This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis.
The authors provide an excellent summary of the key clinical study data utilized in the process of the US Food and Drug Administration (FDA) approval of desferasirox (Exjade). Regular red cell transfusions are used in the management of a number of hematologic disorders including thalassemia, sickle cell disease, myelodysplastic syndrome, and rare anemias such as Diamond-Blackfan anemia, Fanconi anemia, and sideroblastic anemias. This treatment reduces complications of the underlying disorder and can be lifesaving, but in the absence of chelation, progressive iron overload results, causing hepatic disease, endocrinopathies, and cardiac disease. Despite the availability of deferoxamine, death from iron overload still occurs because compliance with deferoxamine is limited by the cumbersome parenteral route of administration. Deferasirox is the first orally administered chelator to receive FDA approval, providing an important treatment option for patients with transfusional iron overload.
Efficacy and Dose Requirements
In the pivotal phase III trial, doses of 20 or 30 mg/kg of deferasirox were as effective as deferoxamine in maintaining or reducing hepatic iron content. With ongoing transfusion therapy, doses of 5 and 10 mg/kg of deferasirox were inadequate in most patients, leading to a rise in hepatic iron content. It is important to note that although, on average, deferasirox at a dose of 20 mg/kg resulted in equal iron balance (able to remove the iron from continued transfusions but not previously accumulated iron), this dose was not effective in all patients. Doses of 30 mg/kg achieved negative iron balance in most patients.
Subsequent analyses have shown that the response to deferasirox (and to deferoxamine) is dependent upon ongoing tranfusional requirements. In those with lower transfusional iron intake averaging < 0.3 mg/kg/d, doses of 10 to 20 mg/kg were effective in reducing hepatic iron content, whereas in those with the highest iron intake of > 0.5 mg/kg/d, higher doses of 20 to 30 mg/kg/d were required.[2,3] Close monitoring of trends in iron burden using serum ferritin or hepatic iron levels (eg, with noninvasive R2 magnetic resonance imaging [MRI] techniques) can also aid in monitoring treatment response. Thus, dosing of deferasirox should be individualized based on the goal of maintenance or reduction of iron stores, ongoing transfusional requirements, and trends in iron burden during treatment.
Removal of Cardiac Iron
Given that cardiac disease is the major cause of death in those with transfusional iron overload, the ability of a chelator to remove cardiac iron is crucial. The deferasirox phase II and III study endpoints assessed change in hepatic iron and ferritin levels; cardiac iron was not assessed, and therefore, the ability of deferasirox to remove cardiac iron and prevent or reverse cardiac complications is still unknown. Hepatic iron concentration is predictive of cardiac complications in patients with thalassemia; those with hepatic iron content greater than 15 mg/g dry weight of liver have the highest risk of heart disease. However, hepatic iron can be low in the presence of substantial cardiac iron loading.
It is becoming evident that various chelators have differential effects on cardiac iron removal. Increasing evidence supports that deferiprone, an oral chelator licensed in Europe but not approved in the United States, is more effective than deferoxamine in reducing both cardiac disease and cardiac iron content, as measured by cardiac T2* MRI.[6,7] This appears to be related to the smaller size and net neutral charge that allows deferiprone to penetrate myocytes.
Preliminary data suggest that deferasirox may be effective in removing cardiac iron. In cultured heart muscle, deferasirox was able to extract intracellular iron and restore iron-impaired contractility. Furthermore, in a preliminary report of 23 patients receiving deferasirox at doses of 10 to 30 mg/kg/d, cardiac T2* MRIa measure of cardiac iron contentimproved from an average of 18 to 23.1 ms over a treatment period of 13 months (lower T2* values signify greater iron loading). Further studies are needed to confirm the effect of deferasirox on cardiac iron and cardiac disease.
The toxicity profile of deferasirox is similar across disease states and appears to be acceptable. The most common side effects of deferasirox are gastrointestinal disturbances, skin rash, mild elevations in serum creatinine levels, and elevations in hepatic transaminases. In the clinical trials as well as in clinical practice, gastrointestinal effects including abdominal pain and diarrhea have led to discontinuation of the drug in some patients. Agranulocytosis, a serious toxicity associated with the chelator deferiprone, was not seen with deferasirox administration. The rare reports of neutropenia with deferasirox were all felt to be related to the underlying hematologic disorder and unlikely to be a drug effect. Importantly, long-term data on treatment with deferasirox are lacking, and less common side effects may only become evident when larger numbers of patients have been treated for a longer duration. Thus, it is crucial to continue to monitor the results of the ongoing extension studies.
In addition, combination therapy with deferasirox and other chelators has not been studied. Beneficial effects on iron removal with combination deferoxamine and deferiprone have been demonstrated, and it is possible that deferasirox administered with another chelator could be advantageous particularly for those with high iron burden and cardiac disease. This requires formal study before clinical recommendations can be made.
In summary, the FDA approval of deferasirox adds an important treatment option for patients with transfusional iron overload. Dosing should be individualized based on hepatic iron content, ongoing transfusional loading, and changes in iron burden over time. Further studies are needed to assess the effect of deferasirox on cardiac iron content, potential rare or long-term toxicities, and the efficacy and toxicity of combination therapies. Finally, although the oral route of administration should in theory lead to improved compliance, adherence to a daily drug regimen is difficult. Side effects such as abdominal bloating, pain, and diarrhea can further hinder compliance. Thus, it will be important for health-care providers to continue to encourage and to monitor compliance in their patients.
Janet L. Kwiatkowski, MD
Dr. Kwiatkowski has served as a consultant for Novartis and she is a coinvestigator in some of the ICL670 studies.
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