American MiniHandbook of Hematologic Malignancies

Oxford American Mini-Handbook of Hematologic Malignancies This material is not intended to be, and should not be considered, a substitute for medical or other professional advice Treatment for the conditions described in this material is highly dependent on the individual circumstances While this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues are constantly evolving, and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation Oxford University Press and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material, including without limitation that they make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material The authors and the publishers not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material The Publisher is responsible for author selection and the Publisher and the Author(s) make all editorial decisions, including decisions regarding content The Publisher and the Author(s) are not responsible for any product information added to this publication by companies purchasing copies of it for distribution to clinicians Oxford American Mini-Handbook of Hematologic Malignancies Gary H Lyman, MD, MPH, FRCP (Edin) Professor of Medicine and Senior Fellow Duke Center for Clinical Health Policy Research Duke University Durham, North Carolina with Jim Cassidy Donald Bissett Roy A.J Spence Miranda Payne 1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Copyright © 2010 by Oxford University Press, Inc Published by Oxford University Press, Inc 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press The Library of Congress has cataloged the Oxford American Handbook of Oncology, 1st edition as follows: Oxford American handbook of oncology / edited by Gary H Lyman p ; cm — (Oxford American handbooks) Adapted from: Oxford handbook of oncology 2nd ed 2006 Includes bibliographical references and index ISBN 978-0-19-536061-2 (flexicover : alk paper) Cancer—Handbooks, manuals, etc Oncology—Handbooks, manuals, etc I Lyman, Gary H., M.D II Oxford handbook of oncology III Title: Handbook of oncology IV Series [DNLM: Neoplasms–Handbooks QZ 39 O9 75 2009] RC262.5.O944 2009 616.99´4–dc22 2008034278 Printed in United States of America on acid-free paper Disclosures v Dr Lyman has been on the Speakers’ Bureau as well a grants/ research support recipient at Amgen He has also been on the Speaker’s Bureau at Ortho Biotech This page intentionally left blank Contents Contributors ix Part I Introduction Molecular cancer pathology Molecular alterations in cancer Cancer biology 11 Part II The hematological malignancies Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL) Part III Chronic leukemias and myelodysplastic syndromes Chronic myeloid leukemia (CML) Myelodysplastic syndromes (MDS) Chronic lymphoid leukemias Multiple myeloma 21 29 37 43 49 59 Part IV Malignant lymphoma 10 11 12 13 Hodgkin lymphoma (HL) Non-Hodgkin lymphomas (NHL) Management strategies for NHL Non-Hodgkin lymphoma and acquired immunodeficiency disorder Part V Treatment and management for hematological malignancies 14 Hematopoietic stem cell transplantation 15 Targeted therapies Index 137 75 83 93 99 105 117 This page intentionally left blank Contributors Anne W Beaven, MD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Carlos M DeCastro, MD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Louis F Diehl, MD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Phuong L Doan, MD Department of Medicine Duke University Medical Center Durham, North Carolina Phillip Febbo, MD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Daphne Friedman, MD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina ix Gerard C Blobe, MD, PhD bendamustine hydrochloride (Treanda) Mechlorethamine derivative, causes DNA cross-linking, active in quiescent and dividing cells Chronic Lymphocytic Leukemia (CLL) Non-Hodgkin Lymphoma (NHL) – second line Subsequent Treatment Cycles: the above cycle should be repeated every weeks It is recommended that patients be treated for a minimum of cycles; however, a complete or partial response may take longer than cycles Treatment may be continued as long as the patient continues to benefit 100 mg/m² administered intravenously over 30 minutes on Days and of a 28-day cycle, up to cycles 120 