Table Of ContentBIOLOGIC THERAPY OF LEUKEMIA
CONTEMPORARY HEMATOLOGY
Gary 1. Schiller,
MD, SERIES EDITOR
Biologic Therapy of Leukemia, edited by MATT KAIAYCIO, 2003
Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis,
and Management, by GUY B. FAGUET, 2003
Modern Hematology: Biology and Clinical Management, by REINHOW
MUNKER, ERHARD HILLER, AND RONALD PAQUETTE, 2000
Red Cell Transfusion: A Practical Guide, edited by MARION E. REID AND
SANDRA J. NANCE, 1998
BIOLOGIC THERAPY
OFLEUKEMIA
Edited by
MATT KALAYCIO, MD
The Cleveland Clinic Foundation, Cleveland, OH
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HUMANA PRESS
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Library of Congress Cataloging-in-Publication Data
Biologic therapy of leukemia 1 edited by Matt Kalaycio.
p.; cm.--
Includes bibliographical references and index.
ISBN 978-1-4684-9777-9 ISBN 978-1-59259-383-5 (eBook)
DOI 10.1007/978-1-59259-383-5
1. Leukemia-Immunotherapy. 2. Leukemia--Gene therapy. 3. Cytokines-Therapeutic
use. 4. Biological products-Therapeutic use. I. Kalaycio, Matt. II. Series.
[DNLM: 1. Leukemia,therapy. 2. Biological Therapy. 3. Cytokines-therapeutic use. 4.
Gene Therapy. 5. Immunotherapy. 6. Oligonucleotides, Antisense-therapeutic use. WH
250 B615 2003]
RC643.B457 2003
616.99'41906---dc21 2002192220
To Linda, Mollie, Jason, and Rachel
PREFACE
In the latter part of the 20th century, hematologists and medical oncologists
were trained to treat leukemia with systemic therapy that was cytotoxic to both
normal and malignant cells. Some of these therapies, such as methotrexate and
L-asparaginase, were developed within the context of known biologic patho
physiology, but most were developed in relative ignorance of biologic mecha
nisms and cannot therefore be considered "biologic." The usual goal of treatment
was to eliminate rapidly dividing, or malignant, cells with DNA-damaging agents
that spared normal tissue only in a relative sense. The paradigm of systemic, non
specific therapy dominated oncologic thought at the time:
Leukemia is by very definition a wide-spread systemic disease at the time of
diagnosis. For this reason systemic therapy which reaches simultaneously
every cell in the body is the most logical form oft reatment and is probably the
only type which offers, theoretically, the possibility of complete cure. (1)
To an extent, the systemic, nonspecific treatment approach was successful and
certainly resulted in cures when before none were possible. However, this
approach failed to cure the majority of patients with leukemia and is usually
associated with significant toxicity. No other way was known, and for a time, no
other way seemed possible.
The frequent failure of nonspecific treatments, remarkable advances in
molecular biology, and well-timed serendipity, led to new approaches that are
revolutionizing the management of leukemia as we enter the 21st century. In
contrast to the treatments of the past, the new approaches can collectively be
classified as truly "biologic" therapies because they take advantage of the known
biology of leukemia. Thus, treatment can often be directed at the leukemia,
sparing normal tissues and causing less tissue damage. These new targeted treat
ments represent the beginning of a new age in leukemia therapeutics.
As exciting as these are, clinicians often find it difficult to access appropriate
medical information on these new treatments when faced with a patient who may
benefit from them. The advances are coming so often, and so quickly, that treat
ments are sometimes approved for use before the information that supports their
claimed efficacy can be published in peer-reviewed literature. Large textbooks
attempting to publish accurate and current information on leukemia are doomed
to obsolescence before reaching print.
These practical concerns prompted the publication of this book. Biologic
Therapy of Leukemia is devoted to these new biologic therapies and provides a
vii
viii Preface
rapidly accessible, authoritative source of practical information for clinicians
attempting to use these treatments for their patients.
Some of the treatments described in this text, such as interferon and all-trans
retinoic acid, have been available for some time and are well-described in the
medical literature. However, that information is difficult to access when contrast
ing their efficacy with newer treatments, such as imatinib mesylate and arsenic
trioxide, which are also described in this text. Other treatments, such as P-glyco
protein inhibitors and interleukins, have been dancing on the edges of clinical
practice and may yet find their place based on emerging data. The graft vs leu
kemia effect has been better defined and promises to completely alter the way
allogeneic stem cell transplant is employed in the future. Finally, therapeutic
approaches that reverse failure of apoptosis, alter genetic codes, and modulate
immunologic mechanism are no longer mere theory, but are now being tested in
the clinic and warrant close attention by the oncologic community.
