Hematology, IRCCS Azienda Ospedaliera Universitaria San Martino – IST
Istituto Nazionale per la Ricerca sul Cancro, Genova. Italy.
2 Hematology and Bone Marrow Transplantation Unit, Ospedale Oncologico di Riferimento Regionale “Armando Businco”, Cagliari, Italy.
3 CRS4, Biomedicine Sector, Scientific and Technology Park of Sardinia, Pula, Cagliari, Italy;
4 Internal Medicine 2, University of Milano-Bicocca, Centre for Disorders of Iron Metabolism, ASST-Monza, S. Gerardo Hospital, Monza, Italy.
Received: December 12, 2016
Accepted: January 27, 2017
Mediterr J Hematol Infect Dis 2017, 9(1): e2017021 DOI 10.4084/MJHID.2017.021
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recent decades we have been fortunate to witness the advent of new
technologies and of an expanded knowledge and application of chelation
therapies to the benefit of patients with iron overload. However,
extrapolation of learnings from thalassemia to the myelodysplastic
syndromes (MDS) has resulted in a fragmented and uncoordinated clinical
evidence base. We’re therefore forced to change our understanding of
MDS, looking with other eyes to observational studies that inform us
about the relationship between iron and tissue damage in these
subjects. The available evidence suggests that iron accumulation is
prognostically significant in MDS, but levels of accumulation
historically associated with organ damage (based on data generated in
the thalassemias) are infrequent. Emerging experimental data have
provided some insight into this paradox, as our understanding of
iron-induced tissue damage has evolved from a process of progressive
bulking of organs through high-volumes iron deposition, to one of
‘toxic’ damage inflicted through multiple cellular pathways. Damage
from iron may, therefore, occur prior to reaching reference thresholds,
and similarly, chelation may be of benefit before overt iron overload
is seen. In this review, we revisit the scientific and clinical
evidence for iron overload in MDS to better characterize the iron
overload phenotype in these patients, which differs from the classical
transfusional and non-transfusional iron overload syndrome. We hope
this will provide a conceptual framework to better understand the
complex associations between anemia, iron and clinical outcomes, to
accelerate progress in this area.
After the development and introduction of oral iron chelators, the possibility to chelate iron overload in MDS patients became a practical option. This review will discuss theoretical basis and rationale for iron chelation therapy in transfusion dependent patients affected by myelodysplastic syndrome.
For a rational approach to this problem, emphasis should be reserved for modern improvements in understanding iron metabolism and iron toxicity.
Iron Balance and Overload
The liver peptide hepcidin (for review see reference) regulates intestinal iron absorption and iron release from storage cells such as macrophages and hepatocytes. Hepcidin binds to ferroportin causing its internalization and degradation, thus exerting a general inhibitory effect on iron release within the body.[3,6] The hepcidin-ferroportin pathway is emerging as a therapeutic target for iron modulation, and a number of animal models have shown how hepcidin mimetics have the capacity to reduce iron overload in response to hepcidin deficiency. Further, genetic deletion of the hepcidin inhibitor, Tmprss6, prevents iron overload in animal models of hemochromatosis and β-thalassemia.[9,10]
Transferrin is a blood protein that acts both as a chelator and transporter for iron, taking it up into cells via the transferrin receptor 1 (TFR1). Increased iron absorption due to inadequate suppression of hepcidin (primary iron overload) that occurs as a consequence of HAMP regulatory network alterations (as seen in hereditary haemochromatosis) or ineffective erythropoiesis (as seen in non transfusion dependent thalassemia = NTDT), causes oversaturation of transferrin, generation of toxic non-transferrin bound iron (NTBI) and parenchymal iron accumulation. In transfusion-dependent patients (as seen in thalassemia major and myelodysplastic syndrome), iron accumulation occurs in the reticuloendothelial system (RES), in the spleen and liver as a consequence of parenteral input from blood transfusions (secondary iron overload). When the excess of iron overwhelms homeostatic mechanisms in RES cells, iron spills out into blood, and transferrin becomes fully saturated leading to NTBI and parenchymal iron overload.
