Deferasirox and children: From clinical trials to the real world
Authors: Raffaella Origa, Antonietta Zappu, Maria Loreta Foschini, Giovanbattista Leoni, Maddalena Morittu, Paolo Moi, Mara Corpino, Carlo Dessì
Journal: American Journal of Hematology (2016)

To the Editor: Since its commercialization, deferasirox has become the most widely used iron chelator in children with thalassemia. Nevertheless, data on its efficacy in young patients are conflicting. In addition, several reports have linked deferasirox use with acute renal failure, Fanconi syndrome, and other tubulopathies, with a prevalence of up to 90% in small cohorts 1, 2. We retrospectively reviewed 77 thalassemia major subjects, who received at least 1 dose of deferasirox before age 18 at Ospedale Microcitemico, Cagliari (Italy). At the time of first deferasirox dose, 37 patients were <5 years, 26 were between 5 and 12 years, and 14 were >12 years. Fourteen continued receiving the chelator in adulthood. Median deferasirox exposure was 4.1 years (range 1 day to 12.8 years) for a total of 393.9 patient-years. The majority had a history of prior iron chelation therapy, while 16 were new to iron chelation. Forty patients treated for more than one year (62.5%) received the mean deferasirox dose of 20–30 mg/kg per day and 14 (21.9%) received a dose above 30 mg. The highest dose of 40 mg/kg per day was administered to five patients. While 96.4% of patients had a compliance with treatment >80% during childhood, this percentage dropped to 92.3% during adolescence and to 71.4% after 18 years of age. Thirty-three discontinued deferasirox (Table 1). All patients except one who discontinued because of the progression of hemosiderosis, heart failure, or left ventricle ejection fraction (LVEF) decrease had poor adherence to treatment. Mean serum ferritin levels slightly increased from 3,816 ± 3,757 to 4,160 ± 2,556 μg/L in patients with insufficient adherence to treatment (P > 0.35) as well as in the 11 children treated for >1 but <3 years (from 1,775 ± 764 to 2,336 ± 1244 μg/L, P = 0.08). On the other hand, it decreased from 1,860 ± 852 to 1,186 ± 692 μg/L in the 45 treated for more than 3 years (P < 0.001). Of those, 20 achieved serum ferritin levels <1,000 μg/L and 6 <500 μg/L (Supporting Information Fig. 1). The magnetic resonance at baseline was available for few patients. However, mean liver T2* measured in 17 subjects 7.5 ± 1.6 years after initiating deferasirox was 7.02 ± 5.9 ms. Liver iron was within the normal limits in two subjects, while hepatic overload was mild in nine, moderate in four, and severe in two. Myocardial iron loading was present in 3/17 patients, of which 1 case was mild and 2 were moderate. LVEF, which was normal in all patients at baseline (65.1 ± 5.5%), changed to 61.8 ± 12.1 during the observation period (P = 0.06) (data available for 47 subjects), becoming abnormally low in 5 patients. Among the three who experienced heart failure, of which one case was fatal, compliance with deferasirox was <20%. Despite a very high prevalence of secondary hypolactasia in Sardinia, gastrointestinal disorders with a suspected relationship to deferasirox were comparable with those described in Study 107 and its extension 3 (Supporting Information Table 1). Ultrasound examination revealed nephrocalcinosis in three patients receiving deferasirox treatment for 4, 7.5, and 8 years. It is known that nephrocalcinosis frequently occurs in patients on other chelators, particularly on desferrioxamine and its causes remain not fully understood. For these reasons, the role of deferasirox in determining or favoring nephrocalcinosis cannot be excluded or considered certain. The most common laboratory abnormality suspected to be deferasirox-related as well as the most challenging adverse event was an increase in ALT (≥ 100 U/L observed ≥ 3 times), with peaks up to 600 U/L. It was more common in patients who had already experienced abnormal ALT values before the start of chelation with deferasirox beyond infections and concomitant drug use (15 subjects). Excluding the most obvious causes such as infections and other drugs, a genetic susceptibility to iron damage as well as to deferasirox hepatic toxicity can be hypothesized 4. Serum creatinine increased slightly with age, but remained in the normal range (Supporting Information Fig. 2). Only one patient had a progressive increase with values above the upper normal limit (highest value 1.8 mg/dL) after an increase in dosage from 20 to 30 mg/kg/day and discontinued the treatment after 4 years. None of the patients were admitted to the hospital because of kidney problems, and none experienced Fanconi syndrome, hypocalcaemia, hypophosphatemia, or hypochloremia. Intermittent proteinuria—defined as three episodes or more of urine protein/creatinine ratio > 0.6 mg/mg—occurred in six patients (7.8%). Thirteen others (16.9%) had at least one episode of urine protein/creatinine ratio > 1 mg/mg. Factors related to proteinuria were intercurrent infections, concomitant drugs, serum ferritin <1,500 μg/L, and recent increase of chelator dosage. In all but one patient, the protein/creatinine ratio fell below 0.6 mg/mg after 1–6 days of withholding deferasirox. As a consequence, our study supports the idea that deferasirox is not nephrotoxic through a direct mechanism but through relative iron depletion in the tubular cells. Proteinuria rapidly reversed after deferasirox interruption or dose reduction. We did not measure b-2 microglobulin and cannot exclude asymptomatic increases. The regular assessment of the protein/creatinine ratio, however, allows us to exclude rises with clinical meaning. Finally, deferasirox use was not associated with growth failure (Supporting Information Fig. 3) 1, 5, 6. This was truer when it was started during childhood, likely because other factors such as early hypophyseal damage with abnormal release of sexual hormones may compromise normal growth during adolescence independent of the use of deferasirox. In conclusion, dose titration guided by serum ferritin trends and safety markers makes deferasirox effective in most children and young patients with thalassemia, reducing serum ferritin and preventing liver as well as heart iron overload. Increases in transaminases are a common event in young patients with thalassemia who are treated with deferasirox; the roles of the chelator, iron, and other unknown causes are not trivial to establish, and thus, the management of the patient's daily routine is not easy. The regular assessment of renal function with monthly evaluation of serum creatinine and urine protein levels and reducing or temporarily stopping deferasirox when necessary seem to be the keys to preventing and avoiding tubulopathies and other important renal diseases. RO designed and performed the research study, analysed the data and wrote the paper. AZ gave a substantial contribute to the acquisition of data. MLF, GBL, MM, MC, PM and CD contributed to acquire, analyze and interpreter the data. All the Authors revised the paper critically and approved the final version. Raffaella Origa*, Antonietta Zappu, Maria Loreta Foschini, Giovanbattista Leoni, Maddalena Morittu, Paolo Moi, Mara Corpino, Carlo Dessì 1Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy; 2Ospedale Pediatrico Microcitemico “a.Cao”– a.O. G.Brotzu, Cagliari, Italy Additional Supporting Information may be found in the online version of this article. 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