mg/m² administered intravenously over 60 minutes on Days and of a 21-day cycle, up to cycles 127 • WARNING: Myelosuppression, infections, infusion reactions , Tumor Lysis Syndrome, skin reactions, other malignancies – associated in clinical trials • Other common adverse reactions include: asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation, stomatitis CHAPTER 15 Targeted therapies 128 CHAPTER 15 Targeted therapies Table 15.1 Continued Generic Name (Brand Name) imatinib mesylate (Gleevec) MOA Indication Dosing Schedule Side Effects/Notes Protein-tyrosine kinase (PTK) inhibitor that inhibits bcr-abl tyrosine kinase, the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and PGDFand SCF-mediated cellular events Induces apoptosis and inhibits proliferation in bcr-abl positive tumors and other PTK-mediated cellular events Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferonalpha (IFN) Therapy Pediatric Patients with Ph+ CML in Chronic Phase 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis • Ph+ Acute Lymphoblastic Leukemia (ALL) 340 mg/m2/day (not to exceed 600 mg)., 260 mg/ m2/day for children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon-alpha therapy 600 mg/day for adult patients with relapsed/ refractory Ph+ ALL Fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema • Hematologic toxicity – neutropenia and thrombocytopenia • Hepatotoxicity – elevation of transaminases nelarabine (Arranon) clofarabine (Clolar) Myelodysplastic/ Myeloproliferative Diseases (MDS/MPD) Hypereosinophilic Syndrome (HES) and/ or Chronic Eosinophilic Leukemia (CEL) T-cell acute Deoxyguanosine analogue 9-E-D-arabinofuranosylguanine lymphoblastic leukemia (ara-G), incorporation into DNA leads to inhibition of T-cell lymphoblastic DNA synthesis and cell death lymphoma – third line Inhibits deoxycytidine kinase and ribonucleotide reductase, leading to inhibition of DNA synthesis and induction of apoptosis 400 mg/day 400 mg/day 1,500 mg/m², IV over hours on Days 1, 3, and repeated every 21 days Pediatric patients to 21 52 mg/m2 IV infusion over years old with relapsed hours daily for consecutive or refractory acute days lymphoblastic leukemia after at least two prior regimens 129 Most common adverse events include fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia Gastrointestinal tract symptoms, including vomiting, nausea, and diarrhea; hematologic effects, including anemia, leukopenia, thrombocytopenia, neutropenia, and febrile neutropenia; and infection CHAPTER 15 Targeted therapies 130 CHAPTER 15 Targeted therapies Table 15.1 Continued Generic Name (Brand Name) MOA Indication Dosing Schedule Side Effects/Notes nilotinib hydrochloride (Tasigna) bcr-abl, PDGF-R and c-kit inhibitor Chronic phase and accelerated phase Ph+ positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib ibritumomab tiuxetan (IV, Zevalin) The chelate tiuxetan, which tightly binds In-111 or Y-90, is covalently linked to ibritumomab (a monoclonal antibody), which binds CD-20 present on B-cells The beta emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells Only as part of Zevalin therapeutic regimen** (w/pre-treatment and co-administration of various agents, including rituximab) of patients with relapsed or refractory, low-grade or follicular B-cell NHL, including patients with rituximab refractory follicular NHL 400 mg orally twice daily, • WARNING: QT prolongation and treatment should continue Sudden Deaths, myelosuppression, as long as the patient does elevated serum lipase, hepatotoxicity, not show evidence of electrolyte abnormalities progression or unacceptable • Other commonly adverse effects toxicity include rash, pruritus, constipation The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia Injection of rituximab • WARNING: Serious infusion reactions, followed by ibritumomab prolonged and severe cytopenias, and tiuxetan on Day 1, and then severe cutaneous and mucocutaneous Day 7, or reactions, Secondary Leukemia and Myelodysplastic Syndrome • Other common effects include neutro**Follow Zevalin penia, thrombocytopenia, anemia, therapeutic regimen for gastrointestinal symptoms (nausea, detailed insturctions vomiting, abdominal pain, and diarrhea), increased cough, dyspnea, dizziness, arthralgia, anorexia, anxiety, and ecchymosis • Because rituximab