Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Comparative efficacy of desferrioxamine, deferiprone and in combination on iron chelation in thalassemic children. A prospective, randomized, double-blind controlled trial of acetaminophen and diphenhydramine pretransfusion medication versus placebo for the prevention of transfusion reactions. Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia. Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients. A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong. Intramuscular desferrioxamine in patients with Alzheimer's disease. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia.
Desferrioxamine (DFX) alone (40-50 mg/kg/d s.c. over 8-12 h, five times weekly) was compared with combined DFX twice weekly and deferiprone (75 mg/kg/d) over 12 months in previously poorly chelated thalassaemia patients. Serum ferritin fell from 5506 +/- 635 microg/l (mean +/- SEM) to 3998 +/- 604 microg/l (P < 0.001; n = 14) in the DFX group and from 4153 +/- 517 microg/l to 2805 +/- 327 microg/l in the combined group (P < 0.01; n = 11). Deferiprone plus DFX produced a greater mean urine iron excretion (1.01 mg/kg/24 h) than iron intake from blood transfusion in each patient. Main side-effects were skin reactions (DFX alone), nausea and arthralgia (combined therapy). As chelation therapy, the combined protocol was as effective as DFX five times weekly. Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis.
                Patients were randomized to receive once-daily deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration.
                Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC. Ascertainment of an appropriate strategy of iron chelation for multi-transfused thalassemic children in developing countries.
                Prospective study from May 2000 to April 2001.
                Urban tertiary care center.
                Thirty thalassemic children having received more than 20 blood transfusions and a serum ferritin greater than 1500 ng/ml were enrolled and randomized into three groups. Group I received desferrioxamine (DFX) at a dose of 40 mg/kg subcutaneously, 5 days/week. Children in group II received oral deferiprone (L1) at a dose of 75 mg/kg/day daily and group III received a combination of daily L1 at a dose of 75 mg/kg/day and DFX at a dose of 40 mg/kg/day two times per week. The assessment of chelation was done by 24-hr urinary iron excretion (UIE) and measurement of serum ferritin levels at start and after 6 months of follow up. Statistical difference of serum ferritin levels between the three groups was assessed by applying analysis of variance. Analysis of covariance was applied to find out the urinary iron excretion keeping serum ferritin values same in each groups.
                Ferritin levels after 6 months of intervention were maximally decreased in group I. There was a significant difference between groups I and II however, no difference was noted between groups I and group III. There was no statistically significant difference in mean urinary iron excretion by keeping the initial serum ferritin levels equal though it was found to be more in group III as compared to other groups.
                DFX is the most effective chelating drug in iron overloaded multi-transfused thalassemic patients. In view of cost and unacceptability of daily DFX injections, combination therapy is an effective method of chelation thus increasing the compliance and cost effectiveness. Deferiprone (L1) alone is not an effective mode of chelation when used for a short period. Acetaminophen and diphenhydramine are commonly used as pretransfusion medications to prevent transfusion reactions. The purpose of this study was to prospectively compare the risk of transfusion reactions in hematology/oncology patients who receive acetaminophen with diphenhydramine or placebo before transfusion.
                A randomized, double-blind, placebo-controlled transfusion reaction study of 315 eligible patients was performed. Inclusion criteria were patients aged 18 to 65 years admitted to the leukemia or bone marrow transplant (BMT) services. Patients were excluded if they had a known allergy to either acetaminophen or diphenhydramine or had a documented history of a febrile or allergic transfusion reaction. All blood products were administered using a leukofilter. Study medications were given 30 minutes before transfusions and no other acetaminophen or diphenhydramine was given within 4 hours of administration of the study medications. Patients were monitored for the development of reaction symptoms within 4 hours after the transfusion.
                A total of 154 active drug patients were compared to 161 placebo patients. There was no significant difference in the overall risk of transfusion reactions between the two groups. However, analysis of specific reaction types revealed a significant decrease in the risk of febrile reactions when pretransfusion medication is used in addition to bedside leukoreduction.
