Impact on Iron Removal of Dose Reduction for Non-Progressive Serum Creatinine Increases during Treatment with the Once-Daily, Oral Iron Chelator Deferasirox (Exjade®, ICL670).

Abstract

Introduction: During the deferasirox clinical development program, mild, non-progressive increases in serum creatinine >33% above baseline were observed in around one-third of patients receiving the chelator. Most increases resolved spontaneously, while the rest were managed by dose reduction. This post-hoc analysis evaluates the impact on efficacy of reducing deferasirox dose following increases in serum creatinine during 1-year core trials.Methods: Patients with a range of transfusion-dependent anemias, including β-thalassemia, sickle cell disease, myelodysplastic syndromes and other anemias, were enrolled into four trials. Creatinine and creatinine clearance levels were assessed monthly, and liver iron concentration (LIC) was measured at baseline and study end.Results: In total, 652 patients received treatment with deferasirox. Non-progressive creatinine increases >33% above baseline were noted in 237 (36.3%) patients, although these increases rarely exceeded the upper limit of normal (4.4%). These non-progressive increases generally occurred early, were dose- and iron intake-dependent, and were consistent across all ages and underlying anemias. Creatinine levels spontaneously reduced in 169 patients (71.3%); the remainder (n=68, 28.7%) underwent dose reduction by 5–10 mg/kg/day. Patients receiving high versus low doses and with low (<7 mL RBC/kg/month) versus high (>14 mL RBC/kg/month) transfusion rates tended to have the greatest and most rapid reductions in LIC. This greater velocity of iron removal tended to result in elevated creatinine levels. Patients with elevated creatinine who required dose reduction actually had more pronounced reductions in LIC than patients with no creatinine increase or with a creatinine increase that did not require dose reduction (Table).Change from baseline in LIC (mg Fe/g dw) by creatinine levelsInitial dose, mg/kg/dayNo creatinine increase (n=415)Creatinine increase (n=237)No dose reduction (n=169)Dose reduction (n=68)AllIron intake, mg/kg/day0.35 ± 0.150.34 ± 0.130.30 ± 0.11AllMedian0.4−3.2−6.9Range(−24.9–15.0)(−42.2–10.8)(−21.6–5.0)5Median4.92.10.8Range(−1.0–11.4)(2.1)(0.8)10Median1.30.2−1.0Range(−11.8–15.0)(−7.3–10.8)(−2.1–3.6)20Median0.0−1.9−3.9Range(−9.4–10.3)(−10.3–6.5)(−10.6–1.1)30Median−5.7−9.9−9.3Range(−24.9–13.3)(−42.2–8.6)(−21.6–5.0)Non-progressive increases in creatinine were more commonly observed in patients with an iron excretion/intake ratio >1.5 (14%) than in those with a ratio 1−1.5 (11%) or <1 (9%).Conclusions: An early-onset, non-progressive, dose- and iron intake-dependent increase in creatinine has been observed in around one-third of patients receiving deferasirox. Most of these increases resolved spontaneously, while the rest were manageable with dose reduction. As decreases in LIC were generally greatest in patients with increased creatinine levels, supported by the iron excretion/intake ratios, it is hypothesized that excessively rapid iron removal may modify renal hemodynamics. A reduction in deferasirox dose maintained efficacy, but allowed the dose to be tailored so that iron was removed at a rate appropriate for an individual patient.