Toward resolving the unsettled role of iron chelation therapy in myelodysplastic syndromes

Abstract

Transfusion dependent low risk myelodysplastic syndromes (MDS) patients, eventually develop iron overload. Iron toxicity, via oxidative stress, can damage cellular components and impact organ function. In thalassemia major patients, iron chelation therapy lowered iron levels with recovery of cardiac and liver functions and significant improvement in survival. Several noncontrolled studies show inferior survival in MDS patients with iron overload, including an increase in transplant-related mortality and infection risk while iron chelation appears to improve survival in both lower risk MDS patients and in stem cell transplant settings. Collated data are presented on the pathophysiological impact of iron overload; measuring techniques and chelating agents’ therapy positive impact on hematological status and overall survival are discussed. Although suggested by retrospective analyses, the lack of clear prospective data of the beneficial effects of iron chelation on morbidity and survival, the role of iron chelation therapy in MDS patients remains controversial.

Keywords::

• chelating agents
• deferasirox
• deferiprone
• deferoxamine
• iron
• myelodysplastic syndrome

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Approximately 60–80% of patients with myelodysplastic syndromes present with symptomatic anemia and, of these, 80–90% require packed red blood cell (RBC) transfusions as a mainstay of supportive therapy.

• In contrast to transferrin-bound iron, which is non-toxic, non-transferrin-bound iron or its labile low-molecular component labile iron pool, the chelatable labile iron pool, is toxic and participates in the production of harmful hydroxyl radicals.

• The simplest way to quantify iron overload is to count the number of RBC units that a patient has been transfused over time, evaluate serum ferritin levels, which correlate with body iron stores. MRI is a non-invasive method that can quantify hepatic and cardiac iron, replacing liver biopsy.

• Overall survival is adversely affected after receiving a median number of 21 RBC units with serum ferritin >1000 ng/ml. Transfusion dependency has negative impact on quality of life, with significant increases in prevalence of diabetes, hepatic diseases, cardiac-related events and increased risk of infections.

• Currently, three iron chelators are available for clinical use:

  • – Deferoxamine administered by subcutaneous infusion over 8–12 h 5–7 days a week. Patients treated with effective dose of deferoxamine have stabilized ferritin levels.

  • – Deferiprone, an oral agent administered three-times daily. Negative iron balance was achieved in most of the treated patients. Side effects were similar to that in thalassemia major, mostly gastrointestinal. Neutropenia was in 13% with 4% agranulocytosis.

  • – Deferasirox oral tablets for once-daily formulation dissolved in fruit juice, with reported compliance of greater than 80%. Side effects were rash, liver function disturbances and raised serum creatinine. Improvement of both erythroid and platelet counts has been reached rapidly after the starting of deferasirox.

• Transfusion-dependent myelodysplastic syndromes patients had reduced survival after transplantation. There are some guidelines recommending lowering iron body stores before transplantation to reduce toxicity.