Efficacy and Safety of Deferasirox (Exjade®) in Patients with Transfusion- Dependent Anemias: Preliminary Results From the First, Retrospective, Multicenter Brazilian Study.
Authors: Cancado Rodolfo , Nicolau Jose E. , Fabron Antonio , França Ana CCV , Angulo Ivan L. , Brunetta Denise , Favarin Maria C. , Pinto Ana CS , Carboni Edna K. , Valdez Luciane , Magalhães Silvia M. M. , Costa Clara MBE , Araújo Ana ALB , Moreira Camila LNSO , Tavares Renato S. , Neto Abrahão E. Hallack , Lobo Clarisse , Pessoa Viviani , Cunha Carolina , Araújo Aderson , Peres Jaqueline C. , Cruz Sonia MP , Nicolau Dario I. , Sousa Aminadab F. , Pereira Victor H. R. L. , Lehugeur Denise , Daudt Liane , Friedrisch João R. , Silla Lúcia MR , Chiattone Carlos 
Published: October 2019

Abstract
Abstract 5096

Background
Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. The retrospective multicenter Brazilian trial included patients (pts) from 14 sites of 10 states with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. Data were available from 105 eligible pts at 6 months of treatment and 73 pts from 1-year follow-up period.

Methods
Pts (aged ≥ 2 yrs) had transfusion-dependent anemia with a history of multiple transfusions (>20 transfusions) and/or SF levels ≥ 1000 ng/mL and serum creatinine level < the upper limit of normal (ULN). Deferasirox starting dose was 10-30mg/kg/day depending on transfusion requirements and subsequent dose adjustments of 5-10 mg/Kg/day (range 0–35 mg/kg/d) were done every 3 months based on changes in SF and safety parameters. Efficacy was assessed monthly by measuring change from baseline in SF levels. Safety was evaluated on a monthly basis according to the incidence and type of adverse events and measurement of laboratory parameters, including serum creatinine and liver enzyme levels.

Results
105 pts (40 M, 65 F; mean age 25.0±16.6 yrs) were enrolled; 46% (n=48) aged <20 yrs; 54% Afro-descendant (n=57). Underlying anemias were: sickle cell disease (n=59), β-thalassemia (n=32), myelodysplastic syndromes (n=6) and other conditions associated with anemia (n=8). Most pts (79%, n=83) had received > 40 units of red blood cell (RBC); 71.5% (n=75) were on regular RBC transfusion, 56% of the pts required < 2 RBC units/month and 44% between 2 and 4 RBC units/month. Only 63% (n=66) had received prior chelation therapy: deferoxamine (DFO; 51.4%) or DFO/deferiprone combination (11.4%). Sixty-four (61%) pts started on 20 mg/kg/d and 41(39%) > 20-30 mg/kg/d, 15.2% of pts had dose increases at a median of 24 weeks after treatment initiation. Mean ± SD SF levels (μg/L) did significantly reduce at 6 months and 12 months compared to baseline (BL) [from 3132.14 ± 2237.47 to 2784.25 ± 1969.7 at 6 months (p=0.0001) and 2327.46 ± 1873.8 at 12 months (p=0.005)]. The proportion of patients with SF levels < 2000, 2000-3000 and > 3000 μg/L from BL to 6 and 12 months by percentage of patients changed from 36% to 47.5% and 52%; from 26% to 26.5% and 24.5%; from 38% to 26% and 23%, respectively. No patient discontinued the treatment. No death was reported by the investigators during the study. The most common drug-related (investigator-assessed) AEs were mild, transient diarrhea (n=15; 14.3%), rash (n=5; 4.7%), nausea (n=9; 8.5%) and headache (n=6; 5.7%). Seven pts (6.6%) had serum creatinine value >33% above BL on two consecutive visits, 3 (2.8%) of whom had creatinine increases above the ULN; there were no progressive increases or renal failure. Eleven (10.5%) pts had an increase in alanine aminotransferase < 5x ULN but no one experience increases ≥ 5x ULN; levels were already elevated in all of them.

Conclusions
This first multicenter Brazilian study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated in pediatric and adult pts with a safety profile consistent with data from previous clinical trials. The availability of deferasirox as a once-daily oral iron chelator would potentially facilitate improved compliance, and thereby reduce morbidity and mortality from iron overload.

Disclosures
No relevant conflicts of interest to declare.