Bmt intro lecture

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  • Slide 10: The graft source used for unrelated donor transplantation has changed significantly over the past decade. Bone marrow was still the main graft source for unrelated transplantation in recipients younger than 20 years; however, more than one third of these patients received umbilical cord blood grafts. Among adults, peripheral blood stem cells are the most common graft source for unrelated donor transplants.
  • Bmt intro lecture

    1. 1. HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR THE TREATMENT OF PEDIATRIC PATIENTS WITH CONGENITAL OR ACQUIRED HEMATOPOIETIC DISORDERS OVERVIEW
    2. 2. NUMBERS TO PUT THINGS IN CONTEXTNumber of patients diagnosed with cancer in the US – 2007 ~30,000/yr potentially treatable with SCT • Adult Cancer -Overall 1,445,000 -Prostate 218,000 -Breast 178,000 -Lung 214,000 -Colon 154,000 -Leukemia 44,000 • Pediatric Cancer -Overall 13,400 -Leukemia 3,400
    3. 3. HISTORICAL BACKGROUND Animal StudiesEarly 1950sHigh doses of total body irradiation caused fatal damage to the GI and CNS systems lower doses resulted in late death from hemorrhage and infectionMarrow from animals genetically identical to treated animals averted deathMarrow from non-identical animals led to an immunologic reaction methotrexate prevented that reaction induced tolerance to skin graftsCyclophosphamide also permitted engraftment of allogeneic marrow.
    4. 4. HISTORICAL BACKGROUND1939 Osgood Infusion of a few ml of marrow into patients with aplastic anemia no benefit1959 Thomas Infusion of large volumes of marrow into patients with refractory leukemia one patient with transient engraftment First paper on BMT in humans1960’s van Rood Human Leukocyte Antigens (HLA) defined Dupont Attempts at sibling donor transplants1968 Good First successful BMT in 2 patients Bortin (SCID and WAS)
    5. 5. THE FIRST 100 ALLO TRANSPLANTS Fred Hutchinson Cancer Research Center - Seattle
    6. 6. WHAT HAPPENED – 1980s to 2007 Progress in the field of transplantation- Early 1980’s: Autologous and matched sibling SCT- Mid 1980s GvHD prophylaxis w/CSA and MTX First T cell depletion techniques- Late 1980’s: Unrelated Donor Allogeneic SCT- Mid 1990’s: Mobilized stem cells from peripheral blood Stem cells from placental cord blood- Late 1990’s: Mismatched related family donors Non-myeloablative (mini) transplants
    7. 7. ANNUAL NUMBERS OF TRANSPLANTS WORLDWIDE 1970-2006 40000 35000 30000 autologous 25000 20000 15000 allogeneic 10000 5000 0 1970 1975 1980 1985 1990 1995 2000 2005
    8. 8. NUMBER OF TRANSPLANTS AT MSKCC ADULT ALLO PEDIATRIC ALLO2002 58 2002 412003 60 2003 312004 58 2004 372005 68 2005 512006 97 2006 41 ADULT AUTO PEDIATRIC AUTO2002 128 2002 312003 154 2003 142004 127 2004 132005 195 2005 72006 142 2006 3
    9. 9. DEFINITIONS &BASIC PRINCIPLES OFTRANSPLANTATION
    10. 10. AUTOLOGOUS AND ALLOGENEIC STEM CELL TRANSPLANT PURPOSE• ALLOGENEIC – Replace marrow that has a cancer (ex: leukemia) or 1 or more abnormal hematopoietic lineages (ex: SCID or AA) – Give a patient allogeneic (immune) T-cells to create a graft- versus-tumor effect (ex: renal cell carcinoma) – Donor can be • Related – syngeneic, HLA matched or mismatched • Unrelated – HLA matched or mismatched• AUTOLOGOUS – Treat a cancer that responds to high dose therapy (dose intensity) and rescue marrow suppression by giving autologous stem cells afterwards (ex: neuroblastoma or lymphoma) – harvested prior to therapy and frozen
