Bone Marrow Transplantation Stem Cell Transplantation - PowerPoint PPT Presentation


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Bone Marrow Transplantation Stem Cell Transplantation


Antigen differences between the donor and the recipient ... hyperacute GVHD (no prophylaxis): 7 days after BMT: exfoliative dermatitis, shock, hyperpyrexia ... – PowerPoint PPT presentation

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Title: Bone Marrow Transplantation Stem Cell Transplantation

Bone Marrow Transplantation (Stem Cell
  • Introduction
  • 1950 first in marrow transplantation
  • 1990, Edward Donnall Thomas Joseph Edward
    Murray, winners of the Nobel prize
  • Allogenic BMT
  • Autologous BMT
  • peripheral blood stem cell transplantation
  • umbilical cord blood transplantation
  • minitransplantation (non-myeloablative)
  • over 200 transplant centers worldwide

Sources of Stem Cell
  • Syngeneic
  • Allogeneic
  • Autologous
  • Bone marrow
  • PB
  • Umbilical cord

Antigen differences between the donor and the
  • Human leukocyte antigen (serotyping or molecular
  • major histocompatibility complex (MHC) several
    closely linked gene loci on 6p
  • Class I A, B, C
  • Class II DR, DRW, DQ, DP
  • other minor antigens HY

Stem Cell Transplantation(Indications in
malignant diseases)
  • acute leukemia
  • high grade lymphoma, Hodgkins disease, sensitive
  • chronic myelogenous leukemia
  • multiple myeloma (allogeneic)
  • solid tumor (breast ca, germ cell tumor,
    neuroblastoma) ?

Stem Cell Transplantation (Indications in
non-malignant diseases)
  • aplastic anemia
  • severe thalalssemia
  • congenital immune deficiency
  • storage disease

Allogeneic Stem Cell Transplantation
  • eradicates of the marrow cells (marrow-ablating
    C/T or R/T)
  • implantation of allogenic stem cells
  • homing of the stem cells to the marrow cavity
  • growth of the stem cells and recovery of the
    blood cells

Preconditioning Regimens
  • Ablate recipients immunity
  • Provide space for engraftment
  • Regimens
  • TBI 175 cGy x 6 d CTX 60 mg/Kg x 2 d mesna 60
    mg/Kg iv 24h x 2 d.
  • Non-myeloablative CTX 60 mg/Kg x 2 d mesna 60
    mg/Kg iv 24h x 2 d fludarabine 25 mg/m2 iv x 5

Doses of Stem Cell Transplantation
  • Allogeneic 1-5 x 108 nucleated cells/Kg
  • Syngeneic 1-5 x 107 nucleated cells/Kg
  • PBSCT 3-4 x 106 CD34 cells/Kg
  • Autologous 1-2 x 106 CD34 cells/Kg
  • 2-4 weeks for recovery, PBSCT more rapid recovery
    of PMN and platelets

Choice of Donors
  • 1st choice syngeneic or matched sibling
  • Partial matched relative, MUD (30-40 available)
    if gt 2 HLA mismatch T-cell depletion
  • UCB (umbilical cord blood) less GVHD but cell
    counts usually too low, high graft failure rate,
    should be considered only if with 1.5-3 x 107
    nucleated cells/Kg

Non-myeloablative transplantion
  • Use non-myeloablative conditioning agents
  • Reduce toxicities
  • Exploit Acute GVHD (graft versus host disease)
  • Disadvantage graft failure, GVHD

Complications of SCT
  • rejection, graft failure
  • GVHD (graft-versus-host disease)
  • infection
  • VOD
  • obliterative bronchiolitis
  • sepsis
  • relapse of disease

Complications of Cytoreductive Chemotherapy
  • infection
  • bacterial infection 50 of recipients
  • aspergilloisis, candida
  • risk factors Catheter, neutropenia,
    immunosuppressant, mucositis (within 3 wks),
  • cardiomyopathy CTX, anthracycline
  • CNS complications, GB syndrome, neuropathy
  • hemorrhagic cystitis CTX, IFX
  • tumor lysis syndrome

Relapse and Rejection
  • Rejection
  • lt 1 in HLA-identical TBI
  • incidence increases in increasing HLA disparity,
    heavily transfused patients
  • Recurrence of primary malignancy
  • early stage leukemia 20
  • advanced leukemia 5070
  • Second transplantation may be successful, but
    mortality high

