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Senigallia 23-24 Ottobre 2008

CONVEGNO REGIONALE SIE Il trapianto a condizionamento ridotto RIC compie 10 anni: è l’ ora dei bilanci STORIA DEL RIC Alberto Bosi Cattedra di Ematologia Università degli Studi di Firenze. Senigallia 23-24 Ottobre 2008. En parcourant la Voie Domitienne entre Nîmes et Beaucaire.

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Senigallia 23-24 Ottobre 2008

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  1. CONVEGNO REGIONALE SIEIl trapianto a condizionamento ridotto RICcompie 10 anni:è l’ ora dei bilanci STORIA DEL RICAlberto BosiCattedra di EmatologiaUniversità degli Studi di Firenze Senigallia 23-24 Ottobre 2008

  2. En parcourant la Voie Domitienne entre Nîmes et Beaucaire

  3. THE BEGINNINGS In the 19th century Brown-Sequard administred bone marrow by mouth in patients with acute leukemia with an understandable lack of success

  4. THEN… • Intramuscolarinjection by Scretzenmayer in 1937 • Intramedullary instillation by Rasjeck in 1939 • and FINALLY …. Intravenous infusion by Osgood in 1939

  5. EARLY STUDIES ON ANIMALSI • During the World War II, Reckers infused bone marrow from normal dogs into dogs exposed to 350 R. • In 1954 Barnes and Loutit reported that letally irradiated mice protected with syngenic marrow survived beyond 100 days. • However, mice given allogeneic marrow survived at 30 days, but died of a “secondary disease”.

  6. EARLY STUDIES ON ANIMALSII • In 1959, Billingham and Brent published a study on runt disease in newborn mice and described the biology of GVH reactions. • In the 1960s studies on dogs performed by Cavins et al showed that hematopoietic stem cells for engraftment could be obtained also from peripheral blood.

  7. STEM CELL MODEL The importance of hematopoietic stem cells in the protection of lethally irradiated animals became clear in the 1950s. With the Till-McCulloch spleen-colony assay it was realised that clonotypic precoursors could give rise to both erythroid and myeloid cells. Murine HSCT are isolated at a frequency of 0.05%.

  8. HUMAN HEMATOPOIETIC STEM CELL CD 34+ Thy-1 +

  9. EARLY CLINICAL STUDIES • In 1959 Mathè reported the infusion of marrow into patients exposed to potentially lethal irradiation in a reactor accident. • At the same time successfull transplants using an identical twin donor were reported.

  10. FRED HUTCHINSON CANCER RESEARCH CENTER SEATTLE

  11. Bob Epstein Dean Buckner Seattle Team in 1965 Don Thomas Rainer Storb

  12. ALLOGENEIC TRANSPLANTATION Allogeneic transplantation was employed in clinics only in patients with advanced and refractory hematological malignancies who were in poor general condition. In 1957 Thomaset al. Reported intravenous infusion of bone marrow in patients receiving radiation and chemotherapy In 1990 E. Donnall Thomas shared the Nobel Prize in Physiology and Medicine with Dr. Joseph Murray

  13. Reported Human Marrow Allografts 1958-68 Bortin, Transplantation 9: 571, 1970

  14. Human Bone Marrow Transplantsfrom 1958 to 1968 (n=203)(Bortin, 1970) 70 60 # ReportedCases 50 40 30 20 ? 10 0 1958 1960 1962 1964 1966 1968 Bortin, Transplantation 9: 571, 1970

  15. D.W. van Bekkum & M.J. de Vries, Radiation Chimeras, Logos Press, London, 1967

  16. Histocompatibility Typing Mid-Late 1960s Humans • Dausset: MAC; v. Rood: 4a + b • Sera from parous women + transfusion recipients • Bach: MLC • Seattle: groups a–h and MLC • Sera from cross-immunized littermates Dogs Tests: Leukoagglutination or lymphocytotoxicity (trypan blue exclusion)

  17. HISTOCOMPABILITY 1958 Elucidation of the genetics of human leukocyte antigen (HLA) by Dausset (photo) and van Rood Application of histocompatibility testing for organ transplantation led the way to frequent application for marrow grafting for hematological disease

  18. 1960 Medawar and Burnett received the Nobel Prize for the discovery of “acquired immunological tolerance”.

  19. Unrelated DLA-Nonidentical Marrow Grafts *Only single drug occasionally resulting in graft-host tolerance in this setting Transplantation 9: 240, 1970 Transplantation 10: 165, 1970 Blood 42: 601, 1973  Transplantation 56: 800, 1993 Bone Marrow Transplantation 15: S98,1995  Yu et al., Blood 91: 2581, 1998.

  20. CYCLOSPORINE In 1972 the immunosuppresive effect of CSA was discovered by Sandoz. CSA used was approved in 1983.

  21. J Clinical Invest. 50: 1272, 1971.

  22. 1968 Canine Long-Term Survivors

  23. Sites of ATG Production

  24. Patient with 1° Refractory AML Blood 44: 57, 1974

  25. Survival after Therapy for Acute GVHD (n=20) (Upjohn – Horse; n=17) Doney et al. Am.J.Hematol 11:1, 1981.

  26. CY / TBI and MTX Thomas, et al.NEJM 301: 597, 1979

  27. UNRELATED DONORS In 1973 at The Memorial Sloan-Kattering Cancer Center of New York City the first unrelated bone marrow transplant was performed on a five-year-old boy with severe combined immunodeficiency syndrome. The donor was found in Denmark through the Blood Bank. Since then….

