First Hedgehog Pathway Inhibitor Approved in AML Patients

Clinicians now have a new treatment to offer elderly patients (75 years or older) with newly diagnosed acute myeloid leukemia (AML) who have comorbidities that preclude the use of intensive induction chemotherapy. The US Food and Drug Administration (FDA) approved the use of glasdegib, a once-daily oral medicine to be used in combination with low-dose cytarabine (LDAC). This agent was one of three new treatments approved for AML in November.

Glasdegib is the first and only FDA-approved Hedgehog pathway inhibitor for AML. The Hedgehog signaling pathway plays an essential role in embryogenesis. In adults, abnormal activation of this pathway is thought to contribute to the development and persistence of cancer stem cells.

The approval is based on results from a randomized clinical trial in which 111 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. The study showed that the median OS was 8.3 months for patients treated with glasdegib plus LDAC compared with 4.3 months for patients treated with LDAC only.

Jorge Cortes, MD, deputy chair and professor of medicine in the department of leukemia at the University of Texas MD Anderson Cancer Center in Houston, noted that glasdegib plus low-dose chemotherapy reduced the risk of death during the study period by 54% compared with chemotherapy alone, in a press release. He said that this provides a much-needed treatment option for patients who are not candidates for intensive chemotherapy.

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

Alexander Perl, MD, an associate professor of hematology-oncology at Penn’s Abramson Cancer Center in Philadelphia, noted that three new oral drugs were approved by the FDA in the span of just 1week for AML (gilteritinib, venetoclax, and glasdegib). Venetoclax and glasdegib were approved in essentially the same population-newly diagnosed and older patients who, due to age or comorbidities, have not benefited from more intensive approaches. “Each drug was approved to be used in combination with standard low-intensity injectable chemotherapy designed for outpatient administration. I think the toxicity profile of glasdegib coupled with the rapid and notably high response rates of venetoclax will make it hard for glasdegib to stand out as the preferred frontline agent in the near future as initial therapy,” Perl told Cancer Network.

In Pfizer’s press release, Mace Rothenberg, MD, chief development officer, oncology, at Pfizer Global Product Development, said the ongoing phase III BRIGHT trials are evaluating glasdegib in combination with other agents commonly used to treat patients with AML to try to more fully understand the potential of this agent.