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Umbilical Cord Blood Transplantation: The First 20 Years
Umbilical Cord Blood Transplantation: The First 20 Years John E. Wagnera and Eliane Gluckmanb In October 1988, the world’s first umbilical cord blood transplant (UCBT) was performed. Despite considerable skepticism initially by both scientists and clinical specialists in the field, umbilical cord blood (UCB) has now become one of the most commonly used sources of hematopoietic stem cells (HSCs) for allogeneic transplantation. Today, an estimated 600,000 UCB units have been banked and 20,000 UCB units have been distributed worldwide for both adults and children with lifethreatening malignant and nonmalignant diseases. During this first generation of UCBT, substantial advances have been made resulting in better outcomes for our patients. UCB serves as an extraordinary example of translational medicine at its best, where clinical problems compel scientists to move basic discoveries into novel therapeutic approaches. This chapter briefly summarizes the highpoints of the history of UCBT with speculations as to what the next generation of research promises to discover. Semin Hematol 47:3–12. © 2010 Elsevier Inc. All rights reserved.
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ransplantation of allogeneic bone marrow has been successfully used in the treatment of highrisk or recurrent hematologic malignancies, bone marrow failure syndromes, selected hereditary immunodeficiency states, and metabolic disorders.1 It is an accepted form of therapy for a host of lymphohematopoietic disease states and storage diseases with success rates often dependent on recipient age, cytomegalovirus (CMV) serostatus, disease and disease status at the time of transplant, and the presence of pre-existing comorbidities.1 Very early in the history of bone marrow transplantation (BMT), it was clear that access to a suitable donor was a major obstacle severely limiting the use of this potentially curative treatment modality. However, even for those patients for whom a human leukocyte antigen (HLA)-matched sibling donor could be identified, the treatment itself was associated with substantial risks, most notably the immunological risk of graft-versus-host disease (GVHD). These risks only magnified as transplant centers explored the possibility of using volunteer adult unrelated donors as an alternative to HLA-matched siblings. Novel immunoproaDivision
of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN. bEurocord, Hôpital Saint Louis, Paris, France. Address correspondence to John E. Wagner, MD, Box 366 UMHC, University of Minnesota, 420 Delaware St, SE, Minneapolis, MN 55455. E-mail: [email protected] 0037-1963/10/$ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2009.10.011
Seminars in Hematology, Vol 47, No 1, January 2010, pp 3–12
phylactic regimens and T-cell depletion methods were explored in an attempt to overcome the barrier of GVHD.2,3 While GVHD prevention was possible with T-cell depletion, it was also clear that the removal of graft lymphocytes concomitantly increased the risks of graft failure, relapse, and opportunistic infections.3 In the absence of better alternative treatment strategies, there was room for considering a new source of hematopoietic stem cells (HSCs)—namely, umbilical cord blood (UCB). In this early phase, UCB had several benefits, albeit mostly theoretical. Of the potential benefits, three were unequivocal: (1) UCB was highly likely to be free of herpes virus contamination; (b) banked HLA-typed UCB was immediately available; and (3) UCB collections could be targeted, a potential strategy for overcoming the under-representation of many ethnic and racial minorities plaguing most adult volunteer donor registries. The other “benefits,” however, were more speculative than known, namely: (1) UCB would contain enough hematopoietic stem and progenitor cells to engraft most adults and children; (2) UCB would be associated with less GVHD as the neonate is immunologically “naive”; and (3) HLA matching would be less stringent again because of the immunological naivete. But UCB was also associated with potential risks. Interestingly, the many opponents of UCB argued vehemently that the immunological naivete of UCB would result in higher relapse rates and risks of opportunistic infection.4,5 Other opponents argued that maternal cell contamination would result in life-threatening acute GVHD. However, it would be the high likelihood of 3
4
graft failure that would most severely limit the usefulness of UCB due the low absolute numbers of HSCs and progenitors. While most of the benefits and few of the risks would indeed be realized, the greatest push for moving UCB forward was the inability of the adult volunteer unrelated donor registries to meet the needs of the patient population.
PROOF OF CONCEPT The concept of using UCB as a clinical source of HSCs was first considered in the late 1960s. Recognizing the potential value of UCB, Ende and Ende6 were among the first to apply UCB to the treatment of a child with leukemia. In the first published report, freshly procured UCB samples from eight donors were infused over a 17-day period in a 16-year-old male with acute lymphocytic leukemia who had previously been treated with 6-mercaptopurine and prednisone.6 While long-term reconstitution was not demonstrated, Ende and Ende documented a transient alteration in red blood cell antigens in the peripheral blood, suggesting a transient mixed chimerism from at least one if not several of the units. Additional studies were performed by Koike7 and Besalduch-Vidal8 in the late 1970s and early 1980s that suggested that UCB may indeed contain sufficient numbers of hematopoietic progenitor cells for transplantation. Preclinical studies compared numbers of hematopoietic progenitors in UCB and marrow. The authors concluded that if a sufficient volume of UCB could be collected, there may be an adequate number of bone marrow progenitors to reconstitute patients.7,8 In anticipation of possible clinical application, Koicke subsequently showed that UCB progenitors could be cryopreserved without significant loss of viability and proliferative capacity.7 The conclusion was that “[cryopreserved] cord blood cells . . . may be useful as a source of hemopoietic progenitor cells for marrow transplantation.” However, it was the pivotal work of Hal Broxmeyer in collaboration with Ted Boyse, Gordon Douglas, Pablo Rubinstein, and Lewis Thomas that moved UCB from laboratory concept to clinical practice as a “viable” source of allogeneic HSCs for transplantation.9 In contrast to earlier investigators, Boyse provided the proof of concept studies in mice and Broxmeyer systematically evaluated the hematopoietic potential of human UCB in vitro, and developed the practical and efficient methods for large-volume collections and storage of UCB, culminating in the first clinical transplant.
Murine Models In 1984 – 85, the hypothesis that UCB contained long-term reconstituting HSCs was first tested in a murine model.10 In the first of four experiments, 7-weekold (B6 ⫻ A-T1ab)F1 hybrid males were irradiated with
J.E. Wagner and E. Gluckman
862.8 rad and then transplanted with heparinized whole blood obtained from near-term (B6 –T1aa ⫻ A)F1 mouse embryos. Thirty-day survivors were subsequently typed for the T1a markers distinguishing donor from recipient lympho-hematopoietic cells. It was clear that animals demonstrated repopulation of donor cells, unequivocally demonstrating that lethally irradiated mice could be reconstituted with blood from near-term embryos. This was subsequently followed by three additional experiments evaluating the engraftment potential of (1) smaller volumes of blood from near-term embryos, (2) blood from neonatal donors ⬍24 hours of age, and (3) smaller volumes of blood from neonatal donors. These three studies demonstrated that nearterm and neonatal blood, even at lower volumes, contained sufficient numbers of HSCs and progenitor cells to allow for lympho-hematopoietic recovery of donor cells. Together these studies provided the “proof of concept” that neonatal/placental blood would be sufficient for engraftment. The next step would be to develop a reliable method for human UCB collection and cryopreservation.
UCB Collection and Storage While Boyse et al10 provided data supporting the hypothesis that small quantities of neonatal blood were sufficient for hematopoietic recovery of donor origin in a murine model, Broxmeyer et al11,12 established practical and efficient methods of collecting and storing UCB for clinical use. Broxmeyer and colleagues evaluated the nucleated cell and progenitor content and sterility of more than 100 UCB specimens before and after cryopreservation. They proved that UCB remained viable at 4oC or 25oC for at least 3 days after collection. This observation confirmed that cell viability during transport between hospitals would not be compromised prior to cryopreservation. Moreover, the collection of UCB proved to be remarkably straightforward. Obstetricians and nurse midwives previously untrained in the collection of UCB could be expected to learn the collection technique in a matter of minutes. In summary, these early results suggested that UCB could be easily collected, tested, and stored without substantial losses of viable hematopoietic cells.
