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EnhancingtheRoleoftheAdvancedPracticeProvider(APP)PostStemCellTransplant:IntegratingPatientsBackintotheCommunity

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OBJECTIVES

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• ImprovethequalityofpostSCTpatientcare• Alleviatethe“unknowns”ofposttransplantcare• Provideguidelinesforposttransplantcare• Increaseeconomic efficiency of theposttransplantprocess

• Contributetotheoverallprinciplesofsurvivorship

BACKGROUND

• SCTprovidesthebestoptionforlong-termsurvivalformanypatientsdiagnosedwithvarioushematologicalmalignancies

• Thetransplantprocessischaracterizedbyadifficultandprotractedtrajectory–itismarkedbytheriskofsignificantcomplications, prolongedhospitaladmissionandfrequentoutpatientvisits

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PROBLEM

• Key Issueforthe transplantteam– challengeofpreparingthecommunityprovidersorreferringhematology/oncologyprovidersforthepatient’sdischarge,providingthemwiththebasicknowledgeofthepatient’sfollow-upneedsandensuringasmoothandsafetransitionofthepatient

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PROBLEM

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• Unanticipated travelback– increasedsocio-economic andemotionalburdentopatientsandcaregivers

• Inconsistentcareand/or lackofcare– riskforposttransplantcomplications

KEY ISSUES

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• Immune systemrecovery• Identificationandmonitoringofinfectious processes• Recognition&treatmentofgraftvshostdisease(GVHD)• Immunization requirements&schedule• Recognitionof lateeffect• Diseaserelapse&restaging

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DISEASESTREATEDWITHALLOGENEICHSCT

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• AcuteMyelogenousLeukemia(AML)• AcuteLymphoblasticLymphoma (ALL)• MyelodysplasticSyndrome(MDS)• ChronicMyelogenousLeukemia(CML)• Lymphoma• Myeloma• Non-malignantdisorders

• Aplastic anemia, Immunodeficiency's, Sicklecell, Thalassemia,Lysosomal StorageDisorders

DISEASESTREATEDWITHAUTOLOGOUSHSCT

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• Multiplemyeloma• RelapsedLymphoma• RelapsedGermCellTumors• Neuroblastoma• Ewing’sSarcoma• Leukemia• Solidtumors

ETHICS

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• Canoccurineveryphaseofthecomplextransplantationprocedure

• HSCTassociatedwithasubstantialrisks• Highcostperpatient

– Controversy- societaldemandstopreservelifewhilesimultaneouslylimitingglobalhealth-careexpenditures

ETHICS

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• Treatmentandeligibilitydecisions– heavilyscrutinizedbybothgovernmentalandprivatepayersand

• Bioethicalproblem– approachestogenetransferandtherapycanusetransplantation

methodologiesandaugmenttheireffects

POSTHSCTCARE

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• IndividualizationofcareplansiscrucialforHSCTsurvivors• Preventivehealthmeasuresshouldbeemphasized• Long-term careprovidedthroughamultispecialtyteamis

optimal

POSTHSCTCARE

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• Screeningforlong-termcomplicationsshouldbebaseduponpatientsHSCThistory– Pre-transplantchemotherapy&/orXRT– Donortype(auto/allo)– Transplantconditioningtherapy– Earlypost-transplantcomplications– Age&genderofpatient

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LONG-TERM TOXICITIESOFALLOGENEIC HSCT

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• Chronic GVHD• Infections• Treatment-related

myelodysplasia/secondaryleukemia

• Secondarysolidtumors• Endocrine abnormalities• Cardiacdisease

• Pulmonarytoxicity• Bone&joints• Dermatologic• OralHealth• Ocular• Psychosocial

CARDIOLOGY

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• Prevalence– 5%atfiveyearsand9%at15years• Contributingfactors:

– Calcineurininhibitors– Corticosteroids– ChronicGVHD– Chemotherapyagents- anthracyclines,high-dosecyclophosphamide– Chestradiation– Diabetes

CARDIOLOGY

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• HeartFailure–– occurswithinthefirstfouryears– maypresentmorethaneightyearsafterHSCT

