A Cure for Sickle Cell Anemia and Thalassemia
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1 IV Simpósio Internacional de Hemoglobinopatias A Cure for Sickle Cell Anemia and Thalassemia Bertram Lubin, MD and Mark Walters, MD 4 September 2007
2 Topics to be covered Cord blood: Importance and biology Sibling cord blood banking for children with sickle cell anemia and thalassemia Related cord blood transplantation Future directions
3 Cord Blood Blood remaining in the placenta after an infant is born. Enriched in proliferative hematopoietic cells. Contains immunologically naive T cells. Less risk of CMV contamination than bone marrow. Can be easily cryopreserved. Can be used without a complete HLA match. Available immediately.
4 Cord Blood Stem Cell Biology Compared to adult blood, CB has more abundant naïve T cells, fewer suppressor T cells, and reduced NK activity Cells in CB respond rapidly to cytokine stimulation CB retains graft-versus-leukemia effect Stimulated CB T-cells have reduced production of IFN-γ and TNF-α
5 CB Transplant Background First related CBT 1988 sibling (E. Gluckman) First unrelated CBT 1991 NYBC (P. Rubinstein) Since 1993 >8,500 unrelated CB transplants have been performed worldwide Transplantation across HLA barriers is possible Access to transplant for underserved minorities Applications for adults using multiple units Overall and disease-free survival with mismatched UCB are similar to those with fully matched unrelated adult stem cells Less severe GVHD
6 The Present and Future for Cord Blood Transplants
7 Cord Blood Banks Public Private Sibling
8 CHORI Sibling Cord Blood Program: The only program of its kind in the world Families with children who have disorders that could be treated by transplantation. Prospective, full sibling pregnancies. Resource to collect, transport, characterize and cryopreserved cord blood units Remote sites & community hospitals, preimplantation diagnostic centers
9 Collection Bag and Custom Sterile Prep Kit
10 Program Logistics Family and physician contact staff and enroll following informed consent. Maternal and patient medical history obtained. Maternal testing for infectious disease. Collection kit sent to family. CB collected at time of delivery by the obstetrician/midwife and shipped to the lab for processing. Samples processed and cryopreserved within 48 hours of collection.
11 Cord Blood Stem Cell Laboratory Processing and storing Determine volume, cellular content, and cellular composition HLA typing Infectious disease testing Genetic testing: hemoglobinopathy Stored in liquid nitrogen and shipped to transplantation center upon request
12 Sibling Cord Blood Units Collected Malignant Disorders 30% 6% 14% Sickle Cell Disease Thalassemia 50% Other Hereditary or Rare Hematological Conditions
13 SDCB Units Collected Vs. Released for Transplantation # Collected # Released % Released Malignant diseases % Sickle Cell % Other/Rare % Thalassemia % Unknown % TOTAL % March 2006
14 SDCB Transplantation for Thalassemia and Sickle Cell Anemia 44 patients received SDCB transplants in 22 transplant centers between 6/94 and 6/01 with median f/u 27 (range, ) months Diagnosis: Sickle cell anemia (n=11) Thalassemia major (n=33) - Lucarelli Class I (n=19) Donor: HLA-identical sibling (n=41) 1-Ag (A-allele) mismatch (n=3) Locatelli et al, Blood 101: , 2003
15 SDCB Transplantation for Thalassemia and Sickle Cell Anemia Outcome (N=44) Disease-free survival: Overall 81% Sickle cell anemia: 90% Thalassemia: 79% OVERALL SURVIVAL: 100% Impact of MTX on DFS: CSP alone: 89% P<0.05 MTX + other: 55% Impact of Preparation : BU/CY/ +/-ATG: 62% P<0.05 Add thiotepa/flu: 94% Locatelli et al, Blood 101: , 2003
16 The CHORI Program: Whom to transplant and when? Patients with severe disease such as recurrent pain, recurrent ACS, stroke Patients at risk for adverse outcomes such as stroke (as determined by TCD) Patients who have transfusion dependent thalassemia Young patients (newborn screening)
17 SDCB Transplantation for SCD and β -thalassemia Major Treatment Day -9 to -6 Day -5 to -2 Day -1 Day 0 Post- Transplant Busulfan/Busulfex X Cyclophosphamide X Thymoglobulin X UCB Infusion X CSP X X Through Day +90 MMF X Through Day +35 April 2004
18 Sibling Donor Cord Blood Transplant for SCA/Thalassemia (N=33) Median follow-up 2.3 years (range: ) 90% 87% Percent Event = death, graft rejection, or disease recurrence. Time (years) after UCBT Oct 2006
19 Cure of Thalassemia Sibling Cord Blood Transplantation For Thalassemia
20 Sibling Cord Blood Transplant for Sickle Cell Anemia: Stroke recovery!
21 General CB Research Directions Cell biology and plasticity of subpopulations Homing and engraftment Immunologic applications: T regulatory cells Expansion of stem cell numbers Efficacy of combined cord blood and bone marrow Combined CB units for adults
22 Specific CB Research Questions Non-myeloablative transplant HLA diagnosis using maternal blood Pre-implantation genetic diagnosis Ideal conditioning regimen Indications Multicenter trials Unrelated donors
23 Cord Blood Banking in Brazil Justification for a national program Designated sibling collection Collaborative opportunities
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