2. Hematopoietic Cell Transplantation

3. Definition Hematopoietic cell transplantation (HCT) is a potentially curative treatment for malignant and nonmalignant diseases, including leukemia, lymphoma, multiple myeloma, aplastic anemia, hemoglobinopathies, and congenital immune deficiencies. 2 Dr.yekehfallah.-phd of nursing - 20159/30/2016

4. History of Bone Marrow Transplantation First successful human bone marrow transplantation procedure (1968). 3 Dr.yekehfallah.-phd of nursing - 20159/30/2016

5. Stem cells Stem cells are ‘ generic ’ cells that develop into particular types of cells. So they may become nerve cells, muscle cells, blood cells … in fact, any cell in the body! Stem cells divide over and over to produce new cells. 49/30/2016 Dr.yekehfallah.-phd of nursing - 2015

6. Stem cells, bone marrow and blood cells One of the main places you find stem cells is in bone marrow. Stem cells in bone marrow produce new blood cells to replace those that have died. When the cells are mature they are released into the bloodstream. A ‘bone marrow’ donation is really a donation of stem cells. Bone marrow is found in the cavities inside the long and flat bones of the body. 5 Dr.yekehfallah.-phd of nursing - 20159/30/2016

7. Types of stem cells: Pluripotent Multipotent Committed progenitor cells Multipotent blood cells: Common lymphoid Common myeloid Committed stem cell makes specific blood cells (CFU) – stimulated by erythropoietin, thrombopoietin, granulocyte-mononcyte CSF 6 6 Dr.yekehfallah.-phd of nursing - 20159/30/2016

8. 7 Leukocytes White blood cells Defend body through: the inflammatory process phagocytosis removal of cell debris immune reactions 7 Dr.yekehfallah.-phd of nursing - 20159/30/2016

9. 8 White Blood Cell Types: Granulocytes and Agranulocytes Granulocytes – visible granules in the cytoplasm. Granules contain: Enzymes Other biochemicals that serve as signals and mediators of the inflammatory response 8 Dr.yekehfallah.-phd of nursing - 20159/30/2016

10. 9 Granulocyte cell types: Neutrophils – phagocytes Eosinophils – red granules, associated with allergic response and parasitic worms Basophils – deep blue granules - Release heparin, histamine and serotonin 9 Dr.yekehfallah.-phd of nursing - 20159/30/2016

11. 10 Agranulocytes Granules too small to be visible Monocytes – become macrophages Lymphocytes – B cells and T cells = immune functions 10 Dr.yekehfallah.-phd of nursing - 20159/30/2016

12. WBC ’ s originate in red bone marrow from stem cells. Granulocytes mature in the marrow and have a lifespan of hours to days Agranulocytes finish maturing in blood, or in other locations. Monocytes live about 2 - 3 months, lymphocytes for years. 11 Dr.yekehfallah.-phd of nursing - 20159/30/2016

13. 12 Production of WBC ’ s increases in response to : Infection Presence of steroids Decreased reserve of leukocyte pool in bone marrow 12 Dr.yekehfallah.-phd of nursing - 20159/30/2016

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16. Diseases Treated with Bone Marrow Transplantation Acute leukemia (ALL, AML) Chronic myelogenous leukemia Aplastic Anemia Myeloproliferative Disorders Multiple Myeloma Non-Hodgkin ’ s lymphoma Hodgkin ’ s Disease Chronic lymphocytic leukemia Genetic Disorders (Thalassemia, others) Solid tumors (RCC, neuroblastoma, germ cell tumors) Congenital immunodeficiency diseases Lymphomas Metabolic disease of childhood Myelodisplasia 15 Dr.yekehfallah.-phd of nursing - 20159/30/2016

17. Stem cell ( “ bone marrow ” ) donation There are three ways to collect stem cells from a donor: Bone marrow A donor has a small operation under general anesthetic. Marrow is harvested from the iliac crest under general anesthesia Circulating blood A donor ’ s circulating stem cells are boosted with a special drug. Then they are connected to a cell separator machine, which collects the stem cells and returns the rest of the blood to the donor. Growth factors are frequently used alone (e.g., granulocyte colony-stimulating factor, or G-CSF) or in combination with chemotherapy (in autologous HCT) for mobilization  of hematopoietic stem cells, which are collected by blood leukapheresis. Mobilizedâ € blood cells engraft faster than marrow-derived cells. Cord blood Selected hospitals offer new mothers the chance to donate the blood that remains in the placenta and umbilical cord after their baby ’ s birth. Collected from the umbilical cord after delivery of a baby. Engraftment takes longer compared with other sources of stem cells. 16 Dr.yekehfallah.-phd of nursing - 20159/30/2016

