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Seyyed Reza Safaee MD www.dr-safaee.blogspot.com.

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2 Seyyed Reza Safaee MD www.dr-safaee.blogspot.com

3 Hematopoietic Stem Cell Transplantation (HSCT) Bone Marrow Transplantation (BMT ) The collection and Transplantation of Hematopoietic Stem Cells : The bone marrow The bone marrow Peripheral blood Peripheral blood Umbilical cord blood Umbilical cord blood

4 The purposes of HSCT 1- Replace an abnormal but nonmalignant lymphohematopietic system with one from a normal donor1- Replace an abnormal but nonmalignant lymphohematopietic system with one from a normal donor 2-Treatmeant malignancy by allowing the administration of higher doses of myelosuppersive therapy than would otherwise be possible2-Treatmeant malignancy by allowing the administration of higher doses of myelosuppersive therapy than would otherwise be possible

5 Features of Hematopoietic Stem Cell make Transplantation clinically feasible including: Its remarkable regenerative capacity: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. 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: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. 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 cryopresevedThe ability of stem cell to be cryopreseved

6 Categories of Hematopoietic Cell Transplantation Syngenic donor (Identical Twins):~1% (no GVHD,no contaminated tumor cells)Syngenic donor (Identical Twins):~1% (no GVHD,no contaminated tumor cells) Allogenic Transplantation (GVHD, graft rejection)Allogenic Transplantation (GVHD, graft rejection) HLA-identical siblings : 1-(0.75) n HLA-identical siblings : 1-(0.75) n Related HLA-mismatched donors Related HLA-mismatched donors HLA-match unrelated donors:1/10000 HLA-match unrelated donors:1/10000 Autologous Transplantation (no GVHD, no rejection, increased relapse)Autologous 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)Bone marrow aspirated from the posterior and anterior iliac crests (10-15mL/kg) Peripheral blood stem cellsPeripheral blood stem cells Umbilical cord bloodUmbilical cord blood

8 Transplantation Procedure

9 The Transplant Preparative Regimens purposes: Eradicated the patient’s underling diseaseEradicated the patient’s underling disease Immunosuppress the patient adequately to prevent rejection of transplanted marrowImmunosuppress the patient adequately to prevent rejection of transplanted marrow Intensive chemotherapy (Busulfan,endoxan, melphalan, thiotepa,carmustine,etoposide)Intensive chemotherapy (Busulfan,endoxan, melphalan, thiotepa,carmustine,etoposide) TBITBI Nonmyeloablative regimensNonmyeloablative regimens

10 Complication following Hematopoietic Cell Transplantation Early direct chemoiradiotoxicities: 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%) 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) (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) (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) Pneumonias (diffuse interstitial Pneumonias)

11 Complication following Hematopoietic Cell Transplantation Late direct chemoiradiotoxicities: Late direct chemoiradiotoxicities: Decreased growth velocity in children Decreased growth velocity in children Delayed development of secondary sex characteristicsDelayed development of secondary sex characteristics Azoospermia Ovarian failureAzoospermia Ovarian failure Thyroid dysfunction (usually well compensated)Thyroid dysfunction (usually well compensated) Cataracts(10-20%)Cataracts(10-20%) Aseptic necrosis of the femoral head (10%)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. 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 transplantationAcute GVHD developing within the first 3 months post transplantation Chronic GVHD developing or persisting beyond 3 months post transplantationChronic GVHD developing or persisting beyond 3 months post transplantation

13 Acute GVHD Skin Erythmatous maculopapular rashSkin Erythmatous maculopapular rash Persistent anorexia or diarrhea or bothPersistent anorexia or diarrhea or both Liver disease, with increased serum levels of bilirubin,SGOT,SGPT,ALKP.Liver 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 : An autoimmune disorder with : Malar rashMalar rash Sicca syndromeSicca syndrome ArthritisArthritis Obliterative BronchiolitiasObliterative Bronchiolitias Bile duct degeneration,CholestasisBile duct degeneration,Cholestasis

15 Graft Failure Marrow function either does not return or after a brief period of engraftment is lost. Marrow function either does not return or after a brief period of engraftment is lost. In autologous HSCT can be the result of Inadequate numbers of stem cells being transplanted Inadequate numbers of stem cells being transplanted Damage during ex vivo treatment or storage Damage during ex vivo treatment or storage Exposure of the patient to myelotoxic agents posttransplant Exposure of the patient to myelotoxic agents posttransplant Infections with CMV and human herpes virus type 6 Infections with CMV and human herpes virus type 6 In allogeneic HSCT can also be due to Immunologic graft rejection of the graft by immunocopetent host cells. Immunologic graft rejection of the graft by immunocopetent host cells. I mmunologically 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. I mmunologically 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 regimenRemoving all potentially myelotoxic drugs from the patient’s regimen Treatment with myeloid growth factorTreatment with myeloid growth factor RetransplantationRetransplantation

17 Infection in HSCT Posttransplantation patients, particularly recipient of allogeneic transplantation complicated with infections:Bacterial,gram positive,Fungi, particularly aspergillus, Viruses, CMV, Pneumcystis carinii pneumpniaPosttransplantation patients, particularly recipient of allogeneic transplantation complicated with infections:Bacterial,gram positive,Fungi, particularly aspergillus, Viruses, CMV, Pneumcystis carinii pneumpnia The risk of infection diminishes considerably beyond 3 months after transplantation unless chronic GVHD develops, requiring continuous immunosupperssionThe risk of infection diminishes considerably beyond 3 months after transplantation unless chronic GVHD develops, requiring continuous immunosupperssion

18 Management of the Infection in HSCT ProphylaxisProphylaxis TreatmentTreatment

19 Treatment of specific disease using HSCT Nonmalignant diseases Nonmalignant diseases Immunodeficiency disorders: Immunodeficiency disorders: ( Severe Combined Immunodeficiency, Wiskott-Aldrich syndrome ( Severe Combined Immunodeficiency, Wiskott-Aldrich syndrome Chediak-Higashi syndrome) Chediak-Higashi syndrome) Aplastic Anemia (All form, PNH, Fanconi’s anemia …..) Aplastic Anemia (All form, PNH, Fanconi’s anemia …..) Hemoglobinopathies (Thalassemias major, Sickle cell 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) 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,….) Severe acquired autoimmune disorder ( SLE,….)

20 Treatment of specific disease using HSCT Malignant Disease Malignant Disease Acute leukemia (AML,ALL)Acute leukemia (AML,ALL) Chronic leukemia (CML, CLL)Chronic leukemia (CML, CLL) MDSMDS Lymphoma (NHL, HL)Lymphoma (NHL, HL) MyelomaMyeloma Solid tumors (Breast cancer, testicular cancer, ovarian cancer, small cell lung cancer,neuroblastoma, pediatric sarcoma,renal cell Ca)Solid tumors (Breast cancer, testicular cancer, ovarian cancer, small cell lung cancer,neuroblastoma, pediatric sarcoma,renal cell Ca)


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