Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS)
1 Columbia University Medical Center, New York, NY, USA
2 University of Rochester, Rochester, NY, USA
3 Cardinal Bernardin Cancer Center, Loyola University Chicago Medical Center, Maywood, IL, USA
4 Telik, Inc., Palo Alto, CA, USA
5 Dana-Farber Cancer Institute, Boston, MA, USA
6 Cancer Care Centers South Texas/US Oncology, San Antonio, TX, USA
7 Center for Cancer & Blood Disorders, Bethesda, MD, USA
8 Hematologic Oncology & Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
9 Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
10 Mayo Clinic, Scottsdale, AZ, USA
Journal of Hematology & Oncology 2012, 5:18 doi:10.1186/1756-8722-5-18Published: 30 April 2012
Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.
Ezatiostat 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.
The 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.