hematopoietic stem cell transplant for … cell disease: ... § in africa, newborn children born...

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KarenSweiss, PharmD,BCOPClinical Assistant Professor

Clinical Pharmacist inHematologyandStemCell TransplantDepartmentofPharmacyPractice

Universityof I llinois College ofPharmacyChicago, IL

HEMATOPOIETICSTEMCELLTRANSPLANTFORSICKLECELLDISEASE:PERSPECTIVESFROM

CHILDHOODTOADULTHOOD

Disclosures• Ihave noactual orpotential conflict of interestin

relation tothis program/presentation.

Objectives• Definethepathogenesisandclinicalsequelaeofsickle

cell disease (SCD) inpediatric and adult patients

• Identify theindicationsforallogeneic hematopoieticstem cell transplantation in pediatricand adultpatientswithSCD

• Explaintheimmunologyunderlyingtheuseof allogeneic hematopoietic stem cell transplantation in SCD

• Compare theefficacyandtoxicityofthevarious preparative regimensusedinpediatricandadultpatientswithSCD

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SickleCellDisease:AGlobalBurden• Incidence1

§ Affects 90,000to100,000Americans§ Occursamong~1outofevery 500BlackorAfrican-American births

§ InAfrica,newborn childrenbornwithSCDestimated tobe200,000to300,000

• Mortality2§ Killsnearlyhalfamillionpeopleannually

• EconomicCosts2

§ ForadultswithSCDthe average annualcostofmedicalcareexceeds 35,000USdollarsperyear

1h ttp ://www.cd c.go v/n cbddd /sicklecel l /d ata.h tml .Accessed November1 0 ,2 0 1 52Bo lano s-Meade Jetal . B lood Reviews.2 0 1 4;2 8:2 43 -8

SCD:Pathophysiology

h ttp ://sgugenetics.pbwo rks.com/w/page/6 1 1 7 2 3 0 4 /P athophysio lo gy%2 0 of%2 0 Sickle%2 0 Cel l%2 0AnemiaAccessed November 1 2 ,2 0 1 5

SCD:ClinicalSequelae

Rees DC etal . Lan cet.2 0 1 0 ;3 76 (9 75 7):2 01 8-3 1.

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SCDMortalityRiskFactorsRisk Factor MSH

n=299CSSCDn=3764

CSSCDn=1056

Episode ofAcute ChestSyndrome (ACS) X X X

≥ 3pain crisis annually X

Hgb F <0.5 g/dL X X

Anemia withlow reticulocyte counts X

Renal Failure X X

Seizure History X

Elevated WBC X

Stroke X

Sickle cell lung disease and retinopathy X

Leg Ulcers XMSH:Mu ltice n te rStudyo fHyd roxyu re a in Sickle Ce ll Anemia,C SSCD:Coope rative StudyofSickle Ce ll Dise ase Hbg F:Fe tal Hemoglob in ,WBC :Wh ite Blood Ce ll

Steinberg MHetal . JAMA. 2 00 3;2 89 (13 ):16 45 -51 .P lattOSetal . NEn gl JMed .1 9 9 4;3 30 (23 ):1 6 39 -44 .P owarsDR etal . Med icin e (Bal timo re).2 0 05 ;84 (6):36 3 -7 6.

SCDManagement

Supportive

ErythropoietinStimulating Agents

Bloodtransfusion

IronChelation

Symptomatic

Analgesics

Bloodtransfusions

Antibiotics

Prevention

Penicillin/Vaccinations

Bloodtransfusions

Hydroxyurea

Rees DC etal . Lan cet.2 0 1 0 ;3 76 (9 75 7):2 01 8-3 1.

TreatmentofAdultSCD

Treatmentchallenges:§ Lack of compliance tolong-term medications§ Overuse and dependence of narcotics§ Loss of productivity§ Psychological symptoms inadulthood

Chakrabarti Setal . B io l B lood MarrowTran sp lan t. 20 04 ;1 0(1 ):23 -31 .

Clinical courseworsens inadulthood

TreatmentChallenges

Mortality sharplyincreases everydecade over 20

years old

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Whatareothertreatmentoptionstoimprove

mortality forAdultSCDpatients?

Hematopoietic CellTransplant

(HCT)

SCDandTransplant:Ahistoricalperspective

As of 2013,there were 1238BMTs forSCT reported toCIBMTR andEBMT-Eurocord

Appelb aum FR . NEn gl JMed ;3 57 :1 4 72 -75C IBMTR:Cen ter fo r In tern ational B lood and MarrowTran sp lan tRegistryEBMT:Eu ropean B lood and MarrowTran sp lan t

SCDandHCTEBMT-Eurocord(1986– 2013)

CIBMTR(1986– 2012)

Transplantations forSCD

Total 611 627

TypeofDonor

HLA-identical 487 430

CordBlood relatedandunrelated

73 71

Haploidentical donor 34 61

Otherunrelateddonor 17 65

Overall Survival

1year 95%± 1% 96%± 2%

2year 94%± 1% 94%± 1%

Gluckman E.ASHedu cation book2 0 13 ;37 0 -3 7 6

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BenefitversusriskinHCTforSCD• Prolonged lifespan• No clinical vaso-occlusive events• Improved quality of life• Cessation of anemia and RBCtransfusions

