Abstract
BackgroundEzatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.ResultsEzatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1–21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone. The most common non-hematologic AEs related to ezatiostat in combination with lenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting; hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. One of 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroid hematologic improvement (HI-E) response by 2006 MDS International Working Group (IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose group experienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependent patients became RBC transfusion independent, including one patient for whom prior lenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients had an HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%), 1 of 3 with HI-E and HI-N (33%), and 1 of 3 with HI-N and HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a complete trilineage response. All multilineage responses were observed in the 2000/10 mg doses recommended for future studies.ConclusionsThe tolerability and activity profile of ezatiostat co-administered with lenalidomide supports the further development of ezatiostat in combination with lenalidomide in MDS and also encourages studies of this combination in other hematologic malignancies where lenalidomide is active.Trial registrationClinicaltrials.gov: NCT01062152
Highlights
Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells
Myelodysplastic syndromes (MDS) represent a diverse group of acquired hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a variable risk of transformation to acute myeloid leukemia (AML) [1]
Patients were excluded for prior allogeneic bone marrow transplantation, a history of International Prognostic Scoring System (IPSS) higher-risk MDS or of AML [10,11], proliferative chronic myelomonocytic leukemia, use of oral corticosteroids at a dose exceeding 10 mg daily, history of hepatitis B/C or human immunodeficiency virus, or an active infection requiring intravenous antibiotics
Summary
Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells. Myelodysplastic syndromes (MDS) represent a diverse group of acquired hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a variable risk of transformation to acute myeloid leukemia (AML) [1]. MDS has been divided into two main groups according to whether there is a higher or lower risk of developing leukemia [2]. A select group of lower-risk patients with clonally restricted deletion of the long arm of chromosome 5 (del[5q]) and transfusiondependent anemia respond to lenalidomide, but lenalidomide is less effective in the majority of patients with MDS who lack del(5q) [3]. While the hypomethylating drugs azacitidine and decitabine are approved by the Food and Drug Administration (FDA) for treatment of patients with a broad range of MDS subtypes, the benefit of these agents for lower-risk patients is not clearly established. Other therapies that have been studied for treatment of MDS include hematopoietic growth factors, immunosuppressive therapy, various biologic response modifiers, and traditional cytotoxic chemotherapies; there remains a major need for new treatment options
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