new oral agents for trea1ng blood malignancies...8/15/16 1 new oral agents for trea1ng blood...
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New Oral Agents for Trea1ng Blood Malignancies
DavidSeastone,DO,Ph.D.UPMC/AGHRegionalCancerCenter
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Chronic hematologic disease for which oral therapy is used: • MyeloproliferaFvedisorders• PolycythemiaVera• Myelofibrosis• ChronicMyeloidLeukemia
• ChronicLymphocyFcLeukemia• Non-Hodgkin’slymphoma• AML(APLorM3)
• Solidtumors(lung,colon,breast,prostate,brain,liver,others)
Differen1a1on of Stem Cells
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Myeloprolifera1ve Disorders
• OverproducFonofbonemarrowcells
• 4primarytypes• PolycythemiaVera–RBCs• EssenFalThrombocytosis–Platelets• ChronicMyeloidleukemia(CML)–WBCs• Myelofibrosis–stromalcellsofbonemarrow
Polycythemia vera
• Primarydisease:bonemarrowproducestoomanyerythrocytes• Aquagenicpruritus• IncreasedriskforthromboFcevents(CVAandVTEs)• R/Osecondarycauses• Jak2V617FmutaFon(95%)• Canprogresstomyelofibrosisoracuteleukemia
• Treatment:• ASA• PhelobotomywithgoalHct<45%• Hydroxyurea• RuxoliFnib(Jakafi)
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Myelofibrosis
• NeoplasFctransformaFonofmyeloidstemcellwithprominentdeposiFonofcollagenandreFculinwithinbonemarrowspace• Causesextramedullaryhematopoiesis• Bonemarrowcellsmatureoutsidethisspaceinspleen,liver,lymphnodes• SplenomegalyischaracterisFc(earlysaFetyandweightloss)
• Usuallyoccurs>60yearsofageorolder• OgencomestoclinicalahenFonbecauseofanemia,faFgue,andnightsweats
Re1culin Stain in MF - fibrosis of bone marrow
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Tear-drop cells (Dacrocytes)
Myelophthisic appearance: geKng ‘squeezed’ out of bone marrow
Splenomegaly
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Splenectomy from MF pa1ent
Jakafi (Ruxoli1nib)
• November2011–FDAapprovedformyelofibrosis• Smallimprovementinoverallsurvival(2months)• Largeimprovementinsymptoms
• Dec2014–FDAapprovedforPCV• Improvementinoverallsurvivalagerfailurewithhydrea• ReducFoninphlebotomy
• Feb2016:Xeljanz(tofaciFnib)approvedforRA
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JAK2 pathway – Leads to cell growth
Side effects to JAK2 inhibitors (< 30%)
• Bruising• Bleeding(gums,urine,stools)• Diarrhea• Dyspnea• Dysuria• Pruritus• Neutropenia• Thrombocytopenia
• Cytopeniascanleadtodose-reducFons
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Chronic Myeloid Leukemia
• 8,000casesper/yearinUS• OverproducFonofgranulocyteswithleg-shigedneutrophilicprecursorsareproduced• Philadelphiachromosomepresent(95%):• t(9;22)whichgeneratestheBCR/ABLfusionprotein• DiscoveredbyPeterNowellin1960–UPenn• MechanismdecipheredbyJanetRowleyin1973–UChicago
• CMLterminatesinblastcrisis(AML)ifuntreated• UnFl2001,averagesurvivalwas5years
CML peripheral smear
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Hypothesis: Blocking BCR-ABL kinase ac1vity might slow growth of CML • PeterDruker–OHSUdevelopedSTI-571(Gleevec)
• Inhibitorofp210BCR/ABLfusionprotein
• AmazingresultswithCMLpaFents
• Mediansurvivalwentfrom5yearsà?
Scien1fic Progress (and $$$)!
