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Volume 7 Supplement 9

JNCCN

Journal of the National Comprehensive Cancer Network

NCCN Task Force Report: Transfusion and Iron Overload in Patients With Myelodysplastic Syndromes Peter L. Greenberg, MD; Cynthia K. Rigsby, MD; Richard M. Stone, MD; H. Joachim Deeg, MD; Steven D. Gore, MD; Michael M. Millenson, MD; Stephen D. Nimer, MD; Margaret R. O’Donnell, MD; Paul J. Shami, MD; and Rashmi Kumar, PhD

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NCCN appreciates that supporting companies recognize NCCN’s need for autonomy in the development of the content of NCCN resources. All NCCN content is produced completely independently. NCCN Guidelines are not intended to promote any specific therapeutic modality. The distribution of this task force report is supported by an educational grant from Novartis Oncology.

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Volume 7 Supplement 9 Journal of the National Comprehensive Cancer Network Masthead

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Editorial Editor-in-Chief: Harold J. Burstein, MD, PhD National Comprehensive Cancer Network Senior Director, Professional and Patient Publications: Kimberly A. Callan, MS, ELS Assistant Managing Editor: Kerrin Robinson, MA Editorial Associate: Genevieve Emberger Hartzman, MA National Comprehensive Cancer Network Chairman of the Board: Al B. Benson III, MD Vice Chair of the Board: Thomas A. D’Amico, MD Chief Executive Officer: William T. McGivney, PhD Executive Vice President/Chief Operating Officer: Patricia J. Goldsmith Senior VP, Finance/Chief Financial Officer: Lisa Kimbro, CPA, MBA Clinical Practice Guidelines Senior VP, Clinical Information and Publications: Joan S. McClure, MS VP, Clinical Information Operations: Kristina M. Gregory, RN, MSN, OCN Associate Director, Clinical Information: Dorothy A. Shead, MS Guidelines Coordinators: Nicole R. McMillian, MS Mary Dwyer Rosario, MS Oncology Scientists/Sr. Medical Writers: Miranda Hughes, PhD Hema Sundar, PhD Susan J. Moench, PhD Rashmi Kumar, PhD Maria Ho, PhD Administrative Coordinators: Mary Anne Bergman Jean Marie Dougherty Business Development and Marketing Director, Pharma/Biotech: C. Lyn Fitzgerald Senior Manager, Communications and Marketing: Jennifer Tredwell, MBA Advertising Harborside Press Director of Business Development: David Horowitz Publishing and Design Harborside Press Executive Editor: Conor Lynch Editorial Assistant: Sarah McGullam Production Coordinator: Wendy McGullam President: Anthony Cutrone Publisher: John A. Gentile, Jr.

JNCCN (ISSN 1540-1405), the official journal of the National Comprehensive Cancer Network, is published 12 times annually by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724. Copyright © 2009 by the National Comprehensive Cancer Network. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from NCCN. Subscriptions: Prices for yearly subscriptions (10 issues plus supplements) are: Individual: Print only or online only, US $440; Can/Mex + Int’l $545; print and online, US $485; Can/Mex + Int’l $610. Institutional: Print only or online only, US $685; Can/Mex + Int’l $790; print and online, US $750; Can/ Mex + Int’l $865. Single Copy: US $70.00; Can/Mex $85.00; Int’l $95.00. Subscription Inquiries should be directed to Wendy McGullam, Harborside Press, at: 631-692-0800 x303 or [email protected]. Online access is available to subscribers through IngentaConnect (www.ingentaconnect.com). Contact Information Editorial Office: Manuscripts, correspondence, and commentaries to be considered for publication should be sent to Kimberly Callan, Senior Director, Professional and Patient Publications, JNCCN, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; or e-mail [email protected]. Correspondence can also be faxed: 215-690-0283 (attn: JNCCN). Questions about requirements for publication or topic suitability can be directed as above or to Harold J. Burstein, MD, PhD, Editor-in-Chief, JNCCN, 275 Commerce Drive, Suite 300, Fort Washington, PA 19034; or e-mail [email protected]. Instructions for authors are published in JNCCN as space allows and can be found on-line at www.nccn. org/jnccn. They can also be requested by calling 215-690-0270 or e-mailing [email protected]. Advertising To purchase advertising space: Contact David Horowitz, Director of Business Development, Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724; phone 631-692-0800 x304; fax 631-692-0805; or e-mail [email protected]. To send film or digital ad materials: Ship to Harborside Press, Attn: Wendy McGullam, (JNCCN, Vol ___ Issue ___), 37 Main Street, Cold Spring Harbor, NY 11724; phone 631-692-0800 x303; fax 631-692-0805; or e-mail [email protected]. To send pre-printed inserts: Ship to Publishers Press, Inc., Attn: Tammy Baugh, 13487 South Preston Highway, Lebanon Junction, KY 40150. Production Reprints: Reprints of individual articles are available. Orders must be for a minimum of 100 copies. Please contact David Horowitz, Director of Business Development, Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724; phone 631-692-0800 x304; fax 631-692-0805; or e-mail [email protected]. Permissions For information about photocopying, republishing, reprinting, or adapting material, please go online to www.nccn.org/about/permissions/default.asp. Indexing JNCCN is indexed by MEDLINE/PUBMED®, Chemical Abstracts, EMBASE, EmCare, and Scopus. This paper meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper) effective with Volume 1, Issue 1, 2003. JNCCN is a member of the Medscape Publisher’s Circle®, an alliance of leading medical publishers whose content is featured on Medscape (http://www.medscape.com). Medscape is part of the WebMD Medscape Health Network, a leading online healthcare resource for professionals and consumers.

Disclaimer The treatment algorithms presented in JNCCN and its supplements are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual circumstances to determine any patient’s care or treatment. The research articles, reviews, and other individually authored papers presented herein are the work of the authors listed. Furthermore, the reader is advised that, except where specifically stated, all of the ideas and opinions expressed in JNCCN are the authors’ own and do not necessarily reflect those of NCCN, the member organizations, the editor, or the publisher. Publication of an advertisement or other product mention in JNCCN should not be construed as an endorsement of the product or the manufacturer’s claims. The information contained in JNCCN is presented for the purpose of educating our readership on cancer treatment and management. The information should not be relied on as complete or accurate, nor should it be relied on to suggest a course of treatment for a particular individual. It should not be used in place of a visit, call, consultation, or the advice of a licensed physician or other qualified health care provider. Patients with health care-related questions or concerns are advised to contact a physician or other qualified health care provider promptly. Although every attempt has been made to verify that information presented within is complete and accurate, the information is provided “AS IS” without warranty, express or implied. NCCN hereby excludes all implied warranties of merchantability and fitness for a particular use or purpose with respect to the Information. Furthermore, NCCN makes no warranty as to the reliability, accuracy, timeliness, usefulness, adequacy, completeness, or suitability of the information.

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Volume 7 Supplement 9 Journal of the National Comprehensive Cancer Network Mission Statement NCCN Member Institutions City of Hope Comprehensive Cancer Center Los Angeles, California Dana-Farber/Brigham and Women’s Cancer Center| Massachusetts General Hospital Cancer Center Boston, Massachusetts Duke Comprehensive Cancer Center Durham, North Carolina Fox Chase Cancer Center Philadelphia, Pennsylvania Huntsman Cancer Institute at the University of Utah Salt Lake City, Utah Fred Hutchinson Cancer Research Center/ Seattle Cancer Care Alliance Seattle, Washington The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois Memorial Sloan-Kettering Cancer Center New York, New York H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute Columbus, Ohio Roswell Park Cancer Institute Buffalo, New York Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, Missouri St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute Memphis, Tennessee Stanford Comprehensive Cancer Center Stanford, California University of Alabama at Birmingham Comprehensive Cancer Center Birmingham, Alabama UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan UNMC Eppley Cancer Center at The Nebraska Medical Center Omaha, Nebraska The University of Texas M. D. Anderson Cancer Center Houston, Texas Vanderbilt-Ingram Cancer Center Nashville, Tennessee For more information, visit www.NCCN.org

JNCCN is dedicated to improving the quality of cancer care locally, nationally, and internationally while enhancing the collaboration between academic medicine and the community physician. JNCCN is further committed to disseminating information across the cancer care continuum by publishing clinical practice guidelines and reporting rigorous outcomes data collected and analyzed by experts from the world’s leading care centers. JNCCN also provides a forum for original research and review papers focusing on clinical and translational research and applications of the NCCN Guidelines in everyday practice, as well as correspondence and commentary.

