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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
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
DoseDose--response relationshipresponse relationship
Dose of Therapy
Tum
our
Res
pons
e(K
illin
g)
Leth
al D
ose
to B
one
Mar
row
Leth
al D
ose
to O
ther
or
gans
DoseDose--response relationshipresponse relationship
Dose of Therapy
Tum
our
Res
pons
e(K
illin
g)
Leth
al D
ose
to B
one
Mar
row
Leth
al D
ose
to O
ther
or
gans
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
AutologousAutologous SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (10period (10--14 days)14 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment period
AutologousAutologous SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (10period (10--14 days)14 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment period
AutologousAutologous SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (10period (10--14 days)14 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment period
AutologousAutologous SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (10period (10--14 days)14 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment period
AutologousAutologous SCTSCT
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
AutologousAutologous SCTSCT
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))
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
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (0period (0-->21 days)>21 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment period
AllogeneicAllogeneic SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (0period (0-->21 days)>21 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment period
AllogeneicAllogeneic SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (0period (0-->21 days)>21 days)
SC reSC re--infusion (D0)infusion (D0)
PostPost--engraftment periodengraftment periodALLOGRAFTALLOGRAFT
AllogeneicAllogeneic SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (0period (0-->21 days)>21 days)
SC reSC re--infusion (D0)infusion (D0)
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
AllogeneicAllogeneic SCTSCT
Conditioning regimenConditioning regimen
NeutropenicNeutropenic
period (0period (0-->21 days)>21 days)
SC reSC re--infusion (D0)infusion (D0)
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