Deferasirox (Exjade?, Novartis) is the first oral treatment approved in the EU for chronic iron overload in patients with non-transfusion-dependent thalassemia (NTDT) syndromes. A pivotal placebo-controlled study data shows that the drug significantly decreases iron burden in NTDT patients versus placebo, with similar overall adverse event rate[1]

Worldwide, at least three quarters of a million people worldwide have NTDT, which can lead to severe and life-altering complications due to excess iron accumulation[2-5, 11]

Prospective placebo-controlled study
The European Commission has approved deferasirox for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients aged 10 years and older with non-transfusion-dependent thalassemia (NTDT) syndromes. It is the first oral treatment approved in the European Union (EU) specifically indicated for the treatment of chronic iron overload in patients with these types of thalassemia.

The approval is based on results from the first prospective placebo-controlled study of iron chelation in NTDT patients, THALASSA, which showed a significant dose-dependent decrease in iron burden compared to placebo (p<0.001)[1]. In this pivotal study, Exjade significantly reduced the concentration of iron in the liver, known as liver iron concentration (LIC), as well as the amount of iron anywhere in the body, measured by serum ferritin[1]. The overall adverse event rate for deferasirox was similar to the placebo arm.[1]>

The THALASSA study showed that deferasirox at a 10 mg/kg per day starting dose significantly reduced LIC from baseline by 3.8 mg of iron per gram of liver dry weight (Fe/g dw) compared to an increase of 0.38 mg Fe/g dw in patients receiving placebo after 52 weeks of treatment (p<0.001)[1].

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The study also determined that a 10 mg/kg per day dose was superior to a 5 mg/kg per day dose (p=0.009)[1]. Additional research has also demonstrated deferasirox continues to provide benefit over the longer term, with LIC levels reduced by 7.14 mg Fe/g dw from baseline after 24 months of treatment[10]. The most common reported adverse events (at least 10% in any deferasirox or placebo group) were headache, upper respiratory tract infection, oropharyngeal pain, pyrexia, rash and diarrhea[1].

Not easy to manage
“NTDT syndromes can be complicated to manage. Without proper treatment, patients with NTDT can suffer severe and life-changing complications from chronic iron overload,” said Professor Maria Domenica Cappellini, MD, Department of Internal Medicine, University of Milan. “The THALASSA data show that these patients now have an effective oral treatment option to help reduce iron concentration in the body.”

A diverse group of genetic disorders
Thalassemia refers to a diverse group of genetic disorders that affect red blood cell production, causing anemia. Unlike patients with other types of thalassemia, those with NTDT syndromes don’t receive regular transfusions, a significant cause of chronic iron overload. However, even without transfusions, NTDT patients still accumulate excess iron through intestinal absorption, leading to debilitating health complications like liver fibrosis and cirrhosis, blood clots, bone disease, pulmonary hypertension, and vascular and endocrine diseases[2],[6].

Critical milestone
“This approval is a critical milestone for patients with NTDT syndromes,” said Herv? Hoppenot, President, Novartis Oncology. “For the first time, deferasirox will be available to thalassemia patients who are not regularly transfused but still suffer from the life-altering effects of excess iron.”

According to published studies, at least three quarters of a million people worldwide have NTDT syndromes, although as understanding of the disease increases, it is probable the number will grow[3-5]. Because NTDT patients are not symptomatic at birth, when most thalassemias are diagnosed, they are often underdiagnosed and undertreated[7]. Many complications associated with chronic iron overload begin to appear as early as age 10 and become increasingly common as patients reach their 20s or 30s[8]. Most NTDT patients are of South and Southeast Asian, Mediterranean or Middle Eastern origin, with immigration broadening the global prevalence.[7][9]

Treatment option
Deferasirox is an oral iron chelation therapy indicated for the treatment of chronic iron overload due to frequent blood transfusions (>=7 ml/kg/month of packed red blood cells) in patients with beta-thalassemia aged 6 years and older).

Blood transfusion
It is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups: patients with beta-thalassemia major with iron overload due to frequent blood transfusions (>=7 ml/kg/month of packed red blood cells) aged 2 to 5 years, patients with beta-thalassemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older and patients with other anemias aged 2 years and older.

Finally, deferasirox is further approved for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassemia syndromes aged 10 years and older.

References
[1] Taher A, Porter J, Viprakasit V, et al. Deferasirox significantly reduces iron overload in non-transfusion-dependent thalassemia: 1-year results from a prospective, randomized, double-blind, placebo-controlled study. Blood. 2012. Published online before print May 15, 2012.
[2] Musallam KM, Cappellini MD, Wood JC, et al. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood Reviews. 2012:26S:S16-S19.
[3] Vichinsky EP. Hemoglobin E syndromes. Hematology Am Soc Hematol Educ Program. 2007;79-83.
[4] Weatherall DJ. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Reviews. 2012:26S:S3-S6.
[5] Vichinsky EP. Changing patterns of thalassemia worldwide. Ann NY Acad Sci. 2005;1054:18-24.
[6] Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamin H, Taher AT. Elevated liver iron concentration is a marker of increased morbidity in patients with ? thalassemia intermedia. Haematologica. 2011 Nov;96(11):1605-12.
[7] Thalassaemia International Federation. The Thalassaemia International Federation’s (TIF) New Focus: Addressing the Management of Non-Transfusion-Dependent Thalassaemias(NTDT). Position Paper 5.2. March 20, 2012 Last accessed: December 19, 2012
[8] Taher AT. Age-related complications in treatment-na?ve patients with thalassemia intermedia. Brit J Haematol. 2010;150:486-489.
[9] Taher A, Cappellini MD, Musallam KM. Recent advances and treatment challenges in patients with non-transfusion-dependent thalassemia. Blood. 2012;26S:S1-2.
[10] Taher AT, Porter JB, Viprakasit V et al. Deferasirox continues to reduce iron overload in non-transfusion-dependent thalassemia: a one-year, open-label extension to a one-year, randomized double-blind, placebo-controlled study (THALASSA). Poster presented at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta, GA (8-11 December 2012). Abstract #3258.
[11]Deferasirox Shows Significant Reduction of Iron Overload in Patients with Non-Transfusion-Dependent Thalassemia, Onco’Zine – The International Cancer Network, December 13, 2011.
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