EvidenceofDexrazoxane(DXZ)&OtherInterven9onstoDecreaseCardiotoxicity

MASCC2018ParallelSession:HowtoPreventCardiotoxicity–ARealChallenge

AndreaD.Orsey,MD,MSCEChair,PediatricStudyGroup

ConnecHcutChildren’s,HarJord,CTUSA

Disclosures

•  Nodisclosures

Objec9ves•  TounderstandtheindicaHonsforDexrazoxane•  Toreviewthebenefits&risksofDexrazoxane•  ToreviewtheevidenceofotherpharmaceuHcalintervenHonstodecreasecardiotoxicity

•  Todiscussexerciseasanon-pharmacologicaltreatmenttodecreasecardiotoxicity

Poten9alTargetsforInterven9on

Lipshultz,NatRevClinOncol,2013

Dexrazoxane(DXZ):PrimaryPreven9on•  Discovered:KurtHellman,Oxford1972•  PotenHalMechanisms–  CyclicderivaHveofEDTA–  IntracellularironchelaHon

•  Conversiontoring-openedchelaHngagent•  Interfereswithiron-mediatedfreeradicalgeneraHon

–  ReducesreacHveoxygenspeciesformaHon•  ↓Femetalioncomplexesàlesssuperoxidefreeradicals

www.totect.com

DXZ:PrimaryPreven9on•  Weaktopoisomeraseinhibitor•  DepletesTopoisomerase2Beta(Topo2β)•  Reducesanthracycline-associatedmyocytedeathinvitro

www.totect.com

DXZ:Pharmacokine9cs

DosageraHoofdexrazoxane:doxorubicinis10:1

gsaJda_docs/label/2012/020212s013lbl

DXZ:Indica9ons•  FDA:doxorubicin>300mg/m2

–  WomenwithmetastaHcbreastcancer

•  ASCO:alladultsdoxorubicin>250mg/m2(Armenian,JCO,2017)•  ESMO:Appropriatecardioprotectantregimentobeconsidered

&plannedforallptsathighriskofcardiotoxicity(Curigliano,AnnOncol,2012)

•  EMA:restrictedin2011toadultswithpriordoxorubicin>300mg/m2&advanced/metastaHcbreastcancer–  Efficacyinpedsnotestablishedbutefficacydemonstratedinadults–  Useinchildrencontraindicated2011unHl19July2017

•  Onlycontraindicatedif0-18yrsold&expectedtoreceive<300mg/m2

DXZ:DataforFDAindica9on

www.accessdata.fda.gov

DXZ:COGTrialP9404•  RCTof537children/

adolescents–  Dx:T-cellALL,lymphoblasHc

non-Hodgkinlymphoma–  Outcomes:oncologic

efficacy,cardioprotecHveeffecHveness,safety

–  Results:Eechocardiographicmeasuresbejerat3yearsinDXZgroup

–  Nodifferenceinsurvival+DXZ

Asselin,JCO,2015

EffectofDXZonMyocardialInjuryAmongChildrenwithALLTreatedwithDoxorubicin

Lipshultz,etal:NEnglJMed,2004.

DXZ:Cardioprotectant

CochraneDatabaseofSystema9cReviews15JUN2011DOI:10.1002/14651858.CD003917.pub4hjp://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003917.pub4/full#CD003917-fig-0001

DXZ:Cardioprotectant

CochraneDatabaseofSystema9cReviews15JUN2011DOI:10.1002/14651858.CD003917.pub4hjp://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003917.pub4/full#CD003917-fig-0001

DXZ:PediatricClinicalCardiotoxicity

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZ:PediatricClinicalCardiotoxicity

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZ:PediatricCardiotoxicity(ClinicalorSubclinical)

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZ:PediatricCardiotoxicity(ClinicalorSubclinical)

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZ:SystemicReviewofSolidTumors•  4782paHentsin22studiesarer2000

–  Osteosarcoma(n=14),Wilm’s(n=3),Neuroblastoma(n=5)

•  With↑ cumulative anthracycline dose, linear survival ↑ & exponential cardiotoxicity ↑

268.2mg/m2withoutDXZ

431.8mg/m2withDXZ

Liesse,JPediatrHematoOnco,2018.

DXZ:SystemicReviewofSolidTumors

•  Cardiotoxicityratesdoublefrom5to20years

•  DXZ↓ rate cardiotoxicity but does not protect from late cardiotoxic effects

•  Are current regimens overvaluing anthracycline doses?

Liesse,JPediatrHematoOnco,2018.