is part of the alemtuzumab (IV Campath) Monoclonal antibody, binds to CD52, an antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocyte The proposed mechanism of action is antibody-dependent cellular-mediated lysis following cell surface binding of alemtuzumab to the leukemic cells B-cell chronic lymphocytic leukemia (B-CLL) • Only as an IV infusion over hours (not bolus or push) • Gradually escalate to the max recommended single dose of 30 mg (in 3–7 d) - mg daily until infusion reactions are d grade 2, then 10 mg d until infusion reactions are d grade 2, then 30 mg/day 3X week on alternate days 131 therapeutic regimen, rituximabassociated adverse effects also occur • WARNING: Cytopenias, infusion reactions, immunosuppression/ infections • Common adverse events/reactions include infusion reactions, cytopenias, infections (e.g., CMV), gastrointestinal symptoms, insomnia, anxiety CHAPTER 15 Targeted therapies 132 CHAPTER 15 Targeted therapies Table 15.1 Continued Generic Name (Brand Name) ofatumumab (IV, Arzerra) MOA Indication Dosing Schedule Side Effects/Notes Binds specifically to both the small and large extracellular loops of the CD20 molecule (present on normal B lymphocytes and on B-cell CLL) Data suggest that possible mechanisms of cell lysis include complementdependent cytotoxicity and antibody-dependent, cellmediated cytotoxicity CLL refractory to fludarabine and alemtuzumab • Dilute and administer as • Warnings and Precautions: • • • • an intravenous infusion Do not administer as an intravenous push or bolus Recommended dose and schedule is 12 doses administered as follows: 300 mg initial dose, followed week later by 2,000 mg weekly for doses, followed weeks later by 2,000 mg every weeks for doses Premedicate with oral acetaminophen, oral or intravenous antihistamine, and intravenous corticosteroid monitor for infusion reactions, cytopenias, progressive multifocal leukoencephalopathy (PML) and Hepatitis B reactivation Discontinue ofatumumab if any of the above is observed or suspected • Most common adverse reactions (t10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections rituximab (IV, Rituxan) Monoclonal antibody, binds specifically to CD20 (expressed on > 90% of B-cell NHLs, but not on hematopoietic stem cells, proB-cells, normal plasma cells or other normal tissues), effects B-cell lysis in vitro, possible complement-dependent cytotoxicity, antibodydependent cell-mediated cytotoxicity For the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent Previously untreated follicular, CD20positive, B-cell NHL in combination with CVP chemotherapy Non-progressing (including stable disease), low-grade, CD20positive, B-cell NHL, as a single agent, after firstline CVP chemotherapy Previously untreated diffuse large B-cell, CD20positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens First Infusion: Initiate at 50 mg/hr In the absence of infusion toxicity, i by 50 mg/hr increments every 30 minutes, to a max of 400 mg/hr Subsequent Infusions: Initiate at 100 mg/hr In the absence of infusion toxicity, i by 100 mg/hr increments at 30-minute intervals, to a max of 400 mg/hr Interrupt the infusion or slow the infusion rate for infusion reactions (see WARNING) • WARNING: infusion reactions, tumor lysis syndrome, severe mucocutaneous reactions, progressive multifocal leukoencephalopathy • Common adverse reactions include infusion reactions, fever, chills, infection, asthenia, and lymphopenia **See prescribing info for detailed dosing instructions 133 CHAPTER 15 Targeted therapies 134 CHAPTER 15 Targeted therapies Table 15.1 Continued Generic Name (Brand Name) MOA Indication Dosing Schedule gemtuzumab ozogamicin (injection, Mylortag) Monoclonal antibody to CD33 antigen (expressed on the surface of leukemic blasts in more than 80% of patients with acute AML) CD33 positive acute • mg/m² , infused over a myeloid leukemia in 2-hour period first relapse who are 60 • Should consider years of age or older and leukoreduction with who are not considered hydroxyurea or candidates for other leukapheresis to reduce cytotoxic chemotherapy the peripheral WBC to below 30,000/μL prior to administration • Patients should receive (1 hr before gemtuzumab) diphenhydramine 50 mg po and acetaminophen 650–1000 mg po; thereafter, two additional