Table Of ContentCLINICAL APPLICATIONS OF CYTOKINES AND
GROWTH FACTORS
CLINICAL APPLICATIONS OF CYTOKINES AND
GROWTH FACT ORS
edited by
JOHN R. WINGARD
University of Florida College of Medicine, USA
and
GEORGE D. DEMETRI
Dana Farber Cancer Institute, Harvard Medical School, USA
~.
"
Library of Congress Cataloging-in-Publication Data
Clinical applications of cytokines and growth factors / edited by John
R. Wingard and George D. Demetri.
p. cm. -- (Developments in oncology ; 80)
Includes index.
ISBN 978-1-4613-7277-6 ISBN 978-1-4615-5013-6 (eBook)
DOI 10.1007/978-1-4615-5013-6
1. Blood--Diseases--Immunotherapy. 2. Hematopoietic growth
factors--Therapeutic use. 3. Growth factors--Therapeutic use.
1. Wingard, John R., 1947- . II. Demetri, George D., 1956-
III. Series.
[DNLM: 1. Cytokines--pharmacology. 2. Cytokines--therapeutic use.
3. Growth Substances--pharmacology. 4. Growth Substances-
-therapeutic use. Wl DE998N v.80 1999]
RC636.C54 1999
616.07'9--dc21
DNLMlDLC
for Library of Congress 99-22740
CIP
Copyright © 1999 by Springer Science+Business Media New York
OriginalIy published by Kluwer Academic Publishers in 1999
Softcover reprint of the hardcover 1s t edition 1999
AII rights reserved. No part of this publication may be reproduced, stored in a
retrieval system or transmitted in any form or by any means, mechanical, photo
copying, recording, or otherwise, without the prior written permission of the
publisher, Springer Science+Business Media, LLC.
Printed on acid-free paper.
TABLE OF CONTENTS
List of Contributors ................................................ viii
Introduetion ....................................................... xi
I. Biology of Hematopoietic and Lymphopoietic Cytokines
1. Cytokines, Growth Faetors, and Hematopoiesis
G. BAGBY and M. HEINRICH ................................ 2
2. The Interaetion of Cytokines with Stern Cell and Stromal Cell
Physiology
P. SIMMONS, D.N. HA YLOCK, J-P LEVESQUE, and
A.C.W. ZANNETTINO ...................................... 56
3. The Interaetion ofCytokines with T-eell and Natural Killer Cell
Physiology
R.A. CARTER and E.K. WALLER ............................ 74
4. Improving on Nature by Re-Engineering Hematopoietie Growth
Faetors
Y.FENG and 1 MCKEARN ................................... 90
11. Management of Neutropenia and Neutropenie Fever
5. The Influenee ofColony Stimulating Faetors on Neutrophil
Produetion, Distribution, and Funetion
1M. GA VIRIA, W.c. LlLES, and D.C. DALE ................... 118
6. Evidenee-Based Use ofHematopoietie Cytokines in Clinieal
Oneology
G.D. DEMETRI ........................................... 137
7. Eeonomie, Publie Health, and Poliey Implieations of Hematopoietie
Growth Faetors, High-Dose Chemotherapy, and Stern Cell Reseue
C.L. BENNETT and T.1 STINSON ........................... 150
8. Outpatient Management ofNeutropenie Fever: Antibioties, Growth
Faetors or Both?
E.B. RUBINSTEIN, L.S. ELTING, C.C. SUN, and
K.V.1. ROLSTON .......................................... 159
9. The Use ofHematopoietie Growth Faetors for Recruitment of
Leukoeytes for Transfusion
D.B. JENDIROBA, B. LICHTIGER, and E. J FREIREICH ......... 178
111. Management of Anemia
10. Pathophysiology ofthe Anemia ofMalignancy
I.W. ADAMSON ......................................... 187
11. The Use ofRecombinant Erythropoietin in the Treatment and
Prevention of Cancer and Chemotherapy Related Anemia
J. L. SPIVAK ............................................ 198
IV Management of Thrombocytopenia
12. Regulation ofHuman Megakaryocytopoiesis
R. HOFFMAN and M.W. LONG ............................. 218
13. The Effects of Multilineage Cytokines on Platelet Recovery
R. VII and J. DIPERSIO .................................... 237
14. Clinical Studies ofThrombopoietin
R. BASSER .............................................. 269
V. The Rofe of Cytokines to Enhance Cancer Chemotherapy
15. Dose Intensification in Solid Tumor Chemotherapy
H. V AN DEVENTER and T. SHEA .......................... 279
16. Conventional and High Dose Chemotherapy for Lymphomas
K.W. V AN BESIEN ....................................... 300
17. Hematopoietic Growth Factors in Acute Leukemia
R. STONE ......................................... , ..... 313
VI. Management of Marrow Failure States
18. Cytokines for the Treatment of Myelodysplastic Syndromes
and Other Bone Marrow Failure States
R. S. NEGRIN ........................................... 326
VII The Use of Cytokines in Blood and Marrow Transplantation
19. Stern Cell Collection for Hematopoietic Transplantation: Stern