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About the NCCN The National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 21 of the world’s leading cancer centers, is dedicated to improving the quality and effectiveness of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives. For more information, visit www.NCCN.org.

Volume 7 Supplement 9

JNCCN

Journal of the National Comprehensive Cancer Network

NCCN Task Force: Transfusion and Iron Overload in Patients With Myelodysplastic Syndromes *PPeter L. Greenberg, MD/Chair‡ Stanford Comprehensive Cancer Center *PH. Joachim Deeg, MDξ‡† Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance *Steven D. Gore, MD‡† The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins *Rashmi Kumar, PhD National Comprehensive Cancer Network

*Michael M. Millenson, MD‡Þ Fox Chase Cancer Center *Stephen D. Nimer, MD‡† Memorial Sloan-Kettering Cancer Center *Margaret R. O’Donnell, MDξ‡ City of Hope Comprehensive Cancer Center *PCynthia K. Rigsby, MD€ Children’s Memorial Hospital *Paul J. Shami, MD‡ Huntsman Cancer Institute at the University of Utah

*PRichard M. Stone, MD‡ Dana-Farber Cancer Institute

KEY: *Writing Committee Member; PPresenter Specialties: ‡Hematology/ Hematology Oncology; ξBone Marrow Transplantation; †Medical Oncology; ÞInternal Medicine; €Pediatric Oncology

Disclosure of Affiliations and Significant Relationships Dr. Greenberg has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. He is an institutional principal investigator for Amgen Inc. and Celgene Corporation. He is an advisory board member and consultant for Novartis Pharmaceuticals Corporation. Dr. Deeg has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Gore has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Kumar has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. She is an employee of the National Comprehensive Cancer Network. Dr. Millenson has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Nimer has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. O’Donnell has disclosed that she has no financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. Dr. Rigsby has disclosed that she has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. She is a principal investigator for Children’s Memorial Hospital. Dr. Shami has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. He is the on the speakers’ bureau for Novartis Pharmaceuticals Corporation. Dr. Stone has disclosed that he has financial interests, arrangements, or affiliations with the manufacturer of products and devices discussed in this report or who may financially support the educational activity. He is a consultant for Bristol-Myers Squibb Company; Celgene Corporation; Eisai, Inc.; Genzyme Corporation; Merck & Co., Inc.; and Novartis Pharmaceuticals Corporation. He is a member of the speakers’ bureau for Celgene Corporation and receives clinical research support for Novartis Pharmaceuticals Corporation.

JNCCN

Volume 7 Supplement 9 Journal of the National Comprehensive Cancer Network Continuing Education Information CME Accreditation The National Comprehensive Cancer Network (NCCN) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The NCCN designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation on the activity. This educational activity was planned and produced in accordance with ACCME Essential Areas and Policies. The NCCN adheres to the ACCME Standards for Commercial Support of Continuing Medical Education. This activity is approved for 1.0 contact hours. NCCN is an approved provider of continuing nursing education by the PA State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Approval as a provider refers to recognition of educational activities only and does not imply ANCC Commission Accreditation of PA Nurses approval or endorsement of any product. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

Target Audience This educational program is designed to meet the needs of oncologists, advanced practice nurses, and other clinical professionals who treat and manage patients with cancer. Educational Objectives After completion of this CME activity, participants should be able to: • Describe risk factors for development of iron overload in patients with MDS; • Give examples of the consequences of iron overload in patients with MDS; • List the essential tests for the monitoring of patients at risk for iron overload; and • Discuss current strategies for the management of iron overload in patients with MDS. The opinions expressed in this publication are those of the participating faculty and not those of the National Comprehensive Cancer Network, Novartis Oncology, or the manufacturers of any products mentioned herein. This publication may include the discussion of products for indications not approved by the FDA. Participants are encouraged to consult the package inserts for updated information and changes regarding indications, dosages, and contraindications. This recommendation is particularly important with new or infrequently used products. Activity Instructions Participants will read all portions of this monograph, including all tables, figures, and references. A post-test and an evaluation form follow this activity, both of which require completion. To receive a continuing education certificate, a score of at least 70% on the post-test is required. The post-test and evaluation form must be completed and returned by December 31, 2010. It should take approximately 1.0 hours to complete this activity as designed. There are no registration fees for this activity. Certificates will be e-mailed within 4 to 6 weeks of receipt of the post-test. Copyright 2009, National Comprehensive Cancer Network (NCCN). All rights reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining written permission from the NCCN.

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NCCN Task Force: Transfusion and Iron Overload in Patients With Myelodysplastic Syndromes Peter L. Greenberg, MD; Cynthia K. Rigsby, MD; Richard M. Stone, MD; H. Joachim Deeg, MD; Steven D. Gore, MD; Michael M. Millenson, MD; Stephen D. Nimer, MD; Margaret R. O’Donnell, MD; Paul J. Shami, MD; Rashmi Kumar, PhD

Key Words Transfusion, iron chelation, iron overload, myelodysplastic syndromes, thalassemia, MRI, non–transferrin-bound iron Abstract The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force to critically review the evidence for iron chelation and the rationale for treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS). The task force was charged with addressing issues related to tissue iron toxicity; the role of MRI in assessing iron overload; the rationale and role of treating transfusional iron overload in patients with MDS; and the impact of iron overload on bone marrow transplantation. This report summarizes the background data and ensuing discussion from the NCCN Task Force meeting on transfusional iron overload in MDS. (JNCCN 2009;7[Suppl 9]:S1–S16)

Background The myelodysplastic syndromes (MDS) represent a heterogeneous group of bone marrow stem cell diseases largely characterized by ineffective hemopoiesis leading to cytopenias and, in many patients, progression to acute myeloid leukemia. The prognosis of patients with MDS may be determined using the International Prognostic Scoring System (IPSS) that emerged from deliberations of the International Myelodysplastic Risk Analysis Workshop.1 Patients with MDS are stratified into 4 risk categories based on the IPSS score: low, intermediate-1, intermediate-2, and high. Physicians use the IPSS risk category to help determine therapeutic strategy. Patients are diagnosed with MDS at a median age of 70 years; comorbid conditions often play a major role in determining optimal therapy. Although increasing the overall survival is usually the most important goal,

improvement in hematologic parameters, suppression of leukemic transformation, and enhancing quality of life often represent key issues in evaluating a given therapy. Novel therapies with potential to improve symptomatic cytopenias and change the natural history of the disease are being developed. The most typical clinical feature of MDS is anemia, which is present in approximately 90% of patients at diagnosis and varies in severity. Red blood cell (RBC) transfusions are currently a key component of supportive care, as highlighted by the NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org).2 These guidelines also suggest platelet transfusions for patients with severe thrombocytopenia or thrombocytopenic bleeding. Iron overload may be a complication of prolonged and frequent RBC transfusions. Iron participates in intracellular reactions that generate free radicals, inducing oxidative stress and apoptosis. In patients with β-thalassemia, it has been well documented that iron overload negatively impacts survival and quality of life.3 Effective iron chelation has been shown to improve overall survival and cardiac, endocrine, and gonadal function in patients with thalassemia.4,5 A major question relates to whether these results can be extrapolated to patients with MDS. Indirect evidence, obtained retrospectively, suggests transfusional iron overload could be a contributor to increased mortality and morbidity in early-stage MDS.6 Iron overload–related oxidative stress and mitochondrial dysfunction may account for these negative findings. Therefore, iron overload has deleterious intracellular physiologic consequences and could be clinically important, making the use of chela-

© Journal of the National Comprehensive Cancer Network | Volume 7 Supplement 9 | December 2009

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tion therapy worthy of consideration. However, the true clinical value of iron chelation in MDS remains unclear. This state of uncertainty is from the lack of prospective evidence documenting improvement in survival or increase in cardiac and other organ function, especially given the side effects and expense of chelation therapy. The NCCN convened a multidisciplinary task force meeting to critically review the evidence for and against iron chelation in treating transfusional iron overload in patients with MDS. The task force, which consisted of 9 members with expertise in MDS within the fields of medical oncology, hematology, bone marrow transplantation, radiology, and interventional radiology, evaluated the issue of iron toxicity and chelation in patients with MDS. All members were from NCCN member institutions and were identified and invited solely by NCCN. The meeting was held on October 26, 2009, in Philadelphia, Pennsylvania. The members provided didactic presentations on topics such as the basic mechanisms of tissue iron toxicity in iron overload states, comparing MDS with thalassemia; the role of MRI in assessing iron overload; the evaluation of iron overload and chelation in MDS; and the impact of iron overload on bone marrow transplantation. The presentations were followed by extensive discussions. This report summarizes the background data and ensuing discussions from the meeting.

