The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic. Transfusion Independence in Patients with Myelodysplastic Syndromes

Transcription

1 2087 Transfusion Independence in Patients with Myelodysplastic Syndromes Impact on Outcomes and Quality of Life Lodovico Balducci, M.D. Department of Interdisciplinary Oncology, Geriatric Section, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Anemia is the most common cytopenia associated with myelodysplastic syndromes (MDS). Current management relies on frequent red blood cell (RBC) transfusions and erythroid growth factors to alleviate symptoms. However, the dependence of patients with MDS on repeated RBC transfusions often results in significant clinical and economic consequences, poorer outcomes, and diminished health-related quality of life. In addition, the intensity and duration of RBC transfusion dependence can influence responses to treatment after disease progression. Erythropoietic growth factors may alleviate the need for RBC transfusions in some patients with MDS, although only a minority of patients experience responses. Emerging treatment strategies to reduce or eliminate the need for RBC transfusions in patients with MDS include immunomodulating drugs, immunosuppressive therapy, and differentiating agents. The immunomodulating drug lenalidomide in patients who have MDS with 5q deletion is unique among emerging approaches, in that cytogenetic remitting activity and durable erythroid responses have been achieved. Newer treatments have the potential to improve the care of patients with MDS by alleviating the clinical, economic, and quality-of-life consequences of long-term RBC transfusion dependence. Cancer 2006;106: American Cancer Society. KEYWORDS: myelodysplastic syndromes, anemia, transfusion, treatment, quality of life. Address for reprints: Lodovico Balducci, M.D., Department of Interdisciplinary Oncology, Geriatric Section, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL ; Fax: (813) ; balducci@moffitt.usf.edu Received July 25, 2005; revision received November 18, 2005; accepted December 12, The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by dysplastic cellular elements and chronic peripheral cytopenias. 1,2 Anemia is the most common type of cytopenia; however, neutropenia and/or thrombocytopenia also may be present. Approximately 39% of patients with MDS have anemia alone, 27% have a decrease in erythrocytes and in 1 other cell type, and 15% have pancytopenia. 3,4 The MDS are clinically heterogeneous and may be mild and stable for many years or may progress rapidly to acute myeloid leukemia (AML). 2 Therefore, the median survival of patients with MDS ranges widely, from 6 years in lower risk patients to only 4 months in higher risk patients. 5 The outcomes of patients with MDS typically correspond to disease characteristics, such as the percentage of bone marrow myeloblasts at diagnosis, the number and severity of hematopoietic lineages affected by cytopenia, and the presence of chromosomal abnormalities. 4 However, the chronicity of cytopenias associated with MDS causes morbidity and mortality even in the absence of disease progression to AML. 6 Greater than 80% of patients with MDS have anemia at the 2006 American Cancer Society DOI /cncr Published online 10 April 2006 in Wiley InterScience (

2 2088 CANCER May 15, 2006 / Volume 106 / Number 10 beginning or during the course of their disease and often require red blood cell (RBC) transfusion support. 7 Because of the chronicity of MDS-associated anemia, these patients may develop long-term dependence on RBC transfusions and require transfusion management measures, such as iron-chelation therapy. 8 Furthermore, transfusion dependence in patients with MDS significantly affects their survival and health-related quality of life (HRQOL) Clinical Management of Anemias Associated with MDS Many patients with MDS are asymptomatic at the time of diagnosis or present with nonspecific symptoms, such as fatigue, weakness, infection, or bleeding, which relate to the presence of cytopenias. 3,11 The majority of patients diagnosed with MDS have anemia, which may remain the most significant clinical problem in patients with lower risk MDS who have an indolent disease course. 3 For medically appropriate management, it is important to differentiate anemia associated with MDS from reactive causes of anemia and from other erythroid disorders, such as aplastic anemia and thalassemia. 5,11 Clinically, the course of MDS ranges widely from indolent with mild cytopenia in some patients to a rapid progression to AML with severe pancytopenia in other patients. 2,12 Supportive care, especially RBC transfusion for the management of anemia, is considered the standard of care for patients with low-risk MDS according to the International Prognostic Scoring System (IPSS). 