Elsevier

Blood Reviews

Volume 32, Issue 6, November 2018, Pages 473-479
Blood Reviews

Review
Iron toxicity – Its effect on the bone marrow

https://doi.org/10.1016/j.blre.2018.04.004Get rights and content

Abstract

Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment.

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

  • Excess iron is toxic to both the bone marrow microenvironment and to hematopoietic stem cells

  • Transfusion-dependent patients are at risk of transfusion-related iron accumulation and iron toxicity

  • Treatment with deferasirox has been shown to alleviate transfusion dependency and may have a direct stimulatory effect on hematopoiesis

  • The mechanisms through which deferasirox exerts this action are currently unknown

Research agenda

  • Understand the background and rationale of iron-mediated toxicity in all bone marrow failures

  • Investigate the mechanism by which deferasirox alleviates transfusion dependency and induces hematological responses

  • Design an efficient strategy to reduce iron toxicity and enhance hematopoietic recovery after hematopoietic stem cell transplantation

  • 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.

References (51)

  • S.C. Meyer et al.

    Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation

    Biol Blood Marrow Transplant

    (2013)
  • S. Shapira et al.

    Selective death of leukemia initiating cells induced by Deferasirox

    Blood

    (2016)
  • B.D. Cheson et al.

    Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia

    Blood

    (2006)
  • B.D. Cheson et al.

    Report of an international working group to standardize response criteria for myelodysplastic syndromes

    Blood

    (2000)
  • W. Lu et al.

    Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells in vitro and suppresses hematopoiesis in iron overload patients

    Eur J Haematol

    (2013)
  • X. Chai et al.

    ROS-mediated iron overload injures the hematopoiesis of bone marrow by damaging hematopoietic stem/progenitor cells in mice

    Sci Rep

    (2015)
  • Y. Zhang et al.

    Effects of iron overload on the bone marrow microenvironment in mice

    PLoS One

    (2015)
  • H. Okabe et al.

    The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice

    Eur J Haematol

    (2014)
  • A. Pardanani et al.

    Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis

    Am J Hematol

    (2013)
  • A. Banerjee et al.

    The oral iron chelator deferasirox inhibits NF-kappaB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia

    Br J Haematol

    (2015)
  • M. Meunier et al.

    Reactive oxygen species levels control NF-kappaB activation by low dose deferasirox in erythroid progenitors of low risk myelodysplastic syndromes

    Oncotarget

    (2017)
  • A.C. Gonçalves et al.

    Oxidative stress and mitochondrial dysfunction play a role in myelodysplastic syndrome development, diagnosis, and prognosis: a pilot study

    Free Radic Res

    (2015)
  • V. Santini et al.

    Hepcidin levels and their determinants in different types of myelodysplastic syndromes

    PLoS One

    (2011)
  • I. Ambaglio et al.

    Inappropriately low hepcidin levels in patients with myelodysplastic syndrome carrying a somatic mutation of SF3B1

    Haematologica

    (2013)
  • H.C. Hasselbalch et al.

    Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression

    PLoS One

    (2014)
  • Cited by (0)

    View full text