View
6
Download
0
Category
Preview:
Citation preview
8/11/16
1
EnhancingtheRoleoftheAdvancedPracticeProvider(APP)PostStemCellTransplant:IntegratingPatientsBackintotheCommunity
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion.
OBJECTIVES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2
• ImprovethequalityofpostSCTpatientcare• Alleviatethe“unknowns”ofposttransplantcare• Provideguidelinesforposttransplantcare• Increaseeconomic efficiency of theposttransplantprocess
• Contributetotheoverallprinciplesofsurvivorship
BACKGROUND
• SCTprovidesthebestoptionforlong-termsurvivalformanypatientsdiagnosedwithvarioushematologicalmalignancies
• Thetransplantprocessischaracterizedbyadifficultandprotractedtrajectory–itismarkedbytheriskofsignificantcomplications, prolongedhospitaladmissionandfrequentoutpatientvisits
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3
PROBLEM
• Key Issueforthe transplantteam– challengeofpreparingthecommunityprovidersorreferringhematology/oncologyprovidersforthepatient’sdischarge,providingthemwiththebasicknowledgeofthepatient’sfollow-upneedsandensuringasmoothandsafetransitionofthepatient
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4
PROBLEM
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5
• Unanticipated travelback– increasedsocio-economic andemotionalburdentopatientsandcaregivers
• Inconsistentcareand/or lackofcare– riskforposttransplantcomplications
KEY ISSUES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6
• Immune systemrecovery• Identificationandmonitoringofinfectious processes• Recognition&treatmentofgraftvshostdisease(GVHD)• Immunization requirements&schedule• Recognitionof lateeffect• Diseaserelapse&restaging
8/11/16
2
DISEASESTREATEDWITHALLOGENEICHSCT
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7
• AcuteMyelogenousLeukemia(AML)• AcuteLymphoblasticLymphoma (ALL)• MyelodysplasticSyndrome(MDS)• ChronicMyelogenousLeukemia(CML)• Lymphoma• Myeloma• Non-malignantdisorders
• Aplastic anemia, Immunodeficiency's, Sicklecell, Thalassemia,Lysosomal StorageDisorders
DISEASESTREATEDWITHAUTOLOGOUSHSCT
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 8
• Multiplemyeloma• RelapsedLymphoma• RelapsedGermCellTumors• Neuroblastoma• Ewing’sSarcoma• Leukemia• Solidtumors
ETHICS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 9
• Canoccurineveryphaseofthecomplextransplantationprocedure
• HSCTassociatedwithasubstantialrisks• Highcostperpatient
– Controversy- societaldemandstopreservelifewhilesimultaneouslylimitingglobalhealth-careexpenditures
ETHICS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 0
• Treatmentandeligibilitydecisions– heavilyscrutinizedbybothgovernmentalandprivatepayersand
• Bioethicalproblem– approachestogenetransferandtherapycanusetransplantation
methodologiesandaugmenttheireffects
POSTHSCTCARE
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 1
• IndividualizationofcareplansiscrucialforHSCTsurvivors• Preventivehealthmeasuresshouldbeemphasized• Long-term careprovidedthroughamultispecialtyteamis
optimal
POSTHSCTCARE
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 2
• Screeningforlong-termcomplicationsshouldbebaseduponpatientsHSCThistory– Pre-transplantchemotherapy&/orXRT– Donortype(auto/allo)– Transplantconditioningtherapy– Earlypost-transplantcomplications– Age&genderofpatient
8/11/16
3
LONG-TERM TOXICITIESOFALLOGENEIC HSCT
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 3
• Chronic GVHD• Infections• Treatment-related
myelodysplasia/secondaryleukemia
• Secondarysolidtumors• Endocrine abnormalities• Cardiacdisease
• Pulmonarytoxicity• Bone&joints• Dermatologic• OralHealth• Ocular• Psychosocial
CARDIOLOGY
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 4
• Prevalence– 5%atfiveyearsand9%at15years• Contributingfactors:
– Calcineurininhibitors– Corticosteroids– ChronicGVHD– Chemotherapyagents- anthracyclines,high-dosecyclophosphamide– Chestradiation– Diabetes
CARDIOLOGY
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 5
• HeartFailure–– occurswithinthefirstfouryears– maypresentmorethaneightyearsafterHSCT
• Risk- anthracycline-relatedcardiomyopathyincreaseswiththecumulativedoseandtimefromexposure
CARDIOLOGYWORK-UP
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 6
• Nocorresponding guidelinesfortheposttreatmentmonitoringofadults