5,11 However, most patients with MDS, regardless of their IPSS risk category, will rely on RBC transfusions at some point during the course of their disease. 2,3 A primary objective of supportive care in MDS is the management of symptoms associated with chronic cytopenias. For patients with anemia, RBC transfusions and/or erythropoietic growth factors are used to alleviate fatigue and other symptoms. 13 Leukocyte-depleted blood products are used to decrease febrile nonhemolytic transfusion reactions and human leukocyte antigen (HLA) alloimmunization. 14 It is particularly important to prevent HLA alloimmunization in patients who may undergo stem cell transplantation; however, in all patients, HLA alloimmunization may lessen the effectiveness of platelet transfusions and increase the risk of bleeding. Because the severity of cytopenias varies substantially among patients with MDS, the most appropriate supportive measures are determined on an individual basis. There is a consensus that patients who experience symptoms and signs of anemia, such as dyspnea on exercise or tachycardia, should receive transfusions irrespective of their hemoglobin levels. A common practice is to order RBC TABLE 1 Red Blood Cell Transfusion Dependence in Patients with Myelodysplastic Syndromes* IPSS Category Low risk 39 Intermediate-1 risk 50 Intermediate-2 risk 63 High risk 79 IPSS: International Prognostic Scoring System; RBC: red blood cells. * See Brechignac et al., RBC Transfusion-Dependent Patients (Mean %) transfusions when hemoglobin levels drop to 8 g/dl (or 10 g/dl for patients with coronary artery disease). An important management objective for MDS is to find a way to correct anemia for a prolonged period and to render the patient independent from blood transfusions. Consequences of Transfusion Dependence in MDS RBC transfusion dependence is associated with significant clinical, economic, and quality-of-life consequences. 10,13 In a practice and treatment survey of 30 European centers, a substantial proportion of patients with MDS in all IPSS categories were considered RBC transfusion-dependent (Table 1). 15 With disease progression, some patients require more frequent transfusions. 10,15 Clinical consequences Frequent RBC transfusions may cause significant clinical complications, such as transfusion reactions, infection, and iron overload. 10,12,13,16,17 In a study of 50 patients with MDS, approximately 80% of transfusions had associated complications. 10 Greater than 50% of patients developed transfusion reactions or required the use of premedications, and approximately 33% of patients developed antibodies to RBCs, platelets, or granulocytes. 10 A substantial number of patients either required specially selected RBC antigen-negative units (27%) because of the presence of antibodies to blood cells or required leukocyte reduction of packed RBCs and platelets by filtration (40%). Iron accumulation is an inevitable and serious complication of long-term RBC transfusion therapy for anemia that results in progressive dysfunction of several organ systems, in particular, the heart, liver, and endocrine system. 12,13 Iron-chelation therapy using deferoxamine is indicated for most patients who have received 20 to 30 transfusions, for patients who have reached a ferritin level of approximately 1500 g/l, or for patients with transfusion-dependent, low-

3 Transfusion Independence in MDS/Balducci 2089 risk MDS who have a survival prognosis of 1 year. 13,18 However, difficulties in the administration of deferoxamine (subcutaneous infusion) result in compliance issues. Oral iron-chelating therapies are in development that may improve iron-overload management in RBC transfusion-dependent patients. 19 In the general population, the degree of dependence on RBC transfusions may have a negative impact on patient outcomes. An analysis of survival rates of patients who received RBC transfusions was assessed in a cohort of 6779 patients in the U.S. 20 The overall annual mortality rate in that analysis was 31% in the first year after transfusion, 14% in the second year, and 10% in each subsequent year through the fifth year after transfusion. Furthermore, the results indicted that the mortality rate increased with age. Compared with patients younger than age 41 years, 1-year mortality rate after transfusion was more than double for patients ages 41 years to 65 years and more than triple for patients age 65 years (10.5%, 27.1%, and 38.2%, respectively). 20 Similarly, results from a recent analysis of transfusion needs in the U.K. indicated that the median age at transfusion was 67 years, and shorter patient survival was associated with increased patient age, increased number of RBC units transfused, transfusion of plasma or platelets, and nonsurgical indications for transfusions. 