• Fewer hospitalizations

Benefits

• GVHD• Infertility• Delayed immunereconstitution/infection

• Treatment-related malignancy• Death

Risks

Shenoy S.Hemato lo gyAmSo c Hemato l Edu c P rogram.2 0 1 1 ;2 73-9

ChallengesinSCDpatients• Patient selection and timingof transplant

§ Stilladebate astowhoandwhentransplant shouldoccur

• Limited patient eligibility§ Disease andage-related comorbiditiesresultinhighermorbidityandmortality inolderpatients

• HCT not available tomost patients§ Socioeconomicsetting§ Absence ofmatchedrelated donor

• Serious concerns about transplant-related mortality§ GVHD, infertility, treatment-induced malignancy

Shenoy S.Hemato lo gyAmSo c Hemato l Edu c P rogram.2 0 1 1 ;2 73-9

ChallengesinSCDpatients

• Donoravailability§ 25% probability of being HLA-matched to sibling§ 19% chance of finding potential alleleic 8/8MUD

• Patientperception§ 62%werewillingto accept >10% TRM§ 30%willingtoaccept 30% TRM§ 50%werewillingto accept infertility§ 20%willingtoaccept chronic GVHD

Chakrabarti S.BoneMarrowTran sp lan t2 0 0 7 ;39 :44 7-4 51

TRM : tran sp lan t-related mo rtal i ty

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HCTOptionsforSCD• Majorityof transplantsperformed• PreferredduetolowGVHD/graftfailure• Siblingswithsicklecell traitaresuitabledonors

Matchedsiblingdonor

• RelatedorunrelatedUCBtransplantshavebeenperformed• SlowerneutrophilrecoveryandlessGVHDUmbilical cord

• LimiteddataevaluatingMUD forSCD• SCURT(Sickle cell unrelateddonortransplant) study

Matchedunrelateddonor

• Post-transplantcyclophosphamide• Lowratesof GVHDandgraftfailure

HLA-haploidentical

Shenoy S.Hemato lo gyAmSo c Hemato l Edu c P rogram.2 0 1 1 ;2 73-9

FirstSCDtransplant

• First successfulHCTinan8yeargirlwithSCD1

§ Matched-siblingdonor(MSD) withsicklecelltrait§ Myeloablative conditioningregimen:CY120mg/kgover2daysandTBI11.5Gy

§ GVHD prophylaxis:MTXandmethylprednisolone§ Patient curedofbothAMLandSCD§ Proof-of-principleforfuture platforms tostudyHCTinSCD

• Walters etal2 studyof22patients§ MSD usingBu/CY/ATG§ EFS andOSat4years 91%and73%,respectively§ Graft failure19%

1John son FL.NEn gl JMed 19 8 4;31 1 :7 8 02WaltersMC etal . NEn gl JMed 1 9 9 6;33 5 (6):36 9 -7 6

IndicationsforHCTinPediatricSCD

Age<16yearsold

HLA-identical sibling

• Stroke• ACSw/recurrenthospitalizationsorpreviousexchangetransfusions• Recurrentvaso-occlusivepainorrecurrentpriapism• AbnormalMRIorimpairedneurophysiologicalfunction• Stage IorIIsickle lungdisease• Sickle nephropathy(moderatetosevereproteinuria,GFR30-50%predictedvalue)

• Bilateralproliferativeretinopathy• Osteonecrosisof multiplejoints• Redcell alloimmunizationduringlong-termtransfusiontherapy

SymptomaticSCD(1ormorebelow)

WaltersMC etal . NEn gl JMed .1 99 6 ;3 35 (6 ):3 69 -76 .

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IndicationsforHCTinAdultSCD

Age≥16yearsold

HLA-identical sibling

• Irreversible end-organdamage• Stroke orclinically signif icant CNS event• Elevated TRV ≥2.6m/s• Sickle-related renal insuff iciency(Cr≥1.5times theULN orbiopsyproven)• Sickle hepatopathy( includingironoverload)• Reversible sickle complicationnotameliorated byhydroxyurea• TwoormoreVOCrequiring hospitalizationsforseveral years• AnyACSwhile onhydroxyurea

SymptomaticSCD(1ormorebelow)

Hsieh MM etal . B lood.20 11 ;11 8(5 ):11 97 -12 07.

HCTinpediatricSCD• Publishedresultsareexcellent

§ Fourlargeseriesreportoutcomesofmorethan250children

§ Medianagelessthan10years• Patients

§ DonorswereHLA-identicalsiblings§ High-riskpatientpopulation§ Receivedfullymyeloablativeconditioningregimens

• Outcomes§ Graftrejection7-18%§ OS93-100%§ HCTeliminatesvaso-occlusivesymptomsandreversessomeof theendorgandamage

Watlers MC etal . B io l B loodMarrowTran sp lan t20 15 ;pi i :S1 0 83 -8 79 1

MSDwithMACregimeninPediatricSCDVermylen etal1(n=50)

Walters etal2(n=50)

Bernaudin etal3 (n=185)

Panepinto etal4(n=67)

Dedeken et al5(n=50)