FIRST-IN-HUMAN CLINICAL TRIAL Concurrent with the seminal work of Broxmeyer and Boyce, Gluckman et al were establishing a new treatment paradigm for children with Fanconi anemia.13 Furthermore, in the mid 1980s it was also known that couples with one child affected by Fanconi anemia were deliberately conceiving children in the hope of having an HLA-matched unaffected child to serve as an HSC donor.14 Ultimately, this led to a remarkable collaboration between Broxmeyer and Douglas, Dr. Arleen
History of umbilical cord transplantation
Auerbach at Rockefeller University and Dr. Marilyn Pollack at Baylor University who had established new methods of prenatal diagnosis and prenatal HLA typing for couples at high risk of Fanconi anemia, Drs. Henry Friedman and Joanne Kurtzberg who were the hematologists caring for a family with a child with Fanconi anemia, and Eliane Gluckman who arguably had the best transplant survival rates for this particular disease. Having verified that the unborn donor was indeed HLAmatched and unaffected by the disease, one of the first cord blood collections with expressed therapeutic intent was collected by Gordon Douglas; shipped, tested, and cryopreserved by Hal Broxmeyer; and hand-carried to Paris for transplant in early October 1988. After low-dose cyclophosphamide and limited-field irradiation, Matthew, age 6 years, was the first human transplanted with cryopreserved UCB (Figure 1) at the Hôpital St. Louis in Paris by the team of Professeur Eliane Gluckman. One month later with complete chimerism demonstrated, the team proved once and for all that UCB indeed contained the pluripotent HSC.15
EARLY CLINICAL RESULTS Since the first report of a successful UCB transplant (UCBT) in 1989,15 investigators worldwide began to explore the potential of UCB as a source of HSCs for transplantation.16 –27 Early on, however, many questions were raised in the form of editorials.4,5 Would this HSC source engraft larger recipients or recipients with diseases other than Fanconi anemia? Would lethal GVHD occur because of maternal lymphocyte contamination, previously shown to occur in some neonates with congenital immunodeficiency? Alternatively, would UCB lymphocytes be less likely to cause a graft-versus-host reaction because of “immunologic naivete” and therefore lead to a greater risk of leukemic relapse?
Figure 1. Matthew Farrow and Eliane Gluckman at the Hôpital St. Louis in October 1988 and October 16, 2008 celebrating the first 20 years of UCBT in Mandelieu, France. Photograph kindly provided by Professor Eliane Gluckman.
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In 1992, the International Cord Blood Transplant Registry was established by John Wagner, Nancy Kernan, Hal Broxmeyer, and Eliane Gluckman as a repository of clinical data on outcomes observed in patients transplanted with UCB in an attempt to more quickly discern the true risks and benefits of this new HSC source. While this registry was little more than boxes of completed forms from investigators across Europe, the United States, and Australia in an office at the University of Minnesota, it was a beginning. In 1995, the Registry merged with the Center for Blood and Marrow Transplant Research (formally the International Bone Marrow Transplant Registry [IBMTR]) in 1995. In 1993, a similar registry was designed in Europe as part of the European Research Project on Cord Blood Transplantation (Eurocord Transplant Registry).
INITIAL RESULTS WITH SIBLING DONOR UCBT Only two reports came directly from the International Cord Blood Transplant Registry. The first was published in The Lancet in 1995 and summarized the findings in the first 44 UCBTs, and the second was an update (N ⫽ 74 patients) published in Blood in 1997.28,29 Briefly, in this first experience, the patients were aged 0.8 to 16.3 years (median, 4.0 years) with 34 having an HLA-matched unit, and 10, one, and five patients having a 1, 2, or 3 HLA antigen mismatched unit, respectively. For most, prophylaxis for acute GVHD consisted of cyclosporine A (CsA) alone or in combination with methylprednisolone (MP) and half received hematopoietic growth factor early after the infusion of UCB by study design. In this first registry report on UCBT, several critical observations were made. For recipients of HLA 0 –1 antigen grafts, the probability of engraftment was 91% (⫾2%) at a median of 22.0 days (range, 9 to 46) for neutrophils and 51 days (range, 15–117) for platelets (5 ⫻ 1010/L). Graft failure occurred in five (9%) patients, all with nonmalignant disease (probability of neutrophil engraftment 69% v 100%). Furthermore, we could not discern (1) a correlation between the number of nucleated cells or granulocyte-macrophage colony-forming units (CFU-GM) and the time to neutrophil recovery or risk of graft failure (Figure 2A), or (2) a beneficial effect of hematopoietic growth factor on speed of recovery (Figure 2B). As hoped, the probability of grade 2– 4 acute GVHD was extraordinarily low (3%; 95% confidence interval [CI], 0 – 8%) with no patient having grade 3– 4 disease. Similarly, the probability of limited and extensive chronic GVHD was low (6%; 95% CI, 0 –15%). For the patients with a 0 –1 HLA-mismatched sibling donor, survival was 72% (95% CI, 57%– 87%). Arguably, this first report effectively addressed the critics’ concerns: (1) UCB contained sufficient numbers of HSCs and progenitors to reliably engraft transplant recipients after a myeloablative therapy without any identifiable
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limiting; and (3) risks of relapse and opportunistic infection were not out of proportion compared to those expected after BMT. While larger numbers of patients and comparative analyses would be required to quell everyone’s concerns, it was clear that UCB warranted further study. In 2000, Rocha et al performed the first comparative analysis between UCBT and BMT in pediatric patients.30 In this joint Eurocord and IBMTR study, the clinical data provided the first compelling evidence that substantiated the claim that acute and chronic GVHD were less common in recipients of UCB. While similar rates of leukemia relapse were listed as a cause of death in this analysis, the lower rates of GVHD only heightened concerns about the graft-versus-leukemia/ lymphoma (GVL) effect of UCBT. This concern would not diminish for several more years.
UNRELATED DONOR UCBT: NEW PROSPECTS As a result of these early successes with sibling donor UCBT, several pilot programs for the banking of unrelated donor UCB were initiated. Pablo Rubinstein and colleagues (New York), Girolamo Sirchia and Francesco Bertolini et al (Milano), and Marc Benbunan (Paris) and Peter Wernet and coworkers (Dusseldorf) initiated placental blood banking programs in 1992 and 1993.31–33 At first, the programs were limited in size, focused primarily on demonstrating the feasibility of large-scale UCB collection and banking. Despite the fact that there were fewer than 1,000 units in the worldwide inventory, an extraordinary event occurred. An UCB unit had been identified for a 3-year-old boy with T-cell acute lymphocytic leukemia at Duke University Medical Center. After total-body irradiation, melphalan and cyclophosphamide with methotrexate, CsA and MP immunoprophylaxis, the first unrelated donor UCBT occurred on August 24, 1993.34 The 2 HLA antigen-mismatched (B and DRB1) graft contained 4.6 ⫻ 107 nucleated cells/kg. With neutrophil recovery and engraftment documented without sign of GVHD, the mission of the international cord blood banking effort was substantially clearer. Figure 2. (A) Comparisons between (a) number of nucleated cells per kilogram (n ⫽ 43) and (b) number of CFU-GM (n ⫽ 42) and time to neutrophil recovery for patients who engrafted (diamonds) and failed to engraft (circles). (B) Comparison of neutrophil recovery in patients treated with G-CSF or GM-CSF and untreated patients. A and B reprinted with permission from The Lancet 1995;346:214 –9.
