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).

Abstract

BACKGROUND:

Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.

RESULTS:

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.

CONCLUSIONS:

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.

• 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: Journal of hematology & oncology (J Hematol Oncol) Vol. 5 Pg. 18 (Apr 30 2012) ISSN: 1756-8722 [Electronic] England
• PMID: 22546242 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• gamma-Glu-S-BzCys-PhGly diethyl ester
• Thalidomide
• Glutathione Transferase
• Lenalidomide
• Glutathione

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Chromosome Deletion
• Chromosomes, Human, Pair 5 (genetics)
• Drug Therapy, Combination
• Female
• Glutathione (analogs & derivatives, therapeutic use)
• Glutathione Transferase (antagonists & inhibitors, metabolism)
• Humans
• Lenalidomide
• Male
• Maximum Tolerated Dose
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, genetics)
• Prognosis
• Thalidomide (analogs & derivatives, therapeutic use)