bone marrow transplantation - queensland health · indications and complications of bone marrow...

Indications and Indications and Complications of Bone Complications of Bone Marrow Transplantation Marrow Transplantation

(BMT)(BMT)Dr Glen KennedyDr Glen Kennedy

Department of HaematologyDepartment of HaematologyRBWHRBWH

Perspective is important…….Perspective is important…….

My perspective……..My perspective……..

Clinical BMT specialist at Clinical BMT specialist at RBWH RBWH Moderately large BMT unitModerately large BMT unitPerform ~120 SCT / yrPerform ~120 SCT / yr

RBWH BMT UnitRBWH BMT Unit120 transplants per year120 transplants per year

2/3 2/3 alloallo 1/3 auto1/3 auto

60% Acute Leukaemia60% Acute Leukaemia 37% NHL37% NHL16% NHL 16% NHL 37% Myeloma37% Myeloma8% MDS8% MDS 14% Hodgkin’s lymphoma14% Hodgkin’s lymphoma

7% Chronic Leukaemia 7% Chronic Leukaemia 12% Solid 12% Solid TumorsTumors5% Myeloma5% Myeloma

5% other (SAA, Hodgkin’s)5% other (SAA, Hodgkin’s)

AgendaAgendaTypes of haematopoietic progenitor (stem) cell Types of haematopoietic progenitor (stem) cell transplantstransplants

Autologous Autologous Allogeneic Allogeneic

Complications of transplantationComplications of transplantationAutologusAutologusAllogeneicAllogeneic

DiseaseDisease--specific indications for SCTspecific indications for SCTAcute leukaemia: AML / ALLAcute leukaemia: AML / ALLMDSMDSChronic leukaemia: CML, CLLChronic leukaemia: CML, CLLNHLNHLHodgkinsHodgkinsMyeloma / amyloidosisMyeloma / amyloidosis

AutologousAutologous SCTSCT

ReRe--infuse preinfuse pre--stored recipient stem cells stored recipient stem cells to support high dose chemo / radiotherapy to support high dose chemo / radiotherapy Requires prior collection and Requires prior collection and cryopreservation of cryopreservation of autologousautologous stem cells stem cells

Autologous SCTAutologous SCT

Traditionally, bone marrow used as stem cell Traditionally, bone marrow used as stem cell sourcesource

Small number of stem cellsSmall number of stem cellsHarvesting relatively painfulHarvesting relatively painful

Now almost exclusively use peripheral blood Now almost exclusively use peripheral blood progenitor cells (PBPC)progenitor cells (PBPC)

“Mobilised” from bone marrow using G“Mobilised” from bone marrow using G--CSF +/CSF +/--chemotherapychemotherapyCollected using cell separator / Collected using cell separator / apheresisapheresis

ApheresisApheresis ProcedureProcedure

DoseDose--response relationshipresponse relationship

Dose of Therapy

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Common conditioning (preparative) Common conditioning (preparative) regimensregimens

RadiationRadiation--basedbasedCy / TBICy / TBI

Many series associated TBI with increase risk 2Many series associated TBI with increase risk 2ndnd MDS / AMLMDS / AML

ChemotherapyChemotherapy--basedbasedBEAM (BCNU / BEAM (BCNU / etoposideetoposide / cytarabine / melphalan)/ cytarabine / melphalan)

+/+/-- rituximabrituximab (anti(anti--CD20 CD20 mAbmAb))LymphomaLymphoma

BuMelTBuMelT ((busulphanbusulphan / melphalan / thiotepa)/ melphalan / thiotepa)LymphomaLymphoma

HDM (melphalan) HDM (melphalan) MyelomaMyeloma

ICE (ICE (ifosfamideifosfamide / / carboplatincarboplatin / / etoposideetoposide) ) Germ cell Germ cell tumorstumors


Conditioning regimenConditioning regimen

NeutropenicNeutropenic

period (10period (10--14 days)14 days)

SC reSC re--infusion (D0)infusion (D0)