• Risk- anthracycline-relatedcardiomyopathyincreaseswiththecumulativedoseandtimefromexposure

CARDIOLOGYWORK-UP

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• Nocorresponding guidelinesfortheposttreatmentmonitoringofadults

• Highdegreeofsuspicionforthedevelopmentof HFamongadultswhohavebeenexposedtoanthracyclines– PeriodicassessmentofLVFrecommended

• ReferraltoCardiologist• Conversationwithtransplantteam

PULMONARY

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• 5%ofnon-relapselatemortalityafterallogeneicHSCT• Mostcommoncauseofnon-relapselatemortalityfollowingautologousHSCT

• Potentialcauses– lunginjuryfromTBI,chemotherapy(e.g.,bleomycin),infection,and

inflammatorypneumonitis,GvHD(BronchiolitisObliterans)

PULMONARY

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• Infectious Risk– Pre-transplantsero-status(e.g.,cytomegalovirus,herpessimplexvirus,

HIV,varicella-zostervirus,Epstein-Barrvirus,toxoplasmosis)– Priorexposures(e.g.,cats,birds,mycobacteria,endemicfungi)and

alsothehistoryofprophylaxisforinfectiousagents

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PULMONARY

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• LungInjury– Historyoftiming,dose,andfieldofradiationtherapydeliveredtothe

chest– Current&previousimmunosuppressiveandchemotherapeuticagents

(e.g.,methotrexate,cyclophosphamide,busulfan,glucocorticoids)

PULMONARY

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• Acuityofillness(e.g.,fever,tachypnea,hypoxemia,leukocytecounts)- guidetherapidityoftheevaluation

• MajorityoffebrileHSCTrecipients– Empiricbroadspectrumantibiotics– Choiceofantibiotic– riskforspecificinfections,potentialsites(lines,

skin)

PULMONARYWORK-UP

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• CXR/CT Scan• SputumCultures• Routinelabs,Bloodcultures• PulmonaryFunctionTests• ReferraltoPulmonologist• Bronchoscopyw/bronchiallavage• LungBiopsy• Conversationwithtransplantteam

ENDOCRINEABNORMALITIES

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• Diabetes/metabolicsyndrome• Hypothyroidism• Hypogonadismandfertilityissues• Hypoadrenalism

DIABETESMELLITUS

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• TypeIIDiabetesincreased3-4fold• Riskfactors

– Use ofglucocorticoidsandcalcineurininhibitorsforthemanagement ofGVHD

• Screening– Annually- usingeitherfastingglucoseorHgbA1cmeasurementand

forhyperlipidemiausingafastinglipidassay

HYPOTHYROIDISM

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• Incidence – roughlydoublethatofsiblingcontrols• AssociatedwithChemotherapy&TBI• Screening–

– Annually– essayofthyroid-stimulatinghormone(TSH)– orearlierifclinicalsuspicionexists

– TSHiselevated- TSHmeasurementshouldberepeatedalongwithaserum-freeT4tomakethediagnosisofhypothyroidism

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HYPOGONADISM&FERTILITYISSUES

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• Hypogonadismismorecommon inwomenthanmen• Myeloablativeallogeneictransplantationalmostalways

causes permanentsterility• Changesinhormone levels

– lossoflibido,erectiledysfunction,vaginaldryness,anddyspareunia– vulvovaginalGVHD,oftenwithmixedmucosalandcutaneous

manifestations

SCREENING- WOMEN

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• Counselingregardingcontraceptionshouldbeprovided• Counselingregardingsafesexualpractices• Routineconversationsaboutsexualhealth– referralforsexual

healthcounseling,ifappropriate• WomenhavemoreimpairedsexualhealthafterHCTthan

menandarelesslikelytorecovernormalsexualfunctioning

SCREENING- WOMEN

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• Womenwithsecondary amenorrhea oroligomenorrhea– pregnancytestandFSH– elevatedFSHisconsistentwithovarianfailure– Estrogentherapy– controversialinwomenover40– fulldisclosureof

risks/benefitsinallwomen• Lowlibido&sexualhealth

– Testosteronepatch– asadjuncttoestrogen&progesterone• Referral toOB/GYN• Conversation withtransplantteam

