1. Introduction to Haematopoietic Stem Cell Transplantation (HSCT) Covenant Health System HSCT Program Lubbock, Texas April 4, 2007

2. HSC: Key Definition Haematopoietic Stem Cell  Cell produced in bone marrow that gives rise to all other blood cells (white cells, red cells, and platelets) Replenishes itself Relatively resistant to injury But, that can be eliminated with high doses of chemotherapy or radiation therapy

3. Key Vocabulary Bone marrow tissue found predominately in spaces of the bones of the hips, legs, arms and spines. Stem Cells produced in the bone marrow and found in circulating blood.

4. Haematopoietic Stem Cell

5. HSCT: Key Vocabulary Stem Cell Transplant to re-infuse HSC in patients who have received high doses of chemotherapy and/or radiation therapy Allogeneic transplant uses stem cells from another person (who is a perfect match) Autologous transplant uses stem cells taken from the patient

6. Types of Transplants Autologous Allogeneic Syngeneic

7. Concepts of HSC Transplant Allows delivery of high dose chemotherapy and/or total body irradiation  Destruction of tumor  Creation of marrow space  Prevention of *graft rejection *stem cells from allo donor

8. Diseases Commonly Treated with HSCT.

9. Indications for Blood & Marrow Transplantation in North America, 2002

10. Overall Numbers of Stem Cell Transplant

11. HSCT How is it done? Patients are carefully screened  Disease responsive to HSCT(i.e.., AML, NHL)  Comorbidities and Performance Status (CHF, COPD, CRI)  Infectious diseases Profile (i.e.. HIV, Hepatitis, etc) Stem cells are collected. From the patient (for autologous HSCT) or the donor (allogeneic)

12. Stem Cell Graft Collection Marrow Peripheral Blood Patient’s own or from somebody else

13. Source of Haematopoietic Stem Cells Bone Marrow  Requires general anesthesia in operating room  Traditional method Peripheral Blood (drawn from veins)  Obtained by apheresis  Accomplished as outpatient procedure  Currently most commonly utilized method

14. Number of Stem Cells Circulating in Peripheral Blood

15. Haematopoietic Stem Cell Graft

16. HSC: Procurement Concepts Amount of stem cells collected based on recipients body weight Minimal number  2 x 10 8 /kg nucleated cells  2 x 10 6 /kg CD 34 + cells CD-cluster differentiation Flow Cytometry

17. HSC from Peripheral Blood Collection Translated on: Mortality rate for autologous transplantation is expected to be below 5%. Development of Outpatient Transplantation Programs.

18. Autologous Stem Cell Sources by Recipient Age, 1996-2002

19. Trends In Autologous Transplants by Recipient Age, * 1990-2002

20. HSCT Process: Kill the Cancer, Injure the Patient Patients are treated with high-dose chemotherapy and/or radiation. Stem Cells are infused (IV) back to the patient. Patient supported with antibiotics, blood transfusions, and treatment for other side-effects

21. Bone Marrow Ablation: High Dose Chemotherapy and TBI Administration

22. Common Complications after HSCT

23. Mucositis

24. Stem Cell Engraftment Engraftment of new stem cells generally takes 10-21 days Patient heals the mucositis Resolves the infectious process Hope the Cancer was Eliminated

26. Transplantation: Long-Term Outcomes

27. Types of Transplants: Why Allogeneic Autologous versus allogeneic  Marrow and Blood “contaminated” with malignant cells.  Stem cells affected by the disease.  No Stem cells available for collection

28. Bone Marrow Ablation: High Dose Chemotherapy and TBI Administration

29. Allogeneic HSCT When stem cells come from a healthy donor, stem cells are “clean” of Malignant Disease, (Donor has to be carefully screened about Infectious diseases too) Grafts, from Donors other than the Patient (sibling or unrelated), bring another weapon to kill the Disease: Graft versus Tumor (GVT) effect Graft versus Tumor, is the condition where donor T-Cells recognize recipients tumor (i.e., Leukemia) and builds an immune reaction to systematically destroy the tumor

30. Allogeneic Transplantation with Full or Reduced- Intensity Preparative Regimens

31. Allogeneic HSCT Allogeneic Stem cells will eventually completely eradicate the patient bone marrow (blood making) and immune system A new bone marrow and immune system is built all with cells from the allo donor This process allows the elimination of the tumor, Graft versus Tumor, at a cost of an enormous immunosupression and Graft vs. Host Disease

32. Copelan, E. A. N Engl J Med 2006;354:1813-1826 Graft-versus-Leukemia Effect from a Minor Histocompatibility Antigen.

33. Postulated Mechanism of Acute GVHD.

34. Graft versus Tumor Graft Versus Patient

35. Limitations of Allogeneic HSCT Scarcity of suitable donors 25% sibling match, not everybody has a donor Graft versus Host Disease Infections

36. Complications after HSCT

37. Graft Versus Host Disease Condition where donor T-Cells recognize recipient as foreign and attacks the patient skin, bowel, liver, and other tissues This graft-versus-host reaction leads to GVHD signs and symptoms

38. HLA Typing Human Leukocyte Antigen HLA are proteins found on short arm of chromosome 6 3-antigens important in HSCT,  HLA-A  HLA-B  HLA-DR one set of 3 from each parent Brings to a total of six antigens to match A full match is “6/6” or “perfect” match

39. HLA Typing Human Leukocyte Antigen Mother Father 25 % chance that each sibling will match

40. HLA or Tissue Typing Rate of GVHD Donor Incidence 6/640% 5/650% 4/680% 3/690%

41. GVHD Prophylaxis

42. Graft vs. Host Disease GVHD Acute Up to Day +100 Skin Liver Gut Chronic After Day +100 Skin Mucous Membranes Gut Liver Scleroderma

43. Acute GVHD Grading

45. Acute GVHD: Skin

46. Lichenoid Lesions of Chronic Graft-versus-Host Disease.

47. Antin, J. H. N Engl J Med 2002;347:36-42 Graft-versus-Host Disease of the Skin

48. Acute and Chronic GVHD Therapy Steroids and Cyclosporine / Tacrolimus Other modalities of immunosupression

49. Late Complications of Allogeneic HSCT 50-60% may develop chronic GVHD Chronic GVHD GVHD after day +100, single major determinant of patients outcome and quality of life after HSCT. Immunosupression and Infections Fungal Infections (Aspergillum), viral reactivation (CMV, HS)

50. Outcomes of Haematopoietic Stem-Cell Transplantation: Allogeneic

51. Copelan, E. A. N Engl J Med 2006;354:1813-1826 Outcomes of Haematopoietic Stem-Cell Transplantation in Selected Diseases

52. Trends in Allogeneic BMT Recipient Age, * 1984 - 2002

53. Potential/Future Applications Autoimmune Disorders  Rheumatoid Arthritis  Lupus  Multiple Sclerosis Other Disorders  Congestive Heart Failure

54. CHS-HSCT Program LS CMC 5th Floor