Prospective performance of the IWG-2023 criteria and IPSS-M in a phase 2 trial of guadecitabine for higher-risk MDS or CMML

Guadecitabine (SGI-110) is a dinucleotide form of decitabine that has been studied in myelodysplastic syndrome (MDS) and acute myeloid leukemia. Here, we present the results of a single-center phase 2 trial of this agent for patients with higher-risk MDS or chronic myelomonocytic leukemia (CMML). Guadecitabine was administered at a dose of 60 mg/m2 subcutaneously for 5 days. Of 100 enrolled patients, 82% had MDS. The median age was 69 years, and International Prognostic Scoring System (IPSS) was intermediate-2 in 78% and high in 14%. Thirty-eight percent had complex cytogenetics, and 32% had TP53^mut. By the International Working Group 2006 (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 rates at 4 and 8 weeks were 0% and 4%, respectively. The median overall survival (mOS) was 16.8 months. Patients who underwent transplantation (21%) had an mOS of 46.6 months. We then reanalyzed this data set using IPSS-Molecular (IPSS-M) and IWG-2023 response criteria. By IPSS-M, 60% of patients were classified as very high and 27% as high risk. By IWG-2023, overall response rate was 52%, with 30% CR, 14% CR with limited count recovery, and 42% NR. IPSS-M provided adequate risk stratification at enrollment. Patients classified as marrow CR 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 at www.ClinicalTrials.gov as #NCT02131597.