Lucarelli etal6(n=40)

Conditioningregimen Bu/CY± TLI Bu/CYATG oralemtuzumab

Bu/CY± ATG Bu/CY Bu/Cy± ATG Bu/Cy/ATG

GVHDprophylaxis CSA,ATG CSA,MTX CSA± MTX CSA,MTX CSA/MTXCSA/MMF formatchedUBT

CSA, MTX,methylprednisolone

Medianfollow-up(mo) 60 38 72 61 7.7years 5years

EFS 82% 84% 91% 85% 85.6% DFS91%

OS 96% 94% 96% 96% 94.1% 91%

GraftRejection 10% 10% 7% 13% 8% 0%

TRM 7% 6% 6.9% 0% 4% 9%

aGVHD≥II 20% 15% 20% 10% 10%(grade¾) 17.5%(grade¾)

cGVHD 20% 12% 14% 22% 20% 5%

1Vermylen etal , BoneMarrowTran sp lan t.1 9 9 8 ;22 (1):1 -62WaltersWC etal . B lood .20 0 0;9 5(6 ):1 91 8 -2 43Bernaud in etal , B lood 2 00 7 ;1 10 :27 4 9-5 64P anep in to etal , B r JHaemato l 2 0 0 7;1 37 :47 9-8 55Dedeken etal , B r JHaemato lo gy 2 0 1 4 ;1 6 5 (3):40 2 -6Lu carel l i etal , BoneMarrowTran sp lan t2 0 1 4 ;49 :1 3 76 -81

MSD:matched sib l in gdono rMAC :myelo ab lativecond ition in g

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HCTinPediatricSCD• Efficacy

§ Mostcenters usedMACregimens§ Childrentransplanted earlier incourseofSCDhadbetterEFS/OS

§ Inpatientswhoengrafted, resolutionofsicklecellphenotype observed

§ Ameliorationofpainfulvaso-occlusivecrises,ACS,hemolyticanemia, andtransfusiondependence

• Toxicity§ Rejection occurred in7-10%ofpatients§ Incidenceofseizures high(anticonvulsanttherapyinstituted)

K ingAetal . B lood2 01 4;1 23 (20 ):30 89 -94

ClinicalOutcomesofHCT

• Noepisodesofpain,strokeorACS• NoSCDCNScomplications• StabilizationofCNSdiseasebycerebral MRI• Variable reversal ofcerebral vasculopathy• Improvement ofosteonecrosisofhumeral head• Correction ofsplenicreticuloendothelialdysfunctionreported

Patients withstableengraftment experiencedresolutionofSCDcomplications:

Vermylen etal . BoneMarrowTran sp lan t.1 9 9 8 ;22 (1):1 -6WaltersWC etal . B lood .20 0 0;95 (6 ):1 91 8 -2 4 .

Longtermoutcomesinchildren

Neurologic

NostrokeeventsafterBMTinpatientswhohadexperiencedstrokebefore

Riskof seizureshighpresumablyduetoBUconditioningandlackof

anticonvulsantprophylaxisRisk↓withIVandtargeted

dosing

Pulmonary

Stableorimprovedatmedianfollowupof 3.2

years afterHCT

Of11patientswithRLDbaseline, 5improved/6

werepersistent

Of2patientswithobstructivechangesatbaseline, 1improved/1

worsened

Gonadal

Mostmaleshadhypogonadotropichypogonadism

Mostfemaleshadovarian

failure

Multicenter trial of 55children whohad successful engraftment afterMSD during the1990s

Walterset al . B io l B lood MarrowTran sp lan t20 1 0;1 6:26 3 -27 2

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Nonmyeloablative (NMA)RegimensinChildren• Effort toreduce transplant-related toxicity• Iannone etal

§ n=7,medianage 9years§ Fludarabine andTBI200cGy§ 2patientsreceived horse ATG§ GVH prophylaxis:MMF+tacrolimusorCSA

• Results§ ANC<0.5x109 formedian5daysand<0.2x109 for0days§ 1patientgrade IIaGVHD, 6/7patientshaddonorchimerism

§ All6patientshadgraft failure,autologoushematopoieticrecovery, anddiseaserecurrence whenimmunosuppressiontaperedoff

Iannone R etal . B io lB lood MarrowTran sp lan t.20 03 ;9:5 19 -52 8

NMARegimensinChildren

• Increaseingraftfailure attributed topatients beingsensitized tominorhistocompatibility antigens frompriorblood transfusions and tobeingimmunocompetent

• DonorTcellengraftmentwasnotsufficient toestablish stable donorchimerism

• Note:ATGwasnotgiven toall patientsand ISwastaperedoffanytimeb/w~30 to200days

Iannone R etal . B io lB lood MarrowTran sp lan t.20 03 ;9:5 19 -52 8

AlloHCT inAdultSCD

• Fewadultswereinpediatrictrials§ ↓ Survival,↑ acute GVHD

• Contributing Factors:§ End-organ damage§ Transfusions =↑ Risk of graftrejection§ Increased age=↑ Riskfor GVHD

• MACregimensaretootoxicforadultSCDpatients

Vermylen etal , BoneMarrowTran sp lan t.1 9 9 8 ;22 (1):1 -6 .Bernaud in Fetal , B lood .2 00 7;1 10 (7):2 74 9-5 6.