• Highdegreeofsuspicionforthedevelopmentof HFamongadultswhohavebeenexposedtoanthracyclines– PeriodicassessmentofLVFrecommended
• ReferraltoCardiologist• Conversationwithtransplantteam
PULMONARY
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 7
• 5%ofnon-relapselatemortalityafterallogeneicHSCT• Mostcommoncauseofnon-relapselatemortalityfollowingautologousHSCT
• Potentialcauses– lunginjuryfromTBI,chemotherapy(e.g.,bleomycin),infection,and
inflammatorypneumonitis,GvHD(BronchiolitisObliterans)
PULMONARY
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 8
• Infectious Risk– Pre-transplantsero-status(e.g.,cytomegalovirus,herpessimplexvirus,
HIV,varicella-zostervirus,Epstein-Barrvirus,toxoplasmosis)– Priorexposures(e.g.,cats,birds,mycobacteria,endemicfungi)and
alsothehistoryofprophylaxisforinfectiousagents
8/11/16
4
PULMONARY
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 1 9
• LungInjury– Historyoftiming,dose,andfieldofradiationtherapydeliveredtothe
chest– Current&previousimmunosuppressiveandchemotherapeuticagents
(e.g.,methotrexate,cyclophosphamide,busulfan,glucocorticoids)
PULMONARY
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 0
• Acuityofillness(e.g.,fever,tachypnea,hypoxemia,leukocytecounts)- guidetherapidityoftheevaluation
• MajorityoffebrileHSCTrecipients– Empiricbroadspectrumantibiotics– Choiceofantibiotic– riskforspecificinfections,potentialsites(lines,
skin)
PULMONARYWORK-UP
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 1
• CXR/CT Scan• SputumCultures• Routinelabs,Bloodcultures• PulmonaryFunctionTests• ReferraltoPulmonologist• Bronchoscopyw/bronchiallavage• LungBiopsy• Conversationwithtransplantteam
ENDOCRINEABNORMALITIES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 2
• Diabetes/metabolicsyndrome• Hypothyroidism• Hypogonadismandfertilityissues• Hypoadrenalism
DIABETESMELLITUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 3
• TypeIIDiabetesincreased3-4fold• Riskfactors
– Use ofglucocorticoidsandcalcineurininhibitorsforthemanagement ofGVHD
• Screening– Annually- usingeitherfastingglucoseorHgbA1cmeasurementand
forhyperlipidemiausingafastinglipidassay
HYPOTHYROIDISM
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 4
• Incidence – roughlydoublethatofsiblingcontrols• AssociatedwithChemotherapy&TBI• Screening–
– Annually– essayofthyroid-stimulatinghormone(TSH)– orearlierifclinicalsuspicionexists
– TSHiselevated- TSHmeasurementshouldberepeatedalongwithaserum-freeT4tomakethediagnosisofhypothyroidism
8/11/16
5
HYPOGONADISM&FERTILITYISSUES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 5
• Hypogonadismismorecommon inwomenthanmen• Myeloablativeallogeneictransplantationalmostalways
causes permanentsterility• Changesinhormone levels
– lossoflibido,erectiledysfunction,vaginaldryness,anddyspareunia– vulvovaginalGVHD,oftenwithmixedmucosalandcutaneous
manifestations
SCREENING- WOMEN
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 6
• Counselingregardingcontraceptionshouldbeprovided• Counselingregardingsafesexualpractices• Routineconversationsaboutsexualhealth– referralforsexual
healthcounseling,ifappropriate• WomenhavemoreimpairedsexualhealthafterHCTthan
menandarelesslikelytorecovernormalsexualfunctioning
SCREENING- WOMEN
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 7
• Womenwithsecondary amenorrhea oroligomenorrhea– pregnancytestandFSH– elevatedFSHisconsistentwithovarianfailure– Estrogentherapy– controversialinwomenover40– fulldisclosureof
risks/benefitsinallwomen• Lowlibido&sexualhealth
– Testosteronepatch– asadjuncttoestrogen&progesterone• Referral toOB/GYN• Conversation withtransplantteam
SCREENING- MEN
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 8
• Counselingregardingcontraceptionshouldbeprovidedto• Serumtestosteroneandfollicle-stimulatinghormone(FSH)
concentrations• AlowtestosteronevalueinconjunctionwithanelevatedFSH
indicateshypogonadism• Testosteronereplacementtherapy• Phosphodiesteraseinhibitors(alternative)
HYPOADRENALISM
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 2 9
• Glucocorticoids - suppress thehypothalamic-pituitary-adrenalfunction andresultinadrenalinsufficiency
• Prolongedexposuretoglucocorticoids shouldbetaperedslowly
• Adrenalcrisismayoccurinpatientswhoareabruptlywithdrawn
• CortisolStimtest– somewillrequirelife-longhydrocortisone
BONE&JOINTHEALTH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 0
