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Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice

S e v e n th E d i t i on

Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice

S e v e n th E d i t i on

Bruce A. Chabner, MD Clinical Director, Emeritus Massachusetts General Hospital Cancer Center

Professor of Medicine Harvard Medical School Boston, Massachusetts

Dan L. Longo, MD Senior Physician Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Deputy Editor New England Journal of Medicine Boston, Massachusetts

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Seventh Edition

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C ontributors

Michail Alevizakos, MD Hematologist/Oncologist Division of Hematology/Oncology Riverside Cancer Specialists of Tidewater Chesapeake, Virginia

Margaret K. Callahan, MD, PhD Chief, Division of Hematology and Oncology Associate Professor Department of Medicine University of Connecticut School of Medicine Farmington, Connecticut

Omar Alhalabi, MD Assistant Professor Department of Genitourinary Medical Oncology Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas Jennifer E. Amengual, MD Associate Professor Department of Medicine Columbia University Irving Medical Center New York, New York Michael J. Andersen Jr, MD Resident Physician Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Aditya Bardia, MD, MPH, FASCO Professor of Medicine Geffen School of Medicine at UCLA Director, Breast Oncology Program Assistant Chief (Translational Research) Division of Medical Oncology Director of Translational Research Integration UCLA Health Jonsson Comprehensive Cancer Center Los Angeles, California

Sofia Castelli, MS PhD Candidate Center for Cellular Immunotherapies

University of Pennsylvania Philadelphia, Pennsylvania

Bruce A. Chabner, MD Clinical Director, Emeritus Massachusetts General Hospital Cancer Center Professor of Medicine

Harvard Medical School Boston, Massachusetts

Cindy H. Chau, PharmD, PhD Pharmacologist Genitourinary Malignancies Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda, Maryland Diana D. Cirstea, MD Instructor in Medicine Harvard Medical School Department of Medical Oncology Assistant in Medicine Mass General Cancer Center Boston, Massachusetts Gregory M. Cote, MD, PhD Associate Professor Harvard Medical School Division of Hematology and Oncology Department of Medicine Assistant in Medicine Massachusetts General Hospital Boston, Massachusetts Ibiayi Dagogo-Jack, MD Assistant Professor Department of Medicine Massachusetts General Hospital Harvard University Boston, Massachusetts

Suzanne M. Barry, PhD Medical Writer Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts Tracy T. Batchelor, MD Chair Department of Neurology Brigham andWomen’s Hospital Boston, Massachusetts

Susan E. Bates, MD Assistant Professor Department of Medicine

Columbia University New York, New York

Contributors

Robert B. Diasio, MD Director Emeritus, Mayo Clinic Cancer Center William J. and Charles H. Mayo Professor Mayo Clinic Rochester, Minnesota

David Gritsch, MD, PhD Clinical Fellow Department of Neuro-Oncology Massachusetts General Hospital Boston, Massachusetts

William D. Figg, PharmD Branch Chief and Senior Investigator Clinical Pharmacology Program Center for Cancer Research National Cancer Institute/NIH Bethesda, Maryland

Monique A. Hartley-Brown, MD, MMSc Assistant Professor and Associate Physician Member of Faculty at Harvard Medical School Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Keith T. Flaherty, MD Professor of Medicine Massachusetts General Hospital Cancer Center Department of Medicine Harvard University Boston, Massachusetts Michael B. Foote, MD Assistant Attending Gastrointestinal Oncology Service Memorial Sloan Kettering Cancer Center New York, New York

Gabriela Hobbs, MD Assistant Professor, Harvard Medical School Clinical Director, Leukemia Service Massachusetts General Hospital Boston, Massachusetts Chi-Joan How, MD Clinical Chief of Hematology Brigham andWomen’s Faulkner Hospital Associate Physician Brigham andWomen’s Hospital

Instructor in Medicine Harvard Medical School Boston, Massachusetts

Justin F. Gainor, MD Associate Professor of Medicine Department of Medicine Massachusetts General Hospital

Carl H. June, MD RichardW.Vague Professor in Immunotherapy Department of Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Harvard Medical School Boston, Massachusetts

I. David Goldman, MD Professor Emeritus Departments of Medicine, Oncology and Molecular Pharmacology Montefiore-Einstein Comprehensive Cancer Center Albert Einstein College of Medicine Bronx, NewYork

Dejan Juric, MD Assistant Professor Massachusetts General Hospital

Harvard Medical School Boston, Massachusetts

Giulia Golinelli, PhD Postdoctoral Researcher Center for Cellular Immunotherapies

Mariko Kaji, MD Research Technician Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

University of Pennsylvania Philadelphia, Pennsylvania

William J. Gradishar, MD, FASCO, FACP Betsy Bramsen Professor of Breast Oncology and Professor of Medicine Chief, Division of Hematology/Oncology Deputy Director, Clinical Network Director, Maggie Daley Center forWomen’s Cancer Care Robert H. Lurie Comprehensive Cancer Center of Northwestern University Feinberg School of Medicine Chicago, Illinois

Howard L. Kaufman, MD Lecturer

Department of Surgery Harvard Medical School Boston, Massachusetts

Niamh Keegan, MB, BCh, BAO Assistant Attending Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York

vii

Contributors

Max F. Kelsten, MD Chief Medical Resident, Instructor Department of Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois James A. Kennedy, MD, PhD, FRCPC Assistant Professor Department of Medicine University of Toronto Toronto, Ontario, Canada E. Bridget Kim, PharmD, BCPS, BCOP Clinical Pharmacy Specialist, Multiple Myeloma Department of Pharmacy Massachusetts General Hospital Boston, Massachusetts

