Top

Published in:

Open Access 01-12-2012 | Research

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)

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

Published in: Journal of Hematology & Oncology | Issue 1/2012

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.

Trial registration

Clinicaltrials.gov: NCT01062152

Steensma DP, Tefferi A: The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res. 2003, 27: 95-120. 10.1016/S0145-2126(02)00098-X.CrossRefPubMed

Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997, 89: 2079-2088.PubMed

Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, Dreisbach L, Schiffer CA, Stone RM, Greenberg PL, Curtin PT, Klimek VM, Shammo JM, Thomas D, Knight RD, Schmidt M, Wride K, Zeldis JB, List AF: Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008, 111: 86-93. 10.1182/blood-2007-01-068833.CrossRefPubMed

Laborde E: Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death. Cell Death Differ. 2010, 17: 1373-1380. 10.1038/cdd.2010.80.CrossRefPubMed

Ali-Osman F, Okamura T, Turley R, Barker A, Keck JG, Laborde E, Cai D, Macsata R: Novel Ezatiostat Analogues Disrupt Binding of GSTP1 to All Three Major MAP Kinases (JNK, ERK and p38) and Exhibit Context-Dependent Antitumor Activity [abstract]. Proceedings of the AACR-NCI-EORTC International Conference. November 12–16, 2011, , San Francisco, Abstract # B229

Stofega M, Hsu SC, Chew J, Keck JG Brown G, Raza A, Cai D: Induction of apoptosis by TLK199 in human leukemia cells [abstract]. Proceedings of the Annual Meeting of the American Association for Cancer Research. April 12–16, 2008, , San Diego, Abstract #2270

Raza A, Raza A, Galili N, Smith SE, Godwin J, Boccia RV, Myint H, Mahadevan D, Mulford D, Rarick M, Allison MA, Melnyk OG, Meng L, Jones M, Brown GL, Young S, Sekeres MA: A Phase 2 Randomized Multicenter Study of 2 Extended Dosing Schedules of Oral Ezatiostat in Low to Intermediate-1 Risk Myelodysplastic Syndrome. Cancer. 2011, 10.1002/cncr.26469.

List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R, for the Myelodysplastic Syndrome-003 Study Investigators: Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion. New Eng J Med. 2008, 355: 1456-1465.CrossRef

Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000, 96: 3671-3674.PubMed

10.

Bernasconi P: Molecular pathways in myelodysplastic syndromes and acute myeloid leukemia: relationships and distinctions-a review. Br J Haematol. 2009, 142: 695-708.CrossRef

11.

Mrozek K, Heerema N, Bloomfield C: Cytogenetics in acute leukemia. Blood Rev. 2004, 18: 115-136. 10.1016/S0268-960X(03)00040-7.CrossRefPubMed

12.

Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H: Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006, 108: 419-425. 10.1182/blood-2005-10-4149.CrossRefPubMed

13.

NCI Common Terminology Criteria for Adverse Events. Common Terminology Criteria for Adverse Events (CTCAE): 1–71. 3-31-2003. CTEP. Cancer Therapy Evaluation Program, Common Terminology Criteria Version 3.0. 2006, DCTD, NCI, NIH, DHHS,

14.

Raza A, Galili N, Smith S, Godwin J, Lancet J, Melchert M, Jones M, Keck JG, Meng L, Brown GL, List A: Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome. Blood. 2009, 113: 6533-6540. 10.1182/blood-2009-01-176032.CrossRefPubMed

15.

Quddus F, Clima J, Seedham H, Sajjad G, Galili N, Raza A: Oral Ezatiostat HCl (TLK199) and Myelodysplastic syndrome: A case report of sustained hematologic response following an abbreviated exposure. J Hem Onc. 2010, 10.1186/1756-8722-3-16.

16.

Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, te Boekhorst P, Sanz G, del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E: A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5Q. Blood. 2011, 118: 3765-3776. 10.1182/blood-2011-01-330126.CrossRefPubMed

17.

Galili N, Tamayo P, Botvinnik OB, Mesirov JP, Zikria J, Brown G, Raza A: Gene Expression Studies May Identify Lower Risk Myelodysplastic Syndrome Patients Likely to Respond to Therapy with Ezatiostat Hydrochloride (TLK199) [abstract]. Proceedings of the American Society of Hematology. December 10–13, 2011, , San Diego, Abstract #2779

Title: 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)
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
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2012
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/1756-8722-5-18

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2012

Prediction of response to therapy with ezatiostat in lower risk myelodysplastic syndrome

Complete remission after first-line radio-chemotherapy as predictor of survival in extranodal NK/T cell lymphoma

The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells

The unfolded von Willebrand factor response in bloodstream: the self-association perspective

Novel therapeutic agents for cutaneous T-Cell lymphoma

MiR-424 and miR-155 deregulated expression in cytogenetically normal acute myeloid leukaemia: correlation with NPM1 and FLT3 mutation status

Keynote webinar | Spotlight on antibody–drug conjugates in cancer