FAQ re Cord Blood Transplants

• What is the need for cord blood donations?
  
• 5. How long does it take to search for a cord blood donor?
• 6. How long does it take cord blood to engraft in a transplant recipient?
• 7. How does Graft Versus Host Disease (GVHD) from cord blood compare to other sources of stem cells?
• 8. Does cord blood carry a Graft-Versus-Leukemia effect?
• 9. What is the minimum dose of stem cells from cord blood needed for engraftment of a new immune system?
• 10. Can the use of cord blood for adults be enhanced by expanding the number of stem cells in vitro?
• 11. Can the use of cord blood for adults be enhanced by combining multiple, mis-matched, cord blood units?
• 12. What is the maximum degree of patient-donor incompatibility (mismatched HLA types) that can be tolerated in cord blood transplants?
• 13. Until what age can a person receive a cord blood transplant?
• 14. How does long-term survival compare among recipients of bone marrow transplants versus cord blood transplants?
• 15. Which poses less risk of passing an inherited disorder, adult bone marrow or infant cord blood?
• 16. What is the probability that a person will require a transplant of stem cells over the course of a lifetime?
• 18. Can cord blood transplants be used for gene therapy?
  

Abstracts for medical research articles on any topic can be found from the on-line search engine of the National Library of Medicine: PubMed.

Originally, patients who received chemotherapy which wiped out the immune system would receive a transplant  of blood stem cells ("hematopoetic" stem cells) from the bone marrow of a matched donor. The USA National Marrow Donor Program (NMDP) maintains a public registry of adults who are willing to consider bone marrow donation, and similar registries exist in other countries. Despite these registries, about 50% of all patients needing a stem cell transplant cannot find a matching bone marrow donor.

Umbilical cord blood is also a rich source of blood stem cells that  can be transplanted to regenerate a patient's immune system.  There are other parts of the human body that contain stem cells, but the only sources which are concentrated enough to be harvested for a transplant are the bone marrow, the circulating blood, and the umbilical cord.

Answer: At least a month less than to find a bone marrow donor. Median time to chose a cord blood unit is 13.5 days (range, 2-387), compared to median time to approve an unrelated bone marrow donor of 49 days (range, 32-293), in a summary of 171 donor searches over the course of a year at the University of Minnesota. The "additional time taken to obtain a BM donor was predominantly due to the additional 30-day interval (range, 10-101 days) required to clear the donor".

Reference:

• Barker, JN et al. (2002) Biology of Blood & Marrow Transplantation vol.8(issue 5):257-260

Back to top

Answer: At least a week longer than it takes bone marrow to engraft. Median engraftment times for bone marrow and cord blood are typically 18 and 26 days.

References:

• Rocha, V., et al. (2000) NEJM 342:1846-54
• Wadlow & Porter (2002) Biology of Blood & Marrow Transplantation vol.8(issue 12):637-647

New Answer: Research is underway to speed up engraftment. Expanding the number of stem cells in cord blood (see question 10.) makes it possible to transplant bigger patients, but does not speed up engraftment. In Aug 2004, a research team at led by Hal Broxmeyer at Indiana University School of Medicine (press release) announced that they can speed up engraftment by inhibiting or deleting CD26, an enzyme on the surface of stem cells. The initial publication describes research on mice, but human trials are planned.

Reference:

• Christopherson, KW II et al., 13 Aug 2004 Science 305(5686), 1000-1003. "Modulation of Hematopoietic Stem Cell Homing and Engraftment by CD26"

Back to top

Answer: GVHD is less severe with cord blood than with bone marrow. In a study where all patients received an HLA-matched transplant from a sibling, and the results were controlled for age, the relative risk of cord blood versus bone marrow was 0.41 for acute GVHD and 0.35 for chronic GVHD.

The accepted explanation is that cord blood carries much less GVHD than bone marrow because the newborn baby is "immunologically immature" -- ie., the immune system has not had time to be exposed to various foreign bodies and develop reactions against them.

Reference:

• Rocha, V., et al. NEJM 2000;342:1846-54

In late 2003 it was announced that a patient's risk for GVHD is also governed by genetics: those patients who carry the gene "C/C interleukin-10" are 2.6 times more likely to get GVHD after a perfectly matched sibling transplant than patients who carry the A/A genotype.

Reference:

• Lin et al. NEJM 2003; 49(23):2201-10

Back to top

Answer: Apparently very little, if any. Graft-versus-Tumor effect is known to be correlated with Graft-Versus-Host Disease (GVHD). Both are mediated by T-cells. While the T-cell content of umbilical cord blood is lower than bone marrow, it is not low enough to be the sole factor explaining the lower incidence of GVHD in cord transplants. Apparently the types of T-cells, their maturity, and their activity also differ. This is a frontier of on-going research.

