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

Azra Raza, Naomi Galili, Scott E. Smith, John Godwin, Ralph V. Boccia, Han Myint, Daruka Mahadevan, Deborah Mulford, Mark Rarick, Gail L. Brown, Dale Schaar, Stefan Faderl, Rami S. Komrokji, Alan F. List, Mikkael Sekeres

Research output: Contribution to journalArticle

32 Scopus citations

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 factora-baseline cytopenia (anemia only vs anemia with additional cytopenias)a-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.

Original languageEnglish (US)
Pages (from-to)2138-2147
Number of pages10
JournalCancer
Volume118
Issue number8
DOIs
StatePublished - Apr 15 2012
Externally publishedYes

Keywords

  • ezatiostat HCl
  • glutathione S-transferase P1-1
  • myelodysplastic syndrome
  • phase 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    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. (2012). A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome. Cancer, 118(8), 2138-2147. https://doi.org/10.1002/cncr.26469