Acute Myelogenous Leukemia PDF
Preview Acute Myelogenous Leukemia
ACUTE MYELOGENOUS LEUKEMIA CONTEMPORARY HEMATOLOGY Judith E.Karp, MD, SERIES EDITOR AcuteMyelogenous Leukemia,editedbyJUDITHKARP,2007 Modern Hematology,SecondEdition, editedbyREINHOLDMUNKER,ERHARDHILLER, JONATHANGLASS,ANDRONALDPAQUETTE,2006 Stem CellTransplanuuionforHematologic Malignancies,editedbyROBERTJ.SOIFFER, 2004 ChronicLymphocyteLeukemia:MolecularGenetics,Biology,Diagnosis, andManagement, edited byGUYB.FAGUET,2004 Biologic Therapy ofLeukemia,edited byMATTKALAYCIO,2003 Modern Hematology: BiologyandClinicalManagement, byREINHOLDMUNKER,ERHARD HILLER,ANDRONALDPAQUETTE,2000 RedCellTransfusion: A PracticalGuide, edited byMARIONE. REIDANDSANDRAJ.NANCE, 1998 ACUTE MYELOGENOUS LEUKEMIA Edited by E. KARP, JUDITH MD The Sidney KimmelComprehensive Cancer Center atJohns Hopkins, Baltimore, MD ~ HUMANA PRESS ~ TOTOWA, NEWJERSEY ©2007 HumanaPress Inc. 999RiverviewDrive, Suite 208 Totowa,NewJersey07512 humanapress.com Foradditionalcopies,pricingforbulkpurchases,andlorinformationaboutotherHumanatitles, contactHumanaattheabove addressoratanyofthefollowingnumbers:Tel:973-256-1699;Fax:973-256-8341;E-mail: [email protected];website athumanapress.com Allrights reserved.Nopartofthisbook maybereproduced,stored inaretrievalsystem, ortransmittedinanyform orbyany means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. Allarticles,comments,opinions,conclusions,orrecommendationsarethoseoftheauthor(s),anddonotnecessarilyreflectthe views ofthepublisher. 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ProductionEditor:RhukeaJ.Hussain CoverIllustration:Inset: Fig. I,panelsAandBfrom Chapter14 Coverdesignby: DonnaNiethe Photocopy AuthorizationPolicy: Authorizationtophotocopyitemsfor internalorpersonaluse, orthe internalorpersonaluseofspecificclients,isgranted byHumanaPressInc.,providedthat thebasefeeofUS$30.00percopyispaiddirectlytotheCopyrightClearanceCenter at222RosewoodDrive.Danvers,MA01923.Forthoseorganizationsthat have beengrantedaphotocopylicensefrom the CCC, aseparatesystemofpaymenthasbeen arrangedandisacceptabletoHumanaPressInc.Thefeecode forusers ofthe TransactionalReportingServiceis: [978-1-58829-621-4·1-58829-621-0107$30.00]. Printedinthe United States ofAmerica. 10 9 8 7 6 5 4 3 2 I e-ISBN: 1-59745-322-6 LibraryofCongressCataloging-in-PublicationData Acute myelogenousleukemia1editedbyJudithKarp. p.;cm. -- (Contemporaryhematology) Includesbibliographicalreferencesandindex. ISBN-13:978-1-58829-621-4(alk. paper) ISBN-IO: 1-58829-621-0(alk. paper) I. Acute myeloidleukemia. I.Karp, Judith. II.Series. [DNLM: I. Leukemia,Myelocytic,Acute. WH250AI8962007] RC643.A3252007 616.99'419071--dc22 2006039397 To my belovedhusband, Stanley H. Freedman, for unwaveringsupport, understanding, andhumor. To my mentors: Stanley Schrier,MD, Philipj. Burke, MD, andSamuelBroder, MD. To ourpatients, whogive usthe humilityandinspiration to do better. PREFACE Acute myelogenous leukemia (AML) is a complex family of malignancies for which we need new treatmentconcepts and agents in orderto increasethe cure rates for all who suffer withthesediseases. Ontheclinicallevel,AMLisanimportantanddevastatingmalignancythat affects allages. Onabiologicalleve1,AML isanoutstandingmodel for understandingcancer biology and the challenges of cancertherapy in general. This isanexcitingtime inleukemiaresearch. Theelegantbasic sciencediscoveries that haveemergedover the precedingtwodecadesarenow leading toaheightenedunderstanding ofleukemiaatits basic genetic and biochemicalroots. This understanding inturn provides a springboardfordevelopingnewtherapiesthatcanmodulateimportantfactors inleukemiacell developmentandsurvival. There isaburgeoningapplicationofnewmolecularconceptstothe development of drugs that target critical leukemia-sustaining factors. In turn, there is rapid movementofthese newly developedagents into the clinicaltesting arena andeventually into the effective armamentarium against AML. The aim of Acute Myelogenous Leukemia is to bring new concepts and findings in the basicandclinicalscienceofAMLtogether"underonecover."Thisjuxtapositionshould serve basic andclinicalinvestigatorswhoareinterestedinAML withinformationthatreaches from newconceptsregardingleukemiapathogenesistocurrentandprospectiveadvancesinmolecu lartherapeutics.This isthetheme ofRavandiandGiles' overviewchapter-thebidirectional flowofknowledgebetweentheclinic andthelaboratory,withtheoverarchinggoalofincreas ing AML cure rates. Part II,MolecularFoundationsof AML Pathogenesis