    11. 11. BASIC PRINCIPLES OF HEMATOPOIETIC STEM CELL TRANSPLANTATION
    12. 12. HEMATOPOIETIC SCTLeukemiasLymphomas Allogeneic Stem cellsAplastic AnemiaSCID = TreatmentOther marrow disorderssome solid tumorsBrain TumorsRetinoblastomaBreast CA (no longer) Autologous Stem cellsOvarian CAWilms Tumor = RescueLymphomas HD-NHL
    13. 13. ALLOGENEIC STEM CELL TRANSPLANTATION INDICATIONSEliminate a defective hematopoietic systemand replace it with a normal/healthy oneDefective hematopoietic system:Any disease in which the pathology is caused by a 1. A hematologic malignancy Ex: Leukemias, MDS 2. A defective marrow with multilineage involvement Ex: AA, Fanconi anemia 3. A defective single hematopoietic cell lineage Ex: SCID, Hemoglobinopathies
    14. 14. INDICATIONS FOR HEMATOPOIETIC SCT UNITED STATES 2005 5,500 5,000 4,500 Allogeneic (Total N=7,880) 4,000Transplants Autologous (Total N=10,840) 3,500 3,000 2,500 2,000 1,500 1,000 500 0 Multiple NHL AML Hodgkin ALL MDS/MPD CML Aplastic Other Other Non- Myeloma Disease Anemia Leuk Cancer Malig Disease
    15. 15. MARROW, PERIPHERAL BLOOD, AND TISSUE POOLSMARROWBLOOD
    16. 16. INDICATIONS FOR ALLOGENEIC HEMATOPOIETIC SCT CML ALL, NHL AML MDS BMF Syndromes1. Hematopoietic Malignancies Leukemias (CML*, AML**, ALL***) Lymphomas* Myelodysplastic Syndromes*2. Bone Marrow Failure Syndromes - Acquired: - Aplastic anemia* - Paroxysmal Nocturnal Hemoglobinuria - Constitutional: - Fanconi anemia*** - Dyskeratosis Congenita
    17. 17. INDICATIONS OF ALLOGENEIC HEMATOPOIETIC SCT3. Lineage Specific DefectsNeutrophil –Kostmann Syndrome (Congenital Agranulocytosis)CGD, Schwachman Diamond, Leukocyte Adhesion DefectChediak Higashi SyndromeMacrophageOsteopetrosis, Metabolic Disorders (Gaucher, Hunter, Hurler, Leukodystrophy)LymphocyteSCID, Wiskott Aldrich Syndrome, Reticular DysgenesisRed CellDiamond Blackfan Anemia, Thalassemias, Sickle Cell DiseasePlateletCongenital Amegakaryocytic Thrombocytopenia, TARSCATHAL CAMT SCID Osteopetrosis WAS
    18. 18. BASIC PRINCIPLES OF HEMATOPOIETIC STEM CELL TRANSPLANTATION- Solid Organ Transplant Donor Host (Graft) rejection (Patient) Rejection T-cells- Bone Marrow Transplant Graft-Versus-Host Disease Donor Host (Graft) rejection (Patient) Rejection T-cells T-cells
    19. 19. MAJOR HISTOCOMPATIBILITY COMPLEX HUMAN LEUCOCYTE ANTIGENS Graft-Versus-Host Disease HOST DONOR HLA Rejection• HLA antigens are glycoproteins expressed on the surface of cells• They are transmitted genetically (chromosome 6)• They determine the presence or absence of reactions between T-cells of donor and patient, and therefore, determine the outcome of allogeneic transplants• Parallel: HLA antigens are for allogeneic transplants, what ABO blood types are to transfusion
    20. 20. MAJOR HISTOCOMPATIBILITY COMPLEX HUMAN LEUCOCYTE ANTIGENS Low A2 B4 DR1 C05 DQB1 01Resolution A11 B44 DR13 C17 DQB1 03 High A0203 B4101 DRB1 0102 C 0502 DQB1 0101Resolution A1102 B4402 DRB1 1301 C 1701 DQB1 0301 6 Antigens 10 Antigens
    21. 21. MAJOR HISTOCOMPATIBILITY COMPLEX HUMAN LEUCOCYTE ANTIGENS Mother Father a A1 B8 DR7 c A2 B44 DR4 b A3 B7 DR2 d A29 B44 DR7 a a b bA1 B8 DR7 A1 B8 DR7 A3 B7 DR2 A3 B7 DR2A2 B44 DR4 A29 B44 DR7 A2 B44 DR4 A29 B44 DR7 c d c d a HLA-matched A1 B8 DR7 Siblings A2 B44 DR4 c
    22. 22. MAJOR HISTOCOMPATIBILITY COMPLEX HUMAN LEUCOCYTE ANTIGENS Mother Father aA01 B08 DR7 A01 B08 DR7 c A02 B44 DR4 b A03 B7 DR2 A02 B44 DR4 d A29 B44 DR7 a A0101 B0803 DR704 c A0202 B4403 DR401 3/6 (haplo) 0/6 3/6A0104 B0807 DR701 A0104 B0802 DR701 A0101 B0807 DR701A0202 B4403 DR401 A0201 B4401 DR404 A0201 B4403 DR401HLA-matched unrelated A0101 B0803 DR704 donor A0202 B4403 DR401
