Inhibition of ATR with AZD6738 (Ceralasertib) for the Treatment of Progressive or Relapsed Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: Safety and Preliminary Activity from a Phase Ib/II Study

Introduction: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are advanced myeloid neoplasms with poor survival and no curative therapy except allogeneic transplant; they are enriched for mutations in the spliceosome complex, including the genes SF3B1, SRSF2, ZRSR2, and U2AF1. Ceralasertib (AZD6738) is a selective and potent orally bioavailable inhibitor of Ataxia Telangiectasis and Rad3 Related (ATR) kinase. Expression of mutant spliceosome genes induces alternative splicing and R loops (DNA:RNA hybrids) in human hematopoietic cells. ATR is a critical mediator for R loop resolution; if ATR is inhibited, cells that have excess R loops undergo apoptosis, whereas normal cells are spared. We hypothesized that inhibition of ATR may be useful in patients with MDS or CMML, particularly those who harbor splicing factor gene mutations.