21 These data may indicate that transfusion dependence poses a significant age-related risk to patients with MDS, who often are age 65 years. Alternatively, the findings may indicate that patients who require more blood transfusions have more serious disease. Among patients with MDS, dependence on RBC transfusion negatively affects the likelihood of survival (Fig. 1). 9 Patients with MDS were grouped according to whether they developed a regular need for RBC transfusions during their disease course. The 2 groups were compared using a Cox proportional hazards regression model with time-dependent covariates. It is believed that the negative effect of transfusion dependence on outcomes in patients with MDS is a consequence of more severe bone marrow insufficiency associated with transfusion dependence and, possibly, of iron overload. 12 Economic consequences RBC transfusion dependence associated with MDS represents an economic burden to health care resources. However, dependence on RBC transfusions is considered inconvenient by most patients because of time required for travel, waiting, and transfusion, and it also has economic consequences for patients. 16 The rising cost of blood collection, testing, and blood product transfusion is a result primarily of FIGURE 1. Survival curves illustrating the impact of transfusion dependence on outcomes of patients with myelodysplastic syndromes (MDS). The curves do not take into account time dependency of the transfusion requirement. Reprinted with permission from Cazzola M, Malcovati L. Myelodysplastic syndromes coping with ineffective hematopoesis. N Engl J Med. 2005;352: Massachussetts Medical Society. All rights reserved. added safety measures, increased use of fractionated products, donor deferral, increased donor screening, and the use of leukoreduction. 22,23 In the U.S., the median unit cost of a blood transfusion per patient has been estimated to be between $500 and $ ,22 In a French study that evaluated the health, economic, and quality-of-life effects of recombinant human erythropoietin (Epo) and recombinant human granulocyte-colony stimulating factor (G-CSF) for the treatment of MDS, 60 patients were randomized to receive either cytokine treatment or supportive care only. 24 The mean costs per subject were 26,723 ( 13,109) in the treatment arm and 8746 ( 6731) in the supportive care arm ( 1 U.S. $1.20). This difference was attributed mainly to the cost of drugs. However, the mean transfusion costs were much lower for responders who completed the study than for those who received supportive care only ( 2085 vs. 7579, respectively). 24 The cost of RBC transfusions has continued to increase significantly over time. For example, in a systematic review of studies evaluating the cost of RBC transfusion, the cost of a transfusion increased 61% between 2000 and 2001 in the U.S. 22 In a 2004 survey of 4 centers, 38 patients with MDS received a median of 42 RBC transfusions over 24 months. 15 The average cost per RBC transfusion was 436 ($526), and the median 24-month cost per patient was 11,118 ($13,395). These costs included 2 filtered RBC units, blood collection, administrative costs, and staff time but did not include the cost of iron-chelation therapy or indirect costs (e.g., time spent at the transfusion

4 2090 CANCER May 15, 2006 / Volume 106 / Number 10 facility, travel time, and waiting time for the patient and a caregiver/family member). HRQOL Patients with MDS exhibit decrements in their HRQOL. 13,25 In a study of 53 patients with MDS, HRQOL scores were significantly lower compared with age-matched and gender-matched, healthy individuals when HRQOL was measured with the European Organisation for Research and Treatment of Cancer assessment tool. 13 In that study, patients with MDS had significant impairment of physical, social, and emotional functioning as well as clinically significant increases in fatigue and dyspnea compared with healthy individuals. The quality-of-life measures fatigue and dyspnea were improved with treatment of anemia. Increasing hemoglobin has resulted in an improved HRQOL for patients with MDS or those with anemia secondary to other cancers. 25,26 However, despite the improvements observed with the use of recombinant Epo for anemia in cancer patients, there is no consensus regarding the effect of erythropoietic growth factors on the quality of life for patients with MDS. 13,24 In a study of 11 patients with low-risk MDS who were treated with high-dose, recombinant human Epo, treatment resulted in improvements in the HRQOL, as measured using the Functional Assessment of Cancer Therapy-Anemia questionnaire, of patients who were responsive to therapy (55%). 27 In that study, the erythroid response was associated with positive changes in HRQOL. In contrast, results from a large, randomized trial demonstrated no effect of Epo plus G-CSF treatment on HRQOL. 