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Selectionofconditioningregimen

Days Days Days

Patient Graft Patient Graft Patient Graft

Myeloablative Reduced-Intensity Nonmyeloablative

WBC

(x1

09/L)

WBC

(x1

09/L)

0 .5 0.5 0.5

Gyu rko cza B etal . B lood 20 14 ;12 4(3 ):34 4-5 3.

MACexperienceinyoungadultSCD• Kuentz et alreport French experience in15patientsolder

than16years ofage whoreceived MSD, medianfollow-up3.4years

• Bu/CY/ATG andGVHprophylaxiswithMTX/CSA

Outcome n=15Complications Cerebralhemorrhage(n=1)

Seizures(n=1)Pericarditis(n=1)Hemorrhagiccystitis(n=1)Subduralhematoma(n=1)Prolongedthrombocytopenia(n=1)

≥ gradeIIaGVHD n=8ModeratecGVHD n=2DFS 93%Chimerismat1year Fulldonor(n=12)

Mixeddonor(n=2)

Kuen tz etal , B lood 2 01 1;1 18 :44 91 -44 92

MACinAdultSCD

• “STRIDE” study: n=17(MSD) andn=5(MUD), medianage 22years• Nograft failure orSCDrecurrence• 1deathduetointracranial hemorrhage (PRES)• 21/22patientswithstableengraftment (median 9.7months)• OSandEFS 95%;2patientswithgradeIaGVHD; 3patientscGVHD

DAY - 8 - 7 - 6 - 5 - 4 - 3

Fludarabine 30mg/m2/dayBusulfan (Bu)13.2mg/kg (total)

Tacrolimus orCyclosporineMethotrexate

K rishnamu rti L, etal . American So cietyo fHemato lo gy (ASH)2 0 1 5 ;Ab str 54 3.

- 2 - 1 0

Bu Bu Bu Bu

Flu FluFlu

Flu Flu

Thymoglobulin 6mg/kg

ATGATG ATG ATG

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Reduced-IntensityConditioning(RIC)inAdultSCD

• 2adultpatientswithend-stage SCDwithHLA-identical siblings• Bothpatients engrafted; however, duetoGVHD complications

diedwithin1year

DAY -5 -4 -3 -2 -1 0

ATG 30mg/kg/dayFludarabine 30mg/m2/day

Melphalan140mg/m2

Stem CellInfusion

TacrolimusMethotrexate onDay 1,3, 6

van Besien etal . BoneMarrowTran sp lan t.2 0 0 0 ;2 6(4 ):4 45 -9 .

FLU FLU FLU FLUMELATG ATG ATG ATG

RICandMUDinAdultSCD

• SCURT trial: n=29; median age 14years; median f/u25.2months• Graft rejection before D+100(n=3, 10%)• 1-year EFS 76%; 1-year OS 86%• Grade II- IV and III- IV aGVHD atD+180 31%and 17%respectively• cGVHD at 1-year was 62%(extensive 38%)• 7deaths (6fromGVHD, 1fromgraft rejection after 2nd transplant)• PRES in 35%of patients; CMV and EBV in23%of patients

DAY - 8 - 7 - 6 - 5 - 4 - 3

Fludarabine 150mg/m2

Melphalan140mg/m2

TacrolimusorCyclosporineMethotrexate7.5mg/m2 D+1,3,6

Methylprednisolone1mg/kg/dD+7toD+28

Shenoy S,etal . American So ciety o fHemato lo gy (ASH)2 0 1 5 ;ab str 7 21 .

- 2 - 1 0

Flu Flu Flu Flu Flu Mel

Alemtuzumab(day-22to-19)

+1 to+28

NMAconditioning

KeyPrinciples

• Stablemixeddonorandrecipientchimerism

• ClassictransplantationregimensusedforhematologicmalignanciestootoxicforSCDadultpatientswhohaveaccumulatedorganfailuresandcomorbiditiesbeforetransplant

• LessTRMandlowratesofacuteandchronicGVHDandgraftfailure

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MixedDonorChimerism

Kean LS,etal . B lood 2 0 03 ;10 2 :4 58 2 -4 5 93

Mixeddonorchimerism

• Use less intense preparative regimens§ Reduced-intensity (RIC)ornonmyeloablative (NMA)§ Completeeradication ofrecipientbonemarrow andGVLnotnecessary

• Red cell compartment replaced with donor red cells§ Donorerythrocytes (HbAA) have survival andmaturationadvantage over recipient erythrocytes (HBSS)

§ Resultsinmajorityofdonor-derived erythropoiesis§ ResolutionofsymptomaticSCDovertime

Bo lano s-Meade,etal . B lood Rev2 0 1 4;28 (6 ):2 43 -8

Alemtuzumabmechanismofaction

• Originally developed for prevention of GVHD andgraftrejection

• Recombinant humanized monoclonal antibody whichbinds toCD52 on the cell surface and triggerscelllysis§ CD8, CD4, NKcells, monocytes- depleted up to 1year

§ B-cells transiently depleted§ Used inconditioning regimens for invivoT celldepletion (replaces ATG)

Haleet al . BoneMarrowTran sp lan t.2 0 02 ;3 0(1 2):7 97 -80 4.Jaglowski et al . B lood .20 10 ;11 6(1 9):3 70 5-1 4.