• Survivorsareatrisk– Glucocorticoidinducedmyopathy– Scleroticchangesinskin&fascia– limitjointmobility– Osteopenia– Avascularnecrosis– Otherhip/jointproblems
8/11/16
6
SCREENING/APPROACH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 1
• Dexa Scan– oneyearpostHSCT&annually• VitaminDmeasurement• PreventativeMeasures
– regularphysicalactivity– supplementalcalcium(upto1200mg/day),vitaminD(800to1000
internationalunitsdaily),&estrogenortestosteronereplacement
SCREENING/APPROACH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 2
• Osteoporosis– Bisphosphonates
• Prolongedcoursesof corticosteroids– Bisphosphonatesareconsidered– Noguidelines
• Avascularnecrosis:4-10%– ReferraltoOrthopedicSpecialist
• Conversationwithtransplantteam
DERMATOLOGIC
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 3
• Mostcommon organinvolvedinacute&chronicGVHD
• Pre-malignantandmalignantskinneoplasms– annualcompleteskinexaminationisrequired– counseledtopreventsunburnanddamage(dermatoheliosis)andto
preventseveredryness(xerosis)
• ReferraltoDermatologist• Conversationwithtransplantteam
ORALHEALTH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 4
• 7-fold increasefororalcancers
• Chronic xerostomia- significantlyincreasestherisk– dentalcaries– mastication&swallowingproblems- leadingtomalnutrition
SCREENING/APPROACH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 5
• Dentalvisits- 6to12monthsaftertransplantation,andatleasttwiceayearthereafter
• Visualoralexamw/allprovidervisits• Commerciallyavailablesalivasubstitute• OraCoat– XyliMelts(allnatural)• Peppermint/Lemon drops
OCULAR
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 6
• Cataracts– highestriskwithTBI&pediatricpatients• Keratoconjunctivitissicca– associatedwithTBI&GvHD• Ischemicmicrovascularretinopathy– associated
w/cyclosporineusedfor GVHD
8/11/16
7
SCREENING/APPROACH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 7
• Yearlyophthalmologycheck-upw/visualacuitytests&Schirmertest(tearproduction)
INFECTIONS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 8
• Common cause ofmorbidityandnon-relapsemortality• Preventionofinfectionisofparamount• Majorityofimmunereconstitutiontakesplaceoverthefirst
12to18monthspostHSCT• Riskofinfection ishighestinthefirsttwoyears
INFECTIONS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 3 9
• Immune reconstitutionisslowerafterallogeneicHSCT• Prolongedforthosewithhumanleukocyteantigen(HLA)-
mismatched donors,T-cell-depleted grafts,andchronicGVHD
INFECTIONS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 0
• Immune reconstitutioncanbemonitoredindirectly– IgGlevels– AbsoluteCD4count– CD4/CD8ratios
• PersistentlowabsoluteCD4counts(<400/microL)areanindicationtocontinueimmune prophylaxis
INFECTIONS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 1
• Severe Infections&PersistentHypogammaglobulinemia– ConsiderIVImmunoglobulin(IVIG)
• Presenceof chronicGvHD– antiviralandanti-pneumocystisprophylaxis
• AcyclovirorValtrex• Bacrtrim,DapsoneorPentamidine
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 2
8/11/16
8
POSTENGRAFTMENTPROPHYLAXIS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 3
• Antibacterial– Levaquin– Penicillin– Bactrim
• Antifungal– Fluconazole– Voriconazole– Posaconazole– Itraconazole
• Antiviral– Acyclovir– Valacyclovir
• Pneumocystis– Bactrim– Dapsone– Pentamidine
PHARMACOLOGY CHALLENGES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 4
• Azoles– interactw/manyothermedications– Especiallycardiology(Amiodorone)
• Levaquin+Azole– QTprolongation• Bactrim– cansuppresscounts
ANTIVIRALS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 5
• Herpessimplexvirus(HSV)– AcyclovirvsValacyclovir
• Valacyclovirconvertedtoacyclovir– betterabsorption &achievesplasmaconcentration3-5 timeshigher thenacyclovir
– Varicella-zostervirus(VZV)• Acyclovir800mgPOBIDfor1yearpostHSCT• Valacyclovir500mgPOBIDfor1yearpostHSCT
CMV- CYTOMEGALOVIRUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 6
• AfterDay100• CMVlevel>1000• CMVlevel>5xbaselineinonemonth
• Valganciclovir(Valcyte)- Induction:900mgPOBIDX21daysMaintenance:900mgdaily
VALGANCICLOVIR
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 7
• AvoidinpatientswithpoorPOintake,severediarrhea,orgutGVHD
• Metabolism:Prodrugconvertedtoganciclovir• Drug/DrugInteractions:Imipenem,mycophenolate,reverse
