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.
authors: Columbia University Medical Center, Milstein Hospital Bldg., 6N-435, 177 Fort Washington Avenue, New York, NY 10032, USA. azra.raza@columbia.edu
authors: Azra
authors: A
authors: Raza
authors: Naomi
authors: N
authors: Galili
authors: Scott E
authors: SE
authors: Smith
authors: John
authors: J
authors: Godwin
authors: Ralph V
authors: RV
authors: Boccia
authors: Han
authors: H
authors: Myint
authors: Daruka
authors: D
authors: Mahadevan
authors: Deborah
authors: D
authors: Mulford
authors: Mark
authors: M
authors: Rarick
authors: Gail L
authors: GL
authors: Brown
authors: Dale
authors: D
authors: Schaar
authors: Stefan
authors: S
authors: Faderl
authors: Rami S
authors: RS
authors: Komrokji
authors: Alan F
authors: AF
authors: List
authors: Mikkael
authors: M
authors: Sekeres
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; C096329:gamma-Glu-S-BzCys-PhGly diethyl ester; D005978:Glutathione