References:

• Wadlow & Porter (2002) Biology of Blood & Marrow Transplantation vol.8(issue 12):637-647

Back to top

Answer: This is the same as asking, "what is the maximum patient size that can be transplanted with a single cord blood collection?" The optimal dose is about 20 million nucleated cells per kilogram of body weight. "patients who received no more than 10 million nucleated cells per kilogram had a 75 percent probability of death, whereas recipients of at least 30 million nucleated cells per kilogram had a 30 percent probability of death."

Reference:

• Editorial by Gluckman, E. NEJM 2001;344:1860

Back to top

Answer: Yes. Many biotech companies are developing techniques to rapidly grow stem cells in a laboratory environment. These methods are being used in clinical trials.

Example: Blood & Marrow Transplant Newsletter issue #51 reports on the first adult to survive a cord blood transplant with expanded stem cells. Published by Pecora et al. 2000 Bone Marrow Transplantion 25:797-799.

References:

• MJ Laughlin et al., 2001; NEJM 344(24):1815-22. Retrospective study of 68 adults who received cord blood; 90% engrafted.
• EJ Shpall et al., 2002; Biology of Blood & Marrow Transplantation vol.8:368-376. "Transplantation of Ex Vivo Expanded Cord Blood". Reports on a clinical trial conducted at the U. of Colorado on 25 adults & 12 children with high-risk diagnosis.
• J Jaroscak et al., 2003; Blood 2003 101:5061-67. Phase I trial on 28 patients of conventional UCB transplants augmented by ex vivo-expanded cells.

Back to top

Answer: Yes. See the next question.

Back to top

Answer: Apparently quite large. Examples:

Several clinical trials presented at the 43rd annual meeting of the American Society of Hematology in Dec. 2001 were transplanting adults with multiple (from 2 to 6) mis-matched cord blood units. Surprisingly, although these patients initially show a mix of HLA types ("chimerism") from the different units, over time most survivors display a single dominant cord blood type.

• Reference: Cord blood transplants: Making do with less by M.D. John Wingard

Report on an adult patient in Britain who recovered after receiving a transplant of 7 cord blood units; one perfect match and 6 mis-matched

• Reference: The Guardian newspaper 7/9/2002

Report on a study at the U. of Minnesota in which 23 patients were transplanted 2000-2003. Each received two partially matched cord blood units (now at 32 patients as of fall 2004). They have not figured out yet how to predict which cord blood unit will dominate in the end!

• Reference: Barker JN, et al. Blood Oct2004; DOI 10.1182/blood-2004-07-2717. "Transplantation of two partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy."

Back to top

Answer: Approximately age 70. A study at the University of Minnesota transplanted patients who were not eligible for high-dose chemotherapy, either due to age, co-existing medical problems, or previous treatment. The median age was 49 (range from 19 to 69). They received reduced conditioning chemo, also known as a "mini transplant". Sustained engraftment was 89% overall, and 98% in patients who had ablative chemotherapy (enough to wipe out bone marrow) within three months prior to transplant.

Reference:

• Wagner J. and Barker J. (Oct2004) Biol Blood Marrow Transplant. 10(10):733-4. "Umbilical cord blood transplantation after a non-myeloablative therapy in high risk adults."

Back to top

Answer: They are comparable. Among pediatric patients, the overall survival rates are comparable for the two transplant types, but the causes of death differ with each. Among cord blood transplants, the most common cause of death was complications during the long wait for engraftment. Among bone marrow transplants, more patients died of severe Graft-Versus-Host Disease. Despite the fact that cord blood seems to lack graft-versus-tumor activity, cord blood transplants were not associated with higher rates of patient relapse.

Reference:

• Wadlow & Porter (2002) Biology of Blood & Marrow Transplantation vol.8(issue 12):637-647 "Umbilical cord blood transplantation: where do we stand?"

Among adult patients, perfectly matched bone marrow is preferable to cord blood, but mis-matched bone marrow and mis-matched cord blood yield comparable outcome. In Nov 2004, two studies were published in the New England Journal of Medicine which announced that cord blood transplants are suitable for adults who lack a perfectly matched HLA donor.

References:

• Laughlin MJ, et al. Nov2004; NEJM 351(22):2265-75. "Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia." This USA study found no difference between outcomes of cord blood transplants (150 patients) with 1 or 2 HLA mis-matches versus bone marrow transplants (83 patients) with one HLA mis-match. Please note, a perfect bone marrow match (367 patients) is still better than cord blood for adult patients.
• Rocha V, et al. Nov2004; NEJM 351:2276-2285. "Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia." This European study compared 98 cord blood transplants (98 patients, 94% of them mis-matched) with bone marrow transplants (584 patients, all matched). There were no significant differences in occurance of chronic GVHD, transplantation-related mortality, relapse rate, and leukemia-free survival.