PostPost--engraftment periodengraftment period

Conditioning / Conditioning / neutropenicneutropenic

11--3mths3mths

>3mths>3mths

ConditioningConditioning--related toxicityrelated toxicityMucositis AnorexiaMucositis Anorexia

VODVODFatigue Fatigue

Bacterial Bacterial enteric GN / line relatedenteric GN / line related

Fungal PCPFungal PCP

ViralViralHSV VZVHSV VZV

InfertilityInfertility22ndnd

malignancymalignancy

22ndnd

MDS / AMLMDS / AML

solid organ cancersolid organ cancer

Limitation of AutoSCT’sLimitation of AutoSCT’sDoes not overcome other (nonDoes not overcome other (non--bone marrow) toxicitiesbone marrow) toxicities

AlopeciaAlopeciaMucosal toxicity e.g. oropharynx, gutMucosal toxicity e.g. oropharynx, gutLiver (VOD)Liver (VOD)

Moderate risk of mortality ~5%Moderate risk of mortality ~5%Cannot cure tumours not otherwise cured by Cannot cure tumours not otherwise cured by chemotherapy chemotherapy

MyelomaMyelomaIndolent lymphomas, CLLIndolent lymphomas, CLL

Risk of tumorRisk of tumor--contamination of contamination of autologousautologous stem cell stem cell product (at collection / mobilization)product (at collection / mobilization)

Contribute to later relapseContribute to later relapse


PostPost--engraftment issuesengraftment issuesImmune reconstitution Immune reconstitution

Infection Infection

Endocrine issuesEndocrine issuesInfertilityInfertility

Women invariably ovarian failureWomen invariably ovarian failureMen impaired spermatogenesis (raised FSH / Men impaired spermatogenesis (raised FSH / SertoliSertoli cell cell damage) but testosterone deficiency relatively uncommondamage) but testosterone deficiency relatively uncommon

2nd malignancies2nd malignancies22ndnd MDS / AMLMDS / AMLSolid tumors Solid tumors

Autologous SCT Autologous SCT –– immune reconstitutionimmune reconstitution

Traditionally: Traditionally: Ig levels recover after 2Ig levels recover after 2--3mths3mthsCD4+ TCD4+ T--cell numbers recover 3cell numbers recover 3--9mths9mths

Addition of monoclonal antibodies (Addition of monoclonal antibodies (rituximabrituximab) ) Depletion of CD27+ memory BDepletion of CD27+ memory B--cellscellsAcquired CVIDAcquired CVID--type phenotypetype phenotypeAssociated Associated

Abnormal BAbnormal B--cell repertoirescell repertoiresProlonged Prolonged hypogammaglobulinaemiahypogammaglobulinaemia 3030--40% up to 140% up to 1--2yrs 2yrs

BJH 2007; 137; 349; EJH 2006; 77: 226; BMT 2006; 38: 433BJH 2007; 137; 349; EJH 2006; 77: 226; BMT 2006; 38: 433

Autologous SCT Autologous SCT –– infectioninfection

Main infection risk in medium term VZV Main infection risk in medium term VZV reactivationreactivation

2020--40% reactivate in 140% reactivate in 1stst 12mths12mthsProlonged prophylaxis only delays onset Prolonged prophylaxis only delays onset (doesn’t prevent)(doesn’t prevent)

Autologous SCT Autologous SCT -- vaccinationsvaccinationsStart vaccinations at 12mthsStart vaccinations at 12mths

Inactivated polio vaccine (Inactivated polio vaccine (eIPVeIPV) ) Adult tetanus/diphtheria toxoid (ADT) Adult tetanus/diphtheria toxoid (ADT) Hepatitis B vaccinationHepatitis B vaccinationPneumoccocalPneumoccocal vaccine vaccine HaemophilusHaemophilus Influenza Type B VaccineInfluenza Type B Vaccine

2 years post transplant2 years post transplantMeasles, mumps, rubella (MMR Measles, mumps, rubella (MMR -- live attenuated vaccine)live attenuated vaccine)

