Alberti Phase II clinical evaluation of deferasirox , a once - daily oral chelating agent , in pediatric patients with β - thalassemia major

Regular blood transfusions are essential support therapy for patients with transfusion-dependent anemias such as thalassemia and sickle cell disease. However, since humans lack a mechanism for the active excretion of excess iron, these patients invariably develop iron overload acquired from chronic blood transfusions. Since each milliliter of packed red blood cells (RBCs) processed for transfusion contains approximately 1 milligram of elemental iron, iron overload can present as early as 2 years of age in pediatric patients who are frequently transfused from infancy. The excess iron is deposited as ferritin and as insoluble hemosiderin in tissues of the body, mainly the liver, heart, spleen and endocrine organs. At the cellular level, accumulated toxic quantities of iron cause damage to membranes, proteins and intracellular organelles which ultimately produces tissue and organ dysfunction. Diverse manifestations of iron overload are commonly seen in regularly transfused children and adolescents with β-thalassemia. These may include growth impairment and delayed sexual maturation due to impaired pituitary function, diabetes mellitus due to damage to pancreatic islet cells, and cardiac complications later in life. Iron overload can be effectively managed by adequate chelation therapy as documented by experience with deferoxamine (Desferal), which has been in clinical use for more than 40 years and is the current reference standard chelating agent. However, many patients’ long-term outcome is negatively affected by poor compliance with deferoxamine treatment due to the demanding regimen of parenteral infusions over an 8–12-hour period, 5–7 times a week. Poor compliance to deferoxamine therapy is even more pronounced among adolescents. There is, therefore, a clear requirement for an effective, well-tolerated iron chelator with a less demanding mode of administration to ensure patient compliance to life-long chelation therapy in transfusion-dependent anemia. Deferasirox (Exjade, ICL670), an Nsubstituted bis-hydroxyphenyl-triazole was selected from more than 700 compounds as part of a rational drug development program. Deferasirox represents a new class of tridentate iron chelators with a high specificity for iron. Selective and efficient mobilization of tissue iron has been demonstrated in animal models, with greater efficiency than with deferoxamFrom the Ospedale Regionale Microcitemie, Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Italy (RG, MLF, GL, AZ); Department of Pediatric Hematology, University of Turin, Italy (AP, EB, FL); Centro della Microcitemia, Ospedale Galliera, Genoa, Italy (GLF, AL); Hôpital Debrousse, Service d'Hématologie, Lyon, France (YB); Clinical Research and Development, Novartis Pharma AG, Basel, Switzerland (HM, NH, RS, RB, DA)