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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

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bone marrow transplantation stem cell transplantation
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
sources of stem cell
Sources of Stem Cell
  • Syngeneic
  • Allogeneic
  • Autologous
  • Bone marrow
  • PB
  • Umbilical cord
antigen differences between the donor and the recipient
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
stem cell transplantation indications in malignant diseases
Stem Cell Transplantation(Indications in malignant diseases)
  • acute leukemia
  • high grade lymphoma, Hodgkin’s disease, sensitive relapse
  • chronic myelogenous leukemia
  • multiple myeloma (allogeneic)
  • solid tumor (breast ca, germ cell tumor, neuroblastoma) ?
stem cell transplantation indications in non malignant diseases
Stem Cell Transplantation(Indications in non-malignant diseases)
  • aplastic anemia
  • severe thalalssemia
  • congenital immune deficiency
  • storage disease
allogeneic stem cell transplantation
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
Preconditioning Regimens
  • Ablate recipient’s 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
doses of stem cell transplantation
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
Choice of Donors
  • 1st choice: syngeneic or matched sibling
  • Partial matched relative, MUD (30-40% available): if > 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
Non-myeloablative transplantion
  • Use non-myeloablative conditioning agents
  • Reduce toxicities
  • Exploit Acute GVHD (graft versus host disease)
  • Disadvantage: graft failure, GVHD
complications of sct
Complications of SCT
  • rejection, graft failure
  • GVHD (graft-versus-host disease)
  • infection
  • VOD
  • obliterative bronchiolitis
  • sepsis
  • relapse of disease
complications of cytoreductive chemotherapy
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
relapse and rejection
Relapse and Rejection
  • Rejection
    • < 1% in HLA-identical + TBI
    • incidence increases in increasing HLA disparity, heavily transfused patients
  • Recurrence of primary malignancy
    • early stage leukemia: 20%
    • advanced leukemia: 50~70%
    • Second transplantation may be successful, but mortality high
gvhd graft versus host disease
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
acute gvhd 1 incidence
Acute GVHD (1) incidence
  • Within the first 3 months after BMT
  • 20~50% of HLA-identical, 80% of HLA non-identical recipients
  • Mortality: 50%
  • incidence increases with
    • patient age
    • degree of HLA disparity
acute gvhd 2 manifestations
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
acute gvhd 3 immunology
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
Chronic GVHD (1) incidence
  • develops > 3 months after BMT
  • 20~50% of allografts, usually following acute GVHD
  • 20~30% develops de novo, without prior acute GVHD
chronic gvhd 2 manifestations like collagen diseases
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: 10~20% (diffuse interstitial pnuemonitis and obliterative bronchiloitis)
  • death usually caused by infection,lowmortality related to de novo onset & less tissue involvement.
chronic gvhd 3 immunology
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
gvhd prophylaxis
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
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
hepatic veno occusive disease 1 incidence
Hepatic Veno-occusive Disease (1) incidence
  • < 2% of BMT without TBI
  • 20~60% 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
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 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
hepatic failure management
Hepatic Failure (management)
  • VOD:
    • restriction of fluid and Na, judicious use of loop diuretics (decrease ascitesbut 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
pneumonia incidence and pathogenesis
Pneumonia (Incidence and Pathogenesis)
  • 40~60% of recipients
  • infectious pneumonia (50%)
    • bacteria
    • fungi (aspergillus, candida )
    • CMV ( 60%) 30~150 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
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
pneumonia presentation 2
Pneumonia (Presentation-2)
  • beyond 30 days; viral pneumonia (CMV), idiopathic interstitial pneumonia, PCP, often progress to respiratory failure
  • late > 100 days: chronic GVHD, (CMV, VZV, PCP less frequent), idiopathic pneumonia due to late radiation or cyclophosphamide
obliterative bronchiloitis
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
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 fornondiagnostic BAL with high risk of infection.
pneumonia diagnostic approach 2
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
pneumonia treatment 1
Pneumonia (treatment 1)
  • Bacterial:
    • high prevalence of coagulase - staphylococcus
    • late (chronic GVHD): pneumococcal, needs PCN or bactrim.
  • Viral CMV pneumonia: fatal in > 85%, treated with ganciclovir 2.5 mg/Kg q8h for >2 weeks, + cytotect 400~500 mg/Kg 3~5 times weekly for 2~3 weeks.
pneumonia treatment 2
Pneumonia (treatment 2)
    • Other herpes viruses iv acyclovir 500 mg/m2 q8h for >7 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
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
infection control
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
sepsis syndrome
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