Bruce L. Levine, PhD Barbara and Edward Netter Professor in Cancer Gene Therapy Center for Cellular Immunotherapies Department of Pathology and Laboratory Medicine Perelman School of Medicine

University of Pennsylvania Philadelphia, Pennsylvania

Dan L. Longo, MD, MACP Professor Department of Medicine Harvard Medical School Senior Physician Brigham andWomen’s Hospital Deputy Editor New England Journal of Medicine Boston, Massachusetts

Janice S. Kim, MD Assistant in Medicine Division of Hematology/Oncology Massachusetts General Hospital Boston, Massachusetts

Samantha O. Luk, PharmD Clinical Oncology/Hematology Pharmacy Specialist Department of Pharmacy Massachusetts General Hospital Boston, Massachusetts

Firas Kreidieh, MD (Hematology-Oncology) Melanoma Medical Oncology Fellow

K. Ina Ly, MD Assistant Professor Department of Neurology Massachusetts General Hospital Boston, Massachusetts Gary H. Lyman, MD, MPH Professor Division of Public Health Sciences Fred Hutchinson Cancer Center Seattle,Washington University of Pennsylvania Philadelphia, Pennsylvania David F. McDermott, MD Chief, Medical Oncology Beth Israel Deaconess Medical Center Professor of Medicine Harvard Medical School Boston, Massachusetts Gautam U. Mehta, MD Senior Physician Division of Oncology US Food and Drug Administration Silver Spring, Maryland

Melanoma Medical Oncology MD Anderson Cancer Center Houston, Texas

Nicole M. Kuderer, MD, MS (Equiv.) Medical Director Oncology Advanced Cancer Research Group Kirkland, Washington Li Lan, MD, PhD Associate Professor Department of Molecular Genetics and Microbiology Duke University Durham, North Carolina

David Mai PhD Candidate Department of Bioengineering and Center for Cellular Immunotherapies

Jacob Laubach, MD, MPP Associate Professor Harvard Medical School Department of Medical Oncology Institute Physician Dana-Farber Cancer Institute Boston, Massachusetts Richard J. Lee, MD, PhD Assistant Professor

Department of Medicine Harvard Medical School Boston, Massachusetts

viii

Contributors

Cornelis J. M. Melief, MD, PhD Emeritus Professor Department of Immunology Leiden University Medical Center Leiden,The Netherlands Chief Scientific Officer ISA Pharmaceuticals Oegstgeest,The Netherlands Constantine S. Mitsiades, MD, PhD

Richard Pazdur, MD Director, Oncology Center of Excellence US Food and Drug Administration Silver Spring, Maryland Zofia Piotrowska, MD, MHS Assistant Professor of Medicine Department of Internal Medicine Division of Hematology/Oncology Massachusetts General Hospital

Associate Professor of Medicine Department of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts Beverly Moy, MD, MPH Professor of Medicine Harvard Medical School Massachusetts General Hospital Cancer Center Boston, Massachusetts Maciej M. Mrugala, MD, PhD, MPH, FAAN Professor of Medicine and Neurology Neurology and Oncology Mayo Clinic and Mayo Clinic Cancer Center Phoenix, Arizona Christopher S. Nabel, MD, PhD Assistant in Medicine Massachusetts General Hospital Cancer Center Instructor in Medicine Harvard Medical School Boston, Massachusetts Rudolph M. Navari, MD, PhD, FACP Director, Cancer Care Program World Health Organization Birmingham, Alabama Steven M. Offer, PhD Associate Professor

Harvard Medical School Boston, Massachusetts

Yves Pommier, MD, PhD Chief, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology Center for Cancer Research, National Cancer Institute National Institutes of Health Bethesda, Maryland Ramya Ramaswami, MBBS, MPH Lasker Clinical Scholar HIV and AIDS Malignancy Branch Center for Cancer Research, National Cancer Institute National Institutes of Health Bethesda, Maryland Mark Roschewski, MD Senior Clinician Lymphoid Malignancies Branch Center for Cancer Research, National Cancer Institute National Institutes of Health Bethesda, Maryland

Rachel P. Rosovsky, MD, MPH Director,Thrombosis Research Division of Hematology

Massachusetts General Hospital Associate Professor of Medicine

Department of Pathology Carver College of Medicine University of Iowa Iowa City, Iowa Adam C. Palmer, PhD Assistant Professor Department of Pharmacology University of North Carolina at Chapel Hill

Harvard Medical School Boston, Massachusetts

David P. Ryan, MD Shelby Memorial Professor of Medicine in the Field of Cancer Therapeutics Harvard Medical School Physician in Chief, Mass General Brigham Cancer Massachusetts General Hospital and Brigham andWomen’s Hospital Boston, Massachusetts

Chapel Hill, North Carolina Rushad Patell, MBBS Attending Physician Hematology and Hematologic Malignancies Beth Israel Deaconess Medical Center Assistant Professor Division of Hematology and Hematologic Malignancies Department of Medicine Harvard University Boston, Massachusetts

Edward A. Sausville, MD, PhD Clinical Professor (Retired)

