The FDA approved oral glasdegib (Daurismo, Pfizer) for use with low-dose cytarabine (LDAC) to treat newly diagnosed acute myeloid leukemia (AML) in older adults who may not be able to receive intensive chemotherapy.

Glasdegib is the first FDA-approved Hedgehog pathway inhibitor for AML. The Hedgehog signaling pathway plays an essential role in embryogenesis. In adults, however, abnormal activation of this pathway is thought to contribute to the development and persistence of cancer stem cells. Preclinical studies have shown that disruption of this pathway can impair the development and survival of these cancer stem cells (Blood 2012;119[10]:2196-2204).

The efficacy of glasdegib was studied in a phase 2, randomized clinical trial, in which 115 adult patients with newly diagnosed AML were treated with either glasdegib in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Of the 77 patients treated with glasdegib plus LDAC, more than half (51%; 39 patients) had secondary AML. Eleven of the 39 patients with secondary AML received prior treatment with a hypomethylating agent; historically, the prognosis is poor for these patients and treatment options have been limited to clinical trials or palliative care.

Median OS was 8.3 months (95% CI, 4.4-12.2 months) for patients treated with glasdegib plus LDAC compared with 4.3 months (95% CI, 1.9- 5.7 months) for patients treated with LDAC alone. This difference represented a 54% reduction in the risk for death among patients treated with glasdegib plus LDAC (hazard ratio, 0.46; 95% CI, 0.30-0.71; P=0.0002).

Glasdegib plus low-dose chemotherapy significantly improved median OS in patients who were not able to receive intensive chemotherapy due to older age or comorbidities—a patient population that is difficult to treat.

“The randomized phase 2 study, which formed the basis for today’s approval, included patients with cardiac disease or mild to moderate kidney disease, who are often excluded from clinical trials,” said Jorge Cortes, MD, the deputy chair and a professor of medicine in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston. “In the trial, [glasdegib] plus low-dose chemotherapy reduced the risk of death during the study period by 54% compared to chemotherapy alone. This provides a much-needed treatment for those patients for whom intensive chemotherapy is not an option.”

Common side effects reported by patients receiving glasdegib in clinical trials include anemia, fatigue, hemorrhage, febrile neutropenia, muscle pain, nausea, edema, thrombocytopenia, dyspnea, dysgeusia, mucositis, constipation and rash.

Health care providers also should monitor patients for QT interval prolongation. In addition, because of the Hedgehog signaling pathway’s role in embryogenesis, the prescribing information for glasdegib includes a boxed warning about the risk for embryofetal death or severe birth defects. Glasdegib should not be used in women who are pregnant or breastfeeding. Females of reproductive age should have a pregnancy test before initiation of glasdegib treatment and should use effective contraception during treatment and for at least 30 days after the last dose. The boxed warning also advises male patients of the potential risk for drug exposure through semen and to use condoms during treatment and for at least 30 days after the last dose if their partner is pregnant or could become pregnant.

Patients also should be advised not to donate blood or blood products during treatment.

Click here for full prescribing information.

U.S. patients have access to Pfizer Oncology Together, which offers personalized support and financial assistance resources to help them access prescribed Pfizer Oncology medications.

—Clinical Oncology News Staff

—Based on FDA and Pfizer statements