    23. 23. A B C DR DQPatient a/b 3201 4002 0202 0701 0202 c 0201 5101 1604 1406 0301Father a 3201 4002 0202 1301 0603 b 2401 4005 0301 0701 0202 1 1 1 1 1Mother c 0201 5101 1604 1406 0301 d 0101 1302 0608 1101 0301 1 1 1 1 1Sister b 2401 4005 0301 0701 0202 d 0101 1302 0608 1101 0301Sister a 3201 4002 0202 1301 0603 c 0201 5101 1604 1406 0301 2 2 2 1 1
    24. 24. PRIORITY OF ALLOGENEIC TRANSPLANTS Patient candidate for allogeneic transplant Family HLA typingHLA-matched Sibling No HLA-matched Sibling (25-30%) Search for an unrelated donor (NMDP – Cord Blood Banks) Transplant HLA-matched Unrelated Donor No matched (50-80%) Unrelated Donor Transplant High Risk Disease Non-High risk DiseaseTransplant Transplant No Transplant Risk (MM Related Donor)
    25. 25. HEMATOPOIETIC STEM CELL SOURCESBONE MARROW CORD BLOODPERIPHERAL BLOOD
    26. 26. HEMATOPOIETIC STEM CELL SOURCES SOURCE OF HEMATOPOIETIC STEM CELLS Marrow cord blood PBSCsAverage cell dose (TNC/kg) 5 x 108 2 x 106 10 x 108how harvesting is performed Under GA at birth G-CSF mobilization and pheresisrisks/excluded Risk of GA None Hypercoag quality of states product SS carrierscell dose sufficient for Limiting in Higher conventional or adults sized matchedcan the product be manipulated Yes No Yes (dose limiting)risk of GvHD with conventional graft Standard Lower Higheravailability of more cells, cells for CTLs Yes No Yes
    27. 27. UNRELATED STEM CELL SOURCES BY RECIPIENT AGE 1999-2006 100 Bone Marrow (BM) Bone Marrow (BM) Peripheral Blood (PB)Transplants, % 80 Cord Blood (CB) (PB) Peripheral Blood Cord Blood (CB) 60 40 20 0 1997-2000 2001-2004 1997-2000 2001-2004 Age ≤20 yrs Age >20 yrs
    28. 28. ALLOGENEIC TRANSPLANTS IN PATIENTS <20yo, REGISTERED WITH THE CMBTR – 1989 -2008 BY DONOR TYPE AND GRAFT SOURCE 5,000 Related 4,500 Unrelated – BM or PB Unrelated – CB 4,000Transplants 3,500 3,000 2,500 2,000 1,500 1,000 500 0 1989-90 1991-92 1993-94 1995-96 1997-98 1999-00 2001-02 2003-04 2005-06
    29. 29. BASIC PRINCIPLES OF HEMATOPOIETIC STEM CELL TRANSPLANTATION CYTOREDUCTION• In order to perform an allogeneic transplant successfully, we need to give a cytoreduction prior to the stem cell infusion for: Immunosuppression Myeloablation Anti-leukemic effect• This is done by using - Radiation therapy (Total body irradiation – TBI) and/or - Chemotherapy (Busulfan, Cyclophosphamide, melphalan, Thiotepa, fludarabine, …)• How much of each effect you need varies by the underlying disease, type of transplant and degree of match
    30. 30. BASIC PRINCIPLES OF HEMATOPOIETIC STEM CELL TRANSPLANTATION CYTOREDUCTION1. Myeloablation2. Immunosuppression Leukemia3. Anti-leukemia1. Myeloablation2. Immunosuppression Aplastic Anemia3. Anti-leukemia1. Myeloablation2. Immunosuppression Hemoglobinopathies3. Anti-leukemia1. Myeloablation2. Immunosuppression SCID3. Anti-leukemia
    31. 31. Stem Cell Transplant Course Thousands25 GvHD2015 ANC Platelets10 BMT50 -14 -10 -7 0 7 14 21 28 90 TBI Cy Days pre/post SCT HOST DONOR
    32. 32. ACUTE COMPLICATIONS OF ALLOGENEIC SCTImmunologic – Graft versus-Host Disease (GvHD) 25-35% – Graft failure / Rejection < 5%Infectious 10-20% – Bacterial / Fungal – Viral / ParasiticOrgan Toxicity 10% pneumonitis veno-occlusive diseaseRelapse Variable
    33. 33. 100 DAY POST-TRANSPLANT MORTALITY 2001-2006HLA-identical Sibling Autologous ) GVHD (13%) y (7% ic it Other Relapse (41%) tox Infection (16%) (8%) Relapse (70%) Infection Other (13%) (17%) Toxicity (13%)