Annually every AprilAnnually every AprilInfluenza vaccineInfluenza vaccine

Vaccinations Vaccinations NOTNOT recommended and / or recommended and / or contraindicatedcontraindicatedMeningococcal vaccine Meningococcal vaccine -- only consider if risk of meningococcal disease only consider if risk of meningococcal disease felt to be significantly increasedfelt to be significantly increasedPertussis vaccine Pertussis vaccine –– not recommendednot recommendedBCG vaccination BCG vaccination -- contraindicated contraindicated

Autologous SCT Autologous SCT –– 22ndnd malignancymalignancy

22ndnd MDS / AML MDS / AML Actuarial risk 2Actuarial risk 2--20% at 220% at 2--10yrs10yrsRisk factors include:Risk factors include:

No prior therapies No prior therapies Age >35Age >35--40yrs 40yrs PBPC grafts (PBPC grafts (espesp if collected off if collected off etoposideetoposide) ) TBITBI--based conditioningbased conditioning

FBC performed at least annuallyFBC performed at least annually

Autologous SCT Autologous SCT –– 22ndnd malignancymalignancy

Solid Solid tumorstumorsIncreased risk 2Increased risk 2--5x 5x Especially breast, lung (smokers) skin and prostateEspecially breast, lung (smokers) skin and prostate

Stop smoking and avoid sunburn Stop smoking and avoid sunburn Annual Annual

Physical exam (including breast exam)Physical exam (including breast exam)Dermatology reviewDermatology reviewPap smears + mammograms (age >40) (women)Pap smears + mammograms (age >40) (women)PSA testing (menPSA testing (men))

Allogeneic SCTAllogeneic SCT

Rationale 1 Rationale 1

Allogeneic stem cell source Allogeneic stem cell source Stem cells (graft) comes from someone else Stem cells (graft) comes from someone else (healthy donor)(healthy donor)

Matched family (sibling)Matched family (sibling)Volunteer unrelated donor (VUD)Volunteer unrelated donor (VUD)Umbilical cord unit (“cord”)Umbilical cord unit (“cord”)

TumorTumor--freefree

Rationale 2Rationale 2

Stem cells (graft) comes from someone Stem cells (graft) comes from someone else (healthy donor)else (healthy donor)

New immune systemNew immune systemImmunotherapy platform to induce pImmunotherapy platform to induce potentialotentialgraft versus malignancy (GVM) effect graft versus malignancy (GVM) effect

Side effect new immune system attacks whole host Side effect new immune system attacks whole host (not just underlying malignancy)(not just underlying malignancy)Graft Graft vsvs host disease (GVHD)host disease (GVHD)

GVM effect GVM effect

Different malignancies varying Different malignancies varying responsiveness to GVM effect responsiveness to GVM effect

FL / CML AML / ALL MM / DLCL / Hodgkin’sFL / CML AML / ALL MM / DLCL / Hodgkin’s

AllogeneicAllogeneic SCTSCTSubSub--classifyclassify

Donor sourceDonor sourceMatched sibling Matched sibling vsvs VUD VUD vsvs haploidenticalhaploidentical vsvs cordcord

Source of stem cellsSource of stem cellsBM BM vsvs primed BM primed BM vsvs PBPC PBPC vsvs cordcord

Graft manipulationGraft manipulationTT--replete replete vsvs TT--depleteddepleted

Conditioning regimenConditioning regimenMyeloablativeMyeloablative vsvs reduced intensity conditioning (RIC)reduced intensity conditioning (RIC)

Complications can varyComplications can vary

AllogeneicAllogeneic SCTSCT



period (0period (0-->21 days)>21 days)


PostPost--engraftment periodengraftment period






PostPost--engraftment periodengraftment periodALLOGRAFTALLOGRAFT






PostPost--engraftment periodengraftment periodALLOGRAFTALLOGRAFT

Immunosuppressive therapy Immunosuppressive therapy Recipient rejecting graftRecipient rejecting graft

Graft rejecting recipient (graft Graft rejecting recipient (graft vsvs

host disease)host disease)Delayed immune reconstitutionDelayed immune reconstitution

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