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Iron Chelation Therapy for patients with MyeloDysplastic Syndrome: important or nonsense?

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Marlijn Hoeks

MD, PhD internist-hematologist

29 October 2020

The question whether iron chelation therapy is beneficial for regularly transfused patients with myelodysplastic syndrome (MDS) is still ‘hot and happening’. This blog provides the most recent insights.

Iron is a vital nutrient for the human body and essential for many physiological processes. When too much iron is present, iron will overload the proteins that can safely transport iron, and consequently free iron will be present in the body. Free iron molecules are readily taken in by body tissues where it can lead to organ and DNA damage.

Red blood cell transfusion still is the cornerstone of supportive care in MDS patients. One bag of red cells contains approximately 200-250 mg of iron. As the body has no means of naturally removing iron when it comes in directly to the blood, regular red blood cell transfusions will lead to iron overload. Iron overload already occurs when receiving 20 to 30 red blood cell transfusions. Importantly, iron overload is a potential problem for frequently transfused patients as it may cause significant organ damage to for example liver and heart and is additionally associated with shorter survival. Moreover, long-standing anemia leads to muscle changes in the heart, iron overload may therefore be an additional risk factor for the occurrence of heart failure, which is the most common non-leukemic cause of death among MDS patients, mostly seen in transfusion-dependent patients. In a recent EUMDS-MDS RIGHT study, we observed that high toxic iron values were indeed associated with a worse survival in lower-risk MDS patients. Those high values were observed in all subgroups, but especially in transfused patients and in patients who have ring sideroblasts.

If iron overload is a problem, how can we solve it?

First, the transfusion scheme must be tailored for the individual patient. It is important to maintain a certain level of quality of life, and deal with iron overload early in the treatment course. In future research we will pay attention to the optimal transfusion scheme for MDS patients also with respect to functional outcomes.

Secondly, iron chelation therapy can be considered. Iron chelation therapy frees iron from the body stores and enhances excretion via the gut. Currently, three iron chelators are available: desferoxamine (Desferal®), deferiprone (Ferriprox®), deferasirox (Exjade®) of which the first is administered subcutaneously or intravenously and the latter two are administered orally. Iron chelation therapy improves overall survival in other patient groups like thalassemia patients, but whether this is also the case in lower-risk MDS patients, was not clear until recently due to many small and/or poorly executed studies.

Everyone was very hopeful in receiving an answer to this important question with the publication of the results of the ‘TELESTO’ trial. This is a randomized controlled trial evaluating survival and safety of deferasirox in lower-risk MDS patients. The results showed a longer ‘event-free’ survival (survival and non-fatal events as cardiac and liver dysfunction and disease progression) of 36.4% in the chelated group as compared with the non-chelated group. The overall survival of both groups did not differ significantly. The results of the ‘TELESTO’ trial, however, may not represent ‘real life’ of mostly older patients usually with multiple comorbidities, as reflected by the relatively young age (61 years) of the participants of the ‘TELESTO’ trial. There were also problems with slow recruitment of patients leading to a change in study design, which then affected the statistical power of the study.

In order to give a better answer to the questions whether iron chelation therapy is beneficial in lower-risk MDS patients, we designed a large, observational study within the EUMDS registry in which we reliably compared chelated and non-chelated patients by taking all kinds of confounding factors into account. We observed a significantly better survival in the patients who received iron chelation therapy. Interestingly, up to 39% of the chelated patients had improved hemoglobin levels when using iron chelation therapy of which some patient reached  transfusion independence. The advantage of our study is that we evaluated ‘real life’ patients, which makes the results generalizable to clinical practice. We conclude that iron chelation therapy may improve survival and hematopoiesis in transfused lower-risk MDS patients.

 

In summary, iron overload is an important problem for transfused lower-risk MDS patients as well as patients who have ring sideroblasts. Smart red blood cell transfusion strategies and early start of iron chelation therapy must be considered in this patient group. My advice to patients is to discuss with your hematologist whether iron chelation therapy would be beneficial in your case.

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