    34. 34. ACUTE GRAFT VERSUS HOST DISEASE• Immune reaction caused by Donor T-cells in the graft, which are activated by minor or major HLA-disparities between donor and host, and attack target organs (skin, GI, liver + BM and immune system)• Occurs after engraftment - day 14-28 (prior to day 100)• Reaction dependent upon HLA-disparities – HLA mismatch: 3 Ag > 2 Ag > 1 Ag • Related donor: Mismatch > Match • Donors: Unrelated > Related
    35. 35. AcuteGraft-versus-Host Disease
    36. 36. GVHD PROPHYLAXIS GvHD GvL• Unmodified stem cell transplant Transplantation of unmodified stem cells +++ ++ (20-40%) followed by post transplant immunosuppression + -• T-cell depleted stem cell transplant (5-10%) Transplantation of stem cells after depletion of T-cells
    37. 37. Unrelated Donor SCT – NMDP
    38. 38. Lancet 2005 Wagner et al Effect of graft-versus-host disease prophylaxis on 3-year disease-freesurvival in recipients of unrelated donor bonemarrow (T-cell Depletion Trial): a multi-centre,randomised phase II–III trial
    39. 39. Acute GvHD (Grades III – IV) Chronic GvHD
    40. 40. Incidence of grade II GvHD 8% (no grade III or IV)Incidence of chronic GvHD 9% Jakubowski, A. A. et al. Blood 2007;110:4552-4559
    41. 41. GRAFT REJECTION• Immune reaction caused by Host T-cells which survived the cytoreductive regimen, and are activated by specific minor or major HLA-disparities between donor and host. They attack the donor’s stem cells with subsequent aplasia and pancytopenia• Occurs early (day 10-20) or late (day 40-60)• Reaction dependent upon HLA-disparities • HLA mismatch: 3 Ag > 2 Ag > 1 Ag • Related donor: Mismatch > Match • Donors: Unrelated > Related• Multiply transfused patients (AA, Hemoglobinopathies) at higher risk because of prior T-cell sensitization
    42. 42. INFECTIONS POST TRANSPLANT• 0-30 days Bacterial* All Fungal Candida Viral RSV, HSV• 1-3 months Fungal* Aspergillus Viral CMV, Adeno, HHV6 VZV, EBV Parasitic Toxo, PCP• 3-6 months Viral CMV, Adeno, HHV6 VZV, EBV Parasitic Toxo, PCP*After 30 days, the risk of bacterial and fungal infections persists if GvHD
    43. 43. OUTCOMESOVERALL AND DISEASE SPECIFIC
    44. 44. THE FIRST 100 ALLO TRANSPLANTS Fred Hutchinson Cancer Research Center - Seattle
    45. 45. VERY HIGH RISK ALL IN CR1 N=21 – OS 84%
    46. 46. ALL IN CR2 OverallDisease-Free Survival OverallRisk of Relapse
    47. 47. Papadopoulos E, et al., Blood. 91(3):1083-90, 1998
    48. 48. BONE MARROW FAILURE SYNDROMES APLASTIC ANEMIA• Disorder of hematopoiesis characterized by severe generalized reduction of all hematopoietic lineages in the bone marrow and peripheral pancytopenia.• Two groups: – ACQUIRED Idiopathic or secondary to drugs, infections, chemicals or irradiation – CONSTITUTIONAL comprises several genetic disorders Fanconi Anemia Dyskeratosis Congenita Schwachman Diamond Osteopetrosis• Indications for SCT: All patients
    49. 49. Kosaka, Y. et al. Blood 2008;111:1054-1059
    50. 50. Kosaka, Y. et al. Blood 2008;111:1054-1059Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.
    51. 51. SEVERE APLASTIC ANEMIA ALLOGENEIC STEM CELL TRANSPLANTATION vs IMMUNOSUPPRESSION TREATMENT Overall Since 1988 BMT BMT N=25 OS = 75.6% IST IST N=23OS = 73.8%
    52. 52. Impact of fludarabine on survival in patients with FA treated withunrelated donor BMT. Wagner JE, Eapen M, MacMillan ML, Harris RE,Pasquini R, Boulad F et al. Blood 2007; 109: 2256–2262.