24 In that study, similar percentages of patients were found to demonstrate HRQOL improvements when they received Epo plus G-CSF compared with supportive care alone. Among transfusion-dependent patients with MDS, fatigue was correlated with hemoglobin level (Fig. 2), but other factors also contributed to diminished HRQOL in these patients. 25 No correlation was observed between HRQOL scores of these transfusiondependent patients with MDS and MDS subtype. 25 Strategies for Reducing Transfusion Dependence in MDS The clinical, economic, and HRQOL burdens of RBC transfusion dependence for patients with MDS underscore the need for new treatment approaches that provide a durable hematologic response leading to a reduction in transfusion requirements or to transfusion independence. For patients with MDS who have chronic cytopenias, hematologic improvement that leads to transfusion independence represents a clinically significant treatment objective. 6 FIGURE 2. Physical fatigue and hemoglobin (Hb) levels are illustrated in transfusion-dependent patients with myelodysplastic syndromes (MDS). A significant correlation was observed between the Hb level and physical fatigue (Spearman correlation coefficient [Rs], 0.31; P.03). Multidimensional Fatigue Inventory (MFI) scores ranged from 4 (best) to 20 (worst). Reprinted with permission from Jansen AJG, Essink-Bot M-L, Beckers EAM, Hop WCJ, Schipperus MR, Van Rhenen DJ. Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes. Br J Haematol. 2003;121: Blackwell Publishing Ltd. To our knowledge, there currently is no widely accepted definition of transfusion-dependence with respect to the number and frequency of units received over a specified time. In addition, there is considerable interpatient variability in the hemoglobin level that triggers the need for RBC transfusion for fatigue management. According to the International Working Group (IWG) standardized response criteria for MDS, a major hematologic improvement in the erythroid lineage is defined as either an increase 2 g/dl in hemoglobin concentration in patients with hemoglobin levels 11 g/dl or transfusion independence in a transfusiondependent patient. 6 A minor IWG erythroid response is defined as an increase of 1 g/dl to 2 g/dl in hemoglobin in a patient whose pretreatment hemoglobin was 11 g/dl or a 50% reduction in transfusions in transfusion-dependent patients. Several strategies currently are under investigations to reduce RBC transfusion requirements in patients with MDS, including treatment with erythropoietic growth factors and treatments aimed at altering the disease. The latter approaches include immunosuppression, differentiation, and immunomodulation. Erythropoietins Treatment with recombinant human Epo decreases transfusion requirements in some patients with MDS. 24,28,29 However, in a metaanalysis of 17 original articles that reported on a total of 205 patients with

5 Transfusion Independence in MDS/Balducci 2091 FIGURE 3. Decision model for erythropoietin plus granulocyte colony-stimulating factor in patients with myelodysplastic syndromes. RA indicates refractory anemia; RARS, RA with ringed sideroblasts; RAEB, RA with excess blasts; CR, complete response; Hb, hemoglobin; PR, partial response; RBC, red blood cell; s-epo, serum erythropoietin; transf, transfusion. Reprinted with permission from Hellstrom-Lindberg E. Approach to anemia associated with myelodysplastic syndromes. Curr Hematol Rep. 2003;2: Current Medicine (Philadelphia). MDS who had been treated with Epo, only 33 patients (16%) had a significant response. 28 That analysis predated the IWG response criteria, and response was defined as an increase in hemoglobin of 1.5 g/dl in patients who had no transfusion needs or a stable hemoglobin level without the need for transfusion in patients who had transfusion needs before entry in the study. 28 Response rates subsequently were improved by the coadministration of G-CSF with Epo, resulting in a response in up to 50% of all patients with MDS. 24,29 For patients with MDS, the likelihood of achieving a response to recombinant erythropoietic growth factors is dependent on several factors, including the French American British subtype of MDS. In a randomized study of 87 patients with low-risk MDS who received Epo, the response rates were 50%, 37.5%, and 16.7%, respectively, for patients with refractory anemia (RA), RA with ringed sideroblasts, and RA with excess blasts. 7 Other studies have shown a lower response rate in patients with ringed sideroblasts or excessive blasts. 2,7 A predictive model was validated in a prospective trial to assist in the selection of patients with MDS for treatment with recombinant human Epo plus G-CSF (Fig. 3). 