Bone Marrow Transplantation Stem Cell Transplantation - PowerPoint PPT Presentation

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Bone Marrow Transplantation Stem Cell Transplantation

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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


1
Bone Marrow Transplantation (Stem Cell
Transplantation)
  • 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

2
Sources of Stem Cell
  • Syngeneic
  • Allogeneic
  • Autologous
  • Bone marrow
  • PB
  • Umbilical cord

3
Antigen differences between the donor and the
recipient
  • Human leukocyte antigen (serotyping or molecular
    typing)
  • 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

4
Stem Cell Transplantation(Indications in
malignant diseases)
  • acute leukemia
  • high grade lymphoma, Hodgkins disease, sensitive
    relapse
  • chronic myelogenous leukemia
  • multiple myeloma (allogeneic)
  • solid tumor (breast ca, germ cell tumor,
    neuroblastoma) ?

5
Stem Cell Transplantation (Indications in
non-malignant diseases)
  • aplastic anemia
  • severe thalalssemia
  • congenital immune deficiency
  • storage disease

6
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

7
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
    d

8
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

9
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

10
Non-myeloablative transplantion
  • Use non-myeloablative conditioning agents
  • Reduce toxicities
  • Exploit Acute GVHD (graft versus host disease)
  • Disadvantage graft failure, GVHD

11
Complications of SCT
  • rejection, graft failure
  • GVHD (graft-versus-host disease)
  • infection
  • VOD
  • obliterative bronchiolitis
  • sepsis
  • relapse of disease

12
Complications of Cytoreductive Chemotherapy
  • infection
  • bacterial infection 50 of recipients
  • aspergilloisis, candida
  • risk factors Catheter, neutropenia,
    immunosuppressant, mucositis (within 3 wks),
    aspiration
  • cardiomyopathy CTX, anthracycline
  • CNS complications, GB syndrome, neuropathy
    cytarabine
  • hemorrhagic cystitis CTX, IFX
  • tumor lysis syndrome

13
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

14
GVHD (Graft versus Host Disease)
  • Immunologic reaction of donor lymphocytes to
    foreign antigens present on the surface of host
    cells
  • foreign antigens
  • HLA antigens
  • minor antigens not detected by current typing
    techniques

15
Acute GVHD (1) incidence
  • Within the first 3 months after BMT
  • 2050 of HLA-identical, 80 of HLA non-identical
    recipients
  • Mortality 50
  • incidence increases with
  • patient age
  • degree of HLA disparity

16
Acute GVHD (2)manifestations
  • Histology lymphocytic infiltration of the
    epidermis and GI tract
  • fever
  • dermatitis diffuse macular dermatitis, bullas,
    desquamation
  • enteritis cramping abdominal pain, watery to
    bloody diarrhea
  • hepatitis jaundice, cholestasis, hepatocellular
    necrosis
  • infection frequently related to mortality
  • hyperacute GVHD (no prophylaxis) 7 days after
    BMT exfoliative dermatitis, shock, hyperpyrexia

17
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

18
Chronic GVHD (1) incidence
  • develops gt 3 months after BMT
  • 2050 of allografts, usually following acute
    GVHD
  • 2030 develops de novo, without prior acute GVHD

19
Chronic GVHD (2) manifestations like collagen
diseases
  • 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
    bronchiloitis)
  • death usually caused by infection, low mortality
    related to de novo onset less tissue
    involvement.

20
Chronic GVHD (3) immunology
  • minor histocompatibility antigen difference and
    deficient thymic function
  • increase in nonspecific suppressor lymphocyte
    function
  • lack specific suppression of cytotoxic reactivity
    to host alloantigens
  • cytokine mediators propagate autoimmune-like
    tissue injury
  • chronic immunodeficiency, increases opportunistic
    and other fatal infection

21
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

22
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
    antibiotics
  • adequate nutrition TPN. Opiate for cramping pain
    and diarrhea
  • care for bleeding, especially GI bleeding

23
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

24
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

25
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
    VOD
  • Dx by image studies, biopsy, culture

26
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
    thrombocytopenia
  • GVHD treatment of GVHD, management of hepatic
    encephalopathy

27
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

28
Pneumonia (Presentation-1)
  • within 30 days
  • Focal patchy infiltrates bacterial or fungal
    infection
  • Diffuse infiltrates pulmonary edema, ARDS,
    hemorrhage, acute GVHD, often progress to
    respiratory failure

29
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

30
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

31
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
    infection.

32
Pneumonia (diagnostic approach 2)
  • Focal lesion
  • High probability of bacterial or fungal
    infection.
  • Bronchopheumonia ?bronchoscopy BAL, peripheral
    lesions ? percutaneous needle aspiration biopsy,
    open lung biopsy or complete surgical resection

33
Pneumonia (treatment 1)
  • Bacterial
  • high prevalence of coagulase - staphylococcus
  • late (chronic GVHD) pneumococcal, needs PCN or
    bactrim.
  • 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
    weeks.

34
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

35
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
    process
  • management same as managing idiopathic pulmonary
    fibrosis, immunosuppression to control the GVHD

36
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
    infection

37
Sepsis Syndrome
  • bacteremia in 50 marrow recipients
  • G(-), G() coagulase - staphylococci, yeast
    (candida)
  • 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
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