18. Advantages / disadvantages for patients Advantages: Cord blood: hasn ’ t been exposed to environment so less likely to contain viral infection; requires less stringent matching; once collected is banked and can be readily available at short notice. Bone marrow and circulating blood: tend to have a greater number of stem cells in the donation, so tend to be accepted into the patient ’ s body more quickly. Disadvantages Cord blood: tends to have less stem cells in the donation. Bone marrow and circulating blood: finding a match and arranging a donation can take weeks, or months (this is time the patient may not have). 17 Dr.yekehfallah.-phd of nursing - 20159/30/2016

19. SOURCE OF STEM CELLS Bone Marrow “ Mobilized ” peripheral blood stem cells Umbilical cord blood Cryopreserved Fresh 18 Dr.yekehfallah.-phd of nursing - 20159/30/2016

20. Potential Donors Self HLA-matched sibling HLA-mismatched sibling Matched unrelated Cord blood 19 Dr.yekehfallah.-phd of nursing - 20159/30/2016

21. Donor Limitations 25 – 30% of patients have an HLA-identical sibling. Marrow procured from unrelated living donor Marrow procured from related HLA- identical or HLA non – identical living donor Autologous transolantation(marroe procured during remession) 20 Dr.yekehfallah.-phd of nursing - 20159/30/2016

22. Stages of Allogeneic Transplantation PreparationTransplantationRecovery Immune suppression Disease treatment IV Infusion GVHD Prevention Infection control Nutrition Hematopoietic recovery 21 Dr.yekehfallah.-phd of nursing - 20159/30/2016

23. RATIONALE FOR BMT High dose chemotherapy (dose - response curve) Allogeneic effect (graft-versus- tumour effect) Replacement of abnormal stem cells (aplastic anaemia, thalassaemia, sickle cell disease, gene therapy etc) Immunological effect (autoimmune disease, solid organ transplants) 229/30/2016 Dr.yekehfallah.-phd of nursing - 2015

24. RISKS OF BONE MARROW TRANSPLANT Short term (TRM)  Sepsis,AGVHD, multi-organ failure or toxic death Longer term  Chronic graft-versus-host disease (lung,liver, skin)  Relapse  Infection  Endocrine 23 Dr.yekehfallah.-phd of nursing - 20159/30/2016

25. Factors influencing survival Disease factors Remission, relapse, refractory Transplant related mortality Donor factors Age, sex, conditioning Recipient factors Age, CMV status, performance status Risk of graft-versus-host disease Donor factors PBSC, matching, age, parity Recipient factors Age 24 Dr.yekehfallah.-phd of nursing - 20159/30/2016

26. GENERAL PRINCIPLES Epidemiology. Current estimates of annual numbers of HCT are 45,000 to 50,000 worldwide. Approximately two thirds of patients have autologous HCT and one third have allogeneic HCT 25 Dr.yekehfallah.-phd of nursing - 20159/30/2016

27. Risk factors The likelihood of developing transplant-related complications depends on: 1/patient age 2/intensity of the preparative regimen 3/type and stage of the underlying disease 4/presence of comorbidities. 5/allogeneic HCT recipients have a greater risk of transplant-related morbidity and mortality than autologous HCT recipients 6/HLA disparity between donor and recipient further increases the risk owing to the greater likelihood of developing GVHD and graft rejection 26 Dr.yekehfallah.-phd of nursing - 20159/30/2016

28. Prognosis Prognosis after HCT is highly variable and is influenced by numerous factors that predict for mortality related to the transplant procedure itself and to recurrent malignancy after surviving the transplant: - Patients with chronic myelogenous leukemia (CML) in chronic phase who have HCT from an HLA-identical sibling, for example, have a greater than 80% to 90% chance of long-term survival -In contrast, less than 50% of patients with more advanced leukemia at the time of HCT will be cured 27 Dr.yekehfallah.-phd of nursing - 20159/30/2016

29. Transplantation Procedure 28 Dr.yekehfallah.-phd of nursing - 20159/30/2016

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31. Anesthesic Management Intravenouse anesthesia sould be procured. Intravenouse, Thiopental, Fentanyl,Vecuronium can be used in common doses Maintanance can be provide with Propofol and Isoflurane. 30 Dr.yekehfallah.-phd of nursing - 20159/30/2016

32. Step 1: Bone marrow transplant with less toxic recipient treatment that includes antibodies.Donor marrow is T cell depleted Wait 1-2 months. Inflammation from preparative treatment subsides. Blood cells are a mixture of donor and host: Mixed chimerism is achieved without GVHR Step 2: Infuse donor T cells. Donor T cells interact with “presenting cells” of mixed chimera to maximize GVHR Tumor is killed Donor T cells are armed to kill tumor cells that express recipient antigens. They stay inside the blood and lymph, where tumor is. T cells don’t go to skin/gut/liver. There is no GVHD. 319/30/2016 Dr.yekehfallah.-phd of nursing - 2015