cell dose threshold; (2) GVHD was extraordinarily low even for children with HLA-matched sibling donors, supporting the hypothesis that there was something biologically unique about the neonatal immune system and that maternal cell contamination would not be
INITIAL RESULTS WITH UNRELATED DONOR UCBT In July 1996, Kurtzberg et al34 and Wagner et al35 published back-to-back reports describing the initial experiences with unrelated donor UCBT. In the Duke series, 25 patients underwent UCBT between August 1993 and November 1995 (median age, 7 year; range, 0.8 –23.5) with 19 (76%) treated for a malignant disease. In the Minnesota/Children’s Hospital of Orange County series, 18 patients underwent UCBT between July 1994 and November 1995 (median age, 2.7 years; range, 0.1–21.3) with 13 (72%) treated for a malignant
History of umbilical cord transplantation
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Table 1. Survival by HLA Match in the First 43 Unrelated Donor UCBTs
University of Minnesota CHOC
Duke
HLA Match
Alive/Total
Alive/Total
Combined Alive/Total
6/6 5/6 4/6 3/6 Summary
3/6 5/7 2/3 0/1 10/18 (56%)
1/1 5/9 6/14 2/5 14/25 (56%)
4/7 (57%) 10/16 (63%) 6/14 (43%) 2/5 (40%)
Data from Kurtzberg J et al34 and Wagner et al.35
disease. Pooling the 43 patients together, several important findings emerge: (1) neutrophil recovery and engraftment were documented in 35 of 40 (88%) patients surviving beyond day 21 at a median of 22 and 24 days in the two reports; (2) grades 2– 4 and 3– 4 acute GVHD occurred in 19 of 35 (54%) and 3 of 35 (9%) patients; and (3) survival was observed in 23 of 43 (53%) patients with 170 –998⫹ days of follow-up among survivors. Notably, there was no clear association between HLA match and survival (Table 1), at least supporting the notion that HLA mismatch even at 2 and 3 antigens would indeed be tolerable. What was inconsistent between the reports was the association between cell dose and speed of hematopoietic recovery. Whether differences in supportive care confounded these results was unknown. However, Minnesota patients did not receive hematopoietic growth factor on the basis of prior observations in recipients of sibling donor UCBT where hematopoietic growth factor failed to speed the rate of neutrophil recovery, and Duke patients received granulocyte colony-stimulating factor (G-CSF) 10 g/kg daily until the absolute neutrophil count exceeded 10 ⫻ 108/L. In August 1995, the first UCBT in an adult with a primary diagnosis of leukemia was performed in Paris at the Hôpital St. Antoine. Like those of Kurtzberg and Wagner, Jean-Philippe Laporte et al36 reported this experience in 1996. In these three reports, four adults over the age of 21 years had been successfully treated with unrelated donor UCBT. Two were alive at 8 and 15 months after transplant, having been treated for chronic myelogenous leukemia in blast crisis and Fanconi anemia with acute myelocytic leukemia. Together, these early results suggested that UCB might serve as a source of allogeneic HSCs for adults as well as children.
AUTOLOGOUS CORD BLOOD BANKING Even prior to the successes of public cord blood banking, it had been suggested that the storage of the infant’s own UCB might be useful both for the child
from which it was collected, as well as other members of the family. Such HSC collection, it was argued, was a form of “biological insurance.” Autologous UCB would be tumor-free and virus-free. Furthermore, privately banked UCB would be available to other family members should they be sufficiently HLA-matched. The Biocyte Corporation, now Pharmastem, was founded on the concept that privately stored UCB would be useful in the treatment of a variety of disorders, including cancers, genetic disorders, and immune deficiency states. Other private companies offering family-centered UCB banking have developed in many countries worldwide. These companies have met with variable successes despite vociferous public debates as to their need. The American Academy of Pediatrics, American College of Obstetrics and Gynecology, and the Royal College of Obstetricians and Gynaecologists Association and other societies have taken stands against private UCB banking,37–39 arguing that the likelihood of autologous use was remarkably low. In part, the controversy stems from questionable advertising practices and the low volume of product (eg, ⬍10 mL) permitted for storage by some private banks. The principal dilemma with the argument on either side of the issue is that the full spectrum of uses of UCB has yet to be determined. Today, the only proven use of UCB is in the setting of conventional blood and marrow transplantation for the treatment of lympho-hematopoietic diseases. Other possible uses, while advertised, are unproven; for example, it is not yet known that UCB is a suitable source of non-hematopoietic cells that will be useful in tissue repair or whether it can be stored indefinitely. Yet, it cannot be denied that there is widening potential for UCB as we consider various nonhematopoietic uses either for regenerative medicine or as lymphoid effector cells (eg, regulatory T cells and natural killer cells). At this point, the efficacy of these cell populations is speculative, but there is considerable interest in exploring these new possibilities.
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The exact number of autologous UCBTs performed to date is unknown. In a recent report by Thornley et al,40 six transplant centers had performed nine autologous UCBTs (four for severe aplastic anemia, one each for neuroblastoma, retinoblastoma, Shwachman-Diamond syndrome, brain tumor, and unidentified indication). However, outcome data are unavailable, except to say that one graft failure has been reported.
PIVOTAL DISCOVERIES—THE FIRST GENERATION OF UCBT
1995
Over the first 21 years (October 1988 –October 2009) of UCBT, it is clear that important strides have been made that have resulted in significant benefits for our patients. While the following list may not be exhaustive, it certainly reflects some of the more important discoveries and milestones during this first generation of UCBT. 1972 Ende and Ende published the first report using multiple aliquots of fresh UCB to treat a child with leukemia after conventional (non-ablative) chemotherapy.6 1982 Ted Boyce, Judith Bard, and Hal Broxmeyer first discuss the possibility of UCB as source of HSC for transplantation. 1985 Biocyte Corporation founded. 1988 Gluckman leads transplant team performing the world’s first UCBT for a child with Fanconi anemia (reported in the New England Journal of Medicine in 1989);15 clinical costs partially supported by Biocyte Corporation. 1989 Broxmeyer demonstrates that UCB contains substantial numbers of primitive hematopoietic progenitors, suggesting that a single UCB unit may be adequate for transplant.11 1990 Wagner et al and Vilmer et al perform the first UCBTs for children with leukemia in the United States and France (reported in Blood and Transplantation in 1992), respectively.16,17 1991 First Biocyte-sponsored symposium in December 1991 in Denver, CO. 1992 Placental Blood Program at the New York Blood Center established, supported by the National Heart, Lung and Blood Institute (Principal Investigator: P. Rubinstein). Creation of the International Cord Blood Transplant Registry at the University of Minnesota. 1993 First UCB unit collected and stored at the New York Blood Center. First International Conference on Cord Blood Transplantation and Biology/Immunology at Indiana University, Indianapolis, IN on November 8 –11, 1993.41
1996
1997
1998
2000
First meeting of the Cord Blood Study Group in Indianapolis, IN on November 7, 1993. Plenary Presentation at the American Society of Hematology in St Louis, MO. Abstract entitled “Allogeneic Umbilical Cord Blood Transplantation: Report of Results in 26 Patients.”42 Public Banks created in Milano (Sirchia and Bertolini), Paris (Benbunan), and Dusseldorf (Wernet). First report of the International Cord Blood Transplant Registry (26 transplant teams) summarizing outcomes in 44 patients transplanted with sibling donor UCB.28 Kohn et al report on the first infusions of genetically modified autologous UCB HSC in young children with adenosine deaminase deficiency.43 National Heart Lung and Blood Institute releases RFP entitled “Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells” (three banks and six transplant centers awarded contracts). Worldwide UCB inventory exceeds 1,000 units. Eurocord project founded under the direction of Eliane Gluckman and sponsored by the European Union. Kurtzberg et al,34 Wagner et al,35 and Laporte et al36 simultaneously publish initial results with unrelated donor UCB. Gluckman et al publishes first report from the Eurocord Registry.44 Worldwide UCB inventory exceeds 10,000 units. Second International Workshop on Cord Blood Transplantation at Indiana University, Indianapolis, IN on March 9 –10, 1997. The Foundation Marcel Merieux hosts the initial Eurocord Meetings in Annecy, France. First clinical trials of culture-expanded UCB HSC. Rubinstein et al publishes first report from the New York Blood Center experience.45 Netcord established. Identification of the cell dose threshold and interaction with HLA match. First trials evaluating “double UCBT.” First trials evaluating UCBT in the setting of non-myeloablative therapy. First UCBT from an HLA-matched sibling donor conceived after embryo selection by preimplantation genetic diagnosis—“savior sibling.”46 First demonstration of reduced risk of GVHD
History of umbilical cord transplantation
2001
2002 2003
2004
2005
2006
2007
9
in recipients of HLA-identical sibling donor UCB versus.30 Third International Workshop on Cord Blood Transplantation at Indiana University, Indianapolis, IN on April 30 –May 1, 2001. Laughlin et al publishes first multi-institutional report on transplant outcomes specifically in adults.47 Worldwide inventory exceeds 100,000 units. First (annual) International Cord Blood Transplantation Conference in Duarte, CA in April 2003. Institute of Medicine of the National Academies establishes Committee to make recommendations on the future of UCB banking in the United States. Identification of non-hematopoietic progenitor cells in UCB.48 Eliane Gluckman awarded the E. Donnall Thomas Lecture and Prize in 2005; lecture entitled “Cord Blood Transplantation.” Stem Cell Therapeutic and Research Act of 2005 provides support specifically for expanding the US cord blood inventory. Netcord and National Marrow Donor Program partner. Adult UCBTs exceed those of children. Hal Broxmeyer awarded the E. Donnall Thomas Lecture and Prize in 2007; lecture entitled
300
“Cutting the Cord Launched the Field of Stem Cell Transplantation.” Eapen et al demonstrate comparability between UCB and HLA-matched marrow from unrelated donors in children with acute leukemia (Lancet 2007;369:1947–54). First clinical trial with UCB-derived T-regulatory cells in humans.49 2008 Worldwide inventory exceeds 300,000 (Figure 3). Twentieth anniversary of UCBT with celebrations as part of the Sixth International Cord Blood Transplantation Conference in Los Angeles, CA in June 2008 and International Conference on Biology and Clinical Applications of Cord Blood Cells in Mandelieu, France in October 2008. 2009 Estimated 20,000 UCBTs performed.
