Red Blood Cell Transfusions and Iron Overload in the Treatment of Patients With Myelodysplastic Syndromes

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1 1089 Red Blood Cell Transfusions and Iron Overload in the Treatment of Patients With Myelodysplastic Syndromes Elias Jabbour, MD 1 Hagop M. Kantarjian, MD 1 Charles Koller, MD 1 Ali Taher, MD 2 1 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2 Department of Internal Medicine, American University of Beirut, Beirut, Lebanon. BACKGROUND. Approximately 15,000 new cases of myelodysplastic syndromes (MDS) are expected in the United States each year. METHODS. The mainstay for the management of myelodysplastic syndromes (MDS) is supportive therapy with red blood cell (RBC) transfusions to improve the patient s quality of life. RBC transfusions enable adequate tissue oxygenation and increase hemoglobin levels, improve fatigue, and improve the physical and intellectual activity of patients. Up to 90% of patients with MDS will receive RBC transfusions during the course of their disease, and many will become chronically dependent on transfusions to manage their anemia. These transfusions lead to an accumulation of excess iron that, in turn, can develop into a condition known as iron overload, causing clinical consequences like hypertransaminasemia and cirrhosis, dilated cardiomyopathy, and progressive dysfunction of the endocrine glands. RESULTS. Studies in patients with MDS have indicated that iron overload because of RBC transfusions was an independent, adverse prognostic factor for overall survival (OS) and leukemia-free survival (LFS): OS and LFS were significantly shorter in transfusion-dependent patients with MDS than in those who were not transfusion dependent. CONCLUSIONS. Although the National Comprehensive Cancer Network guidelines for the treatment of patients with MDS recommend the use of RBC transfusions as supportive care, they further recommend that the iron burden of transfused patients be monitored regularly and that iron chelation therapy be considered to maintain serum ferritin levels of <1000 ng/ml. Cancer 2008;112: Ó 2008 American Cancer Society. KEYWORDS: myelodysplastic syndromes, iron overload, red blood cell transfusions. Address for reprints: Hagop Kantarjian, MD, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd Box 428, Houston, TX 77030; Fax: (713) ; hkantarj@mdanderson.org Received June 27, 2007; revision received September 10, 2007; accepted September 12, Treatment of the myelodysplastic syndromes (MDS) is difficult because of the combination of hyperactive bone marrow and ineffective hematopoiesis. Only a minority of patients with MDS will be candidates for stem cell transplantation, which is the only potentially curative approach for the disease. The symptoms of MDS, particularly fatigue resulting from anemia, which develops in many patients, often are treated with red blood cell (RBC) transfusions. Although this has become the mainstay for supportive therapy in MDS, chronically transfused patients quickly can become iron overloaded, leading to progressive disease in organs like the liver, heart, and endocrine glands. In this review, we cover the potential sequelae facing patients with MDS who are transfused with RBCs and guide physicians on how best to monitor and manage the iron burden in their patients. ª 2008 American Cancer Society DOI /cncr Published online 10 January 2008 in Wiley InterScience (

2 1090 CANCER March 1, 2008 / Volume 112 / Number 5 MATERIALS AND METHODS MDS Incidence and Classification The MDS are a group of heterogeneous disorders characterized by ineffective hematopoiesis. Approximately 15,000 new cases of MDS are expected in the United States each year. 1 3 The incidence of MDS increases with age and affects from 0.02% to 0.045% of the population aged 70 years. Greater than 90% of patients with MDS are aged >50 years at the time of diagnosis (Fig. 1). 1,4 6 The characteristics of MDS are variable, and diagnosis typically is based on abnormalities in bone marrow and peripheral blood. In most patients, the cause of the disease is unknown, although some cases can be linked to previous exposure to genotoxic factors, such as chemotherapy, radiation, and pesticides. 7 Although cytogenetic abnormalities are common, no single, underlying, causative genetic mutation has been identified. 8 Many patients are asymptomatic; whereas others may present with symptoms of bone marrow failure, such as anemia, bleeding or bruising, or splenomegaly. Patients with advanced dysplastic changes in the myeloid elements also are prone to suffer from infections. The effect of MDS on blood cells can be revealed by bone marrow examination, including abnormalities like dysmorphic megakaryocytes, hypolobulated or hypogranular neutrophils, giant or hypogranular platelets, and ringed sideroblasts (RS). 