More in-depth answer: Cord blood stem cells may hold an advantage in telomere length. Telomeres are like molecular caps that tie off the ends of chromosones. As cells replicate, their telomeres get shorter. Literally, telomere shortening is the aging process at the cellular level. For example, when Dolly the sheep was cloned from a six year old cell, she was born with shortened telomeres, as if she was already six years old. Some researchers have suggested that telomere shortening in hematopoietic stem cell transplantation (ex: giving an old person's stem cells to a young patient) is a potential mechanism for late graft failure.

References:

• Awaya, N. et al. (2002) Biology of Blood & Marrow Transplantation vol.8(issue 11):597-600

Another in-depth answer: Cord blood is more effective in repopulating the stem cell "reservoir". Although it is well known that cord bood takes longer than bone marrow to engraft after transplant, a recent study indicates that in the long run (after one year) the cord blood does a better job of re-populating the body's reservoir of blood stem cells. The cause for both of these effects is that the stem cells in cord blood would rather multiply than differentiate into more evolved blood cells.

References:

• Francesco Frassoni et al. 2003 Blood First Edition Paper: prepublished online 4/10/2003 DOI 10.1182/blood-2003-03-0720

Back to top

Answer: This is a toss-up. More and more diseases are now recognized to have a genetic basis. We have always known that some diseases are passed by inheritence. Now we also recognize that some genetic mutations confer a greater predisposition to disease. For example, the "Philadelphia chromosome (translocation)" is associated with a predisposition to developing leukemia at some point in life. Many of these inherited predispositions do not manifest until adulthood. Plus, if the donor has one of these predispositions, some of the drugs that transplant patients take could trigger a malignancy in the donor cells.

On the one hand, older donors are better because they have more medical history to rule out inherited mutations. On the other hand, older donors are worse because they are more likely to have an acquired mutation, from exposure to disease or chemicals, etc. At this time, it is not clear whether older or younger donors are better.

It is possible to test donor cells for inherited mutations, which would be present in every cell. But with hundreds of known mutations, only a limited number can be screened with a reasonable amount of blood.

References:

• McMilin, K., 4/1/2002 Transfusion vol.42(issue 4):495
• Fraser, CJ etal. 23 Aug 2005 Blood;  "First report of donor cell derived acute leukemia as a complication of umbilical cord blood transplantation".
  

Back to top

Answer:

• Over the course of a lifetime up to age 70, the probability that a person will require a transplant of her own stem cells ("autologous" transplant) is 1 in 450 or 0.23%
• Over the course of a lifetime up to age 70, and the probability of requiring any transplant, from yourself or another person ("autologous" or "allogeneic"  transplant), is 1 in 220 or 0.46%.

Reference: Pasquini, MC, Logan, BR, Verter, F, Horowitz, MM, & Nietfeld, JJ 2005 ASH meeting poster#5260 (download 94 KB) or Abstract published in Blood  (2005) 106:1330

Previous references:

• 1 in 2,703 probability of autologous transplant up to age 20: F.L. Johnson, 1997; J Ped Hem Onc 19(3): 183-186 (probability based on diagnosis rates and treatment modalities)
• 1 in 20,000 probability of autologous transplant up to age 20: G.J. Annas, 1999; NEJM 340: 1521-1524. (probability is stated without proof)
• 1 in 10,000 to 1 in 200,000 probability of autologous transplant over a lifetime: R.M. Kline, April 2001; Sci Amer 4: 30-37. (probability is stated without proof)

Back to top

Answer: Yes. Traditionally, patients with severe hereditary disorders of the immune system were given a stem cell transplant to replace the defective gene. This is kind of like fixing a broken transmission by replacing the whole car. Plus, while the patient's hereditary disorder may be fixed, there are new medical problems associated with a transplant that is not a perfect match.

The more sophisticated approach is to transplant the patient's own stem cells after they have been genetically engineered to fix the defective gene. The genetic engineering is done with a virus. The patient's own cord blood is an ideal source of matching stem cells.

Example: Transplants of genetically engineered cord blood have been successfully used to cure some forms of "bubble boy syndrome", or SCID. Initially, the SCID results were touted as the first success story of gene therapy. Unfortunately, this clinical trial was halted in 2003 when two of the children subsequently developed leukemia. It is not clear at present if the leukemia was triggered by the gene insertion process, or if the SCID patients simply had a greater predilection towards leukemia than the population at large.

References:

• Parkman R, et al. 2000, Annual Rev Med 51:33-47 (ADA-SCID)
• Salima Hacein-Bey-Abina, et al. 2002, NEJM 346:1185-1193 (X-linked SCID)
• Antoine C, et al. 2003, Lancet 361(9357):541-2. "Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99."
• Sara M. Mariani 2003, Highlights of the 2003 meeting of the American Association of Immunologists, reported by Medscape 6/3/03

Back to top