A Phase II Study of Clinical Efficacy of Venetoclax in Combination with Azacitidine in Patients with Therapy Related Myelodysplastic Syndrome (t-MDS)

Background: The occurrence of therapy-related myelodysplastic syndrome (t-MDS) is a well-recognized sequelae of cytotoxic treatments for prior neoplasms, including other hematologic malignancies, sarcomas, and ovarian and testicular cancer. t-MDS accounts for 10% to 20% of newly diagnosed MDS, with a median time to development of 3 to 5 years. The prognosis of t-MDS is often poor, as the genetic abnormalities that characterize multiple subtypes can lead to rapid progression to AML and confer resistance to conventional therapies. In general, treatment with conventional anti-leukemic chemotherapy has uniformly poor outcomes, with median survivals of 8.6 months for t-MDS.In patients with high-risk t-MDS, hypomethylating treatment is associated with objective response rates (ORR) of 38% to 42%, among which only 14%-15% achieve complete remission (CR). Innovative strategies using targeted agents provide a unique opportunity to combat the dismal outcomes experienced by this t-MDS patient population. The combination of azacitidine and venetoclax has been a large area of interest in the clinical research field for the MDS and AML population. Whether the combination of azacitidine and venetoclax can similarly benefit a high-risk t-MDS population has yet to be addressed. We hypothesize that the combination therapy of azacitidine and venetoclax will result in improved outcomes for treatment-naïve t-MDS compared to azacitidine alone.