Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome

Jorge E. Cortes, Florian H. Heidel, Andrzej Hellmann, Walter Fiedler, B. Douglas Smith, Tadeusz Robak, Pau Montesinos, Daniel A. Pollyea, Pierre DesJardins, Oliver Ottmann, Weidong Wendy Ma, M. Naveed Shaik, A. Douglas Laird, Mirjana Zeremski, Ashleigh O’Connell, Geoffrey Chan, Michael Heuser

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97 Scopus citations

Abstract

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 < 0.05). Nonhematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%) with glasdegib/LDAC and pneumonia (14.6%) with LDAC. Clinical efficacy was evident across patients with diverse mutational profiles. Glasdegib plus LDAC has a favorable benefit–risk profile and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Original languageEnglish (US)
Pages (from-to)379-389
Number of pages11
JournalLeukemia
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Cortes, J. E., Heidel, F. H., Hellmann, A., Fiedler, W., Smith, B. D., Robak, T., Montesinos, P., Pollyea, D. A., DesJardins, P., Ottmann, O., Ma, W. W., Shaik, M. N., Laird, A. D., Zeremski, M., O’Connell, A., Chan, G., & Heuser, M. (2019). Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia, 33(2), 379-389. https://doi.org/10.1038/s41375-018-0312-9