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CML is ‘possibly curable’ in 2016
• TreatablewithBCR/ABLtyrosinekinaseinhibitors• ImaFnib(Gleevec)–May2001• DasaFnib(Tasigna)–Oct2007• NiloFnib(Sprycel)–Oct2007• BosuFnib(Bosulif)–Sept2012• PomaFnib(Iclusig)–Dec2014
• Deepandindefiniteremissionsoccurin>90%ofpaFentswithCML• $$$(160,000/year)
Common side effects to BCR/ABL inhibitors
• AllformulaFons:• FaFgue• Rashes• Hairthinningorcoarsehair• Muscleachesoccasionally
• Specificside-effects• DasaFnib–diarrhea• NiloFnib–pancreaFFs• PonaFnib–thromboembolicevents
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Chronic Lymphocy1c Leukemia • Lymphocyteexpansioninperipheralblood
• Diseaseinvolvesbonemarrow• >4KcirculaFnglymphocytes• 19,000newcasesperyearinUS• Averageageofdiagnosis:71
• Alsoconsideredalymphomawhenpresentonlyinlymphnodes(CLL/SLL)• Peripheralbloodshowssmudgecells(fragilelymphocytes)
• Usuallyoccursinpersons>50yearsofage• menaffectedtwiceasogenaswomen
• Survivalismuchimprovedoverpastdecade• TradiFonalsurvival:10years• Thinkofthisasachronicdisease• ManytreatmentopFons
• RichtertransformaFon(CLLàDLBCL)
Smudge cells of CLL/SLL
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Smudge cells of CLL/SLL
Treatment of CLL
• Notalwaysnecessary–manyarejustobserved• Reasonsfortreatment:
• B-symptoms(fever,chills,nightsweats,unintenFonalweightloss)• RapidlyexpandingWBCcount(doublinginlessthan6months)• WBCcount>150,000• ImpendingorgandysfuncFon
• TradiFonaltreatmentshavebeenchemotherapy-based• FCR(fludarabine,cyclophosphamide,rituximab)• BR(bendamusFne,rituximab)• Usuallytreatfor3-6months• Obviousside-effectsfromchemotherapy• Notcurable–ogenneedsre-treatment
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Ibru1nib – breakthrough for CLL and others
• Bruton’styrosinekinase(BTK)inhibitor• Nov2013:FDAapprovalforrefractorymantlecelllymphoma
• Feb2014:FDAapprovalforrefractoryCLL• Jan2015:FDAapprovalforWaldenstromsMacroglobulinemia
• Mar2016:FDAapprovalfor1stlineCLL
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Common side effects to ibru1nib
• IniFallymphocytosis• FaFgue• Diarrhea• Muscleaches• Neutropenias
Mul1ple Myeloma
• Plasmacellneoplasmofbonemarrow• OgenarisesfromMGUS• Mproteinlevels>3g/dL• UsuallyIgG,butsomeFmesIgAisproduced
• Bonemarrowplasmacells>10%• SmolderingvssymptomaFc• OnlytreatedwhenitbecomessymptomaFc• (researchisongoinginthisareaforhigh-riskdisease)
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Bone marrow aspirate: plasma cell prolifera1on
CRAB • Organ/Tissuedamage• Calcium• withoutPTHdisease
• RenaldysfuncFon• withoutothercause
• Anemia• withoutothercause
• Bonedisease• x-ray,MRI,PET
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Mul1ple myeloma
• Notreallycurable• ManytreatmentopFonsexist• Low-dosechemotherapyandimmunotherapy• High-dosechemotherapywithAutologousstem-cellrescue
• ManynewtreatmentopFonsbeingdeveloped
• 2015wasalandmarkyearinmyelomatreatment!
Mul1ple myeloma – Work-up
• CBCanddifferenFal• Calcium,sCr,albumin,LDH,B-2macroglobulin,CRP• Serumfreemonoclonallightchain(FLC)measurement• SPEPwithimmunofixaFonandquanFtaFveIgs• Bonemarrowbiopsywithflowcytometry,cytogeneFcs,FISH• MetastaFcbonesurvey• XraysandMRIorPET/CTifneeded
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Mul1ple myeloma – Treatment Op1ons
• BCNU(CarmusFne)• bortezomib(Velcade)• carfilzomib(Kyprolis)• cyclophosphamide(Cytoxan)• liposomaldoxorubicin(Doxil)• lenalidomide(Revlimid)• melphalan(Alkeran)• pomalidomide(Pomalyst)• thalidomide(Synovir)
Approvedin2015:• Daratumumab(Darzalex)• Elotuzumab(EmpliciF)• Ixazomib(Ninlaro)oraltherapy• Panobinostat(Farydak)
Myeloma treatment
• ProteasomeInhibitors• Bortezomib–neuropathy• Carfilzomib-?Hearttoxicity• Ixazomib-neuropathy
• Immunomodulators• Thalidomide–neuropathy• Lenalidomide–neutropenia• Pomalidomide–lessneuropathy
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Oral Agents for Mul1ple Myeloma
• Revlimid(lenalidomide)• June2015:FDAapprovedforMDS5q-• June2013:FDAapprovalforrefractorymantlecelllymphoma• Feb2015:FDAapprovalformulFplemyeloma1stline
• Pomalyst(pomalidomide)• Feb2013:FDAapprovalforrefractorymulFplemyeloma
Ixazomib
• MechanismofacFon:proteasomeinhibitor• Usedwithlenalidomide+dexamethasone• Approvedinrelapsed/refractorydiseaseas2ndlinetherapy• Approvalbasedonrandomizedtrialof722paFentswithrelapsed/refractorydisease• PFScomparedtolenalidomidealone14.7à20.6months
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Other agents to treat solid tumors • LungCancer:
• Tarceva(erloFnib)forEGFRmutantlungcancer(7%)• Xalkori(crizoFnib)forALK+lungcancers(<5%)
• BreastCancer:• Ibrance(palbociclib)
• ProstateCancer:• ZyFga(abiraterone)• Xtandi(enzalutamide)
• ColonCancer:Xeloda(Capecitabine)
Considera1ons:
• DotheseoraltherapiestrulyworkbeherthantradiFonaltherapiesoraretheyjustmoreconvenient?
• Dothesetherapieshavebeheroverallsurvival?
• ShouldthesetherapiesbeusedbeforetradiFonalchemotherapy?
• Whowillpayfortheseexpensivetherapies?