This proposal is a multicenter planning grant toward a future comparative effectiveness research (CER) project aimed at improving the iron burden of transfusion-dependent thalassemia patients. Worldwide, the standard of care for (non-transplanted) thalassemia major patients is ongoing transfusion therapy plus lifelong iron chelation. This therapy has improved lifespan in thalassemia over the last three decades, but chelation adequacy is variable, and the leading cause of death remains cardiac iron overload. Iron measurements by MRI have simplified assessment of total-body and cardiac iron burden, yet chelation status of many patients is suboptimal. Many factors affect adequacy of chelation, including transfusion burden and adherence. Choice of chelator(s) and dose regimen(s) are also vital factors, but the "optimal" strategy is unclear presently. This lack of knowledge is not amenable to randomized clinical trials for many reasons, e.g. (a) unwillingness of patients to be randomized to parenteral therapy when oral chelators are available, (b) varying regulatory approval status of the chelators in different countries, and (c) logistical, financial and corporate impediments for supporting randomized combination therapy approaches between and/or among chelator brands. The working hypothesis for this proposal is that the Thalassemia Longitudinal Cohort (TLC), an ongoing NHLBI-funded project which captures chelator regimens, iron status, transfusion burden, and measures of adherence and end-organ function for ~400 patients, can form the framework of an observational study that will underlie the planned CER study at TLC sites in the US, Canada, the UK and a new planned site in Thailand. The project will be accomplished in two specific aims:
Aim 1 is to develop the framework and infrastructure for a multicenter, international CER study of iron chelation in thalassemia major.
Aim 2 is to provide both feasibility information and exploratory analyses of chelator strategies for the planned R01 application. Feedback from initial analyses in aim 2 will be used iteratively to improve Aim 1 logistics in anticipation of an R01 application in 2012.

Public Health Relevance

The project aims to determine the most effective strategies for iron chelation in chronically transfused thalassemia major patients. Although chelators have greatly improved life- expectancy in thalassemia over the last three decades, many patients have unsatisfactory cardiac and whole-body iron burdens, and cardiac siderosis remains the leading cause of death in young adults with thalassemia in developed countries. The problem is refractory to approaches by randomized clinical trials not only for logistical and financial reasons, but also the impossibility of using parenteral deferoxamine as a randomized comparator arm, now that oral chelators are available worldwide. We therefore propose a Comparative Effectiveness Research approach, which will be based on the ongoing Thalassemia Longitudinal Cohort study, with addition of a large international site to the current multi-site, multinational observational cohort. The R34 project will establish the infrastructure for a full CER trial, and provide pilot data on feasibility and the analysis methods themselves. Thalassemia remains one of the most prevalent genetic conditions worldwide, and the results of this project will lead directly to improved global research collaboration and improved individualized therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Planning Grant (R34)
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Special Emphasis Panel (ZHL1-CSR-D (M2))
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Luksenburg, Harvey
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Children's Hospital Boston
United States
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