8,13 Patients who had serum Epo (s-epo) levels 500 U/L and had a transfusion requirement of 2 units per month had a high probability of achieving a response to treatment. Patients who had s-epo levels 500 U/L and had a transfusion requirement for 2 units per month had a poor probability of response, and the presence of only 1 of these negative prognostic factors predicted an intermediate response to treatment. Studies to determine the optimum dose, frequency, and duration of Epo therapy are ongoing to optimize the management of MDS-associated anemia and the use of costly therapies in MDS populations. Darbepoetin- is a highly glycosylated form of Epo that has a prolonged serum half-life, which allows for dosing weekly or every second week. Preliminary results from a Phase II study in patients with low-risk MDS showed an IWG response rate of 60% (24 of 40 evaluable patients), with responses achieved in 3 of 6 patients who previously were unresponsive to recombinant Epo. 30 In another study of darbepoetin treatment in 37 patients with low-risk to intermediate-risk MDS, 15 patients (40.5%) achieved an erythroid response (13 major and 2 minor responses) according to IWG criteria. 31 Significant factors that were predictive of a response were baseline endogenous s-epo levels 100 U/L, absent or no transfusion needs, no excess blasts, and hypoplastic bone marrow. Thus, darbepoetin- may provide an alternative to Epo plus G-CSF for the management of anemia in a minority of patients with MDS, although more data are needed. Immunosuppressive agents Immunosuppressive agents have been used previously for treating aplastic anemia and subsequently were investigated for efficacy in MDS. In a study of 61 transfusion-dependent patients who received with antithymocyte globulin (ATG), 34% of patients became transfusion-independent. 32 Transfusion dependence was defined as receiving 3 separate transfusions of 2 units of RBCs at intervals of 2 to 4 weeks to maintain hemoglobin levels. Pancytopenia and the MDS RA subtype were significant prognostic factors for response in a multivariate analysis, whereas the presence of hypocellular bone marrow was significant only for response in a univariate analysis. In another study, 20 patients with low-risk MDS received ATG, and the results confirmed hematologic recovery after treatment with ATG. 33 Patients with RA were found to have the best response to ATG therapy. Transfusion independence was achieved by 50% of all patients and by 62% of patients who had RA, with a median response duration of 15.5 months. Other immunosuppressive approaches that are under investigation in patients with MDS (primarily low-risk MDS) include cyclosporine, steroids, and the antitumor necrosis factor- monoclonal antibody infliximab. 34,35 Overall, factors that have been associated with erythroid responses to immunosuppressive therapy include positive D-related HLA-15 status, negative CD59 status, younger age, recent diagnosis, and shorter duration of transfusion dependence. 36,37

6 2092 CANCER May 15, 2006 / Volume 106 / Number 10 TABLE 2 Transfusion Independence Achieved with Lenalidomide Study No. of TD Patients (%) No. of Patients with IPSS Low/Int-1 (%) Duration (Years) Median RBC Transfusions No. of TI Patients (%) MDS-001: List et al., (MDS-TD or symptomatic anemia) 32* NA NA 3 units/mo 20 (63) MDS-002: List et al., (Low/Int-1 MDS) (79) units/8 wk 42 (25) MDS-003: List et al., (del 5q MDS) (82) units/8 wk 95 (65) TD: transfusion-dependent; IPSS: International Prognostic Scoring System; Low/Int: low/intermediate-risk myelodysplastic syndromes; RBC: red blood cells; TI: transfusion-independent; MDS: myelodysplastic syndromes; NA: not available. * Defined by the need for 4 units of RBCs within 8 weeks before enrollment. Defined by the need for 2 units of RBCs within 8 weeks before enrollment. Larger, randomized, prospective trials will be required to characterize further the effectiveness of immunosuppression in reducing transfusion dependence in patients with MDS. Differentiation agents Valproic acid is a short-chain fatty acid that affects differentiation and inhibits histone deacetylase to facilitate the reexpression of suppressed genes. In a study that evaluated valproic acid in patients with MDS or AML secondary to MDS, it was observed that 8 of 18 patients (44%) achieved hematologic improvement according to IWG response criteria. 38 Patients who had IPSS low-risk MDS and patients who had low RBC transfusion requirements prior to valproic acid treatment demonstrated the highest response rates. In another study of valproic acid in a cohort of older, poor-risk patients who had AML or MDS, the results showed only minor erythroid responses (according to World Health Organization response criteria), but major platelet responses leading to platelet transfusion independence were achieved. 