Basic Mechanisms of Tissue Iron Toxicity in Iron Overload States: MDS Versus Thalassemia Presented by Peter L. Greenberg, MD

Total body iron balance depends on several processes: absorption of exogenous iron from dietary sources, recycling of endogenous iron from the hemoglobin of dead or damaged red blood cells, and loss of iron through physiologic means.7 Understanding the critical molecular mechanisms related to iron handling would be optimal for the development of therapeutic interventions. In most cases of iron overload, whether hereditary or from RBC transfusion, the export of iron from the cells overwhelms the ability of transferrin to bind iron (Fe3+) leading to free, non–transferrin-bound iron (NTBI).8 NTBI is higher in patients with lowrisk than in those with high–risk MDS, and is associ-

ated with ineffective erythropoiesis.9 The redox-active component of NTBI, termed labile plasma iron (LPI), is the toxic compound and facilitates entry of iron into cells, causing a marked rise in labile cell iron (LCI).10,11 This in turn mediates tissue damage through superoxide generation, redox reactions, gene modulation, and direct interaction with ion channels. Intracellular iron concentrations control the production of ferritin, which sequesters iron (Fe3+) for later use, whereas unsequestered iron may be transported out of the cell through the export protein ferroportin. Ferroportin expression is negatively regulated by hepcidin.12 Hepcidin, primarily made in hepatocytes, and which increases in response to high liver iron levels (iron overload) and inflammation, is one of the main iron regulatory hormones. Hepcidin binds ferroportin on enterocytes and macrophages and triggers its internalization and lysosomal degradation.12 Increased hepcidin levels block absorption and recycling of iron. Decreased levels of hepcidin occur in response to anemia, hypoxia, and enhanced erythropoiesis (which in MDS could be predominantly from ineffective erythropoiesis). Hepcidin deficiency allows greater export of iron from macrophages, thus lowering macrophage cytoplasmic iron and suppressing secretion of soluble ferritin. Additionally, it results in increased iron absorption, oversaturation of transferrin, and accumulation of NTBI, leading to predominantly parenchymal iron overload. Therefore, low hepcidin expression may lead to iron overload. Because hepcidin normally acts to retain iron in the liver13 and spleen,14 the lack of hepcidin in the high-iron milieu could expose other organs, such as the heart, to iron loading. In contrast, in chronic inflammation and anemia, the excess of hepcidin decreases iron absorption and prevents iron recycling. Although the principal cause of iron overload in patients with MDS is RBC transfusions, increased absorption of iron from the gut and poor use of iron by RBC precursors from ineffective erythropoiesis may also contribute to this process. The hemochromatosis gene mutation or aberrant expression of other regulators of iron metabolism may also cause iron overload through suboptimal levels of hepcidin. In a small study of patients with MDS, urinary hepcidin excretion was undetectable or inappropriately low in most patients despite iron overload,15 similar to findings in thalassemia intermedia and contrary to findings in thalassemia major.16 In thalassemia major,


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Transfusion and Iron Overload in Myelodysplastic Syndromes

iron overload is attributed mainly to blood transfusions required for treatment, but is also caused by increased iron absorption. In contrast, patients with thalassemia intermedia have a milder form of anemia and remain largely transfusion-independent. Nevertheless, patients with thalassemia intermedia also experience iron overload because of increased iron absorption from greatly expanded but ineffective erythropoiesis.17 Low levels of hepcidin seen in patients with MDS15 could be a result of ineffective erythropoiesis. Patients with thalassemia major frequently experience ironinduced heart disease and endocrinopathies. Diagnosis of iron overload is largely based on serum ferritin assays, with the general standard being iron staining of liver biopsies, which is frequently impractical. However, because serum ferritin levels may be a poor predictor of impending cardiac iron overload, more sensitive indicators are needed. MRI is a noninvasive, albeit expensive, test that has been used with encouraging results in monitoring iron overload, and may be useful for gauging the effectiveness of chelation therapy in thalassemia. However, MRI seems to mainly detect inert iron in the form of ferritin, not NTBI, which is a key mediator of damage from iron overload (see The Role of MRI in Assessing Iron Overload; below). Normally when the capacity of plasma transferrin to bind iron is overwhelmed, NTBI (also termed LPI) appears in the plasma. Elevated LPI and LCI seem to be important mediators of tissue damage.10,11 Therefore, mechanisms that may lead to cardiac iron deposition, especially as it relates to hepcidin level, ineffective erythropoiesis, and elevated NTBI/LPI, need further evaluation in larger studies. Prospective studies are needed to evaluate these issues and, most importantly, assess how they correlate with cardiac versus liver iron deposition and improvement in organ function or overall survival with chelation therapy. Other preliminary data suggest that chelation could theoretically improve outcomes of hematopoietic stem cell transplant (HSCT; see The Impact of Iron Overload on HSCT; page S-10).

The Role of MRI in Assessing Iron Overload Presented by Cynthia K. Rigsby, MD

Liver biopsy and serum ferritin have been used to

evaluate total body iron load. However, serum ferritin levels may also be elevated because of ineffective erythropoiesis or inflammatory conditions. Although liver iron content provides a good index of total body iron stores, an elevated liver iron level has no clearcut predictive value for cardiac iron loading. The relationship among serum ferritin, cardiac iron, and liver iron content is complex.18–20 Liver biopsy, which can accurately measure body iron content, is risky in patients with MDS, who typically have neutropenia or thrombocytopenia, and because abnormal platelet function may be prevalent. Not only is cardiac biopsy highly invasive and expensive but also the rightventricular biopsies usually performed may not yield an accurate representation of the iron content of the entire myocardium. MRI is a noninvasive tool for prospectively studying the interplay between hepatic and extrahepatic iron stores.20,21 Superconducting quantum interference device (SQUID), available in only a few centers, is another noninvasive technique that provides a direct evaluation of liver iron deposits. MRI is now considered a primary standard for assessing iron overload in patients with thalassemia because it can detect cardiac and liver iron overload and can accurately measure left-ventricular dimensions and function. Iron causes magnetic field distortion, and the MRI approach involves measuring the proton relaxation rates R2 (R2=1/T2) or R2-star (R2*=1/T2*). Iron burden is indicated by increase in the MRI parameters R2 and R2* and a concomitant decrease in T2 and T2* in a predictable and reproducible manner. T2* values not only inversely correlate with iron burden but also have functional implications in that T2* values less than 20 ms have a clear relationship with the potential for decreased ejection fractions.18 However, not all patients with low T2* values are symptomatic or have evidence of cardiac dysfunction. Nonetheless, myocardial T2* values less than 10 ms are considered severe and may be a reasonable indication for increased iron chelation in thalassemia. Unlike in thalassemia, however, no correlation was observed among increasing serum ferritin levels, hepatic iron overload, and myocardial T2* in patients with MDS22,23 (except those with > 60 units of RBCs). An MRI technique for measuring liver iron content was developed by St. Pierre et al.,24 who found that mean R2 correlated strongly with biopsy-determined liver iron concentration, as demonstrated across a


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broad range of liver iron values. Wood et al.19 confirmed the direct relationship of R2 and R2* with liver iron concentration. Although R2 and R2* data can be acquired on many standard clinical MRI machines, determination of liver iron content from these data requires postprocessing specialized analytical software that is not widely available for clinical use. MRI data from centers without postprocessing capability must be sent to centers that have the software for analysis. Cardiac siderosis occurs in all transfusional anemias, but the relative clinical risk depends on the underlying disease state, transfusional load, and chelation history. Cardiac function remains normal until late in the course of cardiac iron deposition; therefore, systolic dysfunction is a late marker for iron overload. Cardiac failure resulting from transfusional iron overload remains a common cause of death in patients with thalassemia major.3,25 Development of cardiac failure may be unpredictable and rapid. Abnormal T2* may be a helpful adjunct in predicting impending heart failure.18,20,21,26 The cardiomyopathy in thalassemia may be reversible if intensive iron chelation treatment is instituted in time. Introduction of T2* MRI to identify cardiac siderosis and appropriate intensification of iron chelation treatment has been shown to significantly improve survival of patients with thalassemia major.27 After chelation begins, improvement in cardiac function is seen well before T2* MRI improvement (5.7–7.9 ms/y). Iron bound to ferritin produces greater inhomogeneities in the magnetic field, leading to detectable changes in T2 and T2*. The free iron species have little or no effect on MRI measurements. Hence, MRI measures predominantly long-term storage depots of iron rather than the functionally active iron. This observation explains why some individuals may have massive cardiac iron deposition without cardiac symptoms or vice versa. Cardiac Iron in MDS