transcriptaseinhibitors• Monitoring
– CMVlevels,Neutropenia,Anemia,Nephrotoxicity,Neuropathy
ANTIVIRALS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 8
• Ganciclovir(Cytovene)• Foscarnet(Foscavir)• Cidofavir(Vistide)
8/11/16
9
ANTIFUNGALS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 4 9
VORICONAZOLE (VFEND)
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 0
• 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
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 1
• 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
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 2
• 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)
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 3
• Bactrim– willeitherbedosed2tabsSat/Sundayor1tabMon/Wed/Fri
• Dapsone– 100mgDaily
• Pentamidine– 200mgIVQmonthly
SECONDARYMALIGNANCIES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 4
• Solidtumors,acuteleukemia,myelodysplasticsyndromes,andpost-transplantlymphoproliferativedisease(PTLD)
• Typicallyoccurring>3yearsposttransplant– ExceptionPTLD– occurs1st year
8/11/16
10
SCREENING/APPROACH
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 5
• Riskawarenessscreeningannually• Annualdental,dermatologyandophthalmologyvisits– along
withyearlyexam• Routineage-appropriatecancersurveillance• FemalepatientsreceivingchestXRT
– AnnualMRIscreening 8yrs.postXRToratage25(ages 10-35)– Annualmammogrambeginningage 40
GRAFTVSHOSTDISEASE(GVHD)
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 6
• RemainstheprimarylimitingfactorinAllogeneicHSCT• OccurswhendonorTcellsrecognizethepresenceof
histocompatibilityantigensinthehost
GVHD
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 7
• IncidenceofGvHDassociatedwith– Degree ofHLAdisparity– Donorandrecipient gender disparity(female donortomale
recipient)– Intensityofthe transplant conditioningregimen– Acute GvHD prophylactic regimen used– Source ofgraft
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 8
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 5 9 CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 0
8/11/16
11
TACROLIMUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 1
• Tacrolimus(FK506,FK)– Brand:Prograf®– InhibitionofT-cellactivation
• Class:Calcineurininhibitor(CNI)• Availableas capsulesandIVinjection• Initialdosing
– 0.03mg/kg/daycontinuousIVinfusion(CIVI)– 0.12mg/kg/dayPOin2divideddoses– Dosedonleanbodyweight
TACROLIMUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 2
• Trough:10-20ng/ml– 5-10ng/mLwhenusedincombinationwithsirolimus
• Levels>20ng/mLassociatedwithincreasedtoxicity,primarilynephrotoxicity
• Dosereductionbasedonlevelsand/orserumcreatinine
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 3 CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 4
TACROLIMUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 5
• Adverse Reactions– Hypertension– Nephrotoxicity– Hepatotoxicity– Neurotoxicity(whitematterchanges/PRES);(Headaches,seizures, peripheral
neuropathy,corticalblindness)– Tremors– Cosmetic sideeffects(hirsutism, gingivalhyperplasia)– Elevatedtriglycerides– Hypomagnesemia– Thromboticmicroangiopathy(TMA)
CYCLOSPORINE
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 6
• Cyclosporine(CyA,CSA)• Brands:Neoral®,Gengraf®,Sandimmune®
• MechanismofAction:– Inhibition ofT-cell activation
• Class:CalcineurinInhibitor(CNI)• Availableas:
• liquidfilledcapsules:Sandimmune®Gengraf®andNeoral®• Injection50mg/mL(Sandimmune®)
8/11/16
12
CYCLOSPORINE
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 7
• 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
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 8
• 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
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 6 9
• Adverse Reactions– Hypertension– Nephrotoxicity– Hepatotoxicity– Neurotoxicity(whitematterchanges/PRES);(Headaches,seizures, peripheral
neuropathy,corticalblindness)– Cosmetic sideeffects(hirsutism, gingivalhyperplasia, coarsefacialfeatures)– Tremors– Elevatedtriglycerides– Hypomagnesemia– Thromboticmicroangiopathy
SIROLIMUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 0
• Sirolimus:Rapamycin• Mechanismofaction:
– BlocksmTOR(Mammaliantarget ofrapamycin) ultimatelycausingcellarrest intheG1phase.