Department of Medicine University of Maryland Baltimore, Maryland

Contributors

Sophia Z. Shalhout, PhD Assistant Professor Department of Otolaryngology—Head and Neck Surgery Mass Eye and Ear, Harvard Medical School Boston, Massachusetts Geoffrey Shapiro, MD, PhD Professor of Medicine Harvard Medical School Senior Vice President Developmental Therapeutics Dana-Farber Cancer Institute Boston, Massachusetts Padmanee Sharma, MD, PhD Professor Department of Genitourinary Medical Oncology and Department of Immunology The University of Texas MD Anderson Cancer Center Houston, Texas Sierra Silverwood, BA Medical Student Michigan State College of Human Medicine Grand Rapids, Michigan Harpreet Singh, MD Director Division of Oncology 2 Institution US Food and Drug Administration Silver Spring, Maryland David Spriggs, MD

Anish Thomas, MBBS, MD Senior Investigator Developmental Therapeutics Branch Center for Cancer Research National Cancer Institute Bethesda, Maryland Beatrix Bess Thompson, BA Medical Student Massachusetts General Hospital Cancer Center

Harvard Medical School Boston, Massachusetts Seda S.Tolu, MD Assistant Professor Department of Medicine

Columbia University New York, New York Alice Tzeng, MD, PhD Resident Physician Department of Medicine Brigham andWomen’s Hospital Boston, Massachusetts Tony H.Tzeng, MD, PhD Resident Physician Department of Pediatrics Indiana University School of Medicine Indianapolis, Indiana Esmé T. I. van der Gracht, PhD Scientist Immunology Department of Immunology ISA Pharmaceuticals Oegstgeest,The Netherlands Anna-Sophia Wiekmeijer, PhD Director Immunology Immunology Department ISA Pharmaceuticals Oegstgeest,The Netherlands Jedd D.Wolchok, MD, PhD Professor Department of Medicine Weill Cornell Medicine New York, New York Andrew J.Yee, MD Center for Multiple Myeloma Massachusetts General Hospital Cancer Center

Professor in Residence Department of Medicine Harvard Medical School Boston, Massachusetts Laura M. Spring, MD Assistant Professor Department of Medicine Mass General Cancer Center Harvard University Boston, Massachusetts Ryan J. Sullivan, MD

Associate Professor, Harvard Medical School Peter and Ann Lambertus Chair in Cancer Associate Director, Melanoma Program Mass General Cancer Center Boston, Massachusetts Hussein Tawbi, MD, PhD Professor Deputy Chair, Department of Melanoma Medical Oncology Co-Director,Andrew M. McDougall Brain Metastasis Clinic and Program Melanoma Medical Oncology Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center Houston, Texas

Harvard Medical School Boston, Massachusetts Lee Zou, PhD George Barth Geller Distinguished Professor Chair, Department of Pharmacology and Cancer Biology Duke University School of Medicine Durham, North Carolina

P r e fac e

for their serious autoimmune toxicities remains an unsolved problem. Rather than focusing on ever more “me too” checkpoint inhibitors, in dustry needs to devote greater attention to refining and understanding the important immune parameters that lead to new and more success ful treatment and less toxicity. While these advances represent clear progress, chemotherapy con tinues to be an important component of treatment regimens. There have been only a handful of new agents of this class in the past 5 years and little progress in understanding of mechanisms of resistance to these drugs; with the exception of gene arrays in early breast cancer, there are few well-established predictive biomarkers for chemother apy, and this deficiency is only compounded by a discouraging lack of attention to basic principles of pharmacology in medical education. A further challenge is the need to identify patients with node-negative breast, colon, lung, bladder, and other cancers who have residual dis ease after primary surgery. Will circulating tumor DNA or circulat ing tumor cell assays allow us to identify these high-risk patients? It is our hope that recent progress in defining minimal residual disease will allow oncologists to confine treatment to the subset of patients who most profit from further drug exposure. This brief but impressive list of advances and challenges in the past 5 years indicates not only the quickening pace of new cancer treat ments but also the changing nature of the enterprise. The emphasis now is on developing agents that block key targets in tumor growth, with limited effects on normal tissues. Integration of these new thera pies with traditional chemotherapy and with other targeted drugs will require well-planned, biomarker-driven trials. The task ahead of us is daunting. Multiple tumor markers may be required to select the pa tients most likely to benefit from a given agent or combinations of agents.With each new agent acting by a distinct mechanism, the num ber of potential combinations of agents increases factorially. A greater willingness of industry to share their drugs to develop novel combina tion therapies would hasten progress. In planning the new edition of this book, we have sought to provide the wisdom of experts. The facts contained herein can form a frame work from which clinical decisions can be made. However, the facts are not a substitute for excellent clinical judgment.While adherence to protocols is critical, the practice of oncology cannot appropriately be reduced to recipes and algorithms that are universally applicable to ev ery patient. Each physician must develop a sense of what the agents can and cannot do and apply that knowledge to the individual patient, who becomes the host for these foreign molecules. As we have said earlier, pharmacologic thinking is essential to improving therapeutic results. With the continuous expansion of available new agents and the grow ing complexity of treatment options, the challenge of keeping abreast of cancer therapeutics has become immense and the need for teaching in this field ever greater.We hope the information in this book can be a useful guide that will enable the safe and effective practice of cancer medicine and further progress in cancer research.