9,10 FIGURE 1. Age of patients at diagnosis of myelodysplastic syndromes. 6 Reprinted with permission from Germing U, Strupp C, Kuendgen A, et al. No increase in age-specific incidence of myelodysplastic syndromes. Haematologica. 2004;89: (with kind permission from the Ferrata Storti Foundation, Pavia, Italy). TABLE 1 Age-related Median Survival for Patients with Myelodysplastic Syndromes According to International Prognostic Scoring System* Median survival, y Low Int-1 Int-2 High Age, y All age groups > > Int indicates intermediate. * Compiled from Greenberg, and Greenberg Although MDS was referred to previously as preleukemia, this was somewhat misleading, because only approximately 30% of patients transform to acute myeloid leukemia (AML). 11 The risk of transformation to AML depends on the type of MDS, which can be classified according to several systems. In 1982, the French-American-British (FAB) morphologic classification system was developed to evaluate the potential clinical outcomes for patients with MDS. 11 Although this system served as the gold standard for MDS classification for 2 decades, the morphologic recognition of MDS can be difficult, particularly in patients with low-grade disease. Since the FAB classification was developed, other risk classification systems have been developed for the prognostic classification of MDS. The International Prognostic Scoring System (IPSS) was developed in 1997 based on a multivariate analysis of the characteristics of patients with MDS. 12 With the IPSS, scores of low, intermediate (Int-1 and Int-2) and high risk, regarding both survival and transformation to AML, are derived from 3 variables: the proportion of bone marrow blasts, the karyotype, and the presence of 1 or more cytopenias. 12 The age-related median survival of patients with MDS according to IPSS subgroup is shown in Table 1. 13,14 To improve the clinical prognosis and to develop a consensus for prognostic risk, a classification system based on morphology, karyotype, and clinical features was adapted from the FAB classification in 2001 under the aegis of the World Health Organization (WHO). In the WHO classification, MDS can be subdivided into categories according to findings for both blood and bone marrow. The subgroups are refractory anemia (RA), RA with RS (RARS), refractory cytopenia with multilineage dysplasia (RCMD), RCMD and RS (RCMD-RS), RA with excess blasts-1

3 Iron Overload in Patients With MDS/Jabbour et al (RAEB-1), RAEB-2, unclassified MDS (MDS-U), and MDS associated with isolated del(5q). 3,15 17 RESULTS AND DISCUSSION Treatment Options for MDS Treatment of MDS is challenging and should be tailored to the subtype as well as the prognostic group. Treatment options for MDS can be divided into those that are therapeutic or potentially curative and those that are supportive. Therapeutic or potentially curative treatment options include stem cell transplantation (either allogeneic or autologous) 18,19 ; chemotherapy 20 ; treatment with immunosuppressive agents (such as antithymocyte globulin, antilymphocyte globulin, and cyclosporine A 3 ), or demethylating agents (such as azacytidine [Vidaza; Pharmion Corporation, Boulder, Colo] and decitabine [Dacogen; MGI Pharma, Minn]), as well as antiangiogenic compounds, including thalidomide 24,25 and lenalidomide (Revlimid; CC-5013; Celgene, San Diego, Calif). 26,27 Supportive therapies are directed at treating symptoms that are secondary to the underlying cytopenias. Fatigue is one of the principal symptoms of anemia, and patients suffer from lethargy, decreased mental alertness, physical weakness, and poor concentration. 28 The mainstay for treatment of MDS has been supportive therapy with RBC transfusions, which can mitigate the symptoms of anemia, particularly fatigue, as well as improve patients healthrelated quality of life (HRQoL) and help maintain independence. 29 Chronic transfusions increase hemoglobin (Hb) levels and enable adequate tissue oxygenation, which has a positive correlation with HRQoL 28 and improves the physical and intellectual activity of patients. Guidelines for the treatment of MDS suggest that RBC transfusions should be considered in any patient with symptoms of anemia. 5,10 It is not possible to stipulate a particular Hb level below which RBC transfusions should be initiated, because individual patients should be considered separately; this depends on factors like age, comorbidities, lifestyle, and working conditions. Recent observations suggest that initiating RBC transfusions at an Hb level of 8 g/dl may not be sufficient to prevent severe symptoms of anemia. 