Study Evaluates Addition of Glasdegib in AML and High-Risk MDS Patients

Adding the Hedgehog pathway inhibitor glasdegib to low-dose cytarabine (LDAC) may benefit patients with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Researchers reported in the journal Leukemia that this combination therapy has a favorable benefit-risk ratio and may be a promising option for AML patients unsuitable for intensive chemotherapy.

Led by Jorge E. Cortes, investigators at the University of Texas MD Anderson Cancer Center in Houston conducted a phase II, randomized, open-label, multicenter study (ClinicalTrials.gov identifier: NCT01546038). A total of 132 patients were evaluated, 88 of whom received glasdegib/LDAC and 44 of whom received LDAC.

In this ongoing study, the first patient randomization began in January 2014, and the primary analysis included individuals treated until January 2017. The patients received glasdegib 100 mg administered orally in continuous 28-day cycles, and LDAC was administered 20 mg subcutaneously for 10 per 28 days.

The median follow-up for overall survival was 21.7 months with glasdegib/LDAC and 20.1 months for LDAC. Significantly fewer deaths occurred in the glasdegib/LDAC arm than in the LDAC alone (77.3% vs 93.2%). In both arms, the main cause of death was disease progression. The median OS rate was 8.8 months with glasdegib/LDAC compared to 4.9 months with LDAC. A total of 15 complete remissions (17%) occurred in the glasdegib/LDAC arm compared to 1 complete remission (2.3%) in the LDAC arm. 

In the glasdegib/LDAC arm, the non-hematologic grade 3/4 all-causality adverse events included pneumonia (16.7%) and fatigue (14.3%). In the LDAC arm, pneumonia (14.6%) was the most common non-hematologic grade 3/4 all-causality adverse event. The researchers concluded that the patients treated with glasdegib/LDAC achieved a 49% reduction in the risk of death relative to LDAC. In addition, clinical efficacy was demonstrated across patients with diverse mutational profiles, suggesting the potential for broad efficacy.

Currently, a variety of agents that target distinct pathways are in development. In addition, agents such as azacitidine and venetoclax are offering new hope. “We are in a new era,” said Mark James Levis, MD, PhD, who is the program leader, Hematologic Malignancies and Bone Marrow Transplant Program and Sidney Kimmel Comprehensive Cancer Center Professor of Oncology at Johns Hopkins in Baltimore. “The drug approvals are coming so fast now we have to figure out how to combine these agents and figure out how to use less chemotherapy in both young[er] and older patients.”

Nikolaos Papadantonakis, MD, an assistant professor in UAB’s Division of Hematology & Oncology, Birmingham, Alabama, said that, until recently, this patient population has had limited treatment options outside [of] clinical trials.

“The median OS [overall survival], including MDS patients, for good/intermediate cytogenetics was 12.2 months for the combination arm but 4.8 months for LDAC. The median OS was less than five months in both arms of the study for poor cytogenetic risk. A clear association of response with mutational status did not emerge, but it is difficult to draw [a] conclusion given the number of patients,” Papadantonakis told Cancer Network.