andPathophysiology, focuses on specificgeneticlesions thatdisruptthenormal growthandsurvivalinhematopoieticstemcells and subvert the cellular machinery to prevent differentiation and death. Toward that end, Friedman (Chapter 2) examines the disruption of orderly transcriptional regulation as a key mechanismof leukemogenesis, leading toloss of the normal obligatory link between prolif eration, terminal differentiation and cell death. The next two chapters provide additional powerful insights into the complex process of leukemogenesis by discussing the multistep cellularchangesthatoccurwhenAMLevolvesfrommyelodysplasia(ParkerandMufti,Chap ter 3) or when it arises in the setting ofprevious cytotoxic therapies (Godley and LeBeau, Chapter4).InChapter5,SteensmaaddressestheformativerolethatdiminishedrepairofDNA damage(asexemplifiedbyfamilialsyndromeswithheightenedleukemiarisk)canplayinboth the initiation and perpetuation of genomic instability, whereas in Chapter 6, Mesa and Kaufmanndiscussthecriticalcontributionsofalteredapoptoticresponsestocellularstress to AML cell survival and inherent drug resistance. In the final chapter in this section, Ross expands on the issue of drug resistance as related to diverse transporterproteins that protect cells, perhaps most importantly stem cells, from cytotoxic drugs. PartIIIemphasizestranslationofAML biologyintoclinicalapplication. Inthis context, Grimwade(Chapter8)addressestheformativeimpactofspecificcytogeneticaberrations(and, byextrapolation,themolecularresults ofthose aberrations)onunderstandingclinicalbiology andindividualprognosis.Innodisease isthis sowellexemplifiedasinacute progranulocytic Vll Vlll Preface leukemia (APL), and Frankfurt et al., in Chapter 9, provide a detailed discussion of this remarkablysensitivedisease andthe"bench-to-bedside"(andbackagain) investigationsthat exemplify "molecularmedicine" atits finest. The theme ofmolecularmedicineiscarriedforth inPartIV,beginningwith Sausville's (Chapter 10)overviewofmechanisticallynovel agents, both cytotoxic and"biological," that target selectedkeymoleculesorpathwaysandarenowinclinicaldevelopmentforAML.This informativeoverviewis followed by discussions of new agents that interrupt specific signal transduction effectors such as FLT-3 (Levis, Chapter 11) and famesyltransferase (Lancet, Chapter 12), modulate the expression of inappropriately silenced genes by inhibiting DNA methyltransferases and/or histonedeacetylases (Fandy et al., Chapter 13),and overcomethe blockadetodifferentiationthat characterizestheleukemiccell (LinandMatsui, Chapter 14). Thefinaltwochaptersofthissection focusonimmunomodulatoryapproachesincludingstem cell transplantation (Bolafios-Meade and Jones, Chapter 15) and vaccine development (Borrello, Chapter 16). AML isaheterogenousdiseaseand,assuch,there areissues thatdemandspecial thera peutic considerations. In this regard, Arceci (Chapter 17) addresses the unique biology of pediatricAML includingdistinctivedrugdevelopmentissues suchasage-specificpharmaco logicalmetabolism,theimplicationsoflong-termsequelaethatmaynotariseinadults, andthe importanceofrisk-stratificationinclinicaltrialdesign. Attheotherendofthespectrum,Stone (Chapter 18)presents the unique challengesoftreating AML in the elderly, where both host and disease factors contribute to an especially poor prognosis and where new strategies are desperately needed. In Chapter 19,Gotlib discusses the recently discoveredJAK2 mutation that serves asaunifying thread among the disparatefamily members ofthe so-calledmyelo proliferativedisorders,agroupofmyeloidmalignanciesthathasbeenconsideredtobehetero geneous but with a high propensityto evolveinto AML. Finally, as we continue to uncover new molecular pathways, we in tum develop new drugs toexploitand modulatethose pathways. Inthelastchapter, Estey addressestheconun drum that conventional clinical trials designs and classical clinical endpoints may not be applicabletoeffectiveandefficientdrugdevelopment,andthat newparadigmsareneeded to address the complexities underlying clinical outcome and response to new agents. In summary, progress incuring AML will come ultimately from both an enhancedun derstanding of the molecular foundations of these diseases and from rigorous clinical and correlativelaboratorytesting ofnewagents thatalterthosemolecularfoundations. Ihope that Acute Myelogenous Leukemiawill stimulate the readerto think about the diverse molecular componentsofAMLpathogenesisandpathophysiologyasabasisfornewtreatmentstrategies and multimodalityapproaches. Itisthroughfluent translationbetweenthelaboratoryand the clinic that we will be able tochange the face of AML from adevastating disease to a highly curable one. Judith E. Karp,MD CONTENTS Preface vii Contributors xi Page Plates xiii PART I: OVERVIEW OF AML 1 Approaching the Treatmentof AML from aBiological Perspective: An Overview.............................................................................................................. 