FUTURE OF UCBT—THE SECOND GENERATION Despite early skepticism, it is unequivocally clear that UCB is a viable source of HSC for allogeneic transplantation. While it was initially thought that there would be too few HSCs for routine use, particularly in adult recipients, the increasing availability of larger units with high cell doses and the ability to co-infuse two partially HLA-matched units makes this HSC source available to nearly all patients considering transplant. Just as hypothesized, differences in the neonatal im-
Umbilical Cord Blood Units
200 Thousands Thousands
100
0 1989
0 -1 3 -2 -3 5 -4 -5 MillionsMillions -6 7 -7 9 -8 -9 11 -10 -11 13 -12
1991
1994
1997
2000
2003
2006
2009
Adult Marrow Donors
Figure 3. Total number of adult volunteers registered with marrow donor registries worldwide (in millions) and total number of UCB units in cord blood banks worldwide (in thousands) as reported by Bone Marrow Donors Worldwide (www:\\BMDW.org on October 4, 2009).
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mune system permitted greater HLA disparity without a concomitant increase in risk of GVHD. Yet, despite lower risks of GVHD, UCB retains a potent GVL effect. In more recent analyses, it is clear that UCB is now associated with survival rates comparable to those observed with HLA-identical marrow, the “gold standard.” The question is how to make this HSC source better. On the basis of the number of publications on UCBT occurring annually (Figure 4), the future looks promising. As shown in Table 2, innovative strategies are already being explored to address two important obstacles to the successful use of UCB, namely, delayed hematopoietic recovery and slow immune reconstitution. Recent developments with ex vivo expansion culture suggest that faster neutrophil recovery may be possible. The target is 2 weeks as currently observed with mobilized peripheral blood (Figure 5). However, new uses of UCB as a source of lymphoid effector cells and non-hematopoietic stem cells are also being explored. Discoveries resulting from these studies will define the second generation. If successful, public banking efforts will expand and interest in private storage will increase.
SUMMARY The history of UCB serves as one of the best examples of the potential of translational medicine where interactions between basic/translational scientists and clinical investigators can alter the care of patients. However, it must also be noted that this historical review reflects the authors’ recollection of the events
Table 2. Future Directions With UCB
Improved engraftment Enhanced homing to the marrow microenvironment Ex vivo expansion culture Improved conditioning regimens Enhanced immune reconstitution Ex vivo expansion of common lymphocyte progenitors Reduced pharmacological immunosuppression Adoptive transfer of pathogen specific cytotoxic T lymphocytes New uses of UCB T-regulatory cells Natural killer cells Mesenchymal stem/stromal progenitors Other non-hematopoietic stem cell populations
that unfolded over the past 20 years. As with any other “revolutionary idea,” the early days of UCB met with resistance and research cliques. While there continues to be some skepticism about the benefits of UCB, resistance is mostly driven by institutional/investigator preference. While investigators still partner with specific collaborators, widening interest in UCB has heightened the pace of discovery. Much has been accomplished since those first discussions in Dr Boyse’s office at Memorial Sloan-Kettering in 1982.
Manuscripts on the Clinical Use of UCB Literature Review by Year Number of reports
450 400 350 300 250 200 150 100 50 0
19 1 9 19 19 19 19 20 20 20 20 20 2 0 88 90 9 2 94 96 98 00 02 04 06 08 10
Figure 4. Since 1992, there has been a steady increase in the number of reports on the uses of UCB in transplant medicine annually (extracted from PubMed search between 1988 to current).
Figure 5. Delayed neutrophil recovery and suboptimal engraftment is common in adult recipients of umbilical cord blood (CB) as compared to that observed in recipients of mobilized peripheral blood progenitor cells (PBPC). Data from the University of Minnesota.
History of umbilical cord transplantation
REFERENCES 1. Copeland EA. Hematopoietic stem cell transplantation. N Engl J Med. 2007;354:1813–26. 2. Immunomodulation and pharmacological strategies in the treatment of graft-versus-host disease. Exp Opin Pharmacother. 2008;9:2305–16. 3. Wagner JE, Thompson JS, Carter SL, Kernan NA. Effect of graft-versus-host disease prophylaxis on 3-year diseasefree survival in recipients of unrelated donor bone marrow (T-cell depletion trial): a multi-centre, randomized phase II-III trial. Lancet. 2005;366:733– 41. 4. Linch DC, Brent L. Can cord blood be used? [letter]. Nature. 1989;340:676. 5. Nathan DG. The beneficence of neonatal hematopoiesis. N Engl J Med. 1989;321:1190 –1. 6. Ende M, Ende N. Hematopoietic transplantation by means of fetal (cord) blood. Virginia Med J. 1972;99: 276 – 80. 7. Koike K. Cryopreservation of pluripotent and committed hemopoietic progenitor cells from human bone marrow and cord blood. Acta Paediatr Jpn. 1983;25:275. 8. Besalduch-Vidal J. Nature and characterization of granulocyte-macrophage precursors in cord blood. University of Valencia School of Medicine (Doctoral Dissertation); Spain; 1985. 9. Broxmeyer HE. Investigator profile. J Hematother Stem Cell Res. 2000;9:597– 605. 10. Boyse EA, Broxmeyer HE, Douglas GW. Preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood. US Patent 5,004,681 issued April 2, 1991 (assigned to Biocyte Corporation). 11. Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. 1989;86:3828 –32. 12. Broxmeyer HE, 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 –13. 13. Gluckman E, Berger R, Dutreix J. Bone marrow transplantation for Fanconi anemia. Semin Hematol. 1984;21: 20 – 6. 14. Auerbach AD. Umbilical cord blood transplants for genetic disease: diagnostic and ethical issues in fetal studies. Blood Cells. 1994;20:303–9. 15. Gluckman E, Broxmeyer HE, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical cord blood from an HLAidentical sibling. N Engl J Med. 1989;321:1174 – 8. 16. Wagner JE, Broxmeyer HE, Byrd RL, et al. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood. 1992;79:1874 – 81. 17. Vilmer E, Sterkers G, Rahimy C, et al. HLA-mismatched cord blood transplantation in a patient with advanced leukemia. Transplantation. 1992;53:1155–57. 18. Vanlemmens P, Plouvier E, Amsallem D, et al. Transplantation of umbilical cord blood in neuroblastoma. Nouv Rev Fr Hematol. 1992;34:243– 6. 19. Kernan NA, Scroeder ML, Ciavarella D, et al. Umbilical cord blood infusion in a patient for correction of Wiskott-Aldrich syndrome. Blood Cells. 1994;20:242– 4.
