Tài liệu HEMATOPOIETIC GROWTH FACTORS IN ONCOLOGY BASIC SCIENCE AND CLINICAL THERAPEUTICS pptx

Edited by

George Morstyn, MBBS, PhD, FRACP

MaryAnn Foote, PhD

Graham J. Lieschke, MBBS, PhD, FRACP

CANCER DRUG DISCOVERY AND DEVELOPMENT CANCER DRUG DISCOVERY AND DEVELOPMENT

Hematopoietic

Growth Factors

in Oncology

Basic Science and Clinical

Therapeutics

Hematopoietic

Growth Factors

in Oncology

Basic Science and Clinical

Therapeutics

Edited by

George Morstyn, MBBS, PhD, FRACP

MaryAnn Foote, PhD

Graham J. Lieschke, MBBS, PhD, FRACP

HEMATOPOIETIC GROWTH FACTORS IN ONCOLOGY

CANCER DRUG DISCOVERY AND DEVELOPMENT

Beverly A. Teicher, Series Editor

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HEMATOPOIETIC GROWTH

FACTORS IN ONCOLOGY

BASIC SCIENCE AND CLINICAL THERAPEUTICS

HUMANA PRESS

TOTOWA, NEW JERSEY

Edited by

GEORGE MORSTYN, MBBS, PhD, FRACP

Amgen, Australia, Pty. Ltd.

Monash University, Victoria, Australia

MARYANN FOOTE, PhD

Amgen Inc., Thousand Oaks, CA

GRAHAM J. LIESCHKE, MBBS, PhD, FRACP

Ludwig Institute for Cancer Research, Royal Melbourne Hospital

Melbourne, Australia

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Hematopoietic growth factors in oncology basic science and clinical therapeutics / edited by George Morstyn, MaryAnn Foote,

Graham J. Lieschke.

p. ; cm. -- (Cancer drug discovery and development)

Includes bibliographical references and index.

ISBN 1-58829-302-5 (alk. paper)

1. Hematopoietic growth factors--Therapeutic use. 2. Hematopoietic growth factors--Mechanism of action. 3. Cancer--

Chemotherapy.

[DNLM: 1. Hematopoietic Cell Growth Factors--therapeutic use. 2.

Hematopoietic Cell Growth Factors--pharmacology. 3.

Neoplasms--therapy. WH 140 H487383 2004] I. Morstyn, George, 1950- II.

Foote, MaryAnn. III. Lieschke, Graham J. IV. Series.

RC271.H43H45 2004

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2003017466

v

PREFACE

Several hematopoietic growth factors (HGFs) have achieved widespread clinical

application. In the United States alone, more than US $5 billion per year of the health care

budget is spent on these factors. The first patients were treated with recombinant human

erythropoietin (rHuEPO, epoetin alfa, Epogen®) in 1985 and the first patients received

recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF,

filgrastim, Neupogen®) or recombinant human granulocyte-macrophage colony￾stimulating factor (rHuGM-CSF, sargramostim, Leukine® or Prokine®) in 1986. The first

agent promoting platelet recovery was formally approved in 1997 (recombinant human

interleukin-11 [rHuIL-11], oprelvekin, Neumega®). In 2002, sustained-duration

derivative r-metHuG-CSF (pegfilgrastim, Neulasta®) was formally approved for clinical

use. Likewise in 2002, a new erythropoietic protein (darbepoetin alfa, Aranesp®) with a

longer serum half-life and increased biologic activity compared with rHuEPO was

formally approved for clinical use. Pharmaceutical forms of several other agents have

been assessed in clinical studies but are yet to find a widespread clinical utility or niche

(e.g., stem cell factor, thrombopoietin, interleukin-3, colony-stimulating factor-1

[macrophage colony-stimulating factor]). The efficacy of the marketed agents to

ameliorate the complications of cancer and the side effects of chemotherapy has led to

their broad clinical application; however, their cost has led to efforts to ensure that their

use is focused onto clinically appropriate indications. Hematopoietic Growth Factors in

Oncology: Basic Science and Clinical Therapeutics is a further contribution to this

endeavor.

