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


Authors: Raza, A.; Galili, N.; Smith, S. E.; Godwin, J.; Boccia, R. V.; Myint, H.; Mahadevan, D.; Mulford, D.; Rarick, M.; Brown, G. L.; Schaar, D.; Faderl, S.; Komrokji, R. S.; List, A. F.; Sekeres, M.
Article Title: A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome
Abstract: 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.
Journal Title: Cancer
Volume: 118
Issue: 8
ISSN: 1097-0142; 0008-543X
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 2138
End Page: 2147
Language: eng
DOI/URL:
Notes: LR: 20131121; CI: Copyright (c) 2011; JID: 0374236; 0 (Antineoplastic Agents); 0 (gamma-Glu-S-BzCys-PhGly diethyl ester); GAN16C9B8O (Glutathione); 2011/04/19 [received]; 2011/06/09 [revised]; 2011/07/05 [accepted]; 2011/09/01 [aheadofprint]; ppublish