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

Naomi Galili, Pablo Tamayo, Olga B Botvinnik, Jill P Mesirov, Margarita R Brooks, Gail Brown, Azra Raza

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.