The combination of the hedgehog pathway inhibitor (HHI) sonidegib and the hypomethylating agent azacitidine for the treatment of myeloid neoplasms such as myelofibrosis (MF) and myelodysplastic syndrome (MDS) appears to be safe and well tolerated, according to a recently published study in Cancer.

Because of the limited therapeutic options available for patients with refractory/relapsing myeloid neoplasms, the overall survival is currently less than 12 months. Therefore, there is a high need to develop new therapeutic strategies for this subgroup of patients.

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The hedgehog pathway has emerged as a promising therapeutic target in skin and myeloid malignancies. The HHI sonidegib has recently received US Food and Drug Administration (FDA) approval for the treatment of basal cell carcinoma. Azacitidine is considered a therapeutic cornerstone for patients with acute myeloid leukemia (AML) and MDS who are unable to receive aggressive chemotherapy.

The authors aimed to assess the safety and tolerability of a sonidegib/azacitidine combination through a phase 1/1b clinical trial including 62 patients with myeloid neoplasms. The study enrolled 38 patients with AML, 18 patients with MDS, 4 patients with chronic myelomonocytic leukemia, and 2 patients with MF. The study employed a classical 3+3 dose escalation method.

According to the results of the dose-finding component of the trial, which included 10 patients, 200 mg of sonidegib on days 1 to 28 of each cycle was the most appropriate dose. All of the included patients experienced a grade 3 or higher adverse effect, including fatigue, constipation, insomnia, and abdominal pain. Four patients died during the study; in all cases, the cause of death was not treatment related.

Patients were divided into 2 cohorts to assess efficacy: a relapsing/refractory cohort and a newly diagnosed cohort. The response rates were 7.1% and 24%, respectively. One patient from each cohort experienced complete remission.

“In conclusion, addition of the smoothened inhibitor, [sonidegib], to [azacitidine] was well‐tolerated and showed good overall survival in higher risk newly diagnosed MDS patients but did not seem to increase response rate compared to historical data,” the authors concluded


Tibes R, Kosiorek HE, Dueck AC, et al. Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms. Cancer. Published online April 11, 2023. doi:10.1002/cncr.34800