A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS)

Leuk Res. 2019 Jun;81:56-61. doi: 10.1016/j.leukres.2019.03.008. Epub 2019 Mar 30.


Hypomethylating agent (HMA) failure myelodysplastic syndrome (MDS) patients have poor outcomes and urgent need for novel therapies. Hedgehog pathway signaling upregulation plays a central role in myeloid neoplasm pathogenesis and leukemia stem cell survival. We evaluated the efficacy and safety of the smoothened inhibitor glasdegib in HMA-failure MDS (n = 35, median age 73 years). According to the International Prognostic Scoring System and the MD Anderson Global Risk Model, 54% and 77% had higher risk disease, respectively. Overall response was 6% (n = 2), and best response was marrow complete remission with hematologic improvement in both patients. Median OS and median follow-up were 10.4 and 42.8 months, respectively. Drug response/stable disease (SD) resulted in better OS than treatment failure (20.6 [95% CI, 10.4-] vs 3.9 months [95% CI, 0.7-9.1]; P< .0001). Response/SD was confirmed to be an independent covariate for improved OS (P < .0001). Grade 3 or higher infections occurred in 11% of patients (n = 4); non-hematologic toxicities were rare. Early mortality (< 30 days) occurred in 11% of patients (n = 4). Glasdegib was well tolerated among HMA-failure MDS patients, although single-agent activity was limited. SD or better resulted in notably superior OS. These results support further investigation of glasdegib, potentially in novel drug combinations, in MDS patients.

Keywords: Glasdegib; Hedgehog; Hypomethylating agent failure; MDS; PF-04449913.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Benzimidazoles / administration & dosage*
  • Biomarkers, Tumor / analysis
  • Cohort Studies
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Follow-Up Studies
  • Humans
  • Leukemia, Myelomonocytic, Chronic / drug therapy*
  • Leukemia, Myelomonocytic, Chronic / pathology
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / pathology
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Phenylurea Compounds / administration & dosage*
  • Prognosis
  • Salvage Therapy*
  • Survival Rate


  • Benzimidazoles
  • Biomarkers, Tumor
  • Phenylurea Compounds
  • glasdegib