ReviewIron toxicity – Its effect on the bone marrow
Section snippets
The role of free iron on bone marrow function
Excess iron, caused by transfusion-related iron accumulation or increased absorption through the gut, can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Transferrin is the only protein in the body to transport iron and its saturation is an important source of systemic iron. In situations of transfusion dependency, transferrin becomes rapidly saturated (up to 70–80%) and the iron ion circulates freely in the plasma.
In the bone marrow, iron
Iron toxicity in MDS
MDS are a large heterogeneous group of hematopoietic stem cell malignancies characterized by ineffective hematopoiesis. As anemia is a common symptom, the majority of patients will become transfusion dependent leading to iron toxicity.
Oxidative stress and mitochondrial dysfunction appear to be involved in the pathogenesis of MDS, with increased levels of ROS and decreased glutathione (GSH) levels identified in blasts, erythroid precursors, and granulocytes from patients with MDS compared with
Iron toxicity in MF
Primary and secondary (post-essential thrombocythemia/polycythemia vera) MF is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and progressive cytopenias [13]. At diagnosis, approximately 40% of MF patients present with anemia (hemoglobin levels <10 g/dL) with around 25% already transfusion dependent [14]. >60% of patients develop clinically significant anemia during disease progression.
MF disorders are more complex than
Iron toxicity in AA
AA is a rare but heterogeneous disorder caused by failure of bone marrow development [17]. Immunosuppressive therapy, with anti-thymocyte globulin and cyclosporine, is recommended for patients with non-severe AA who are transfusion dependent, and for patients with severe AA who are >40 years of age or are younger but do not have a matched sibling donor for transplantation [17]. Supportive care with RBC and platelet transfusions is also essential to maintain adequate hemoglobin levels, but can
Iron chelation therapy in MDS
Iron chelation therapy has a positive impact on overall survival of patients with MDS and transfusion-related iron toxicity [[20], [21], [22]], with a number of early studies reporting a reduction in transfusion requirements and achievement of transfusion independence (albeit over a treatment period of 8–26 months) as well as an improvement in hematopoiesis, which was sometimes associated with increased platelet and neutrophil levels [[23], [24], [25]].
More recently, the effects of deferasirox
Iron chelation therapy in MF
Patients with primary MF frequently become transfusion dependent due to anemia, however the impact of iron chelation therapy in MF is not as well defined as it is in MDS. Nonetheless, case reports and case series or small single-center studies have demonstrated an improvement of hematological parameters and loss of transfusion dependency following iron chelation treatment with deferasirox in patients with primary MF [[36], [37], [38], [39]]. Positive outcomes were also shown in clinical
Iron chelation therapy in AA
In patients with AA, treatment with deferasirox was associated with a reduction in iron burden and may improve hematological parameters in a subset of patients (i.e. those without concomitant immunosuppressive treatment), as discussed below [41,42].
Deferasirox was an effective and well tolerated iron chelator in a sub-group analysis of 116 AA patients from the EPIC study [42]. Serum ferritin levels decreased significantly after 1 years' treatment (1854 vs 3254 ng/mL at baseline, p < 0.001) and
Iron toxicity and iron chelation therapy in patients undergoing hematopoietic stem cell transplantation
In patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), iron toxicity is frequently observed both pre- and post-transplantation due to the need for multiple blood transfusions in some patients, especially those with leukemia. Difficulties may arise as a result of impaired hematopoiesis after HSCT, as well as persistent neutropenia and thrombocytopenia. In addition, high levels of ferritin are associated with increased morbidity and mortality after transplantation, with
Discussion
In the hematopoietic stem cell niche there is a balance between hematopoietic stem cells and mesenchymal stem cells, which is regulated by the production of growth factors, cytokines and adhesion molecules with stimulating and inhibitory function. Hematopoietic improvement after iron chelation in patients with excess iron suggests iron toxicity may have a negative impact on the hematopoietic microenvironment. Importantly, preclinical studies in mouse models of iron overload are helping to
Conclusions
It is imperative to raise disease awareness of free iron and possible mechanisms of iron toxicity at the bone marrow level and in the bone marrow microenvironment. In order to do this, it is first necessary to understand the background and rationale of iron-mediated toxicity in all bone marrow failures. Preclinical studies, which have investigated the role of free iron on bone marrow function, have demonstrated that the presence of excess iron leads to the accumulation of ROS, interference of
Practice points
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Excess iron is toxic to both the bone marrow microenvironment and to hematopoietic stem cells
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Transfusion-dependent patients are at risk of transfusion-related iron accumulation and iron toxicity
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Treatment with deferasirox has been shown to alleviate transfusion dependency and may have a direct stimulatory effect on hematopoiesis
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The mechanisms through which deferasirox exerts this action are currently unknown
Research agenda
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Understand the background and rationale of iron-mediated toxicity in all bone marrow failures
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Investigate the mechanism by which deferasirox alleviates transfusion dependency and induces hematological responses
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Design an efficient strategy to reduce iron toxicity and enhance hematopoietic recovery after hematopoietic stem cell transplantation
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Develop a ‘bone marrow iron concentration’ score
Conflict of interest statement
The authors declare that they have no conflicts of interests.
Role of funding source
Novartis Farma, Italy, funded the assistance for medical writing.
Acknowledgements
The Authors thank Melanie Gatt (PhD), an independent medical writer, who provided medical writing assistance on behalf of Springer Healthcare Communications. This assistance was funded by Novartis Farma, Italy.
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