A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate‐1 risk myelodysplastic syndrome

BACKGROUND: Ezatiostat is a glutathione analog prodrug glutathione S‐transferase P1‐1 (GSTP1‐1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate‐1 risk myelodysplastic syndrome (MDS). METHODS: Patients were randomized by 1 stratification factor—baseline cytopenia (anemia only vs anemia with additional cytopenias)—to 1 of 2 extended dosing schedules. Multilineage hematologic improvement (HI) responses were assessed by International Working Group 2006 criteria. RESULTS: Overall, 11 of 38 (29%) red blood cell (RBC) transfusion‐dependent patients had HI‐Erythroid (HI‐E) response. The median duration of HI‐E response was 34 weeks. Multilineage responses were observed. There was 1 cytogenetic complete response in a del (5q) MDS patient. An important trend was the effect of prior therapy on response. A 40% HI‐E rate (6 of 15 patients) was observed in patients who had prior lenalidomide and no prior hypomethylating agents (HMAs), with 5 of 11 (45%) patients achieving significant RBC transfusion reduction and 3 of 11 (27%) achieving transfusion independence. A 28% HI‐E rate (5 of 18 patients) was observed in patients who were both lenalidomide and HMA naive, with 4 of 8 (50%) patients achieving clinically significant RBC transfusion reductions. Most common ezatiostat‐related adverse events were grade 1 and 2 gastrointestinal including: nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%). CONCLUSIONS: Ezatiostat is the first GSTP1‐1 inhibitor shown to cause clinically significant and sustained reduction in RBC transfusions, transfusion independence, and multilineage responses in MDS patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS. Cancer 2012. © 2011 American Cancer Society. Ezatiostat is the first glutathione analog prodrug glutathione S‐transferase P1‐1(GSTP1‐1) inhibitor shown to cause clinically significant and sustained reduction in red blood cell (RBC) transfusions, transfusion independence, and multilineage responses in myelodysplastic syndrome (MDS) patients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS.