Recent Developments in Iron Chelation Therapy

 

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Abstract

Since 1962, desferrioxamine (deferoxamine, DFO) has been utilized for the treatment of secondary hemosiderosis. For about 30 years, DFO therapy has been performed as nightly continuous subcutaneous infusion. About 20 years ago, the first oral iron chelator (deferiprone, DFP) was presented. Concerns about potential side effects were responsible for the late acceptance and license of this drug which is limited to the use as second-line therapy for patients with thalassemia major. During recent years, chelation therapy and its evaluation started to progress rapidly. Clinical research and drug development as well as the introduction of new methods for the assessment of iron overload contributed to these advances. By using cardiac T2^* MRI it was possible to examine the specific effect of a chelator on myocardial siderosis. Clinical studies using this method indicated superiority of DFP compared to DFO with respect to the treatment of myocardial siderosis. Several retrospective and first prospective clinical trials seem to confirm this observation.

In parallel, treatment strategies based on the combination of DFO and DFP have been developed. Using both drugs simultaneously or sequentially, additive and synergistic effects contribute to the fast elimination of iron from different organs at risk for siderotic damage.

Deferasirox (DSX) is a recently developed oral chelator which shows good efficacy and tolerability in patients with transfusional hemosiderosis due to various underlying disorders. Long-term studies will define the future importance of DSX for iron chelation treatment.

For the first time, there is a choice between three commercially available chelating agents for patients with transfusional iron overload. This will allow a highly effective, individually tailored treatment hopefully leading to a fundamental improvement of patients' life expectancy and quality.

Zusammenfassung

Seit 1962 wird Desferrioxamin (Deferoxamin, DFO) zur Behandlung der transfusionsbedingten Hämosiderose eingesetzt, seit fast dreißig Jahren in Form einer nächtlichen subkutanen Infusion. Große Hoffnungen wurden später in den vor 20 Jahren in Studien entwickelten, ersten oralen Chelatbildner Deferipron (DFP) gesetzt. Vor allem Bedenken hinsichtlich des Nebenwirkungspotentials führten zur späten Akzeptanz des Chelators und zur Begrenzung des Einsatzes von DFP auf die Sekundärtherapie bei Patienten mit Thalassaemia major.

In den letzten Jahren kam es zu Entwicklungen, die zu grundlegenden Änderungen der Therapie der transfusionsbedingten Eisenüberladung führen könnten. Neben neuen Medikamenten haben dazu auch neue Untersuchungsverfahren beigetragen, die es u.a. erstmals ermöglichen, den spezifischen Effekt von Chelatbildnern auf die Myokardsiderose zu untersuchen. So haben MRT-Studien Hinweise darauf ergeben, dass DFP in Bezug auf die Myokardsiderose eine im Vergleich zu DFO überlegene Wirksamkeit besitzt. Retrospektive Analysen sowie erste prospektive Studien scheinen dies zu bestätigen.

Parallel wurden Konzepte einer Behandlung mit einer Kombination von DFO und DFP entwickelt. Dabei tragen additive und synergistische Effekte dazu bei, in kurzer Zeit in verschiedenen gefährdeten Organen eine deutliche Eisenelimination zu erreichen.

Die jüngste Entwicklung ist die eines zweiten oralen Chelatbildners, des Deferasirox (DSX). Klinische Studien bei Patienten mit transfusionsbedingter Hämosiderose bei verschiedenen Grunderkrankungen ergaben eine gute Wirksamkeit und Verträglichkeit dieses Chelatbildners. Sollten Langzeitdaten die bisherigen Ergebnisse bestätigen, könnte DSX in zunehmendem Maße eine zentrale Rolle in der Eiseneliminationstherapie einnehmen. Nach vielen Jahren ist damit durch die genannten Entwicklungen erstmals eine Situation entstanden, in der der behandelnde Arzt die für seinen Patienten in einer bestimmten Situation bestgeeignete medikamentöse Eiseneliminationstherapie wählen kann.

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