Selinexor in combination with azacitidine or ruxolitinib in myelodysplastic/myeloproliferative neoplasm overlap syndromes: A multicenter prospective study.

Abstract

Therapeutic strategies for myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) remain suboptimal. Selinexor, an oral selective inhibitor of exportin 1, represents a mechanism-based therapeutic approach. Preclinical and clinical evidence indicated synergistic antileukemic effects when selinexor was combined with hypomethylating agents or janus kinase inhibitors. A prospective, single-arm trial was conducted to evaluate selinexor plus either azacitidine (for MDS-dominant features) or ruxolitinib (for MPN-dominant features) in patients with MDS/MPN. The primary end point was the overall response rate at 6 months, which was assessed according to 2015 International Working Group criteria. Secondary end points included safety, progression, and survival. Twenty patients were enrolled (four with MDS-dominant features, 16 with MPN-dominant features). The median age was 66 years in the MDS group and 62.5 years in the MPN group. The overall response rate was 60% (12 of 20 patients; 95% confidence interval [CI], 36.1%-80.5%) overall, 75% (three of four patients; 95% CI, 31.1%-95.4%) in the MDS group, and 56.3% (nine of 16 patients; 95% CI, 33.2%-76.9%) in the MPN group. In the MDS group, clinical benefits included improvements in the total symptom score, erythroid response, platelet response, and spleen response (one in each of four patients; 25% for each response). In the MPN group, partial responses occurred in two of 16 patients (12.5%), and partial bone marrow responses occurred in three of 16 (18.8%), with additional benefits including spleen response (five of 16; 31.3%), total symptom score improvement (two of 16; 12.5%), erythroid response (two of 16; 12.5%), and platelet response (one of 16; 6.3%). Adverse events occurred in 14 patients (70%). Three patients experienced grade 3 or greater events, including two disease-related fatalities. After a median follow-up of 6 months (range, 2-15 months), one patient's disease transformed to acute myeloid leukemia. Selinexor combined with azacitidine or ruxolitinib showed encouraging efficacy with a manageable safety profile in patients with MDS/MPN.