8/15/16

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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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BCR-ABL Fusion Protein

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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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Rouleaux forma1on in mul1ple myeloma

Ly1c bone lesions

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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?

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ThankYou!