NTBI and its component labile plasma iron (LPI) are able to enter the cells via an unregulated automatic way and disturb the delicate intracellular balance between iron utilization, storage, and reactive oxygen species (ROS) formation, finally leading to organelle damage and cell death. As a consequence of this new acquisition, it follows that iron toxicity might develop long before the clear evidence of overload through the production of tissue reactive iron and consequent reactive oxygen species. Subsequently, iron overload constantly causes toxicity by continuing to produce tissue reactive iron and ROS. In this setting, the capacity to counteract these toxic effects might be relevant to the development of cellular damage.
As MDS is a disease characterized by ineffective erythropoiesis, in which patients may eventually become regularly transfused, both mechanisms are believed to be responsible for the generation of free iron reactive species and iron overload, although to varying degrees and at different stages of transfusion-dependence. The kinetics of iron release from RES cells has been partially studied in MDS, where there is a wide dispersion of hepcidin levels. Figure 1 illustrates iron homeostasis in pathologic conditions and the sequence of events that leads to end-organ damage in response to iron overload.
|Figure 1. Schematic diagram illustrating iron homeostasis in pathologic conditions, and the sequence of events that leads to end organ damage in response to iron overload.|
Iron Overload in Myelodysplastic Syndromes
Moreover, novel disease-modifying agents and stem cell therapies have now extended the life expectancy of these patients, allowing increased supportive care in the form of blood transfusions.[14,15] In those patients with IPSS low to intermediate risk MDS and probably even in those successfully receiving disease modifying agents, life expectancy is sufficiently long for chronic transfusion therapy to generate iron free form and clinically relevant doses of iron. With the emergence of acceptable oral chelating agents, examining the prognostic effect of iron toxicity in MDS is warranted.
The baseline cardiovascular risk in these individuals is significant: of 1,000 newly diagnosed patients with low and intermediate-1 risk in the European Leukemianet MDS (EUMDS) registry, 46% of patients had hypertension, 18% diabetes mellitus, 12% arrhythmia, and 12% thyroid disease. Survival data were further confirmed by a recent update of the European registry. Malcovati et al. reported that 51% of non-leukemic causes of death were due to cardiac failure in low-risk MDS, compared with 31% due to infection and 8% due to hepatic cirrhosis. In a retrospective analysis of 840 MDS patients, 25% had cardiovascular comorbidities, and 63% of deaths were due to cardiac failure. Multivariate analyses showed that any cardiovascular comorbidity increased non-leukemic deaths significantly, with an HR of 3.7. This risk is even more pronounced in patients who are transfused. Indeed, the only study that do not report a correlation between transfusion burden and survival was the retrospective study from the Mayo Clinic, which examined a group of patients with RARS and limited follow up. Hepatic dysfunction also correlates, although to a lesser degree, with both transfusion history and ferritin levels.
It is tempting to link the cardiovascular events in MDS with data on transfusion history and prognosis to speculate that iron loaded from transfusions leads to cardiac siderosis, which then triggers cardiovascular events.
A key confounding factor is, however, the presence of anemia per se. In addition, aging and age-related disorders may have a clinical impact on iron overload in MDS. It is well established that chronic anemia is associated with adverse cardiac outcomes. Anemia triggers a compensatory process of increased cardiac output to achieve sufficient oxygen delivery, which overtime results in maladaptive cardiac morphology. Malign remodeling has a higher metabolic demand, which is pro-ischemic and overtimes leads to chamber dilatation and failure. Cardiac remodeling is prevalent in individuals with transfusion dependence and reduced mean haemoglobin levels. Furthermore, in MDS, anemia has been shown to be associated with left ventricular hypertrophy, exacerbations of acute coronary syndromes, and coexistence of renal disease, which in turn may result in decreased erythropoietin (EPO) production and increasing severity of anemia.[29,30] Moreover, transfusion therapy causes abrupt changes in cardiac preload, which leads to altered haemodynamic.
Data from MRI studies of patients with MDS do not support a role for high-volume iron accumulation in the heart. Our study, conducted on 27 chronic transfusion dependent patients with acquired anemias revealed that only 3 patients with severe hepatic iron overload (T2* <1.4 ms) showed cardiac T2* value indicative of dangerous myocardial iron deposition as defined in young patients with thalassemia. It should be noted that these studies are small, and the comparisons have been drawn against functional thresholds, established in thalassemia, but not validated in MDS. Similarly, thresholds for tissue toxicity and consequent fibrosis and cirrhosis have not been established in MDS cohorts. It is conceivable that iron may play a different role in these patients, and perhaps not cause damage through the traditional paradigm of transfusional siderosis. A more recent study reporting on a larger patient series did detect iron overload using T2* values in 18.2% of regularly transfused MDS patients, with severe overload in 4% (T2* ≤10 ms). They reported reduced T2* values correlated with compromised left ventricular ejection fraction (LVEF) using echocardiography.
These data, taken together, suggest that, although iron infrequently accumulates to the degree seen with iron-related target organ damage in thalassemia, its mild overload is still associated with poor prognosis in patients with MDS. A mechanistic illustration of disordered calcium handling and multiple ion channel disruption as a result of iron influx into the cardiac myocyte is shown in figure 2.
2) circulating “reactive iron species - free iron forms” in myocyte cells can damage without clear evidence of overload.
MDS and other Diseases
|Table 1. Different pattern of iron overload in different diseases.|
Therapeutic Potential in MDS Patients
Iron Chelation and Survival
Iron overload does, however, remain prognostically important in multivariate analyses,[20,21] suggesting a contributing role of iron on survival. More debate is on the role of iron overload in leukemia transformation.
Recent data from a prospective US registry of 600 lower-risk MDS patients with transfusional iron overload over 5 years report improved median overall survival in those patients chelated for a minimum of 6 months, as compared with non-chelated individuals – in both low-risk and intermediate-1 patients (median survival 98.7 vs. 53.6 months and 70 vs. 44.7 months, respectively). However, there were no statistically significant differences in the causes of deaths between groups, although there was a signal towards shorter AML-free survival in non-chelated patients. A matched-pair analysis of 188 patients with iron overload or a history of chronic iron transfusion in the Düsseldorf registry showed no association between chelation therapy and the risk of leukemic transformation, although there was improved mean survival in chelated versus non-chelated patients (74 vs. 49 months, respectively). Inconsistencies in these data may reflect both limitations in registry data, such as selection bias (those patients with better overall performance status are chosen for treatment with chelation), as well as inherent challenges in MDS cohorts, including very high-dropout rates.
Recent meta-analyses further support this statement: of 8 studies, comparing chelation versus not chelation in MDS, 7 showed a significant statistical benefit on survival, while the other one showed a not statistically significant advantage for chelation. However, it should be underlined that evidence of these study is limited being or retrospective or match paired or prospective but not a randomized study. Existing data, taken collectively, indicate a role for iron chelation therapy in MDS, and this is reflected by its inclusion in a number of societies and national guidelines.[17,61,62] We are currently coordinating the phase II randomized TELESTO trial (URL: http://clinicalTrials.gov/ct2/show/NCT00940602), which has completed the recruitment of patients with low and intermediate-1 risk MDS to receive either deferasirox monotherapy or placebo. The trial will include a composite primary endpoint of death and non-fatal cardiac and hepatic events in lower risk MDS patients (with secondary outcomes including metabolic effects and disease progression). This will hopefully provide definitive evidence for the efficacy of iron chelation therapy in MDS. When considering the heterogeneity of MDS, the complexity of the patient cohort, with an elderly population and multiple comorbidities, a “blanket” approach to treatment is unlikely to be the best by utilizing chelating agents. A more sophisticated approach will require a better understanding of pathophysiology and toxicity of iron in specific subgroups of MDS.
Ultimately, if the basis in which we treat patients and design trials is incorrect, advancing the management and therapeutic framework will be severely hindered. As the iron overload phenotype in MDS remains uncharacterized, we urgently require further experimental studies in models of MDS, in tandem with dedicated clinical trials, to build a legitimate evidence base for iron toxicity and the role of chelation therapy in MDS.
All Authors and has approved the final submitted version of the manuscript.
AcknowledgementsEditorial assistance was provided by Kaivan Khavandi, MD.
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