All substances are poisonous; there is none that is not a poison.The right dose differentiates a poison from a remedy. —Paracelsus (1538 AD) For physicians who care for patients with cancer, Paracelsus was clair voyant. Cancer therapy as presently practiced has clear benefits but for most regimens carries the potential for substantial toxicity. Stem cell transplantation probably represents the most extreme example of this conundrum, but, with the exception of hormonal therapies, most cancer treatments possess this duality of risk and reward. However, remarkable progress in the past few years has significantly broadened the therapeutic landscape and improved the outlook for patients with advanced disease. Neoadjuvant, adjuvant, and perioperative therapies have become effective partners of surgery and irradiation for the ini tial treatment of apparently localized disease.We particularly take no tice of the development of new and less toxic targeted therapies, the established long-term benefit of immunotherapies for patients with advanced disease, and continued progress in supportive and pallia tive care. Since the sixth edition of this text 5 years ago, research has proven the value of more than 60 new chemical entities and has estab lished the value of new biomarkers and diagnostic tests.Antibody drug conjugates, bispecific antibodies, and CAR-T therapies are now rou tinely used in multiple disease settings. Genomic testing is indispens able in allowing oncologists to select the right treatment for patients with lung, melanoma, thyroid, breast, and gastroesophageal cancers, contributing to improved survival in patients with the most common forms of malignancy.And these new therapies are rapidly being moved into first-line and adjuvant or neoadjuvant regimens. However, with this expansion of options comes the challenge of understanding drug action, interactions, and toxic potential. The task of including all newly approved drugs in this text is for midable. Third-generation drugs, based on an understanding of resis tance mechanisms to initial drugs, are now primary therapies for EGFR , EML4-ALK , and ROS1 mutant lung cancers. BTK inhibitors that are less toxic and more active than ibrutinib have been approved in many lym phomas and chronic lymphocytic leukemias (CLLs). Significant benefit has accrued from advances in hormonal therapy with receptor degrad ing molecules and inhibitors of adrenal steroid biosynthesis. Novel tar gets of drug action have led to surprising results with novel agents, including the CDK4/6 inhibitors in breast cancer and the poly (ADP ribose) polymerase (PARP) inhibitors in breast and ovarian cancer, and the IDH1 and 2 inhibitors in acute leukemia, brain tumors, and cholan giocarcinoma. Discovery of the mechanism of action of the IMiD class of compounds has led to promising new agents (PROTACs) in clinical trial targeting the ubiquitin ligases and associated proteins. Most impressive has been the rapid evolution of immunotherapies in the past 5 years, as checkpoint antibodies and CAR-T cell therapies are now essential components of clinical practice. Much work needs to be done to make these expensive and at times dangerous therapies less toxic and more selective.The challenge of understanding their mecha nism of action, developing suitable biomarkers to guide patient selec tion, and developing rational therapies (aside from glucocorticoids)

Bruce A. Chabner, MD Dan L. Longo, MD

A cknowledgments

its earliest days of exploration of single alkylating agent activity, radi cal surgery, and localized radiation therapy to the amazing expansion in the number of available tools. Radical surgery, the first curative intervention, is largely being replaced by more limited operations often performed robotically. Technology has continuously improved the capacity to deliver radiation to various tumors with increasing focus and specificity. The improvements in surgery and radiation therapy have led to a closer interdigitation of these treatments with chemotherapy and biologic therapies in earlier phases of disease, making the knowledge of pharmacology of even greater importance to multidisciplinary care. The burgeoning of effective drug classes aiming at an increasing number of targets has steadily improved re sponse rates and survival and, somewhat paradoxically, has compli cated the process of developmental therapeutics given that we are still quite naive about how to combine agents that interfere with distinct (or even overlapping) targets to achieve optimal anticancer effects at acceptable levels of toxicity. The field of immunotherapy is also beginning to deliver on its enormous promise after years of modest results.We experienced the disappointment when the much hyped interferon was introduced to enormous fanfare but produced only modest successes in a few rare tumor types and settings at a cost of often intolerable toxicity. However, persistence and accumulat ing new knowledge are paying off as immune interventions are now achieving long-term disease control in advanced solid tumors that were formerly universally fatal. Antibodies, naked and armed with drugs and radionuclides, cytokines, and adoptive cellular therapies, are now essential tools for physicians treating patients with cancer. And the advances are not only helping cancer patients.Therapies such as rituximab and technologies such as bone marrow transplantation, initially developed for cancer, are improving the lives of patients with nonmalignant autoimmune or inherited diseases. We have moved from the initial successes of single-agent (cho riocarcinoma) and combination chemotherapy (lymphoma, adjuvant therapy) and are now seeing the emerging successes of myriad novel interventions. It is extremely gratifying to have witnessed the change from the revolutionary findings of first our mentors, then our col leagues, and now our mentees.We dedicate this book to all of them in the hope that something between these covers stimulates a thought that leads to something new and better for our patients.

