Prospective performance of the International Working Group 2023 and the International Prognostic Scoring System - Molecular in a phase II trial of guadecitabine in higher-risk myelodysplastic syndrome or chronic myelomonocytic leukemia

Guadecitabine (SGI-110) is a dinucleotide form of decitabine that has been studied in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Here we present the results of a single center phase II trial of this agent for patients with higher-risk MDS or CMML. Guadecitabine was administered at a dose of 60 mg/kg subcutaneously for five days. Of 100 enrolled patients, 82% had MDS. Median age was 69 years, International Prognostic Scoring System (IPSS) was intermediate-2 in 78% and high in 14%. Thirty-eight percent had complex cytogenetics and 32% had TP53mut. By IWG-2006 criteria, 25% achieved complete remission (CR), 30% marrow CR, and 33% no response (NR). Common grade 3 events were febrile neutropenia (32%) and infection (25%). Mortality rate at 4 and 8 weeks was 0% and 4%, respectively. Median overall survival (mOS) was 16.8 months. Transplanted patients (21%) had a mOS of 46.6 months. We then reanalyzed this dataset using IPSS-Molecular and International Working Group (IWG) 2023 response criteria. By IPSS-M, 60% of patients were classified as very high risk and 27% as high. By IWG-2023, overall response rate (ORR) was 52%, 30% CR, 14% CR with limited count recovery (CRL), with 42% no response (NR). IPSS-M provided adequate risk stratification at enrollment. Patients classified as mCR had widely different outcomes when reclassified by IWG-2023. In conclusion, SGI-110 was active in high risk MDS but survival is unlikely to be superior to current hypomethylating agents. The study is registered as NCT02131597.