Study Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Deferasirox in Patients With Myelodysplastic Syndromes (Low/Int-1 Risk) and Transfusional Iron Overload (TELESTO)
Sponsor:
Novartis, Inc.
ClinicalTrials.gov Identifier:
Participating Centers:
This is an international trial with a goal accrual of 630 patients (2:1 deferasirox : placebo randomization) at approximately 125 centers in North America, Latin America, Europe, South Africa, and Asia.
Study Design:
Disease-specific eligibility criteria include chelation-naïve MDS patients classified as low risk or intermediate-1 risk based on International Prognostic Scoring System (IPSS) criteria. Study patients will have a history of 20 to 50 red blood cell transfusions and a serum ferritin concentration of > 1,000 to < 2,500 mcg/L. Patients are permitted to receive treatment with hypomethylating agents, lenalidomide, and erythropoietin. The primary objective is to evaluate event-free survival, a composite endpoint that includes death and non-fatal events related to cardiac dysfunction (i.e., worsening of left ventricular ejection fraction, hospitalization for congestive heart failure) and liver impairment (i.e., clinicopathologic evidence of progressive liver dysfunction, cirrhosis, or both). The study will also explore secondary endpoints including overall survival, endocrine function (e.g., thyroid function and glycemic control), changes in the serum ferritin concentration, and disease outcomes such as evolution to higher-risk MDS and acute myeloid leukemia.
Rationale:
Prospective studies have established that iron chelation can significantly reduce morbidity and mortality from transfusional iron overload in patients with thalassemia. To date, phase II trials have shown that deferasirox can reduce serum ferritin concentration and liver iron content in transfusion-dependent, lower-risk MDS patients. However, no prospective studies have yet been performed in MDS to establish the benefits of iron chelation on organ function, MDS natural history, and overall survival despite retrospective studies suggesting improvements in these endpoints. This pivotal study aims to close that data gap.
Comment:
Therapeutic nihilism regarding iron chelation in MDS is still pervasive despite infusional deferoxamine being supplanted by oral agents. This attitude commonly prevails among physicians treating older patients with higher-risk disease where life expectancy is limited and a chelation program would not be expected to have a meaningful impact on overall survival. However, in chronically transfused lower-risk patients, reversal of organ dysfunction, improvement of impaired hematopoiesis, and prolongation of overall survival (endpoints achieved in prior observational or retrospective studies) are eminently reasonable clinical objectives. This phase III study may also clarify the optimal serum ferritin concentration or the appropriate cumulative number of red blood cell transfusions at which to initiate iron chelation.
