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This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3/7, 48% higher caspase-8 and 88% higher caspase-9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl-2 (BCL2), (-27·3%/year), and caspase-9 activity (-13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.

Summary This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23·2 years (range 6·1–75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = −0·73 ± 1·24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12·8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

The most widely used drug for iron chelation is deferoxamine (DFO) mesylate. While effective in promoting iron excretion, it requires prolonged daily infusions, often resulting in poor compliance. A clinical trial was conducted using starch-conjugated DFO (S-DFO; 40SD02), a high-molecular-weight iron chelator possessing prolonged vascular retention. Single doses of S-DFO were infused intravenously into groups of four transfusion-dependent patients with beta-thalassaemia at doses of 150, 300, 600 and 900 mg/kg. Urinary iron excretion and various pharmacologic parameters were evaluated for 1 week and safety for 3 weeks. No drug-related effects were observed on clinical chemistries, haematological and coagulation parameters, urinalyses, vital signs or electrocardiograms. Drug-related adverse events were limited to four urticarial reactions, none requiring termination of the infusion. The drug stimulated clinically significant urinary iron excretion, with the highest dose (900 mg/kg) inducing excretion of 1.31 mg of iron/kg (range 0.79-1.90 mg/kg) over 1 week, with residual iron-binding capacity present in the plasma for over 6 d. In summary, treatment with S-DFO, administered weekly, has the potential to achieve iron balance in the poorly compliant patient.

Summary. Fifteen compounds with a high affinity to ferric iron have been screened for in vivo iron-chelating efficiency in a rat model. One of the most potent of these drugs was ethylenediamine-N,N′-bis(o-hydroxyphenylglycine) (EHPG). EHPG-induced iron excretion was up to 8 times higher than iron excretion induced by identical doses of desferrioxamine (DF). Studies employing selective radio-iron probes of reticuloendothelial and parenchymal iron stores showed that although EHPG is able to interact with both storage iron compartments, its effect on parenchymal iron is much more pronounced. Unlike DF which has two alternative routes of excretion, EHPG-induced iron excretion is restricted mainly to the gut. Although EHPG seems to be superior to DF in both its chelating efficiency and preferential interaction with hepatic parenchymal iron stores, information on its in vivo toxicity is at present insufficient and it cannot yet be recommended for clinical use.

Summary. 2,3-Dihydroxybenzoic acid was evaluated as a potentially useful, orally effective iron-chelating drug by performing iron balance studies in patients with β-thalassaemia major. The administration of this substance at 25 mg/kg/d to five patients for 8 d caused an average increase in iron excretion of 4.5 mg/d. When the drug was administered at 25 mg/kg q.i.d. to eight patients for 21 d, iron excretion increased to 6.5 mg/d. Chelation was highly specific for iron with changes in magnesium and calcium excretion being insignificant. The drug was well tolerated with side effects limited to gastrointestinal complaints which ameliorated when the drug was taken with food. These studies provide a rationale for further evaluation of 2,3-dihydroxybenzoic acid in patients with iron overload.

The relative proportions of T-cell (OKT3-positive, OKT4-positive and OKT8-positive) and B-cell (SIg-positive) populations in peripheral blood obtained from 29 chronically transfused patients with beta-thalassaemia major were compared with those of 17 healthy controls. Changes attributable to blood transfusion and/or splenectomy are described. The percentage of OKT8-positive (T-suppressor) cells found in the thalassaemic patients increased linearly (P less than 0.001) with the number of units transfused, irrespective of splenectomy. The percentage of OKT4-positive (T-helper) cells varied inversely with increasing transfusion in nonsplenectomized patients while in those who were splenectomized no significant correlation was apparent. Thus, in both groups of patients the T4/T8 ratio declined in a transfusion-related manner. The splenectomized patients experienced a marked and persistent lymphocytosis due to an increase in the number of both T- and B-cells. When the results were expressed as percentages, the greatest increase occurred in the number of B-cells, this increase being unrelated to the number of transfusions received. None of the serum parameters usually associated with iron overload or abnormal liver function correlated with the observed increases in T-suppressor and SIg-positive cells. These findings corroborate reports that transfusion of blood products may lead to decreased T4/T8 ratios. However, none of the patients studied manifested clinical signs of acquired immune deficiency syndrome (AIDS). Accordingly, studies which define transfusion related AIDS on the basis of analyses with monoclonal antibodies must be viewed with caution.