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Am J Hematol. 2018 Nov;93(11):1301-1310. doi: 10.1002/ajh.25238. Epub 2018 Sep 9.

Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results.

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Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, Texas.
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
Leukemia Service, Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Fred Hutchinson Cancer Research Center, Seattle, Washington.
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Division of Hematology, University of Colorado School of Medicine, Aurora, Colorado.
Leukemia Program, Cleveland Clinic, Cleveland, Ohio.
Department of Hematology, Medical University of Lodz, Lodz, Poland.
Pfizer Oncology, New York, New York.
Division of Oncology, Washington University School of Medicine, St Louis, Missouri.


Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) 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% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.

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