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20. Kurtzberg J, Graham M, Casey J, et al. The use of umbilical cord blood in a mismatched related and unrelated hematopoietic stem cell transplantation. Blood Cells. 1994;20:275– 84. 21. Pahwa RN, Fleischer A, Than S, et al. Successful hematopoietic reconstitution with transplantation of erythrocyte-depleted allogeneic human umbilical cord blood cells in a child with leukemia. Proc Natl Acad Sci U S A. 1994;91:4485– 8. 22. Bogdanic V, Nemet D, Kastelan A, et al. Umbilical cord blood transplantation in a patient with Philadelphiachromosome positive chronic myeloid leukemia. Transplantation. 1993;56:477–9. 23. Vowels MR, Lam PO, Tang R, Berdoukas V, et al. Brief report: correction of X-linked lymphoproliferative disease by transplantation of cord-blood stem cells. N Engl J Med. 1993;329:1623–5. 24. Kohli-Kumar M, Shahidi NT, Broxmeyer HE, et al. Haematopoietic stem/progenitor cell transplant in Fanconi anaemia using HLA-matched sibling umbilical cord blood cells. Br J Haematol. 1993;85:419 –22. 25. Issaragrisil S, Visuthisakchai S, Suvatte V, et al. Transplantation of cord blood stem cells into a patient with severe thalassemia. N Engl J Med. 1995;332:367–9. 26. Neudorf SML, Blatt J, Corey S, et al. Graft failure after an umbilical cord blood transplant in a patient with severe aplastic anemia [letter]. Blood. 1995;85:2991–2. 27. Miniero R, Busca A, Roncarolo MG, et al. HLA haploidentical umbilical cord blood stem cell transplantation in a child with advanced leukemia: clinical outcome and analysis of hematopoietic recovery. Bone Marrow Transplant. 1995;16:229 – 40. 28. Wagner JE, Kernan NA, Steinbuch M, Broxmeyer HE, Gluckman E. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet. 1995;346:214 –9. 29. Cairo MS, Wagner JE. Review: placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood. 1997;90:4665–78. 30. Rocha V, Wagner JE, Sobocinski K, Klein JP, Zhang MJ, Horowitz MM, et al. Comparison of graft-versus-host disease in children transplanted with HLA identical sibling umbilical cord blood versus HLA identical sibling bone marrow transplant. N Engl J Med. 2000;342:1846 –54. 31. Rubinstein P, Adamson JW, Stevens C. The placental/ umbilical cord blood program of the New York Blood Center: a progress report. Ann NY Acad Sci. 2006;872: 328 –35. 32. Hackenberg P, Kögler G, Wernet P. NETCORD: a cord blood allocation network. Bone Marrow Transplant. 1998;22:S17– 8. 33. Lazzari L, Corsini C, Curioni C, Lecchi L, Scalamogna M, Rebulla P, et al. The Milan Cord Blood Bank the Italian Cord Blood Network. J Hematother. 1996;5:117–22. 34. Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin ED, et al. Placental blood as a source of hematopoietic stem cells for transplantation in unrelated recipients. N Engl J Med. 1996;335:157– 66. 35. Wagner JE, Rosenthal J, Sweetman R, Shu XO, Davies S, Ramsay NKC, et al. Successful transplantation of HLAmatched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. Blood. 1996;88:795– 802.
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36. Laporte J-P, Gorin N-C, Rubinstein P, Lesage S, Portnoi MF, Barbu V, et al. Cord-blood transplantation from an unrelated donor in an adult with chronic myelogenous leukemia. N Engl J Med. 1996;335:167–70. 37. American Academy of Pediatrics; Working Group on Cord Blood Banking. Cord blood banking for potential future transplantation: subject review. Pediatrics. 1999; 104:116 – 8. 38. Committee on Obstetrical Practice ACoOaG. Routine storage of umbilical cord blood for potential future transplantation. Int J Gynaecol Obstet. 1997;58:257–9. 39. http://parentsguidecordblood.org/content/media/m_pdf/ RCOG_opinion2006.pd. 40. Thornley I, Eapen M, Sung L, Lee SJ, Davies SM, Joffe S. Private cord blood banking: experiences and views of pediatric hematopoietic cell transplantation physicians. 41. International Conference on Cord Blood Transplantation and Biology/Immunology. Indianapolis, Indiana, November 8 –11, 1993. Blood Cells. 1994;20:223– 69. 42. Wagner JE, Kernan NA, Broxmeyer HE, Gluckman E. Allogeneic umbilical cord blood transplant. Report of results in 26 patients (abstract). Blood. 1993;82(Suppl 1):86a. 43. Kohn DB, Weinberg KJ, Nolta JA, Heiss LN, Lenarsky C, Crooks GM, et al. Engraftment of gene-modified umbilical cord blood cells in neonates with adenosin deaminase deficiency. Nat Med. 1995;1:1017–23.
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44. Gluckman E, Rocha V, Boyer-Chammard A, Cocatelli F, Arcese W, Pasquini R, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337: 378 – 81. 45. Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR, Berkowitz RL, Cabbad M, Dobrila NL, Taylor PE, Rosenfield RE, Stevens CE. Outcomes amoung 562 recipients of placental-blood transplants for unrelated donors. N Engl J Med. 1998;339:1565–77. 46. Grewal SS, Kahn JP, MacMillan ML, Ramsay NK, Wagner JE. Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotypeidentical sibling selected using preimplantation genetic diagnosis. Blood. 2004;103:114 –51. 47. Laughlin M, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, et al. Hematopoietic engraftment and survival in adult recipients of umbilical cord blood from unrelated donors. N Engl J Med. 2001;344:1815–22. 48. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 2004;200:123–35. 49. Eapen M, Rubinstein P, Zhang MJ, Stevens C, Kurtzberg J, Scaradavou A, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369:1947–54.
T
ransplantation of allogeneic bone marrow has been successfully used in the treatment of highrisk or recurrent hematologic malignancies, bone marrow failure syndromes, selected hereditary immunodeficiency states, and metabolic disorders.1 It is an accepted form of therapy for a host of lymphohematopoietic disease states and storage diseases with success rates often dependent on recipient age, cytomegalovirus (CMV) serostatus, disease and disease status at the time of transplant, and the presence of pre-existing comorbidities.1 Very early in the history of bone marrow transplantation (BMT), it was clear that access to a suitable donor was a major obstacle severely limiting the use of this potentially curative treatment modality. However, even for those patients for whom a human leukocyte antigen (HLA)-matched sibling donor could be identified, the treatment itself was associated with substantial risks, most notably the immunological risk of graft-versus-host disease (GVHD). These risks only magnified as transplant centers explored the possibility of using volunteer adult unrelated donors as an alternative to HLA-matched siblings. Novel immunoproaDivision
of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN. bEurocord, Hôpital Saint Louis, Paris, France. Address correspondence to John E. Wagner, MD, Box 366 UMHC, University of Minnesota, 420 Delaware St, SE, Minneapolis, MN 55455. E-mail: [email protected] 0037-1963/10/$ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2009.10.011
Seminars in Hematology, Vol 47, No 1, January 2010, pp 3–12
phylactic regimens and T-cell depletion methods were explored in an attempt to overcome the barrier of GVHD.2,3 While GVHD prevention was possible with T-cell depletion, it was also clear that the removal of graft lymphocytes concomitantly increased the risks of graft failure, relapse, and opportunistic infections.3 In the absence of better alternative treatment strategies, there was room for considering a new source of hematopoietic stem cells (HSCs)—namely, umbilical cord blood (UCB). In this early phase, UCB had several benefits, albeit mostly theoretical. Of the potential benefits, three were unequivocal: (1) UCB was highly likely to be free of herpes virus contamination; (b) banked HLA-typed UCB was immediately available; and (3) UCB collections could be targeted, a potential strategy for overcoming the under-representation of many ethnic and racial minorities plaguing most adult volunteer donor registries. The other “benefits,” however, were more speculative than known, namely: (1) UCB would contain enough hematopoietic stem and progenitor cells to engraft most adults and children; (2) UCB would be associated with less GVHD as the neonate is immunologically “naive”; and (3) HLA matching would be less stringent again because of the immunological naivete. But UCB was also associated with potential risks. Interestingly, the many opponents of UCB argued vehemently that the immunological naivete of UCB would result in higher relapse rates and risks of opportunistic infection.4,5 Other opponents argued that maternal cell contamination would result in life-threatening acute GVHD. However, it would be the high likelihood of 3
4
graft failure that would most severely limit the usefulness of UCB due the low absolute numbers of HSCs and progenitors. While most of the benefits and few of the risks would indeed be realized, the greatest push for moving UCB forward was the inability of the adult volunteer unrelated donor registries to meet the needs of the patient population.