A recent study identified congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD) as independent predictors of survival in a large cohort of patients with newly diagnosed MDS. Not surprisingly, anemia and infection, common in MDS, severely exacerbated CHF and COPD.28 Data are limited concerning the role of cardiac iron overload in cardiac damage in patients with MDS. Cardiac iron deposits were observed at autopsy in patients with acute leukemia and those

with chronic anemias who had a very large number of prior RBC transfusions (> 75).29 Retrospective evidence shows increased cardiac mortality among patients who had increased ferritin or transfusion dependence.30,31 However, whether this effect is mediated by transfusional iron overload or is from the severity of the transfusion-dependent anemia per se is unknown.32 Recent studies using the MRI T2* technique have shown that cardiac iron accumulation, when detectable, is variable among patients, with no correlation among cardiac, serum ferritin, or hepatic iron.22,23,33 Di Tucci et al.23 used MRI T2* to study patients with MDS with chronic transfusion-dependent anemias and found that patients with hepatic iron overload, which was commonly detected on T2* MRI, showed no evidence of cardiac disease. Cardiac iron deposition was found only in a subset of patients with a heavy transfusion burden (approximately 60–100 RBC units). However, because MRI T2* does not detect NTBI/LPI, whether this parameter correlates with clinically important cardiac overload in MDS remains to be determined. Determining a possible relationship between cardiac iron loading and cardiac function is more complex in patients with MDS than in those with thalassemia because of the potential coexistence additional risk factors for cardiac disease. Park et al.34 evaluated the correlation between the T2* value and left ventricular ejection fraction in patients with MDS. Patients who received an RBC transfusion of 200 to 400 mL/kg showed a progressive decrease of T2* values, without a reduction in ejection fraction, even though patients who received an RBC transfusion of 400 mL/kg or more showed progressive cardiac failure. Although the study failed to show a linear correlation between T2* value and left ventricular ejection fraction, the results indicate that the T2* value of MRI could detect cardiac iron deposition before apparent myocardial dysfunction.34 Larger clinical studies are necessary to determine the relationship between iron overload and cardiac dysfunction in adults with MDS. The current NCCN guidelines2 recommend monitoring serum ferritin levels to help assess iron overload. Although ferritin measurements are less precise than cardiac or hepatic MRI or SQUID, ferritin measurements are currently the only practical way to assess iron stores in common clinical practice.


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Prior Studies Evaluating Iron Overload and Chelation in MDS Presented by Richard M. Stone, MD

Transfusion, Iron Overload, and Organ Dysfunction: Anemia has long been recognized as a potential risk factor for cardiac disease because it leads to increased cardiac demand and possibly high-output CHF. Most patients with MDS receive RBC transfusions at some point to treat symptomatic anemia. These patients have a significantly higher risk for cardiac-related events and death than nontransfused patients, indicating that secondary iron overload may be clinically problematic.6,35,36 The WHO prognostic scoring system (WPSS), which incorporates the WHO-based morphologic categories, has shown that the requirement for RBC transfusions is a negative prognostic factor for patients with MDS.37 Although most important in patients with lower-risk disease, the depth of anemia per se also has negative prognostic import for the intermediate IPSS categories.32 Limited evidence suggests that organ dysfunction can result from iron overload in patients with MDS. More than 25 years ago, Schafer et al.38 reported the clinical consequence of transfusional iron overload in 15 nonthalassemic adults older than 50 years who had anemia requiring transfusion. In most patients, the transfusion dependence was less than 4 years. Although no assessment of cardiac iron content was performed, liver biopsy indicated increased levels of iron in 10 of 15 patients. The authors also noted widespread cardiac, endocrine, and hepatic organ dysfunction that was attributed to transfusional iron overload. Another retrospective study showed iron overload and cardiac toxicity in heavily transfused MDS patients.39 No prospective data have compared different cohorts from the general population to confirm cardiac dysfunction as a significant problem in the natural history of MDS. In a retrospective analysis, Goldberg et al.40 compared the clinical sequelae in patients with newly diagnosed MDS followed up over 3 years with that in patients without MDS in the Medicare population. The patients with MDS in this study (n = 705) were older than the overall Medicare population, and consisted of more men (49% vs. 42%). The diagnosis of MDS was confirmed with bone marrow evaluation in 57% of patients (n = 400), and the MDS diagnostic code was applied by

the treating physician based on clinical impression in the remaining 43%. During the 3-year followup, diabetes, hepatic problems, and infections were more common in patients with MDS receiving RBC transfusions than in those who were not and those in the overall Medicare population. Importantly, among patients with MDS, 522 (74%) experienced a cardiac-related event, compared with 42% in the non-MDS population. Furthermore, 80% of patients with MDS who received transfusions experienced a cardiac event, compared with 69% of patients who were not transfused, suggesting that either chronic anemia or transfusional iron overload contributed to cardiac dysfunction. Prospective studies correlating iron overload with increased mortality in patients with MDS are lacking. In a large retrospective analysis of 467 patients with MDS, Malcovati et al.37 found that patients who were RBC transfusion–dependent had significantly decreased overall survival than those who were not. The hazard ratio for overall survival was 1.36 for every 500 ng/L increase in serum ferritin level greater than 1000 ng/L. In addition, cardiac deaths were more common in the transfusion-dependent group. The number of transfusions needed per month, adjusted for cytogenetics, had a negative impact on overall survival in all low-risk histologies.37 In contrast, a study by Chee et al.41 found that neither the serum ferritin nor the number of RBC transfusions predicted survival in 126 patients with refractory anemia with ringed sideroblasts. The results of the study confirmed previous observations that RBC requirement at diagnosis was an IPSS-independent adverse prognostic factor, thus suggesting that transfusion dependency is a marker of more advanced disease.6 However, although no evidence showed that serum ferritin or numbers of transfusions contributed to the 83 deaths, only 47 patients had available autopsy information. Of interest are the recent preliminary data from Sanz et al.42 They sought to evaluate the independent prognostic value of transfusion dependency (as defined in WPSS) and iron overload (defined as serum ferritin level > 1000 ng/mL) in a large series of 2994 patients (median age, 74 years) with de novo MDS according to French-American-British (FAB) criteria (2107 with MDS according to WHO criteria). Median overall survival for patients who were transfusiondependent at diagnosis, those transfused during the


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course of their disease, and those who were nontransfused was 19, 60, and 96 months, respectively. Multivariate analyses in a set of 902 cases with complete data confirmed that serum ferritin and transfusion dependency were strongly and independently associated with overall survival. Furthermore, multivariate analyses showed that serum ferritin and transfusion dependency carried independent risks for AML transformation. This study confirms the negative impact of transfusion dependency on poorer outcomes.6,41 Large randomized prospective studies are needed to confirm that transfusional iron overload is independently associated with an increased risk for AML transformation and decreased overall survival, as opposed to being a marker of more aggressive disease. Prospective trials are also needed to evaluate whether chelation therapy to reduce iron overload will improve overall survival and reduce the risk for AML transformation in patients with MDS. A retrospective analysis showed that an elevated pretransplantation serum ferritin level adversely affects the outcome of patients with MDS undergoing HSCT after conventional conditioning35 (see “The Impact of Iron Overload on HSCT”). In patients with high serum ferritin, lower overall and disease-free survival was attributable to a significant increase in treatment-related mortality with a trend toward an increased risk for veno-occlusive disease. A clinical trial is underway to prospectively examine the feasibility of chelation therapy in the pretransplant setting. Taken together, the RBC transfusional need and markedly elevated serum ferritin levels correlate with worse outcome in patients with MDS, although the exact cause is not known. No prospective studies have shown that reducing either the number of transfusions

or the serum ferritin level is associated with longer or better quality of life in patients with MDS. Whether the increased risk for cardiac disease and death in transfused patients is because of the depth of anemia itself or because of iron or related moieties such as NTBI/LPI is unknown, highlighting the urgent need for prospective studies to answer these questions. Iron Chelation in MDS: Several studies have shown that chronic chelation therapy effectively reduces iron levels as measured by ferritin or LPI levels. Although strong prospective evidence shows that iron chelation improves overall survival and cardiac, endocrine, and gonadal function in patients with thalassemia,5 no prospective data are available for patients with MDS. Retrospective studies suggest that patients with MDS who undergo chelation live longer than those who do not;31,43 however, only small numbers of highly selected patients were included. In one small study, Jensen et al.44 found that patients who underwent long-term treatment with deferoxamine had improved hematopoiesis, lower transfusional requirements, and better blood counts than before therapy.44 However, the impact of chelation per se on survival is difficult to determine given the inherent biases in these analyses. Two iron-chelating agents are currently available in the United States: deferoxamine and deferasirox (see Table 1). A third iron-chelating agent, deferiprone, is approved in other countries, including Canada. Deferoxamine, the first iron-chelating agent approved by the FDA, is typically administered at doses of 20 to 60 mg/kg per day through subcutaneous infusion for 8 to 12 hours, 5 to 7 nights per week.45,46 Poor patient compliance attributable to its cumbersome administration schedule, and dermatologic and ocular side effects, limit its usefulness.

