CANCER DRUG DISCOVERY AND DEVELOPMENT 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 Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004 Nucleic Acid Theapeutics in Cancer, edited by Alan M Gewirtz, 2004 Cancer Chemoprevention, Volume 1: Promising Cancer Chemopreventive Agents, edited by Gary J Kelloff, Ernest T Hawk, and Caroline C Sigman, 2004 DNA Repair in Cancer Therapy, edited by Lawrence C Panasci and Moulay A AlaouiJamali, 2004 Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics, edited by George Morstyn, MaryAnn Foote, and Graham J Lieschke, 2004 Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D Figg and Howard L McLeod, 2004 Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, Second Edition, edited by Beverly A Teicher and Paul A Andrews, 2004 Handbook of Cancer Vaccines, edited by Michael A Morse, Timothy M Clay, and Kim H Lyerly, 2004 Drug Delivery Systems in Cancer Therapy, edited by Dennis M Brown, 2003 Oncogene-Directed Therapies, edited by Janusz Rak, 2003 Cell Cycle Inhibitors in Cancer Therapy: Current Strategies, edited by Antonio Giordano and Kenneth J Soprano, 2003 Chemoradiation in Cancer Therapy, edited by Hak Choy, 2003 Fluoropyrimidines in Cancer Therapy, edited by Youcef M Rustum, 2003 Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins, edited by Nicholas B La Thangue and Lan R Bandara, 2002 Tumor Targeting in Cancer Therapy, edited by Michel Pagé, 2002 Hormone Therapy in Breast and Prostate Cancer, edited by V Craig Jordan and Barrington J A Furr, 2002 Tumor Models in Cancer Research, edited by Beverly A Teicher, 2002 Tumor Suppressor Genes in Human Cancer, edited by David E Fisher, 2001 Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J Clendeninn and Krzysztof Appelt, 2001 Farnesyltransferase Inhibitors in Cancer, edited by Saïd M Sebti and Andrew D Hamilton, 2001 Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R Kelland and Nicholas P Farrell, 2000 Apoptosis and Cancer Chemotherapy, edited by John A Hickman and Caroline Dive, 1999 Signaling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases, edited by J Silvio Gutkind, 1999 Antifolate Drugs in Cancer Therapy, edited by Ann L Jackman, 1999 Antiangiogenic Agents in Cancer Therapy, edited by Beverly A Teicher, 1999 Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval, edited by Beverly A Teicher, 1997 Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A Teicher, 1997 HEMATOPOIETIC GROWTH FACTORS IN ONCOLOGY BASIC SCIENCE AND CLINICAL THERAPEUTICS 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 HUMANA PRESS TOTOWA, NEW JERSEY © 2004 Humana Press Inc 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com All rights reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher All articles, comments, opinions, conclusions, or recommendations are those of the author(s), and not necessarily reflect the views of the publisher Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices The contributors herein have 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organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to the Humana Press The fee code for users of the Transactional Reporting Service is 1-58829-302-5/04 $25.00 Printed in the United States of America 10 E-ISBN 1-59259-747-5 Library of Congress Cataloging-in-Publication Data 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) Hematopoietic growth factors Therapeutic use Hematopoietic growth factors Mechanism of action Cancer-Chemotherapy [DNLM: Hematopoietic Cell Growth Factors therapeutic use Hematopoietic Cell Growth Factors pharmacology Neoplasms therapy WH 140 H487383 2004] I Morstyn, George, 1950- II Foote, MaryAnn III Lieschke, Graham J IV Series RC271.H43H45 2004 