PROOF OF CONCEPT The concept of using UCB as a clinical source of HSCs was first considered in the late 1960s. Recognizing the potential value of UCB, Ende and Ende6 were among the first to apply UCB to the treatment of a child with leukemia. In the first published report, freshly procured UCB samples from eight donors were infused over a 17-day period in a 16-year-old male with acute lymphocytic leukemia who had previously been treated with 6-mercaptopurine and prednisone.6 While long-term reconstitution was not demonstrated, Ende and Ende documented a transient alteration in red blood cell antigens in the peripheral blood, suggesting a transient mixed chimerism from at least one if not several of the units. Additional studies were performed by Koike7 and Besalduch-Vidal8 in the late 1970s and early 1980s that suggested that UCB may indeed contain sufficient numbers of hematopoietic progenitor cells for transplantation. Preclinical studies compared numbers of hematopoietic progenitors in UCB and marrow. The authors concluded that if a sufficient volume of UCB could be collected, there may be an adequate number of bone marrow progenitors to reconstitute patients.7,8 In anticipation of possible clinical application, Koicke subsequently showed that UCB progenitors could be cryopreserved without significant loss of viability and proliferative capacity.7 The conclusion was that “[cryopreserved] cord blood cells . . . may be useful as a source of hemopoietic progenitor cells for marrow transplantation.” However, it was the pivotal work of Hal Broxmeyer in collaboration with Ted Boyse, Gordon Douglas, Pablo Rubinstein, and Lewis Thomas that moved UCB from laboratory concept to clinical practice as a “viable” source of allogeneic HSCs for transplantation.9 In contrast to earlier investigators, Boyse provided the proof of concept studies in mice and Broxmeyer systematically evaluated the hematopoietic potential of human UCB in vitro, and developed the practical and efficient methods for large-volume collections and storage of UCB, culminating in the first clinical transplant.
Murine Models In 1984 – 85, the hypothesis that UCB contained long-term reconstituting HSCs was first tested in a murine model.10 In the first of four experiments, 7-weekold (B6 ⫻ A-T1ab)F1 hybrid males were irradiated with
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862.8 rad and then transplanted with heparinized whole blood obtained from near-term (B6 –T1aa ⫻ A)F1 mouse embryos. Thirty-day survivors were subsequently typed for the T1a markers distinguishing donor from recipient lympho-hematopoietic cells. It was clear that animals demonstrated repopulation of donor cells, unequivocally demonstrating that lethally irradiated mice could be reconstituted with blood from near-term embryos. This was subsequently followed by three additional experiments evaluating the engraftment potential of (1) smaller volumes of blood from near-term embryos, (2) blood from neonatal donors ⬍24 hours of age, and (3) smaller volumes of blood from neonatal donors. These three studies demonstrated that nearterm and neonatal blood, even at lower volumes, contained sufficient numbers of HSCs and progenitor cells to allow for lympho-hematopoietic recovery of donor cells. Together these studies provided the “proof of concept” that neonatal/placental blood would be sufficient for engraftment. The next step would be to develop a reliable method for human UCB collection and cryopreservation.
UCB Collection and Storage While Boyse et al10 provided data supporting the hypothesis that small quantities of neonatal blood were sufficient for hematopoietic recovery of donor origin in a murine model, Broxmeyer et al11,12 established practical and efficient methods of collecting and storing UCB for clinical use. Broxmeyer and colleagues evaluated the nucleated cell and progenitor content and sterility of more than 100 UCB specimens before and after cryopreservation. They proved that UCB remained viable at 4oC or 25oC for at least 3 days after collection. This observation confirmed that cell viability during transport between hospitals would not be compromised prior to cryopreservation. Moreover, the collection of UCB proved to be remarkably straightforward. Obstetricians and nurse midwives previously untrained in the collection of UCB could be expected to learn the collection technique in a matter of minutes. In summary, these early results suggested that UCB could be easily collected, tested, and stored without substantial losses of viable hematopoietic cells.
FIRST-IN-HUMAN CLINICAL TRIAL Concurrent with the seminal work of Broxmeyer and Boyce, Gluckman et al were establishing a new treatment paradigm for children with Fanconi anemia.13 Furthermore, in the mid 1980s it was also known that couples with one child affected by Fanconi anemia were deliberately conceiving children in the hope of having an HLA-matched unaffected child to serve as an HSC donor.14 Ultimately, this led to a remarkable collaboration between Broxmeyer and Douglas, Dr. Arleen
History of umbilical cord transplantation
Auerbach at Rockefeller University and Dr. Marilyn Pollack at Baylor University who had established new methods of prenatal diagnosis and prenatal HLA typing for couples at high risk of Fanconi anemia, Drs. Henry Friedman and Joanne Kurtzberg who were the hematologists caring for a family with a child with Fanconi anemia, and Eliane Gluckman who arguably had the best transplant survival rates for this particular disease. Having verified that the unborn donor was indeed HLAmatched and unaffected by the disease, one of the first cord blood collections with expressed therapeutic intent was collected by Gordon Douglas; shipped, tested, and cryopreserved by Hal Broxmeyer; and hand-carried to Paris for transplant in early October 1988. After low-dose cyclophosphamide and limited-field irradiation, Matthew, age 6 years, was the first human transplanted with cryopreserved UCB (Figure 1) at the Hôpital St. Louis in Paris by the team of Professeur Eliane Gluckman. One month later with complete chimerism demonstrated, the team proved once and for all that UCB indeed contained the pluripotent HSC.15
EARLY CLINICAL RESULTS Since the first report of a successful UCB transplant (UCBT) in 1989,15 investigators worldwide began to explore the potential of UCB as a source of HSCs for transplantation.16 –27 Early on, however, many questions were raised in the form of editorials.4,5 Would this HSC source engraft larger recipients or recipients with diseases other than Fanconi anemia? Would lethal GVHD occur because of maternal lymphocyte contamination, previously shown to occur in some neonates with congenital immunodeficiency? Alternatively, would UCB lymphocytes be less likely to cause a graft-versus-host reaction because of “immunologic naivete” and therefore lead to a greater risk of leukemic relapse?
Figure 1. Matthew Farrow and Eliane Gluckman at the Hôpital St. Louis in October 1988 and October 16, 2008 celebrating the first 20 years of UCBT in Mandelieu, France. Photograph kindly provided by Professor Eliane Gluckman.
5
In 1992, the International Cord Blood Transplant Registry was established by John Wagner, Nancy Kernan, Hal Broxmeyer, and Eliane Gluckman as a repository of clinical data on outcomes observed in patients transplanted with UCB in an attempt to more quickly discern the true risks and benefits of this new HSC source. While this registry was little more than boxes of completed forms from investigators across Europe, the United States, and Australia in an office at the University of Minnesota, it was a beginning. In 1995, the Registry merged with the Center for Blood and Marrow Transplant Research (formally the International Bone Marrow Transplant Registry [IBMTR]) in 1995. In 1993, a similar registry was designed in Europe as part of the European Research Project on Cord Blood Transplantation (Eurocord Transplant Registry).
INITIAL RESULTS WITH SIBLING DONOR UCBT Only two reports came directly from the International Cord Blood Transplant Registry. The first was published in The Lancet in 1995 and summarized the findings in the first 44 UCBTs, and the second was an update (N ⫽ 74 patients) published in Blood in 1997.28,29 Briefly, in this first experience, the patients were aged 0.8 to 16.3 years (median, 4.0 years) with 34 having an HLA-matched unit, and 10, one, and five patients having a 1, 2, or 3 HLA antigen mismatched unit, respectively. For most, prophylaxis for acute GVHD consisted of cyclosporine A (CsA) alone or in combination with methylprednisolone (MP) and half received hematopoietic growth factor early after the infusion of UCB by study design. In this first registry report on UCBT, several critical observations were made. For recipients of HLA 0 –1 antigen grafts, the probability of engraftment was 91% (⫾2%) at a median of 22.0 days (range, 9 to 46) for neutrophils and 51 days (range, 15–117) for platelets (5 ⫻ 1010/L). Graft failure occurred in five (9%) patients, all with nonmalignant disease (probability of neutrophil engraftment 69% v 100%). Furthermore, we could not discern (1) a correlation between the number of nucleated cells or granulocyte-macrophage colony-forming units (CFU-GM) and the time to neutrophil recovery or risk of graft failure (Figure 2A), or (2) a beneficial effect of hematopoietic growth factor on speed of recovery (Figure 2B). As hoped, the probability of grade 2– 4 acute GVHD was extraordinarily low (3%; 95% confidence interval [CI], 0 – 8%) with no patient having grade 3– 4 disease. Similarly, the probability of limited and extensive chronic GVHD was low (6%; 95% CI, 0 –15%). For the patients with a 0 –1 HLA-mismatched sibling donor, survival was 72% (95% CI, 57%– 87%). Arguably, this first report effectively addressed the critics’ concerns: (1) UCB contained sufficient numbers of HSCs and progenitors to reliably engraft transplant recipients after a myeloablative therapy without any identifiable
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limiting; and (3) risks of relapse and opportunistic infection were not out of proportion compared to those expected after BMT. While larger numbers of patients and comparative analyses would be required to quell everyone’s concerns, it was clear that UCB warranted further study. In 2000, Rocha et al performed the first comparative analysis between UCBT and BMT in pediatric patients.30 In this joint Eurocord and IBMTR study, the clinical data provided the first compelling evidence that substantiated the claim that acute and chronic GVHD were less common in recipients of UCB. While similar rates of leukemia relapse were listed as a cause of death in this analysis, the lower rates of GVHD only heightened concerns about the graft-versus-leukemia/ lymphoma (GVL) effect of UCBT. This concern would not diminish for several more years.
