Adult & Umbilical Cord Stem Cell Research (Ethical)

The Promise of Cord Blood

National Marrow Donor Program Facts and Figures
http://www.marrow.org/MEDIA/Facts_and_Figures/facts_figures.pdf

 

Each year, thousands of people are diagnosed with life-threatening diseases such as leukemia, lymphoma and genetic and immune system disorders. For many patients, the best treatment is a transplant of healthy blood-forming cells from an adult donor or a cord blood unit.

Why Cord Blood Banking Is Important
Physicians can select from three hematopoietic cell sources for their transplant patients — marrow, peripheral blood cells (PBSC) and umbilical cord blood. Although comparable outcomes have been achieved with all three sources, selection of the hematopoietic cells is based on several patient factors.

Studies show that cord blood transplant is used for children and adult patients when:

*More tolerant matching is required because the patient has an uncommon HLA tissue type
*Disease stage or other factors pose an immediate need to proceed to transplant
*Blood-forming cell quantity required may be smaller due to patient's size

These characteristics are unique to cord blood:

More Tolerant Matching
Marrow and cord blood transplants require human leukocyte antigen (HLA) matching certain tissue traits of the donor and patient. A close match between the patient and the donor or cord blood unit can improve a patient's outcome.

Umbilical cord blood holds special promise for patients who lack a suitably matching adult donor. While a closely matched cord blood unit is preferred, clinical studies suggest the match may not have to be as close as is needed for marrow or peripheral blood transplants. This is especially promising for minority patients, whose diverse tissue types are often difficult to match. Expanding the inventory of cord blood, particularly with units from racially and ethnically diverse communities, would significantly reduce the gap in finding many patients a suitable match for transplant.

More Quickly Available
Cryopreserved and ready to use, cord blood units are prescreened and meet NMDP donor eligibility guidelines and health requirements prior to storage. Transplant centers can count on the unit's quality and availability at the time of selection. A cord blood unit from the NMDP Center for Cord BloodSM can be selected and delivered to the transplant center in less than two weeks. This is important for patients whose disease stage or other health factors require that a transplant take place at the earliest possible time.

Expanding Patient Selection to Include Cord Blood
Cord blood is used more often in children or small adults because an umbilical cord holds a limited amount of blood. The number of blood-forming cells used in a transplant needs to match the size of the patient — smaller patients need fewer cells and larger patients need more cells.

Some cord blood units may not have enough blood-forming cells for some patients. Doctors are trying different ways to increase the number of cells in a cord blood unit so they can use cord blood for larger patients. One method being studied is to give a patient two cord blood units. Another method being studied is to grow the number of cells in a cord blood unit in a laboratory before giving it to the patient.

To learn more about donating your baby's umbilical cord blood, call a cord blood bank near you using the listings on this page, or call the NMDP at 1 (800) MARROW-2 (1-800-627-7692) — or view a list of cord blood participating hospitals by state.
[http://www.marrow.org/ABOUT/Cord_Blood/The_Promise_of_Cord_/index.html]
Last Updated: November 2005

 

Federal Cord Blood Legislation
http://www.marrow.org/ABOUT/Cord_Blood/Federal_Cord_Blood_Legislation/index.html

 

http://www.marrow.org/PATIENT/Undrstnd_Disease_Treat/Lrn_about_Disease/index.html
Learning More about Your Disease
If you are diagnosed with leukemia, a bone marrow (BMT) or cord blood transplant may be a treatment option for you. A transplant may also be a treatment option for certain immune system and genetic disorders. The diseases listed below are those that may be treated by a bone marrow or cord blood transplant. The list includes diagnoses for which transplant is a standard treatment as well as diagnoses for which the role of transplant is a newer option.

Diseases Treatable
Leukemias and lymphomas, including:
Acute myelogenous leukemia
Acute lymphoblastic leukemia
Chronic myelogenous leukemia
Chronic lymphocytic leukemia
Juvenile myelomonocytic leukemia
Hodgkin's lymphoma
Non-Hodgkin's lymphoma
Multiple myeloma and other plasma cell disorders

Severe aplastic anemia and other marrow failure states, including:

Severe aplastic anemia
Fanconi anemia
Paroxysmal nocturnal hemoglobinuria (PNH)
Pure red cell aplasia
Amegakaryocytosis / congenital thrombocytopenia
SCID and other inherited immune system disorders, including:

Severe combined immunodeficiency (SCID, all sub-types)
Wiskott-Aldrich syndrome

Hemoglobinopathies, including:

Beta thalassemia major
Sickle cell disease

Hurler's syndrome and other inherited metabolic disorders, including:

Hurler's syndrome (MPS-IH)
Adrenoleukodystrophy
Metachromatic leukodystrophy
Myelodysplastic and myeloproliferative disorders, including:

Refractory anemia (all types)
Chronic myelomonocytic leukemia
Agnogenic myeloid metaplasia (myelofibrosis)
Familial erythrophagocytic lymphohistiocytosis and other histiocytic disorders

Other malignancies

Childhood Cancers
To learn more about childhood leukemias and other childhood cancers, visit the National Cancer Institute Web site at
www.cancer.gov/cancertopics/types/childhoodcancers.

