Cord Blood Transplantation: Umbilical Blood As Hematopoietic Stem Cell Source Analysis of theoretical/clinical advantages/disadvantages Comparison with born marrow transplantation Documentation and statistical report Conclusion and recommendation

Allogenetic Hemopoietic Stem Cell Transplantation: Acute leukemia (AL) Hematologic malignancies Sickle cells anemia & Thalassemia Aplastic Anemia Children with inborn errors (immunodeficiency) Wiskott-Aldrich syndrome

Conventional Treatment: BMT: Need HLA - matched donors (histocompatibility) Current matching test not comprehensive (type I,II) Graft vs. Host disease (GVHD) Delayed immune reconstitution Graft failures

CBT -the Theoretical Advantages : 1. Proliferative advantage 2. Relative immaturity of immune system at birth -lymphocyte enriched in double-negative cd3+ -naïve phenotype: - produce fewer cytokines, - express less mRNA transcript for INF, IL4, IL10 - but little IL2 3. Have fully constituted polyconal t cells repertoire, protected from apoptosis (low level of cd95) 4. NK function reduced, but inducible, early NK, T cells cytotoxicity impaired (no acute GVHD vs. BMT)

5. Easy of procurement -absence of risk for mother/child 6. Reduced likely hood of transmitting infections, especially cmv 7. 20,000 units currently available for immediate use 8. Average cost about 1/5 of BMT

Current: 1K Cases Reported Worldwide, Since 1988 Surprisingly, related CBT better than unrelated but not in all cases Survival rate better at: 1. Younger patients 2. Inborn errors 3. Acute leukemia in 1st & 2nd remission 4. Nucleated cells 5. Recipient negative cytomegalovirus (cmv)

Based on 300 Patients From 80 Centers, 20 Nations: Overall: 1 year survival: 64% + 5% -HLA identical: 73% + 5% -HLA non-identical: 30% + 10% CBT that are more likely to be successful: x 10^7 4. Recipient-negative CMV serology 5. Sex match

Unrelated CBT in Adults: Neutrophil recovery (60d): 76% + 12% Acute GVHD (> grade II): ~30% 1yr event free survival (EFS): % Source for unrelated homeopathic stem cells Concern: -delayed engraftment due to low stem cell # -total body irradiation as a risk (also in BMT)

Hemoglobinopathies: CBT: 100% survival 49% 2yr EFS Sustained engraftment: 50% Recommendation: -reserving CBT for younger patients in order to increase the dose of cells infused

Inborn Errors: Immunodeficiency Wiskott-Aldrich syndrome (WAS) Hunter’s disease Bare lymphocyte syndrome Adrenoleukodystrophy Neutrophil recovery: RCBT-83%, UCBT-86% 1yr EFS: RCBT= 71+17%, UCBT= 70+11% 2yr EFS: RCBT= 57+19%, UCBT= 56+13%

Children With Acute Leukemia: RCBT neutrophil recovery (60d): 84% + 7% UCBT neutrophil recovery (60d): 79% + 6% RCBT 2yrs event free survival (EFS): 39+8% UCBT 2yrs EFS: 30% + 7% Conclusion: CBT from either R/UCBT is a feasible procedure able to cure a significant proportion of children with AL with standard risk factors

Summary: 1. Is there enough stem cells in a single cord blood for short/long term engraftment? A: high # of nucleated cell infused is a good prognostic factor for engraftment/survival -medium for each unit of CB: 11x10^8 NC -# of NC infused after thawing was a major factor for neutrophil/plalet recovery -adult none received CBT < 1x10^7 NC/kg survived

Summary: Recommendation: - Standardize CD34+ cell count - Improving thawing process - Usage of hematopoietic growth factor, such as G-CSF, kit ligand or thrombopoietin TPO - In vitro expansion (cytokine cocktails: TPO & FLT 3)

Summary: 2. Immunological immaturity of cord blood cells decreases incidence & severity of acute GVHD even in HLA-mismatched situation 3. Does immune reconstitution delayed after CBT? A: similar to BMT in HLA identical sibling transplants 4. Possibility to enhance other transplantation*