HGFs are produced in the bone marrow, kidney, brain, and fetal liver by a wide variety

of cells, and they exhibit exquisite selectivity of action dependent on the expression of

specific receptors by target cells. The factors stimulate proliferation and differentiation,

have antiapoptotic effects, and enhance the function of mature cells.

Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics

introduces the molecular basis for the activity of HGFs and discusses their specific role

in the treatment of various malignancies. The clinical application of these agents continues

to expand because of their benefits and relative lack of side effects. Chemotherapy

remains a mainstay of cancer treatment despite the introduction of newer therapeutic

approaches, and so there remains a need to optimize chemotherapy-related supportive

care. In the chapters presented from a systematic oncology perspective, we hope to help

oncologists treating patients with particular tumor types to make informed evidence￾based decisions about adjunctive HGF therapy within disease-focused treatment

regimens. The volume also describes progress in various areas of basic science that may

lead to further advances in hemopoietic cell regulation. There are also sections on the

utility of growth factors in infectious disease settings such as AIDS.

Some notes about the preparation of the book are in order. Because of the nature of

scientific inquiry, the editors have allowed overlap in chapter topics and varying opinions.

We encouraged the authors to be comprehensive regarding the available HGFs, and we

actively sought chapters covering the currently available agents. The opinions expressed

vi Preface

are not necessarily the opinions of the editors or the publisher. Great care has been taken

to ensure the integrity of the references and drug doses, but the package inserts of any drug

should always be consulted before administration.

Readers will realize that many scientists and clinicians worldwide have worked and

continue to work in the fields of basic and applied research of HGFs. We would, however,

like to recognize one of our colleagues, Dr. Dora M. Menchaca. Dora joined Amgen in

July 1991 as a clinical manager and was a close colleague of MaryAnn Foote and George

Morstyn. She was involved in the design and conduct of many clinical trials, including

the use of filgrastim in the setting of acute myeloid leukemia and myelodysplastic

syndromes; the use of stem cell factor in many clinical settings; the use of megakaryocyte

growth and development factor for the treatment of thrombocytopenia and for harvesting

peripheral blood progenitor cells; and several other molecules. Dora was an advocate for

patients enrolled in clinical trials and worked diligently to help get new therapeutic

molecules registered and marketed to help patients worldwide. Dora was returning on an

early morning flight after a meeting with the FDA and was on American Airlines flight

77 that was hijacked and crashed into the US Pentagon on September 11, 2001. We still

mourn the loss of this dedicated scientist and continue to miss her enthusiasm, her

intelligence, her warm and caring personality, and her infectious smile and laughing eyes.

We dedicate this book to Dora.

George Morstyn, MBBS, PhD, FRACP

MaryAnn Foote, PhD

Graham J. Lieschke, MBBS, PhD, FRACP

vii

CONTENTS

Preface ............................................................................................................................ v

Contributors...................................................................................................................ix

Part I. Basic Research

1 Introduction to Hematopoietic Growth Factors: A General Overview ............... 3

George Morstyn and MaryAnn Foote

2 Animal Models of Hematopoietic Growth Factor Perturbations

in Physiology and Pathology .......................................................................... 11

Graham J. Lieschke

3 The Jak/Stat Pathway of Cytokine Signaling .................................................... 45

Ben A. Croker and Nicos A. Nicola

4 Small-Molecule and Peptide Agonists: A Literature Review ............................ 65

Ellen G. Laber and C. Glenn Begley

Part II. Hematopoietic Growth Factors

5 Granulocyte Colony-Stimulating Factor............................................................ 83

Graham Molineux

6 Erythropoietic Factors: Clinical Pharmacology and Pharmacokinetics .......... 97

Steven Elliott, Anne C. Heatherington, and MaryAnn Foote

7 Thrombopoietin Factors ................................................................................... 125

David J. Kuter

8 Stem Cell Factor and Its Receptor, c-Kit ......................................................... 153

Keith E. Langley

9 Hematopoietic Growth Factors: Preclinical Studies of Myeloid

and Immune Reconstitution .......................................................................... 185

