Glasdegib in newly diagnosed acute myeloid leukemia

ABSTRACT

Introduction

Acute myeloid leukemia (AML) is an aggressive blood cancer that proves fatal for the majority of affected individuals. Older patients are particularly vulnerable due to more unfavorable disease biology and diminished ability to tolerate intensive induction chemotherapy (ICT). Safer, more efficacious therapies are desperately needed.

Areas covered

We briefly summarize the challenges facing AML treatment and introduce the rapidly expanding therapeutic landscape. Our focus is on the Hedgehog (Hh) pathway and how preclinical evidence has spurred the clinical development of selective inhibitors for oncology indications. Glasdegib is the first Hh pathway inhibitor approved for the treatment of a hematologic malignancy, and we review its pharmacology, safety, efficacy, and potential clinical impact in AML patients.

Expert opinion

Advances in the mechanistic understanding of AML have started to translate into improved therapeutic options for patients with contraindications to ICT. Glasdegib improved overall survival in this population when combined with low-dose cytarabine. While an encouraging development for these difficult to treat patients, alternative combination therapy approaches such as venetoclax plus azacitidine have gained greater clinical traction. Further investigation of glasdegib combination strategies and predictive biomarkers, particularly in regard to overcoming chemoresistance and preventing relapse, is needed to better define its clinical utility.

KEYWORDS:

• AML
• myelogenous leukemia
• hedgehog proteins
• molecular targeted therapy
• combination drug therapy

Article highlights

• Hedgehog signaling is an important molecular target that has been implicated in leukemia stem cell maintenance and may be especially relevant in preventing AML relapse and/or overcoming resistance to standard AML treatments

• Glasdegib is the first Hedgehog pathway inhibitor to receive regulatory approval for the treatment of newly diagnosed AML in combination with low-dose cytarabine

• Glasdegib represents a safe and tolerable adjunct therapy to low-dose cytarabine for the treatment of older AML patients who are not good candidates for intensive induction chemotherapy

• Frontline use of glasdegib plus low-dose cytarabine in AML patients ineligible for induction chemotherapy is uncommon in the era venetoclax plus azacitidine and further investigation is required to define the optimal clinical use of glasdegib

Declaration of interest

ML Heaney has served as a consultant for; Novartis, PharmEssentia, CTI Biopharma and Abbvie, and has received trial sponsorship from; Blueprint, Deciphera, Incyte, Constellation, CTI Biopharma, Sierra Oncology and BMS/Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A peer reviewer on this paper has served on an independent review committee for AbbVie and has received honoraria from Agios, BMS/Celgene, Daiichi-Sankyo, Genentech, Pfizer, and Takeda. They also received research funding from AROG, Forty Seven, Merck, Sumitomo Dainippon Pharma, and Takeda. Other reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper received funding from the American Society of Hematology (Research Training Award for Fellows).