SCREENING- MEN

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• Counselingregardingcontraceptionshouldbeprovidedto• Serumtestosteroneandfollicle-stimulatinghormone(FSH)

concentrations• AlowtestosteronevalueinconjunctionwithanelevatedFSH

indicateshypogonadism• Testosteronereplacementtherapy• Phosphodiesteraseinhibitors(alternative)

HYPOADRENALISM

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• Glucocorticoids - suppress thehypothalamic-pituitary-adrenalfunction andresultinadrenalinsufficiency

• Prolongedexposuretoglucocorticoids shouldbetaperedslowly

• Adrenalcrisismayoccurinpatientswhoareabruptlywithdrawn

• CortisolStimtest– somewillrequirelife-longhydrocortisone

BONE&JOINTHEALTH

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• Survivorsareatrisk– Glucocorticoidinducedmyopathy– Scleroticchangesinskin&fascia– limitjointmobility– Osteopenia– Avascularnecrosis– Otherhip/jointproblems

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SCREENING/APPROACH

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• Dexa Scan– oneyearpostHSCT&annually• VitaminDmeasurement• PreventativeMeasures

– regularphysicalactivity– supplementalcalcium(upto1200mg/day),vitaminD(800to1000

internationalunitsdaily),&estrogenortestosteronereplacement

SCREENING/APPROACH

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• Osteoporosis– Bisphosphonates

• Prolongedcoursesof corticosteroids– Bisphosphonatesareconsidered– Noguidelines

• Avascularnecrosis:4-10%– ReferraltoOrthopedicSpecialist

• Conversationwithtransplantteam

DERMATOLOGIC

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• Mostcommon organinvolvedinacute&chronicGVHD

• Pre-malignantandmalignantskinneoplasms– annualcompleteskinexaminationisrequired– counseledtopreventsunburnanddamage(dermatoheliosis)andto

preventseveredryness(xerosis)

• ReferraltoDermatologist• Conversationwithtransplantteam

ORALHEALTH

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• 7-fold increasefororalcancers

• Chronic xerostomia- significantlyincreasestherisk– dentalcaries– mastication&swallowingproblems- leadingtomalnutrition

SCREENING/APPROACH

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• Dentalvisits- 6to12monthsaftertransplantation,andatleasttwiceayearthereafter

• Visualoralexamw/allprovidervisits• Commerciallyavailablesalivasubstitute• OraCoat– XyliMelts(allnatural)• Peppermint/Lemon drops

OCULAR

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• Cataracts– highestriskwithTBI&pediatricpatients• Keratoconjunctivitissicca– associatedwithTBI&GvHD• Ischemicmicrovascularretinopathy– associated

w/cyclosporineusedfor GVHD

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SCREENING/APPROACH

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• Yearlyophthalmologycheck-upw/visualacuitytests&Schirmertest(tearproduction)

INFECTIONS

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• Common cause ofmorbidityandnon-relapsemortality• Preventionofinfectionisofparamount• Majorityofimmunereconstitutiontakesplaceoverthefirst

12to18monthspostHSCT• Riskofinfection ishighestinthefirsttwoyears

INFECTIONS

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• Immune reconstitutionisslowerafterallogeneicHSCT• Prolongedforthosewithhumanleukocyteantigen(HLA)-

mismatched donors,T-cell-depleted grafts,andchronicGVHD

INFECTIONS

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• Immune reconstitutioncanbemonitoredindirectly– IgGlevels– AbsoluteCD4count– CD4/CD8ratios

• PersistentlowabsoluteCD4counts(<400/microL)areanindicationtocontinueimmune prophylaxis

INFECTIONS

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• Severe Infections&PersistentHypogammaglobulinemia– ConsiderIVImmunoglobulin(IVIG)

• Presenceof chronicGvHD– antiviralandanti-pneumocystisprophylaxis

• AcyclovirorValtrex• Bacrtrim,DapsoneorPentamidine

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POSTENGRAFTMENTPROPHYLAXIS

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• Antibacterial– Levaquin– Penicillin– Bactrim

