Combined chelation therapy with deferasirox and deferoxamine in thalassemia

Abstract

Iron overload is the primary cause of mortality and morbidity in thalassemia major despite advances in chelation therapy. We performed a pilot clinical trial to evaluate the safety and efficacy of combined therapy with deferasirox (DFX, 20-30 mg/kg daily) and deferoxamine (DFO, 35-50mg/kg on 3-7 days/week) in 22 patients with persistent iron overload or organ damage. In the 18 subjects completing 12 months of therapy, median liver iron concentration decreased by 31% from 17.4 mg/g (range 3.9-38.2mg/g) to 12.0mg/g (range 0.96-26.7 mg/g, p<0.001). Median ferritin decreased by 24% from 2465 ng/mL (range 1110-10,700 ng/mL) to 1875 ng/mL (range 421-5800 ng/mL, p=0.002). All 6 subjects with elevated myocardial iron showed improvement in MRI T2* (p=0.031). The mean±S.E. plasma non-transferrin-bound iron (NTBI) declined from 3.10±0.25μM to 2.15±0.29μM (p=0.028). The administration of DFX during infusion of DFO further lowered NTBI (-0.28±0.08 μM, p=0.004) and labile plasma iron (LPI, -0.03±0.01 μM, p=0.006). The simultaneous administration of DFO and DFX rapidly reduced systemic and myocardial iron, and provided an excellent control of the toxic labile plasma iron species without an increase in toxicity.

Trial registration: ClinicalTrials.gov NCT00901199.

Conflict of interest statement

Disclosure of Conflicts of Interest

E.V. has received consultancy fees and research funding from Novartis and reports membership of the Novartis Speakers’ Bureau. J.P. has received research funding from Novartis and reports membership of Novartis advisory boards and Speakers’ Bureau. P.H. has received research funding from Novartis.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1. Doses of deferoxamine and deferasirox

The median and range of doses of DFO (a) and DFX (b) at baseline, 6 months and end of therapy for group A (open symbols, n=7) and B (solid symbols, n=11). The average daily dose of DFO is shown in Figure 1a.

Figure 2. Improvement in systemic iron burden with combined chelation therapy

The magnitude of change in LIC (a) and ferritin (b) over 12 months is shown as decrease or increase in the measured value compared with baseline for each subject. The inset graph shows group medians and range. P values evaluate the significance of improvement in LIC at 6 months and 12 months.

Figure 2. Improvement in systemic iron burden with combined chelation therapy

The magnitude of change in LIC (a) and ferritin (b) over 12 months is shown as decrease or increase in the measured value compared with baseline for each subject. The inset graph shows group medians and range. P values evaluate the significance of improvement in LIC at 6 months and 12 months.

Figure 3. Control of plasma NTBI and LPI with combined chelation therapy

Trend in NTBI and LPI over 12 months is shown in figure 3a. Symbols represent means and standard error at 4 different visits. The baseline sample (solid symbols) was obtained 72 hours after stopping all chelation. Later samples (open symbols) were obtained 24 hours from the previous dose of DFX while infusing DFO. P values evaluate the significance of difference from baseline. The effect of DFX on NTBI in presence of DFO is shown in figure 3b. A decrease in NTBI was observed when DFX was administered alone (time 0) or during infusion of DFO (time 1, 6 and 12 months). Samples were drawn before and 2 hours following administration of DFX. P values evaluate the difference (post-pre) at each time point.

Figure 4. Monitoring for hepatic and renal toxicity

Median and range of alanine aminotransferase (a) and creatinine (b) at baseline and during study. The trend line connects the medians. Each time-point represents between 13-22 observations.