Correspondence
Transplantation of Cord-Blood Cells
N Engl J Med 1995; 333:67-69July 6, 1995
- Article
To the Editor:
The editorial by Dr. Gale (Feb. 9 issue)1 highlights potential benefits and theoretical obstacles associated with the use of cryopreserved umbilical-cord blood as a source of hematopoietic stem cells. Dr. Gale asks the valid, though outdated, question, ``Should the United States develop a bank of cord-blood cells?'' He juxtaposes this technique with the cryogenic suspension of Woody Allen and the attempt to clone a complete leader from a fragment of his nose in the movie Sleeper. This may have led readers to infer that cryopreservation of cord blood and transplantation in unrelated recipients remain the subject of science fiction, confined to Hollywood or, at best, to the distant future. We feel compelled to take issue with Dr. Gale on two specific points.
First, Dr. Gale states that immature hematopoietic progenitor cells are ``readily detected in cord blood, but considerably less frequently than in adult bone marrow.'' A multitude of in vitro studies have demonstrated the opposite: the frequency of progenitor cells, as detected by both short-term and long-term culture assays, is higher in cord blood than in bone marrow.2,3
Second, cord-blood banks have been or are being established in the United States (in September 1992), Europe, and Australia.4,5 With the use of cord blood from the Placental Blood Bank at the New York Blood Center, established with the support of the National Heart, Lung, and Blood Institute, 25 patients have been treated with cells from unrelated donors, including 8 patients whose weight exceeded 35 kg. Two of us were the primary care physicians for 13 of these patients, and we can attest to the fact that the use of banked umbilical-cord blood from unrelated donors as an alternative source of stem cells is not science fiction.5 We believe that the rapidly expanding use of this technique has already answered the nonfictional aspects of many of the questions that Dr. Gale poses.
5 ReferencesGeoffrey B. McCowage, M.B., B.S.
Joanne Kurtzberg, M.D.
Duke University Medical Center, Durham, NC 27710Pablo Rubinstein, M.D.
New York Blood Center, New York, NY 100211
Gale RP . Cord-blood-cell transplantation -- a real Sleeper? N Engl J Med 1995;332:392-394
Full Text | Web of Science | Medline2
Broxmeyer HE ,Hangoc G ,Cooper S , et al. Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci U S A 1992;89:4109-4113
CrossRef | Web of Science | Medline3
Lu L ,Xiao M ,Shen R-N ,Grigsby S ,Broxmeyer HE . Enrichment, characterization, and responsiveness of single primitive CD34+++ human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential. Blood 1993;81:41-48
Web of Science | Medline4
Gluckman E ,Wagner J ,Hows J ,Kernan N ,Bradley B ,Broxmeyer HE . Cord blood banking for hematopoietic stem cell transplantation: an international cord blood transplant registry. Bone Marrow Transplant 1993;11:199-200
Web of Science | Medline5
Kurtzberg J ,Graham M ,Casey J ,Olson J ,Stevens CE ,Rubinstein P . The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation. Blood Cells 1994;20:275-284
Medline
To the Editor:
The transplantation of cord-blood cells poses some practical ethical problems. At the Children's Hospital in Sydney, Australia, we have made available the storage of umbilical-cord blood from siblings of patients since 1991. Because of the attention that the media have paid to cord-blood transplantation, the procedure has usually been performed at the request of the parents. Since 1991, we have stored cord blood from 12 healthy newborn siblings of patients. None of those cord-blood samples have been used for transplantation. Even in the one case in which there was a match between the new baby and the patient and a transplantation was performed, we still preferred to use bone marrow, because of the slower neutrophil recovery associated with cord blood, the specific need in this patient for the neutrophil count to reach a normal level as quickly as possible, and the possibility that cord-blood cells might be of use to the donor in the future.
What are our obligations to the parents of the patient and the normal sibling, now that we have stored the sibling's cord blood? For most of the patients, there is no longer a risk of relapse. I believe we have an ethical obligation to preserve the cord-blood cells, once they have been frozen. Is this a legal obligation? Our marrow and stem-cell storage facility is designed to store cells temporarily for clinical use. Greater use of this facility for the storage of cord-blood cells would soon overload the system. Should we then start to charge for storing the normal sibling's cord blood, as is now being done by private corporations in the United States? The parents asked us to store the cord blood not for the benefit of the donor but for that of the patient. If we tell the parents that they must pay for storage or we will dispose of the cells, we impose an unacceptable pressure on the family to pay.
I do not know whether it is the right of every newborn to have his or her cord blood stored for future use. For the time being, we continue to store umbilical-cord blood without cost to the parents. We continue to offer cord-blood storage for siblings, but I try to restrict this offer to cases in which the cells might realistically be used as a substitute for bone marrow transplantation.
Peter J. Shaw, M.B., B.S.
Royal Alexandra Hospital for Children, Camperdown, NSW 2050, AustraliaTo the Editor:
Dr. Gale's editorial contains an error. He states, ``The only successful cord-blood transplantations have been performed in small children.'' A report published in 1972 described the use of umbilical-cord blood as a source of hematopoietic stem cells for transplantation in a 16-year-old patient with leukemia.1
1 ReferencesMark Ende, M.D.
Frederick I. Ende, M.D.