39 Grade 3 neurocortical toxicity was observed in 4 of 20 enrolled patients in that study. Immunomodulatory drugs Thalidomide. The use of thalidomide for the treatment of patients with MDS has resulted in transfusion independence, even in patients who had long-term, transfusion-dependent anemia. 40 Several clinical studies have shown IWG response rates of at least 25% with thalidomide therapy in patients with MDS However, tolerability of the dosing regimens used has been problematic in some patients, leading to discontinuation due to fatigue, constipation, dyspnea, or disease progression. Preliminary results from a recent study of thalidomide in low-risk, transfusion-dependent patients with MDS showed that thalidomide improved erythropoiesis in 28% of patients, especially those with RA, and had a low response rate on neutrophils and platelets. The investigators concluded that thalidomide should be considered at a dose of 50 mg per day or 100 mg per day only in patients with RA who require RBC transfusions. 44 Lenalidomide. Lenalidomide treatment has significantly reduced dependence on RBC transfusions and restored normal cytogenetics in patients with MDS, particularly those with a chromosome 5q deletion (Table 2) In 43 patients with MDS who had low or intermediate IPSS scores and had either no response to recombinant Epo or had a low probability of response to Epo therapy, treatment resulted in RBC transfusion independence for 20 of 32 patients (63%) who were transfusion-dependent at baseline. 46 After a median follow-up of 81 weeks, the median duration of major erythroid responses had not been reached ( 48 weeks; range, weeks). Among the patients who had MDS with del(5q), 83% (10 of 12 patients) had both a cytogenetic response and an erythroid response (RBC transfusion independence) after treatment. 46 Preliminary results from a larger study of patients with del(5q) MDS with or without additional chromosomal abnormalities have confirmed the sensitivity of these MDS subtypes to lenalidomide treatment. 47 Dose-dependent myelosuppression was the most frequent Grade 3 or 4 adverse event, whereas adverse events often associated with thalidomide therapy, such as sedation, constipation, and nausea, were uncommon. Conclusions In conclusion, transfusion independence is an important treatment objective for patients with MDS

7 Transfusion Independence in MDS/Balducci 2093 who may experience long-term dependence on frequent RBC transfusions for the management of their anemia. Dependence on RBC transfusions is associated with significant clinical, economic, and qualityof-life burdens. However, new treatment approaches have the potential to achieve RBC transfusion independence in various MDS patient subsets and, thus, to alleviate the negative consequences of transfusion dependence for these patients. REFERENCES 1. Hofmann W-K, Lubbert M, Hoelzer D, Koeffler HP. Myelodysplastic syndromes. Hematol J. 2004;5: Hellstrom-Lindberg E. Treatment of adult myelodysplastic syndromes. Int J Hematol. 1999;70: Lawrence LW. Refractory anemia and the myelodysplastic syndromes. Clin Lab Sci. 2004;17: Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes [erratum appears in Blood. 1998;91:1100]. Blood. 1997;89: National Comprehensive Cancer Network (NCCN) Myelodysplastic Panel Members. NCCN practice guidelines: myelodysplastic syndromes, version 1, Available at URL: mds.pdf [accessed August 12, 2005]. 6. Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96: Italian Cooperative Study Group for rhuepo in Myelodysplastic Syndromes. A randomized double-blind placebocontrolled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br J Haematol. 1998;103: Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, et al, for the Scandinavian MDS Group. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120: Cazzola M, Malcovati L. Myelodysplastic syndromes coping with ineffective hematopoiesis. N Engl J Med. 2005;352: Gupta P, LeRoy SC, Luikart SD, Bateman A, Morrison VA. Long-term blood product transfusion support for patients with myelodysplastic syndromes (MDS): cost analysis and complications. Leuk Res. 1999;23: Bowen D, Culligan D, Jowitt S, et al, of the UK MDS Guidelines Group. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol. 2003;120: Cazzola M, Anderson JE, Ganser A, Hellstrom-Lindberg E. A patient-oriented approach to treatment of myelodysplastic syndromes. Haematologica. 1998;83: Hellstrom-Lindberg E. Approach to anemia associated with myelodysplastic syndromes. Curr Hematol Rep. 2003;2: British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines on the clinical use of leucocyte-depleted blood components. Transfus Med. 1998; 8: Brechignac S, Hellstrom-Lindberg E, Bowen DT, DeWitt TM, Cazzola M, Fenaux P. Quality of life and economic impact of red blood cell (RBC) transfusions on patients with myelodysplastic syndromes (MDS) [abstract 4716]. Blood. 