Optimizing the Use of Deferasirox: Evidence of Synergy When Combined with Deferoxamine
Authors: Grady Robert W , Galanello Renzo , Kleinert Dorothy A , Paley Carole S. , Giardina Patricia J. 
Published: October 2019

Abstract
Abstract 5163

Introduction:
Deferasirox (Exjade, ICL670) is an orally effective iron chelating agent approved for use in patients 2 years of age and older with transfusional iron overload. While it is effective as a single agent, there are patients who do not attain net negative iron balance despite being at the upper limit of approved dosing (40 mg/kg/day). Deferiprone (Ferriprox, L1) is another orally effective iron chelator. Through a series of metabolic iron balance studies we were able to demonstrate that various regimens involving the combined use of deferiprone and deferoxamine (Desferal, DFO) were capable of placing all patients into net negative iron balance with the potential to adjust dosing schedules and the ratio of drugs to maximize effectiveness while minimizing toxicity. A variety of such regimens are now in widespread clinical use. We have taken the same approach in order to optimize the use of deferasirox.

Methods:
Six patients with thalassemia major were enrolled in a 34-day metabolic iron balance study wherein deferasirox and deferoxamine were evaluated alone and in combination, each patient serving as his/her own control. Deferoxamine (40 mg/kg) was administered on days 5 – 10 as an 8-hour subcutaneous infusion during the night. On days 15 – 20, deferasirox (30 mg/kg) was given orally, 30 minutes prior to breakfast. Both drugs were given on days 25 – 30, the same doses and dosing schedules being employed. Non drug days allowed for washout of stool iron induced by the previous treatment. The patients consumed a fixed low-iron diet consisting of four individualized meal plans. Daily collections of urine and stool were made and their iron content determined by atomic absorption, a correction being made for all uneaten food.

Results:
As in previous studies, there was significant patient to patient variability in terms of the amount of drug-induced iron excretion. Combination therapy placed all patients into iron balance exceeding 200% (206% - 270%, mean 251%). The combination was synergistic in two patients (35% and 57%), additive in three patients, and less than additive in one patient. Where iron excretion was more than additive, all of the excess appeared in the urine (a 2.1- and 3.4-fold increase). Deferasirox proved to be less effective than deferoxamine in all six patients (relative iron excretion: 23% - 59%, mean 42%), stool iron excretion in response to the respective drugs being 94% -100% (mean 98%) and 49% - 74% (mean 59%). Net negative iron balance was achieved in 2/6 patients when on deferasirox (iron balance 28% - 129%, mean 72%) and 6/6 patients when infusing deferoxamine (iron balance 125% - 219%, mean 167%).

Discussion:
These results suggest that chelation therapy can be tailored to the individual needs of each patient, selectively removing iron from different pools while minimizing any side effects. Deferasirox appears to shuttle iron to deferoxamine for excretion in the urine, not unlike the situation when deferiprone and deferoxamine are combined, although the source of the iron may be somewhat different. It is hoped that these results will provide patients with further options to optimize their chelation regimens.

Disclosures:
Grady: Novartis Pharmaceuticals: Research Funding. Off Label Use: Deferasirox and Deferoxamine are both iron chelating agents. Their use in combination is not indicated on their labeling. Galanello:Novartis Pharmaceuticals: Speakers Bureau. Paley:Novartis Pharmaceuticals: Employment. Giardina:Novartis Pharmaceuticals: Research Funding.