A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate‐1 risk myelodysplastic syndrome
- 1 September 2011
- Vol. 118 (8), 2138-2147
- https://doi.org/10.1002/cncr.26469
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. Cancer 2012. © 2011 American Cancer Society.Keywords
This publication has 15 references indexed in Scilit:
- Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell deathCell Death & Differentiation, 2010
- Oral Ezatiostat HCl (TLK199) and Myelodysplastic syndrome: A case report of sustained hematologic response following an abbreviated exposureJournal of Hematology & Oncology, 2010
- Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndromeBlood, 2009
- Estimation of economic costs associated with transfusion dependence in adults with MDSCurrent Medical Research and Opinion, 2009
- Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndromeJournal of Hematology & Oncology, 2009
- Characteristics of US Patients with Myelodysplastic Syndromes: Results of Six Cross-sectional Physician SurveysJNCI Journal of the National Cancer Institute, 2008
- Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions–a reviewBritish Journal of Haematology, 2008
- Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1–risk myelodysplastic syndromes with karyotypes other than deletion 5qBlood, 2008
- Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasiaBlood, 2006
- Cytogenetics in acute leukemiaBlood Reviews, 2003