ter-199 and Myelodysplastic-Syndromes

Myelodysplastic syndromes (MDSs) are associated with significant morbidity due to ineffective hematopoiesis. Given the limited number of drugs approved by the FDA, there is a need for new therapeutic options. Ezatiostat is a novel agent targeting oxidative stress via inhibition of glutathione S-transferase 1.. Herein, the authors summarize the standard of care in order to build the framework for therapeutic advancements. The purpose of this paper is to review the body of preclinical and clinical research literature on the investigational agent ezatiostat hydrochloride (TLK199) for the treatment of MDSs. The article includes details of the pathophysiology, pharmacology, toxicity and efficacy of ezatiostat hydrochloride from controlled studies in patients with myelodysplasia.. MDS clonal heterogeneity and clonal architecture complexity has presented a significant technical challenge in developing effective therapies. Ezatiostat offers a unique and specific mechanism to improve the transfusion burden associated with myelodysplasia. Since it is tolerable as a monotherapy, combining ezatiostat with agents such as lenalidomide may have the most potential benefit.

Topics: Animals; Enzyme Inhibitors; Glutathione; Glutathione Transferase; Humans; Myelodysplastic Syndromes; Oxidative Stress

Hypomethylating agents such as 5-azacytidine or decitabine have been a major breakthrough in the treatment of patients with myelodysplastic syndromes (MDS). They have been shown to improve transfusion requirements and to change the natural history of the disease. However, with increasing cumulative clinical experience, it has become apparent that these agents are not curative and have their own shortcomings. There is a subgroup of patients who do not respond to frontline therapy and a large, growing cohort of patients that lose response or progress while on hypomethylating agent-based therapy. There are no standard treatment options in this arena and it is therefore a focus of significant research interest. Since the mechanisms of resistance to hypomethylating agents are not known, selection of therapy is largely empiric but must take into account the age, comorbidities, and performance status of the patient, as well as the characteristics of the disease at the time of treatment failure. Higher intensity approaches and allogeneic stem cell transplant can yield improved response rates and long-term disease control but should be limited to a selected cohort of patients who can tolerate the treatment-related morbidities. For the majority of patients who likely will be better candidates for lower intensity therapy, several novel, investigational approaches are becoming available. Among these are newer nucleoside analogues, inhibitors of protein tyrosine kinases, molecules that interact with redox signaling within the cell, immunotherapy approaches, and others. Patients with MDS whose disease has failed to respond to hypomethylating agent therapy should be referred for clinical trials when available. As we learn more about the patterns and mechanisms of failure, the next challenge will be to determine which therapies are suitable for each individual patient.

Topics: Adenine Nucleotides; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Arabinonucleosides; Azacitidine; Clofarabine; Cytosine; Decitabine; Drug Resistance; Drug Substitution; Enzyme Inhibitors; Glutathione; Glycine; Humans; Myelodysplastic Syndromes; Stem Cell Transplantation; Sulfones; Treatment Failure

Preliminary therapeutic successes have prompted a new wave of clinical trials enrolling patients with myelodysplastic syndromes (MDS), using compounds with a broad range of potential mechanisms of action. This article discusses several of the agents currently in development for MDS, reviewing clinical trial data related to five classes of novel therapeutics: clofarabine, a halogenated purine nucleoside analog; ezatiostat (TLK199), a glutathione analog that indirectly activates c-Jun kinase; tipifarnib, a farnesyltransferase inhibitor; laromustine (cloretazine), an alkylating agent with a metabolite that inhibits one mechanism of DNA damage repair; and eight drugs that inhibit histone deacetylase. Although MDS are still difficult clinical problems, and most patients with MDS still succumb to disease-related complications within 3 to 5 years of diagnosis, ongoing development of novel agents promises that there will be new treatment options for patients within the next 5 to 10 years.

