Intraindividual Comparison between Deferasirox and Deferoxamine in Thalassemia.
Authors: Fischer Roland , Grosse Regine , Engelhardt Rainer , Nielsen Peter , Leismann Oliver , Janka Gritta E. 
Published: October 2019

Abstract
In patients with iron overload from chronic blood (RBC) transfusion a new era of chelation treatment has been started with the availability of 3 chelators, their combinations, and other potential modifiers of tissue iron distribution. The decision about the chelator type and its dose would be facilitated if a mean chelation response could be forecasted. With the knowledge of a chelator’s molar efficacy, one could calculate the dose necessary to compete with the iron influx from blood transfusions. An open compartment model as developed for deferoxamine (DFO) and deferiprone (DFP) (Brit J Haematol2003;121:938–48) would additionally allow to forecast the total body iron store for a given blood transfusion and chelator dose rate over time, also for deferasirox. In a prospective study of the oral chelator deferasirox (DSX, Exjade®), 17 patients with b-thalassemia (age: 4 – 32 y) have been followed for 8 to 38 months by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months. Retrospectively, the same patients were followed in the past during s.c. DFO treatment. Liver iron concentration LIC, liver volumes, RBC transfusion and chelation dose rates were assessed. Of major importance was the stability of the hematocrit in the RBC units used in our department of 60 ± 3% over more than 6 years. Total body iron stores were calculated from total liver iron taking into account that 80 ± 10% of the total body storage iron is accumulated in the liver. For each measurement interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron stores per interval time, and the molar dose rate of DFO or DSX. Additionally, total body iron elimination (TBIE) rate constants were calculated for each interval and fitted as function of the chelatable iron pool. LIC values, liver volumes, and ferritin levels were measured in the range of 498–8009 μg/g-liver, 654-3208 ml, and between 787 and 14866 μg/l. During DSX and DFO treatment, molar chelation efficacies of 11.2–53.1% and 6.1–23.7% were found for mean dose rates of 0.5–3.2 mmol/d (21–39 mg/kg/d) and 0.9–5.2 mmol/d (25–53 mg/kg/d) applied to iron influx rates of 7.6–30.6 mg/d and 9.7–28.5 mg/d from blood transfusion, respectively. In 6/17 (13/15 for DFO) patients with at least 3 treatment intervals, the intraindividual the molar efficacy ranged from 13.3±1.9% to 39.0±7.2% for DSX and from 7.8±2.0% to 19.4±2.9% for DFO in the same patients. Compliance assessed from tablet count protocols (> 90%) did not influence these data significantly. The mean molar efficacies of 29±10% and 15±5% in our patient group agreed with reference values (Blood2005;106(11):#2690 and Brit J Haematol2003;121:938–48) for DSX and DFO, respectively. In contrast to DFO and DFP, the compartment model calculations resulted in a linear function of the TBIE rate constant for DSX with no saturation effect over the whole range of chelator doses and LIC. In summary, deferasirox was as efficient as deferoxamine at only half the molar dose even on an intraindividual patient basis. Once the individual molar efficacy has been assessed, a minimum chelator dose can be calculated to compete with the daily iron input from blood transfusions. The compartment model parameters of the total body iron elimination rate constant for deferasirox may allow to forecast the gross time pattern of liver iron concentration changes for practical treatment periods.