UNRELATED DONOR UCBT: NEW PROSPECTS As a result of these early successes with sibling donor UCBT, several pilot programs for the banking of unrelated donor UCB were initiated. Pablo Rubinstein and colleagues (New York), Girolamo Sirchia and Francesco Bertolini et al (Milano), and Marc Benbunan (Paris) and Peter Wernet and coworkers (Dusseldorf) initiated placental blood banking programs in 1992 and 1993.31–33 At first, the programs were limited in size, focused primarily on demonstrating the feasibility of large-scale UCB collection and banking. Despite the fact that there were fewer than 1,000 units in the worldwide inventory, an extraordinary event occurred. An UCB unit had been identified for a 3-year-old boy with T-cell acute lymphocytic leukemia at Duke University Medical Center. After total-body irradiation, melphalan and cyclophosphamide with methotrexate, CsA and MP immunoprophylaxis, the first unrelated donor UCBT occurred on August 24, 1993.34 The 2 HLA antigen-mismatched (B and DRB1) graft contained 4.6 ⫻ 107 nucleated cells/kg. With neutrophil recovery and engraftment documented without sign of GVHD, the mission of the international cord blood banking effort was substantially clearer. Figure 2. (A) Comparisons between (a) number of nucleated cells per kilogram (n ⫽ 43) and (b) number of CFU-GM (n ⫽ 42) and time to neutrophil recovery for patients who engrafted (diamonds) and failed to engraft (circles). (B) Comparison of neutrophil recovery in patients treated with G-CSF or GM-CSF and untreated patients. A and B reprinted with permission from The Lancet 1995;346:214 –9.
cell dose threshold; (2) GVHD was extraordinarily low even for children with HLA-matched sibling donors, supporting the hypothesis that there was something biologically unique about the neonatal immune system and that maternal cell contamination would not be
INITIAL RESULTS WITH UNRELATED DONOR UCBT In July 1996, Kurtzberg et al34 and Wagner et al35 published back-to-back reports describing the initial experiences with unrelated donor UCBT. In the Duke series, 25 patients underwent UCBT between August 1993 and November 1995 (median age, 7 year; range, 0.8 –23.5) with 19 (76%) treated for a malignant disease. In the Minnesota/Children’s Hospital of Orange County series, 18 patients underwent UCBT between July 1994 and November 1995 (median age, 2.7 years; range, 0.1–21.3) with 13 (72%) treated for a malignant
History of umbilical cord transplantation
7
Table 1. Survival by HLA Match in the First 43 Unrelated Donor UCBTs
University of Minnesota CHOC
Duke
HLA Match
Alive/Total
Alive/Total
Combined Alive/Total
6/6 5/6 4/6 3/6 Summary
3/6 5/7 2/3 0/1 10/18 (56%)
1/1 5/9 6/14 2/5 14/25 (56%)
4/7 (57%) 10/16 (63%) 6/14 (43%) 2/5 (40%)
Data from Kurtzberg J et al34 and Wagner et al.35
disease. Pooling the 43 patients together, several important findings emerge: (1) neutrophil recovery and engraftment were documented in 35 of 40 (88%) patients surviving beyond day 21 at a median of 22 and 24 days in the two reports; (2) grades 2– 4 and 3– 4 acute GVHD occurred in 19 of 35 (54%) and 3 of 35 (9%) patients; and (3) survival was observed in 23 of 43 (53%) patients with 170 –998⫹ days of follow-up among survivors. Notably, there was no clear association between HLA match and survival (Table 1), at least supporting the notion that HLA mismatch even at 2 and 3 antigens would indeed be tolerable. What was inconsistent between the reports was the association between cell dose and speed of hematopoietic recovery. Whether differences in supportive care confounded these results was unknown. However, Minnesota patients did not receive hematopoietic growth factor on the basis of prior observations in recipients of sibling donor UCBT where hematopoietic growth factor failed to speed the rate of neutrophil recovery, and Duke patients received granulocyte colony-stimulating factor (G-CSF) 10 g/kg daily until the absolute neutrophil count exceeded 10 ⫻ 108/L. In August 1995, the first UCBT in an adult with a primary diagnosis of leukemia was performed in Paris at the Hôpital St. Antoine. Like those of Kurtzberg and Wagner, Jean-Philippe Laporte et al36 reported this experience in 1996. In these three reports, four adults over the age of 21 years had been successfully treated with unrelated donor UCBT. Two were alive at 8 and 15 months after transplant, having been treated for chronic myelogenous leukemia in blast crisis and Fanconi anemia with acute myelocytic leukemia. Together, these early results suggested that UCB might serve as a source of allogeneic HSCs for adults as well as children.
AUTOLOGOUS CORD BLOOD BANKING Even prior to the successes of public cord blood banking, it had been suggested that the storage of the infant’s own UCB might be useful both for the child
from which it was collected, as well as other members of the family. Such HSC collection, it was argued, was a form of “biological insurance.” Autologous UCB would be tumor-free and virus-free. Furthermore, privately banked UCB would be available to other family members should they be sufficiently HLA-matched. The Biocyte Corporation, now Pharmastem, was founded on the concept that privately stored UCB would be useful in the treatment of a variety of disorders, including cancers, genetic disorders, and immune deficiency states. Other private companies offering family-centered UCB banking have developed in many countries worldwide. These companies have met with variable successes despite vociferous public debates as to their need. The American Academy of Pediatrics, American College of Obstetrics and Gynecology, and the Royal College of Obstetricians and Gynaecologists Association and other societies have taken stands against private UCB banking,37–39 arguing that the likelihood of autologous use was remarkably low. In part, the controversy stems from questionable advertising practices and the low volume of product (eg, ⬍10 mL) permitted for storage by some private banks. The principal dilemma with the argument on either side of the issue is that the full spectrum of uses of UCB has yet to be determined. Today, the only proven use of UCB is in the setting of conventional blood and marrow transplantation for the treatment of lympho-hematopoietic diseases. Other possible uses, while advertised, are unproven; for example, it is not yet known that UCB is a suitable source of non-hematopoietic cells that will be useful in tissue repair or whether it can be stored indefinitely. Yet, it cannot be denied that there is widening potential for UCB as we consider various nonhematopoietic uses either for regenerative medicine or as lymphoid effector cells (eg, regulatory T cells and natural killer cells). At this point, the efficacy of these cell populations is speculative, but there is considerable interest in exploring these new possibilities.
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The exact number of autologous UCBTs performed to date is unknown. In a recent report by Thornley et al,40 six transplant centers had performed nine autologous UCBTs (four for severe aplastic anemia, one each for neuroblastoma, retinoblastoma, Shwachman-Diamond syndrome, brain tumor, and unidentified indication). However, outcome data are unavailable, except to say that one graft failure has been reported.