Topics: Adenine Nucleotides; Aged; Alkylating Agents; Antimetabolites; Arabinonucleosides; Clinical Trials as Topic; Clofarabine; DNA Repair; Drug Therapy, Combination; Drugs, Investigational; Enzyme Activation; Enzyme Inhibitors; Farnesyltranstransferase; Glutathione; Histone Deacetylase Inhibitors; Humans; Hydrazines; JNK Mitogen-Activated Protein Kinases; Myelodysplastic Syndromes; Quinolones; Sulfonamides; Therapies, Investigational

As opposed to the treatment landscape for myelodysplastic syndromes (MDS) two decades ago, potential therapies now abound for the treatment of lower-risk and higher-risk populations. In lower-risk patients, decision tools can be used to determine the likelihood of response to erythropoiesis stimulating agents (ESAs), which have demonstrated survival advantages in retrospective studies in patients with MDS, and whether these patients should be treated initially with ESAs or non-growth factor ("active") therapies. Lenalidomide has shown good activity in transfusion-dependent patients with the del(5q) cytogenetic abnormality and modest activity in other lower-risk patients. In higher-risk patients, the DNA methyltransferase inhibitors produce complete and partial responses in 20% to 30% of patients, and for the first time, the MDS drug azacitidine has demonstrated a survival advantage when compared with conventional therapies. Newer therapies stimulate platelet production and target novel pathways, while a panoply of combination studies are underway or recently completed and that likely represent the next frontier in MDS therapy.

Topics: Azacitidine; Benzoates; Blood Transfusion; Bone Marrow Diseases; Chromosome Deletion; Chromosomes, Human, Pair 5; Clinical Trials as Topic; Combined Modality Therapy; Decitabine; DNA-Cytosine Methylases; Glutathione; Hematinics; Humans; Hydrazines; Immunologic Factors; Lenalidomide; Myelodysplastic Syndromes; Pyrazoles; Randomized Controlled Trials as Topic; Receptors, Fc; Recombinant Fusion Proteins; Risk; Thalidomide; Thrombopoietin

The management strategy for patients with myelodysplastic syndromes (MDS) has evolved from sole reliance on supportive measures to active treatment guided by disease risks. Recent progress in understanding the molecular pathogenesis of MDS has accelerated the discovery of new therapeutic targets, and consequently launched the development of several novel therapeutics that are currently in varied stages of clinical testing. One such agent is lenalidomide, which has shown remarkable effectiveness in the cytogenetically defined subset of MDS with the chromosome 5q31 deletion. The advent of new and effective targeted therapeutics may beneficially affect outcomes of an ever-increasing number of patients with MDS. This discussion summarizes the preliminary results of selected novel therapeutics.

Topics: Amifostine; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Enzyme Inhibitors; Glutathione; Humans; Immunosuppressive Agents; Indoles; Myelodysplastic Syndromes

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).. 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.. 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%).. 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.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Administration Schedule; Female; Glutathione; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Risk Factors

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.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 5; Drug Therapy, Combination; Female; Glutathione; Glutathione Transferase; Humans; Lenalidomide; Male; Maximum Tolerated Dose; Middle Aged; Myelodysplastic Syndromes; Prognosis; Thalidomide

Phase 1 testing of ezatiostat, a glutathione S-transferase P1-1 inhibitor, for the treatment of myelodysplastic syndrome was conducted in a multidose-escalation study. Patients received 10 dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000, and 6000 mg) of ezatiostat tablets in divided doses on days 1 to 7 of a 21-day cycle for a maximum of 8 cycles. The safety and pharmacokinetics of ezatiostat were evaluated. Forty-five patients with low to intermediate-2 International Prognostic Scoring System risk myelodysplastic syndrome were enrolled. No dose-limiting toxicities were observed. The most common grade 1 or 2, respectively, treatment-related adverse events were nonhematologic: nausea (56%, 9%), diarrhea (36%, 7%), vomiting (24%, 7%), abdominal pain (9%, 0%), constipation (4%, 9%), anorexia (3%, 7%), and dyspepsia (3%, 7%). Concentration of the primary active metabolite, TLK236, increased proportionate to ezatiostat dosage. Seventeen hematologic improvement (HI) responses by International Working Group criteria were observed at dose levels of 200 to 6000 mg/day with 11 HI responses at doses of 4000 to 6000 mg/day. HI responses occurred in all lineages including 3 bilineage and 1 complete cytogenetic response. Decreased number of red blood cell and platelet transfusions and in some cases transfusion independence were attained. Extended dose schedules of ezatiostat tablets are under investigation.

