July 1999

Cord Blood Banking and Transplantation Richard Moldwin, MD, Ph.D. Medical Director ITxM Cord Blood Services Introduction: Hematopoietic stem cell transplantation can provide a cure for a variety of malignant and non-malignant disorders (Table 1). In autologous transplants, the patient’s own stem cells are collected and stored for later transplantation. In allogeneic transplants, the transplanted stem cells are derived from a related or unrelated donor. In many cases, an allogeneic, rather than autologous, transplant is preferred for treating malignant and non-malignant diseases. Siblings who match the patient for cell surface HLA proteins offer the best option for allogeneic graft compatibility and a good outcome. HLA Matching: Unfortunately, matched sibling (allogeneic) donors are available to only about 30% of those in need of an allogeneic transplant. To help provide matched unrelated donors for these patients, large registries of volunteers willing to donate marrow (or peripheral blood stem cells) to unrelated recipients have been established (e.g. the National Marrow Donor Program). However, finding appropriate matches for many patients remains difficult. Cord Blood Stem Cell Transplants: One solution to the shortage of matched donors may be found with umbilical cord blood (CB), which is a rich source of hematopoietic stem cells. CB has been used successfully in place of bone marrow in children and a few adults undergoing stem cell transplantation. Since the first CB transplant in 1987, more than 800 such transplants have been done in the US and Europe. Graft versus Host Disease is Decreased with Cord Blood: Recent data indicate that CB transplantation is associated with significantly decreased severity of T cell-mediated graft-versus-host disease (GvHD), when compared with historical data from matched unrelated bone marrow transplants. Acute GvHD is a syndrome of dermatitis, enteritis, and hepatitis occurring within 100 days of the transplant. Chronic GvHD, by definition, develops after 100 days post-transplant. Chronic GvHD is similar in many respects to collagen-vascular diseases such as scleroderma and lupus. Both acute and chronic forms of GvHD are major causes of morbidity and mortality for patients undergoing allogeneic stem cell transplantation. With CB transplants, the decreased incidence of severe GvHD now permits the routine use of relatively mismatched CB units. The ability to use mismatched CB units therefore allows many more patients to be transplanted. However, engraftment and survival rates are still improved with close HLA matches. Cord Blood’s Other Advantages: Although CB T cells are less likely to produce serious GvHD, early data suggests that they can still be effective in suppressing or eliminating malignant cells remaining in the transplant patient. The presence of a graft-versus-tumor effect is being closely studied in CB recipients. There are several other advantages to CB as well. Since CB units are stored frozen, they can be released immediately to patients in need of a transplant. In contrast, setting up an unrelated donor stem cell harvest (bone marrow or peripheral blood stem cells) can take several months. CB collection also poses no risk to the mother or baby, whereas both bone marrow harvests and G-CSF-mobilized peripheral blood stem cell harvests have been associated with occasional serious morbidity and even mortality. Cord Blood’s Disadvantages: Since the numbers of CB stem cells may be insufficient to engraft a large patient (i.e. an adult or large child), the patient may die before engraftment takes place. Even in small patients, where the stem cell numbers are sufficient, engraftment is usually significantly delayed (~28 days for neutrophils, ~90 days for platelets) when compared with peripheral blood stem cells (~7 days for neutrophils, ~9 days for platelets). A further problem is that a patient who does not engraft cannot easily obtain more stem cells from the CB donor (who is probably still a small child). In contrast, adult unrelated donors may donate stem cells more than once for the same transplant patient. The Growing Use of Cord Blood: The shortage of matching CB units can addressed by the establishment of CB "banks" throughout the world. There are currently about 25,000 units of CB stored worldwide in CB banks. These CB banks are a life-saving resource for many patients, who would otherwise die for lack of a suitable stem cell donor. There is a pressing need for the expansion of CB donor banks to ensure that all patients needing a stem cell transplant are offered a CB unit with a suitable HLA match. Autologous Cord Blood Storage: CB stem cells have not yet been used for autologous transplants (i.e. using a child’s stored CB for a transplant in that same child, later in life). However, commercial CB banks have begun to sprout up throughout the country, advertising autologous CB storage services. The charges for these services range from about $275 to about $1500, not including yearly storage fees (usually $50-100 per year). Estimates on the chances of a child ever using such an autologous CB unit for transplant range from 1/10,000 to about 1/50,000. If the family has many children, the stored CB may be of most benefit to an HLA-matched sibling who needs a transplant. However, even in this case, the sibling CB donor should still be available to donate peripheral blood stem cells or marrow. Although the future uses of stored autologous CB are unknown, autologous CB storage would appear to be of marginal benefit. Public Cord Blood Banking: In contrast to autologous CB banking, "donor banks" or "public banks" have been established throughout the world for the cost-free collection of units for use in stem cell transplantation. The Institute of Transfusion Medicine (ITxM) has recently established a public cord blood bank. ITxM Cord Blood Services (ICBS) collects, tests, and freezes units of umbilical CB. It is a community resource dedicated to providing units of CB for stem cell transplantation and medical research. CB units collected in the Chicago and Pittsburgh areas will be released in the US as well as abroad, in conjunction with the NMDP. Recruitment of Donors: Recruitment to donate CB is done by word of mouth or through interested obstetricians, nurses and nurse-midwives. The potential donor (mother) is asked to consent to: Providing medical, ethnic, and related information Donating CB to the CB bank for transplantation and/or research Providing 7 cc of maternal blood for tests, including HIV testing Providing information about the newborn's medical history Collection: After delivery of the newborn, the obstetrician, midwife, or nurse collects the cord blood using two 60 ml syringes containing an anti-coagulant (CPD-A1). CB stem cells survive for at least 2 days in the collection syringes at room temperature. No blood is drawn from the infant for testing. Processing: When the CB arrives at the processing facility, it is separated into red cell, white cell, and plasma components. The white cell component, which contains the stem cells, is cryopreserved using DMSO and Dextran as cryoprotectants. The CB is cultured to detect microbial contamination, and assays of stem cell activity are performed before freezing. In addition the mother’s blood is tested for HIV, Hepatitis B & C, HTLV I & II, Syphilis, and CMV. Once the CB is safely frozen, it is HLA-typed, and registered for searching through the NMDP. Future Prospects: Although there are still hurdles to be overcome using cord blood, this new approach offers a new chance at life for many patients. In the future, new developments in stem cell expansion, amelioration of GvHD, and immunotherapy should further refine cord blood transplantation into a cure for many more patients. TABLE 1 Some Diseases Treated with Cord Blood Transplantation Acquired Hematologic Disorders: ALL, AML, CML, Myelodysplastic Syndromes, Non Hodgkin Lymphoma, Aplastic Anemia Solid Tumors: Neuroblastoma, Breast Cancer Histiocytic Disorders: Langerhan's Cell Histiocytosis, Familial Erythrophagocytic Lymphohistiocytosis Congenital Hematologic Disorders: Blackfan-Diamond Anemia, Congenital Amegakaryocytic Thrombocytopenia, Congenital Pure Red Cell Aplasia, Kostmann's Syndrome, Fanconi Anemia Congenital Hemoglobinopathies: Sickle Cell, Thalassemia Congenital Immunodeficiencies: Leucocyte Adhesion Deficiency, Bare Lymphocyte Syndrome, Sever Combined Immunodeficiency, X-linked Lymphoproliferative Disease, Wiscott-Aldrich Misc. Congenital Disorders: Gunther's Disease, Osteopetrosis, Dyskeratosis Congenita, Hurler's, Hunters, Inherited Neuronal Lipoid Fuscinosis, Lesch-Nyhan, Adreno leukodystrophy

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