33. TRANSPLANT RELATED COMPLICATIONS 32 Dr.yekehfallah.-phd of nursing - 20159/30/2016

34. The problems after HCT that typically cause procedure-related morbidity and mortality can broadly be categorized into five groups: *hemolysis, ** toxicity of the preparative regimen, ***infection, **** bleeding, ***** GVHD 33 Dr.yekehfallah.-phd of nursing - 20159/30/2016

35. Hemolysis General principles. The inheritance of blood group antigens (e.g., ABO, Rh) is independent of that of the HLA antigens. 34 Dr.yekehfallah.-phd of nursing - 20159/30/2016

36. Hemolysis Etiology/pathophysiology: 1/ Acute (at the time of infusion) or delayed (5 to 15 days after HCT) immunohemolytic complications due to ABO incompatibility occur in patients with minor ABO-incompatibility. 2/ Immediate hemolysis occurs if the graft contains preexisting isohemagglutinins that lyse recipient RBCs. 35 Dr.yekehfallah.-phd of nursing - 20159/30/2016

37. Hemolysis Etiology/pathophysiology: 3/ Delayed hemolysis is due to generation of new  isohemagglutinins by passenger lymphocytes  in the graft. 4/Delayed hemolysis due to minor ABO incompatibility is a rare complication but can be dramatic and life-threatening. 5/ Major ABO incompatibility (recipient- derived isohemagglutinins directed against donor RBCs) may lead to chronic hemolysis and pure red cell anemia (PRCA). 369/30/2016 Dr.yekehfallah.-phd of nursing - 2015

38. Hemolysis Diagnosis 1/Clinical presentation: a/ Mild hemolysis due to major ABO incompatibility may be associated with prolonged RBC transfusion requirements. b/Delayed hemolysis due to minor ABO incompatibility may cause rapid lysis of all recipient RBCs over a few days. This may lead to acute renal failure or pulmonary edema and may be fatal. Plasma exchange in the recipient and plasma removal or RBC removal from the graft are standard procedures that minimize the risk of preventable hemolytic complication after ABO-mismatched HCT. 37 Dr.yekehfallah.-phd of nursing - 20159/30/2016

39. Hemolysis Diagnosis 2/Laboratory and radiologic studies: a/Emergence of donor-derived RBC and isohemagglutinin titers should be monitored after allogeneic HCT b/Serum levels of (indirect) bilirubin and lactate dehydrogenase (LDH), reticulocyte counts, and the direct agglutinin test (DAT) are useful markers of hemolysis 38 Dr.yekehfallah.-phd of nursing - 20159/30/2016

40. Hemolysis Diagnosis 3/Differential diagnosis: a/Parvovirus 19 infection may cause PRCA after HCT. b/NonABO-related Coombs-positive autoimmune hemolytic anemia (AIHA) may develop late after HCT c/Drugs such as fluarabine or infections with mycoplasm may also produce hemolysis. Thrombotic microangiopathy (TM) is frequently related to cyclosporine or tacrolimus and associated with RBC fragmentation (schistocytes) d/Hyperbilirubinemia after HCT may have many other causes (e.g., sinusoidal obstruction syndrome [SOS] of the liver; drug effects) e/Dimethylsulfoxide (DMSO), a cryoprotectant used to store autologous stem cells, may cause anaphylactic and nonallergic reactions (e.g., hypotension, dyspnea, flushing, diarrhea) during infusion of thawed stem cell products. 399/30/2016 Dr.yekehfallah.-phd of nursing - 2015

41. Hemolysis Treatment: 1/ Chronic hemolysis due to major ABO incompatibility is usually self-limited. 2/ Patients with refractory or more acute immune hemolysis may require interventions aimed at suppressing ongoing donor-directed isohemagglutinin production (corticosteroids, donor lymphocyte infusion, rituximab) or removal of the offending antibody (plasma exchange). 3/Supportive care measures to maintain renal function are critical 40 Dr.yekehfallah.-phd of nursing - 20159/30/2016

42. Toxicity of the preparative regimen Cytotoxic chemotherapy with or without total body irradiation (TBI) may compromise the function of the lungs, heart, kidneys, nervous system, and gastrointestinal tract including the liver. This type of toxicity occurs predominantly within the first 3 to 4 weeks after HCT. 41 Dr.yekehfallah.-phd of nursing - 20159/30/2016