GVHD (Graft versus Host Disease)
  • Immunologic reaction of donor lymphocytes to
    foreign antigens present on the surface of host
  • foreign antigens
  • HLA antigens
  • minor antigens not detected by current typing

Acute GVHD (1) incidence
  • Within the first 3 months after BMT
  • 2050 of HLA-identical, 80 of HLA non-identical
  • Mortality 50
  • incidence increases with
  • patient age
  • degree of HLA disparity

Acute GVHD (2)manifestations
  • Histology lymphocytic infiltration of the
    epidermis and GI tract
  • fever
  • dermatitis diffuse macular dermatitis, bullas,
  • enteritis cramping abdominal pain, watery to
    bloody diarrhea
  • hepatitis jaundice, cholestasis, hepatocellular
  • infection frequently related to mortality
  • hyperacute GVHD (no prophylaxis) 7 days after
    BMT exfoliative dermatitis, shock, hyperpyrexia

Acute GVHD (3) immunology
  • Effector cells donor cytotoxic T lymphocytes
  • in response to host histocompatibility antigens
  • lymphokines recruit mononuclear cells
  • Donor T lymphocyte removal can lessen GVHD but
    increase graft rejection and recurrent malignancy

Chronic GVHD (1) incidence
  • develops gt 3 months after BMT
  • 2050 of allografts, usually following acute
  • 2030 develops de novo, without prior acute GVHD

Chronic GVHD (2) manifestations like collagen
  • skin pigmentation, sclerosis
  • mucosa lichenoid oral plaque, esophagitis,
    polyserositis, oral and eye sicca syndrome
  • liver elevated ALP and GOT in 90 cases
  • chronic wasting due to anorexia
  • chronic pulmonary disease 1020 (diffuse
    interstitial pnuemonitis and obliterative
  • death usually caused by infection, low mortality
    related to de novo onset less tissue

Chronic GVHD (3) immunology
  • minor histocompatibility antigen difference and
    deficient thymic function
  • increase in nonspecific suppressor lymphocyte
  • lack specific suppression of cytotoxic reactivity
    to host alloantigens
  • cytokine mediators propagate autoimmune-like
    tissue injury
  • chronic immunodeficiency, increases opportunistic
    and other fatal infection

GVHD Prophylaxis
  • Prevention is of paramount importance, no
    prevention ? 100 develop acute GVHD
  • GVHD may lead to fatal hepatic failure, GI
    bleeding, diffuse exfoliative dermatitis,
    increase CMV enteritis, pneumonia, bacterial and
    fungal infection
  • prophylaxis with MTX cyclosporine or
    tacrolimus? acute GVHD decreases to 25

GVHD management
  • Diagnosis needs biopsy of skin, liver or GI tract
  • Treatment is difficult methylprednisolone 2
    mg/Kg/day, ATG, continue MTX cyclosporine,
    anti-T lymphocyte monoclonal antibodies
  • surveillance for infection, prophylactic
  • adequate nutrition TPN. Opiate for cramping pain
    and diarrhea
  • care for bleeding, especially GI bleeding

Hepatic Veno-occusive Disease (1) incidence
  • lt 2 of BMT without TBI
  • 2060 of BMT with C/T and TBI
  • higher rate in older age and prior hepatitis
  • mortality 30, no effective treatment

Hepatic Veno-occusive Disease (2) presentation
  • occurs within 2 weeks of BMT
  • weight gain with peripheral edema
  • increased GOT, GPT, jaundice
  • ascites
  • painful hepatomegaly
  • metabolic encephalopathy and coma
  • hepatorenal syndrome

Hepatic Failure (diagnosis)
  • hepatic VOD, GVHD (majority), drugs toxicity
    (cyclosporine, antibiotics, antimetabolites),
    infections (hepatitis B, C, CMV, HSV, EBV, and
    bacterial, fungal)
  • VOD GOT peaks within 2 weeks
  • GVHD occur after day 20, ALP much higher than in
  • Dx by image studies, biopsy, culture

Hepatic Failure (management)
  • VOD
  • restriction of fluid and Na, judicious use of
    loop diuretics (decrease ascites but avoid
    compromising renal perfusion) blood products
    transfusion, hemodialysis may be needed
  • anticoagulant or thrombolytic therapy risk in
  • GVHD treatment of GVHD, management of hepatic

