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Drugs Today (Barc). 2019 Sep;55(9):545-562. doi: 10.1358/dot.2019.55.9.3020160.

Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy.

Author information

1
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Pharmacy, Barnes-Jewish Hospital, St. Louis, Missouri, USA.
3
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA. markschroeder@wustl.edu.

Abstract

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.

KEYWORDS:

Acute myeloid leukemia; Glasdegib; Hedgehog signaling inhibitors; Hematologic malignancies; Myelodysplastic syndrome; PF-04449913

PMID:
31584572
DOI:
10.1358/dot.2019.55.9.3020160
[Indexed for MEDLINE]

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