DXZ:PossibleRisks•  SecondMalignantNeoplasms(SMNs)•  Increasedmortality•  ImpairChemotherapyEfficacy•  InfecHon•  Cytopenias

DXZ:SMNs•  Reportof↑incidence AML/MDS

in children with Hodgkin’s lymphoma who received dexrazoxane

•  Possible synergistic effect with etoposide on DNA repair –  Both bind topoisomerase II at

different sites •  Contributed to EMA ban use of

dexrazoxaneTebbiCKetal.JCO,2007.

DXZ:SMNs•  IniHalborderlinerisknotseenonlongerfollow-up

•  NodifferenceisOS,EFS,deathfromsecondcancer,deathfromothertoxicity

(Chow,JCO,2015)

PHISData:Varia9on&SMNs•  From1999-2009,2.4%(207/8,733)ALL

and2.0%(52/2,556)AMLgivenDXZ(Walker,PBC,2013)–  Olderchildren,blackpaHents,males

withALL–  VariedbyHme/regionforALLbutnot

AML–  Timingoffirstdosevaried

•  From1999-2011,SecondaryAML0.21%(3/1406)inDXZgroup&0.55%(77/14,126)unexposedgroup(Seif,PBC,2015)–  OR=0.38(CI0.11-1.26)

DXZ:PediatricSMNs

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZ:PediatricSMNs

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZ:RiskFactorAnalysis•  NaHonwideKoreanstudy:1,453ptsreceivedanthracycline

–  15hospitals–  1,035receivedDXZwitheachanthracycline–  418didnotreceivedDXZ

•  DXZimprovedcardiacevent-freesurvivalratesamong>400mg/m2

•  SMNsnotrelatedtoDXZinmulHvariateanalysis–  6yrSMNincidencerate0.67+0.24%

Kimet.Al,KoreanCancerAssociaHon,2018

DXZ:PediatricEFS

ShaikhFet.al,JNCIJNatlCancerInst(2016)108(4):djv357

DXZinAML •  44ptsAMLdx0-21yrsatsingleinsHtuHon2008-2011•  Adopteddexrazoxanepriortoanthracyclines2011•  NodifferenceineventrateorOS•  ImprovedcardiacfuncHon

(Schloemeret.al,JPediatrHematolOncol,2017)

DXZ:An9tumorEffects•  Cochranemeta-analysisofPRorCRnotdifferentinRCTswithDXZrandomlyassigned(vanDalen,CochraneDatabaseSyst,2011)

– PFSnotdifferentbetweengroups+/-DXZ•  AmongwomenwithbreastCA,responseratesnotdifferent+/-DXZ(Abdel-Qadir,AnnOncol,2017)

DXZ:Cytopenias•  Commoninchildrenreceivingchemotherapy•  Hematologicaleventslikelyduetochemotherapy

•  1RCTwithgrade3or4hematologicaltoxicityidenHcal(89.0%withDXZvs89.8%withoutDXZ;p=0.26)(Asselin,JCO,2016)

•  RouHnehematologicaltesHng&bloodproductsupport

LiposomalAnthracyclines•  Concentratesdrugintumorcells– ↓ blood concentration

•  Decreased cardiotoxicity 5x with same efficacy (O’Brien, Ann Oncol, 2004)

•  Limited pediatric studies – COG study AAML1421 (CPX-351)

Carvedilol:Chemoprophylaxis

•  N=50(25eachgroupofRCT)•  AnthracyclineRx•  Carvedilol12.5mgvsplacebo•  Startedbeforechemoand

conHnued6moslater•  Echo@baseline&6mospost

KalayNet.al.JAmCollCardiol2006;48:2258–62

Carvedilol:COGALTE1621•  PREVENT-HF:PharmacologicReversalofVentricular

RemodelinginChildhoodCancerSurvivorsatRiskforHeartFailure

•  Phase2bRCTofCarvedilolvsPlacebo•  Outcomes:LVthickness(echo)&biomarker

Randomize

Carvedilol3.125mgQDx2weeks6.25mgQDx4-6wks6.25mgBIDx2yearsChildhoodCASurvivors

Exposedto>250mg/m2

withoutDXZPlacebo

Randomize

•  N=45(27/18)•  BreastCA•  Nebivolol5mgdailyor

placebo•  TTEdataatbaseline

and6months

Nebivolol:Chemoprophylaxis

Kaya,IntJofCard,2013.

Sta9nsasProtec9veTherapy

•  N=628,breastCA•  67onstaHnsduring

anthracyclineRxvs134propensitymatchedcontrols

•  HR0.3(CI0.1-0.9)fordevelopmentofsymptomaHcheartfailure

Seicean,JAmCollCardiol2012.