• Antifungal– Fluconazole– Voriconazole– Posaconazole– Itraconazole

• Antiviral– Acyclovir– Valacyclovir

• Pneumocystis– Bactrim– Dapsone– Pentamidine

PHARMACOLOGY CHALLENGES

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• Azoles– interactw/manyothermedications– Especiallycardiology(Amiodorone)

• Levaquin+Azole– QTprolongation• Bactrim– cansuppresscounts

ANTIVIRALS

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• Herpessimplexvirus(HSV)– AcyclovirvsValacyclovir

• Valacyclovirconvertedtoacyclovir– betterabsorption &achievesplasmaconcentration3-5 timeshigher thenacyclovir

– Varicella-zostervirus(VZV)• Acyclovir800mgPOBIDfor1yearpostHSCT• Valacyclovir500mgPOBIDfor1yearpostHSCT

CMV- CYTOMEGALOVIRUS

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• AfterDay100• CMVlevel>1000• CMVlevel>5xbaselineinonemonth

• Valganciclovir(Valcyte)- Induction:900mgPOBIDX21daysMaintenance:900mgdaily

VALGANCICLOVIR

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• AvoidinpatientswithpoorPOintake,severediarrhea,orgutGVHD

• Metabolism:Prodrugconvertedtoganciclovir• Drug/DrugInteractions:Imipenem,mycophenolate,reverse

transcriptaseinhibitors• Monitoring

– CMVlevels,Neutropenia,Anemia,Nephrotoxicity,Neuropathy

ANTIVIRALS

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• Ganciclovir(Cytovene)• Foscarnet(Foscavir)• Cidofavir(Vistide)

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ANTIFUNGALS

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VORICONAZOLE (VFEND)

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• Prophylaxiso 200mgPOBIDo 3mg/kg IVq12h

• AspergillosisTreatment– Initial:6mg/kgevery 12

hoursfor2doses– Maintenance dose:4

mg/kg IVorPOevery 12hours

– 6-12weeksoftherapy

• Monitoring– Renalfunction-– Liver functiontests– QTprolongation– Visualchanges

• Drug interactions-CYP3A4metabolized

POSACONAZOLE

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• BrandName: Noxafil• Dosing

– DelayedReleasetablets-prophylaxisonly• 300mgtwicedailyonday1;

Maintenance:300mgoncedaily– Suspension

• Prophylaxis:200mgTID• Treatment::200mg4timesdaily

initially,then400mgBID• Poorabsorption-administerwith

fullmealoracidicbeverage• Erraticlevels

• Monitoring– Renalfunction-– Liverfunctiontests– QTprolongation– Visualchanges– Druginteractions-

CYP3A4metabolized

MICAFUNGIN

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• Brand:Mycamine• Availableas:IVInjection• Dosing

– Prophylaxis:50mgIVoncedaily

– Treatment:100-150mgIVoncedaily

• Monitoring– Liverfunctiontests

• Metabolism– SubstrateCYP3A4

(minor)• ADR

– Hemolyticanemia– Renalimpairment– Hepaticimpairment

PNEUMOCYSTIS JIROVECI PNEUMONIA(PJP),FORMERLY KNOWNASPNEUMOCYSTIS CARINIIPNEUMONIA(PCP)

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• Bactrim– willeitherbedosed2tabsSat/Sundayor1tabMon/Wed/Fri

• Dapsone– 100mgDaily

• Pentamidine– 200mgIVQmonthly

SECONDARYMALIGNANCIES

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• Solidtumors,acuteleukemia,myelodysplasticsyndromes,andpost-transplantlymphoproliferativedisease(PTLD)

• Typicallyoccurring>3yearsposttransplant– ExceptionPTLD– occurs1st year

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SCREENING/APPROACH

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• Riskawarenessscreeningannually• Annualdental,dermatologyandophthalmologyvisits– along

withyearlyexam• Routineage-appropriatecancersurveillance• FemalepatientsreceivingchestXRT