616.99'4061 dc22 2003017466 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 colonystimulating 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 evidencebased 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 v 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 CONTENTS Preface v Contributors ix Part I Basic Research Introduction to Hematopoietic Growth Factors: A General Overview George Morstyn and MaryAnn Foote Animal Models of Hematopoietic Growth Factor Perturbations in Physiology and Pathology 11 Graham J Lieschke The Jak/Stat Pathway of Cytokine Signaling 45 Ben A Croker and Nicos A Nicola Small-Molecule and Peptide Agonists: A Literature Review 65 Ellen G Laber and C Glenn Begley Part II Hematopoietic Growth Factors Granulocyte Colony-Stimulating Factor 83 Graham Molineux Erythropoietic Factors: Clinical Pharmacology and Pharmacokinetics 97 Steven Elliott, Anne C Heatherington, and MaryAnn Foote Thrombopoietin Factors 125 David J Kuter Stem Cell Factor and Its Receptor, c-Kit 153 Keith E Langley 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 vii 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 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 ix 464 Part V / Future Directions 91 Chatterjee M, Honemann D, Lentzsch S, et al In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway Blood 2002; 100:3311–3318 92 Honemann D, Chatterjee M, Savino R, et al The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal cell-mediated drug resistance of multiple myeloma cells Int J Cancer 2001; 93:674–680 93 Tassone P, Galea E, Forciniti S, Tagliaferri P, Venuta S The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells Int J Oncol 2002; 21:867–873 94 Ranson M, Hammond LA, Ferry D, et al ZD1839, a selective oral epidermal growth factor receptortyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial J Clin Oncol 2002; 20:2240–2250 95 Hainsworth JD, Litchy S, Burris HA, et al Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin’s lymphoma J Clin Oncol 2002; 20:4261–4267 96 Vogel CL, Cobleigh MA, Tripathy D, et al Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer J Clin Oncol 2002; 20:719–726 97 Croom KF, Perry CM Imatinib mesylate: in the treatment of gastrointestinal stromal tumours Drugs 2003; 63:513–522 98 Edmonson JH, Marks RS, Buckner JC, Mahoney MR Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas Cancer Invest 2002; 20:605–612 99 Herbst RS, Langer CJ Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers Semin Oncol 2002; 29:27–36 100 Baselga J, Yano K, Giaccone G, et al Initial results from a phase II trial of ZD 1839 (Iressa), as second- and third-line monotherapy for patients with advanced non-small cell lung cancer (IDEAL1) Clin Cancer Res 2001; 7:3780S (abstract 630A) 101 Natale RB, Skarin A, Maddox A-M, et al Improvement in symptoms and quality of life for advanced non-small cell lung cancer patients recieving ZD 1839 (‘Iressa’) in IDEAL2 Proc Am Soc Clin Oncol 2002; 21:292a (abstract 1167) 102 Stopeck A, Sheldon M, Vahedian M, Cropp G, Gosalia R, Hannah A Results of a phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies Clin Cancer Res 2002; 8:2798–2805 103 Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET Interleukin-6 and prostate cancer progression Cytokine Growth Factor Rev 2001; 12:33–40 104 Okamoto M, Lee C, Oyasu R Autocrine effect of androgen on proliferation of an androgen responsive prostatic carcinoma cell line, LNCAP: role of interleukin-6 Endocrinology 1997; 138:5071–5074 105 Okamoto M, Lee C, Oyasu R Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro Cancer Res 1997; 57:141–146 106 Steiner H, Godoy-Tundidor S, Rogatsch H, et al Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway Am J Pathol 2003; 162:655–663 107 Borsellino N, Bonavida B, Ciliberto G, Toniatti C, Travali S, D’Alessandro N Blocking signaling through the Gp130 receptor chain by interleukin-6 and oncostatin M inhibits PC-3 cell growth and sensitizes the tumor cells to etoposide and cisplatin-mediated cytotoxicity Cancer 1999; 85:134–144 108 Chen T, Wang LH, Farrar WL Interleukin activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells Cancer Res 2000; 60:2132–2135 109 Lin DL, Whitney MC, Yao Z, Keller ET Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression Clin Cancer Res 2001; 7:1773–1781 110 Purohit A, Singh A, Ghilchik MW, Serlupi-Crescenzi O, Reed MJ Inhibition of IL-6+IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts Br J Cancer 2003; 88:630–635 Chapter 22 / Potential for HGF Antagonists in Oncology 465 111 Baldwin GC, Gasson JC, Kaufman SE, et al Nonhematopoietic tumor cells express functional GMCSF receptors Blood 1989; 73:1033–1037 112 Rivas CI, Vera JC, Delgado-Lopez F, et al Expression of granulocyte-macrophage colony-stimulating factor receptors in human prostate cancer Blood 1998; 91:1037–1043 113 Dieras V, Beuzeboc P, Laurence V, Pierga JY, Pouillart P Interaction between Herceptin and taxanes Oncology 2001; 61:43–49 114 Giaconne G, Johnson DH, Maegold C, et al A phase III clinical trial of ZD 1839 (‘Iressa’) in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (INTACT 1) Ann Oncol 2003; 13:3 (abstract 40) 115 Klement G, Baruchel S, Rak J, et al Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity J Clin Invest 2000; 105:R15–R24 116 Inoue K, Slaton JW, Davis DW, et al Treatment of human metastatic transitional cell carcinoma of the bladder in a murine model with the anti-vascular endothelial growth factor receptor monoclonal antibody DC101 and paclitaxel Clin Cancer Res 2000; 6:2635–2643 117 Zhang L, Yu D, Hicklin DJ, Hannay JA, Ellis LM, Pollock RE Combined anti-fetal liver kinase monoclonal antibody and continuous low-dose doxorubicin inhibits angiogenesis and growth of human soft tissue sarcoma xenografts by induction of endothelial cell apoptosis Cancer Res 2002; 62:2034–2042 118 Bruns CJ, Shrader M, Harbison MT, et al Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice Int J Cancer 2002; 102:101–108 119 Moasser MM, Basso A, Averbuch SD, Rosen N The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells Cancer Res 2001; 61:7184–7188 120 Camirand A, Lu Y, Pollak M Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells Med Sci Monit 2002; 8:BR521–BR526 121 Shaheen RM, Ahmad SA, Liu W, et al Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors Br J Cancer 2001; 85:584–589 122 Jung YD, Mansfield PF, Akagi M, et al Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model Eur J Cancer 2002; 38:1133–1140 Acronyms and Selected Abbreviations 5-FU 5-fluorouracil AA aplastic anemia Ab antibody ABV chemotherapy with doxorubicin, bleomycin, and vincristine ABVD chemotherapy with doxorubicin, bleomycin, vincristine, and dacarbazine AC chemotherapy with doxorubicin and cyclophosphamide ACD anemia of chronic disease ACE angiotensin-converting enzyme ACNU nimustine ADCC antibody-dependent cell-mediated cytotoxicity ADP adenosine diphosphate Ag antigen AGC absolute granulocyte count AIDS acquired immunodeficiency syndrome ALG antilymphocyte globulin ALL acute lymphoblastic/lymphocytic leukemia AlloBMT allogeneic bone marrow transplantation ALT alanine aminotransferase AML acute myeloid/myelogenous leukemia ANC absolute neutrophil count APL acute promyelocytic leukemia ASCO American Society of Clinical Oncology ATG antithymocyte globulin AuBMT autologous bone marrow transplantation AUC area under the curve βc beta common BEACOPP