30 Transfusions should be continued to maintain Hb levels above the lowest concentration not associated with symptomatic anemia. Although many patients are asymptomatic at an Hb level of 8 g/dl, patients with Hb levels >12 g/dl report less fatigue and better HRQoL. 31 TABLE 2 Percentage of Patients With Myelodysplastic Syndromes Who Will Become Transfusion-dependent Classified According to International Prognostic Scoring System Risk Group IPSS risk group Mean % Low 39 Int-1 50 Int-2 63 High 79 IPSS indicates International Prognostic Scoring System; Int, intermediate. Approximately 60% to 80% of patients with MDS will develop anemia during the course of their disease, 32 and from 80% to 90% will receive transfusions at some point during their clinical course. 30 Severe anemia leading to the need for chronic transfusions is common in patients with MDS. According to the MDS Foundation, a large proportion of these patients will become RBC transfusion-dependent, as indicated in Table It is likely that, as medical care and information surrounding MDS continue to improve and patients survive longer, the use of blood transfusions will become more common. RBC transfusions have several disadvantages, including transmission of infection, the development of alloantibodies, the socioeconomic burden on the patient, and the clinical consequences of iron overload. 34 Iron Accumulation in Patients With MDS and the Risk of Iron Overload Accumulation of excess iron is a significant clinical consequence of RBC transfusions. 20 Because there is no physiologic mechanism for the excretion of excess iron, ongoing transfusions result in iron accumulation, leading to iron overload. 35 Because each unit of RBCs contains from 200 mg to 250 mg of iron, patients who are transfused with 2 RBC units per month receive from 5 g to 6 g of iron per year. Such chronically transfused patients can become iron overloaded after 10 to 20 transfusions or 20 to 40 RBC units. 36 Iron overload can be compounded by increased absorption of dietary iron as a result of anemia and ineffective erythropoiesis. Although the exact mechanism that influences uptake is unknown, the ferroportin gene and the hepcidin peptide hormone are the focus of current research. 37,38 Genotypic testing of randomly selected patients with MDS has indicated a higher incidence rate of hemochromatosis (HFE) gene mutations compared with healthy blood donors. Mutations in this gene are responsible for

4 1092 CANCER March 1, 2008 / Volume 112 / Number 5 most cases of hereditary hemochromatosis and may contribute to the accumulation of iron in some patients with MDS. 39 Morbidity and Mortality Data on the clinical effects of iron overload in patients with MDS are scarce. There are abundant data from studies in patients with thalassemia major, in which the consequences of iron overload are well established. There are likely to be key differences between these populations that should be considered. Patients with MDS will be older and are unlikely to have received transfusion therapy for such extended periods as patients with thalassemia, who may have required therapy since infancy. Patients with MDS will have a range of different comorbidities that can prove difficult to differentiate from iron overload-related morbidity. MDS-specific data are beginning to emerge. In the liver, which is the main repository of iron in patients with transfusional iron overload, serious clinical consequences can arise, such as hypertransaminasemia, portal fibrosis, and inflammatione. 40 Iron overload also can cause dilated cardiomyopathy, manifesting as systolic or diastolic dysfunction. One study in 46 patients with MDS indicated that >40% of patients had signs and symptoms of heart failure, which, in some patients, were accompanied by cardiac arrhythmias. 41 Iron overload also can cause progressive dysfunction of the endocrine glands, leading to diabetes, hypothyroidism, and hypogonadism In a large, retrospective analysis of 467 patients who were diagnosed with de novo MDS, Malcovati et al. demonstrated that iron overload because of transfusions was an independent, adverse prognostic factor for survival. 42 Patients who received a median of 21 units of RBCs had serum ferritin levels beyond a threshold of 1000 ng/ml, which distinguishes between mild and clinically relevant iron burden. 