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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

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Bone Marrow Transplantation (Stem Cell Transplantation)

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  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, Hodgkin’s 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 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

  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 > 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 • < 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

  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 • 20~50% 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 > 3 months after BMT • 20~50% of allografts, usually following acute GVHD • 20~30% 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: 10~20% (diffuse interstitial pnuemonitis and obliterative bronchiloitis) • death usually caused by infection,lowmortality 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 • < 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

  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 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

  27. 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

  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 > 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 fornondiagnostic 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 > 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.

  34. 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

  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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