Dan L.Longo,MD (left) and Bruce A.Chabner,MD (right)

The seventh edition of Cancer Chemotherapy, Immunotherapy and Biother apy: Principles and Practice was a labor of love.The last six editions were published by Lippincott Williams & Wilkins, which was acquired by Wolters Kluwer.We were guided atWolters Kluwer by Stacey Sebring, developmental editor, and Varshaanaa Muralidharan, editorial coordi nator, who were helpful at every turn.The distinguished roster of con tributors wrote remarkably up-to-date chapters and were patient with the iterative process of making requested revisions in a timely fashion. Their motivation to educate the reader about the rapidly changing can cer treatment landscape drove the project to fruition. And lastly, our colleagues have been the inspiration for this book, as they show us how to employ these agents in increasingly effective ways. The editors are also grateful for having been able to watch and contribute to the development of the field of cancer treatment from

C on t e n t s

Contributors v Preface x Acknowledgments xi SECTION I: BASIC PRINCIPLES OF CANCER TREATMENT 1 Clinical Strategies for Cancer Treatment:The Role of Drugs

13 Topoisomerase Inhibitors

236

Anish Thomas and Yves Pommier

14 Bleomycin, Mitomycin C,Yondelis, and Other Antibiotics

257

Bruce A. Chabner

15 Epigenetic Agents in Hematology and Oncology Seda S.Tolu, Jennifer E.Amengual, and Susan E. Bates

272

Bruce A. Chabner and Adam C. Palmer

2 Target Identification and Drug Discovery

16 Differentiating Agents in

Acute Promyelocytic Leukemia

290

Edward A. Sausville and Bruce A. Chabner

Bruce A. Chabner

3 Clinical Drug Development and Approval Gautam U. Mehta, Harpreet Singh, and Richard Pazdur 4 Pharmacogenomics and Cancer Therapeutics 5 Delivering Anticancer Drugs to BrainTumors David Gritsch, K. Ina Ly,Tracy T. Batchelor, and Maciej M. Mrugala Steven M. Offer and Robert B. Diasio

17 Asparaginase

296

Bruce A. Chabner

18 Proteasome Inhibitors

303

Diana D. Cirstea, E. Bridget Kim, and Andrew J. Yee

19 Cereblon-Mediated Degraders Monique A. Hartley-Brown, Mariko Kaji, Jacob Laubach, and Constantine S. Mitsiades

323

SECTION II: TARGETED AGENTS

6 Antifolates

20 Tyrosine Kinase Inhibitors Alice Tzeng,Tony H.Tzeng, Zofia Piotrowska, and Justin F. Gainor 21 Mitogen-Activated Protein Kinase Pathway

338

I. David Goldman and Bruce A. Chabner

7 5-Fluoropyrimidines

120

David P. Ryan, Janice S. Kim, and Bruce A. Chabner

8 Cytidine Analogues

142

361

Christopher S. Nabel

Ibiayi Dagogo-Jack, Ryan J. Sullivan, and Keith T. Flaherty

9 Purine Analogues

158

22 The PI3K/AKT/mTOR Signaling System

375

Christopher S. Nabel

Janice S. Kim, Dejan Juric, and Bruce A. Chabner

10 Antimitotic Drugs

173

23 Cyclin-Dependent Kinase Inhibitors 391 Geoffrey I. Shapiro and Suzanne M. Barry 24 DrugsTargeting the ABL and Janus Kinases 427 Chi-Joan How, James A. Kennedy, Samantha O. Luk, and Gabriela Hobbs

Cindy H. Chau, William D. Figg, and Bruce A. Chabner

11 Alkylating and Methylating Agents Bruce A. Chabner, Li Lan, Gregory M. Cote, and Lee Zou

195

Bruce A. Chabner and Beatrix Bess Thompson

xiii

xiv

Contents

25 BrutonTyrosine Kinase Inhibitors

451

32 CancerVaccines

590

Mark Roschewski

Cornelis J. M. Melief,Anna-SophiaWiekmeijer, and Esmé T. I. van der Gracht

26 Angiogenesis Inhibitors Max F. Kelsten and William J. Gradishar

463

33 Viral Xenogenization

595

Sophia Z. Shalhout and Howard L. Kaufman

34 Immunotherapeutic Control of Cancer

SECTION III: HORMONE ANTAGONISTS FOR BREAST CANCER 27 EndocrineTherapy of Breast Cancer 480 Laura M. Spring, Beverly Moy, and Aditya Bardia 28 HormonalTherapy for Prostate Cancer 499 Richard J. Lee

607

Michael B. Foote, Margaret K. Callahan, Niamh Keegan, Sierra Silverwood, Firas Kreidieh, Omar Alhalabi, Hussein Tawbi, Padmanee Sharma, and Jedd D.Wolchok

SECTIONV: SUPPORTIVE CARE

35 Antiemetics

642

Rudolph M. Navari

SECTION IV: IMMUNE-BASEDTHERAPIES

36 Hematopoietic Growth Factors

656

Gary H. Lyman and Nicole M. Kuderer

29 Monoclonal Antibodies

514

37 Cancer and Coagulopathy

670

Ramya Ramaswami, Dan L. Longo, and David Spriggs

Michael J.Andersen Jr, Rushad Patell, and Rachel P. Rosovsky

30 CytokineTherapy for Cancer

544

Michail Alevizakos and David F. McDermott

Index 691

31 Adoptive CellularTherapy

566

Bruce L. Levine, David Mai, Sofia Castelli, Giulia Golinelli, and Carl H. June

Bleomycin, Mitomycin C,Yondelis, and Other Antibiotics Bruce A. Chabner 14 CHAPTER

Bleomycin

14.1

Key Features of Bleomycin Pharmacology

Introduction

Mechanism of action

Oxidative cleavage of DNA initiated by hydrogen abstraction Activated by microsomal reduction Degraded by hydrolase found in multiple tissues None clearly established at a biochemical level Oxygen enhances pulmonary toxicity Cisplatin induces renal failure and in creases the risk of pulmonary toxicity Pulmonary interstitial infiltrates and fibrosis Desquamation, especially of fingers, elbows Raynaud phenomenon Hypersensitivity reactions (fever, anaphy laxis, eosinophilic pulmonary infiltrates) Pulmonary toxicity increased in patients with underlying pulmonary disease Age > 70 y Renal insufficiency Prior chest irradiation O 2 during surgery Reduce dose if creatinine clearance < 60 mL/min t 1/2 : 2-4 h Renal: 45%-70% in the first 24 h