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Pharmacyconsiderations:Alemtuzumab

• Test dose: 0.03mg/kg IV onD-7; 0.1mg/kg IVD-6; 0.3mg/kg IVD-5 toD-3• Infuse IVPB over 2hours

DOSINGANDADMINISTRATION

• APAP650-1000mgPO, diphenhydramine 50mg PO, hydrocortisone 100mg IVPoncall, epinephrine 0.4 mg SC oncall, meperidine 25-50mgIVP oncall

PRE-MEDICATIONS

• Bloodpressure, heart rate, temperature ( infusionreaction)• CMV PCRforCMV reactivation

MONITORING

• Infusion reactions (fever, chills, hypotension, rigors, etc)• Infection(CMV, HSV,PJP)

ADVERSEREACTIONS

Campath ® P rescrib in g in fo rmation

Sirolimus• Discovered in1975inEasterIsland(RapaNuitonative

islanders)hence itsoriginalname

• Chemicalstructure: carbocycliclactone-lactam macrolideantibiotic

• Pharmacokinetics§ Highlylipophilicdrug,highlyboundtoredbloodcells§ Poorbioavailability(~15%)§ Extensive hepaticmetabolism(CYP3A4)§ Substrate forp-glycoprotein§ Longhalflife(~57-62hours)henceoncedailydosing

IngleGR ,etal . Ann P harmaco ther 2 0 0 0 ;34 (9):1 04 4-5 5

Pharmacyconsiderations:Sirolimus

• Loading: 5mg PO every 4hoursx3doses; Maintenance: 5mg PO daily

DOSINGANDADMINISTRATION

• Target trough8-12ng/dL

THERAPEUTICDRUGMONITORING

• CYP3A4inhibitors ( i.e., voriconazole, diltiazem) and inducers ( i.e, phenytoin,rifampin)

DRUG INTERACTIONS

• Cytopenia• Myalgias/arthralgias• Delayedwound healing• Interstitial pneumonitis• Stomatitis/aphthous-like oralulcers• Hypercholesterolemia/hypertriglyceridemia

ADVERSEREACTIONS

• Proteinuria• Peripheral edema• Hypertension• Acneiformrash

IngleGR ,etal . Ann P harmaco ther 2 0 0 0 ;34 (9):1 04 4-5 5

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Sirolimusmechanismofaction(MOA)• MacrolideantibioticwhichformsacomplexwithFKBP-12thatbinds

toinhibitmammaliantargetofrapamycin (mTOR)• HaltsT-cellproliferationbyinhibitingprogressionfromG1 toSphase

IngleGR ,etal . Ann P harmaco ther 2 0 0 0 ;34 (9):1 04 4-5 5

Sirolimusandmixedchimerism• MixedchimerismMOA

§ SirolimusdoesnotblockT-cellactivation(signal1)butbindstomTOR blockingproliferation(signal2)1

§ Signal1inabsenceofsignal2rendersTcellanergy andpromotesT celltolerance

• Murinemousetransplantationmodels2§ Compared 30daycourseofCSAtosirolimus§ Long-term highlevelchimerismwasattained onlyinsirolimus-treated mice

§ Mixedlymphocyte reactions demonstrated tolerance todonorcells

1Powel l JDetal . J Immuno l 1 9 9 9;1 62 (5):22 7 5-2 78 42P owel l JDetal . Tran sp lan tation 2 0 05 ;80 (11 ):15 41 -15 45

Sirolimusstomatitis• ClinicalPresentation

§ Solitary ormultiplelesionswithrapidonsetafter initiation§ Ovoidshapew/centralgray area surrounded byerythematous halo

§ Canbepainfulanddebilitating

• Villa etalreportedcaseseries§ Mediantime toonset55daysafter allogeneic SCT§ 92.9%ulcersonnon-keratinizedmucosa(mostlyventrolateral tongue)

§ 13patientsreceived topicalsteroids§ Clinicalimprovementinallpatients§ Mediantime toresolutionwas14days

1Vi l la Aetal . B io lB loodMarrowTran sp lan t.2 01 5;2 1(3 ):50 3-8

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NonmyeloablativeConditioninginAdultSCD

• 2adultpatientswithendstageSCDandHLA-identicalsiblings• 1- successfullyengraftedandSCDcomplicationfreeat27monthsout• 1- Rejectedgraft3monthsoutfromtransplant

DAY -5 -4 -3 -2 -1 0

ATG10mg/kg/day withtitration

200cGYofTBI

Stem CellInfusion

CyclosporineMycophenolate Mofetil (MMF)

Ho ran etal . BoneMarrowTran sp lan t.2 0 05 ;3 5(2 ):17 1-7

Fludarabine 25mg/m2/day

-6

Hsiehetal.