chemotherapy with bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone BFU-E erythroid blast-forming unit bid twice a day BMT bone marrow transplantation 467 468 Acronyms and Selected Abbreviations BSA bovine serum albumin BSF B-cell stimulating factor-3 CAE CALGB CBC CDE CDE-C chemotherapy with cyclophosphamide, doxorubicin, and etoposide The Cancer and Leukemia Group B complete blood count chemotherapy with cyclophosphamide, doxorubicin, and etoposide chemotherapy with cyclophosphamide, doxorubicin, etoposide, and cisplatin cost-effectiveness ratio granulocyte colony-forming cell colony-forming unit(s) erythroid colony-forming unit mixed colony-forming unit Chinese hamster ovary chemotherapy with cyclosphosphamide, doxorubicin, vincristine, and prednisone chemotherapy with cyclosphosphamide, doxorubicin, vincristine, prednisone, and etoposide chemotherapy with cyclophosphamide, doxorubicin, teniposide, vincristine, bleomycin, and prednisone confidence interval cytokine-induced SRC homology; cytokine-inducible SH2-containing protein chronic lymphocytic leukemia chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil chronic myelogenous leukemia chronic myelomonocytic leukemia cytomegalovirus chemotherapy with cyclophosphamide, doxorubicin, etoposide, and prednisone chemotherapy with cyclophosphamide doxorubicin, vincritine, and prednisone ciliary neurotrophic factor chemotherapy with cisplatin, oncovin, doxorubicin, and etoposide chemotherapy with cyclophosphamide, vincristine, prednisolone, bleomycin, doxorubicin, and procarbazine chemotherapy with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine colony-stimulating factor colony-stimulating factor-1 (or macrophage colony-stimulating factor) C/E CFC-G CFU CFU-E CFU-Mix CHO CHOP CHOPE CHVmP + VP CI CIS CLL CMF CML CMML CMV CNEP CNOP CNTF CODE COP-BLAM COPP/ABVD CSF CSF-1 Acronyms and Selected Abbreviations 469 CT computed tomography or cardiotrophin CTL cytotoxic T lymphocyte C/U cost-utility ratio Dexa-BOM chemotherapy with dexamethasone, carmustine, melphalan, cytarabine, and etoposide DHAP chemotherapy with cisplatin, cytarabine, and dexamethasone DMAP chemotherapy with dacarbazine, mitomycin, doxorubicin, and cisplatin DSN days of severe neutropenia E-BFC erythroid blast-forming cell EBMT European Group for Blood and Marrow Transplantation EC50 median effective concentration ECOG Eastern Cooperative Oncology Group ED50 median effective dose EGF epidermal growth factor ELISA enzyme-linked immunosorbent assay E-LTC-IC extended leukotriene cysteinyl initiating cell EMP1 EPO mimetic peptide EPO erythropoietin EPOR erythropoietin receptor ESBC early-stage breast cancer ESHAP chemotherapy with etoposide, solumedrol, cytarabine, and cisplatin ESMO European Society for Medical Oncology EVI chemotherapy with epirubicin, vindensine, and ifosfamide FAC chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide FACS fluorescence-activated cell sorting FACT Functional Assessment of Cancer Therapy FACT-An FACT dealing with anemia FACT-F FACT dealing with fatigue FACT-N FACT dealing with neutropenia FATR febrile-associated transfusion reaction FDA Food and Drug Administration FGF fibroblast growth factor FIH factor inhibiting hypoxia-inducible factor FISH fluorescence in situ hybridization 470 Acronyms and Selected Abbreviations FLICE caspase-activating enzyme FN febrile neutropenia G-CSF granulocyte colony-stimulating factor GDP guanosine diphosphate GEF guanine nucleotide exchange factor GH growth hormone GI gastrointestinal GIST gastrointestinal stromal tumor GM-CFC granulocyte-macrophage colony-forming cell GM-CSF granulocyte-macrophage colony-stimulating factor GTP guanosine triphosphate GvHD graft-vs-host