Glasdegib, a Hedgehog Inhibitor, Nearly Doubles Survival in Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Web Exclusives - Conference Correspondent, In the News
Wayne Kuznar

Adding the investigational smoothened (SMO) receptor inhibitor glasdegib to low-dose cytarabine (Depo­Cyt) significantly increased overall survival (OS) compared with low-dose cytarabine monotherapy in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) who were ineligible for intensive chemotherapy, according to a phase 2 study presented by Jorge E. Cortes, MD, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at the 2016 American Society of Hematology meeting.

The median OS was nearly 4 months longer in patients who received glas­degib, reported Dr Cortes.

Glasdegib is an orally active inhibitor of the hedgehog-signaling pathway through inhibition of the SMO receptor. SMO of hedgehog signaling affects tumor biology by disrupting the regulation of cancer stem-cell survival.

“The hedgehog pathway is activated in many cancers, including chronic myeloid leukemia, AML, and MDS, and this leads to the maintenance of the leukemic stem cell,” said Dr Cortes.

The study randomized 88 patients with AML or MDS in a 2:1 ratio to receive low-dose cytarabine (20 mg administered subcutaneously twice daily for 10 days every 28 days) plus glasdegib (100 mg daily); or low-dose cytarabine monotherapy for as long as patients received clinical benefit. The patients’ median age was 77 years in the combination treatment arm and 75 years in the low-dose cytarabine monotherapy arm. More than 50% of patients in each treatment arm had secondary AML. Patients were stratified according to cytogenetic classification (ie, good/intermediate or poor risk).

The median treatment duration was 83 days for patients who received low-dose cytarabine plus glasdegib compared with 47 days for patients who received low-dose cytarabine monotherapy. All patients who received low-dose cytarabine monotherapy discontinued treatment, and 11% of patients who received low-dose cytarabine plus glasdegib continued treatment.

Glasdegib plus Low-Dose Cytarabine versus Low-Dose Cytarabine Monotherapy

The primary end point was OS, with a median follow-up of 14.3 months in the combination treatment arm compared with 12.4 months in the low-dose cytarabine monotherapy arm. The median OS was 4.9 months in patients who received low-dose cytarabine monotherapy compared with 8.8 months in patients who received low-dose cytarabine plus glasdegib (hazard ratio, 0.51; P = .0003).

Researchers observed a survival benefit with the addition of glasdegib to low-dose cytarabine in patients with good/intermediate-risk cytogenetics; in these patients, the median OS was 12.2 months compared with 6 months in patients who received low-dose cytarabine monotherapy (P = .0035). In poor-risk patients, the median OS was 4.4 months with the combination therapy versus 2.3 months with low-dose cytarabine monotherapy (P = .0422).

The patients with AML who received low-dose cytarabine plus glas­degib had a median OS of 8.3 months versus 4.3 months in patients who received low-dose cytarabine monotherapy (P = .0004). There was no significant difference in OS between treatments in patients with high-risk MDS.

Patients aged ≥75 years who received the combination therapy had a median OS of 7.7 months compared with 5.1 months in patients who received low-dose cytarabine monotherapy. Patients aged ≤75 years who received the combination therapy had a median OS of 10.1 months versus 4.8 months with low-dose cytarabine monotherapy.

Overall, 23% of patients who received the combination treatment achieved complete response compared with 5% of patients who received low-dose cytarabine monotherapy, which is consistent with previously reported studies, said Dr Cortes.

Cytogenetic analysis revealed that 29% of patients with good/intermediate-risk cytogenetics who received the combination treatment achieved complete response versus 4% of patients who received low-dose cytarabine monotherapy. In addition, 12% of patients with poor-risk cytogenetics who received the combination treatment achieved complete response compared with 6% of patients who received low-dose cytarabine monotherapy.

The median time to complete response with low-dose cytarabine plus glasdegib was 59 days or approximately 2 cycles.

Gastrointestinal toxicities, cytopenias, fatigue, muscle spasms, and dysgeusia were more common with glas­degib than with low-dose cytarabine monotherapy. No significant differences in grade 3 or 4 adverse events were reported between the 2 treatment groups. More patients who received low-dose cytarabine monotherapy discontinued therapy because of adverse events than patients who received the combination therapy (29% vs 20%, respectively). The most common cause of death in both treatment arms was disease progression.

“With these results, we think that the combination represents a novel strategy that may offer potential benefits for patients with these characteristics,” said Dr Cortes.

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Last modified: February 19, 2019