Phase 1- 2ProspectiveTrial

Inclusion Criteria:• 16years or older• Hemoglobin SS orSC• HLA identical family member• Severe SCD

Hsieh etal . NEn gl JMed .2 0 09 ;3 61 (2 4):23 09 -17

Severe end-organcomplication-Previous CVA

-SCD nephropathy-Elevated tricuspid

regurgitation- jet velocity

Potential reversiblecomplication

-Frequent VOCcomplications

-ACS-Osteonecrosis

-Red-cellalloimmunization

Endpoints:Primary:- Stem cellengraftmentSecondary:- Avoidance ofGVHD- Adverse Events- Hemoglobin values- Hemolytic variables

88patients didnothavematched

donors

112patients

24patients

10patients Included

ConditioningRegimen

DAY -7 -6 -5 -4 -3 -2 -1 0

Alemtuzumab1mg/kg/total

300cGYTBI

Stem CellInfusion

Sirolimus

RESTDAY

Hsieh etal . NEn gl JMed .2 0 09 ;36 1(2 4):2 30 9-1 7

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GraftOutcomes

• All10patientsalive,1graftrejection• Meanpercentageofdonormyeloidcellswas83.3%

Pt #Time sinceASCT

(months)Duration ofNeutropenia

(days)Duration ofLeucopenia

(months)Hgb(g/dl)

1 54 21 3.5 12

2 36 18 2.5 11.1

3 42 12 6 14.8

4 33 29 6 11.4

5 30 10 4 14.3

6 32 10 6 14.7

7 29 19 8 12.2

8 30 11 1.5 12.1

9 16 15 3.5 11.7

10 15 18 4 10.5

Median 30 15.5 4 12.65

Hsieh etal . NEn gl JMed .2 0 09 ;36 1(2 4):2 30 9-1 7

AdverseEvents

• AcuteorchronicGVHDdidnotoccurinanypatientEvent # of

patientsTimeafter

ASCTOutcome

CMVreactivation 1 14days Treatedwithfoscarnetand resolvedNarcotic withdrawal 3 Varying Hospital admittotapernarcotics

Abdominal Pain 2 3&12months Resolved

Transfusion-associated babesiosis 1 8months ResolvedExercise-related rhabdomyolosis 1 3 months Switched bactrimtopentamidineVentriculartachycardia 1 Previous to

ASCTRatecontrolled

Clostridium difficilecolitis 1 4months ResolvedCholelithiasis- induced acutepancreatitis

1 15months Resolved

Fever 1 1months Resolved

Hsieh etal . NEn gl JMed .2 0 09 ;36 1(2 4):2 30 9-1 7

Hsiehetal,2014• Study

• High riskSCDpatients• NMAregimen (extensionofpreviously reporteddata)

• Outcomes§ n=30§ 29patientssurvived median3.4years,noNRM§ 1patientdiedofintracranial bleedafter relapse§ 87%patientswithlong-term stable donorengraftment§ Mean donorTcelllevel48%andmyeloid86%§ NoaGVHD orcGVHD§ 15patientsdiscontinuedISTsuccessfully§ ↓ annualhospitalizationrate,↓mean weekly narcotic use

Hsieh etal , JAMA2 0 1 4;3 12 (1):4 8-5 6

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Sirolimuscomplications

• 3patientsbeingtreatedforhyperlipidemia

Complication # ofpatients TimeafterASCT OutcomePneumonitis

Patient 3 1 16months Sirolimus switched tocyclosporine

Patient 9 1 4months Reduction ofgoal trough

Arthralgias

Patient 9 1 3months Reduction ofgoal trough andsupportive care

Patient 1 1 4months Reduction ofgoal trough andsupportive care

Hsieh etal . NEn gl JMed 2 0 0 9 ;36 1(2 4):2 30 9-1 7

NMAinadultSCD– UICexperience

DAY -7 -6 -5 -4 -3 -2 -1 0

Alemtuzumab1mg/kg/total

300cGYTBI

Stem CellInfusion

Sirolimus

RESTDAY

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

UICexperience• Conditioning regimen

§ Alemtuzumab/TBI300cGy§ GVHD prophylaxiswithSirolimus§ n=13,age 17-40§ Manypatients hadhighhematopoietic celltransplantation-specificcomorbidityindex(HCT-CI) ≥3

• Outcomes§ 11patientshadsevereneutropenia(ANC<500)formediandurationof6days

§ Medianhospitalization33days§ 1patienthadsecondarygraftfailure(noncompliantwithIST)§ NocasesofaGVHDorcGVHD§ At1year,12/13patientsmaintainedstabledonorchimerism§ 1patienthadsirolimus pulmonarytoxicity§ 4/13patientsdevelopedinfection;3/13hadCMVreactivation

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

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Transientneutropenia

0

1

2

3

4

5

6

7

8

9

10

1 8 15 22 29

Neu

trop

hil C

ount

(x

109 /L

)

Day Post-Transplant

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

Hemoglobinconcentration

0

2

4

6

8

10

12

14

16

18

Pre-HSCT 3 6 9 12

Hemoglobin

(g/dL)

Months Post-HSCT

Female

Male

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

Sirolimusandchimerism

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Hemoglobinfractionation

0

10

20

30

40

50

60

70

80

90

100

Pre-transplant Day+30 Day+60 Day+90 Day+180 1 Year

Hem

oglo

bin

A (%

)

Hb AA Donor

Hb AS Donor

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

PatientQualityofLife(SF-36score)