disease GvL graft-vs-leukemia HAART highly active antiretroviral therapy HADS Hospital Anxiety and Depression Scale Hb hemoglobin HCL hairy cell leukemia HCP hematopoietic cell phosphatase Hct hematocrit HD Hodgkin’s disease HGF hematopoietic growth factor HIF hypoxia-inducible factor HIF-PH hypoxia-inducible factor prolyl hydroxylase H-IL-6 hyper-IL-6 HIV human immunodeficiency virus HLA human leukocyte antigen HMO health maintenance organization HPP-CFC high proliferative-potential colony-forming cell HRQOL health-related quality of life HSA human serum albumin HSC hematopoetic stem cell HTS high-throughput screening IC50 mean inhibitory concentration, 50% IEL intraepithelial lymphoctye Acronyms and Selected Abbreviations IFN interferon IGF insulin-like growth factor IGF-1R insulin-like growth factor-1 receptor IL interleukin ip intraperitoneal or intraperitoneally IPSS International Prognostic Scoring System iv intravenous, intravenously Jak or JAK Janus kinase JH Jak or JAK homology JMML juvenile myelomonocytic leukemia kDa kilodalton KGF keratinocyte growth factor KIR kinase inhibitory region LDH lactate dehydrogenase LGL large granular lymphocyte LIF leukemia inhibitory factor LNH84 chemotherapy with cyclophosphamide, doxorubicin, vindesine, bleomycin, methylprednisolone, and methotrexate LOS length of stay LPS lipopolysaccharide LTBMC long-term bone marrow culture LTC cysteinyl leukotriene LTC-IC cysteinyl leukotriene initiating cell LTR long-term multilineage reconstitution MAb monoclonal antibody MAP mitogen-activated protein MAPK mitogen-activated protein kinase MASCC Multinational Asociation of Supportive Care of Cancer M-CSF macrophage colony-stimulating factor or CSF-1; monocyte colonystimulating factor MDR multidrug resistance MDS myelodysplastic syndromes Meg-CFC megakaryocyte colony-forming cell MGDF megakaryocyte growth and development factor 471 472 Acronyms and Selected Abbreviations MIP macrophage inflammatory protein MOPP chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone MOPP/ABVD chemotherapy with mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine MRT mean residence time MTD maximum tolerated dose MVAC chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin MVP chemotherapy with mitocycin C, vindestine, and cisplatin NASBP The National Surgical Adjuvant Breast and Bowel Project NGF nerve growth factor NHL non-Hodgkin’s lymphoma NK natural killer NNT novel neutrophin-1 NSCLC nonsmall-cell lung cancer ODD oxygen-dependent domain O/P observed to predicted values OSM oncostatin M PAIS Psychological Adjustment to Illness Scale PBPC peripheral blood progenitor cell PDGF platelet-derived growth factor PEG polyethylene glycol PEG-rHuMGDF pegylated recombinant human megakaryocyte growth and development factor PI3K phosphatidylinositol kinase PIAS protein inhibitor of activated Stat PLC phospholipase C PLL prolymphocytic leukemia PMEF primary mouse embryonic fibroblast PMP promegapoietin PRL prolactin ProGP progenipoietin ProMACE-CytaBOM chemotherapy with cyclophosphamide, doxorubicin, etoposide, prednisone, cytarabine, bleomycin, vincristine, methotrexate, and leucovorin Acronyms and Selected Abbreviations 473 PSA prostate-specific antigen QALY quality-adjusted life-year qd twice a day QOL quality of life Q-TWIST quality-adjusted time without symptoms of disease or toxicity of treatment RA refractory anemia RAEB refractory anemia with excess blasts RAEB-T refractory anemia with excess blasts in transformation RARα retinoic acid receptor RARE retinoic acid response element RARS refractory anemia with ring sideroblasts RBC red blood cell RCT randomized clinical trial RDI relative dose intensity rEBP recombinant EPO binding protein rHu