– T-cells are the mostsensitive.• Class:mTORKinaseInhibitor,Immunosuppressant• Availableas:
– Rapamunesolutionandtablets
SIROLIMUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 1
• Initialdose:12mgfollowedby4mgPOqday• Troughgoal:3-12ng/ml
– <10ng/mlwhencombinedwithCNI– Half-life:~60hours
• Trough<3– Increaseby25%
• Trough>12– Decreaseby25%orholdifsignificantlyelevated
SIROLIMUS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 2
• Druginteractions– CYP3A4substrate andweak inhibitor
• Sirolimus dose reductions– 90%withvoriconazole– 75%withposaconazole– 25%withfluconazole
• AdverseEffects– Cytopenia, hypertriglyceridemia, nephrotoxicity, neurotoxicity
whencombinedwithCNIs
8/11/16
13
MYCOPHENOLATE
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 3
• Mycophenolate:MMF• Mechanism ofaction:• Class:Immunosuppressant• Availableas:
– CellCept capsules,Myfortic DRtablets, suspension,IVsolution– Myfortic 720mg=Cellcept1000mg
MYCOPHENOLATE
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 4
• Initialdose:1000mgBIDorTIDIVorPO• Levelsarenotcurrentlyrecommended• AdverseReactions
– Cytopenias– GItoxicity(abdominalpain,diarrhea,nausea)– Nephrotoxicity
• Metabolism:conjugatedintheliverbyglucuronyltransferase• Druginteractions
– Decreaseefficacyofbirthcontrolpills,Flagyl
PSYCHOSOCIAL
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 5
• Researchers atthe International BoneMarrowTransplant Registry (IBMTR)attheMedical CollegeofWisconsininMilwaukee, andat theDana-FarberCancer Institute foundthatpatientswithdepressivesymptomssixmonthsafter their transplant havethreetimeshigher riskofdeathbyoneyear post-transplant thandonon-depressedpatients
DEPRESSION
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 6
• Ratesofdepressionamong generalcancerpatientsrangefrom10%–25%,whereasinsomestudies,ratesofdepressionamongthetransplantpopulationarehigher,rangingfrom25%to50%
RELAPSE/RESTAGING
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 7
• HighMortalityfromRelapse• Somepatientsdorespond&havesustainedremissions• Minorityhaveasecondchangeofcure
PROGNOSIS
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 7 8
• Dependson fourfactors– TimeelapsedfromSCTtorelapse
• Within6months– worstprognosis– Diseasetype(withchronicleukemia'sandsomelymphomashavinga
secondpossibilityofcurewithfurthertreatment)– Diseaseburdenandsiteofrelapse– Conditionsofthefirsttransplant
8/11/16
14
ISITALLWORTHIT?
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 8 1
• Despitethefactthatthetransplantcanbeatryingexperience,mostfindthatthepleasurethatcomesfrombeingaliveandhealthyafterthetransplantiswellworththeeffort.
REFERENCES
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 8 2
• 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.
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion. 8 3
THANKYOU!
CONFIDENTIAL – Containsproprietary in formation .Not in tended forextern al d istribu tion.
Recommended