10 In a Cox regression analysis with time-dependent covariates, iron overload significantly affected overall survival (OS) (P <.001) with a hazard ratio (HR) of 1.36 for every 500 ng/ml of increase in serum ferritin above 1000 ng/ml. OS was significantly shorter in transfusion-dependent patients than in patients who were not transfusion dependent (HR, 2.16; P <.001). Leukemia-free survival (LFS) of transfusion-dependent patients also was significantly worse (HR, 2.02; P 5.001). In a multivariate analysis that accounted for cytogenetics, the number of RBC transfusions per month had a statistically significant impact on OS in patients with RA, RARS, or MDS with del(5q) (HR, 1.54; P <.001) and in patients with RCMD or RCMD- RS (HR, 1.45; P 5.03). 42 FIGURE 2. Overall survival of patients with myelodysplastic syndromes according to the World Health Organization criteria. 42 Reprinted with permission from the American Society of Clinical Oncology. Malcovati L, Della Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23: Ó2005 American Society of Clinical Oncology. RA indicates refractory anemia; RARS, refractory anemia with ringed sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; RAEB-1, refractory anemia with excess blasts-1; RAEB-2, refractory anemia with excess blasts-2; AML, acute myeloid leukemia. Malcovati et al. also demonstrated significant differences in OS between patients with RA/RARS and patients with RCMD/RCMD-RS (Fig. 2) and in both OS and LFS between patients with RAEB-1 and patients with RAEB-2. The median survival was 108 months in patients with RA/RARS compared with 49 months in patients with RCMD/RCMD-RS (P <.001). Patients with RA also had a significantly longer LFS (P 5.005). A significant difference in OS also was noted between patients with RAEB-2 and patients with AML from MDS (P 5.004) (Fig. 2). Thus, patients with RA are at greater risk for developing the sequelae of iron overload, because these patients have longer survival and receive transfusions for a more extended duration. 42 In patients without excess blasts who died as a result of nonleukemic causes, cardiac deaths were significantly more frequent in patients who were dependent on transfusions (P 5.01). 42 An earlier retrospective analysis of transfusion data from 46 patients with MDS who had received cumulative RBC transfusions of 50 units also indicated that 20 patients had cardiac hemosiderosis, 9 patients had arrhythmias, and 14 patients died from heart failure. Furthermore, 12 patients suffered from hepatic impairment, and 5 patients developed diabetes mellitus. 40

5 Iron Overload in Patients With MDS/Jabbour et al Monitoring Body Iron Levels The degree of iron overload varies greatly in patients with MDS, because the number of RBC transfusions patients receive differs. 43 Given the morbidity and mortality associated with iron overload, the measurement of body iron stores is important to guide treatment decisions and can be undertaken by using several different techniques. The liver contains >70% of the body iron stores. Measurement of the liver iron concentration (LIC) is regarded as one of the best predictors of total body iron and can be measured by direct biochemical measurement using a needle biopsy. This is invasive and is not recommended routinely in patients with MDS, because it can lead to complications like bleeding, infection, and hemobilia. 44 LIC also can be measured by using a superconducting quantum interference device (SQUID), which measures the paramagnetic response of iron in ferritin and hemosiderin. However, there are relatively few SQUID devices worldwide. 45 Body iron levels also can be measured noninvasively in the liver or heart by using magnetic resonance imaging, which indirectly measures parameters known as T2* or R2*. These parameters are related to the concentration of paramagnetic iron in the organ. 44 R2* is gaining more acceptance and wider use to measure LIC because of its noninvasive nature. An LIC value >7 mg iron/g dry weight of liver has been associated with an increased risk of iron-induced complications, such as hepatic fibrosis and diabetes mellitus. 46 Body iron burden also can be determined noninvasively by measuring the serum ferritin concentration, which is particularly useful when serial measurements are obtained. 44,46,47 A serum ferritin value 1000 ng/ml has been associated with an increased risk of iron-induced complications and is the level at which treatment should be initiated. 48 Managing Body Iron Levels Practical steps can be taken to reduce the risks associated with transfusion therapy, particularly iron overload. Alloimmunization can be reduced through typing and cross-matching blood products, 49 and viral infections can be prevented by screening blood products before transfusion. In the absence of established optimal Hb levels for transfusion-dependent patients, thresholds for initiating transfusions vary in different countries. 