                Pretransfusion medication of leukemia or BMT patients without a history of transfusion reaction does not decrease the overall risk of transfusion reactions. However, pretransfusion medication may decrease the risk of febrile nonhemolytic transfusion reactions to leukoreduced blood products. To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) was compared with that of subcutaneous desferrioxamine in 26 patients with transfusional iron overload. Immediately after red-cell transfusion, 20 patients were randomised to receive either desferrioxamine (50 mg/kg daily as a 12 h subcutaneous infusion), or L1 (50 mg/kg daily by mouth). Patients were evaluated during treatment with the other drug after transfusion the next month. Mean (SD) daily urinary iron excretion was lower during L1 than during desferrioxamine (12.3 [6.7] vs 18.2 [15.3] mg/day). In 5 patients the dose of L1 was raised from 50 to 75 mg/kg daily; mean urinary iron excretion rose from 13.8 (7.0) mg/day to 26.7 (17.8) mg/day, comparable with that during desferrioxamine (24.9 [24.3] mg/day). Faecal iron excretion rose slightly over baseline in 6 patients studied during L1 administration (from 8.5 [0.9] mg/day to 12.2 [0.9] mg/day). Pharmacokinetic studies showed an elimination half-life for L1 of 117-237 min. Studies in dogs and in volunteers showed no absorption of the L1-iron complex, excluding a contribution of absorption of intraluminal complexes of L1 and food iron to urinary iron excretion. Further animal toxicity testing is needed before L1 can be studied in a broader group of patients. A controlled, open-label and randomized study was conducted to evaluate the safety and efficacy of the oral iron chelator deferiprone (L1) in thalassemia major patients from Hong Kong. Forty-nine patients were recruited in total (median age: 20 years; range: 8 to 40 years). The division of the patients was determined based on liver iron content and put into either the poorly-chelated (Group I) or well-chelated (Group II) groups. In Group I, 20 patients received combined therapy of L1 daily plus desferrioxamine (DFO), in a reduced frequency of twice weekly, while the control group consisted of 16 patients who were treated with DFO alone. In Group II, six patients received L1 only, while the control group consisted of seven patients treated with DFO alone. Only patients who participated for longer than 6 months were analyzed for efficacy (n = 44). The median study period was 18 months. Transient and mild gastrointestinal upset (31%), joint pain (15%) and liver enzyme elevation (23%) were the most common side effects noted for L1. No case of neutropenia was observed in this study. Serum ferritin (SF) levels showed significant decline in the poorly-chelated patients using combined therapy (L1 and reduced frequency DFO) as compared to those on DFO alone. However, their pre- and post-study liver iron content was not significantly different. Evaluation of the well-chelated group demonstrated no significant change in SF or liver iron content in both the study and control arms. We conclude that the short-term use of L1, with or without DFO, was safe and efficacious in our Chinese patient cohort. The long-term efficacy of reducing iron overload by treatment regimens including L1 requires further study. Although epidemiological and biochemical evidence suggests that aluminium may be associated with Alzheimer's disease (AD), there is no convincing proof of a causal link for aluminium in disease progression. We have completed a two year, single-blind study to investigate whether the progression of dementia could be slowed by the trivalent ion chelator, desferrioxamine. 48 patients with probable AD were randomly assigned to receive desferrioxamine (125 mg intramuscularly twice daily, 5 days per week, for 24 months), oral placebo (lecithin), or no treatment. No significant differences in baseline measures of intelligence, memory, or speech ability existed between groups. Activities of daily living were assessed and videorecorded at 6, 12, 18, and 24 month intervals. There were no differences in the rate of deterioration of patients receiving either placebo or no treatment. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills as assessed by both group means (p = 0.03) and variances (p less than 0.04). The mean rate of decline was twice as rapid for the no-treatment group. Appetite (n = 4) and weight (n = 1) loss were the only reported side-effects. We conclude that sustained administration of desferrioxamine may slow the clinical progression of the dementia associated with AD. Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.
We found no reason to change current treatment recommendations. However, considerable uncertainty continues to exist about the optimal schedule for desferrioxamine in people with transfusion-dependent thalassaemia.