43. Infection General principles Infections are frequent complications after autologous and allogeneic HCT. Their pattern of occurrence is determined by a number of factors, including the recipient's pretransplant history and underlying disease, the intensity of the preparative regimen, the regimen used for infection prevention, the microbiological flora of the patient and of the individual transplant unit, and the degree of immunosuppression after transplant. 42 Dr.yekehfallah.-phd of nursing - 20159/30/2016

44. Bleeding Etiology/pathophysiology: Bleeding can occur as a result of thrombocytopenia or coagulopathy. Breakdown of mucosal barriers as a result of regimen-related toxicity and/or GVHD increases the likelihood of hemorrhage. CNS hemorrhage can be rapidly fatal. High- dose cyclophosphamide and BK virus infection are causes of hemorrhagic cystitis 43 Dr.yekehfallah.-phd of nursing - 20159/30/2016

45. Bleeding Diagnosis: Oropharyngeal bleeding and epistaxis are obvious. Endoscopic evaluation (colonoscopy, esophagogastroduodenoscopy, bronchoscopy) or CNS imaging may be indicated according to the clinical picture 44 Dr.yekehfallah.-phd of nursing - 20159/30/2016

46. Bleeding Treatment: A platelet count below 10,000/mm3 increases the risk of spontaneous bleeding and should be treated prophylactically with platelet transfusion. The decision to transfuse platelets above the prophylactic  threshold of 10,000/mm3 should be guided by the clinical situation. Patients who have received multiple transfusions can become alloimmunized and demonstrate poor response to platelet transfusion. Transfusion of unpooled (single-donor) or HLA- matched platelets may be helpful. Bleeding can be seen on bronchoscopy. The treatment consists of high doses of corticosteroids (e.g., 1 g per day for 3 days). 459/30/2016 Dr.yekehfallah.-phd of nursing - 2015

47. Graft-versus-host disease General principles GVHD is a major cause of morbidity and mortality after allogeneic HCT. Patients who develop GVHD, however, have lower relapse rates than patients without GVHD, which can be explained by an immunologic graft-versus-tumor effect that helps eradicate the underlying malignancy 46 Dr.yekehfallah.-phd of nursing - 20159/30/2016

48. Graft-versus-host disease Etiology/pathophysiology The GVHD syndrome is caused by donor T cells that are activated by immunologically disparate HLA or non- HLA antigens in the recipient, resulting in an inflammatory immune response. Older patient age, HCT from a mismatched and/or unrelated donor, and a female donor increase the risk of developing GVHD 47 Dr.yekehfallah.-phd of nursing - 20159/30/2016

49. Graft-versus-host disease Diagnosis Clinical presentation : Acute GVHD (defined as occurring before posttransplant day 100) tends to have a more sudden onset and may involve the skin, gastrointestinal tract, and liver. Signs and symptoms include an erythematous rash, nausea, vomiting, diarrhea, and liver function abnormalities. Clinical features of chronic GVHD (defined as occurring after posttransplant day 100), which typically has a more insidious onset, may involve the skin, eyes, joints, and liver and are reminiscent of autoimmune diseases such as systemic sclerosis. 489/30/2016 Dr.yekehfallah.-phd of nursing - 2015

50. Graft-versus-host disease Laboratory and radiologic studies: Skin punch biopsy, gastrointestinal endoscopy with biopsy, and liver biopsy confirm the diagnosis in the appropriate clinical setting. Cholestatic jaundice is the hallmark of liver involvement. Pulmonary function test and lung biopsy in patients with presumed BOOP to rule out infectious etiologies. 49 Dr.yekehfallah.-phd of nursing - 20159/30/2016

51. Graft-versus-host disease Treatment: Despite prophylaxis against GVHD (e.g., cyclosporine plus methotrexate), 40% to 80% of allogeneic HCT recipients develop this complication. Corticosteroids are standard first-line therapy of GVHD (e.g., prednisone 2 mg/kg per day; slow taper after 2 weeks). 50 Dr.yekehfallah.-phd of nursing - 20159/30/2016

52. Graft-versus-host disease Treatment: Immunosuppressive treatment of GVHD with corticosteroids contributes to the increased susceptibility of patients with GVHD to a variety of bacterial, viral, and fungal infections. Steroid-refractory patients require second- line immunosuppressive therapy and usually have a poor prognosis. 51 Dr.yekehfallah.-phd of nursing - 20159/30/2016

53. Complications Rejection by hte host of the marow graft Acute graft-vs,-host disease (GVHD) Infections Chronic GVHD Prolonged immunodeficiency Disease recurrence 52 Dr.yekehfallah.-phd of nursing - 20159/30/2016

54. ? 53 Dr.yekehfallah.-phd of nursing - 20159/30/2016