recombinant human rHuEPO recombinant human erythropoietin rHuG-CSF recombinant human granulocyte colony-stimulating factor rHuGM-CSF recombinant human granulocyte-macrophage colony-stimulating factor rHuIL recombinant human interleukin rHuMGDF recombinant human megakaryocyte growth and development factor rHuTPO recombinant human thrmbopoietin r-methHUG-CSF filgrastim rMuTPO recombinant murine thrombopoietin RT-PCR reverse transcriptase polymerase chain reaction sc subcutaneous, subcutaneously SCF stem cell factor SCID/Hu human severe combined immunodeficiency SCLC small-cell lung cancer SCN severe chronic neutropenia SCNIR Severe Chronic Neutropenia International Registry SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis SF-36 Short-Form 36 474 Acronyms and Selected Abbreviations SOCS supressor of cytokine signaling STAT or Stat signal transducer and activator of transcription sTfR serum transferrin receptor STR short-term radioprotection TBI total body irradiation TCR T-cell receptor or transcription-coupled repair TGF transforming growth factor TNF tumor necrosis factor TPO thrombopoietin TRAP transfusion-related alloimmunization TRIM transfusion-related immunomodulation UV ultraviolet VEGF vascular endothelial growth factor VICE chemotherapy with vincristine, ifosfamde, carboplatin, and etoposide WBC white blood cell WHO World Health Organization Index 475 Index Gaucher’s, 170 graft–vs–host, 199, 200, 239, 280, 324 Hodgkin’s disease (HD), 275–282, 312, 357, 358, 367–368 AIDS-related malignancy, 357–371 American Society of Clinical Oncology (ASCO), 7, 8, 211–216, 277, 293, 325, 429, 438 American Society of Hematology (ASH), 7, Anemia, 101, 163, 174, 249, 250–261, 312– 313 aplastic, 86, 89, 163, 333–347 of chronic disease, 101, 111, 313 Antibiotics, 225–226, 228 Antibodies, monoclonal, 281, 314, 449 Aspergillus spp., 225 E Escherichia coli, 68, 69, 83, 224 European Society for Medical Oncology (ESMO), 221–216 F Felty’s syndrome, 397, 398 Food and Drug Administration (FDA), 211, 212, 238, 255, 376 Fusarium spp., 225 B G Bleomycin, 360, 397 Gene therapy, 116, 169–170 Growth factor(s), 155, 200 economics of, 409–439 epidermal (EGF), 448, 449 mast cell (MGF), 156, 157, 334 platelet–derived (PDGF), 155, 156, 157, 452 transforming (TGF), 175, 290, 313, 448, 449 tumor necrosis (TNF), 167, 168, 175, 222, 250, 313 vascular endothelial (VEGF), 155, 157, 448, 449, 458 C Cancer/carcinoma, 213, 357, 458, breast, 213, 222, 285–307 cervical, 358, 365–367 lung, 212, 213, 224, 249–269, 458 Candida spp., 235 Chemotherapy/regimens, 29–32, 221–225, 277, 279, 280, 287, 289, 361, 364, 365, 367, 416, BEACOPP, 289–290 CDE, 212, 228, 263, 264, 365 CHOP, 216, 223, 277, 279, 362, 363, 364, 365, 416, 417, 425, 434 CMF, 222, 285, 286, 288 COP–BLAM, 363–364 Ciliary neurotrophic factor, 448 Clostridia spp., 224 H Hematopoiesis, Hematopoietic growth factors (HGFs) (includes recombinant forms), 4, 126, 155 ancestim, 6, 171–172 animal models of, 11–34, 185–202 D Disease chronic renal, 101 475 476 antagonists of, 447–460 daniplestim, 187, 194 darbepoetin alfa, 5, 8, 25,78, 97, 99, 101, 102, 109–112, 249, 257–260, 306, 318, 329, 382–384 development and discovery of, 6–7 epoetin alfa, 5, 7, 99, 103, 104, 108, 316, 382 beta, 5, 99, 104, 106, 108, 317, 382 omega, 99 erythropoietic, 97–117 erythropoietin (EPO), 4, 5, 14–15, 24, 25– 26, 31, 65, 69, 70, 73, 74–76, 125, 126, 127, 128, 129, 131, 133, 163, 171, 186, 201, 226, 249, 250–261, 306, 313, 314–320, 334, 335–337, 338–340, 342–343, 345 filgrastim, 4, 84, 193, 194, 198, 226, 227, 228, 229, 269, 289, 291–293, 322, 324, 325, 395–406 granulocyte colony-stimulating factor (GCSF), 4, 5, 15–17, 24, 26–28, 30, 66, 69, 83–90, 126, 131, 133, 138, 