Combination of Two Orally Active Iron Chelating Agents: Efficacy and Safety In a Clinical Setting

For patients with transfusion dependent anemias, in particular thalassemia major, as part of a compassionate –use program that was approved by the hospital's IRB, we report the efficacy and safety outcomes of combining therapy with deferasirox (DFX) and deferiprone (DFP). The combination of DFP and deferoxamine (DFO)has been shown to be effective in reducing cardiac iron overload but some patients are unable or unwilling to use DFO. DFP alone has also been reported to be cardioprotective. Based on concerns for their welfare in the presence of excessive cardiac iron load, a reduced left ventricular ejection fraction and either severe allergy or intolerance to DFO, 4 adult patients with thalassemia major have been treated with the combination of DFX and DFP for between 6 and 60 months (mean 18 months). All four patients were initially treated with DFO or DFX but DFP at 75–100 mg/kg/day was initiated because of severe cardiac iron overload. DFX at 15–40 mg/kg/day was added based upon high liver iron concentrations(LIC). Efficacy was evaluated by monthly ferritin levels and semiannual cardiac T2* and LIC estimates (using MRI R2 and R2*). All 4 patients had at least two MRI assessments. Table 1shows the changes in ferritin, cardiac T2*, LVEF and mean LIC. Cardiac T2* improved from 5.8 ±1.5 to 7.0 ± 1.5 ms., (p=0.15). If the T2* is recalculated as cardiac iron concentration then the change was from 4.1± 1.3 to 3.3± 1.1 mg/g dry weight (p=0.09). One patient who has been receiving the treatment for 6 months has shown a 1% per month deterioration in T2*. The patients who have been on the combination for 12, 24 and 60 months, have had reductions of 2.7%, 0.5% and 1.5% per month respectively. LVEF improved overall from the baseline value of 52.8% to 58.9% (p=0.02). Ferritin fell from a mean of 5826 to 5544 ng/L (p=0.86). LIC increased from a mean of 20.7 to 28.1 mg/g dry weight (p=0.36). Table 2 shows the baseline and minimum absolute neutrophil counts and baseline and final ALT (IU/L). No drug-related neutropenia (ANC of <1.5 ×10⁹/L), agranulocytosis or arthralgia were observed. No patients demonstrated significant proteinuria and mean creatinine levels were unchanged. ALT's showed fluctuations that were compatible with the degree of LIC. It is important to note that compliance was extremely variable in that one patient (P3), only took DFX once monthly with many lapses in her DFP treatment as well. The other patients also had significant lapses in their compliance as well as long vacation periods during which they did not receive treatment. These results indicate that the combined use of the two oral chelators (DFP & DFX) prevented further cardiac iron loading with a tendency for its reduction, significant improvement in left ventricular ejection fraction, maintenance of ferritin levels and LIC. It is also possible that the DFP cardioprotective effect may be activated even in the presence of poor compliance with it. The combination was well tolerated and easier to manage. It is more acceptable for life-long chelation and positively influenced patients’ quality of life. It seems likely that maximum doses of both medications need to be prescribed for better outcomes and longer periods of follow up are essential. In particular, a prospective randomized study in patients with excessive cardiac iron will be necessary before this combination could be considered standard therapy.

Berdoukas:ApoPharma Inc.: Consultancy. Wood:Novartis Inc.: Research Funding; ApoPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coates:Novartis: Research Funding, Speakers Bureau.