Abstract

Background: Maintaining SF levels below 1000 ng/mL offers significant clinical benefits in patients with transfusional iron overload. However, low SF levels can be associated with an increased risk for iron chelator toxicity. This analysis was performed to assess safety parameters during deferasirox treatment in patients with transfusion-dependent anemias who reached SF levels ≤1000 ng/mL on at least two consecutive visits during the extension phases of four core studies.

Methods: Patients (≥2 years old) with β-thalassemia, MDS, sickle cell disease or other transfusion-dependent anemias enrolled in four clinical trials were treated for 1 year with deferasirox 5–30 mg/kg/d, followed by extension phases of 4 years. In the extension phases, patients either continued receiving deferasirox (deferasirox cohort) or crossed over from DFO to deferasirox (crossover cohort), while receiving dose modifications based on efficacy and safety parameters. Efficacy was monitored by monthly SF readings; safety was assessed by the incidence and type of adverse events (AEs).

Results: Following dose adjustments at the end of the core trials, 163/652 (25%) patients in the deferasirox cohort reached SF levels ≤1000 ng/mL on at least two consecutive visits after a median of 1.2 years on deferasirox therapy. Median SF levels over the course of the studies are presented in Table. At month 22, the overall mean dose was 20 mg/kg/d, which was generally maintained in all dose groups until month 42. At baseline, overall mean (±SD) ALT and AST values were 44.2 (36.2) and 39.2 (27.4) U/L, respectively. Overall ALT and AST levels decreased by 16.5 (±38.7) and 11.7 (±30.5) U/L, respectively, at month 42.

Median SF (ng/mL)

Initial dose group
Month5 and 10 mg/kg/d20 mg/kg/d30 mg/kg/d
(n)(n)(n)
*Dose modifications to most appropriate dose 
Baseline 1295 (55) 1520 (43) 2311 (65) 
1475 (54) 1616 (42) 2284 (65) 
1612 (54) 1383 (39) 1596 (60) 
12* 1697 (53) 1165 (42) 1168 (62) 
18 1818 (45) 1362 (39) 1307 (51) 
24 1287 (49) 1161 (34) 1236 (52) 
30 966 (44) 1046 (33) 1047 (54) 
36 788 (37) 1010 (30) 991 (50) 
42 884 (37) 1040 (34) 850 (50) 
Initial dose group
Month5 and 10 mg/kg/d20 mg/kg/d30 mg/kg/d
(n)(n)(n)
*Dose modifications to most appropriate dose 
Baseline 1295 (55) 1520 (43) 2311 (65) 
1475 (54) 1616 (42) 2284 (65) 
1612 (54) 1383 (39) 1596 (60) 
12* 1697 (53) 1165 (42) 1168 (62) 
18 1818 (45) 1362 (39) 1307 (51) 
24 1287 (49) 1161 (34) 1236 (52) 
30 966 (44) 1046 (33) 1047 (54) 
36 788 (37) 1010 (30) 991 (50) 
42 884 (37) 1040 (34) 850 (50) 

10 (6.1%) patients experienced two consecutive serum creatinine increases >33% above baseline and >ULN. Most of these increases were only marginally >ULN and none were >2 x ULN. Creatinine increases were non-progressive and generally fell promptly following dose reductions of 5–10 mg/kg/d. No new AEs or safety concerns have been reported thus far in this population.

Conclusions: With appropriate deferasirox dosing, iron overloaded patients can effectively achieve and maintain low SF levels. There were no major safety issues observed in achieving SF levels of ≤1000 ng/mL in this population. Decreases in liver enzymes suggest improvement in liver function, probably as a result of reduced iron burden.

Author notes

Disclosure:Employment: JM Ford and B Rabault are employees of Novartis. Consultancy: J Porter and E Vichinsky are consultants for Novartis. Research Funding: J Porter has received research funding from Novartis. E Vichinsky is a research investigator for Novartis. Honoraria Information: J Porter and E Vichinsky have received honoraria from Novartis. Paid Export Testimony Information: J 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). J Porter has participated in Speakers’ bureau for Novartis.