139, 143, 163, 170, 171, 186, 187, 188, 192, 201, 211, 212, 277, 278, 279, 288–290, 320–321, 334, 335, 337–339, 342–343, 345, 358–368, 385–389, 448 granulocyte–macrophage colony-stimulating factor (GM-CSF), 4, 5, 17– 19, 24–25, 28–29, 30–31, 33, 100, 163, 167, 170, 188, 192, 198, 211, 266, 276, 279, 280, 288–290, 321– 322, 334, 339–340, 345, 358–368, 385–389, 396, 448, 449, 451 lenograstim, 4, 84, 85, 226, 228, 229 leridistim, 194, 194–195 macrophage (M-CSF), 88, 155, 156, 157, 448 megakaryocyte growth and development factor (MGDF), 6, 125, 134, 137, 138, 139, 140, 141–144, 169, 186, 187, 188, 189, 192, 201, 202, 242, 244, 342, 396 Index molgramostim, 4, 236, 321, 396 monocyte colony-stimulating factor (MCSF), 5, 133 myelopoietin, 193–194 nartograstim 84, 85 pegfilgrastim, 4, 27, 85–86, 87, 88, 196, 198, 202, 227, 228, 236, 293–303, 306 progenipoietin, 197–198 promegapoietin, 126, 134–135, 192 safety of, 375–389 sargramostim, 4, 226, 269, 322, 325, 396, 405 stem cell factor (SCF), 4, 100, 131, 153– 176, 342, 396, 346, 379–381 thromobopoietin (TPO), 4, 5, 6, 7, 65, 69, 71–73, 76–77, 88, 102, 125–145, 169, 185, 186, 189, 192, 201, 226, 244, 341–342, 383–385 Highly-active antiretroviral therapy (HAART), 359, 360, 365 High-throughput, 66 HIV, 213, 235, 236, 357–368, 395 Hormone(s) human growth (HGH), 66, 73, 128 I Immune therapy, 281 Interferon- (IFN- ), 359 Interleukin antagonists, 453–454 interleukin-2 (IL-2), 73, 164, 166, 290 interleukin-3 (IL-3), 5, 168, 164, 168, 169, 192, 290, 340–341, 345–346, 448, 451 interleukin-5 (IL-5), 5, 169, 448 interleukin-6 (IL-6), 131, 168, 169, 189, 232, 243, 290, 313, 334, 341, 448, 449 interleukin-7 (IL-7), 5, 164, 165, 199– 200 interleukin-11 (IL-11), 4, 7, 19, 25, 29, 31, 73, 115, 186, 189, 190–192, 198, 202, 222, 242–244, 341, 376–379 Index J Jak/Stat, 45–59, 130 K Kaposi’s sarcoma, 357, 358, 359–362, 365 Klebsiella spp., 224, 237 L Leukemia, 212, 239, 398 acute, 214–215 chronic lymphocytic, 311–329 graft–vs–leukemia, 324 inhibitory factor (LIF), 168, 448 myeloid/myeloblastic, 33–34, 215, 334, 381 Listeria monocytogenes, 321 Lymphoma, 362, 365 Hodgkin’s, 275–282, 312 immunoblastic, 362 non-Hodgkin’s, 213, 216, 222, 223, 275– 282, 357, 358, 362–365 M Mycobacterium spp., 224 Myelodysplastic syndromes, 163, 214–215, 333–347, 395 N Neutropenia, 88, 219, 277, 288 cyclic, 404–405 febrile, 211, 212, 213, 214, 215, 219– 230, 261–264, 267, 277, 288, 290, 361, 362, 395, 410–439 severe chronic (SCN), 399–404 Neutrophil, 220–221 elastase, 32–33, 399, 400, 404 O Oncostatin M (OSM), 448 P Paclitaxel, 360 477 Peptostreptococcus, 400 Pneumocystis spp., 228, 321 Pseudomonas spp., 224, 400 Pure red cell aplasia, 312–313 Q Quality-of-life measures, 253, 258, 318, 423–439 R Radiotherapy, 29–34 S Serratia spp., 237 Small molecules, 65–78 Staphylococcus spp., 225, 234, 237 STAT, 130 Syndrome(s) Richter’s syndrome, 312 Schwachman–Diamond syndrome, 401, 403 Sjögren’s syndrome, 397 Sweet’s syndrome, 397 T T-cell receptor (TCR), 198–199 Transfusions platelet, 235–244 red cell, 238, 249, 253, 254–255, 335 Transplantation bone marrow, 235, 395, 398, 418 peripheral blood cell/stem cell, 89, 212, 214, 235, 276, 280, 314, 323, 325, 395, 398, 418 V Vinca alkaloid, 360 Virus cytomegalovirus, 237–238 hepatitis, 235, 236–237 Z Ziduvidine, 359, 361 Zilcitabine, 361 ABOUT THE EDITORS Dr Morstyn received a MBBS at Monash University in 1975, achieving first class honors at graduation; obtained his doctorate from The Walter and Eliza Hall Institute of Medical Research at Melbourne University in 1982; and completed a fellowship program in medical oncology at the National Cancer Institute in Bethesda, MD in 1983, when he also became a fellow of the Royal Australasian