48 In general, the higher the Hb target and the greater the quantity of blood transfused, the more rapidly iron overload occurs. A strategy to reduce the risk of iron overload is the judicious timing of transfusions. Less frequent transfusions deliver less iron to the patient; however, this only lessens the degree of iron overload and is insufficient for prevention. Furthermore, transfusion frequency should be guided by a patient s symptoms. The use of iron chelation therapy should be considered to reduce serum ferritin levels to a safe threshold and to manage patients iron burden. 14 The National Comprehensive Cancer Network (NCCN) in the United States published a set of clinical practice guidelines regarding the management of MDS. The guidelines recommend that patients with MDS be monitored regularly and that iron chelation therapy should be initiated in patients who have previously received 20 to 30 units of RBCs, are likely to receive ongoing RBC transfusions, have a low or Int- 1 risk score, or have a serum ferritin level >2500 ng/ ml. This threshold, which is associated with a reduced risk of cardiac complications, 46 may be too high for the initiation of iron chelation therapy, because there is an HR of 1.36 for every 500 ng/ml increase in serum ferritin above 1000 ng/ml, as reported by Malcovati et al. 42 Indeed, the guidelines also recommend maintaining serum ferritin levels at <1000 ng/ml. 5 Several studies in transfused patients with MDS have demonstrated benefit with iron chelation, which has been used clinically to treat iron overload in various anemias for several decades. Jensen et al. demonstrated that, in long-term follow-up data from 11 transfused patients with MDS who were receiving iron chelation therapy, an improvement in hematopoiesis was evident. Seven of 11 patients had a reduction in RBC transfusion requirement, and 5 patients became independent of transfusion. Nine patients had a rise in their platelet and/or neutrophil counts, and 5 patients who initially had pancytopenia demonstrated a trilineage response. 43 More recently, Leitch et al. presented a nonrandomized, retrospective report from 178 patients with MDS. In that study, a Cox regression analysis indicated that median OS was correlated significantly with IPSS score (P <.008) and treatment with iron chelation therapy (P <.02). 50 For patients with low or Int-1 risk IPSS scores who received chelation therapy (n 5 18), the median OS was not reached at 160 months compared with a median OS of 40.1 months for nonchelated patients (n 5 160). Takatoku et al., in a retrospective analysis of 292 Japanese patients primarily with MDS (n 5 152) or aplastic anemia (n 5 90), also demonstrated that morbidity and mortality were influenced strongly by the occurrence of iron overload. The most heavily iron-overloaded patients had abnormal laboratory parameters, increased risks of cardiac and liver failure, and other complications. Patients who received daily chelation treatment (n 5 11) had improvements in serum

6 1094 CANCER March 1, 2008 / Volume 112 / Number 5 ferritin, serum alanine aminotransferase, serum aspartate aminotransferase, and fasting blood glucose levels. 51 Although several therapeutic and supportive treatment options exist for the care of patients with MDS, the majority will benefit from supportive care with RBC transfusions to manage their anemia. Fatigue is one of the most significant symptoms of MDS, and RBC transfusions can alleviate this and improve patients HRQoL. Many patients become chronically dependent on transfusions and develop iron overload. Damage of sensitive tissues, such as the liver, heart, and other major organs, is a severe clinical consequence of iron overload, and death from cardiac dysfunction is significantly more frequent in patients who are dependent on transfusions. Malcovati et al. demonstrated that iron overload significantly worsened the survival of patients with MDS and that patients who were dependent on RBC transfusions had a significantly shorter OS. 42 Along with recommending supportive therapy with RBC transfusions for patients with MDS, the NCCN guidelines for MDS recommend the use of iron chelation therapy to maintain iron burden at an acceptable level. Optimizing transfusions and regulating body iron levels with iron chelation therapy will help to minimize the risk of iron overload to patients with MDS, improve their quality of life, and possibly extend their survival. REFERENCES 1. Cazzola M, Malcovati L. Myelodysplastic syndromes coping with ineffective hematopoiesis. N Engl J Med. 2005; 352: Oscier DG. ABC of clinical haematology. The myelodysplastic syndromes. BMJ. 1997;314: Steensma DP, Bennett JM. The myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc. 2006;81: Leukemia Research Fund. 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