1. Stem Cell Transplantation H. Atilla Özkan, MD.

2. The Nobel Prize, 1990 E. Donnall Thomas first succsessful HSCT in treatment of acute leukemias Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 1957; 257: 491.

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4. Definition  Infusion of hematopoietic stem cells from oneself or another person  Usually follows high dose chemotherapy and/or irradiation

6. CD34+ CD38- CD38+ 6

7. Hematopoietic Stem Cell Transplantation 1. Hematologic Malignancies Acute and Chronic Myeloid Leukemia Acute and Chronic lymphocytic leukemia Myeloddysplastic Syndrome Lymphomas – Hadgkins and Non Hodgkins Multiple Myelomas 2. Non Malignant Disorders Severe Aplastic Anemias (SAA) Hurler’s Syndrome Wiskott – Aldrich Syndrome Diamond – Blackfan Anemia Osteopetrosis 3. Inherited Blood Disorders Beta Thalassaemia Major 4. Severe combined immunodeficiency (SCID) 5. Pathologic States including autoimmune diseases 6. Solid Tumors (Breast cancer, Teratomas, ovarian tumors etc.)

8. Stem Cell Sources

9. 9 Hematopoietic Nich

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12. PBSC Collection

13. BoneMarrow Harvest

15. Peripheral blood stem cell mobilization 1.G-CSF 2.G-CSF + Plerixafor (Mozobil) 3.Chemotherapy + G-CSF 4.Chemotherapy + G-CSF + Plerixafor

19. Mobilization of Stem Cells Goal collection:  > 2 x 10 6 cells/kg (auto-SCT)  > 5 x 10 6 cells/kg (allo-SCT)

20. Factors Influencing Successful Mobilization  Pelvic or abdominal irradiation  Marrow hypocellularity  Prior stem cell toxic agents  Prior no of chemo. regimens  Age  Type of underlying disease

21. Autologous BMT  Reinfusion of patient’s own cells  Regimens do not include immunosuppression  Older patients  Worry about reinfusion of cancer cells  Chemotherapy associated toxicity

22. Allogeneic BMT  Reinfusion of someone else’s (donor) cells into patient (recipient)  Regimens usually aggressive and contain immunosuppression  Younger patients  Finding a HLA-matched donor is difficult  GVHD and infectious complications  Chemotherapy toxicity

23. Allogeneic BMT  HLA Matched sibling  HLA matched unrelated donor (MUD)  HLA mismatched related donor  HLA mismatched unrelated donor

24. Compatible Donor Search - Matching HLA Family- ¼ chance Unrelated – 1/500 - 0/10 million chance of match 70% patients do not have family donor

25. Chromosome 6 Gene map of the HLA region Class II Class III Class I 1.8 Mb 40 % of which have assumed immune functions tel. Long arm cen. short arm tel. tel. Long arm cen. short arm tel. 6p 21.3 HLA region Bf DPDMDQDR C4 C2Hsp70TNF B C E A G F B C E A G F 128 functional genes Most polymorphic Ag presentation, crucial in organ and HSCT

28. Syngeneic BMT  Reinfusion of identical twin’s cells  Need to insure twins are identical

29. Deciding on type of SCT  Type and stage of disease  Availability of stem cells  Age  Performance status  Clinical condition of patient

31. Preparative Regimen Purpose  Kill tumor cells  Provide space in marrow  Suppress immune system

32. Components of Ideal Regimen  Myeloablative  Immunosuppressive  Non-overlapping toxicities

33. Myeloablative Regimens  Cyclophosphamide/TBI  Busulfan/Cyclophosphamide  Carmustine/Etoposide/Cytarabine/Cyclophosph amide  Carmustine/Etoposide/Cytarabine/Melphalan  Melphalan

34. Nonmyeloablative Regimens  Fludarabine/Melphalan  Fludarabine/cyclophosphamide  Fludarabine/busulfan

36. Regimen Related Toxicities  Nausea/vomiting  Diarrhea  Mucositis  Myelosuppression  Electrolyte abnormalities  Pulmonary  Hemorrhagic cystitis  Sterility  Cardiomyopathy  Hepatotoxicity  Nephrotoxcitiy  Peripheral neuropathies  Ototoxicity  Secondary malignancies  Infections

38. Hepatic Veno-occlusive  Day +14 - 28  Hyperbilirubinemia  Weight gain  Ascites  Hepatomegaly

39. Infectious Complications  Bacterial  Fungal  CMV  VZV  PCP

42. Graft Versus Host Disease (GVHD)  Reaction of donor T-cells against host tissues PBSCT or BMT Blood transfusions  Billingham criteria Graft must contain immunocompetent cells Recipient must express antigens not present in donor Recipient incapable of mounting immune response against graft

43. Pathophysiology  Afferent phase Recipient tissues active donor T lymphocytes Antigen presentation T cell activation Proliferation and differentiation of T cells  Efferent phase Attack of donor cells on host target tissues Activated T cells secrete cytokines Secondary effector cells damage tissues

44. Acute GVHD  Occurs in 25-70% of all BMT patients  Graded based on combination of severity of presentation  Survival based on grade (0-90%)  Death usually due to infections, hemorrhage or organ failure

45. Risk Factors  MHC disparity (Histocompatibility)  Age  Sex mismatch  CMV serology  Intensity of preparative regimen  Prior donor transfusions  Disease stage

46. aGVHD Prevention  Cyclosporine  Tacrolimus  Methylprednisolone  Methotrexate  Cyclophosphamide  ATG

47. aGVHD Treatment  Methylprednisolone  Antithymocyte globulin  Supportive care  Monoclonal antibodies  PUVA  Thalidomide

48. Chronic GVHD  Incidence 15-60%  Increased risk if AGVHD  Skin  Mucosal changes  Esophageal strictures  Liver disease  Thrombocytopenia

49. cGVHD Treatment  Prednisone  Cyclosporine  Supportive care  Other PUVA Photopheresis Thalidomide Mycophenolate mofetil

50. Late BMT Complications  Endocrine dysfunction  Pulmonary fibrosis  Sterility  Cataract formation  Infections

52. Otolog Hematopoetik Kök Hücre nakli endikasyonları  Malign hastalıklar: AML, HL, NHL, KLL Myeloma, Germ hücreli tümör, nöroblastoma, medullablastoma  Malign hastalıklar dışı: Otoimmün hastalıklar, Amiloidozis

53. Allojeneik Hematopoetik Kök Hücre nakli endikasyonları  Malign hastalıklar: AML,ALL, MDS HL, NHL, KML, KLL Myeloma,  Malign hastalıklar dışı: Otoimmün hastalıklar, orak hücreli anemi, aplastik anemi, fankoni anemi, thal majör, wiskot aldrich, PNH, osteopetrozis, ciddi kombine immün yetmezlik

54. HKHN neyi sağlar?  Kemik iliği yetmezliği durumlarında normal hematopoezin oluşmasını sağlar  Hastalıklı kemik ilğinin yerini sağlıklı kemik iliği alır  Kemik ilği ablasyonu sonrası tekrar hematopoezi sağlar  Konjenital immün yetmezlikleri düzeltir  Graft versus tümör etkisi sağlar 08.05.2015 54

55. Bone Marrow  Engraftment  Transfusion support  Longer hospital stay  # stem cells  # T cells  Acute GVHD  Chronic GVHD

56. PBSC  Engraftment  Transfusion support  Shorter hospital stay  # stem cells  # T cells  Acute GVHD  Chronic GVHD

58. Reinfusion of Cells