College of Physicians (medical oncology) Dr Morstyn has conducted clinical and laboratory research at The Ludwig Institute for Cancer Research and at Melbourne University in Australia, as well as directing the department of medical oncology at The Austin Hospital in 1990 Dr Morstyn has authored more than 120 publications on various aspects of cancer research Dr Morstyn is currently an advisor to Amgen, serves on the boards of Bionomics and Cancer Trials Australia, and is a member of the department of microbiology at Monash University He was previously Sr Vice President, Development, and Chief Medical Officer at Amgen MaryAnn Foote, PhD, is Director, Global Medical Writing, Amgen Inc., Thousand Oaks, CA Dr Foote started the medical writing department at Amgen in 1991, after working at Schering-Plough, Kenilworth, NJ, in both the medical writing and regulatory affairs departments Dr Foote is the author, coauthor, or acknowledged writer of more than 100 journal articles and book chapters as well as the editor of ten books She is an editor for Biotechnology Annual Review Dr Foote is a Fellow of the American Medical Writers Association and a past president of the organization, as well as a member of Drug Information Association, American Society of Hematology, and American Society of Clinical Oncology She assisted in establishing medical writing as a career path in Japan and has lectured extensively for several groups in Japan Dr Foote is on the Advisory Board at University of Southern California, Los Angeles, for the masters degree in regulatory sciences, and teaches medical writing there and at the Graham School, University of Chicago Dr Foote received the BS (magna cum laude) and MS degrees from Fairleigh Dickinson University, Teaneck, NJ, and the PhD degree from Rutgers University, New Brunswick, NJ Dr Graham Lieschke reads medicine at the University of Melbourne and was trained at the Royal Melbourne Hospital for his specialist qualification in medical oncology He undertook his PhD project at the Melbourne Branch of the Ludwig Institute for Cancer Research After postdoctoral training at the Whitehead Institute (Cambridge, MA), he returned to Australia to establish his research laboratory at the Ludwig Institute, along with a clinical practice as clinical hematologist at the Royal Melbourne Hospital He has held the John Maynard Hedstrom Fellowship of the Anticancer Council of Victoria, a Howard Hughes Medical Institute Postdoctoral Research Fellowship for Physicians, and a Wellcome Trust Senior Research Fellowship in Medical Sciences in Australia In 2002, the Ludwig Institute awarded him the inaugural George Hodgson Medal for Medical Science for his contributions to clinical and basic hematology research His interest in hemato-oncology research followed from wrestling with megakaryocyte progenitor cell culture during an undergraduate research project in Prof Don Metcalf’s laboratory at the Walter and Eliza Hall Institute of Medical Research While a clinical research fellow, he was part of a team in Melbourne working on the early clinical trials of the myeloid hematopoietic growth factors, and as a doctoral student, generated and analyzed murine models of myeloid growth factor deficiencies His laboratory continues to focus on in vivo models of hematopoietic disease in murine and zebrafish models ... forms, and they have utility in From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G Morstyn, M A Foote, and. .. and clinical use Blood 1997; 89:3897–3908 113 Turner KJ, Clark SC Interleukin-11: Biological and clinical perspectives In: Mertelsmann R, Herrmann F, eds., Hematopoietic Growth Factors in Clinical. .. 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