The authors and I hope that clinicians treating patients will find Biologic
Therapy ofL eukemia helpful. We all share the goal of eradicating leukemia and
I believe the information contained in these pages moves us closer to that goal.
I thank the contributors for their expertise and willingness to share it. I stand in
awe of their knowledge and dedication.
Matt Kalaycio, MD
REFERENCE
1. Burchenal, J.H. Treatment of the leukemias. Semin HematoI1966;3: 122.
CONTENTS
Preface ........................................................................................................... vii
Contributors .................................................................................................... xi
PART I: IMMUNOTHERAPY
1 Human Leukemia-Derived Dendritic Cells as Tools
for Therapy .......................................................................................... 3
David Claxton
2 The Graft vs Leukemia Effect.. ............................................................. 13
Brian J. Bolwell
3 Unconjugated Monoclonal Antibodies ................................................. 29
Matt Kalaycio
4 Drug Immunoconjugate Therapy of Acute Myeloid
Leukemia ........................................................................................... 43
Arthur E. Frankel, Bayard L. Powell, Eli Estey,
and Martin S. Tallman
5 Radiolabeled Monoclonal Antibodies .................................................. 59
John M. Burke and Joseph G. Jurcic
PART II: CYTOKINES
6 Interferons .............................................................................................. 81
Thomas Fischer
7 Interleukin-2 Treatment of Acute Leukemia ........................................ 93
Peter Kabos and Gary J. Schiller
PART III: TARGETED THERAPEUTICS
8 Antisense Therapy ............................................................................... 109
Stanley R. Frankel
9 Signal Transduction Inhibitors ............................................................ 127
Michael E. O'Dwyer and Brian J. Druker
10 P-Glycoprotein Inhibition in Acute Myeloid Leukemia .................... 145
Thomas R. Chauncey
ix
x Contents
11 Targeting the Apoptotic Machinery as a Potential
Antileukemic Strategy .................................................................... 163
Benjamin M. F. Mow and Scott H. Kaufmann
PART IV: DIFFERENTIATION AGENTS
12 Arsenicals: Past, Present, and Future ................................................ 189
Chadi Nabhan and Martin S. Tallman
13 All-Trans-Retinoic Acid in the Treatment of Acute
Promyelocytic Leukemia ................................................................ 205
Pierre Fenaux and Laurent Degos
PART V: GENE THERAPY
14 Gene Therapy ...................................................................................... 225
Paul J. Orchard and R. Scott McIvor
Index ............................................................................................................. 261
CONTRIBUTORS
BRIAN J. BOLWELL, MD· Bone Marrow Transplant Program, Department
of Hematology and Medical Oncology, Cleveland Clinic Foundation,
Cleveland, OH
JOHN M. BURKE, MD • Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New York, NY
THOMAS R. CHAUNCEY, MD, phD· University of Washington School
of Medicine, VA Pugent Sound Health Care System, Seattle, WA
DAVID CLAXTON, MD· Division of Hematology/Oncology, Penn State Hershey
Medical Center, Hershey, PA
LAURENT DEGOS, MD, phD • Institut d'Hematologie, Hopital Saint Louis, Paris,
France
BRIAN J. DRUKER, MD· Leukemia Center, Oregon Health & Science
University Cancer Institute, Portland, OR
ELI ESTEY, MD· Section of Acute Leukemia and Myelodysplastic Syndromes,
MD Anderson Cancer Center, Houston, TX
PIERRE FENAUX, MD • Service des Maladies du Sang, CHU, Lille, France
THOMAS FISCHER, MD • Johannes Gutenberg University of Mainz, Mainz, Germany
ARTHUR E. FRANKEL, MD • Department of Medicine, Wake Forest University
School of Medicine, Winston Salem, NC
STANLEY R. FRANKEL, MD, FACp· Medical Operations, Genta Incorporated,
Chicago, IL, and Department of Medicine, Greenbaum Cancer Center,
University of Maryland, Baltimore, MD
JOSEPH G. JURCIC, MD· Leukemia Service, Memorial Sloan-Kettering Cancer
Center, New York, NY
PETER KABOS, MD • Maxine Dunitz Neurosurgical Institute, Cedars-Sinai
Medical Center, Los Angeles, CA.
MATT KALAYCIO, MD· Leukemia Program, Department of Hematology
and Medical Oncology, Cleveland Clinic Foundation, Cleveland, OH
SCOTT H. KAUFMANN, MD, phD • Division of Oncology Research, Mayo Clinic,
and Department of Molecular Pharmacology, Mayo Graduate School,
Rochester, MN
R. SCOTT McIVOR, MD, phD • Department of Genetics, Cell Biology,
and Development, Institute of Human Genetics, University of Minnesota,
Minneapolis, MN
BENJAMIN M. F. Mow, MD • Division of Hematology, National University
Hospital, Singapore
xi
