Single-center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox

Abstract

Background Iron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as “last resort” therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic. Methods and findings Under an IRB-approved study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox. Results Although deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2–18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1–6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron. Conclusions Deferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the ...

The History of Deferiprone (L1) and the Complete Treatment of Iron Overload in Thalassaemia

“…Such debates are mostly focused on past practises of ineffective therapies and not issues associated with the current "golden era" period of iron chelation therapy in thalassaemia, namely the achievement and maintenance of normal iron stores. [81][82][83][128][129][130][131] The molecular, therapeutic, and other properties of L1 as a potent chelator and antioxidant with access to most tissues and organs make it a unique pharmaceutical with broad spectrum clinical applications. 75,95 This prospect/dilemma is similar to that of the introduction of L1 as the first oral iron chelating drug about 30 years ago and needs further investigations to be confirmed.…”

Institutional conflict of interest: attempting to crack the deferiprone mystery

“…The PLOS ONE Study data3 show that, after Olivieri’s dismissal from her position as Director, the UHN thalassaemia Clinic began almost immediately to switch patients to (unlicensed) deferiprone. Olivieri has described how her UHN research work, from this time forward, was marginalised (https://inthepatientsinterest.org/wp-content/uploads/2019/12/2018-12-20-GallieOlivieri-to-SmithHodges.pdf).…”

“…The ethical concern is to explain and to explore possible justifications for how and why so many patients at one particular thalassaemia treatment centre were prescribed a drug whose safety and efficacy were unproven in face of availability of licensed effective drugs. The urgency of the concern derives partly from the paper’s finding that those patients who were switched to deferiprone displayed evidence of increases in body iron and experienced the harms associated with body iron increase 3. This finding raises a second troubling ethical question: Why were patients not switched back to a first-line licensed therapy after they began to experience serious adverse effects from treatment with unlicensed deferiprone?…”

“…Under the SAP, the treating physician must confirm to Health Canada that ‘conventional therapies have failed, or are unsuitable or unavailable’. Although some of the UHN patients’ records indicate that deferiprone was released under the SAP, Olivieri et al report that they ‘could identify no explanation for a proposed switch to deferiprone that was supported by evidence of failure of licensed therapy prescribed as recommended’3; indeed, the authors write that many patients appear to have been switched to deferiprone despite optimal responses, or improvements during treatment with first-line therapies. Here’s the relevant paragraph from their PLOS ONE article:…”

“…A newly published study by Olivieri, Sabouhanian and Gallie3 analyses and assesses the comparative efficacy and safety profile of two drugs: deferiprone (Ferriprox; Apotex) and deferasirox (Exfade; Novartis). Both of these ‘iron-chelating’ drugs remove (‘chelate’) iron deposited, as a result of transfusions, in the tissues of patients with thalassaemia.…”