In a search for new antimicrobial and antineoplastic agents, natural products from plants, fungal cultures, and marine organisms have yielded structurally and mechanistically unique products. The task of identifying and developing such material into a drug involves a number of challenging steps: collection of raw material, isolation of the ac tive principle, its chemical and mechanistic characterization, and total synthesis of the product, and, finally, clinical development. Among the great pioneers in this field, Umezawa et al 1 discovered bioactive mate rials for the treatment of infectious disease and cancer, among which were the bleomycins, small glycopeptides from culture broths of the fungus Streptomyces verticillus . The most important product, bleomycin , has important activity against Hodgkin disease and testicular cancer. Bleomycin combined with vinblastine, etoposide, and cisplatin cures most patients with germ cell tumors of the testis. The drug has at tracted great interest because of its unique structure and biochemical action, its virtual lack of toxicity for normal hematopoietic tissue, and its unfortunate ability to cause pulmonary fibrosis. Its primary pharma cologic and pharmacokinetic features are shown in Table 14.1 . The bleomycin peptides contain a number of unusual amino acids and have a molecular weight of approximately 1,500 ( Fig. 14.1 ). All contain a unique structural component, bleomycinic acid, and differ only in their terminal alkylamine group. Bleomycin A 2 , the predominant peptide, has been prepared by total chemical syn thesis, as have more than 100 bleomycin analogues, but none has emerged as a superior drug. 2 The clinical mixture of bleomycin peptides is formulated as a sulfate salt, and its potency is measured in units (U) of antimicrobial activity. Each unit contains between 1.2 and 1.7 mg of polypeptide protein. 3 The powdered clinical mixture is stable for 4 weeks after reconsti tution in aqueous solution at 4°C. The predominant A 2 peptide con stitutes 70% of the commercial preparation. The native compound isolated from S. verticillus is a blue-colored Cu(II) coordinated com plex, although the peptide will complex in vitro with other metals, including iron, cobalt, zinc, and manganese, in various valence states. 4 The iron and copper complexes are believed to be the active forms in vivo.The Co(III) complex has no biologic activity, retains its bound Structure and Mechanism of Action

Metabolism

Pharmacokinetics

Elimination

Drug

interactions

Toxicity

Precautions

t 1/2 , half-life.

257 metal tightly, and was formerly used for tumor imaging as the 57 Co(III) isotope. Bleomycin has the highest affinity for Cu(II). In initial clinical trials with Cu(II)·bleomycin, patients experienced profound phlebitis. The white apo-bleomycin, lacking metal, was soon adopted for clinical use. After systemic administration, apo-bleomycin rapidly complexes with Cu(II) derived from plasma transporters. 5 The ability of Cu(II) bleomycin complex to cross membranes depends upon the presence of the disaccharide (l-glucose and 3- O -carbamoyl-d-mannose) moiety of bleomycin and its bound metal, Cu(II). 6 Intracellularly, Cu(II) com plex is reduced to Cu(I), which is then replaced by the more abundant Fe(II). 4 Nuclear translocation of the Fe(II)·bleomycin complex leads to DNA damage mediated by the drug’s generation of free radicals.

258

Section I • Basic Principles of Cancer Treatment

F igure 14.1 Structure of bleomycin·Fe(II) complex. The various substitutions on the amino-terminal end of the molecule are shown for bleomycin A 2 (BLM A2) and for bleomycin B 2 (BLM B2); also a component of the clinical preparation).

Bleomycin binds Fe(II) by forming a square-pyramidal complex, as indicated in Figure 14.1 . Six distinct moieties are required for this metal coordination complex with the pyrimidine, the imidazole, and a secondary amine as undisputed participants. 4 Debate still exists about the arrangement of the remaining ligands.

O 2

BLM Hydrolase

Cu(II)-BLM Fe(II)-BLM Activated Fe(II) BLM-O 2

Inactive BLM

DNA

Fet(II)-BLM-O 2 -DNA

Mechanism of Antitumor Action

Nucleophilic attack

On deoxyribose of DNA

Single- and double-strand DNA breaks are observed in cultured cells and isolated DNA incubated with bleomycin.This breakage is reflected in the chromosomal gaps, deletions, and fragments seen in cytoge netic studies of cells incubated with the drug. Other targets, such as RNA and lipid, are attacked by bleomycin and the oxygen radicals it generates. 7 Fe(II)·bleomycin cleaves viral, bacterial, mammalian, and syn thetic DNAs. Bleomycin is unlike most DNA-damaging agents in that it attacks deoxyribose rather than the nucleic acids. In the multistep process, an “activated” Fe(II)·bleomycin·O 2 complex is formed that di rectly cleaves DNA. 8 The production of activated bleomycin is outlined in Figure 14.2 . A ternary Fe(II)·bleomycin·O 2 species, which can be trapped with isocyanide, CO, or NO in vitro, is activated by a 1 e − reduction. The e − can be supplied by a second Fe(II)·bleomycin·O 2 molecule, by H 2 O 2 , by microsomal and nuclear reductases, by nicotinamide-adenine dinu cleotide phosphate (reduced form) (NADPH) or nicotinamide-adenine dinucleotide (reduced form) (NADH). 9-11 In the absence of DNA, the activated species will self-destruct. The association of O 2 Fe(II)·bleomycin with duplex DNA occurs rapidly. The interaction of bleomycin with DNA shows nucleotide sequence selectivity, cleav age occurring preferentially at the start sites of active transcription. 12 The guanine-rich telomeric region of chromosome ends is a favored

