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What is the Expected Clinical Outcome after BMT

What is the Expected Clinical Outcome after BMT. ?. Blood Counts for BMT Recipients Surviving more than 15 Years. Clonogenic Progenitors in the Graft and the Recipient post BMT. 1.0. 0.8. 0.6. 0.4. 0.2. 0.0. 0. 2000. 4000. 6000. 8000. 10000.

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What is the Expected Clinical Outcome after BMT

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  1. What is the Expected Clinical Outcome after BMT ?

  2. Blood Counts for BMT Recipients Surviving more than 15 Years

  3. Clonogenic Progenitors in the Graft and the Recipient post BMT

  4. 1.0 0.8 0.6 0.4 0.2 0.0 0 2000 4000 6000 8000 10000 Overall Survival of all Patients Receiving an Allogeneic BMT at PMH Survival Days after BMT

  5. Outcome by Disease Status at BMT in Recipients Transplanted since 1986 CR1 / CP1 ----- Other ___ Survival Days after BMT

  6. Long-term Survival of Patients alive 6 Years by Disease Status at BMT Survival AML/CML CR1/CP1 ------ AML/CML other - - - - Days after BMT

  7. The Probability of Survival Remains lower than that of the Normative Population even more than a Decade after BMT

  8. Lessons learned for Allogeneic Transplants • High transplant related morbidity and mortality • Low relapse rate • Disease control predominantly related to anti-tumor effects by donor derived cells of the immune system

  9. Evidence for Graft vs Malignancy Effects (GvM) • High relapse rate in syngeneic transplants. • Increased relapse rate in T cell depleted transplants in some diseases • Lower relapse rate in patients with GvHD compared to patients without • Leukocyte Infusions (DLI) in recipients relapsing after a transplant may result in remissions and long-term disease control

  10. Strategies to provide treatment for more patients in need of a transplant Reduced Intensity Transplants Haplo-identical Donors Cord Blood Transplants Matched Unrelated Donors

  11. Unrelated donor registries

  12. Matched unrelated donors • 13 million donors worldwide • Improved donor recruitment • Improved HLA-typing • Outstanding international cooperation • International standards • Outcomes similar to those achieved with related donors

  13. Donor availability for allogeneic transplants

  14. (O’Brien TA et al MJA 2006; 184: 407 – 410)

  15. Cord Blood Transplants • Principles: • Utilization of a waste product • High proportion of primitive progenitors • Presence of mainly naïve T cells • Product readily available

  16. Outcome of CBT from related donors by diagnosis (Rocha V et al EUROCORD) Survival Months

  17. Lessons learned • Cord blood cells are a viable alternative source of hemopoietic progenitor cells • In the pediatric age group CBT may be preferable because of decreased acute and chronic GvHD and the requirement for a lesser degree of HLA matching • The outcome of mismatched transplants can be overcome by higher cell doses • Cell dose remains a limiting problem particularly for adults. This problem is being addressed by the use of double cords.

  18. Transplants from Haplo-identical Donors • Principles: • Intensive preparation • High stem cell numbers • Extensive T cell depletion • Preparation with regimens that • maintain regulatory T cell • populations • Availability of donors for nearly everyone

  19. Event-free Survival by Disease Status Aversa et al Rev Clin Hematol

  20. Non-myeloablative Transplants • Principles: • Immune suppression with purine analog • based regimens of low intensity • Slow replacement of recipient marrow by • donor cells • Engraftment fostered by decreasing immune • suppression and administration of DLI • Reduction of early transplant related toxicity • Reliance on a GvM effect as mechanism of • disease control

  21. Engraftment Process afterNon-myeloablative Allografting Immune- suppression Recipient DLI Mixed Chimera Full Chimera Donor

  22. Non-myeloablative Transplants

  23. Non-myeloablative Transplants • Decrease of early transplant related toxicity • Broadened eligibility to include patients with otherwise non-permissive co-morbidities • Inclusion of patients with chronic non life threatening diseases • Reliance on a GvM effect for disease control in patients with malignancies

  24. Disease-free Survival of Patients with AML/MDS by Disease Status Giralt In: NST, 2000

  25. Novel Strategies for Allogeneic BMT

  26. Objectives Reduction of other TRM Avoidance of GvHD Disease Elimination

  27. Risk factors for Transplantation Recipient Donor Graft Transplant Procedure

  28. Risk factors for Transplantation Age Disease (AA, CML) HLA compatibility Minor histocompatibility antigens Non-HLA immunogenic polymorphisms Gender Immune status Recipient Age HLA compatibility Gender (F M) Unrelated donor Donor PBSC Cord blood Cell count T cell depletion Tregs Graft Preparative Regimen GvHD Prophylaxis and Management Transplant Procedure

  29. Malignant stem cells and their protective microenvironment Mobilization Reestablishment of potential to undergo apoptosis Myeloablative therapy and transplant

  30. Events during mobilization (Winkler I, Levesque JP Exp Hematol 2006; 34: 996 – 1009) Steady state Mobilization with G-CSF

  31. LSC LSC

  32. Allogeneic transplants:A platform for Cell therapy

  33. Donor derived Cells after BMT can be found in strange places • Myelopoiesis • Lymphopoiesis • von Kupffer cells • Pulmonary alveolar macrophages • Langerhans cells • Osteoclasts • Macro and Microglia • Hepatocytes

  34. Male recipient cells in female cardiac allografts (Schwartz and Curfman NEJM 2002; 346: 2 – 4)

  35. Intracoronary Mononuclear Marrow Cell Transplantation Strauer BE et al Circulation 106: 1913 – 1918, 2002

  36. Intracoronary injection of BM cells in acute myocardial infarction • Lunde K et al (NEJM 2006; 355: 1199 – 1209) 100 patients randomized to marrow cell injections or no intervention NO differences in global left ventricular function • Schachinger V et al (NEJM 2006; 355: 1210 – 1221) 204 patients randomized to marrow cell injections or placebo Improved recovery of left ventricular contractility after marrow cell infusion • Assmus B et al (NEJM 2006; 355: 1222 – 1232) 75 patients randomized to circulating blood cells, marrow, or no cells Moderate but significant improvement of left ventricular ejection fraction after marrow cell infusion

  37. Stem cell recruitment to ischemic infarcts (Kim DE et al Stroke 2004; 35: 952 – 957) Cells positive for neuronal marker NeuN

  38. Neurogenic Regions in the Mouse (Seaberg R, van der Kooy D J.Neurosci 2002; 22: 1784 – 1793) Subventricular zone Dentate gyrus (DG)

  39. a Str Str LV LV BrdU BrdU Newly generated cells in the subventricular zone with EGF or EGF plus EPO EGF + EPO EGF Courtesy Sam Weiss, Calgary

  40. Histological analyses reveal new tissue in the lesion cavity of rats that received EGF+EPO infusions Lesion + EGF/EPO No Lesion Lesion Courtesy Sam Weiss, Calgary

  41. Embryonal Stem Cells (Langston JW J Clin Invest 2005; 115: 23 – 25)

  42. The promise of stem cellresearch

  43. Conclusions (I) • Stem cell transplants are a major treatment modality for patients with marrow failure, hemopoietic malignancies and diseases with immune dysfunction • Stem cell sources include marrow, peripheral blood and cord blood • Stem cells can be derived from autologous and allogeneic sources • Currently available strategies facilitate their use for patients with more advanced age

  44. Conclusions (II) • Advances are being made to test whether or not stem cells may facilitate repair of defective organs in general

  45. Probability of Survival PBSC BM P=0.036 Months post Transplant

  46. Survival of Patients with more Advanced Disease PBSC BM Months post Transplant

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