Abstract

Background: In deferasirox 1-yr core trials, doses were initially assigned according to baseline liver iron concentration. However, these trials demonstrated that transfusional iron intake has a profound impact on the outcome of chelation therapy and should therefore be considered when assigning deferasirox dose. A large number of patients (pts) were initially assigned 5 and 10 mg/kg/d doses, which were insufficient to balance iron intake from ongoing transfusions. Generally, deferasirox 20/30 mg/kg/d effectively maintained/reduced body iron. This analysis from the 4-yr extension trials evaluates the impact on serum ferritin (SF) of subsequent dose increases in pts who initially received 5/10 mg/kg/d, and the long-term effects of 20 and 30 mg/kg/d doses.

Methods: Data for this analysis were pooled from 4 extension trials (106–109E). In the extensions, deferasirox doses were modified based on efficacy and safety markers, including iron burden and transfusional iron intake. SF was measured monthly.

Results: In total, 227 pts initially received deferasirox 5 or 10 mg/kg/d, while 182 and 243 received 20 and 30 mg/kg/d, respectively. Underlying diseases included β-thalassemia (n=421), sickle cell disease (n=132), MDS (n=47) and other anemias (n=52). To date, pts have been receiving treatment for a median 3.4 (range: 0–4.5) yrs. Overall, median SF was maintained in the 20 mg/kg/d cohort (Table). In the 30 mg/kg/d cohort, SF levels decreased overall from baseline to month 42 (3734 ng/mL to 2025 ng/mL). However, levels plateaued at around 24 mos in this cohort, reflecting a decrease in mean dose to around 25 mg/kg/d. Median baseline SF in the 5/10 mg/kg/d dose group was 2051 ng/mL, which steadily increased during the first 18 mos of treatment. Subsequent dose increases during the extension phase generally resulted in decreased SF levels, which returned to baseline and below during the remainder of the study.

Conclusions: In regularly transfused pts who initially received deferasirox 5/10 mg/kg/d in the core 1-yr clinical trials, SF steadily decreased below baseline once doses were increased to an appropriate level in the extensions. This highlights the importance of ensuring that pts receive the correct deferasirox dose to achieve the goal of therapy, based on iron burden and transfusional iron intake. If a pt is not achieving their therapeutic goal based on SF trends, deferasirox dose should be increased in steps of 5 or 10 mg/kg/d. This analysis confirms that deferasirox 30 mg/kg/d effectively reduces body iron, whereas doses of 20–25 mg/kg/d are generally effective in maintaining iron levels.

Median change from baseline in SF (ng/mL) during deferasirox treatment of up to 3.4 years

Initial dose, mg/kg/d
5/10 (n=227*)20 (n=182*)30 (n=243*)
MonthMean dose ± SD†Change in SF (ng/mL)Mean dose ± SD†Change in SF (ng/mL)Mean dose ± SD†Change in SF (ng/mL)
*Baseline; †At time point 
Baseline  2051  2375  3734 
9.4 ± 1.7 90 19.5 ± 2.6 30 29.2 ± 4.3 −212 
10.3 ± 3.9 399 18.9 ± 3.5 −15 28.2 ± 5.7 −532 
12 13.0 ± 5.4 613 19.0 ± 4.0 −118 26.8 ± 6.6 −716 
18 18.5 ± 6.7 831 18.2 ± 7.7 174 23.1 ± 8.6 −676 
24 21.7 ± 6.6 635 21.5 ± 6.5 −125 24.5 ± 7.6 −901 
30 22.6 ± 7.0 317 22.0 ± 8.5 −205 24.4 ± 8.0 −959 
36 21.1 ± 8.7 −211 22.8 ± 7.7 −159 24.3 ± 8.5 −1002 
42 21.8 ± 9.3 −65 23.2 ± 8.2 −204 25.8 ± 9.8 −955 
EOS  1345  1667  2025 
Initial dose, mg/kg/d
5/10 (n=227*)20 (n=182*)30 (n=243*)
MonthMean dose ± SD†Change in SF (ng/mL)Mean dose ± SD†Change in SF (ng/mL)Mean dose ± SD†Change in SF (ng/mL)
*Baseline; †At time point 
Baseline  2051  2375  3734 
9.4 ± 1.7 90 19.5 ± 2.6 30 29.2 ± 4.3 −212 
10.3 ± 3.9 399 18.9 ± 3.5 −15 28.2 ± 5.7 −532 
12 13.0 ± 5.4 613 19.0 ± 4.0 −118 26.8 ± 6.6 −716 
18 18.5 ± 6.7 831 18.2 ± 7.7 174 23.1 ± 8.6 −676 
24 21.7 ± 6.6 635 21.5 ± 6.5 −125 24.5 ± 7.6 −901 
30 22.6 ± 7.0 317 22.0 ± 8.5 −205 24.4 ± 8.0 −959 
36 21.1 ± 8.7 −211 22.8 ± 7.7 −159 24.3 ± 8.5 −1002 
42 21.8 ± 9.3 −65 23.2 ± 8.2 −204 25.8 ± 9.8 −955 
EOS  1345  1667  2025 

Author notes

Disclosure:Employment: JM Ford is an employee of Novartis. Consultancy: JB Porter has taken part in advisory boards for Novartis. Research Funding: JB Porter and AR Cohen have received research funding from Novartis for deferasirox trials. Honoraria Information: JB Porter has received honoraria from Novartis. Paid Export Testimony Information: JB Porter was an expert advisor to Novartis for registration of deferasirox in the US (FDA) and EU (EMEA). Membership Information: JB Porter has participated in Speakers’ Bureau for Novartis. MD Cappellini has taken part in advisory boards for deferasirox trial 107 (Novartis).