  28. The program started on 1974 to find a donor for Anthony Nolan, born in 1971 affected by Wiskott Aldrich syndrome. Anthony died in 1979 without a transplant "It's good to be alive.“ A bone marrow transplant recipient. Antony and Shirley Nolan

  29. BONE MARROW REGISTRIES • In the early 1980s individual registries of HLA-typed people were established in Milwaukee, Saint Paul, Seattle and Iawo City. • In July 1986 The American National Bone Marrow Donor Registry began to operate. • Since then stem cell donor registries have been created worlwide. • From 1999 all the registries offered all the three stem sources of stem cell used in transplants: BM, PB and CB.

  30. PERIPHERAL BLOOD 1978 John Goldman reported the first use of blood cells for autologous transplantation after high dose cytotoxic therapy in patients with CML

  31. CORD BLOOD TRANSPLANTATION 1989 Eliane Gluckman reported the first successful transplat using cord blood

  32. NON MYELOABLATIVE TRANSPLANTATION Rainer Storb was one of the first investigators to show that non myeloablative HSCT can be done safely and effectively in elderly and in poor performance status patients

  33. Rational for non-myeloablative transplants High dose chemo-radiation cannot completely sterilize many malignancies even with pre-transplant intensification Burchenal JH et al, Cancer Res 1960 Thomas ED et al, NEJM 1975

  34. Rational for non-myeloablative transplants Many cures can be attributed to immunological anti-tumor reactions brought about by lymphocytes contained in the allograft Barnes DWH, Loutit FJ. Br J Haematol 1957 Mathè G et al, Cancer Res 1965 Weiden et al, NEJM 1979; NEJM 1981

  35. Much of the Success of Allogeneic Hematopoietic Cell Transplantation in Cancer Due to Graft vs. Tumor Effects Weiden et al., NEJM 304: 1529, 1981  NEJM 300: 1068, 1979.

  36. Rational for non-myeloablative transplants The curative potential of the GVT effect has been directly confirmed with DLI that could produce complete remission in patients relapsed after HSCT Kolb HJ et al, Blood 1990 Kolb HJ et al, Blood 1995

  37. Rational for non-myeloablative transplants • High dose chemo-radiation cannot completely sterilize many malignancies even with pre-transplant intensification • The transplant effect may often be attribute to immunological anti-tumor reaction of lymphocytes contained in the allograft Conceptual emphasis has shifted away from trying to eradicate malignant cells through toxic therapy towards using allogeneic effectors cells to eliminate the malignancy

  38. Reduced toxicity Extend the eligibility for transplantation to patients older and with comorbidities

  39. Ages at Diagnoses vs. Ages at Myeloablative HCT Molina et al.,Current Opinion Org Transpl 5: 366, 2000.

  40. Rational for non-myeloablative transplants Improvement of post-transplant immunossuppression regimen in a preclinical canine model for decreasing the risk of GVHD and reducing HVG reactions Storb R et al, Blood 1997

  41. T lymphocytes are effectors cells that mediate host-versus-graft (HVG) and graft versus host (GVHD) Pretransplant immunosuppression to reduce HVG Post-transplant immunosuppression to suppress residual HVG and to control GVHD → create a stable tolerance with the co-existence of donor and host cells (mixed chimerism)

  42. PRECLINICAL CANINE MODEL 200 cGy TBI MMF for 4 weeks CSA for 5 weeks after HSCT Storb R Blood 1997 STABLE MIXED CHIMERISM 450 cGy nodal irradiation MMF for 4 weeks CSA for 5 weeks after HSCT Storb R Blood 1999

  43. Novel Allogeneic HCT Approach • Substitute nonmyeloablative conditioning for toxic high-dose chemoradiotherapy • Use novel postgrafting immunosuppression to both prevent graft rejection and control GVHD • Grafted immune cells eliminate cancer

  44. Creation of marrow space by cytotoxic agents is not required for stable engraftment • Pretransplant irradiation may be replaced by non-toxic and more specific T-cell immunosuppression • The post-grafting immunosuppression facilites the development of a stable state of tolerance with mixed chimerism

  45. Marrow Grafts From DLA-Identical Canine Littermates After Single-Dose TBI (7 cGy/min) *LD99 = 8 Gy Blood 86: 4376, 1995 Blood 89: 3048, 1997 BBMT 9: 489, 2003.

  46. Clinical Treatment Protocol 2 Gy TBI HCT Chimerism Analyses FLU 30 mg/m2/d 180 -4 -3 -2 -1 0 28 35 40 56 84 100 CSP 6.25 mg/kg po BID Related MMF15 mg/kg po BID CSP 6.25 mg/kg po BID Unrelated MMF15 mg/kg po BID / TID

  47. Reduced intensity conditioning SCT OBJECTIVES: -> Reduce the early toxicity of allogeneic SCT -> Keep the Graft-versus-leukemia effect • Mainly proposed to: - older patients (> 55 y) - patients with comorbidity • Reduces the duration of neutropenia • Reduces mucosal and liver toxicity • Does not solve the problem of GVHD

  48. Candidates for HLA-Matched Related and Unrelated Nonmyeloablative HCT • Ineligible for conventional HCT because of: • Age • Medical contraindications • Previous high-dose HCT • Comorbidities

  49. Acute GVHD – Grades Related (n=426) Unrelated (n=301) Days after HCT Sandmaier et al., ASH 2005.

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