Deferasirox in thalassemia patients with end‐stage renal disease
Authors: Hassan G. Beydoun, Antoine N. Saliba, Ali T. Taher
Journal: American Journal of Hematology (2016)

Patients with transfusion-dependent thalassemia are at risk of transfusional iron overload, which is associated with significant morbidity and mortality 1. In addition, iron overload is considered one of the nontraditional risk factors for cardiovascular disease in patients with end-stage renal disease (ESRD) 2. Deferasirox is a well-known iron chelating agent used to treat iron overload. Its use in ESRD patients has been reported in case reports but has not been systematically studied in randomized clinical trials or other prospective studies. Given the need for an effective iron chelating agent in ESRD patients, we report the use of deferasirox in two thalassemia patients with ESRD and review the literature for other cases. A review of the literature resulted in a few case reports and a case series reporting the use of deferasirox in ESRD patients, none of whom had thalassemia 3-6. Our report is the first to describe the safe use of deferasirox in two patients with transfusion-dependent thalassemia on hemodialysis. Patient A is a 50-year-old man with β-thalassemia major and iron overload who is currently on hemodialysis three times per week. His baseline liver iron concentration estimated by R2 MRI was 25.8 mg/g dry weight at baseline before administration of deferasirox. He was started on deferasirox at a dose of 15 mg/kg/day with the dose gradually increased to 25 mg/kg/day. Since being started on deferasirox, the ferritin level has steadily decreased from 3,846 to 1,447 ng/mL over the course of 11 months. He had an episode of asymptomatic hypocalcemia 6 months after initiation of treatment with the level reaching 6.5 mmol/L and subsequently improving to 8.4 mmol/L in 1 month without any intervention. Patient B is a 59-year-old woman with transfusion-dependent β-thalassemia intermedia. Her baseline liver iron concentration estimated by R2 MRI was 26.1 mg/g dry weight at baseline before administration of deferasirox. She was started on deferasirox 15 mg/kg/day and the dose was gradually increased to 25 mg/kg/day. Her ferritin levels have shown only mild improvement going down from 4,300 to 4,120 ng/mL over the course of 8 months before going back up to 4,479 ng/mL 11 months after initiation of treatment. She did not have any episodes of hypocalcemia while on treatment. Deferasirox and its metabolites are primarily excreted through the fecal route (84% of the dose), while renal excretion of deferasirox and its metabolites is minimal (8% of the dose) 6. Despite this, ESRD profoundly affects deferasirox pharmacokinetics. Maker et al. reported a nearly 10-fold increase in mean plasma concentration for deferasirox at a dose of 15 mg/kg compared with 10 mg/kg in their hemodialysis cohort suggesting that uremia may reduce fecal excretion or enhance intestinal reabsorption of deferasirox resulting in higher than predicted plasma levels 7. In 2008, Yusuf et al. were the first to report the use of deferasirox in a female patient on peritoneal dialysis secondary to sickle cell nephropathy for 6 months 4. At 20 mg/kg/day, treatment with deferasirox was associated with a decrease in serum ferritin but was discontinued due to symptomatic hypocalcemia. This was the first time severe symptomatic hypocalcemia was reported with deferasirox use. In another report by Yusuf et al., a male patient with paroxysmal nocturnal hemoglobinuria on hemodialysis received deferasirox at doses ranging between 15 and 30 mg/kg/day 3. There were no significant complications and an improvement in serum ferritin was achieved. Hiraga et al. reported the safe treatment of a male patient with aplastic anemia who is on hemodialysis with deferasirox at a dose of 20 mg/kg/day 5. Chen et al. retrospectively reviewed the data pertaining to eight hemodialysis patients who were treated with deferasirox for iron overload associated with transfusion-dependent anemia of renal disease 6. A dose of 15 mg/kg/day reduced the iron burden. No serious adverse events were observed and none of the patients required drug discontinuation 7. Deferasirox was also safely used in our two patients. No adverse events were noted except for asymptomatic hypocalcemia in one of the patients (Table 1). The doses we reached in our patients (up to 25 mg/kg/day) were higher than those reported in the literature before. Deferasirox appears to be safe to use in ESRD patients up to a dose of 25 mg/kg/day. Therefore, deferasirox seems to hold a promise in managing iron overload in thalassemia patients with ESRD especially in the light of the lack of alternative agents. Hassan G. Beydoun,1 Antoine N. Saliba,2 and Ali T. Taher3* 1Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 2Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; 3Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon