The practice of transfusion medicine saves lives of patients. Transfusion of red blood cells (RBCs) enhances the oxygen available within the vascular beds of vital tissues. Transfusion of platelets and plasma enhances hemostasis in patients suffering from or at risk of severe hemorrhage. An often overlooked consequence of performing these lifesaving procedures is the impact that blood transfusion has on the iron status of both the blood donor and the transfusion recipient.
Regular blood donation causes many donors to become iron deficient.1–3 The development of iron deficiency in blood donors should be prevented and is of particular concern in 16- to 18-year-old donors that are continuing to undergo cognitive development.4,5 Current issues in donor management include defining the appropriate donation intervals for different donor demographic groups to allow for iron repletion between donations and establishing effective procedures for iron replacement therapy in targeted donor groups.6,7
Transfusion recipients are at risk of severe and potentially lethal side effects from transfusion-associated iron overload because humans do not have a physiologic mechanism for excretion of excess iron contained in the transfused RBCs. This adverse event occurs most often in chronically transfused patients, such as those with sickle cell disease, thalassemia, or myelodysplastic syndrome (MDS). The severity of the iron overload varies with the pathology of the underlying disease, but patients who have received more than 20 units of RBCs may be considered at risk for transfusion-associated iron overload. The excess iron deposits within the liver, pancreas, and heart of these patients where it can result in development of cirrhosis, diabetes, and cardiomyopathy. In addition, transfused iron may increase the risk of infection in the recipient. This risk may occur acutely through elevated non–transferrin-bound iron that has been observed in healthy volunteers within 4 hours of receiving an “older” unit (stored 40–42 days) of RBCs8 or with chronic iron overload. This increased risk of infection in the presence of total body iron overload was dramatically demonstrated recently in the tragic case of a laboratory worker with unrecognized hemochromatosis who died after infection with an attenuated strain of Yersinia pestis.9
Iron chelation therapy with subcutaneously administered desferoxamine became available in the 1970s and has proved to be lifesaving for children with thalassemia who require chronic transfusion because of severe anemia, but then suffered from fatal tissue iron overload.10 Similarly, iron chelation therapy is considered to be clinically effective for preventing side effects from transfusion-associated iron overload in children with sickle cell disease receiving prophylactic transfusion therapy to prevent stroke.11
Since 2005, two oral iron chelation agents have become available to treat iron overload. In the United States, deferasirox is approved for the treatment of iron overload secondary to blood transfusions, inclusive of patients with MDS, whereas deferiprone is only approved for the treatment of transfusion-related iron overload in patients with thalassemia. These agents are effective at reducing iron deposits in the liver and heart. In addition to their widespread use in thalassemia and sickle cell disease, these oral iron chelators, and deferasirox in particular, have been considered for use in transfusion-dependent patients with MDS.12 These patients are typically elderly and the potential risks and benefits for iron chelation therapy are quite different than those of patients with hemoglobinopathies primarily because of their shorter life expectancy. Thus, iron chelation is most often recommended for transfusion-dependent patients with MDS with a long enough life expectancy to be at risk for development of liver and heart damage.12 This therapy is not without risk as deferasirox may cause renal and hepatic failure or gastrointestinal bleeding, reactions observed most frequently in patients with advanced age and high-risk MDS. However, the side effects of these drugs are generally mild and chelation therapy has been considered for broader use as an active measure to prevent disease progression to leukemia.13,14 Those arguing against the use of iron chelation in MDS patients site lack of data from prospective studies indicating a significant impact on organ function, survival, or quality of life.14 The studies performed to date have been retrospective15 and all agree that additional prospective studies are needed to define the appropriate clinical use of iron chelation for treatment of transfusion-associated iron overload in MDS.15,16
In this issue of TRANSFUSION, Goldberg and colleagues17 from Hackensack University Medical Center describe results from a retrospective review of Medicare claims of patients with MDS newly diagnosed in the first quarter of 2003 with 3 years of follow-up to assess resource use and costs for treatment. Patients receiving transfusions had increased cardiac events, infections, and dyspnea compared to those not transfused. These data confirm previous studies that have demonstrated that transfusion is strongly associated with poor prognosis in MDS. The authors further demonstrated that transfusion-dependent patients have much greater use of hospital services and associated costs for their care. This study nicely highlights the significant clinical and financial resources that transfusion-dependent patients with MDS require and raises the following question: will the clinical benefit of iron chelation therapy outweigh the added costs and risks in patients with MDS?
If retrospective studies are used to answer important clinical questions, as in this study by Goldberg and colleagues, study design shortcomings will have to be addressed. A limitation of this study is that established prognostic risk factors for MDS included in the international prognostic scoring system (IPSS), number of cell lines affected, percentage of blasts, and poor-risk cytogenetics, were not available for analysis.18 Likely, there was a close association between the transfusion-dependent and high-risk MDS study subjects, confounding a determination of the effects of RBCs on clinical outcomes.
In lieu of expensive and time-consuming prospective studies, well-designed retrospective studies can provide useful, if not conclusive, evidence to address whether iron contributes to disease progression and mortality in patients with transfusion-dependent MDS. In the case of a retrospective cohort study, key design considerations include an appropriate cohort, availability of adequate predictor variables, and accurate follow-up data. For this clinical question, knowledge of established baseline MDS prognostic factors is critical along with accurate follow-up data describing RBC transfusions and morbidity and mortality. Another possibility would be a case–control study of newly diagnosed IPSS low-risk MDS patients who within 3 years after diagnosis were dead (cases) versus alive (controls) to evaluate the association with transfusion burden while adjusting for confounding variables. Although it is tempting to examine a large existing database to address clinical questions, such as the Medicare database, future retrospective studies in the area of transfusion-related iron overload and MDS should carefully consider the limitations of available data. A lack of vital data may produce results that do not provide clear guidance to physicians caring for patients with transfusion-dependent MDS. Without quality evidence showing morbidity and mortality advantages of iron chelation in MDS, providers should be cautious about assuming benefit based on data largely derived from the hemoglobinopathy literature.
In the absence of clear data from either prospective or carefully designed retrospective studies, the role for iron chelation therapy for a patient with MDS remains undefined. Expert panel guidelines differ in the specifics about when to initiate iron chelation therapy (ferritin between 1000 and 2500 ng/mL) and which low-risk MDS patients might benefit (life expectancy of 6 months-2 years).12 These approaches seem reasonable, recognizing that the basis for recommending a ferritin of 1000 ng/mL is based on limited data. We can speculate that lower-risk MDS patients are more likely to suffer from adverse consequences of tissue iron deposition and would benefit from chelation therapy compared to high-risk MDS patients. Treatment of higher-risk MDS patients with hopes of delaying progression to leukemia or preventing other potential, but unproven, adverse consequences of transfusion-associated iron overload also remains speculative at this time and recommendation of iron chelation therapy in these patients should be reserved for transfusion medicine physicians who are interested in carefully tracking patient outcomes.