A Randomized, Controlled Phase II Trial in Sickle Cell Disease Patients with Chronic Iron Overload Demonstrates That the Once-Daily Oral Iron Chelator Deferasirox (Exjade®, ICL670) Is Well Tolerated and Reduces Iron Burden.
Authors: Vichinsky E. , Fischer R. , Fung E. , Onyekwere O. , Porter J. , Swerdlow P. , Coates T. , Lane P. , Files B. , Mueller B. U. , Bernaudin F. , Forni G. L. , Ressayre-Djaffer C. , Gathmann I. , Holland J. , Alberti D. , Marks P. 
Published: April 2020

Abstract
Repeated blood transfusion to prevent complications places patients with sickle cell disease at risk for morbidity from chronic iron overload. Parenteral chelation with deferoxamine (DFO) is effective at reducing iron overload but patient compliance is generally poor. Deferasirox (DSX) is an investigational iron chelator given orally once-daily.
Demonstration of the safety and tolerability of DSX over a 1-year period was the primary objective and efficacy was a secondary objective of the study. Adult and pediatric patients (n=195; n=98 aged &lt;16) were randomized 2:1 to receive treatment with DSX (n=132) or DFO (n=63). Dosing of DSX from 5 to 30 mg/kg/day and DFO from 20 to 60 mg/kg/day was based upon baseline liver iron concentration (LIC) as determined by liver susceptometry using a superconducting quantum interference device (SQUID). Initial DSX doses &lt;20 mg/kg were increased midway through the trial based upon emerging data from other DSX trials. Safety assessments included hematology, chemistry, eye exams, hearing tests and ECGs. Efficacy was measured by LIC, change in serum ferritin, and iron balance.
Discontinuations were similar in the DSX and DFO groups (11.4 vs 11.1%). The mean ± SD doses of DSX and DFO given were 17.3 ± 6.0 and 36.0 ± 11.4 mg/kg, and transfusional iron intake was 0.21 ± 0.13 and 0.23 ± 0.12 mg/kg/day, respectively. The most common adverse events associated with DSX were generally mild and consisted of nausea, vomiting, diarrhea, abdominal pain and skin rash. Mild non-progressive increases in serum creatinine greater than 33% of baseline and above the upper limit of normal were observed in three patients receiving DSX. One patient on DSX developed an elevated ALT most likely related to drug administration that resolved with its discontinuation.
Median mg/kg/day Parameter n Mean ± SD n Mean ± SD DSX DFO DSX DFO LIC change (mg Fe/g dw) 113 −1.3 ± 3.1 54 −0.7 ± 2.6 16.7 32.7 Ferritin change (μg/L) 83 −183 ± 1651 33 −558 ± 951 Ratio iron excretion/intake 105 1.14 ± 0.60 52 1.20 ± 0.78
With both DSX and DFO there was a statistically significant reduction in LIC from baseline (P&lt;0.0001 for DSX, P=0.022 for DFO). Efficacy of DSX and DFO was similar after 1 year of therapy. A dose-effect relationship was observed: patients assigned to receive DSX 30 mg/kg and DFO ≥ 50 mg/kg had an absolute change in serum ferritin of −1196 ± 2674 (n=10) and −936 ± 1115 μ g/L (n=7), respectively. Although serum ferritin varied during the trial with both treatments, the reduction at end of study was consistent with the effect on LIC. The ratio of iron excretion to iron intake of &gt;1 also indicates that DSX was able to induce negative body iron balance. Once-daily oral DSX is well tolerated and appears to have similar efficacy to DFO in reducing iron burden in transfused patients with sickle cell disease.