Iron-Chelating Therapy and the Treatment of Thalassemia

Abstract

improved control of body iron burden, 6,7 compared with a transfusion schedule (termed ''supertransfusion'') in which HE LAST 3 decades have witnessed profound changes in the management of patients with thalassemia major. Regular red blood cell (RBC) transfusions eliminate the baseline hemoglobins are permitted to exceed 11 g/dL. 8 complications of anemia and compensatory bone marrow Type of RB C Concentrates (BM) expansion, permit normal development throughout childhood, and extend survival. 1 In parallel, transfusions re-Early studies of the use of neocytes, or young RBCs, sult in a ''second disease'' while treating the first, 2 that predicted that prolonged survival in vivo of these concenof the inexorable accumulation of tissue iron that, without trates should reduce the RBC mass required to maintain treatment, is fatal in the second decade of life. Further alterappropriate baseline hemoglobin concentrations. 8-11 Clinical ing the prognosis of thalassemia major over the last 20 years investigations confirmed that an extension of transfusion inhas been progress in the development of iron-chelating therterval of 13% to 25% in thalassemia could be achieved with apy for iron overload. Deferoxamine mesylate, first introthe use of neocytes. 12-16 A recent study found that a 15% duced in short-term studies in iron-loaded patients in the extension of transfusion interval during administration of early 1960s, gained acceptance as standard therapy over a neocyte concentrates, expected to minimally reduce the redecade later in countries able to support the high costs of quirement for iron chelation therapy, could be achieved but this therapy. Twenty years later, extended survival free of at the cost of an increased exposure to donated units and a iron-induced complications, and dramatically improved fivefold increment in preparation expenses over those of quality of life, are observed in well-chelated patients. Indeed, standard concentrates. 16 Hence, the use of neocytes should over this period, iron-chelating therapy for thalassemia major have a limited impact on the long-term management of most has resulted in one of the most dramatic alterations in morchronically transfused patients. In contrast, the use of autobidity and mortality associated with a genetic disease. In this mated RBC exchange transfusions in regularly transfused review the experience gained in the use of deferoxamine, patients with sickle cell disease has been reported to substanthe benefits of and problems associated with this agent in tially reduce transfusional iron accumulation, permitting rethe treatment and prevention of iron overload, and recent duction in the intensity of chelation therapy. 17 Pilot studies progress in the development of orally effective iron-chelating in thalassemia major 18 suggest that a similar approach may drugs will be reviewed. warrant careful evaluation in this disorder.

Purging iron from the heart

“…All of the thalassaemic patients studied using T2* by Anderson et al (2002) had received chelation therapy since the mid to late 1970s or early childhood. Their mean serum ferritin was about 2000 lg/l, and liver iron <240 lmol/g dry weight, values that would be considered satisfactory for cardioprotection according to several previous studies (Olivieri & Brittenham, 1997). Hence, the subgroup of patients identified at high risk of myocardial disease by abnormally low T2* represented those patients in whom DFO treatment effectively controlled liver iron and serum ferritin but failed to protect the heart from siderosis.…”

A randomised comparison of deferasiroxversusdeferoxamine for the treatment of transfusional iron overload in sickle cell disease

“…Deferasirox (n ¼ 132) (n ¼ 4) (n ¼ 64) (n ¼ 46) (n ¼ 18) Protocol assigned dose 5 mg/kg 10 mg/kg 20 mg/kg 30 mg/kg Reported mean LIC ± SD* 2AE5 ± 0AE4 7 AE9 ± 5AE5 9 AE8 ± 1AE9 1 7 AE5 ± 3AE0 Adjusted mean LIC ± SD 5AE0 ± 0AE8 1 5 AE8 ± 11AE0 1 9 AE6 ± 3AE8 3 5 AE0 ± 6AE0 Deferasirox dose (mg/kg) *For the reported LIC values a correction factor of 3AE33 was used to convert the wet weight to dry weight values (Brittenham et al, 1982); for the adjusted values a correction factor of 6AE66 was used (Olivieri & Brittenham, 1997). Average daily doses are reported for the 1-year period of drug administration.…”

Studies in haemoglobin E beta‐thalassaemia

“…It was not clear why these patients were receiving transfusions; their pretransfusion haemoglobin levels (mean 70 g/l) showed little difference from those who were not (mean 61 g/l). As judged by initial serum ferritin or hepatic iron concentrations, many transfused patients already had dangerously high body iron burdens (Olivieri & Brittenham, 1997). Accordingly, it was decided to stop transfusion and observe the patients closely; progress was followed from 1997 to the present day.…”