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THE MYELODYSPLASTIC SYNDROMES
Pathobiology and Clinical Management

edited by
John M. Bennett
James P. Wilmot Cancer Center and
University of Rochester Medical Center
Rochester, New York

Marcel Dekker, Inc. New York • Basel

TM

Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.

ISBN: 0-8247-0782-6
This book is printed on acid-free paper.

Headquarters
Marcel Dekker, Inc.
270 Madison Avenue, New York, NY 10016
tel: 212-696-9000; fax: 212-685-4540

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tel: 41-61-261-8482; fax: 41-61-261-8896

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The publisher offers discounts on this book when ordered in bulk quantities. For more
information, write to Special Sales/Professional Marketing at the headquarters address
above.

Copyright  2002 by Marcel Dekker, Inc. All Rights Reserved.

Neither this book nor any part may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, microfilming, and recording,
or by any information storage and retrieval system, without permission in writing from
the publisher.

Current printing (last digit):

10 9 8 7 6 5 4 3 2 1

PRINTED IN THE UNITED STATES OF AMERICA

 BASIC AND CLINICAL ONCOLOGY

Editor
Bruce D. Cheson, M.D.
National Cancer Institute
National Institutes of Health
Bethesda, Maryland

1. Chronic Lymphocytic Leukemia: Scientific Advances and Clinical Developments,

edited by Bruce D. Cheson
2. Therapeutic Applications of Interleukin-2, edited by Michael B. Atkins and James
W. Mier
3. Cancer of the Prostate, edited by Sakti Das and E. David Crawford
4. Retinoids in Oncology, edited by Waun Ki Hong and Reuben Lotan
5. Filgrastim (r-metHuG-CSF) in Clinical Practice, edited by George Morstyn and T.
Michael Dexter
6. Cancer Prevention and Control, edited by Peter Greenwald, Barnett S. Kramer,
and Douglas L. Weed
7. Handbook of Supportive Care in Cancer, edited by Jean Klastersky, Stephen C.
Schimpff, and Hans-Jörg Senn
8. Paclitaxel in Cancer Treatment, edited by William P. McGuire and Eric K.
Rowinsky
9. Principles of Antineoplastic Drug Development and Pharmacology, edited by
Richard L. Schilsky, Gérard A. Milano, and Mark J. Ratain
10. Gene Therapy in Cancer, edited by Malcolm K. Brenner and Robert C. Moen
11. Expert Consultations in Gynecological Cancers, edited by Maurie Markman and
Jerome L. Belinson
12. Nucleoside Analogs in Cancer Therapy, edited by Bruce D. Cheson, Michael J.
Keating, and William Plunkett
13. Drug Resistance in Oncology, edited by Samuel D. Bernal
14. Medical Management of Hematological Malignant Diseases, edited by Emil J
Freireich and Hagop M. Kantarjian
15. Monoclonal Antibody-Based Therapy of Cancer, edited by Michael L. Grossbard
16. Medical Management of Chronic Myelogenous Leukemia, edited by Moshe
Talpaz and Hagop M. Kantarjian
17. Expert Consultations in Breast Cancer: Critical Pathways and Clinical Decision
Making, edited by William N. Hait, David A. August, and Bruce G. Haffty
18. Cancer Screening: Theory and Practice, edited by Barnett S. Kramer, John K.
Gohagan, and Philip C. Prorok

19. Supportive Care in Cancer: A Handbook for Oncologists: Second Edition,

Revised and Expanded, edited by Jean Klastersky, Stephen C. Schimpff, and
Hans-Jörg Senn
20. Integrated Cancer Management: Surgery, Medical Oncology, and Radiation
Oncology, edited by Michael H. Torosian
21. AIDS-Related Cancers and Their Treatment, edited by Ellen G. Feigal, Alexandra
M. Levine, and Robert J. Biggar
22. Allogeneic Immunotherapy for Malignant Diseases, edited by John Barrett and
Yin-Zheng Jiang
23. Cancer in the Elderly, edited by Carrie P. Hunter, Karen A. Johnson, and Hyman
B. Muss
24. Tumor Angiogenesis and Microcirculation, edited by Emile E. Voest and Patricia
A. D’Amore
25. Controversies in Lung Cancer: A Multidisciplinary Approach, edited by Benjamin
Movsas, Corey J. Langer, and Melvyn Goldberg
26. Chronic Lymphoid Leukemias: Second Edition, Revised and Expanded, edited by
Bruce D. Cheson

ADDITIONAL VOLUMES IN PREPARATION

 To my wife, Carol, and my children, Robert, Elizabeth, and Douglas,
without whose support and encouragement over the years
my career in academic medicine and the study of hematological malignancies
would never have occurred.

To Patricia Foley,
for outstanding technical support for my cytomorphology investigations.

To the thousands of patients with MDS,

who have taught me more about life and disease
than could be found in the medical literature.
Series Introduction

The current volume, The Myelodysplastic Syndromes: Pathobiology and Clinical

Management, is the twenty-seventh in the Basic and Clinical Oncology series.
Many of the advances in oncology have resulted from close interaction between
the basic scientist and the clinical researcher. The current volume illustrates the
success of this relationship as demonstrated by new insights into clinical drug
resistance and means of circumventing this potential obstacle to effective cancer
treatment.
As editor of the series, my goal is to recruit volume editors who not only
have established reputations based on their outstanding contributions to oncology,
but who also have an appreciation for the dynamic interface between the labora-
tory and the clinic. To date, the series has consisted of monographs on topics
that are of a high level of current interest. The Myelodysplastic Syndromes cer-
tainly fits into this category and is a most important addition to the series.