121 S. Market St., Petersburg, VA 23803To the Editor:
The editorial by Gale, although amusing, contains an error. He states that the National Marrow Donor Program can identify fully matched volunteer donors for only one third of the patients who need a marrow transplant from an unrelated donor and that this number would increase only slightly with a substantial increase in the potential pool of donors. As Table 1Table 1
Identification of HLA-A,B,DR-Identical Donors during Initial Seaches of the National Marrow Donor Program's Registry shows, 61 percent of initial searches of the program's registry in 1994 resulted in the identification of HLA-A,B,DR-identical donors. This percentage has risen as a function of both the increased number of donors and the increased racial and ethnic diversity among donors, the latter trend resulting in additional unique HLA phenotypes in the donor pool. In the past year 32 percent of all newly registered potential donors were members of racial or ethnic minorities. Although the efficacy of cord-blood transplantation awaits confirmation in clinical trials, it is reassuring to know that more than 3000 marrow transplants from unrelated donors have been used and that the chances of identifying a donor have improved considerably.Craig W.S. Howe, M.D., Ph.D.
National Marrow Donor Program, Minneapolis, MN 55413Author/Editor Response
Dr. Gale replies:
To the Editor: A major question in biology is whether evolution is gradual, driven by selection, or cataclysmic, driven by mutational events, only subsequently modified by selection. A similar question applies to the evolution of science and medicine. The search for bone marrow donors is an example.
A 1988 consensus conference sponsored by the National Institutes of Health (NIH) concluded that there were insufficient scientific data to justify establishing a national registry of unrelated bone marrow donors; a preliminary trial was recommended. A clear concern was the diversion of NIH funds away from projects with higher scientific priorities. Undaunted, supporters of unrelated-donor transplants used political pressure to have funds in the Navy budget allocated for the establishment of such a registry. As a result, the successful National Marrow Donor Program was born. Once the funds had been allocated, the NIH sought control of the program, arguing that it was a scientific undertaking (and thereby increasing rather than decreasing the NIH budget). When it became clear that the program focus was predominantly service, partial control was transferred to the Health Resources and Services Administration.
Does this tale make sense to scientists? No. Does the National Marrow Donor Program work? Yes, it works quite well. Is it wise to plan a national pool of cord-blood-cell donors on the basis of the preliminary results in 25 cases of unrelated-donor transplantation, fewer than 10 of which have been reported in peer-reviewed scientific journals? Obviously not, though a preliminary trial seems appropriate. What should those who support a national pool of cord-blood-cell donors do? Avoid NIH consensus conferences, watch for cataclysmic mutational events, and find a friend in Washington.
Some other issues in these letters deserve comment. There seems to be little point in debating the relative frequencies of progenitor cells in cord blood and bone marrow when stem cells, difficult or impossible to define let alone assay in humans,1 are more important in the context of transplants. Data in the first report cited by McCowage and colleagues clearly indicate that the frequency of progenitor cells in cord blood, as compared with the frequency in bone marrow, depends on the growth factor (or factors) used for stimulation.2 For example, there were more granulocyte-macrophage colony-forming units in bone marrow than in cord blood when granulocyte-macrophage colony-stimulating factor was used but fewer when steel factor was used (see the footnote to 1 of Broxmeyer et al.2). The second report indicates a higher ``cloning [plating] efficiency'' of CD34-positive cord blood than of bone marrow cells.3 However, the results should be adjusted for the higher frequency of CD34-positive cells in bone marrow than in cord blood. A final consideration is that there are many more cells in bone marrow grafts than in cord-blood-cell grafts and many more T cells, which, as I note, may be important in ensuring engraftment and mediating at least some antileukemic effects.
Dr. Howe indicates that HLA-A,B,DR-identical donors were identified in 61 percent of recent searches for unrelated donors. However, a substantially smaller proportion of patients received transplants from HLA-A,B,DR-identical unrelated donors. There are two reasons for this: a substantial proportion of serologic HLA-DR matches prove to be unsuitable after detailed molecular analyses have been conducted, and many patients have a relapse or die before a transplantation can be performed.
Dr. Shaw raises important fiscal and ethical issues that merit discussion but are beyond the scope of my editorial.
Drs. Ende and Ende report on a young man with leukemia who received infusions of cord-blood cells from several donors after chemotherapy. HLA typing was not performed for any of the grafts, and the chemotherapy was mild by transplantation standards. I would not expect engraftment to occur under these conditions and am not convinced by the data reported, which relied on red-cell typing rather than HLA typing or cytogenetic analyses.4
4 ReferencesRobert Peter Gale, M.D., Ph.D.
Salick Health Care, Los Angeles, CA 90048-45201
Lansdorp PM . Developmental changes in the function of hematopoietic stem cells. Exp Hematol 1995;23:187-191
Web of Science | Medline2
Broxmeyer HE ,Hangoc G ,Cooper S , et al. Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci U S A 1992;89:4109-4113
CrossRef | Web of Science | Medline3
Lu L ,Xiao M ,Shen R-N ,Grigsby S ,Broxmeyer HE . Enrichment, characterization, and responsiveness of single primitive CD34+++ human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential. Blood 1993;81:41-48
Web of Science | Medline4
Ende M ,Ende N . Hematopoietic transplantation by means of fetal (cord) blood: a new method. Va Med Mon 1972;99:276-280