3 FarhadRavandiandFrancis Giles PART II: MOLECULAR FOUNDATIONS OF AML PATHOGENESIS AND PHYSIOLOGY 2 AberrantTranscriptionFactors in AML 27 AlanD. Friedman 3 Myelodysplasia-Related AML 43 Jane E. Parker 4 Therapy-Related AML 71 LucyA. GodleyandMichelle M. Le Beau 5 The DNA Damage Response, DNA Repair, and AML 97 DavidP.Steensma 6 Altered Apoptosis in AML: PotentialImplicationsfor Pathogenesis andTherapeutic Response 133 RubenA. Mesa andScottH. Kaufmann 7 Drug Resistance Transporters in AML 163 Douglas D. Ross PART III: TRANSLATING BIOLOGY INTO CLINICALAPPLICATION 8 Impactof Cytogenetics on Clinical Outcome in AML 177 David Grimwade 9 APL: AClassic Tale of Benchto Bedside 193 OlgaFrankfurt, LoAnne C. Peterson, RobertGallagher, andMartin S. Tallman PART IV: MOLECULARTHERAPEUTICS OF AML: SELECTEDTARGETED APPROACHES 10 Emerging Therapeutics for AML 231 Edward A. Sausville 11 FLT3: A Prototype ReceptorTyrosine Kinase Targetin AML 247 Mark Levis ix x Contents 12 Farnesyl Transferase Inhibitors intheTherapy ofAML 263 JeffreyE. Lancet 13 Modulating Gene Expression asaTherapeutic Approach intheTreatment ofAML 275 TamerFandy,Hetty Carraway, andSteven D. Gore 14 Differentiation Therapy inAML 293 TaraL. Lin andWilliam Matsui 15 StemCellTransplantation forAML 313 JavierBolaiios-MeadeandRichardJ. Jones 16 Tumor Vaccines inLeukemia 329 Ivan Borrello PARTV: SPECIAL CHALLENGES 17 Treatment, Outcomes, andChallenges ofNewly DiagnosedAML inChildren andAdolescents 345 RobertJ. Arceci 18 AMLin Older Adults 373 RichardM. Stone 19 Dameshek Smiles: Molecular Clues to the Chronic Myeloproliferative Disorders Unmasked ........ 385 Jason Gotlib 20 NewDesigns forClinical Trials 399 ElihuEstey Index 417 CONTRIBUTORS Robert J. Arceci»DirectorandKing Fahd Professor ofPediatric Oncology, Kimmel Comprehensive Cancer Center at Johns Hopkins,Baltimore, Maryland Javier Bolaiios-Meade •AssistantProfessor ofOncology,Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Ivan Borrello •Sidney Kimmel Comprehensive CancerCenterat Johns Hopkins, Balti more, Maryland Hetty Carraway •Division ofHematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Elihu Estey» Leukemia Department, University ofTexas M.D.Anderson Cancer Center, Houston, Texas Tamer Fandy •Division ofHematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Olga Frankfurt • Division ofHematology and Oncology,Northwestern University Feinberg School ofMedicine, RobertH. Lurie Comprehensive Care Center ofNorthwestern University,Chicago, Illinois Alan D. Friedman» Division ofPediatric Oncology, Johns Hopkins University, Baltimore, Maryland RobertGallagher •Montefiore Medical Center, AlbertEinstein School ofMedicine, Bronx, New York Francis Giles» DepartmentofLeukemia, University ofTexas M.D. Anderson Cancer Center, Houston, Texas Lucy A. Godley •Section ofHematology/Oncology and the University ofChicago Cancer Research Center, University ofChicago, Chicago, Illinois Steven D. Gore •Associate ProfessorofOncology, Division ofHematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center atJohns Hopkins, Baltimore,Maryland Jason Gotlib •AssistantProfessor ofMedicine (Hematology),Stanford Cancer Center, Stanford, California DavidGrimwade •DepartmentofMedical and Molecular Genetics, King's College London, andDepartmentofHaematology, University College London Hospitals, London, United Kingdom RichardJ. Jones •Professor ofOncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,Maryland Scott H. Kaufmann • Division ofOncology Research, Mayo Clinic, Rochester, Minnesota Jeffrey E.Lancet •Hematologic Malignancies Program,DepartmentofInterdisciplinary Oncology,H. Lee Moffitt Cancer Centerand Research Institute, University ofSouth Florida, Tampa, Florida Michelle M. Le Beau •Section ofHematology/Oncology andthe University ofChicago Cancer Research Center, University ofChicago, Chicago, Illinois Mark Levis •Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland Tara L. Lin • Division ofHematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,Maryland xi
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