Bone marrow transplantation stem cell transplantation
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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)

  • 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

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Sources of Stem Cell

  • Syngeneic

  • Allogeneic

  • Autologous

  • Bone marrow

  • PB

  • Umbilical cord

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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

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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) ?

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Stem Cell Transplantation(Indications in non-malignant diseases)

  • aplastic anemia

  • severe thalalssemia

  • congenital immune deficiency

  • storage disease

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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

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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

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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

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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

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Non-myeloablative transplantion

  • Use non-myeloablative conditioning agents

  • Reduce toxicities

  • Exploit Acute GVHD (graft versus host disease)

  • Disadvantage: graft failure, GVHD

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Complications of SCT

  • rejection, graft failure

  • GVHD (graft-versus-host disease)

  • infection

  • VOD

  • obliterative bronchiolitis

  • sepsis

  • relapse of disease

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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%

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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.

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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

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    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

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    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

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    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