2004; 104(Part 2):263b. 16. Fitzgerald M, Hodgkinson B, Thorp D. Blood transfusion from the recipient s perspective. J Clin Nurs. 1999;8: Pomeroy C, Oken MM, Rydell RE, Filice GA. Infection in the myelodysplastic syndromes. Am J Med. 1991;90: Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331: Cappellini MD. Iron-chelating therapy with the new oral agent ICL670 (Exjade). Best Pract Res Clin Haematol. 2005; 18: Kleinman S, Marshall D, AuBuchon J, Patton M. Survival after transfusion as assessed in a large multistate US cohort. Transfusion. 2004;44: Wallis JP, Wells AW, Matthews JN, Chapman CE. Long-term survival after blood transfusion: a population based study in the North of England. Transfusion. 2004;44: Amin M, Fergusson D, Aziz A, Wilson K, Coyle D, Hebert P. The cost of allogeneic red blood cells a systematic review. Transfus Med. 2003;13: Amin M, Fergusson D, Wilson K, et al. The societal unit cost of allogenic red blood cells and red blood cell transfusion in Canada. Transfusion. 2004;44: Casadevall N, Durieux P, Dubois S, et al, for The Groupe Francais des Myelodyplasies. Health, economic, and qualityof-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood. 2004;104: Jansen AJG, Essink-Bot M-L, Beckers EAM, Hop WCJ, Schipperus MR, Van Rhenen DJ. Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes. Br J Haematol. 2003;121: Patrick DL, Gagnon DD, Zagari MJ, Mathijs R, Sweetenham J, for the Epoetin Alfa Study Group. Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. Eur J Cancer. 2003;39: Clavio M, Nobili F, Balleari E, et al. Quality of life and brain function following high-dose recombinant human erythropoietin in low-risk myelodysplastic syndromes: a preliminary report. Eur J Haematol. 2004;72: Hellstrom-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol. 1995;89: Negrin RS, Stein R, Doherty K, et al. Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood. 1996;87: Mannone L, Gardin C, Quarre MC, Bernard JF, Giraudier S, Rosenthal E. High response rate to darbopoietin alfa in low risk MDS: results of Phase II study [abstract 69]. Blood. 2004;104(Part 1):24a. 31. Musto P, Lanza F, Balleari E, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2005;128: Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002;137:

8 2094 CANCER May 15, 2006 / Volume 106 / Number Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with low-risk myelodysplasia. Br J Haematol. 2003;120: Shimamoto T, Tohyama K, Okamoto T, et al. Cyclosporin A therapy for patients with myelodysplastic syndrome: multicenter pilot studies in Japan. Leuk Res. 2003;27: Raza A, Candoni A, Khan U, et al. Remicade as TNF suppressor in patients with myelodysplastic syndromes. Leuk Lymphoma. 2004;45: Saunthararajah Y, Nakamura R, Wesley R, Wang QJ, Barrett AJ. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood. 2003;102: Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55 CD59 blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107: Kuendgen A, Strupp C, Aivado M, et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004;104: Pilatrino C, Cilloni D, Messa E, et al. Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer. 2005;104: Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001;98: Strupp C, Germing U, Aivado M, Misgeld E, Haas R, Gattermann N. Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia. 2002;16: Musto P. Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives. Leuk Res. 2004;28: Moreno-Aspitia A, Geyer S, Li C-Y, et al. N998B: multicenter Phase II trial of thalidomide (Thal) in adult patients with myelodysplastic syndromes (MDS) [abstract 354]. Blood. 2002;100:96a. 44. Bouscary D, Quarre MC, Vassilief D, et al. Thalidomide for the treatment of low risk myelodysplasia. The Thal-SMD- 200 Trial from the French Group of Myelodysplasia (GFM) [abstract 1438]. Blood. 2004;104(Suppl):403a. 45. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004;4: List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352: List AF, Dewald G, Bennett J, et al. Hematologic and cytogenetic (CTG) response to lenalidomide (CC-5013) in patients with transfusion-dependent (TD) myelodysplastic syndrome (MDS) and chromosome 5q31.1 deletion: results of the multicenter MDS-003 Study [abstract 5]. J Clin Oncol. 2005;23:2s. 48. List AF, Gewald G, Bennett J, et al. Results of the MDS-002 and -003 international Phase II studies evaluating lenalidomide (CC-5013; Revlimida) in the treatment of transfusiondependent (TD) patients with myelodysplastic syndrome (MDS) [abstract 0772]. Haematologica. 2005;90(Suppl 2): Bartlett JB, Tozer A, Stirling D, Zeldis JB. Recent clinical studies of the immunomodulatory drug (IMiD ) lenalidomide. Br J Cancer. 2005;93: