Long-Term Safety and Tolerability of the Once-Daily, Oral Iron Chelator Deferasirox (Exjade®, ICL670) in Patients with Transfusional Iron Overload.
Authors: Cappellini M.D. , Giardina P. , Porter J. , Coates T. , Della Porta M.G. , Siegel J. , Glimm E. , Ford J. 
Published: October 2019

Abstract
Introduction: The safety and tolerability profile of the oral iron chelator deferasirox has been established in five comprehensive trials (with a 1-year core phase) in adults and children with a range of transfusion-dependent anemias. Following completion of the core phase, pts entered an extension phase that will last for 4 years. This analysis presents cumulative long-term safety data during deferasirox treatment.
Methods: Safety was assessed monthly, primarily by evaluating the incidence and type of adverse events (AEs) and measuring laboratory parameters.
Results: A total of 1033 pts have received deferasirox: 703 initially received it during the core phases (deferasirox cohort) and 330, who initially received deferoxamine (DFO), crossed over to deferasirox in the extension phases (crossover cohort); 433 (41.9%) were pediatric pts aged 2-<16 years (289 and 144 in the deferasirox and crossover cohorts, respectively). Underlying disorders were: β-thalassemia (n=749), sickle cell disease (n=185), myelodysplastic syndromes (n=47), Diamond-Blackfan anemia (n=30), other anemias (n=22). To date, deferasirox has been administered for a median of 2.5 and 1.5 years in the deferasirox and crossover cohorts, with mean doses during treatment of 20.5 and 21.0 mg/kg/day, respectively. Crossover pts had previously received a mean DFO dose of 42.2 mg/kg/day.
The reasons for discontinuation across both the core and extension phases in pts receiving deferasirox were: AEs (n=72; 7.0%), consent withdrawal (n=62, 6.0%), unsatisfactory therapeutic effect (n=29, 2.8%), other (n=37, 3.6%). Fifteen deaths (1.5%) occurred during deferasirox treatment, all considered unrelated to study drug by the Program Safety Board (one was reported as possibly related by an investigator).
Drug-related AEs during deferasirox treatment were generally transient and of mild to moderate severity (Table). The AE pattern and incidence rates were comparable across all ages and underlying anemias, and in the deferasirox and crossover cohorts.
Most common (>4% overall) drug-related AEs during deferasirox treatment (median 1.5–2.5 years; n=1033) AE Frequency, n (% of all pts) Severity, n (% of all pts) Mild Moderate Severe Nausea 99 (9.6) 85 (8.2) 12 (1.2) 2 (0.2) Diarrhea 91 (8.8) 71 (6.9) 18 (1.7) 2 (0.2) Abd pain 52 (5.0) 37 (3.6) 11 (1.1) 4 (0.4) Vomiting 49 (4.7) 40 (3.9) 8 (0.8) 1 (0.1) Rash 49 (4.7) 29 (2.8) 16 (1.5) 4 (0.4) Upper abd pain 44 (4.3) 34 (3.3) 9 (0.9) 1 (0.1)
During the extension phases there were no changes in markers of liver or renal function that were consistently or significantly different from the core study. Ten pts (1.0%) had urinary total protein/creatinine ratio >1.0 at 2 consecutive visits. There have been no cases of progressive increases in serum creatinine, indicative of renal insufficiency or failure. Physical and sexual development proceeded normally in all pediatric pts.
Conclusions: The safety and tolerability of deferasirox in pts receiving up to 2.5 years of treatment was similar to that observed during the 1-year core trials, with most AEs being mild, transient and easily manageable. These data demonstrate that long-term treatment with deferasirox is generally well tolerated in adults and children with a variety of transfusion-dependent anemias.