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.
RCT Entities:
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) MDSpatient. 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 MDSpatients. The tolerability and activity profile of ezatiostat may offer a new treatment option for patients with MDS.
Authors: A Toma; O Kosmider; S Chevret; J Delaunay; A Stamatoullas; C Rose; O Beyne-Rauzy; A Banos; A Guerci-Bresler; S Wickenhauser; D Caillot; K Laribi; B De Renzis; D Bordessoule; C Gardin; B Slama; L Sanhes; B Gruson; P Cony-Makhoul; B Chouffi; C Salanoubat; R Benramdane; L Legros; E Wattel; G Tertian; K Bouabdallah; F Guilhot; A L Taksin; S Cheze; K Maloum; S Nimuboma; C Soussain; F Isnard; E Gyan; R Petit; J Lejeune; V Sardnal; A Renneville; C Preudhomme; M Fontenay; P Fenaux; F Dreyfus Journal: Leukemia Date: 2015-10-26 Impact factor: 11.528
Authors: David H McMillan; Jos Lj van der Velden; Karolyn G Lahue; Xi Qian; Robert W Schneider; Martina S Iberg; James D Nolin; Sarah Abdalla; Dylan T Casey; Kenneth D Tew; Danyelle M Townsend; Colin J Henderson; C Roland Wolf; Kelly J Butnor; Douglas J Taatjes; Ralph C Budd; Charles G Irvin; Albert van der Vliet; Stevenson Flemer; Vikas Anathy; Yvonne Mw Janssen-Heininger Journal: JCI Insight Date: 2016-06-02
Authors: Azra Raza; Naomi Galili; Deborah Mulford; Scott E Smith; Gail L Brown; David P Steensma; Roger M Lyons; Ralph Boccia; Mikkael A Sekeres; Guillermo Garcia-Manero; Ruben A Mesa Journal: J Hematol Oncol Date: 2012-04-30 Impact factor: 17.388
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