doses of acetaminophen 650–1000 mg po, one every hours as needed • Vital signs should be monitored during infusion and for hours following infusion Side Effects/Notes • Fever and chills common on day of administration • Severe myelosuppression is the major toxicity associated with gemtuzumab (98% Grade or Grade neutropenia, 52% Grade or Grade anemia and 99% patients experienced Grade or Grade thrombocytopenia) • 13% patients experienced Grade or Grade bleeding • Other common side effects include mucositis/stomatitis – 25% and hepatotoxicity – 29% • Less common adverse events include VOD and skin effects (less than 10%) arsenic trioxide (injection, Trisenox) • in vivo MOA not completely understood • Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in vitro Induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression Recommended course: doses with 14 days between the doses Full recovery from hematologic toxicities is not a requirement for administration of the second dose • Induction Treatment Schedule: IV 0.15 mg/kg daily until bone marrow remission Total induction dose should not exceed 60 doses • Consolidation Treatment Schedule: Consolidation treatment should begin to weeks after completion of induction therapy IV 0.15 mg/kg daily for 25 doses over a period up to weeks 135 Most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness CHAPTER 15 Targeted therapies This page intentionally left blank Index ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) therapy, for HL, 79 Acute graft-versus-host disease (aGVHD), 109, 110t, 111–112 See also graft-versus-host disease Acute lymphoblastic leukemia (ALL), 29–33, 116, 126t, 128t Acute myeloid leukemia (AML), 21–27, 116, 133t Acute promyelocytic leukemia (APL), 26, 134t Acyclovir for viral prophylaxis in HSCT, 114 Adriamycin, 53, 54, 79, 93, 94, 95 Afinitor (Everolimus), 120 Aggressive lymphomas (DLBCL), 94–96 AIDS-related non-Hodgkin lymphoma, 99–101 Alemtuzumab (Campath1H), 33, 54–55, 57, 97, 111, 120, 131t ALL See acute lymphoblastic leukemia (ALL) All-trans retinoic acid (ATRA), 26 Allogenic hematopoietic stem cell transplantation (HSCT), 26, 40–41, 46, 69, 94, 106 Allopurinol, 25 Alternate nucleoside analogues See cladribine; pentostatin AML See acute myeloid leukemia (AML) Anemia, 32, 39, 44, 45 Angiogenesis, 3, 15 Anthracyclines, 24, 25, 32, 97 See also idarubicin Anthraquinones See mitoxantrone Anti-interleukin-2 receptor antibody, 111 Anti-tumor necrosis factor (TNF) antibody, 111 Antibodies, 120–121 See also alemtuzumab; bevacizumab; cetuximab; panitumumab; rituximab; trastuzumab Antiemetic therapy, 25 Antileukemic therapy, 32–33, 97 Antilymphocyte globulin (ALG) treatment, 46 Apheresis, 40 Aplastic anemia, 21 Ara-C chemotherapy, 46 Arranon (nelarabine), 129t Arsenic trioxide (Trisenox), 135t Arzerra, 132t Asparaginase, 32 ATG in aGVHD, 111 Atypical chronic myelomonocytic leukemia (aCMML), 44t Autologous hematopoietic stem cell transplantation (HSCT), 26, 96, 105–106 Avastin (bevacizumab), 120 B B-cell chronic lymphocytic leukemia (B-CLL), 131t B-cell mature lymphoid leukemia, 49t BCR-ABL kinase inhibitors, 117–118 See also dasatinib; imatinib; nilotinib BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) therapy, 79 Bendamustine hydrochloride (Treanda), 127t Bevacizumab (Avastin), 120 Bexxar (tositumomab), 122 Bisphosphonates in MM, 69t, 70t Blast crisis phase in CML, 38, 39, 41, 118, 128t Bleomycin in BEACOPP HL therapy, 79 Blood and platelet transfusion in MDS, 45 Bortezomib (Velcade), 65, 70t, 122, 124t with dexamethasone, 66t, 68t with dexamethasone, doxorubicin, 66t with dexamethasone, thalidomide, 66t with liposomal doxorubicin, 68t Burkitt cell lymphoma (mature B-cell ALL), 6t, 12, 30 Burkitt lymphoma, 95, 96, 96, 97 C Campath-1H (alemtuzumab), 33, 54–55, 57, 97, 111, 120, 131t Cancer biology, 11–17 CAP (cyclophosphamide, Adriamycin, prednisolone), for CLL, 54 Carcinogenesis, 3–4 CD97 ligand, 15 Ceftriaxone for HSCT infection, 113 CellCept for aGVHD, 111 Central nervous system (CNS) leukemia, 30 Cetuximab (Erbitux), 120–121 Chlorambucil, for CLL, 53, 55 CHOP (cyclophosphamide, hydroxorubicin, vincristine, prednisolone), 54 Chronic eosinophilic leukemia (CEL), 39, 129t Chronic graft-versus-host disease (cGVHD), 112 Chronic lymphoid leukemias (CLL), 49–57, 