Table 1 Available Iron Chelation Agents Agent

Route of Administration

Half-life (hr)

Schedule

Clearance

Toxicity

Deferoxamine

SQ, IV

0.5

8–24 hr x 5–7 d/wk

Renal and hepatic

Infusion site and allergic reactions, ocular, auditory

Yes

Deferiprone, L1

Oral

2–3

tid

Renal

Neutropenia, agranulocytosis, nausea/vomiting, arthropathy

No

Deferasirox, ICL670

Oral

12–16

1x/d

Hepatobiliary

Transient nausea, diarrhea, rash, renal toxicity

Yes

Abbreviations: IV, intravenous; SQ, subcutaneous.


FDA approval

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In November 2005, the FDA granted expedited approval for deferasirox, an oral iron-chelating agent with a long enough half-life to allow once-daily dosing.47,48 Patients with thalassemia taking deferasirox have reported increased patient satisfaction and improved quality of life (> 90% of those treated with deferasirox vs. < 20% of those treated with deferoxamine were satisfied with treatment).49 Several studies have evaluated the safety and efficacy of deferasirox in patients with MDS. A recent study of 14 patients with lower-risk MDS who received deferasirox (500–1000 mg/d) for approximately 2 years50 showed that ferritin levels decreased during therapy in 13 patients, and in some of these patients, elevated liver enzymes at baseline decreased progressively. No substantial change in transferrin saturation or transfusion frequency was noted. Side effects were mild and tolerable in most patients; deferasirox treatment was stopped in one patient because of impaired kidney function. The large multicenter EPIC trial included patients with various transfusion-dependent anemias, including MDS. It was designed to evaluate whether fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin trends and safety markers, could provide clinically acceptable chelation as measured by changes in serum ferritin levels.51 All patients in the trial received an initial dose of 10 or 30 mg/kg per day of

Mean LPI + SD (μmol/L)

1.0

deferasirox, depending on their degree of transfusion dependence. Overall, median serum ferritin decreased from baseline by 264 ng/mL after 1 year (P < .0001), at an average actual received dose of deferasirox of 22.2 ± 5.9 mg/kg per day. LPI, which is a toxic, directly chelatable form of NTBI (see section “Basic Mechanisms of Tissue Toxicity in Iron Overload States: MDS Versus Thalassemia”), seems to be a useful marker of tissue damage. Eliminating or reducing accumulation of LPI could potentially minimize iron-related morbidity and mortality. LPI may be a more specific marker of the biologic causes of tissue damage than serum ferritin.9–11 The effect of deferasirox on LPI levels was evaluated in patients with transfusion-dependent anemias enrolled in the EPIC trial.52 Of these patients, 305 had MDS. Deferasirox starting dose was determined based on RBC transfusion frequency. Dose adjustments in steps of 5 to 10 mg/kg per day (in the range of 0–40 mg/kg per day) were based on serum ferritin trends and safety markers. Results from the 1-year study (Figure 1) confirm that deferasirox provides sustained reduction in toxic LPI levels across various transfusion-dependent anemias, including MDS.52 Gattermann et al.,53 assessed the efficacy of deferasirox over 1 year in reducing body iron as indicated by changes in serum ferritin in patients with MDS enrolled in the EPIC trial. Median serum ferritin values at baseline, and at 3, 6, 9, and 12 months were

Pre-administration Post-administration

0.8 MDS (n = 305) 0.6 Normal threshold

0.4 0.2 0 Baseline

Week 12

Week 28

Week 52

Figure 1 Effect of deferasirox on labile plasma iron (LPI) levels in heavily iron-overloaded patients with MDS and transfusion-

dependent anemias. The dotted line represents the normal threshold for LPI (< 0.4 μmol/L). Data from Porter JB, Cappellini MD, ElBeshlawy A, et al. Effect of deferasirox (Exjade(R)) on labile plasma iron levels in heavily iron-overloaded patients with transfusiondependent anemias enrolled in the large-scale, prospective 1-Year EPIC trial [abstract]. Blood 2008;112:Abstract 3881.


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Median serum ferritin (ng/mL)

3,000 2,500 2,000 All patients (n = 341) 1,500 1,000 500

Decrease from baseline: −253.0 ng/mL (last observation carried forward), P = .0019 Mean (± SD) dose: 19.2 ± 5.4 mg/kg per day

0 BL

3

6

9

12

Years Figure 2 Serum ferritin during 1 year of deferasirox treatment in transfusion-dependent patients with MDS. Data from Gattermann

N, Schmid M, Porta MD, et al. Efficacy and safety of deferasirox (Exjade(R)) during 1 year of treatment in transfusion-dependent patients with myelodysplastic syndromes: results from EPIC trial [abstract]. Blood 2008;112:Abstract 633.

2729.5 (range, 951–9465 ng/mL; n = 336), 2358.0 (range, 534–46,569 ng/mL; n = 263), 2209.5 (range, 357–10,066 ng/mL; n = 230), 2076.0 (range, 358– 25,839 ng/mL; n = 197), and 1903.5 ng/mL (range, 141–10,155; n = 174), respectively (see Figure 2). Overall, 49% of patients with MDS (n = 166) discontinued deferasirox therapy; 78 patients (23%) withdrew because of adverse events, of whom 44 (13%) experienced drug-related adversities and 26 (8%) died (no deaths were believed to be treatment-related, per investigator assessment). The most common investigator-assessed drug-related adverse events were diarrhea (n = 110; 32%), nausea (n = 45; 13%), vomiting (n = 26; 8%), abdominal pain (n = 26; 8%), upper abdominal pain (n = 25; 7%), skin rash (n = 23; 7%), and constipation (n = 21; 6%); 25 discontinued study drug for drug-related gastrointestinal adversities. Most adverse events were mild-tomoderate (95%) in severity. In total, 14.7% had 2 consecutive serum creatinine values more than 33% greater than baseline (in normal range), 10.6% had 2 values above upper limit of normal (ULN), and 85 (24.9%) had both 2 consecutive values greater than 33% and greater than ULN; no progressive increases occurred. Increase in alanine aminotransferase greater than 10 times ULN on 2 consecutive visits occurred in 1 patient (< 1%) who had normal levels at baseline.53 US03 was a phase II, open-label, 3-year trial de-

signed to evaluate the long-term efficacy and safety of deferasirox in patients with lower-risk MDS.54 The initial deferasirox dose was 20 mg/kg per day and was increased to 40 mg/kg per day based on tolerability and response. Serum ferritin was monitored monthly; LPI was assessed quarterly. The major inclusion criteria for patients in this study included low- or intermediate-1 IPSS-risk MDS; transfusional iron overload (serum ferritin, 1000 ng/mL, and RBC transfusions, > 20 units); serum creatinine less than 2 times ULN; minimal or no proteinuria; with or without prior chelation. Results after 12 months of chelation in 176 enrolled patients (mean age, 70 years) showed that the mean dose of deferasirox was 21 mg/kg per day and the mean transfusion rate was 3.4 units per month. The mean serum ferritin values at baseline and at 3, 6, 9, and 12 months were 3397 ± 233 (n = 176), 3057 ± 144 (n = 143), 2802 ± 128 (n = 126), 2635 ± 148 (n = 109), and 2501 ± 139 (n = 93), respectively (see Figure 3). In patients with elevated baseline LPI, sustained suppression of mean LPI to the normal range was achieved after 3 months of treatment (see Figure 4). Hematologic improvement by International Working Group (IWG) 2000 criteria was achieved in 8 patients (5%): erythroid response in 5 (major 3; minor 2), platelet response in 1 (major), neutrophil response in 1 (major), and combined platelet and neutrophil response in 1. Serious and other ad-