Ann M. Farese and Thomas J. MacVittie

Part III. Use of Hematopoietic Growth Factors in Oncology

10 Commentary on the ASCO and ESMO Evidence-Based Clinical Practice

Guidelines for the Use of Hematopoietic Colony-Stimulating Factors............ 211

Richard M. Fox

11 Neutropenia and the Problem of Fever and Infection

in Patients With Cancer ................................................................................ 219

David C. Dale

12 Thrombocytopenia and Platelet Transfusions in Patients With Cancer.......... 235

Lawrence T. Goodnough

viii Contents

13 Hematopoietic Growth Factors in Lung Cancer .............................................. 249

Johan F. Vansteenkiste and Christophe A. Dooms

14 Role of Hematopoietic Growth Factors As Adjuncts

to the Treatment of Hodgkin’s and Non-Hodgkin’s Lymphomas............... 275

Marcie R. Tomblyn and Jane N. Winter

15 Use of Granulocyte Growth Factors in Breast Cancer .................................... 285

Eric D. Mininberg and Frankie Ann Holmes

16 Role of Cytokines in the Management

of Chronic Lymphocytic Leukemia.............................................................. 311

Carol Ann Long

17 Hematopoietic Growth Factor Therapy

for Myelodysplastic Syndromes and Aplastic Anemia ................................ 333

Jason Gotlib and Peter L. Greenberg

18 Use of Hematopoietic Growth Factors in AIDS-Related Malignancies ......... 357

MaryAnn Foote

Part IV. Safety and Economic Implications

19 The Safety of Hematopoietic Growth Factors ................................................. 375

Roy E. Smith and Barbara C. Good

20 Long-Term Safety of Filgrastim in Chronic Neutropenias ............................. 395

Karl Welte

21 Economics of Hematopoietic Growth Factors................................................. 409

Gary H. Lyman and Nicole M. Kuderer

Part V. Future Directions

22 Potential for Hematopoietic Growth Factor Antagonists in Oncology ........... 447

Hayley S. Ramshaw, Timothy R. Hercus, Ian N. Olver,

and Angel F. Lopez

Acronyms and Selected Abbreviations ..................................................................... 467

Index ........................................................................................................................... 475

CONTRIBUTORS

ix

C. GLENN BEGLEY, MBBS, PhD, FRACP, FRCPath, FRCPA • Senior Director, Basic Research

in Hematology, Amgen Inc., Thousand Oaks, CA

BEN A. CROKER, BSC • Cancer and Hematology Division, The Walter and Eliza Hall

Institute of Medical Research, Victoria, Australia

DAVID C. DALE, MD • Professor, Department of Medicine, University of Washington,

Seattle, WA

CHRISTOPHE A. DOOMS, MD • Respiratory Oncology Unit (Pulmonology), University

Hospital Gasthuisberg, Leuven, Belgium

STEVEN ELLIOTT, PhD • Fellow, Hematology Department, Amgen Inc., Thousand Oaks,

CA

ANN M. FARESE, MS, MT (ASCP) • Greenebaum Cancer Center, University of Maryland,

Baltimore, Maryland

MARYANN FOOTE, PhD • Director, Medical Writing, Amgen Inc., Thousand Oaks, CA

RICHARD M. FOX, MB, PhD, FRACP • Department of Medical Oncology, Royal Melbourne

Hospital, Melbourne, Australia

BARBARA C. GOOD, PhD • Director, Scientific Publications, National Surgical Adjuvant