127t Chronic myeloid leukemia (CML), 37–41, 112, 128t, 130t Chronic myelomonocytic leukemia (CMML), 39, 44, 44t Chronic neutrophilic leukemia, 39 Ciprofloxacin for HSCT infection, 113 Cisplatin in DCEP therapy for MM, 66t in DT-PACE therapy for MM, 66t Cladribine, for CLL, 55 Clear-cell carcinoma, 15–16 Clofarabine (Clolar), 129t Colon cancer, Colon cancer (hereditary non-polyposis), 9t Conjugated agents, 121–122 See also denileukin diftitox; ibritumomab; tositumomab 137 A INDEX 138 Consolidation chemotherapy, 57, 134t for ALL, 33 for AML, 25 for auto-BMT, 56 for Burkitt lymphoma, 97 Corticosteroid eye drops, 25 Cowden disease, 9t Cyclin-dependent kinases (CDKs), 11 Cyclophosphamide, 54, 66t, 79, 93, 109 Cyclophosphamide, Adriamycin, prednisolone (CAP), 54 Cyclophosphamide, vincristine, prednisolone (CVP), 54 Cyclosporine, 109, 111 Cytarabine for AIDS-related NHL, 101 for ALL, 33 for AML, 25 in APL, 26 for Burkitt lymphoma, 97 D Dasatinib (Sprycel) for ALL, 33 for Burkitt lymphoma, 33 for CML, 40, 41 description, 118 Daunorubicin for AML, 25 in APL, 26 DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), for MM, 66t Decitabine, 46, 126t Defibrotide prophylaxis for hepatic VOD, 115 Demethylation agents, 122–123 Denileukin diftitox (Ontak), 122 Dexamethasone in DCEP therapy for MM, 66t in DT-PACE therapy for MM, 66t with lenalidomide, for MM, 66t, 68t for lymphoblastic lymphoma, 97 for MM, 66t, 67t, 69t with thalidomide, for MM, 66t Diffuse large cell B-cell lymphoma (DLBCL), 92, 92t, 95, 96,t 100, 105 Disseminated intravascular coagulation (DIC), in APL, 26 DLBCL See diffuse large cell B-cell lymphoma (DLBCL) DNA mutations, Donor lymphocyte infusion (DLI), 116 Donor lymphocyte transfusions, 41 Donor selection in HSCT, 106, 107 Doxorubicin in BEACOPP HL therapy, 79 in DVD therapy for MM, 68t in R-CVP, for NHL, 93 DT-PACE (dexamethasone, thalidomide, cisplatin, cyclophosphamide, etoposide, doxorubicin), 66t DVD (doxil, vincristine, dexamethasone) therapy, 66t, 68t E Endemic Burkitt lymphoma, 96 Epidermal growth factor receptor (EGFR), 13 inhibitors, 118–119 Epratuzumab for ALL, 33 for Burkitt lymphoma, 97 Epstein-Barr virus (EBV) infection, 96, 99, 101 Erbitux (cetuximab), 120–121 Erlotinib (Tarceva), 118–119 Erythropoietin (EPO) treatment in MDS, 45 in MM, 69t Etoposide in BEACOPP HL therapy, 79 in DCEP therapy for MM, 66t in myeloablative conditioning, 109 Everolimus (Afinitor), 120 F FAB L3 acute lymphocytic leukemia, 96 Familial adenomatous polyposis coli, 9t Familial cancer syndrome, 9t Familial clear-cell carcinoma, 15–16 Farnesyltransferase inhibitors, 26 Fibroblast growth factor (FGFR), 13 Fibroblast growth factor receptors (FGF), 13 5-Azacytidine, for MDS, 46 Flavopiridol, for CLL, 57 FLT-3 inhibitors, 26 Fluconazole for fungal prophylaxis (in HSCT), 114 Fludarabine (F) for CLL, 54, 55 in myeloablative conditioning, 109 in R-FC, for NHL, 93 Fludarabine, cyclophosphamide (CF), 54 Fluoroquinolones for HSCT infection, 113 Follicle center cell lymphoma, 49t Follicular lymphoma, 15, 92, 92t, 95 Follicular non-Hodgkin lymphoma, 94, 95 Fungal prophylaxis in HSCT, 114 Furosemide, in MM, 70t G Gall-Mallory classification system, 83 Ganciclovir for viral prophylaxis in HSCT, 114 Gemtuzumab ozogamicin (Mylortag), 134t for ALL, 33 for AML, 27 for Burkitt lymphoma, 97 Gemtuzumab ozogamicin (GO), for APL, 26 Germinal-center B-cell DLBCL, 92 Gleevec (imatinib), 32, 39–40, 41, 97, 117–118 Glucocorticoids for children with ALL, 32 Gorlin syndrome, 9t Graft-versus-host disease (GVHD), 105, 109, 110t, 111 See also acute graftversus-host disease Granulocyte colonystimulating factor (G-CSF) treatment, 45 H Hairy cell leukemia (and variants), 49t Haploidentical-related donor-matched transplant, 107, 111 Hematological malignancies, 5, 6t–7t, 16, 21–27 Hematopoietic growth factor treatment, in MDS, 45 Hematopoietic stem cell transplantation (HSCT) See also acute graft-versus-host disease; autologous I Ibritumomab (Zevalin), 121, 130t Idarubicin, for AML, 25 Imatinib mesylate (Gleevec), 32, 118, 128t, 130t J Juvenile myelomonocytic leukemia (JMML), 39, 44t K Kidney cancer, 15 Kinase inhibitors See dasatinib; nilotinib L L-asparaginase for ALL, 32 for children with ALL, 33 Lenalidomide (Revlimid), 62, 65, 69t, 124t for CLL, 57 coagulopathy/thrombisis, 