Dr Bose on the Use of Zilurgisertib With/Without Ruxolitinib to Reduce Anemia in Myelofibrosis

Prithviraj Bose, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses key data on the use of zilurgisertib alone or in combination with ruxolitinib (Jakafi) to reduce disease-related anemia in patients with primary or secondary myelofibrosis.

Patients with myelofibrosis will often experience anemia due to dysregulation of the iron regulator hepcidin. This has been associated with poorer prognosis. Inhibition of ALK-2may combat hepcidin overexpression, making it a potential target for anemia management.

The open-label, phase 1/2 INCB 00928-104 study (NCT04455841) evaluated the selective ALK-2 inhibitor zilurgisertib in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. A total of 36 patients were enrolled on the study, including 20 who received zilurgisertib monotherapy (group A) and 16 who received zilurgisertib plus a stable dose of ruxolitinib (group B), Bose explains. All patients had symptomatic anemia or were transfusion-dependent, he notes.

Both the single-agent and combination regimen showed preliminary efficacy signals in patients with symptomatic anemia who were non–transfusion dependent, Bose reports. However, anemia response was not seen in patients with transfusion dependence at baseline, he states.

Moreover, a decrease in hepcidin levels was observed in both treatment groups, Bose continues. Although this was observed across all dose levels administered, greater hepcidin control was seen with 400 mg of zilurgisertib alone and 200 mg of the combination, Bose expands. Pharmacokinetic analysis revealed that the agent's exposure at trough surpassed target thresholds for inhibition of hepcidin and pSMAD1 when administered at the highest dose level, Bose adds.

No dose-limiting toxicities (DLTs) were reported in those who received either regimen, and the maximum-tolerated dose (MTD) had not been reached at the time of analysis. Ultimately the regimen was deemed safe, tolerable, and clinically active in this population.

Disclosures: Dr Bose reported serving as a consultant or in an advisory role for AbbVie, Bristol-Myers Squibb/Celgene, GlaxoSmithKline/Sierra Oncology, Karyopharm Therapeutics; he received honoraria from AbbVie, Blueprint Medicines, Bristol-Myers Squibb/Celgene, Cogent Biosciences, CTI BioPharma Corp, GlaxoSmithKline/Sierra Oncology, Incyte; Karyopharm Therapeutics, Novartis, PharmaEssentia; he received institutional research funding from Astellas Pharma, Blueprint Medicines, Bristol-Myers Squibb/Celgene, Cogent Biosciences, Constellation Pharmaceuticals, CTI BioPharma Corp, Disc Medicine, Incyte, Ionis Pharmaceuticals, Kartos Therapeutics, NS Pharma, Pfizer, Promedior, and Telios.