PIVOTAL DISCOVERIES—THE FIRST GENERATION OF UCBT
1995
Over the first 21 years (October 1988 –October 2009) of UCBT, it is clear that important strides have been made that have resulted in significant benefits for our patients. While the following list may not be exhaustive, it certainly reflects some of the more important discoveries and milestones during this first generation of UCBT. 1972 Ende and Ende published the first report using multiple aliquots of fresh UCB to treat a child with leukemia after conventional (non-ablative) chemotherapy.6 1982 Ted Boyce, Judith Bard, and Hal Broxmeyer first discuss the possibility of UCB as source of HSC for transplantation. 1985 Biocyte Corporation founded. 1988 Gluckman leads transplant team performing the world’s first UCBT for a child with Fanconi anemia (reported in the New England Journal of Medicine in 1989);15 clinical costs partially supported by Biocyte Corporation. 1989 Broxmeyer demonstrates that UCB contains substantial numbers of primitive hematopoietic progenitors, suggesting that a single UCB unit may be adequate for transplant.11 1990 Wagner et al and Vilmer et al perform the first UCBTs for children with leukemia in the United States and France (reported in Blood and Transplantation in 1992), respectively.16,17 1991 First Biocyte-sponsored symposium in December 1991 in Denver, CO. 1992 Placental Blood Program at the New York Blood Center established, supported by the National Heart, Lung and Blood Institute (Principal Investigator: P. Rubinstein). Creation of the International Cord Blood Transplant Registry at the University of Minnesota. 1993 First UCB unit collected and stored at the New York Blood Center. First International Conference on Cord Blood Transplantation and Biology/Immunology at Indiana University, Indianapolis, IN on November 8 –11, 1993.41
1996
1997
1998
2000
First meeting of the Cord Blood Study Group in Indianapolis, IN on November 7, 1993. Plenary Presentation at the American Society of Hematology in St Louis, MO. Abstract entitled “Allogeneic Umbilical Cord Blood Transplantation: Report of Results in 26 Patients.”42 Public Banks created in Milano (Sirchia and Bertolini), Paris (Benbunan), and Dusseldorf (Wernet). First report of the International Cord Blood Transplant Registry (26 transplant teams) summarizing outcomes in 44 patients transplanted with sibling donor UCB.28 Kohn et al report on the first infusions of genetically modified autologous UCB HSC in young children with adenosine deaminase deficiency.43 National Heart Lung and Blood Institute releases RFP entitled “Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells” (three banks and six transplant centers awarded contracts). Worldwide UCB inventory exceeds 1,000 units. Eurocord project founded under the direction of Eliane Gluckman and sponsored by the European Union. Kurtzberg et al,34 Wagner et al,35 and Laporte et al36 simultaneously publish initial results with unrelated donor UCB. Gluckman et al publishes first report from the Eurocord Registry.44 Worldwide UCB inventory exceeds 10,000 units. Second International Workshop on Cord Blood Transplantation at Indiana University, Indianapolis, IN on March 9 –10, 1997. The Foundation Marcel Merieux hosts the initial Eurocord Meetings in Annecy, France. First clinical trials of culture-expanded UCB HSC. Rubinstein et al publishes first report from the New York Blood Center experience.45 Netcord established. Identification of the cell dose threshold and interaction with HLA match. First trials evaluating “double UCBT.” First trials evaluating UCBT in the setting of non-myeloablative therapy. First UCBT from an HLA-matched sibling donor conceived after embryo selection by preimplantation genetic diagnosis—“savior sibling.”46 First demonstration of reduced risk of GVHD
History of umbilical cord transplantation
2001
2002 2003
2004
2005
2006
2007
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in recipients of HLA-identical sibling donor UCB versus.30 Third International Workshop on Cord Blood Transplantation at Indiana University, Indianapolis, IN on April 30 –May 1, 2001. Laughlin et al publishes first multi-institutional report on transplant outcomes specifically in adults.47 Worldwide inventory exceeds 100,000 units. First (annual) International Cord Blood Transplantation Conference in Duarte, CA in April 2003. Institute of Medicine of the National Academies establishes Committee to make recommendations on the future of UCB banking in the United States. Identification of non-hematopoietic progenitor cells in UCB.48 Eliane Gluckman awarded the E. Donnall Thomas Lecture and Prize in 2005; lecture entitled “Cord Blood Transplantation.” Stem Cell Therapeutic and Research Act of 2005 provides support specifically for expanding the US cord blood inventory. Netcord and National Marrow Donor Program partner. Adult UCBTs exceed those of children. Hal Broxmeyer awarded the E. Donnall Thomas Lecture and Prize in 2007; lecture entitled
300
“Cutting the Cord Launched the Field of Stem Cell Transplantation.” Eapen et al demonstrate comparability between UCB and HLA-matched marrow from unrelated donors in children with acute leukemia (Lancet 2007;369:1947–54). First clinical trial with UCB-derived T-regulatory cells in humans.49 2008 Worldwide inventory exceeds 300,000 (Figure 3). Twentieth anniversary of UCBT with celebrations as part of the Sixth International Cord Blood Transplantation Conference in Los Angeles, CA in June 2008 and International Conference on Biology and Clinical Applications of Cord Blood Cells in Mandelieu, France in October 2008. 2009 Estimated 20,000 UCBTs performed.
FUTURE OF UCBT—THE SECOND GENERATION Despite early skepticism, it is unequivocally clear that UCB is a viable source of HSC for allogeneic transplantation. While it was initially thought that there would be too few HSCs for routine use, particularly in adult recipients, the increasing availability of larger units with high cell doses and the ability to co-infuse two partially HLA-matched units makes this HSC source available to nearly all patients considering transplant. Just as hypothesized, differences in the neonatal im-
Umbilical Cord Blood Units
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100
0 1989
0 -1 3 -2 -3 5 -4 -5 MillionsMillions -6 7 -7 9 -8 -9 11 -10 -11 13 -12
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Adult Marrow Donors
Figure 3. Total number of adult volunteers registered with marrow donor registries worldwide (in millions) and total number of UCB units in cord blood banks worldwide (in thousands) as reported by Bone Marrow Donors Worldwide (www:\\BMDW.org on October 4, 2009).
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J.E. Wagner and E. Gluckman
mune system permitted greater HLA disparity without a concomitant increase in risk of GVHD. Yet, despite lower risks of GVHD, UCB retains a potent GVL effect. In more recent analyses, it is clear that UCB is now associated with survival rates comparable to those observed with HLA-identical marrow, the “gold standard.” The question is how to make this HSC source better. On the basis of the number of publications on UCBT occurring annually (Figure 4), the future looks promising. As shown in Table 2, innovative strategies are already being explored to address two important obstacles to the successful use of UCB, namely, delayed hematopoietic recovery and slow immune reconstitution. Recent developments with ex vivo expansion culture suggest that faster neutrophil recovery may be possible. The target is 2 weeks as currently observed with mobilized peripheral blood (Figure 5). However, new uses of UCB as a source of lymphoid effector cells and non-hematopoietic stem cells are also being explored. Discoveries resulting from these studies will define the second generation. If successful, public banking efforts will expand and interest in private storage will increase.
SUMMARY The history of UCB serves as one of the best examples of the potential of translational medicine where interactions between basic/translational scientists and clinical investigators can alter the care of patients. However, it must also be noted that this historical review reflects the authors’ recollection of the events
Table 2. Future Directions With UCB
Improved engraftment Enhanced homing to the marrow microenvironment Ex vivo expansion culture Improved conditioning regimens Enhanced immune reconstitution Ex vivo expansion of common lymphocyte progenitors Reduced pharmacological immunosuppression Adoptive transfer of pathogen specific cytotoxic T lymphocytes New uses of UCB T-regulatory cells Natural killer cells Mesenchymal stem/stromal progenitors Other non-hematopoietic stem cell populations
that unfolded over the past 20 years. As with any other “revolutionary idea,” the early days of UCB met with resistance and research cliques. While there continues to be some skepticism about the benefits of UCB, resistance is mostly driven by institutional/investigator preference. While investigators still partner with specific collaborators, widening interest in UCB has heightened the pace of discovery. Much has been accomplished since those first discussions in Dr Boyse’s office at Memorial Sloan-Kettering in 1982.
Manuscripts on the Clinical Use of UCB Literature Review by Year Number of reports
450 400 350 300 250 200 150 100 50 0
19 1 9 19 19 19 19 20 20 20 20 20 2 0 88 90 9 2 94 96 98 00 02 04 06 08 10
Figure 4. Since 1992, there has been a steady increase in the number of reports on the uses of UCB in transplant medicine annually (extracted from PubMed search between 1988 to current).
Figure 5. Delayed neutrophil recovery and suboptimal engraftment is common in adult recipients of umbilical cord blood (CB) as compared to that observed in recipients of mobilized peripheral blood progenitor cells (PBPC). Data from the University of Minnesota.
History of umbilical cord transplantation
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