Topics: Abdominal Pain; Aged; Aged, 80 and over; Biotransformation; Dose-Response Relationship, Drug; Female; Fever; Food-Drug Interactions; Gastrointestinal Diseases; Glutathione; Humans; Male; Maximum Tolerated Dose; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Prodrugs; Tablets

Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.. 54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.. Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.. Clinicaltrials.gov: NCT00035867.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Female; Glutathione; Humans; Hydrochloric Acid; Injections; Liposomes; Male; Middle Aged; Myelodysplastic Syndromes; Prodrugs; Young Adult

Approximately 70% of all patients with myelodysplastic syndrome (MDS) present with lower-risk disease. Some of these patients will initially respond to treatment with growth factors to improve anemia but will eventually cease to respond, while others will be resistant to growth factor therapy. Eventually, all lower-risk MDS patients require multiple transfusions and long-term therapy. While some patients may respond briefly to hypomethylating agents or lenalidomide, the majority will not, and new therapeutic options are needed for these lower-risk patients. Our previous clinical trials with ezatiostat (ezatiostat hydrochloride, Telentra®, TLK199), a glutathione S-transferase P1-1 inhibitor in clinical development for the treatment of low- to intermediate-risk MDS, have shown significant clinical activity, including multilineage responses as well as durable red-blood-cell transfusion independence. It would be of significant clinical benefit to be able to identify patients most likely to respond to ezatiostat before therapy is initiated. We have previously shown that by using gene expression profiling and grouping by response, it is possible to construct a predictive score that indicates the likelihood that patients without deletion 5q will respond to lenalidomide. The success of that study was based in part on the fact that the profile for response was linked to the biology of the disease.. RNA was available on 30 patients enrolled in the trial and analyzed for gene expression on the Illumina HT12v4 whole genome array according to the manufacturer's protocol. Gene marker analysis was performed. The selection of genes associated with the responders (R) vs. non-responders (NR) phenotype was obtained using a normalized and rescaled mutual information score (NMI).. We have shown that an ezatiostat response profile contains two miRNAs that regulate expression of genes known to be implicated in MDS disease pathology. Remarkably, pathway analysis of the response profile revealed that the genes comprising the jun-N-terminal kinase/c-Jun molecular pathway, which is known to be activated by ezatiostat, are under-expressed in patients who respond and over-expressed in patients who were non-responders to the drug, suggesting that both the biology of the disease and the molecular mechanism of action of the drug are positively correlated.

Topics: Biomarkers, Tumor; Bone Marrow Cells; Gene Expression Profiling; Glutathione; Glutathione S-Transferase pi; Humans; Myelodysplastic Syndromes; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Risk Factors; Signal Transduction

Treatment options for patients with lower risk non-del(5q) myelodysplastic syndromes (MDS) who fail erythroid stimulating agents are restricted to one of the hypomethylating drugs with an expected response rate of approximately 50%. Ezatiostat HCl, an agent with the potential for producing multi-lineage responses in this population is currently in clinical investigation phase. This case report describes a 77 year old male who received less than two cycles of therapy with ezatiostat HCl which had to be aborted due to intolerable side effects, but which produced a sustained normalization of all three blood counts. This trilineage response has now lasted for more than a year. Interestingly, the patient began with a del(5q) abnormality and responded briefly to lenalidomide. Upon relapse of the anemia, a bone marrow showed the disappearance of the del(5q) but the appearance of a new clonal abnormality t(2;3). Given that the patient had a complete cytogenetic response to a truncated exposure to lenalidomide followed by a trilineage response to an even briefer course of ezatiostat HCl suggests a potential role for ezatiostat HCl in del(5q) patients who relapse following lenalidomide.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 5; Erythroid Cells; Glutathione; Hemoglobins; Humans; Lenalidomide; Male; Myelodysplastic Syndromes; Remission Induction; Thalidomide; Treatment Outcome