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MDS.55 Among 15 iron-overloaded patients with lower-risk MDS (5 men and 10 women; mean age, 66 years), 12 received 20 mg/kg per day of deferasirox and 3 received a lower dose of 4 to 6 mg/kg per day (because of side effects, mainly gastrointestinal, increased creatinine, and rash) for an average of 95 days (range, 63–163 days). The mean number of transfusions was 65 RBC units and the mean ferritin level before treatment was 3008 ng/mL (+/– 1797 ng/mL). Results showed a statistically significant decrease in reactive oxygen species (28%), lipid peroxidation (138%), and the cellular labile iron pool (23%) of RBC, with a concomitant increase in levels of the antioxidant reduced glutathione (123%). In 8

verse events seen in this study were similar to those observed in prior studies with deferasirox; 17 deaths (10%) occurred, all believed to be unrelated to deferasirox. The 2-year extension phase of this study will assess the long-term safety and efficacy of deferasirox and the clinical impact on organ function. LPI and LCI play an important role in generating reactive oxygen species with resultant cellular, tissue, and organ damage (see section “Basic Mechanism of Tissue Toxicity in Iron Overloaded States: MDS Versus Thalassemia”). Preliminary data suggest that treatment with deferasirox reduces not only the toxic iron species but also several other parameters of oxidative stress in iron overloaded patients with

Mean serum ferritin (ng/mL)

A 4000

3397 ± 233

3057 ± 144

2802 ± 128

2635 ± 148

2501 ± 139

Baseline (n = 176)

3 Mo (n = 143)

6 Mo (n = 126)

9 Mo (n = 109)

12 Mo (n = 93)

3500 3000 2500 2000 1500 1000 500 0

Timepoint

Mean serum ferritin (ng/mL)

B 200

-365 ± 210

-682 ± 262

-881 ± 303

-760 ± 148

9 Mo (n = 109)

12 Mo (n = 93)

0 -200 -400 -600 -800 -1000 -1200 3 Mo (n = 143)

6 Mo (n = 126)

Timepoint

Figure 3 Serum ferritin of transfusion-dependent patients with MDS at baseline and after treatment of deferasirox. (A) Mean serum

ferritin level at baseline and at every 3 months for 1 year. (B) Change in serum ferritin levels compared with baseline at quarterly intervals. Data from (A) and adapted from (B) List AF, Baer MR, Steensma D, et al. Iron chelation with deferasirox (Exjade(R)) improves iron burden in patients with myelodysplastic syndromes (MDS) [abstract]. Blood 2008;112:Abstract 634. Copyright © 2008 by American Society of Hematology (ASH). Reproduced with permission of American Society of Hematology (ASH); permission conveyed through Copyright Clearance Center, Inc.


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Mean LPI (µmol/L)

1.0

P ≤ .00001*

0.8 0.6

Threshold of normal LPI (< 0.5 µmol/L)

0.4 0.2 0 BL

3

55

38

6

9

12

37

34

Months from baseline (BL) Patients, n

39

Figure 4 Change in labile plasma iron (LPI) compared with baseline levels over 12 months of deferasirox treatment in patients with MDS. *Comparison of baseline LPI versus each treatment time point. From List AF, Baer MR, Steensma D, et al. Iron chelation with deferasirox (Exjade(R)) improves iron burden in patients with myelodysplastic syndromes (MDS) [abstract]. Blood 2008;112:Abstract 634. Copyright © 2008 by American Society of Hematology (ASH). Reproduced with permission of American Society of Hematology (ASH); permission conveyed through Copyright Clearance Center, Inc.

patients the mean initial LPI levels of 0.39 units decreased to 0.12 units.55 Additional larger randomized studies assessing the correlation of these changes to the long-term morbidity, mortality, and quality of life of patients with MDS are warranted. A multicenter, randomized, double-blind, placebo-controlled trial of deferasirox in patients with MDS is planned. The primary end point of the trial will be event-free survival (death or nonfatal cardiac or hepatic event). Secondary end points include overall survival, organ function, and safety. The results from this trial are likely to provide clinically useful answers about the true value of iron chelation in patients with MDS who have transfusion dependence and iron overload. Therefore, the task force panel members highly recommend that eligible patients participate in this trial.

The Impact of Iron Overload on HSCT Presented by H. Joachim Deeg, MD

Allogeneic HSCT is currently the only treatment with curative potential for patients with MDS.56,57 This treatment can be associated with considerable morbidity and mortality; many elderly patients are not eligible for “standard” allogeneic transplanta-

tion, and careful patient selection is key to treatment success. More than 90% of MDS patients are likely to receive RBC transfusions at some point in their clinical course for treatment of symptomatic anemia. Consequently, most patients have a history of transfusions at HSCT. Transfusion requirement has been found to affect the outcome of patients with MDS and is considered an independent indicator of disease severity.6,37,41 Transfusion dependence also seems to be associated with reduced probability of survival after transplantation.6 In transfusion-dependent patients with thalassemia undergoing allogeneic HSCT, iron-related tissue damage is an important adverse prognostic factor.58 Iron overload may also be a factor that influences the timing of HSCT or impacts on transplant outcome in patients with MDS. Available data, such as those presented by Armand et al.35 (Figure 5), suggest that iron overload, as measured with serum ferritin levels, is associated with poor outcome after transplantation These results were confirmed in several additional retrospective transplantation studies. Platzbecker et al.36 showed that elevated ferritin levels had a negative impact on survival because of increased nonrelapse mortality and possibly more severe acute graft-versus-host disease (GVHD). The investigators also analyzed the effects of transfusion dependence


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on various MDS risk groups. The analysis suggested that transfusion independence, particularly among patients with intermediate-risk cytogenetics, is associated with better outcomes. Overall survival was inferior in patients with serum ferritin levels greater than 1000 ng/L (see Figure 6, in basic agreement with the findings of Armand et al.35). Kataoka et al.59 retrospectively evaluated 264 patients (including those with MDS) undergoing allogeneic HCT for hematologic malignancies from 1996 through 2006, and used pretransplantation serum ferritin levels as a surrogate marker of iron overload. At 5 years, patients with ferritin levels of 599 ng/mL or higher had significantly lower overall survival (33% vs. 64%) and higher nonrelapse mortality (35% vs. 14%) rates than those with lower ferritin levels.

In another recent retrospective study, Alessandrino et al.60 reevaluated the prognostic significance of pretransplantation transfusion history and secondary iron overload in a cohort of patients with MDS who underwent allogeneic HSCT between 1997 and 2007. They observed an inverse relationship between transfusion burden and probability of survival after transplantation. The posttransplantation outcome was comparable in patients who received 20 (or fewer) RBC units and those who were transfusionindependent. In multivariate analysis, transfusion dependence was found to be a risk factor for acute GVHD. In patients who underwent transplantation after conventional conditioning regimens, pretransplantation serum ferritin levels were inversely related to overall survival and correlated with nonrelapse

A

B 100

100 Ferritin 1st–3rd quartile Ferritin highest quartile

Ferritin 1st–3rd quartile Ferritin highest quartile

80

DIsease-free survival (%)

Overall survival (%)

80

60

40

20

P < .001

0

60

40

P < .001

20

0 0

1

2

3

4

5

6

7

8

0

1

2

Years from transplantation

4

5

6

7

8


D

C

100

100 Ferritin 1st–3rd quartile Ferritin highest quartile

80

Ferritin 1st–3rd quartile Ferritin highest quartile

80

60

Relapse (%)

Treatment-related mortality (%)

3

40

60

40

20

20

P = .7

P = .005 0

0 0

1

2

3

4

5


6

7

8

0

1

2

3

4

5

6

7

8


Figure 5 Outcome of patients with MDS stratified by pretransplantation ferritin level. Patients are stratified using the fourth quartile (ferritin 2515 ng/mL) versus the lower 3 quartiles. (A) Overall survival. (B) Disease-free survival. (C) Cumulative incidence of treatment-related mortality. (D) Cumulative incidence of relapse. From Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007;109:45864588. Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.


