A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes

Mikkael A. Sekeres, Michael Schuster, Magalie Joris, Jürgen Krauter, Johan Maertens, Dimitri Breems, Emmanuel Gyan, Tibor Kovacsovics, Amit Verma, Paresh Vyas, Eunice S. Wang, Keith Ching, Thomas O’Brien, Corrado Gallo Stampino, Weidong Wendy Ma, Arthur Kudla, Geoffrey Chan, Amer M. Zeidan

Research output: Contribution to journalArticlepeer-review

Abstract

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug–drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2–14.0) months and 15.8 (9.3–21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits. Trial registration: ClinicalTrials.gov NCT02367456.

Original languageEnglish (US)
Pages (from-to)1689-1701
Number of pages13
JournalAnnals of Hematology
Volume101
Issue number8
DOIs
StatePublished - Aug 2022
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • Chronic myelomonocytic syndromes
  • Clinical trials
  • Glasdegib
  • Myelodysplastic syndromes

ASJC Scopus subject areas

  • Hematology

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