30.1 31

36.8 37

42.137.6

48.245.5

GENERALHEALTH BODILYPAIN

NormBasedSF-36Score

Pre-HSCT Day+30 Day+90 1Year

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

HCT–specificComorbidityIndex(HCT-CI)HCT-CIscore

• TooldevelopedbySeattleFredHutchinsonCancerResearchCentertocaptureinformationon17differentorgan-specificco-morbidities

• HCT-CI>8associatedwith30%NRM

UICexperience• HCT-CIassessedbaselineinallpatientsatUIC

• AdultSCDpatientshavemanyco-morbiditiesandthisshowsthatthisregimensafeandeffectiveinpatientswithhighHCT-CI

Sorro r etal , B lood 2 00 5;1 06 :29 12 -2 91 9Saraf etal . B io l B loodMarrowTran sp lan t 2 01 5 .p ii :S1 08 3-8 79 1

HCT-CIscoreof UICcohort*Figure courtesyof Damiano Rondelli

andPritesh Patel

LowHCT-CI (n=2)Intermediate HCT-CI (n=1)High HCT-CI (n=10)

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UICexperience• NMAregimenofalemtuzumab and low-doseTBI

§ Normalizeshemoglobinin92%ofpatientswithclinicallyaggressive SCD

§ ReducesSCD-related complications§ Improvescardiopulmonary function§ Improvesqualityoflife

• Sirolimus trough levels§ Lower trough levelsofsirolimus resultedinchimerismlevelsequivalent tothose observed withhigherlevels

§ Lesstoxicity(arthralgias, mucositis,pneumonitis)

• ABO incompatibility§ 2patientswere ABOmismatchedandsuccessfullyengrafted (firstreported)

ALTERNATIVEDONORTRANSPLANTATIONUMBILICALCORD

HLA-HAPLOIDENTICAL

Umbilicalcordbloodtransplant(UCBT)• CBisanalternativesourceofhematopoietic

stemcellsforpatientswithmalignantandnonmalignantdiseases

• HLA-identicalsiblingUCBT§ ↓ aGVHD and cGVHD§ Graft failure in10% of patients1

§ Not studied inadults

• UnrelatedUCBTmuchlesssatisfactory2§ High rateof primary graftfailure and TRM§ DFSonly 50%2

1Locatel l i etal . B lood2 0 1 3 ;12 2 (6):1 07 2 -782Ruggeri etal . B io l B lood MarrowTran sp lan t2 0 1 1 ;17 (9 ):1 3 75 -1 38 2

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BMversuscordinpediatricSCDLocatellietal(n=389)

Locatellietal(n=96)

Stemcellsource BM HLA-siblingCBTConditioningregimen Bu/CY/Flu,or

Bu/Flu/TT±ATGBu/CY,Bu/CY/Flu,Bu/Flu/TT,Bu/Flu,orBu/CY/TT±ATG

GVHDprophylaxis CSA±MTX(76%) CSA ± MTX(30%)

Medianfollow-up(mo)

72 72

EFS 88% 83%OS 95% 97%GraftFailure n=29 (7.4%) n=10(10.4%)TRM n=18 n=3aGVHD ≥II 21% 10%cGVHD 42/355(12%) 6/84(7%)

• Eurocord and EBMT1

• Median f/u70months• Median age 8.1years (BMT) and

5.9(UCBT)• Thalassemia major orSCD• CBT versus BM

• Slower neutrophil recovery(19versus 23days)

• Less aGVHD• No extensive cGVHD• No dif ference inOS (p=0.92)• DFS 92%(BM)and90%(CB)• 21patients died of

transplant-related causes (18BMT and 3CB)

• Related UCBT suitable option forpatients

Lo catel l i etal . B lood 2 0 13 ;12 2(6 ):10 72 -78

RICandUCBTinPediatricAdultSCD

• SCURT trial: n=8; median age 13.7years, median follow-upof 1.8years• Neutrophil recovery @median of 22days; 6of 8patients had platelet recovery

(>50,000/mm3)by day 100• 3patients whoengrafted had 100%donorcells byday 100,5had autologous recovery• 2patients had grade II aGVHD, 1chronicextensive cGVHD (died of respiratory failure)• Conclusion: high incidence of graftfailure; SCURT cordblood arm suspended

DAY - 8 - 7 - 6 - 5 - 4 - 3

Fludarabine 150mg/m2

Melphalan140mg/m2

TacrolimusorCyclosporineMMF

B io l B lood MarrowTran sp lan t20 12 ;18 :12 65 -12 7 2

- 2 - 1 0

Flu Flu Flu Flu Flu Mel

Alemtuzumab(startingD-21)

+1 to+28

HaploidenticalSCT• Rationale

§ HLA-identical matched donors difficult tofind§ MAC prohibited inmost adult patients§ GVTeffect not necessary in non-malignantdiseases

• Post-transplantcyclophosphamide (PT-CY)§ Targets proliferating, allo-reactive Tcells§ Spares hematopoietic stem cells because of highlevelsof aldehyde dehydrogenase

§ Similar GVHDrisk and immune reconstitutioncompared toMSD

Bolano s-Meade.B lood 20 12 ;20 :42 85 -4 29 1

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HLA-haploidenticalSCTinadults