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90% 80%

% Patients

70% 60% 50% 40% 30% 20% 10% 0% 0

1

2

3

4

5

6

HCT-CI Figure 6 Pretransplant ferritin levels and hematopoietic stem cell transplant comorbidity index (HCT-CI). Reprinted from Platzbecker U, Bornhauser M, Germing U, et al. Red blood cell transfusion dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndrome (MDS). Biol Blood Marrow Transplant 2008;14:1217– 1225, Copyright © 2009, with permission from The American Society for Blood and Marrow Transplantation.

mortality. The impact of transfusion dependence was restricted to patients with MDS undergoing conventional (high-dose) conditioning, an approach that is known to confer a higher risk for transplant-related toxicity, whereas no significant effect was noticed in patients undergoing a reduced-intensity conditioning regimen before transplantation. Thus, several retrospective studies have confirmed the prognostic significance of transfusion history and pretransplantation serum ferritin levels in patients who undergo allogeneic HSCT. Other adverse consequences of iron overload in the HSCT setting may include increased risk for infections, which could lead to nonrelapse mortality. However, the relationship between iron and posttransplant toxicity and mortality, related to GVHD and infections, is not clearly understood. An association between iron overload and invasive fungal infections has been shown in several small studies. Altes et al.61 determined the frequency and severity of iron overload in a group of 59 patients who died after conventional-intensity autologous (n = 24) or allogeneic (n = 35) HSCT. Of these patients, 36 had myeloid malignancies, including MDS; 17 lymphoma; 4 myeloma; and 2 aplastic anemia. Of 32 patients with hepatic iron content less than 150 μmol/g dry weight, 4 (12%) showed invasive aspergillosis at autopsy, compared with 10 of 27

(37%) who had hepatic iron content of 150 μmol/g or greater. This study suggests a relationship between severe iron overload and invasive aspergillosis. However, this study is limited by its small size and potential confounding variables. Strasser et al.62 determined the iron content in marrow and liver in 10 consecutive allogeneic HSCT recipients, aged 10 to 59 years, who died 0.5 to 8.7 (median 2.2) years after transplantation. Patients had received 47.6 +/– 25.9 RBC units from disease diagnosis to death, including 30.2 +/– 17.4 units of red cells during the peri- and posttransplantation period. The median hepatic iron content was 4307 mg/g dry weight (range, 1832–13,120; normal, 530–900), and the median biochemically determined marrow iron was 1999 mg/g dry weight (range, 932–3942). A strong correlation was seen between morphometric marrow iron content and biochemical hepatic iron index. Again, data from these patients could be biased because only autopsy samples were evaluated. The liver is a target organ of GVHD. In one small report,63 6 patients (age range, 29–63 years) suspected of having hepatic GVHD were found in fact to have severe iron overload with serum ferritin concentrations of 2398 to 11159 ng/mL (4 patients also had liver biopsies showing high hepatic iron concentrations). Liver function improved with erythropoietin-assisted phlebotomy, resulting in nor-


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malization of liver function at a median of 7 months and serum ferritin at a median of 11 months. Immunosuppressive therapy (for presumed GVHD) was successfully tapered in all 4 patients who completed the phlebotomy program. This observation suggests that iron overload may have presented with features that were confused with GVHD but were, in fact, the cause of post–HSCT liver dysfunction. At a median follow-up of 50 months (range, 18–76 months) from transplantation and 25 months (range, 5–36 months) from ferritin normalization, all 4 patients still required maintenance phlebotomy. In summary, iron overload related to prior transfusion burden is common among patients with MDS who undergo HSCT. The WPSS, which includes transfusion dependence as a prognostic variable, may offer a better prognostic assessment of transplant outcome than the IPSS alone. Data indicate that transfusion-dependent patients with MDS have a reduced survival probability after conventional conditioning for HSCT.6,37 The increased risk for nonrelapse mortality is believed to be related to organ dysfunction secondary to iron overload (for which serum ferritin levels serve as a surrogate marker). Transfusions are also associated with increased rates of fungal infections and GVHD, possibly linked to increased serum ferritin levels. These factors support the study of iron chelators in the setting of clinical trials in patients with low- and intermediate-1– risk MDS who have had excessive RBC transfusions in the months or years pre-HSCT. Given that all studies have been retrospective, prospective studies are needed to arrive at a definitive answer.

Management Strategies for Iron Overload in MDS Panel Discussion

MDS presents significant health issues among older patients with substantial economic implications.64 Organ dysfunction is common in patients with transfusion dependency, although the cause is often unknown. Indirect evidence suggests that chronic anemia along with transfusional iron overload may lead to cardiac dysfunction. Therefore, strategies to improve anemia and maintain normal iron balance are desirable in patients with MDS receiving blood transfusions. The issue of chelation therapy in MDS remains highly controversial; although this approach

can lead to a more negative iron balance, the clinical benefit has not been established. Therefore, the panel members strongly support prospective, randomized, placebo-controlled trials designed to evaluate the clinical benefit of iron chelation for treating lower-risk MDS. Based on the available evidence, patients with lower-risk MDS may receive many RBC transfusions over an extended duration and are particularly at risk for developing transfusional iron overload, although the clinical consequences of this remain undefined. The NCCN guidelines2 and published consensus statements concur that patients with low-/intermediate-1–risk MDS receiving a high number (> 20–30) of RBC transfusions are most likely to benefit from iron chelation. Although serum ferritin levels are currently accepted as a surrogate marker for iron overload, serum ferritin may be elevated in acute or chronic inflammation, despite normal iron stores, and therefore levels should be interpreted with caution. MRI T2* may be used to measure tissue iron levels, when detectable, in cardiac and liver tissue. No prospective studies in MDS have validated a threshold for serum ferritin levels that should be used to initiate chelation therapy, if used at all. The threshold suggested in the literature for initiating chelation ranges from 1000 to 2500 ng/mL. Extrapolating from the thalassemia studies, the NCCN task force members recommend considering chelation therapy in patients with low- or intermediate-1–risk MDS who have undergone or are anticipated to undergo more than 20 units of RBC transfusions, for whom ongoing RBC transfusions are anticipated, and who have serum ferritin levels greater than 2500 ng/mL, aiming to decrease the levels to less than 1000 ng/mL. This is particularly important for those with preexisting cardiac disease. The currently available oral iron chelators deferipone (outside of the United States) and deferasirox, and the parenterally administered drug deferoxamine are potentially useful for treating iron overload states. These drugs can be given to patients with MDS, with careful consideration of the respective potential toxicities.

Conclusions This task force review discusses several critical is-


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sues involving iron overload in patients with MDS. The biologic mechanisms and consequences of iron overload in these patients who are frequently heavily transfused are described, with an emphasis on how NTBI and organ iron deposition contribute to the potential toxicity of tissue iron excess. Discussion of the potential usefulness of T2* MRI, an important noninvasive method for evaluating organs that are potentially damaged by iron overload, highlighted the value of assessing this parameter for the liver and heart. However, the implications of this technology in determining clinical outcomes of patients need further evaluation; one reason is that the MRI measures iron deposition but not NTBI. Evidence-based data were reviewed and reported from several retrospective studies showing parameters of iron overload in polytransfused patients with MDS. These patients seemed to be at risk for shortened survival and cardiac dysfunction. However, the number of transfusions associated with these findings is likely greater than that for patients with thalassemia. The current clinical guidelines and their limitations were reviewed. A critical issue requiring direct evaluation is whether iron chelation alters the natural history of patients with MDS who are frequently transfusiondependent. Although retrospective data have indicated the ability of iron chelation to decrease serologic and MRI parameters of iron overload in MDS, no prospective data on these patients indicate the clinical efficacy of iron chelation (e.g., improved survival, preservation of cardiac function) in contrast with clear data being available in patients with thalassemia major. Retrospective data indicate that patients with iron overload pre-HSCT are at risk for increased morbidity and mortality. Prospective controlled studies are clearly warranted to assess the clinical value of iron chelation in modifying these negative outcomes and to better define patients who should receive this therapy.

References 1. Greenberg P. The role of hemopoietic growth factors in the treatment of myelodysplastic syndromes. Int J Ped Hem-Onc 1997;4:231–238. 2. Greenberg P, Attar E, Battiwalla, M, et al. NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes, version 2.2010. Available at: http://www.nccn.org. Accessed December 11, 2009.

