ORLANDO, Fla.Oral ezatiostat demonstrated clinically significant efficacy in patients with myelodysplastic syndromes (MDS) who were both lenalidomide-naïve and lenalidomide-treated, a phase 2 study has shown.

In addition, ezatiostat is the first GSTP1-1 inhibitor to cause clinically significant reduction in red blood cell (RBC) transfusions, including transfusion independence. These data suggest ezatiostat may offer an important treatment option for patients with low to intermediate (int)-1 risk MDS, Azra Raza, MD, of Columbia University Medical Center, New York, and colleagues concluded. Ezatiostat, a glutathione S-transferase inhibitor, activates Jun kinase, promoting growth and maturation of hematopoietic progenitors while inducing apoptosis in leukemic blasts.

The purpose of the study was to determine efficacy and safety of ezatiostat on extended dose schedules. Patients with an International Prognostic Scoring System risk of low or intermediate (int)-1 MDS were enrolled. Initial dose ranging was conducted in 14 patients. Subsequently, patients were randomized to one of 2 dose schedules: 37 received ezatiostat 3 g/day (2 weeks on/1 week off) and 36 received 2 g/day (3 weeks on/1 week off) until lack of MDS response or unacceptable toxicity. Logistic regression analysis was conducted to identify significant MDS disease factors associated with hematologic improvement-erythroid (HI-E) rates as determined by International Working Group (2006) criteria, the investigators told those attending the 52nd American Society of Hematology Annual Meeting and Exposition.

A total of 73 patients were enrolled in the study. Median age was 73 years (range, 48–89) and 70% were male. World Health Organization classification of patients was as follows: 9 with refractory anemia (RA); 11 RA with ring sideroblasts; 4 RA with excess blasts-1; 24 refractory cytopenia with multilineage dysplasia; 14 refractory cytopenia with multilineage dysplasia with ringed sideroblasts, 4 MDS-unclassified; 2 MDS/myeloproliferative disorder-U; 4 MDS-del 5q; and 1 unknown. Fifty patients (68%) were int-1 risk; 23 (32%) low risk, and 28 (38%) had abnormal karyotypes, 23 (82%) complex/poor prognostic types. Prior treatments included 34 (47%) DNA methyltransferase (DMTI), 28 (38%) lenalidomide, 56 (77%) erythropoietin, and 32 (44%) growth factors.


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Evaluable patients on the 2-dose schedules had a similar HI-E response rate; therefore, data for these 60 patients were pooled. Overall HI-E rate was 22% (95% CI, 12.1–34.2). Median duration of response was 34 weeks.

Six of 15 patients (40%; 95% CI, 16.3–67.7) who had prior lenalidomide but no prior DMTI treatment had a HI-E response; 5 of 11 patients (45%) achieved significant RBC transfusion reduction and 3 of 11 (27%) achieved transfusion independence. Of 18 patients who were both lenalidomide- and DMTI-naïve, 5 (28%; 95% CI, 9.7-53.5) had an HI-E response and 4 of 8 (50%) achieved clinically significant RBC transfusion reduction. Of 16 patients who had received prior DMTI but no prior lenalidomide, the HI-E rate was 0% (95% CI, 0-20.6). The investigators noted that prior DMTI treatment predicted a 6-fold decrease in odds for HI-E response to ezatiostat (P=0.027).

In 21 patients with neutropenia, HI-neutrophil (HI-N) rate was 19% (95% CI, 5.4–41.9; 4 patients); bi-lineage (HI-E and HI-N) rate was 20% (95% CI, 5.7–43.7) in 4 of 20 patients with anemia and neutropenia. One patient (3.7%; 95% CI, 0.1–19) of 27 with thrombocytopenia had a HI-platelet (P) response and 1 of 11 patients with tri-lineage (HI-E, HI-N, HI-P) cytopenia responded (9.1%; 95% CI, 0.2–41.3). There were 2 cytogenetic complete responses, 1 with 45X,-Y[4], 46, XY [16], and 1 with del5q.

Thirty-eight patients who were RBC transfusion-dependent required a median of 6 units (range, 4–19) 8 weeks prior to study entry. Of these, 11 (29%) had transfusion reductions to 4 units every 8 weeks and 4 (11%) achieved transfusion independence.

A median of 4 cycles (range, 1-14) of ezatiostat was administered; the total was 431 cycles. Dose reduction was required in 15 cycles (3.5%) and dose delays occurred in 37 cycles (8.6%). The most commonly reported ezatiostat-related adverse events (AEs) were non-hematologic grade 1 or 2 gastrointestinal (GI), including nausea (45%, 17%), diarrhea (26%, 7%), and vomiting (30%, 12%). Grade 3 events were nausea (1%), diarrhea (3%), and vomiting (2%). Prior DMTI treatment was associated with an increased incidence of GI AEs. Patients with prior DMTI use had the following GI AEs, by grade (1, 2, 3): nausea (51%, 20%, 2%), vomiting (34%, 7%, 2%), and diarrhea (22%, 10%, 5%). Patients who were DMTI-naïve had fewer GI AEs: nausea (39%, 15%, 0%), vomiting (26%, 15%, 2%), and diarrhea (30%, 4%, 2%).