The NMDP Office of Patient Advocacy (OPA) offers free, confidential support services to patients, families and their caregivers. Trained case managers are available to help you find the information you need to make informed decisions about your treatments for your disease. OPA offers printed information and can answer questions about marrow and cord blood transplants and diseases that may be treated with transplants.

To contact the National Marrow Donor Program Office of Patient Advocacy: Inside the United States, call 1 (888) 999-6743. This call is toll-free in the United States. Outside the United States, call 1 (612) 627-8140. This call may have long-distance or international charges. NMDP OPA staff are available Monday – Friday, 8 a.m. to 5 p.m. Central time. You can also send an e-mail message to [email protected]g
Last Updated: June 2005

 

 

http://www.marrow.org/PHYSICIAN/Adv_in_Auto_Allo_Tx/Hematopoietic_Cell_Sources_Tai/index.html
Choosing a Hematopoietic Cell Source for Allogeneic Transplant

A transplant physician chooses among the three sources of hematopoietic cells for a patient based on:
*Published outcomes data
*Availability of an appropriately matched, suitable donor (related or unrelated) or cord blood unit
*Patient's disease, status and age
*The level of urgency of the patient's need for transplant
When considering cord blood, the total nucleated cell count of matching cord blood units in relation to the patient's weight. 

Marrow, PBSC and umbilical cord blood cells differ in the match requirements, cell dose, time to donor availability, time to engraftment, risk of GVHD, and availability of cells, as shown in Table 1.

Hematopoietic Cell Sources for Allogeneic Transplant
Characteristic                          Marrow                 PBSC                Umbilical Cord Blood
HLA matching requirements    Marrow: Close matching is a key factor influencing outcomes. For unrelated donor transplants, NMDP requires a minimum 5 of 6 HLA match.  PBSC: Close matching is a key factor influencing outcomes. For unrelated donor transplants, NMDP requires a minimum 5 of 6 HLA match. UCB: More permissive matching than marrow or PBSC. For unrelated donor transplants, NMDP requires a minimum 4 of 6 HLA match.

Time to neutrophil engraftment Marrow: Generally slower than PBSC, but faster than cord blood. PBSC: Generally faster than marrow and cord blood. [1,3] UCB: Generally slower than marrow or PBSC.

CD34+ cell dose Marrow: A sufficient cell dose can be collected in all but rare instances. PBSC: Allows collection of a higher number of cells than marrow. UCB: Cell dose is limited by size of the cord blood unit; some units may have an insufficient cell dose for larger patients.

Time to identify and collect cells from unrelated donors Marrow: Average search time is 2 months. PBSC: Same as marrow. UCB: Often available within 1 month.

Risk of acute GVHD in recipient  Marrow: Risk is lower than PBSC. [7]  PBSC: Risk is higher than marrow. [7]  UCB: Associated with reduced risk of acute GVHD. [4,5,6,8]

Risk of chronic GVHD in recipient Marrow: Risk is lower than PBSC. PBSC: Associated with more chronic GVHD and/or chronic GVHD that is more difficult to treat. [1,3,9,10] UCB: Less risk than PBSC.

Second donation (to salvage graft failure or relapse) Marrow: Potentially available, depending on donor availability. PBSC: Potentially available, depending on donor availability. UCB: Not available; however a second unit may be quickly available.
Table 1. Characteristics of hematopoietic cell sources.

Studies Continue on PBSC and Cord Blood
Both PBSC and cord blood are being studied under FDA investigational new drug (IND) protocols. Studies continue to investigate rates of GVHD and other characteristics of both cell sources.

In addition:
The National Marrow Donor Program (NMDP) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) are currently conducting a large, phase III clinical trial to determine whether there are differences in patient outcomes and/or donor experiences between marrow and PBSC unrelated donor transplants. [11]

Ways to overcome the limited cell dose of cord blood to enable transplants for larger adults are currently being studied. Methods include combining two or more closely matched cord blood units and ex vivo expansion of the cells. [4,6]

References
Bacigalupo A, Frassoni F, Van Lint MT. Bone marrow or peripheral blood as a source of stem cells for allogeneic tran

splants. Curr Opin Hematol. 2000; 7:343-347.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11055506

Eapen M, Horowitz MM, Klein JP, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol. 2004; 22(24):4872-4880.
http://www.jco.org/cgi/content/abstract/22/24/4872

Schmitz N. Peripheral blood hematopoietic cells for allogeneic transplantation. In: Blume KG, Forman SJ, Appelbaum FR, eds. Thomas' Hematopoietic Cell Transplantation, 3rd ed. Malden, Mass: Blackwell, 2004:588-598.

Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003; 101(11):4233-4244.
http://www.bloodjournal.org/cgi/content/full/101/11/4233

Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002; 100(5):1611-1618. http://www.bloodjournal.org/cgi/content/full/100/5/1611

Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005; 105(3):1343-1347.
http://www.bloodjournal.org/cgi/content/full/105/3/1343

Eapen M, Haagenson M, Logan B, et al. Use of peripheral blood grafts is associated with increased acute and chronic graft-versus-host disease without improved survival after unrelated donor transplantation [abstract]. Blood. 2005; 106:443a.
http://meeting.bloodjournal.org/cgi/content/abstract/106/11/443

Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004; 351(22):2265-2275.
http://content.nejm.org/cgi/content/abstract/351/22/2265

Flowers MED, Parker PM, Johnston LJ, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood. 2002; 100(2):415-419. http://www.bloodjournal.org/cgi/content/full/100/2/415

Remberger M, Beelen DW, Fauser A, et al. Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Blood. 2005; 105(2):548-551.
http://www.bloodjournal.org/cgi/content/full/105/2/548

BMT CTN. A phase III randomized, multi-center trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors. 2004.
http://spitfire.emmes.com/study/bmt/
protocol/0201__protocol/0201__protocol.html
Last Updated: September 2006

 

 

http://www.bloodjournal.org/cgi/content/full/100/5/1611#SEC3
Blood, 1 September 2002, Vol. 100, No. 5, pp. 1611-1618

Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases

Discussion. It has been established that a single UCB (umbilical cord blood) unit contains sufficient numbers of HSCs for durable engraftment in most patients.2-5,31-33 Importantly, the results presented here indicate that the proportion achieving neutrophil engraftment by day 42 and platelet engraftment by 6 months after unrelated donor UCB (umbilical cord blood) transplantation is similar to that observed after unrelated donor bone marrow transplantation (BMT)34; neutrophil engraftment occurred in 88% of UCB patients and 90% of BMT patients, and platelet engraftment occurred in 50% of UCB patients and 55% of BMT (bone marrow transplant) patients.

It is noteworthy that UCB units engraft successfully, considering the low numbers of CD34 cells infused. In contrast to the typical bone marrow allograft, which contains a median of 3 × 106 CD34 cells per kilogram recipient body weight, recipients of UCB receive a C

D34 cell dose more than 1 log lower (median, 2.7 × 105 CD34 cells per kilogram). In fact, the incidence of engraftment is similar to that observed after unrelated donor BMT until the CD34 cell dose approaches 1.7 × 105/kg, below which the rate of recovery and incidence of engraftment are unsatisfactory.

These data, therefore, support the contention that a threshold dose exists, defining which UCB units are acceptable for each transplantation candidate. As a result of these findings, a dose of 1.7 × 105 CD34/kg (when available) has now been established as the threshold dose for patients at the University of Minnesota. Arguably, differences in preparative and supportive care therapies as well as methods of CD34 analysis may prevent the establishment of a universally applicable threshold value. Importantly, Thompson et al9 and Laughlin et al10 did not observe an association between CD34 cell dose and engraftment and survival, possibly due to differences in treatment and methods of CD34 analysis or smaller patient numbers. Nonetheless, these data suggest a need for the quantification of CD34 cells in each UCB unit, using a standardized method of CD34 analysis, by all cord blood banks so that a threshold limit can be defined.

An advantage of UCB (umbilical cord blood) is its apparent reduced alloreactive response as compared with bone marrow.35-37

The data would suggest that UCB, despite HLA (human leukocyte antigen) mismatching, is associated with low GVHD (graft-versus-host disease)  risk.

…the infrequent development of severe acute GVHD and extensive chronic GVHD after unrelated donor UCB transplantation as compared with unrelated BMT is striking.38 Although it may be related to treatment factors such as the use of pretransplantation ATGAM, the explanation for such a low incidence of GVHD in recipients of unrelated donor UCB is unclear. Although the cytotoxic T-cell precursor frequency has been found to be similar in UCB and adult peripheral blood,39 the median CD3 cell dose of 8 × 106/kg in UCB units makes it similar to a marrow graft after modest T-cell depletion. However, neither such a level of T-cell depletion nor the choice of immunoprophylaxis fully explains the low incidence of GVHD observed by us and others.40-42 It is more likely that functional differences, such as a defective cytotoxic response reported with UCB lymphocytes,43 an altered cytokine profile,31,44 or other differences may explain the decreased incidence of severe GVHD (graft-versus-host disease).