    53. 53. FANCONI ANEMIA OVERALL SURVIVAL OS 74% (N=23) Sept 2005
    54. 54. OS 94.4% Overall Survival β−thalassemiaMSKCC Experience N = 20 DFS 91.7%Disease Free Survival DFS 44.8%
    55. 55. OS 91.7% Overall SurvivalSickle Cell AnemiaMSKCC Experience N = 12 DFS 91.7% Disease Free Survival
    56. 56. SCID – OVERALL EXPERIENCESince 1973: 94 transplants for SCID14 (2-4/year) over the past 5 years.Transplant Type T cell depleted HLA Haplo-disparate related donors SBA-E- bone marrow 69 CD34+E- PBSC 4 Unmodified HLA matched and partially mismatched bone marrow grafts 21Cytoreduction Matched sibling none Haplo-disparate TCD 37/69Basis for cytoreduction NK function
    57. 57. SURVIVAL BY TIME TO DIAGNOSIS OF SCID 1 MREL <3 months = 100% n=8 0.9 0.8 0.7 MREL >3 months = 72.73% n=11 0.6Proportion 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 Time Post Transplant (months)
    58. 58. LATE COMPLICATIONS OF ALLOGENEIC SCTImmunologic – Chronic Graft versus-Host Disease (GvHD) – InfectionsLong term organ toxicity - Endocrine: Growth, Gonadal, Thyroid - CNS - Cardiac - Pulmonary - Hepatic - Renal - OtherSecondary Malignancies - Solid TumorsPsychological Late effects
    59. 59. CHRONIC GVHD
    60. 60. WHAT’S NEW AND EXCITINGNON-MYELOABLATIVE TRANSPLANTS (MINI- TRANSPLANT)ADOPTIVE CELL THERAPY Use of broad unselected or selected donor lymphocytes prophylaxis or treatment of infections or disease Use of NK cellsVACCINES of donor (in the pre-transplant period) or host (in the post-transplant period)GENE THERAPY for inborn errors especially those where a selective advantage may exist for corrected cells
    61. 61. NON-MYELOABLATIVE TRANSPLANTSPrinciple:•avoid use of high dose therapy •decreases toxicity in older or heavily pre-treated •high doses of donor T-cells•Cytoreduction limited to immuno-ablation•Advantages: •Transplants less toxic •Graft versus leukemia (or tumor)•Dis-advantages •higher incidence of GvHD – especially chronic •takes time to establish full donor chimerism
    62. 62. CONVENTIONAL CYTOREDUCTION Graft-Versus-Host Disease Donor Host (Graft) Rejection (Patient) T-cells T-cellsBone Marrow Bone Marrow NON-MYELOABLATIVE CYTOREDUCTION Graft-Versus-Host Disease Donor Host (Graft) Rejection (Patient) T-cells T-cellsBone Marrow Bone Marrow
    63. 63. ADOPTIVE CELL THERAPY – T CELLSDonor Patient Donor Lymphocytes (T-cells) Ex-vivo expanded Antigen-specific T-cells T-cells containing HSV-TK suicide gene Infection (EBV, CMV) Leukemia (CML)
    64. 64. ADOPTIVE CELL THERAPY – NK CELLS• Adoptive transfer of NK cells to enhance engraftment and leukemia resistance.• Selection of KIR*-mismatched HLA-compatible donors conferring NK-mediated leukemia resistance*KIR = Killer-cell Immunoglobulin-like Receptor
    65. 65. GENE THERAPYInsertion of a normal gene into deficient stem cellAlready trials for X-linked SCID, ADA-SCID, CGDOther target genes already in or close to trials: - ADA-deficient SCID - Thalassemia / Sickle cell disease - Wiskott Aldrich Syndrome - Fanconi Anemia - Hemophilia
    66. 66. THALASSEMIA Gene Therapy E A N D C G-CSF R M Infusion a O I Autologous t L S Hematopoietic h L S M e I Busulfan Stem Cells t Transduced E O Pre-SCT e Pre-SCTScreening N N with THALAGEN Work-up1 r Work-up 2 Work-up T PBSCT Cytotherapy Lab CD34 selection Gene Therapy Lab Lentiviral mediated human β Globin Gene transfer
    67. 67. STEM CELL TRANSPLANTATIONPROGRESS IN THE LAST 30 YEARS 2000’s 1977

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