Cell Sources, Mobilization Strategies, and Factors that Influence
Yield
lR. WINGARD and F.M. WEEKS ........................... 341
20. Mechanisms ofGrowth Factor Mobilization ofHematopoietic
Progenitors
D. LINK ................................................. 357
vi
21. The Use ofCytokines to Enhance Collection ofStem Cells for
Marrow and Blood Transplantation
S. ROMAN-UNFER and E.J. SHPALL ........................ 369
22. The Use of Cytokines During Blood and Marrow Transplantation
J. NEMUNAITIS ......................................... 381
Index .......................................................... 403
vii
List of Contributors
JOHN w. ADAMSON, M.D., Director of Research, Lindsley F. Kimball Research
Institute, New York Blood Center, New York, NY 10021
GROVER BAGBY, M.D., Professor of Medicine and Molecular Medical Genetics,
Director, Oregon Cancer Center, Oregon Health Sciences University, Portland, OR
97201
RUSSELL BASSER, MBBS., Centre for Developmental Cancer Therapeutics, Royal
Melboume Hospital, Victoria, Australia, 3050
CHARLES L. BENNETT, M.D., Ph.D., Associate Professor, Northwestem University,
VA Chicago Health Care Systems, Lakeside Division, Medical Science Building,
Chicago, IL 60611
RICHARD A. CARTER, M.D., Assistant Professor of Medicine, Emory University
School ofMedicine, Atlanta, GA 30322
DAVID C. DALE, M.D., Professor ofMedicine, Department ofMedicine, University
of Washington, Seattle, W A 98195
GEORGE D. DEMETRI, M.D., Assistant Professor ofMedicine, Department of Adult
Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
02115
JOHN DIPERSIO, M.D., Professor of Medicine, Pathology, and Pediatrics, Chief,
Division ofBMT and Stern Cell Biology, Washington University School ofMedicine,
St. Louis, MO 63110
LINDA S. ELTING, Dr.P.H., Associate Professor ofEpidemiology, MD Anderson
Cancer Center, Houston, TX 77030
YIQING FEN, Ph.D., Senior Research Investigator, SEARLE/A Monsanto Company,
st. Louis, MO 63198
EMIL J FREIREICH, M.D., D.Sc. (Hon), Professor ofMedicine, University ofTexas
MD Anderson Cancer Center, Houston, TX 77030
J. MILTON GAVIRIA, M.D., Senior Fellow, Division of Infectious Disease,
Department ofMedicine, University ofWashington, Seattle, WA 98195
DAV ID N. HA YLOCK, B.App.Sci.,Hanson Centre for Cancer Research, Division of
Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia,
SA5000
MICHAEL HEINRICH, M.D., Associate Professor of Medicine, Oregon Health
Sciences University, Portland, OR 97201
RONALD HOFFMAN, M.D., Eileen Heidrick Professor of Oncology, Chief,
Hematology/Oncology Section, Molecular Biology Research Laboratory, University
of Illinois College of Medicine, Chicago, IL 60607
DA VID B. JENDIROBA, M.D., Graduate Research Assistant, University of Texas
MD Anderson Cancer Center, Houston, TX 77030
JEAN-PIERRE LEVESQUE, PH.D, Hanson Centre for Cancer Research, Division of
Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia,
SA5000
BENJAMIN LICHTIGER, M.D., Ph.D., Professor ofMedicine, University ofTexas
MD Anderson Cancer Center, Houston, TX 77030
W. CONRAD LILES, M.D., Ph.D., Assistant Professor, Division of Infectious
Diseases, Department of Medicine, University of Washington, Seattle, WA 98195
DANIEL LINK, M.D., Assistant Professor, Washington University School of
Medicine, St. Louis, MO 53110
MICHAEL W. LONG, M.D., Associate Professor, Pediatric Hematology/Oncology
Section, University ofMichigan School ofMedicine, Ann Arbor, MI
JOHN MCKEARN, Ph.D., Executive Director ofDiscovery Research, SEARLE/A
Monsanto Company, St. Louis, MO 63198
ROBERT S. NEGRIN, M.D., Associate Professor ofMedicine, Stanford University
Hospital, Stanford, CA 94305
JOHN NEMUNAITIS, M.D., Regional Director, PRN Research, Inc.; Director, TOPA
Research, Physician Reliance Network, Dallas, TX 75246
KENNETH V.I. ROLSTON, M.D., Professor of Medicine, MD Anderson Cancer
Center, Houston, TX 77030
SUSAN ROMAN-UNFER, M.D., Bone Marrow Transplant Fellow, University of
Colorado Health Science Center, Bone Marrow Transplant Program, Denver, CO
80262
EDWARD B. RUBENSTEIN, M.D., Associate Professor, University of Texas MD
Anderson Cancer Center, Houston, TX 77030
ix
THOMAS SHEA, M.D., Professor ofMedicine, Department ofMedicine, Division of
Hematology/Oncology, University ofNorth Carolina, Chapel Hill, NC 27599
ELIZABETH J. SHPALL, M.D., Professor ofMedicine, University ofColorado Health
Science Center Bone Marrow Transplant Program, Denver, CO 80262
PAUL SIMMONS, M.D., Matthew Roberts Laboratory, Division of Hematology,
Hanson Centre for Cancer Research, Adelaide, Australia, SA5000.
JERRY L. SPIV AK, M.D., Professor of Medicine and Oncology, Johns Hopkins
University School ofMedicine, Baltimore, MD 21205
TAMMY 1. STINSON, M.S., Research Analyst, VA Chicago Health-Care Systems,
Lakeside Division, Medical Science Building, Chicago, IL 60611
RICHARD STONE, M.D., Associate Professor of Medicine, Harvard University,
Dana Farber Cancer Institute, Boston, MA 02114
CHARLOTIE C. SUN, M.P.H., Graduate Research Assistant, University ofTexas MD
Anderson Cancer Center, Houston, TX 77030
KOEN B. VA N BESIEN, M.D., Associate Professor ofMedicine, Director, Stern Cell
Transplantation, University ofIllinois-Chicago, Chicago, IL 60612
HENRIK VA N DEVENTER, M.D., Research Fellow, Department of Medicine,
Division of Hematology/Oncology, University of North Carolina, Chapel Hili, NC
27599
RA VI VIJ, M.D., Fellow, Division ofBone Marrow Transplantation and Stern Cell
Biology, Washington University School ofMedicine, st. Louis, MO 63110
EDMUND K. WALLER, M.D., Ph.D., Assistant Professor of Medicine, Emory
University School ofMedicine, Atlanta, GA 30322
FREDERICK M. WEEKS, M.D., Assistant Professor of Medicine, Division of
Hematology/Oncology, University ofFlorida College ofMedicine, Shands Hospital,
Gainesville, FL 32610
JOHN R. WINGARD, M.D., Professor of Medicine, Director, Bone Marrow
Transplant Program, Division ofHematology/Oncology, University ofFlorida College
ofMedicine, Shands Hospital, Gainesville, FL 32610
ANDREW C.W. ZANETTINO, Ph.D., Hanson Centre for Cancer Research, Division
of Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia,
SA5000
x
Introduction
The hematopoietic system plays roles that are crucial for survival of the host: delivery
of oxygen to tissues, arrest of accidental blood leaking from blood vessels, and fending
off of invading microbes by humoral, cell-mediated, and phagocytic immunity.
The activity of the hematopoietic system is staggering: daily, a normal adult
produces approximately 2.5 billion erythrocytes, 2.5 billion platelets, and 1 billion
granulocytes per kilogram of body weight. This production is adjusted in a timely
fashion to changes in actual needs and can vary from nearly none to many times the
normal rate depending on needs which vary from day to day, or even minute to minute.
In response to a variety of stimuli, the cellular components of the blood are promptly
increased or decreased in production to maintain appropriate numbers to optimally
protect the host from hypoxia, infection, and hemorrhage.
How does this all happen and happen without over or under responding? There
has been extraordinary growth in our understanding ofhematopoiesis over the last two
decades. Occupying center stage is the pluripotent stern cell and its progeny.
Hematopoietic stern cells have been characterized by their capacity for self renewal
and their ability to proliferate and differentiate along multiple lineages. Few in
number, the stern cell gives rise to all circulating neutrophils, erythrocytes, lymphoid
cells, and platelets. In hematopoietic transplantation, the stern cell is capable of
restoring long-term hematopoiesis in a lethally irradiated host.
Expansion of the numbers of progeny of stern cells provides the host with an
enormous capacity for hematopoietic homeostasis. As important as stern cells are,
however, it is now recognized that it is only through very complex interactions with
other cells in the stromal microenvironment, physical contact with matrix proteins in
the bone marrow, and exposure to soluble proteins which have growth stimulatory and
growth inhibitory properties, such as hematopoietic growth factors and various
adhesion molecules, that stern cells can do their jobs. Thus, these "supporting actors"
are every bit as important as stern cells in the regulation ofhematopoiesis. The growth
factors, their actions, and their clinical roles, are the subject of this volume.
Hematopoietic growth factors are a family of glycoproteins that regulate
proliferation, differentiation, and function of hematopoietic cells. The specific
function ofthese molecules are complex and redundant. Their activity may be lineage
specific or affect cells of multiple lineages. These moleeules are synthesized by
lymphocytes, monocytes, stromal cells, and a host of other cell types as weIl.
The identification and isolation of their genes has led to mass production of
recombinant hematopoietic growth factor molecules. The availability of these
molecules, in turn, have made possible in vitro studies on progenitor cell proliferation
and function to achieve better understanding of hematopoiesis and, subsequently,
clinical trials.
Today, several growth factors are available to the clinician as treatments for
various pathologicpertubations of hematopoiesis. Their use has also advanced our
capacity to safely deliver cancer chemotherapy. Hematopoietic growth factors have
become an everyday tool for the practicing oncologist.
In this volume, recognized experts review the biological interactions between