70t for MDS, 46 for MM, 66t, 68t Lenalidomide, dexamethasone, for MM, 66t, 68t Leukostasis, 31 Li-Fraumeni syndrome, 9t Liposomal vincristine, for ALL, 33 M Mammalian target of rapamycin (mTOR) inhibitors, 120–121 See also temsirolimus Mantle cell lymphoma, 49t, 124t Matched unrelated donors (MUD), 107 Mature B-cell ALL (Burkitt cell lymphoma), 30 Mature lymphoid leukemia, classifications, 49 Methotrexate for aGVHD, 109 for AIDS-related NHL, 101 for children with ALL, 33 for lymphoblastic lymphoma, 97 Methylprednisolone, in aGVHD, 111 Mitoxantrone, for AML, 25 Monoclonal antibodies See alemtuzumab; epratuzumab; gemtuzumab; rituximab MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) therapy, for HL, 79 Mozobil (plerixafor injection), 125t MP (melphalan, prednisolone), for MM, 67t MP (melphalan, prednisone), for MM, 66t MPT (melphalan, prednisolone, thalidomide), for MM, 66t, 67t MPV (melphalan, prednisolone, bortezomib), for MM, 66t, 67t Multiple myeloma (MM), 59–70, 124t, 125t MYC transcription factor, 12 Mycosis fungoides/Sézary syndrome, 49t Myeloablative conditioning regimens for aGVHD, 109 for AML, 26 described, 108–109 for GVHD, 107 Molecular cancer pathology Lovenox, for MM, 70t Low-grade non-Hodgkin lymphoma, 93, 130t Lumiliximab, for CLL, 57 Lymphoblastic lymphoma, 96, 96–97 Lymphoid tumors, 6t Lymphoplasmacytoid lymphoma, 49t CHAPTER for ALL, 32, 118 for Burkitt lymphoma, 97 for CML, 39–40, 41, 118 description, 117–118 Induction therapy for ALL, 32 for AML, 25 for MDS, 46 Interferon-D for CML, 40 for relapsed CML patients, 41 International Bone Marrow Transplant Registry (IBMTR), 110t International Prognostic Index (IPI), 91, 92t, 95 International Prognostic Scoring System (IPSS), 46–47, 78t International Staging System (ISS), 64t Intrathecal liposomal cytarabine, for ALL, 33 Involved-field (IF) radiation therapy for DLBCL, 94 for HL, 78–79, 80 for MM, 69t Ionizing radiation exposure, 37 IPSS See International Prognostic Scoring System (IPSS) IwCLL Working Group, 52t, 53 139 hematopoietic stem cell transplantation; chronic graft-versus-host disease; graft-versus-host disease advantages/disadvantages, 66, 68–69 for ALL, 33 conditioning regimens, 108–109 donor lymphocyte infusion, 116 donor selection, 106–107 hepatic veno-occlusive disease, 114–115 imatinib vs., 39 infection, 113–114 long term complications, 115–116 for MM, 66, 68–69 post-transplant complications, 109–111, 110t pretransplant evaluation, 108 types of, 105–106 Heparin prophylaxis for hepatic VOD, 115 Hepatic veno-occlusive disease (VOD), 114–115 Hepatosplenomegaly, 44 Herceptin (trastuzumab), 121 Hereditary non-polyposis colon cancer, 9t Highly active retroviral treatment (HAART), 100 Highly aggressive lymphomas See Burkitt lymphoma; lymphoblastic lymphoma Histone deacetylase (HDAC) inhibitors, 26, 123 See also vorinostat HIV infection, 96 HLA (human leukocyte antigens) typing, 106 Hodgkin lymphoma (HL), 75–82 Hydroxorubicin, in CHOP, for CLL, 54 Hydroxyurea for CML-associated leukocytosis, 40 for CML-associated thrombocytosis, 40 Hypereosinophilic syndrome (HES), 129t Hyperphosphatemia, 31 Hypocalcemia, secondary, 31 Hypogammaglobulinemia, 51 Hypomethylating agents See 5-Azacytidine; lenalidomide INDEX Myelodysplastic syndromes (MDS), 24, 39, 43–47, 44t, 124t, 126t, 129t Myeloid tumors, 6t–7t Myeloproliferative disorders, 21, 37, 44, 44t, 129t Mylortag (gemtuzumab ozogamicin), 33, 134t 140 N Nelarabine (Arranon), 129t Nexavar (sorafenib), 119 Nilotinib hydrochloride (Tasigna), 130t for ALL, 33 for CML, 40, 41, 118 description, 118 Nitrogen mustard therapy, in MOPP, Stanford V HL therapy, 79 See also Stanford V therapy NK-cell leukemia, 49t non-Hodgkin lymphomas (NHL), 83–92, 96, 125t, 127t See also aggressive lymphomas; AIDS-related non-Hodgkin lymphoma; diffuse large cell B-cell lymphoma; follicular lymphoma; low-grade non-Hodgkin lymphoma treatment, 127t non-Hodgkin lymphomas (NHL), management strategies, 93–97 R-CHOP, 93 R-CVP, 93 R-FC, 93 rituximab, 93 Nonendemic Burkitt lymphoma, 96 Nonmyeloablative conditioning regimens, 26, 109, 111 O Ofatumumab (CD 20-directed cytolytic monoclonal antibody), 55, 132t Oncaspar (pegaspargase), 126t Ontak (denileukin diftitox), 122 Opioids, for in MM, 69t Osteosarcoma, 9t Ozogamicin See gemtuzumab ozogamicin (Mylortag) P