• NMA regimen using Flu/CY/ATG andGVHD prophylaxis withCY andFK /MMF orsirolimus/MMF

• Median followup of 711days, median age 30years• n=14(HLA-haploidentical) and n=3 (HLA-matched sibling donors)• 11patients engrafted; median time toneutrophil and platelet recovery was 24days• 10patients asymptomatic and 6patients off IS• 1patient developed aGVHD (skin, resolved withouttreatment)• No deaths reported

DAY - 9 - 8 - 7 - 6 - 5 - 4

Flu 150mg/m2

CY14.5mg/kgD-6andD-5TBI2GyD-1

- 3 - 2 -1

RabbitATG0.5mg/kgonD-9and2mg/kgonD-8

andD-7

0 +1 +2 +3 +4

ATG ATG ATGFLU FLU FLU FLU FLU FLUCY CY TBI

CY CY

CY50mg/kg/dD+3andD+4FK/sirolimus (1year) andMMF(D+35)

Bo lano s-Meade.B lood 20 12 ;20 :42 85 -4 29 1

Conclusions• SCD patients need tobe completely immunoablated

§ Immunocompetent patients§ Alloimmunization

• Encouraging data in pediatrics usingMAC regimens§ Bu/Cy/ATG§ Longtermcomplications(gonadal,neurologic)

• MAC regimens have not been successful in adults§ HighTRMinadultswhohavemoreadvancedSCD§ NMAregimenssafeandeffectiveinadults§ SmalllevelchimerismamelioratesSCDsymptoms§ Alternativetransplantsbeingexplored(haplo-HCT,UBCT)

OverallSurvivalbyDonorSource

The3-yearOS~90%regardless of thesourceofHSCsGlu ckman E.ASHedu cation book2 0 13 ;37 0 -3 7 6

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Supportivecaresconsiderations

• RBCexchange priortoHCT• Goal HBS < 30%

ALLOSENSITIZATION

• Penicillin VK• Acyclovir• Sulfamethoxazole-trimethoprim orpentamidine forPJPprophylaxis• Fluconazole

INFECTIONPROPHYLAXIS

• Maintain platelet count>50Kand Hemoglobin >9• Avoid use of growthfactoras it has showntoexacerbate SCD crises

PRECAUTIONS/CONTRAINDICATIONS

• These patients are opioid dependent and pain symptoms take time toresolveafter HCT

PAINMANAGEMENT

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

ConclusionGrowing adultSCDpopulation:

↑ morbidity andmortality↑ hospitalizations andhealthcarecosts

Limited treatments for refractoryseveredisease

Addition ofalemtuzumab andsirolimus toAlloHCT processachievesmixedchimerism anddemonstrates asafeandeffectiveoption forAdultSCDwith severedisease

AlloHCT proven successful ineliminating symptomsandcomplications forpediatric SCDpatients, tootoxicforadults SCDpatients

Saraf etal . B io l B loodMarrowTran sp lan t.2 01 5 .p ii : S10 8 3-8 79 1

ARSQuestion#1

Myeloablativeconditioningregimensarepreferredforadultpatientsovernon-myeloablativeconditioningregimensduetodecreasetransplantrelatedmortalityandincreasechimerism.A. TrueB. False

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Case1

PTisa21year-oldfemalewithSCDandisbeingconsideredforHCT.Shehasbeenadmittedseveraltimesforpaincrisisandacutechestsyndrome.Shehasosteonecrosisinherrightkneeandhadastroke1yearago.Sheisonchronicpartialexchangetransfusions.

ARSQuestion#2• Basedonthispatient’s PMH,whatisthe

indication forHCT?A. Multiple pain crisisB. History of strokeC. Osteonecrosis of 1jointD. None of theabove. Thispatient does not have

an indication for HCT

ARSQuestion#3

Themostappropriateconditioning regimenforheris?A. Bu16mg/kg,TBI800cGyB. Bu14mg/kg,FLU180mg/m2,ATGC. Bu12mg/kg,CY200mg/kg,alemtuzumabD. BU6.4mg/kg,FLU180mg/m

2

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ARSQuestion#4MAisa5year-oldmalewithSCD.HehasanHLA-identicalsibling.HisPMHissignificantfor2episodesofACS,4episodesofvaso-occlusivecrises,andrecurrent priapism.BecauseofhisPMH,heisbeingconsideredforHCT.

ARSQuestion#4Whatisthemostappropriateconditioningregimenforthispatient?

A. Bu 16mg/kg, CY 200mg/kgB. TBI 200 cGy, FLU 24mg/m2, Cy500mg/m2

C. BU 6.4mg/kg IV, FLU180mg/m2

D. TBI 200 cGy, FLU 150mg/m2

KarenSweiss, PharmD,BCOPClinical Assistant Professor

Clinical Pharmacist inHematologyandStemCell TransplantDepartmentofPharmacyPractice

Universityof I llinois College ofPharmacyChicago, IL

HEMATOPOIETICSTEMCELLTRANSPLANTFORSICKLECELLDISEASE:PERSPECTIVESFROM

CHILDHOODTOADULTHOOD