3 Hematopoietic Stem Cell Transplantation (HSCT) Bone Marrow Transplantation (BMT) The collection and Transplantation of Hematopoietic Stem Cells :The bone marrowPeripheral bloodUmbilical cord blood
4 The purposes of HSCT1- Replace an abnormal but nonmalignant lymphohematopietic system with one from a normal donor2-Treatmeant malignancy by allowing the administration of higher doses of myelosuppersive therapy than would otherwise be possible
5 Its remarkable regenerative capacity: Features of Hematopoietic Stem Cell make Transplantation clinically feasible including:Its remarkable regenerative capacity:Red cells ,granulocytes, B and T lymphocytes, platelets, kupffer cells of the liver, pulmonary alveolar macrophages, osteoclasts, langerhans cells of the skin, brain microglial cells.Its ability to home to the marrow space following intravenous injection:At least in part, by the interaction of specific cell molecules, termed selectins, on bone marrow endothelial cells with their unique ligands, termed integrins, on early hematopoietic cells.The ability of stem cell to be cryopreseved
6 Categories of Hematopoietic Cell Transplantation Syngenic donor (Identical Twins):~1% (no GVHD ,no contaminated tumor cells)Allogenic Transplantation (GVHD, graft rejection)HLA-identical siblings :1-(0.75)nRelated HLA-mismatched donorsHLA-match unrelated donors:1/10000Autologous Transplantation (no GVHD, no rejection , increased relapse)
7 The Source of Hematopoietic Stem Cells for Transplantation Bone marrow aspirated from the posterior and anterior iliac crests (10-15mL/kg)Peripheral blood stem cellsUmbilical cord blood
8 Transplantation Procedure Transplantation procedure: The transplantation procedure is relatively straightforward. Patients are given high doses of chemotherapy and/or total body irradiation. The marrow is then aspirated from the iliac crests of an HLA-compatible donor and infused IV into the patient. Patients are severely pancytopenic until engraftment, usually within 2 to 3 wk after reinfusion of the marrow
9 The Transplant Preparative Regimens purposes: Eradicated the patient’s underling diseaseImmunosuppress the patient adequately to prevent rejection of transplanted marrowIntensive chemotherapy (Busulfan ,endoxan , melphalan, thiotepa,carmustine,etoposide)TBINonmyeloablative regimens
10 Complication following Hematopoietic Cell Transplantation Early direct chemoiradiotoxicities:nausia , vomiting , mild skin erythema hemorrhagic cystitis ,acute hemorrhagic carditis (rare) , oral mucositis ,hair loss , pancytopenia, venoocclusive disease of the liver(~10%)(tender hepatomegaly ,ascits , jaundice, fluid retention)(Direct cytotoxic injury to hepatic-venular and sinusoidal endothelium ,with subsequent deposition of fibrin and the development of a local hypercoagulable state)Pneumonias (diffuse interstitial Pneumonias)
11 Complication following Hematopoietic Cell Transplantation Late direct chemoiradiotoxicities:Decreased growth velocity in childrenDelayed development of secondary sex characteristicsAzoospermia Ovarian failureThyroid dysfunction (usually well compensated)Cataracts(10-20%)Aseptic necrosis of the femoral head (10%)
12 Graft-Versus-Host-Disease GVHD is the result of allogeneic T-cells that were either transferred with the donor’s stem cell inoculums or develop from it, reacting with antigenic targets on host cells.Acute GVHD developing within the first 3 months post transplantationChronic GVHD developing or persisting beyond 3 months post transplantation
13 Acute GVHD Skin Erythmatous maculopapular rash Persistent anorexia or diarrhea or bothLiver disease, with increased serum levels of bilirubin,SGOT,SGPT,ALKP.***In all these organs, endothelial damage and lymphocytic infiltration are seen .***The incidence of acute GVHD is higher in recipients of stem cells from mismatched (30%)or unrelated donors(60%), in older patients, and in patients unable to receive full doses of drugs used to prevent the disease.
14 Chronic GVHD (20-50% allogeneic transplantation) An autoimmune disorder with :Malar rashSicca syndromeArthritisObliterative BronchiolitiasBile duct degeneration ,Cholestasis
15 Graft FailureMarrow function either does not return or after a brief period of engraftment is lost.In autologous HSCT can be the result ofInadequate numbers of stem cells being transplantedDamage during ex vivo treatment or storageExposure of the patient to myelotoxic agents posttransplantInfections with CMV and human herpes virus type 6In allogeneic HSCT can also be due toImmunologic graft rejection of the graft by immunocopetent host cells.Immunologically based graft rejection is more common following use of less immunosuppressive preparative regiment, in recipients of T-cell-depleted stem cell products, and in patients receiving grafts from mismatched donors.
16 Treatment of graft failure Removing all potentially myelotoxic drugs from the patient’s regimenTreatment with myeloid growth factorRetransplantation
17 Infection in HSCTPosttransplantation patients, particularly recipient of allogeneic transplantation complicated with infections:Bacterial ,gram positive ,Fungi, particularly aspergillus, Viruses, CMV, Pneumcystis carinii pneumpniaThe risk of infection diminishes considerably beyond 3 months after transplantation unless chronic GVHD develops, requiring continuous immunosupperssion
18 Management of the Infection in HSCT ProphylaxisTreatment
19 Treatment of specific disease using HSCT Nonmalignant diseasesImmunodeficiency disorders:(Severe Combined Immunodeficiency , Wiskott-Aldrich syndromeChediak-Higashi syndrome)Aplastic Anemia (All form, PNH, Fanconi’s anemia …..)Hemoglobinopathies (Thalassemias major, Sickle cell Anemia)Congenital disorders of white blood cells (Kostmann’s syndrome, Chronic granulomatus disease, Leukocyte adhesion deficiency, Congenital anemia such as Black-Fan-Diamond anemia ,Malignant Infantile osteopetrosis, Storage disease)Severe acquired autoimmune disorder ( SLE,….)
20 Treatment of specific disease using HSCT Malignant DiseaseAcute leukemia (AML,ALL)Chronic leukemia (CML, CLL)MDSLymphoma (NHL, HL)MyelomaSolid tumors (Breast cancer, testicular cancer, ovarian cancer, small cell lung cancer ,neuroblastoma, pediatric sarcoma ,renal cell Ca)
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