Panitumumab (Vectibix), 121 Paranasal disease, 101 Paraspinal disease, 101 Paroxysmal nocturnal hemoglobinuria, 21 Pegaspargase (Oncaspar), 126t Pentostatin for aGVHD, 111 for CLL, 55 for relapsed NHL, 94 Philadelphia chromosome, 37–38, 39, 117–118, 128t Platelet-derived growth factor receptors (PDGFR), 13, 15 Plerixafor (injection, Mozobil), 125t Pneumocystic jiroveci pneumonia, 32 Posaconazole fungal prophylaxis (in HSCT), 114 PP2A signaling protein, Precursor B-cell ALL, 30 Prednisolone, 54 in BEACOPP HL therapy, 79 in CAP, for CLL, 54 in CHOP, for CLL, 54 in CVP, for CLL, 54 in R-CHOP, for NHL, 93 in R-CVP, for NHL, 93 Prednisone in MOPP therapy, for HL, 79 in R-CVP therapy, for lowgrade NHL, 93 in Stanford V HL therapy, 79 Procarbazine in BEACOPP, MOPP HL therapy, 79 Proteasome inhibitors, 122 See also bortezomib R R-CHOP (rituximab, cyclophosphamide, Adriamycin, vincristine, prednisolone) regimen for aggressive lymphomas, 94 for diffuse large-B-cell lymphoma, 94, 95 for NHL in younger patients, 93 R-CVP (rituximab, cyclophosphamide, vincristine, prednisone, doxorubicin), 93 R-FC (rituximab, fludarabine, cyclophosphamide), 93 Radiolabeled anti-CD20 antibodies, 94 Radiotherapy, 56, 69t Refractory acute lymphoblastic leukemia, 129t Refractory anemia, 44t Refractory cytopenia, 44t Relapsed acute lymphoblastic leukemia, 129t Relapsed B-cell NHL, 132t Relapsed Hodgkin lymphoma, 105 Relapsed non-Hodgkin lymphomas, 94 Retinoblastoma, 9t Revlimid (lenalidomide), 46, 57, 62, 65, 66t, 68t, 69t, 124t Rituximab (Rituxan), 133t for AIDS-related NHL, 100 for ALL, 33 for Burkitt lymphoma, 97 for CLL, 54 described, 121 for DLBCL, 94 with ibritumomab, 130t IPP index for, 92t in low-grade NHL, 93 for NHL, 93 in R-CHOP, for NHL, 93 in R-CVP, for NHL, 93 in R-FC, for NHL, 93 for relapsed NHL, 94 S Salvage chemotherapy, 56, 82, 96 Sézary syndrome, 49t Sirolimus, for aGVHD, 111 6-mercaptopurine, for lymphoblastic lymphoma, 97 Small noncleaved-cell lymphoma, 96 Somatic molecular alteration, Sorafenib (Nexavar), 119 Splenic marginal zone lymphoma with circulating villous lymphocytes (SLVL), 49t Sporadic cancer, 9t Sprycel (dasatinib), 33, 40, 41, 118 Stanford V (nitrogen mustard, doxorubicin, vinblastine, prednisone, vincristine, bleomycin, etoposide, with radiation) therapy, 79 Stem cell transplantation See hematopoietic stem cell transplantation (HSCT) Sunitinib (Sutent), 119 Sutent (sunitinib), 119 T T-cell acute lymphoblastic leukemia, 30, 129t T-cell acute lymphsoblastic lymphoma, 129t T-cell large granular lymphocytic leukemia (T-LGL), 49t Umbilical cord blood (UCB) transplantation, 107 V Vascular endothelial cell growth factor (VEGF) inhibitors, 26, 119 See also sorafenib; sunitinib Vascular endothelial cell growth factor receptors (VEGFR), 13, 15 Vectibix (panitumumab), 121 Velcade (bortezomib), 66t, 68t, 124t Vincristine for ALL, 33 for Burkitt lymphoma, 97 for children with ALL, 32 in CHOP, for CLL, 54 in CVP, for CLL, 54 in MOPP, Stanford V HL therapy, 79 in R-CHOP, for NHL, 93 W Warfarin, in MM, 70t WHO-based prognostic scoring system (WPSS), 46 Wnt (APC) gene, 9t World Health Organization (WHO) classifications See also WHO-based prognostic scoring system of AML, 23 of HL, 76t of mature lymphoid leukemia, 49t of MDS, 43, 44t, 47 for NHL, 83, 84 Z Zevalin (ibritumomab), 121 Zoledronic acid (Zometa), 69t, 125t Zolinza (vorinostat), 123 UPLOADED BY [STORM] Molecular cancer pathology U in R-CVP, for NHL, 93 Vincristine, doxorubicin, dexamethasone (VAD), 66t Viral prophylaxis in HSCT, 114 von Hippel-Lindau syndrome, 9t Voriconazole for fungal prophylaxis (in HSCT), 114 Vorinostat (Zolinza), 123 CHAPTER Trisenox (arsenic trioxide), 135t 2-chlorodeoxyadenosine, for relapsed NHL, 94 Tyrosine kinase inhibitors See dasatinib; imatinib; nilotinib Tyrosine kinase receptors See erlotinib 141 T-cell mature lymphoid leukemia, 49t T-cell prolymphocytic leukemia (T-PLL), 49t Tacrolimus, for aGVHD, 109, 111 Tarceva (erlotinib), 118–119 Targeted therapies, 117–135 antibodies, 120–121 BCR-ABL kinase inhibitors, 117–118 conjugated agents, 121–122 demethylation agents, 122–123 EGFRs, 118–119 HDAC inhibitors, 123 mTOR inhibitors, 119–120 proteasome inhibitors, 122 VEGFR-1, VEGFR-2, VEGFR-3, 119 Tasigna (nilotinib), 33, 40, 41, 118 Temsirolimus (Torisel), 119–120 Thalidomide (Thalomid), 57, 65, 69t, 70t, 125t for MM, 66t, 67t, 68t side effects, 62 Thiotepa, 109 Thrombocytopenia, 32, 39, 45 Thrombocytosis (CMLassociated), 40 Torisel (temsirolimus), 119–120 Tositumomab (Bexxar), 122 Trastuzumab (Herceptin), 121 Treanda (bendamustine hydrochloride), 127t [...]