Breast and Bowel Project, Pittsburgh, PA

LAWRENCE T. GOODNOUGH, MD • Professor, Departments of Medicine and Pathology

and Immunology, Washington University School of Medicine, St. Louis, MO

JASON GOTLIB, MD • Clinical Research Fellow, Hematology Division, Stanford

University Medical Center, Stanford, CA

PETER L. GREENBERG, MD • Professor, Department of Medicine, Stanford University

Medical Center, Stanford, CA; Head, Hematology, VA Palo Alto Health Care

System, Palo Alto, CA

ANNE C. HEATHERINGTON, PhD • Research Scientist, Department of Pharmacokinetics

and Drug Metabolism, Amgen Inc., Thousand Oaks, CA

TIMOTHY R. HERCUS, PhD • Cytokine Receptor Laboratory, Hanson Institute, Adelaide,

Australia

FRANKIE ANN HOLMES, MD, FACP • US Oncology; Texas Oncology, Houston, TX

NICOLE M. KUDERER, MD • James P. Wilmot Cancer Center, University of Rochester

Medical Center, Rochester, NY

DAVID J. KUTER, MD, DPhil • Chief of Hematology, Massachusetts General Hospital,

and Associate Professor of Medicine, Harvard Medical School, Boston, MA

ELLEN G. LABER, PhD • Senior Medical Writer, Medical Writing, Amgen Inc., Thousand

Oaks, CA

x Contributors

KEITH E. LANGLEY, PhD • Principal Medical Writer, Medical Writing, Amgen Inc.,

Thousand Oaks, CA

GRAHAM J. LIESCHKE, MBBS, PhD, FRACP • Assistant Member and Laboratory Head,

Cytokine Biology Laboratory, Ludwig Institute for Cancer Research, Melbourne

Tumour Biology Branch, Parkville, Victoria, Australia; Clinical Hematologist,

Department of Clinical Hematology and Medical Oncology, The Royal Melbourne

Hospital, Parkville, Victoria, Australia

CAROL ANN LONG, PhD • Newbury Park, CA

ANGEL F. LOPEZ, MD, PhD • Cytokine Receptor Laboratory, Hanson Institute, Adelaide,

Australia

GARY H. LYMAN, MD, MPH, FRCP • James P. Wilmot Cancer Center, University

of Rochester Medical Center, Rochester, NY

THOMAS J. MACVITTIE, PhD • Greenebaum Cancer Center, University of Maryland,

Baltimore, MD

ERIC D. MININBERG, MD • MD Anderson Cancer Center, University of Texas,

Houston, TX

GRAHAM MOLINEUX, PhD • Associate Director, Hematology Department, Amgen Inc.,

Thousand Oaks, CA

GEORGE MORSTYN, MBBS, PhD, FRACP • Special Advisor, Development, Amgen Inc.,

Thousand Oaks, CA; Department of Microbiology, Monash University, Clayton,

Victoria, Australia

NICOS A. NICOLA, PhD • Professor, Molecular Hematology, and Assistant Director,

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria,

Australia

IAN N. OLVER, MD, PhD • Clinical Director, Royal Adelaide Hospital Cancer Center,

Adelaide, Australia

HAYLEY S. RAMSHAW, PhD • Cytokine Receptor Laboratory, Hanson Institute,

Adelaide, Australia

ROY E. SMITH, MD • Director, Medical Affairs and Medical Oversight, National

Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA

MARCIE R. TOMBLYN, MD • Fellow, Division of Hematology/Oncology, Feinberg

School of Medicine, Northwestern University; Robert H. Lurie Comprehensive

Cancer Center, Chicago, IL

JOHAN F. VANSTEENKISTE, MD, PhD • Respiratory Oncology Unit (Pulmonology),

University Hospital Gasthuisberg, Leuven, Belgium

KARL WELTE, MD, PhD • Professor of Pediatrics, Hannover Medical School; Head,

Department of Pediatric Hematology and Oncology, Children Hospital,

Hannover, Germany

JANE N. WINTER, MD • Professor of Medicine, Division of Hematology/Oncology,

Feinberg School of Medicine, Northwestern University; Robert H. Lurie

Comprehensive Cancer Center, Chicago, IL

I BASIC RESEARCH

1. INTRODUCTION

A complex, inter-related, and multistep process called hematopoiesis controls the

