Abstract
Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels <1000 ng/mL.
Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level <1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was <1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of <1000 ng/mL, irrespective of future SF levels.
Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF<1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level <1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value <1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the <1000 and >1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown).
Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels <1000 ng/mL and patients who did not
. | Patients who achieved SF <1000 ng/mL . | Patients who did not achieve SF <1000 ng/mL . |
---|---|---|
*Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase | ||
n | 174 | 300 |
Male:female | 85:89 | 145:155 |
Mean age ± SD, years | 23.8 ± 16.7 | 23.5 ± 18.2 |
<16, n (%) | 65 (37.4) | 123 (41.0) |
≥16, n (%) | 109 (62.6) | 177 (59.0) |
Enrolled from study 107:108 | 120:54 | 175:125 |
Median exposure to deferasirox, months | 56.3 | 45.2 |
Mean actual deferasirox dose, mg/kg/day | 20.3 | 22.9 |
Median baseline SF, ng/mL | 1791 | 2883 |
Drug-related AEs* (≥5% in either group), n (%) | ||
Nausea | 26 (14.9) | 38 (12.7) |
Diarrhea | 17 (9.8) | 42 (14.0) |
Vomiting | 14 (8.0) | 25 (8.3) |
Abdominal pain | 12 (6.9) | 32 (10.7) |
Upper abdominal pain | 6 (3.4) | 20 (6.7) |
Rash | 9 (5.2) | 16 (5.3) |
Audiological abnormalities | 7 (4.0) | 4 (1.3) |
Ophthalmological abnormalities | 4 (2.3) | 5 (1.7) |
Two consecutive SCr increases >33% above baseline and above ULN | 26 (14.9) | 36 (12.0) |
Increase in ALT >10×ULN on at least 1 visit | 12 (6.9) | 20 (6.7) |
Baseline levels elevated | 6 (3.4) | 16 (5.3) |
. | Patients who achieved SF <1000 ng/mL . | Patients who did not achieve SF <1000 ng/mL . |
---|---|---|
*Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase | ||
n | 174 | 300 |
Male:female | 85:89 | 145:155 |
Mean age ± SD, years | 23.8 ± 16.7 | 23.5 ± 18.2 |
<16, n (%) | 65 (37.4) | 123 (41.0) |
≥16, n (%) | 109 (62.6) | 177 (59.0) |
Enrolled from study 107:108 | 120:54 | 175:125 |
Median exposure to deferasirox, months | 56.3 | 45.2 |
Mean actual deferasirox dose, mg/kg/day | 20.3 | 22.9 |
Median baseline SF, ng/mL | 1791 | 2883 |
Drug-related AEs* (≥5% in either group), n (%) | ||
Nausea | 26 (14.9) | 38 (12.7) |
Diarrhea | 17 (9.8) | 42 (14.0) |
Vomiting | 14 (8.0) | 25 (8.3) |
Abdominal pain | 12 (6.9) | 32 (10.7) |
Upper abdominal pain | 6 (3.4) | 20 (6.7) |
Rash | 9 (5.2) | 16 (5.3) |
Audiological abnormalities | 7 (4.0) | 4 (1.3) |
Ophthalmological abnormalities | 4 (2.3) | 5 (1.7) |
Two consecutive SCr increases >33% above baseline and above ULN | 26 (14.9) | 36 (12.0) |
Increase in ALT >10×ULN on at least 1 visit | 12 (6.9) | 20 (6.7) |
Baseline levels elevated | 6 (3.4) | 16 (5.3) |
Conclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels <1000 ng/mL was similar to that observed in patients who did not achieve SF levels <1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels <1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases >33% above baseline and ULN or with ALTs >10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.
Disclosures: Porter:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Membership on an entity’s Board of Directors or advisory committees. Piga:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cohen:Apotex: Member of DSMB, Membership on an entity’s Board of Directors or advisory committees; Novartis: Research Funding. Ford:Novartis: Employment, Equity Ownership. Bodner:Novartis: Employment. Rojkjaer:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.
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