Pneumonia (Incidence and Pathogenesis)
  • 4060 of recipients
  • infectious pneumonia (50)
  • bacteria
  • fungi (aspergillus, candida )
  • CMV ( 60) 30150 days after BMT
  • HSV, VZV, effectively prevented by acyclovir PCP
    by bactrim
  • noninfectious lung infiltrates
  • pulmonary hemorrhage, edema, ARDS, idiopathic
    interstitial pneumonia, thromboemboli, leukemia

Pneumonia (Presentation-1)
  • within 30 days
  • Focal patchy infiltrates bacterial or fungal
  • Diffuse infiltrates pulmonary edema, ARDS,
    hemorrhage, acute GVHD, often progress to
    respiratory failure

Pneumonia (Presentation-2)
  • beyond 30 days viral pneumonia (CMV), idiopathic
    interstitial pneumonia, PCP, often progress to
    respiratory failure
  • late gt 100 days chronic GVHD, (CMV, VZV, PCP
    less frequent), idiopathic pneumonia due to late
    radiation or cyclophosphamide

Obliterative Bronchiloitis
  • 10 of recipients
  • among long term survival of chronic GVHD
  • manifestations
  • PFT airway obstruction, CXR may be normal
  • insidious progression of DOE, wheezing, often
    progresses to respiratory failure and death.
  • progression rate predicts the outcome,
  • mx control of chronic GVHD

Pneumonia (diagnostic approach 1)
  • Diffuse infiltrate
  • Early 30 days ? empiric broad-spectrum
    antibiotics, diuresis and Na restriction (may
    guided by pulmonary artery wedge measurement)
    correction of bleeding disorder. If deteriorates
    ?bronchoscopy BAL
  • After 30 days bronchoscopy BAL, detection for
    viral, especially CMV, bacterial, fungal, and
    cytologic stains, culture. Thoracotomy is
    reserved for nondiagnostic BAL with high risk of

Pneumonia (diagnostic approach 2)
  • Focal lesion
  • High probability of bacterial or fungal
  • Bronchopheumonia ?bronchoscopy BAL, peripheral
    lesions ? percutaneous needle aspiration biopsy,
    open lung biopsy or complete surgical resection

Pneumonia (treatment 1)
  • Bacterial
  • high prevalence of coagulase - staphylococcus
  • late (chronic GVHD) pneumococcal, needs PCN or
  • Viral CMV pneumonia fatal in gt 85, treated with
    ganciclovir 2.5 mg/Kg q8h for gt2 weeks,
    cytotect 400500 mg/Kg 35 times weekly for 23

Pneumonia (treatment 2)
  • Other herpes viruses ?iv acyclovir 500 mg/m2 q8h
    for gt7 days
  • RSV and parainfluenza ?aerosolized ribavirin
  • Fungal aspergillus, mucor, rhizopus high
    mortality, candida (common) ? iv amphotericin B
    10 mg/Kg/d until resolution. Surgical resection
    of localized lesion.
  • Other infections PCP, legionella, nocardia,
    treatment same as in usual patients

Idiopathic pneumonia
  • Early idiopathic pneumonia
  • no proven treatment
  • biopsy diffuse alveolar damage
  • Late idiopathic interstitial pneumonia
  • pathology mononuclear cells interstitial
    infiltrates, may be immunologically mediated
  • management same as managing idiopathic pulmonary
    fibrosis, immunosuppression to control the GVHD

Infection Control
  • oral bactrim for the 2 weeks prior to BMT, twice
    weekly after PMN engraftment
  • laminar airflow (LAF) environment for neutropenia
    (reduce infection, but reduce mortality only in
    aplastic anemia)
  • oral nonabsorbable antibiotics for GI
    decontamination (eliminate G(), not G(-))
  • LAF decreases incidence of acute GVHD
  • prophylactic acyclovir after BMT suppress HSV

Sepsis Syndrome
  • bacteremia in 50 marrow recipients
  • G(-), G() coagulase - staphylococci, yeast
  • viral infection (CMV) seen in previous infected
    patients who develop acute GVHD. CMV viremia
    high cardiac output, low SVR, sepsis syndrome
  • coexist with acute GVHD
  • empiric antibiotic coverage, modified with
    culture results and endemic infection and
    resistance pattern
  • careful iv volume expansion