F igure 14.2 Model for the activation of BLM to the cleavage-competent bleomycin complex with Fe(II) and O 2 .

site as well. 13 The binding between bleomycin and DNA proceeds through partial intercalation (insertion between base pairs) of the amino-terminal tripeptide of bleomycin (the S tripeptide ). 14 The bithia zole of the S tripeptide binds to guanine groups in the favored sequence of GpT or GpC. 15 Once bound to DNA, bleomycin generates DNA breaks. During the DNA cleavage process, under aerobic conditions, Fe(II)·bleomycin resembles a ferrous oxidase, catalyzing the conversion Fe(II) to Fe(III) and releasing electrons that generate oxygen radicals and other reac tive species. 14 Bleomycin bound to DNA consumes oxygen rapidly in vitro, with a maximum velocity of 27 mol oxygen per minute per mole of bleomycin. The DNA fragments produced after incubation with activated bleomycin indicate an attack at the C-3 ′ to C-4 ′ deoxyribose bond. A proton is extracted at C-4 ′ , leading to a break in the phosphodies ter linkage, producing a 5 ′ -oligonucleotide terminating at its 3 ′ -end with a phosphoglycolic acid moiety and a 3 ′ -oligonucleotide contain ing a 5 ′ -phosphate. In addition, a 3 ′ -(thymin-9 ′ -yl)-propenal is re leased 16 ( Fig. 14.3 ). In cells exposed to bleomycin, free bases and base

259

Chapter 14 • Bleomycin, Mitomycin C, Yondelis, and Other Antibiotics

F igure 14.3 Scheme for the cleavage of the 3 ′- 4 ′ deoxyribose bond by the activated bleomycin·Fe(II)·O 2 complex. In pathway A, the activated drug complex initially abstracts a hydrogen radical from the 4 ′ -position. The unstable intermediate [1] then decomposes in the presence of oxygen [2 and 3], opening the deoxyribose ring [5], releasing a 5 ′ -phosphate [6], producing the free base propenal [7] and leaving a 3 ′ -phosphoglycolate ester [8]. Under conditions of limited oxygen, Pathway B, the bleomycin·Fe(II)·O 2 complex releases a free base [9], and the DNA strand is susceptible to breakage by alkali.

the 3 ′ side of G seems to be absolute. A schematic of the intercala tion and cleavage processes as conceived by Grollman andTakeshita 17 is summarized in Figure 14.3 .

propenals are detected. The base propenal compounds have intrinsic cytotoxicity and may contribute to cellular damage. 17 Bleomycin produces single- and double-strand DNA breaks in a ratio of 10:1. The highly electronegative 3 ′ -phosphoglycolate and 5 ′ -phosphate groups remaining at the site of single-strand cleav age promote access of a second bleomycin molecule to the opposing strand, resulting in a double-strand break (DSB). Analysis of the products of DNA cleavage, using either viral or mammalian DNA, has consistently shown a preferential release of thymine or thymine-propenal, with lesser amounts of the other three bases or their propenal derivatives. 7 The propensity for attack at thy mine results from the preference for partial intercalation of bleomycin between base pairs in which at least one strand contains the sequence 5 ′ -GpT-3 ′ . The specificity for cleavage of DNA at a residue located at

Cellular Pharmacology

The cellular uptake of bleomycin depends upon glucose or carotene transporters or endoplasmic vesicles. 6 In the cytosol, it can be de graded by bleomycin hydrolase, 18 which cleaves the carboxamide amine from β -aminoalaninamide, yielding inactive deaminobleomycin. Both the primary amino acid sequence and higher order structure determined by x-ray crystallography reveal that bleomycin hydrolase is a member of self-compartmentalizing or sequestered intracellular