... oncogenesis Genetic alterations can take the form of mutations (changes in the sequence of the DNA code), deletions (loss of sections of DNA), amplifications (multiple copies of the same DNA section), or epigenetic changes (altering the methylation status of DNA, resulting in activation or repression of genes in the region) In the aggregate, multiple changes in the DNA of cancer cells alter normal cellular physiology... VEGF Signaling in Hematologic Malignancies This research was originally published in Blood Podar K, Anderson KC (2005) The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood 105:1383–1395 © American Society of Hematology carcinoma and in sporadic clear-cell carcinoma, mutations in the von Hippel–Lindau (VHL) gene are found approximately 85% of the time VHL normally... instability with accumulation of multiple gene mutations 13 • Failure to trigger cell cycle arrest or programmed cell death in pres- Cancer biology CHAPTER 3 • Self-production of growth promoting factors (autocrine) • Constitutive activation of downstream members of growth- promoting signaling pathways A paradigm of the last point, constitutive activation of downstream members of growth-promoting signaling... “Guardian of the genome” • Most frequently mutated gene in human cancer MYC is a transcription factor that regulates the expression of genes promoting proliferation Burkitt lymphoma is a type of cancer caused primarily by amplification of the MYC gene, but many more common types of cancers also have amplification of the MYC oncogene Interestingly, if MYC is amplified in a normal cell, apoptosis often results... formation In hematological malignancies, angiogenesis occurs in the bone marrow, which is composed of malignant cells, endothelial cells, pericytes, fibroblasts, and other cell types These in turn closely interact with the extracellular matrix Inhibition of angiogenesis therefore has not only a hypoxic effect, as a result of limited oxygen delivery, but also the effect of disrupting the interaction of these... commonly as cancer “stem cells”) are often in the G0 phase Many of the molecules that drive and regulate the cell cycle have been identified One important group consists of proteins called cyclins that can propel cells through the cycle by the activation of cyclindependent kinases (CDKs) Regulation of the cell cycle normally ensures that cells have precise control of DNA duplication and subsequent cell... protecting 11 Deregulation of the cell cycle Cancer biology CHAPTER 3 Cell cycle control is essential to protect the integrity of normal genes 12 against a loss of genetic information A number of checkpoints exist within the cell cycle, and these are crucial in this protection of the normal genome Mechanisms to detect DNA damage due to incomplete or inaccurate replication often result initially in cell... number of growth factors and a number of critical genes, including p53 p53 plays a key role in maintaining genomic stability Normal cells with DNA damage become arrested in G1 and/or undergo programmed cell deaths (apoptosis) under the control of this gene p53 is the most commonly mutated gene in human cancer, which is not surprising since loss of control of genomic stability is a central feature of cancers... Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Mark C Lanasa, MD, PhD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Jacob Laubach, MD Division of Medical Oncology, Dana Farber Cancer Institute Harvard University Medical Center Boston, MA Joseph Moore, MD Division of Medical Oncology, Department of Medicine Duke... cancers have constitutive activation of an RTK or downstream signaling member of an RTK pathway A paradigmatic example of how this mechanism is important in cancer oncogenesis includes small deletions of the EGFR gene encoding for the intracellular portion of the receptor The subsequent change in the protein results in constitutive activation that is independent of any extracellular signals These mutations