Invited reviewUpdated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome – Emphasis on optimized dosing schedules and new formulations
Introduction
Myelodysplastic syndromes (MDS) are bone marrow failures that show an increasing incidence in the elderly [1]. They are recognized as oligoclonal hematopoietic disorders characterized by peripheral cytopenias with anemias being the most prevalent cytopenic feature. The majority of patients is either transfusion dependent for red blood cells or becomes transfusion dependent during the course of the disease. Particularly patients with MDS and low risk for transformation into acute myeloid leukemia and low risk of early death will receive packed red blood cell (PRBC) transfusions on a regular basis, which puts them at high risk for transfusional iron overload (IOL) since the human organism has no natural means of removing excess iron. Transfusion dependence has been associated with negative impact on organ function and reduced life expectancy [2], [3], though data are conflicting [4].
IOL leads to deposition of iron in organs such as the liver, the heart and the endocrine glands. In patients with inherited anemias such as patients suffering from thalassemia or sickle cell disease, repetitive transfusions and consecutive IOL can cause organ damage leading to liver cirrhosis, cardiac failure or diabetes mellitus [5], [6], [7].
In addition to transfusion associated IOL, some patients with MDS exhibit high ferritin levels although they have never received any transfusions, indicating a disturbed iron metabolism. Advances in the understanding of iron physiology and pathophysiology suggest, that insufficient erythropoiesis in MDS patients leads to decreased hepcidin levels and consecutively increased intestinal iron absorption. In fact, the recently discovered erythroid regulator erythroferrone links aberrant erythropoiesis to hepcidin suppression with consecutive increased dietary iron absorption [8]. Of note, erythroid progenitors in MDS patients show a particularly high expression of erythroferrone, which provides a plausible explanation, that IOL can be evident in MDS patients, who never received any transfusions of PRBC [9].
The introduction of efficacious iron chelation with deferioxamine (DFO) improved the outcome of patients with transfusion dependent anemias such as thalassemia and sickle cell disease dramatically [5], [6]. This might be mainly due to the elimination of the so-called labile plasma iron (LPI), which catalyzes the generation of reactive oxygen species (ROS). ROS exert a high reactivity with cellular organelles and structures such as the plasma membrane, mitochondria, intracellular enzymes and nucleic acids inducing cellular dysfunction and cell death [10].
Although DFO has demonstrated high efficacy in treatment of IOL continuous and subcutaneous administration is necessary to provide sufficient coverage of LPI due to the short plasma half-life of DFO. It has been shown that this way of application is a major obstacle for providing a sufficient iron chelation (IC). Patients are affected by the inconvenient administration, which subsequently leads to lower adherence to the treatment and insufficient IC resulting in increased morbidity and mortality [5], [6]. Interestingly, IC has been shown to improve hematopoiesis in some patients [11], [12], [13]. Although the exact mechanism is not clear yet improvement of hematopoiesis might be due to a reduction of oxidative stress in hematopoietic progenitors in general and erythropoietic progenitors in particular [10].
Deferasirox (DFX) is an orally administered iron chelator, which has demonstrated high efficacy in reduction of iron burden in patients with transfusional IOL. The plasma half-life of DFX is approximately 13 h, which allows a once daily administration providing 24 h coverage of LPI [14]. It showed a similar efficacy in lowering iron burden as compared to DFO in MDS patients [15], [16].
Recently, several retrospective but also some prospective studies have indicated, that transfusion dependent patients with MDS might benefit from consequent iron chelation with regard to morbidity and mortality [17], [18], [19], [20], [21], [22], [23], [24]. However, gastrointestinal adverse events leading to reduced quality of life in these patients are associated with low treatment adherence and are considered as a major obstacle in achieving consequent and effective iron chelation with DFX. Here, we will update our recommendations on the management of gastrointestinal disturbances during treatment of iron-overloaded patients with MDS using DFX [25].
Section snippets
Potential benefits of iron chelation in transfusion dependent patients with MDS
It is well established that IOL has a deleterious effect in patients with inherited anemia, i.e. thalassemia and sickle cell disease. Introduction of iron chelation significantly improved survival in those patients by preventing particularly cardiac failure, but also hepatic and pancreatic damage and pituitary insufficiency [5], [6]. The effect of IOL in MDS patients, however, is controversial. The pros and cons for and against iron chelation range from consideration of excess iron as a toxin
Gastrointestinal disturbances during Deferasirox treatment
Although DFX is highly effective in removing excess iron from iron overloaded MDS patients, high dropout rates of approximately 50% of patients within one year were observed in the majority of clinical studies [30], [32], [33], [34]. The main reasons for discontinuation were adverse events, gastrointestinal in nature in the majority of patients as discussed below.
Gattermann et al. reported, that of 327 MDS patients 66% experienced adverse events, that were considered to be drug related.
Management of gastrointestinal adverse events
On July 18th 2014 an expert panel had an extensive discussion regarding optimal dosing schedules and procedures to manage gastrointestinal disturbances that frequently impair the success of iron chelation in iron overloaded MDS patients using DFX. The panel agreed that gastrointestinal disturbances interfere with the daily routines of the patients and affect their quality of life and should therefore be prevented as far as possible. If adverse events cannot be prevented they should be treated
Alternative iron chelators and new formulations of Deferasirox
In case DFX is judged inadequate in a patient, other chelators can be considered. As mentioned above, DFO has shown efficacy in patients with MDS and IOL. Nevertheless, treatment adherence to DFO often is hampered by the inconvenience of its administration i.e. continuous subcutaneous application for 24 h a day for several days. Deferiprone is another oral available iron chelator that is approved for treatment of IOL. Although it has shown its efficacy in removing excess iron, Deferiprone is
Brief summary and practical advice
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Data regarding IC in MDS patients are controversial, but multiple analyses suggest a benefit including erythroid improvement and transfusion independence.
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Patients should be informed in detail about the nature of gastrointestinal disturbances.
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DFX dosing should be done pre-prandial in the evening for patients with GI side effects.
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DFX should be initiated at low dose levels, e.g. 500 mg per day.
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Escalation of DFX dose to target dose should be done in a timely fashion.
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Target dose should be calculated
Acknowledgement
We thank Christiane Schumann for critically reviewing the manuscript.
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