TRM (treatment-related mortality) is the principal obstacle to successful transplantation outcome in recipients of unrelated donor BMT and is the major reason for evaluating UCB as an alternate source of HSCs.

Of the 3 risk factors associated with risk of TRM (treatment-related mortality) in Cox regression analysis (ie, recipient's age, development of severe acute GVHD, and CD34 cell dose), CD34 cell dose is the only pretransplantation variable that can be manipulated. Half the patients in this study received a CD34 cell dose of more than 2.7 × 105/kg, and these patients had a TRM of only 15% at 1 year. This compares favorably with a TRM (treatment-related mortality) of 24% to 51% reported for pediatric recipients of unrelated BMT.45-47

However, patients receiving UCB grafts that contained 1.7 to 2.7 × 105 CD34/kg and less than 1.7 × 105 CD34/kg had higher rates of TRM (29% and 68%, respectively). Although an interaction between low cell dose and age older than 18 years may exist, the small number of patients in the adult age range prevents further analyses. These results underscore the argument that UCB units containing less than 1.7 × 105 CD34/kg should be considered inadequate for routine use.

Survival in this study was somewhat higher than that reported by registries.3,4,36 However, direct comparisons with registry data are difficult because differences are multifactorial, reflecting differences in eligibility criteria, treatment and supportive care plans, and definitions of end points. Further investigations are under way as part of a national study sponsored by the National Heart, Lung, and Blood Institute.48

Regardless, pediatric patients in this study had a high survival rate (71% and 63% for patients aged 0-1 and 2-17 years, respectively), with poorer results for adults (30%) at 1 year. As might be expected on the basis of results with unrelated donor BMT, HLA (human leukocyte antigen) mismatch, lower cell doses, history of severe GVHD, and history of prior autologous transplantation were all factors associated with poorer survival in univariate analysis. With HLA disparity and CD34 cell dose both being independent risk factors for survival, the major question is how to weigh the relative risks of HLA disparity and CD34 cell dose. The answer will not only aid the clinician in the instruction of prospective patients on the relative importance of UCB CD34 cell dose and HLA disparity but will also aid in the development of a UCB graft selection algorithm.

As previously suggested by Rubinstein et al,49 our results indicate that a higher CD34 cell dose partially overcomes the negative impact of HLA (human leukocyte antigen) for each level of HLA disparity. For example, in recipients of UCB grafts disparate in 2 HLAs, patients who received transplants of more than 1.7 × 105 CD34 cells/kg had a higher survival (0.61 [CI, 0.43-0.79], n = 30) than those receiving a lower cell dose (0.11 [CI, 0.00-0.32], n = 9). For each degree of HLA disparity, the data presented here indicate that there is a critical infused cell dose below which survival is significantly impaired, particularly in recipients of UCB units with 2-HLA disparity. Resolution of this issue will require larger patient numbers.

As with unrelated donor BMT (bone marrow transplant), it is important to note that the most common causes of death after UCB (umbilical cord blood) transplantation were infection and relapse. Owing to the profound influence of CD34 cell dose on rate of neutrophil engraftment, TRM (treatment-related mortality), and survival, risk of infection is likely related in part to the prolonged length of neutropenia in recipients of lower cell doses rather than to an impairment of neutrophil function, as has been suggested.31

Although defects in neutrophil function could play a role, most recipients of UCB with an adequate cell dose do not die of infection. Relapse, however, was the major limiting factor. Although decreased GVHD (graft-versus-host disease) raised the concern that the graft-vs-leukemia ratio might be decreased, relapse after unrelated donor UCB transplantation is similar to that previously reported for unrelated BMT patients.46,47 Although only a randomized trial with larger numbers of patients will answer the question of relative risk of relapse after UCB transplantation as compared with BMT, these results are similar to those reported by Locatelli et
al,50 who observed a 40% incidence of relapse in recipients with acute leukemia, with disease status being the only risk factor.

Together, these results provide clear justification for the further development of UCB (umbilical cord blood) banks worldwide. Banks should focus not only on the collection of larger units with greater numbers of CD34+ cells but also on collecting UCB units from ethnic and racial minorities. Greater HLA disparity between donor and recipient adversely affects survival, which has particular relevance for patients of ethnic minority descent. Targeting collection centers with large minority populations may help reduce the degree of HLA (human leukocyte antigen) disparity for minority patients and serve as an important adjunct to marrow donor registries worldwide. In addition, these results suggest that there should be routine quantitation of CD34 cells, preferably by UCB banks using a standardized procedure, so that rapid decisions can be made as to the optimal unit for a specific patient.
http://www.bloodjournal.org/cgi/content/full/100/5/1611#SEC3

Comprehensive Publications List of the National Marrow Donor Program
http://www.nmdpresearch.org/STUDIES/abstracts.pdf