•  Preclinicaldata:↓oxidaHvestress,pro-inflammatorycytokines&caspase-mediatedapoptosis(Riad,CancerRes,2009)

Sta9nsasProtec9veTherapy•  RCTof40pts•  40mg/dayatorvastaHnvsplacebox6mo

•  No↓ LV EF in atorvastatin groupAcar,JAmCollCardiol,2011

Sta9nsasProtec9veTherapy•  51pts–  BreastCA,lymphoma,leukemia

•  14staHns,37nostaHns•  LFEFdidnotdecreaseinstaHngroup

Chotenimitkhunetal,CanJCardiol,2015.

ACE-Inhibitors•  N=114•  EarlycTnIarerhighdosechemo

•  Enalaprilvsplacebo•  1montharerchemoto1year

Cardinale,Circula?on.2006.

ACE-I&Carvedilol

•  N=90(36leukemia,54HSCT)•  RandomizedtoControl(45)vs

Enalapril+Carvedilol(45)•  TTE+CMRI,6mosbeforeand

arerrandomizaHon•  Combinedtreatmentprevented

lerventricularsystolicdysfuncHon

Boschet.al,JamCollCard,2013.

L-Carni9ne•  L-CarniHnealteraHonsincancersurvivors

–  ↓ plasma carnitine & ↑ essential & long chain fatty acids (LCFA) associated with decreased systolic function

–  Primary & secondary carnitine deficiency results in cardiomyopathy & arrhythmias due to accumulation of LCFA & acylcarnitines

–  EHology&Hming/onsetofdepleHonisunclear•  Preliminarystudiessuggestroleinprimaryand

secondaryprevenHonofcardiotoxicity•  LargerRCTsareneeded

Armenan,AnnNutrMetab,2016.

FitnessinChildhoodCancerSurvivors•  30-50%meetCDCguidelinesforphysicalacHvity(Gilliam,2013)

•  PhysicalacHvitysimilarorlowerthansedentarygeneralpopulaHon(Stolley,2010&Hocking2013)

•  Moresedentarythansiblings(Zhang,2013)•  ↓Exercisecapacity,↓Endurance&↓Anaerobicthreshold(Miller,2013)

–  FemaleshadhighCRP&proBNP•  ConsistentwithinflammaHon&neurohormonalacHvaHonofcardiomyopathy•  Greaterriskforlateeffectsthanmales

AerobicExercise(ET)A[enuatesDox-inducedchangesinMouse

Dolinsky,VW,etal.AmJPhysiolEndocrinolMetab.2013.

ClinicalExerciseInterven9onsinPediatricOncology•  Feasible&safe•  Noadverseeffectsdescribed•  PosiHveeffects:

–  ↓FaHgue–  ↑MuscleStrength–  ↑QualityofLife

BaumannFTetal.PedatricResearch,2013.

ExerciseImprovesCardiacFunc9onofChildhoodALLSurvivors

•  21long-termsurvivorsofALL(age16-30years)&matchedcontrols

•  Homebasedexercisefor12weeks–  8musclestrengthexercises3-4x/wk–  30minaerobicexerciseatleast3x/week

•  ↑earlydiastolicmitralinflowvelocity•  ImprovedpeakcircumferenHalsystolic&diastolicstrainrates

atmid-level

JarvelaLS,etal.PBC,2016.

CanExerciseDuringorA\erTreatmentProtectAgainst

Cardiotoxicity?•  InnovaHve&tailoredphysicalacHvityprograms

areneededtoimprovecardiaccondiHonsofcancersurvivors

•  Exerciseprogramswithclosemonitoring•  Inclusionoffamilymembers

Children’sOncologyGroup(COG):LongTermFollow-upGuidelineofPhysicalAc9vity•  Promptlyreporttophysicianssymptomsof

Hrednessordifficultyinbreathingthatdonotresolvewithrest.

•  Aerobicexerciseisgenerallysafe&shouldbeencouraged.

MajorRiskCategories

•  Age•  Gender•  Radia9on•  Alkyla9ngAgents•  Anthracycline•  HighdoseCyclophosphamide•  PreviousHeartDisease•  IronOverload•  Hypertension•  BoneMarrowTransplant•  SF<29%orSVEF<55%DuringTreatment

MinorRiskCategories

• BMI• Lipids• Prediabetes/Diabetes• SedentaryLifestyle

Conclusions•  Dexrazoxane:– EffecHveascardioprotectantinadults&children– Notassociatedwith↑ SMNs – Not associated with excess mortality – Does not impair antitumor efficacy of

anthracyclines – Need more prospective long-term studies

Conclusions•  FurtherresearchneededforL-CarniHne,staHns&neurohormonalantagonists

•  Exerciseestablishedtobesafe&feasibleduringtreatment&survivors–  Inhospital&home

•  RCTsneededtodetermineeffectsize,opHmalexerciseformat&durability