% CI, 31.9–48.1)
- CR rate in patients aged < 55 years (n = 9): 9% (80% CI, 75.5– 100.0)
- Median duration of CR: 94 days (range, 1–480)
- Median duration of CR in patients aged ≥ 55 years: 103 days (1–480)
- Median duration of CR in patients aged < 55 years: 50 days (1–268)
- Median OS: 14.9 months (80% CI, 13.4–19.3)
- Twenty-four patients proceeded to receive allogeneic stem cell transplantation
- Median OS after censoring for transplant: 17.7 months (80% CI, 14.5–not estimable)
- There was no significant association between mutational status and clinical response
- The most common adverse events (AEs) occurring in ³ 50% of patients were diarrhea, febrile neutropenia, nausea, and hypokalemia
- The most common grade > 3 AEs occurring in ³30% of patients were febrile neutropenia, anemia, and thrombocytopenia
- Five (7.2%) treatment-emergent deaths occurred within 28 days of the last dose of treatment as a result of disease progression (n = 2), sepsis, pneumonia, and septic shock (n = 1 each)
Key limitation of this study was the small patient number, hence the researchers noted that the findings of the study would “require validation in a larger prospective trial”.
In conclusion, glasdegib plus cytarabine and daunorubicin was well tolerated and was associated with clinical activity in untreated patients with AML or high-risk MDS. The authors described the results of the study “encouraging”.