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25. Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med 1994;331:574–578. 26. Wood JC. Cardiac iron across different transfusion-dependent diseases. Blood Rev 2008;22(Suppl 2):14–21. 27. Modell B, Khan M, Darlison M, et al. Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2008;10:42. 28. Wang R, Gross CP, Halene S, Ma X. Comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes. Leuk Res 2009;33:1594–1598. 29. Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. Am J Med 1971;51:209–221. 30. Delea TE, Hagiwara M, Phatak PD. Retrospective study of the association between transfusion frequency and potential complications of iron overload in patients with myelodysplastic syndrome and other acquired hematopoietic disorders. Curr Med Res Opin 2009;25:139–147. 31. Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol 2007;78:487–494. 32. Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J Hematol 2008;83:765–770. 33. Konen E, Ghoti H, Goitein O, et al. No evidence for myocardial iron overload in multitransfused patients with myelodysplastic syndrome using cardiac magnetic resonance T2 technique. Am J Hematol 2007;82:1013–1016. 34. Park J, Ohyashiki K, Akata S, et al. Evaluation of cardiac iron overload in transfusion-dependent adult marrow failure patients by magnetic resonance imaging. Leuk Res 2009;33:756–758. 35. Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007;109:4586– 4588. 36. Platzbecker U, Bornhauser M, Germing U, et al. Red blood cell transfusion dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndrome (MDS). Biol Blood Marrow Transplant 2008;14:1217–1225. 37. Malcovati L, 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;23:7594–7603. 38. Schafer AI, Cheron RG, Dluhy R, et al. Clinical consequences of acquired transfusional iron overload in adults. N Engl J Med 1981;304:319–324. 39. Jaeger M, Aul C, Sohngen D, et al. Secondary hemochromatosis in polytransfused patients with myelodysplastic syndromes [in German]. Beitr Infusionsther 1992;30:464–468. 40. Goldberg SL, Mody-Patel N, Chen ER. Clinical and economic consequences of myelodysplastic myndromes in the United

42. Sanz G, Nomdedeu B, Such E, et al. Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome [abstract]. Blood 2008;112:Abstract 640. 43. Leitch HA. Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using iron chelation therapy. Leuk Res 2007;31(Suppl 3):S7–9. 44. Jensen PD, Heickendorff L, Pedersen B, et al. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol 1996;94:288–299. 45. Porter JB. Practical management of iron overload. Br J Haematol 2001;115:239–252. 46. Mahesh S, Ginzburg Y, Verma A. Iron overload in myelodysplastic syndromes. Leuk Lymphoma 2008;49:427–438. 47. Shashaty G, Frankewich R, Chakraborti T, et al. Deferasirox for the treatment of chronic iron overload in transfusional hemosiderosis. Oncology (Williston Park) 2006;20:1799–1806, 1811. 48. Goldberg SL. Novel treatment options for transfusional iron overload in patients with myelodysplastic syndromes. Leuk Res 2007;31(Suppl 3):S16–22. 49. Cappellini MD, Bejaoui M, Agaoglu L, et al. Prospective evaluation of patient-reported outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with beta-thalassemia. Clin Ther 2007;29:909–917. 50. Wimazal F, Nosslinger T, Baumgartner C, et al. Deferasirox induces regression of iron overload in patients with myelodysplastic syndromes. Eur J Clin Invest 2009;39:406–411. 51. Cappellini MD, El-Beshlawy A, Kattamis A, et al. Efficacy and safety of deferasirox (Exjade(R)) in patients with transfusiondependent anemias: 1-year results from the large, prospective, multicenter EPIC study [abstract]. Blood 2008;112:Abstract 3875. 52. Porter JB, Cappellini MD, El-Beshlawy A, et al. Effect of deferasirox (Exjade(R)) on labile plasma iron levels in heavily iron-overloaded patients with transfusion-dependent anemias enrolled in the large-scale, prospective 1-Year EPIC trial [abstract]. Blood 2008;112:Abstract 3881. 53. Gattermann N, Schmid M, Porta MD, et al. Efficacy and safety of deferasirox (Exjade(R)) during 1 year of treatment in transfusiondependent patients with myelodysplastic syndromes: results from EPIC trial [abstract]. Blood 2008;112:Abstract 633. 54. List AF, Baer MR, Steensma D, et al. Iron chelation with deferasirox (Exjade(R)) improves iron burden in patients with myelodysplastic syndromes (MDS) [abstract]. Blood 2008;112:Abstract 634. 55. Rachmilewitz E, Merkel D, Ghoti H, et al. Improvement of oxidative stress parameters in MDS patients with iron overload treated with deferasirox [abstract]. Blood 2008;112:Abstract 2675. 56. De Witte T, Zwaan F, Hermans J, et al. Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG). Br J Haematol 1990;74:151–155. 57. Deeg HJ, Shulman HM, Anderson JE, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 2000;95:1188–1194.


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Greenberg et al. 58. Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990;322:417–421. 59. Kataoka K, Nannya Y, Hangaishi A, et al. Influence of pretransplantation serum ferritin on nonrelapse mortality and nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2009;15:195–204. 60. Alessandrino EP, Della Porta MG, Bacigalupo A, et al. Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica 2009; in press. 61. Altes A, Remacha AF, Sarda P, et al. Frequent severe liver iron overload after stem cell transplantation and its possible association

with invasive aspergillosis. Bone Marrow Transplant 2004;34:505– 509. 62. Strasser SI, Kowdley KV, Sale GE, McDonald GB. Iron overload in bone marrow transplant recipients. Bone Marrow Transplant 1998;22:167–173. 63. Kamble RT, Selby GB, Mims M, et al. Iron overload manifesting as apparent exacerbation of hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006;12:506–510. 64. Greenberg PL, Cosler LE, Ferro SA, Lyman GH. The costs of drugs used to treat myelodysplastic syndromes following National Comprehensive Cancer Network Guidelines. J Natl Compr Canc Netw 2008;6:942–953.


S-17

Post-test

Please circle the correct answer on the enclosed answer sheet.

1. Low levels of hepcidin seen in MDS patients could be a result of ineffective erythropoiesis. a. True b. False 2. The current NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes recommend using MRI-T2* to help assess iron overload. a. True b. False 3. MRI predominantly measures long-term storage depots of iron rather than the functionally active iron; therefore, individuals may have massive cardiac iron deposition without cardiac symptoms. a. True b. False 4. There is evidence suggesting that iron overload and transfusion dependency are independently associated with risk for AML transformation. a. True b. False

6. Iron overload (for which serum ferritin levels serve as a surrogate marker) is associated with increased rates of fungal infections and graft versus host disease (GVHD) thus increasing the risks for non-relapse mortality after allogeneic stem cell transplantation. a. True b. False 7. The use of deferoxamine in iron chelation therapy is limited by poor patient compliance attributable to its cumbersome schedule of administration and its dermatologic and ocular side-effects. a. True b. False 8. Deferasirox provides sustained reduction in toxic labile plasma iron (LPI) levels across various transfusion-dependent anemias, including MDS. a. True b. False

5. The NCCN Transfusion and Iron Overload in Patients With MDS Task Force recommends considering chelation therapy in low- or intermediate-1–risk patients who have received or are anticipated to receive greater than 20 units of RBC transfusions, for whom ongoing RBC transfusions are anticipated; and who have serum ferritin levels less than 1000 ng/mL, aiming to decrease the levels to less than 1000 ng/mL. a. True b. False


S-18

Please circle the correct answer below. Post-Test Answer Sheet Please circle one answer per question. A score of at least 70% on the post-test is required. 1.

a

b

5.

a

b

2.

a

b

6.

a

b

3.

a

b

7.

a

b

4.

a

b

8.

a

b

The activity content helped me to achieve the following objectives: (1 = Strongly disagree; 3 = Not sure; 5 = Strongly agree) Describe risk factors for development of iron overload in patients with MDS. 1 2 3 4 Give examples of the consequences of iron overload in patients with MDS.

5

1 2 3 4 List the essential tests for the monitoring of patients at risk for iron overload.

5

1 2 3 4 Discuss current strategies for the management of iron overload in patients with MDS.

5

5

1

2

3

4

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The activity presented scientifically rigorous, unbiased, and balanced information.

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Disagree

Strongly disagree

Individual presentations were free of commercial bias.

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S-19

Registration for Credit

NCCN Task Force Report: Transfusion and Iron Overload in Patients With Myelodysplastic Syndromes Release Date: December 31, 2009 Expiration Date: December 31, 2010

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