production and development of specific bone marrow cells from immature precursor

cells to functional mature blood cells. The earliest cells are stem cells and are multipo￾tential and able to self-renew. Up to 1011 blood cells are produced in an adult human

each day. The proliferation of precursor cells, the commitment to one lineage, the mat￾uration of these cells into mature cells, and the survival of hematopoietic cells require

the presence of specific growth factors, which act individually and in various combina￾tions in complex feedback mechanisms. The hematopoietic growth factors (HGFs)

stimulate cell division, differentiation, maturation, and survival, convert the dividing

cells into a population of terminally differentiated functional cells (Fig. 1), and in some

cases also activate their mature functions (1–4). Because the literature concerning

every aspect of HGF discovery, cloning, function, and clinical use is burgeoning, in this

chapter, we mention only a few of the most significant works and cite general refer￾ences where possible.

These factors are important for both maintaining the steady state and mediating

responses to infection. More than 20 HGFs have been identified. The properties of some

are described in Table 1. The structure and function of these growth factors have been

characterized and the gene that encodes for each factor identified and cloned. Several

HGFs are commercially available as recombinant human forms, and they have utility in

3

From: Cancer Drug Discovery and Development

Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics

Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

1 Introduction to Hematopoietic

Growth Factors

A General Overview

George Morstyn, MBBS, PhD, FRACP

and MaryAnn Foote, PhD

CONTENTS

INTRODUCTION

DISCOVERY OF HEMATOPOIETIC GROWTH FACTORS

CLINICAL DEVELOPMENT OF HEMATOPOIETIC GROWTH FACTORS

FUTURE DIRECTIONS

REFERENCES

clinical practice. These factors include the recombinant forms of two myeloid hematopoi￾etic growth factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte￾macrophage colony-stimulating factor (GM-CSF); erythropoietin (EPO), the red cell

factor; stem cell factor (SCF), an early-acting HGF; and thrombopoietin (TPO) and

interleukin-11 (IL-11), platelet factors. T lymphocytes, monocytes/macrophages, fibrob￾lasts, and endothelial cells are the important cellular sources of most HGFs, excluding

EPO and TPO (5,6). EPO is produced primarily by the adult kidney (7–9), and TPO is

produced in the liver and in the kidney (10–12).

G-CSF (recombinant products: filgrastim, lenograstim, pegfilgrastim) maintains neu￾trophil production during steady-state conditions and increases production of neutrophils

during acute situations, such as infections (13). Recombinant human G-CSF (rHuG-CSF)

reduces neutrophil maturation time from 5 d to 1 d, leading to the rapid release of mature

neutrophils from the bone marrow into the blood (14). rHuG-CSF also increases the cir￾culating half-life of neutrophils and enhances chemotaxis and superoxide production (15).

Pegfilgrastim is a sustained-duration formulation of rHuG-CSF that has been developed

by covalent attachment of a polyethylene glycol molecule to the filgrastim molecule (16).

GM-CSF (recombinant products: molgramostim, sargramostim) is locally active and

remains at the site of infection to recruit and activate neutrophils (13). Like G-CSF,

4 Part I / Basic Research

Fig. 1. Hematopoietic tree. EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor;

GM-CSF, granulocyte-macrophage colony-stimulating factor; mGDF, megakaryocyte growth and

development factor; SCF, stem cell factor; TPO, thrombopoietin. (Courtesy of Amgen, Thousand

Oaks, CA.)