– AnnualMRIscreening 8yrs.postXRToratage25(ages 10-35)– Annualmammogrambeginningage 40

GRAFTVSHOSTDISEASE(GVHD)

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• RemainstheprimarylimitingfactorinAllogeneicHSCT• OccurswhendonorTcellsrecognizethepresenceof

histocompatibilityantigensinthehost

GVHD

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• IncidenceofGvHDassociatedwith– Degree ofHLAdisparity– Donorandrecipient gender disparity(female donortomale

recipient)– Intensityofthe transplant conditioningregimen– Acute GvHD prophylactic regimen used– Source ofgraft

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TACROLIMUS

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• Tacrolimus(FK506,FK)– Brand:Prograf®– InhibitionofT-cellactivation

• Class:Calcineurininhibitor(CNI)• Availableas capsulesandIVinjection• Initialdosing

– 0.03mg/kg/daycontinuousIVinfusion(CIVI)– 0.12mg/kg/dayPOin2divideddoses– Dosedonleanbodyweight

TACROLIMUS

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• Trough:10-20ng/ml– 5-10ng/mLwhenusedincombinationwithsirolimus

• Levels>20ng/mLassociatedwithincreasedtoxicity,primarilynephrotoxicity

• Dosereductionbasedonlevelsand/orserumcreatinine

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TACROLIMUS

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• Adverse Reactions– Hypertension– Nephrotoxicity– Hepatotoxicity– Neurotoxicity(whitematterchanges/PRES);(Headaches,seizures, peripheral

neuropathy,corticalblindness)– Tremors– Cosmetic sideeffects(hirsutism, gingivalhyperplasia)– Elevatedtriglycerides– Hypomagnesemia– Thromboticmicroangiopathy(TMA)

CYCLOSPORINE

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• Cyclosporine(CyA,CSA)• Brands:Neoral®,Gengraf®,Sandimmune®

• MechanismofAction:– Inhibition ofT-cell activation

• Class:CalcineurinInhibitor(CNI)• Availableas:

• liquidfilledcapsules:Sandimmune®Gengraf®andNeoral®• Injection50mg/mL(Sandimmune®)

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CYCLOSPORINE

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• Cyclosporineconversionfactors(IV:PO)• IVtoPO(Sandimmune®)=1:4• IVtoPO(Neoral®Gengraf®)=1:2

• InitialdosinginHCT3mg/kg/dayIVq12h• Troughlevels

• 200-400ng/mLforfirst3-4weeksthen100-200ng/mL• CsAprophylaxisis6monthsintheabsenceofGVHD

• Lessdatatocorrelatelevelswith toxicityincludingnephrotoxicity

CYCLOSPORINE

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• MetabolizedbyCYP3A4– Increasecyclosporine levels (3A4 inhibitors)

• Amiodarone,voriconazole,posaconazole, f luconazolediltiazem,verapamil, cimetidine,macrolides, grapefruitjuice

– Decreasecyclosporine levels (3A4 inducers)• Phenytoin,Carbamazepine,Rifampin

– P- Glycoprotein• Atorvastatin• Omeprazole• Dabigatran• Dronedarone

– Enhancethenephrotoxiceffects: Aminoglycosides, Amphotericin B,NSAIDs

CYCLOSPORINE

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• Adverse Reactions– Hypertension– Nephrotoxicity– Hepatotoxicity– Neurotoxicity(whitematterchanges/PRES);(Headaches,seizures, peripheral

neuropathy,corticalblindness)– Cosmetic sideeffects(hirsutism, gingivalhyperplasia, coarsefacialfeatures)– Tremors– Elevatedtriglycerides– Hypomagnesemia– Thromboticmicroangiopathy

SIROLIMUS

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• Sirolimus:Rapamycin• Mechanismofaction:

– BlocksmTOR(Mammaliantarget ofrapamycin) ultimatelycausingcellarrest intheG1phase.