Bruce D. Cheson

v
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Preface

The myelodysplastic syndromes (MDS) are a group of potentially acute myeloid

leukemic disorders that have attracted considerable interest over the past two
decades. A delicate balance exists between accelerated program cell death
(apoptosis) and proliferation of the leukemic hematopoietic stem cell that permits
many patients to survive for years, but when the balance shifts toward prolifera-
tion of the leukemic clone, acute myeloid leukemia (AML) develops, with a poor
outcome for most but not all patients. Best estimates indicate that the incidence
of MDS is at least twice as common as AML. With the vast majority of cases
occurring over the age of 70 years, therapeutic options that have been available
for ‘‘de novo’’ AML are often not utilized.
As the median age of our population increases, more cases will be recog-
nized. In addition, the successful application of combination chemotherapy and
radiation therapy has resulted in long-term remissions and cure of an increasing
number of neoplasms. Unfortunately, a small percentage of these patients (vary-
ing from 1% to as high as 15%) will develop MDS/AML as a result of the
therapy. This could contribute an additional 10% to the overall incidence.
Progress in understanding the pathobiology of MDS has evolved rapidly,
as have an increasing number of myeloablative and supportive care strategies.
In this book I have solicited chapters from many of the world’s leading authorities
to provide current and timely information for those involved with the diagnosis
and management of patients with MDS.
The book contains 18 chapters that cover the entire range of MDS, includ-
ing the recent changes in classification by the World Health Organization; a re-
view of the incidence and prevalence of MDS; insights into possible exogenous
factors that could contribute to the causation of MDS; cytogenetics and molecular
vii
viii Preface

genetics; the relationship between hypocellular MDS, AML, and aplastic anemia;
and the critical importance of the role of apoptosis. The mid-section encompasses
prognostic factors and response criteria, mechanisms of drug resistance, and a
most provocative chapter on pediatric MDS patients. The final chapters discuss
the importance of recognizing patients who would benefit from supportive care
programs including erythropoietin, growth factors and immune modulation as
well as new approaches, including anti-antigenic agents, anti-cytosine agents and
new agents that appear to interfere with important biological pathways such as
farnesyl transferase inhibitors. The book concludes with detailed discussions of
intensive chemotherapy, auto- and allo-bone marrow transplantation, and a sum-
mary chapter on overall approaches to patient care management.
This volume provides a wealth of information by many of the world’s lead-
ing authorities on the pathogenesis, staging, and management strategies on the
most common neoplastic hematological disorder recognized today. It should be
of considerable interest to hematopathologists, hematologists, and clinicians who
are involved in the diagnosis and care of patients with MDS. In addition, scientists
engaged in developing new agents for hematological neoplasms will find the
chapters of considerable value in understanding the rationale for the urgent need
for novel pharmaceuticals to improve the survival and quality of life for our
patients.

John M. Bennett
Contents

Series Introduction v
Preface vii
Contributors xiii

1. Myelodysplastic Syndromes: Historical Aspects

and Classification 1
John T. Phelan II, Peter A. Kouides, and John M. Bennett

2. Epidemiology of the Myelodysplastic Syndromes 15

Terry J. Hamblin

3. Causative Agents in the Etiology of Myelodysplastic Syndromes

and the Acute Myeloid Leukemias 29
Martyn T. Smith, Martha S. Linet, and Gareth J. Morgan

4. Immunology Aspects of the Myelodysplastic Syndromes 65

Terry J. Hamblin

5. The Cytogenetics and Molecular Biology

of Myelodysplastic Syndromes 89
Harold J. Olney and Michelle M. Le Beau

6. Hypocellular Myelodysplastic Syndromes and Hypocellular

Acute Myeloid Leukemia: Relationship to Aplastic Anemia 121
Masao Tomonaga and Kazuhiro Nagai

ix
x Contents

7. The Syndrome of Therapy-Related Myelodysplasia

and Myeloid Leukemia 139
Lucy A. Godley and Richard A. Larson

8. The Role of Apoptosis in the Myelodysplastic Syndromes 177

Yataro Yoshida

9. Application of Single and Multiple Prognostic Factors in the

Assessment of Patients with the Myelodysplastic Syndromes 203
Carlo Aul, Aristoteles Giagounidis, and Ulrich Germing

10. Response Criteria for Myelodysplastic Syndromes 251

Bruce D. Cheson

11. Mechanisms of Drug Resistance in Myelodysplastic Syndromes

and Acute Myeloid Leukemia 265
Robert B. Geller and Alan F. List

12. Myelodysplastic Syndrome and Juvenile Myelomonocytic

Leukemia in Children 299
Henrik Hasle and Charlotte Niemeyer

13. Treatment of Anemia in Myelodysplastic Syndromes 345

David T. Bowen and Eva Hellström-Lindberg

14. Immune Mediation of Pancytopenia in Myelodysplastic

Syndromes: Pathophysiology and Treatment 373
Neal S. Young and A. John Barrett

15. New Investigational Strategies in Patients

with Myelodysplastic Syndromes 399
Guillermo Garcia-Manero and Hagop M. Kantarjian

16. Intensive Chemotherapy, Including Autologous Stem Cell

Transplantation, in the Myelodysplastic Syndromes 421
Theo M. de Witte and Margriet Oosterveld

17. Allogeneic Bone Marrow Transplantation

in the Myelodysplastic Syndromes 435
Jeanne E. Anderson
Contents xi

18. Therapeutic Strategies in the Care of Patients

with Myelodysplastic Syndromes 465
Dragana Milojković and Ghulam J. Mufti

Index 517
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