The Sequenced Combination Of Rigosertib And Azacitidine Has Modulatory Effects On Cxcl8, Rig-I Like Receptor (Rlr) And Wnt/Beta-Catenin Signaling And Downstream Hematopoiesis Pathways In An In Vitro Model Of The Myelodysplastic Syndrome

Background: MDS is characterized by ineffective hematopoiesis and multiple cytopenias. Azacitidine (AZA), a hypomethylating agent (HMA), the standard therapy for higher-risk MDS patients (pts), improves hematopoiesis in 50% of MDS pts, with a median response of 14-24 months. Those pts who initially respond to AZA either relapse or progress with bone marrow failure and have a median survival of 4 to 6 months. Both primary and secondary resistance is a significant challenge and results in poor survival. Rigosertib (RIGO), a small molecule Ras mimetic, as a single agent improved hematopoiesis in 15% of MDS pts who had failed a prior HMA. In vitro data of synergy of RIGO combined with AZA that was sequence dependent (Skiddan et al. AACR 2006), led to a Phase I/II study of the combination of RIGO/AZA and demonstrated an overall response rate of 90% in HMA naïve and 54% in HMA failures pts (Navada et al. ASH 2018). Restoration of functional hematopoiesis in response to treatment with AZA when combined with RIGO in pts, who had failed an HMA, is a unique observation in overcoming the HMA clinical resistance phenotype. Elucidating mechanisms leading to restoration of HMA effects on hematopoiesis could have profound clinical benefit.