Abstract

Background: The efficacy and safety of deferasirox was established during five 1-year core trials. As many patients will require lifelong chelation therapy, assessing long-term efficacy and safety is important. In the core trials, initial doses were assigned by baseline liver iron concentration (LIC). A clear dose response was observed: 5/10 mg/kg/d doses were generally insufficient to balance iron intake from ongoing transfusions, while 20 and 30 mg/kg/d maintained or reduced iron balance, respectively. This analysis evaluates serum ferritin (SF) levels and cumulative safety data during 4-year extension trials.

Methods: In the extensions, dose modifications were based on safety and efficacy parameters. Safety and SF were assessed monthly. Due to methodological differences in study 105, the SF data from this trial are not included in this analysis.

Results: 1034 patients with β-thalassemia (n=750), sickle cell disease (n=185), MDS (n=47) and other anemias (n=52) have received deferasirox. 703 patients received deferasirox in the core trials and have been on treatment for a median of 3.4 years; 331 crossed over to deferasirox in the extensions. 210 (20%) patients have discontinued treatment due to: AEs (74), consent withdrawal (64), unsatisfactory therapeutic effect (29) and other (43). Only 17 (1.6%) patients have discontinued in the past 12 months (9 AEs; 1 death; 4 lost to follow-up; 2 withdrew consent; 1 other). 16 patients have died, 6 in the core and 10 in the extensions. 5 patients (4 β-thalassemia, 1 sideroblastic anemia) aged 18-24 years with inadequate chelation and severe iron overload before study entry died with cardiac failure in the extensions. Other deaths were due to other complications/progression of the underlying disease. At month 42, mean (SD) dose in the 5/10, 20 and 30 mg/kg/d dose groups was 21.8 (9.3), 23.2 (8.2) and 25.4 (9.8) mg/kg/d, respectively. Median SF levels (ng/mL) are shown in the Table (n=652, deferasirox cohort only).

Drug-related AEs during deferasirox treatment were generally transient, of mild/moderate severity, and showed a reduction in frequency from the core trials. No patient has developed progressive increases in serum creatinine or values >2 x ULN. 2 patients discontinued due to stable creatinine increases of 1.5 x ULN and confounding circumstances (concomitant cyclosporine and multiple infections, respectively). 1 patient discontinued due to recurrent episodes of proteinuria. 12 patients discontinued due to increases in transaminases (4 core study, 8 extension [3 crossover patients]). Drug-induced liver toxicity was likely in 2 patients with early onset and positive rechallenge. Increasing LIC due to under-chelation was the likely explanation in at least some patients.

Conclusions: Over 3.5 years’ treatment, deferasirox 20/30 mg/kg/d maintained/reduced SF levels in patients with various transfusion-dependent anemias. There was no increase in frequency of drug-related AEs or changes in markers of liver or renal function that differed significantly from the 1-year core trials.

Initial dose, mg/kg/d
*Dose adjustments 
Month 5/10 (n=227) 20 (n=182) 30 (n=243) 
Baseline 2051 2375 3734 
12* 2650 2161 2649 
24 2481 2508 2271 
36 1439 1844 2071 
42 1345 1667 2025 
Initial dose, mg/kg/d
*Dose adjustments 
Month 5/10 (n=227) 20 (n=182) 30 (n=243) 
Baseline 2051 2375 3734 
12* 2650 2161 2649 
24 2481 2508 2271 
36 1439 1844 2071 
42 1345 1667 2025 

Author notes

Disclosure:Employment: P Williamson is an employee of Novartis. Consultancy: E Vichinsky, JB Porter and A Piga have received consultancy fees from Novartis. Research Funding: E Vichinsky is a research investigator for Novartis. JB Porter, R Galanello and A Piga have received research funding from Novartis. Honoraria Information: E Vichinsky, JB Porter and R Galanello have received honoraria from Novartis. Paid Export Testimony Information: JB Porter advised Novartis on the registration of deferasirox in the US (FDA) and EU (EMEA). Membership Information: MD Cappellini has been a member of an advisory board for deferasirox trial 107 (Novartis). JB Porter and A Piga have participated in Speakers’ Bureau for Novartis.