260

Section I • Basic Principles of Cancer Treatment

proteases. 19 Both yeast and human enzymes are homohexamers with a ring- or barrel-like structure that has the papain-like active sites situ ated within a central channel. The hydrolase structure resembles the organization of the active sites in the 20S proteasome.The central chan nel, which has a strongly positive charge in the yeast protein, is slightly negative in human hydrolase, thus attracting the cationic bleomycin. Bleomycin hydrolase is the sole bleomycin-degrading enzyme in normal and malignant tissue. 20 It is present in relatively low concen trations in the lung and skin, the two normal tissues most susceptible to bleomycin damage. 20 Interestingly, pulmonary bleomycin hydrolase levels correlate with the sensitivity of various animal species to the pulmonary toxicity of bleomycin. 21 A polymorphism, A1450G, in the coding region, found in 10% of patients with testicular cancer, is asso ciated with a 20% decrease in survival in patients receiving bleomycin, perhaps related to drug toxicity. 22 The molecular lesions caused by bleomycin include chromosomal breaks and deletions and both single-strand and (less frequently) dou ble strand breaks. In nonmitotic cells, DNA is organized into nucleo somes, or small beads of heavily transcribed genes, which are joined by long strands, or linker regions. The primary point of attack seems to be in the linker regions of DNA, between nucleosomes. 23,24 Interest ingly, the resulting 180- to 200-base-pair fragments are similar in size to those formed by endonucleases activated during apoptosis. 24,25 Cells are able to repair bleomycin-induced DNA breaks. Exposure to bleomycin induces p53 phosphorylation and its translocation from the cytoplasm to the nucleus, where it initiates DNA repair. p53 levels and activity are controlled by its inactivation within a complex with MDM-2 and with HERC2 (both are ubiquitin E3 ligases), and with NEURL4. Bleomycin exposure induces DNA breaks, the detection of which, in turn, dissociates MDM-2 from the complex and activate p53, leading to repair or apoptosis. 26 In the repair process, the 3 ′ -phosphoglycolate and 5 ′ -deoxyribose ends of DNA strands produced by bleomycin are removed by tyrosyl-DNA phosphodiesterase 1 (TDP 1). 27 TDP 1 – deficient cells are hypersensitive to oxidative damage. Both single- and double-strand repair processes are also involved in repair. Homologous recombination (HR) is critical to re pair, as HR suppression by Wwox protein, a binding partner of BRCA1, enhances strand breakage, while loss ofWwox induces HR foci, increasing DSB repair and promoting bleomycin resistance. 28 The role of other re pair pathways in bleomycin damage repair is less clear. Bleomycin exposure rapidly induces base excision repair (BER) and PARP-1 enzyme activity. 29 PARP-1 has an essential role in BER as well as promoting HR and non homologous DNA end – joining (NHEJ) repair. However, no specific role of BER in bleomycin toxicity has been defined. Cells from patients with ataxia-telangiectasia, an inherited defect in double-strand repair, are highly sensitivity to bleomycin, 30 as are cells deficient in BRCA1 or in mismatch repair. 31

Clinical Pharmacology

High-performance liquid chromatography (HPLC) is the preferred and most specific technique for assay of bleomycin in biologic fluids, allowing resolution of the component peptides. 35 The hallmark of bleomycin pharmacokinetics in patients with nor mal serum creatinine is a rapid two-phase drug disappearance from plasma; 45% to 70% of the dose is excreted in the urine within 24 hours. For intravenous bolus doses, the primary half-life for drug dis appearance in plasma is 2 to 4 hours. 36 Peak plasma concentrations reach 1 to 10 mU/mL for intravenous bolus doses of 15 U/m 2 . Intramuscular injection of bleomycin (2-10 U/m 2 ) provides peak plasma levels of 0.13 to 0.6 mU/mL or approximately one-tenth the peak level achieved by an intravenous bolus. 37 The mean half-life in plasma after intramuscular injection is 2.5 hours. Bleomycin pharmaco kinetics also have been studied in patients receiving intrapleural or intra peritoneal injections, routes used in controlling malignant effusions due to breast, lung, and ovarian cancers. Intracavitary bleomycin (60 U/m 2 ) gives peak plasma levels of 0.4 to 5.0 mU/mL, with a plasma half-life of 3.4 hours after intrapleural doses and 5.3 hours after intraperitoneal injection. 38 Intracavitary levels are 10- to 22-fold higher than simultane ous plasma concentrations. 39 About 45% of an intracavitary dose enters the systemic circulation, and 30% is excreted in the urine. Bleomycin pharmacokinetics are markedly altered in patients with abnormal renal function, particularly those with a creatinine clearance (CrCl) of less than 35 mL/min. A high frequency of pulmonary toxic ity is found in patients with renal dysfunction. 40 Doses should be re duced in proportion to the reduction in CrCl for patients with CrCl less than 60 mL/min, or a regimen substituting ifosfamide for bleomy cin for germ cell tumors may be employed. The most important toxic actions of bleomycin affect the lungs and skin; myelosuppression is not usually evident, except in patients with severely compromised bone marrow function due to extensive previ ous chemotherapy. 41 Fever occurs during the 48 hours after drug ad ministration in one-quarter of patients. Some investigators advocate using a 1-U test dose before an initial dose, as rare instances of fatal allergic reactions have been reported. 42 Pulmonary Toxicity of Bleomycin Pulmonary toxicity is manifest as a subacute or chronic interstitial pneumonitis that progresses over weeks to months to fibrosis, hypoxia, and death. 43 Clinically apparent pulmonary toxicity, heralded by cough and dyspnea, and accompanied by bibasilar pulmonary infiltrates on chest radiographs, occurs in 3% to 5% of young men with testicular cancer receiving a total dose of less than 450 U bleomycin; it increases significantly in those treated with higher cumulative doses ( Fig. 14.4 ). A higher incidence of up to 30% of patients receiving the doxo rubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen for Hodgkin disease has been reported, but the incidence of pul monary toxicity varies with the level of clinical monitoring. 44 De pending on the total dose, regimen, and age of patients, subclinical evidence of pulmonary toxicity is elicited by spirometry in up to 50% of patients; findings indicate restrictive function, hyperinflation, Clinical Toxicity and Side Effects

Resistance

Several intracellular factors contribute to bleomycin tumor resistance: increased drug inactivation by hydrolase, decreased drug accumula tion, and increased repair of double-strand DNA breaks. 32,33 Tumor lines with elevated levels of glutathione, selected for resistance to doxorubicin, are collaterally sensitive to bleomycin, perhaps due to in creased capacity to regenerate bleomycin (Fe(II)). 34 Bleomycin is not affected by the mdr efflux transporter.

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