– T-cells are the mostsensitive.• Class:mTORKinaseInhibitor,Immunosuppressant• Availableas:

– Rapamunesolutionandtablets

SIROLIMUS

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• Initialdose:12mgfollowedby4mgPOqday• Troughgoal:3-12ng/ml

– <10ng/mlwhencombinedwithCNI– Half-life:~60hours

• Trough<3– Increaseby25%

• Trough>12– Decreaseby25%orholdifsignificantlyelevated

SIROLIMUS

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• Druginteractions– CYP3A4substrate andweak inhibitor

• Sirolimus dose reductions– 90%withvoriconazole– 75%withposaconazole– 25%withfluconazole

• AdverseEffects– Cytopenia, hypertriglyceridemia, nephrotoxicity, neurotoxicity

whencombinedwithCNIs

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MYCOPHENOLATE

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• Mycophenolate:MMF• Mechanism ofaction:• Class:Immunosuppressant• Availableas:

– CellCept capsules,Myfortic DRtablets, suspension,IVsolution– Myfortic 720mg=Cellcept1000mg

MYCOPHENOLATE

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• Initialdose:1000mgBIDorTIDIVorPO• Levelsarenotcurrentlyrecommended• AdverseReactions

– Cytopenias– GItoxicity(abdominalpain,diarrhea,nausea)– Nephrotoxicity

• Metabolism:conjugatedintheliverbyglucuronyltransferase• Druginteractions

– Decreaseefficacyofbirthcontrolpills,Flagyl

PSYCHOSOCIAL

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• Researchers atthe International BoneMarrowTransplant Registry (IBMTR)attheMedical CollegeofWisconsininMilwaukee, andat theDana-FarberCancer Institute foundthatpatientswithdepressivesymptomssixmonthsafter their transplant havethreetimeshigher riskofdeathbyoneyear post-transplant thandonon-depressedpatients

DEPRESSION

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• Ratesofdepressionamong generalcancerpatientsrangefrom10%–25%,whereasinsomestudies,ratesofdepressionamongthetransplantpopulationarehigher,rangingfrom25%to50%

RELAPSE/RESTAGING

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• HighMortalityfromRelapse• Somepatientsdorespond&havesustainedremissions• Minorityhaveasecondchangeofcure

PROGNOSIS

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• Dependson fourfactors– TimeelapsedfromSCTtorelapse

• Within6months– worstprognosis– Diseasetype(withchronicleukemia'sandsomelymphomashavinga

secondpossibilityofcurewithfurthertreatment)– Diseaseburdenandsiteofrelapse– Conditionsofthefirsttransplant

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ISITALLWORTHIT?

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• Despitethefactthatthetransplantcanbeatryingexperience,mostfindthatthepleasurethatcomesfrombeingaliveandhealthyafterthetransplantiswellworththeeffort.

REFERENCES

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• GoldStandard,Inc.ClinicalPharmacology[databaseonline]. Availableat:http://www.clinicalpharmacology.com.

• https://bethematchclinical.org/post-transplant-care/vaccinations/• https://www.cibmtr.org/ReferenceCenter/Patient/Guidelines/pages/index.aspx• https://www.fredhutch.org/content/dam/public/Treatment-Suport/.../physician.pdf• http://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-grading-of-

acute-graft-versus-host-disease• Lexi-Comp,Inc.(Lexi-Drugs®).Lexi-Comp,Inc.;January2016• McCuneJS,Bemer,MJ.Pharmacokinetics,PharmacodynamicsandPharmacogenomics

ofImmunosuppressant'sinAllogeneicHematopoieticCellTransplantation:PartI. ClinPharmacokinet.2015Nov13.

REFERENCES

• Przepiorka D, Devine S, Fay J, Uberti J,Wingard J.Practical considerations intheuse of tacrolimus forallogeneic marrow transplantation.BoneMarrowTransplant. 1999Nov;24(10):1053–6.

• Oncology Pharmacy Preparative Review CourseHandbook 2013.American Society of Health-System Pharmacists, Inc.

• RuutuT, Gratwohl A, deWitte T, Afanasyev B, Apperley J, etal. (2014) Prophylaxisandtreatment of GVHD: EBMT-ELN working grouprecommendations forastandardized practice.BoneMarrow Transplant 49:168–173.

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THANKYOU!

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