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Double umbilical cord blood transplantationNavneet S Majhail, Claudio G Brunsand John E Wagn Unrelated umbilical cord blood (UCB) is an alternative donor identifying an unrelated adult donor takes many weeks to source for allogeneic haematopoietic cell transplantation and, compared with unrelated donor bone marrow, has theadvantages of rapid availability, greater tolerance of HLA To expand the donor pool, unrelated umbilical cord blood disparity and lower incidence of severe graft-versus-host (UCB) has been investigated as an alternate haemato- disease. Graft cell dose is an important determinant of poietic stem cell source. In vitro and in vivo studies have haematopoietic recovery and overall outcome following UCB shown that, compared with adult bone marrow, UCB has a transplantation, and the limited cell dose of single UCB units greater proportion of primitive haematopoietic progenitor has been a major barrier to its more widespread use.
cells that have a higher potential for expansion and Transplantation with two unrelated UCB units is feasible, safe proliferation []. Although the first successful transplant and effective and can overcome the limitation of cell dose of using a HLA-matched UCB donor was reported by Gluckman et al. in 1989 the clinical applications of unrelated umbilical cord blood transplantation (UCBT), 1 Department of Medicine, Blood and Marrow Transplant Program, especially in adults, have become more evident only University of Minnesota, Minneapolis, MN 55455, USA 2 Department of Pediatrics, Blood and Marrow Transplant Program,University of Minnesota, Minneapolis, MN 55455, USA UCB offers certain advantages over unrelated adult donors ]. Because UCB is collected from the pla-centa after delivery there is no risk to the donor. Also,HLA typing of UCB units is performed before storage Current Opinion in Immunology 2006, 18:571–575 and, once identified, banked units are immediately avail- able for transplantation. UCB grafts also have a lower risk of transmission of infectious organisms; a prototypical example is cytomegalovirus, because nearly all donorunits are negative for this virus. Furthermore, despite the use of grafts with greater donor–recipient HLA dis- parity, UCBT has been shown to be associated with a # 2006 Elsevier Ltd. All rights reserved.
similar or even lower risk of acute and chronic graft-versus-host disease (GVHD) Whereas grafts from unrelated adult or sibling donors have to be matched tothe recipient at least at five of six HLA-A, -B and -DRB1antigens, UCB units matched at only four of these six HLA foci have been found to be acceptable for trans- Allogeneic haematopoietic cell transplantation offers the plantation with comparable rates of GVHD and trans- potential for curing a variety of high-risk hematological plant-related mortality. However, the presence of a malignancies. However, lack of suitable donors is one of limited number of haematopoietic progenitor cells in the major limitations to successful transplantation a single unit, lack of access to donor lymphocytes for because almost half of all eligible patients who need an donor lymphocyte infusion if needed, and the brief allogeneic transplant will not have a human leukocyte clinical experience to date are some of the limitations antigen (HLA)-matched donor. Although an HLA- of UCBT compared with the use of unrelated adult matched sibling is the preferred donor source, it is not available for $70% of all patients ]. An HLA-matchedunrelated donor, however, can be identified for another In order to take advantage of the proven benefits of UCB, 30% of patients from the pool of almost 10 million adult the aim of this review is to address one potential strategy volunteers registered with donor registries worldwide.
for overcoming the cell dose limitation, namely the use of The probability of finding a suitable donor also depends upon the ethnic and racial background, with the lowestrate in patients of ethnic and racial minority descent [].
Furthermore, a significant proportion of patients being The total nucleated cell (TNC) and CD34+ cell dose has considered for unrelated donor transplantation will die, been shown to be a crucial determinant of haematopoietic have progressive disease or otherwise become ineligible recovery and overall outcome following UCBT before they can get a transplant because the process of and the limited cell dose of single UCB units is clearly the Current Opinion in Immunology 2006, 18:571–575 most important barrier to its more widespread use, espe- (2 Â 105). Although different patterns of engraftment cially in adults. Currently, a TNC dose of 2.5 Â 107 cells/ were observed in mice that received double UCBT, it kg is generally considered to be the threshold, with was dominated by one donor in the majority of their significantly higher rates of graft failure and transplant- related mortality reported in patients transplanted withsingle UCB units that contain lower numbers of TNCs.
However, only 25% of adult patients meet this cell dose We first reported haematopoietic cell transplantation requirement and hence the majority are ineligible for using two UCB units in an adult patient who had accel- UCBT [Also, because of the limited inventory of erated phase chronic myeloid leukaemia, and subse- suitable UCB units, most adults have access to only four quent experience in a larger cohort of patients has out of six HLA-matched grafts and there is increasing established the safety and efficacy of double UCBT evidence to show that increasing HLA disparity might using both myeloablative and reduced-intensity condi- lead to poorer engraftment with UCBT []. A variety of approaches are being studied to overcome the nega- no study has conducted a head-to-head comparison of tive impact of low cell dose on engraftment following double UCBT with transplantation using unrelated single unit UCBT. These include ex vivo expansion donor bone marrow, the outcomes from reported series culture to increase the number of haematopoietic pro- genitor cells, use of intra-bone marrow injection of UCBto minimize nonspecific loss of circulating haematopoie- Patients who receive UCBT using two UCB units, tic stem cells and the infusion of multiple UCB units.
because of the unavailability of a single unit that has a This review focuses on the current results with double satisfactory TNC dose, do as well as patients transplanted with a single adequately sized UCB unit. Importantly, noincrease in the incidence of severe acute GVHD has been noted with the use of two partially HLA-matched UCB Cotransplantation of two or more partially HLA-matched units instead of one. In a recent analysis that compared unrelated UCB units is one approach that is being single unit (n = 21) and double unit (n = 50) UCBT in explored to overcome the limitation of low cell dose in consecutive adult patients using myeloablative condition- single unit UCBT. Preclinical studies in nonobese dia- ing of Flu/Cy/TBI (fludarabine 25 mg/m2 intravenously betic/severe combined immunodeficient (NOD/SCID) daily from days À8 through À6, cyclophosphamide mice have shown enhanced engraftment by the addition 60 mg/kg intravenously on days À7 and À6, and 165 cGy total body irradiation [TBI] twice-daily fromdays À4 to À1), we found no significant difference in Liu et al. [investigated the effect of donor competition the rates of transplant-related mortality, acute GVHD, on haematopoietic progenitors during methylcellulose neutrophil and platelet engraftment, disease-free survival and long-term culture-initiating cells coculture of equal or overall survival (JEW et al., unpublished data). In a numbers of mononuclear cells from two units. Using similar analysis in adult patients undergoing UCBT with colony-forming unit analysis during mixed UCB culture, reduced-intensity conditioning using Flu/Cy/TBI regi- they demonstrated an early and progressive dominance men (fludarabine 40 mg/m2 intravenously daily from of one donor; the predominating unit had a higher days À6 through À2, cyclophosphamide 50 mg/kg intra- CD3+ content. They proposed that an immediate and venously on day À6, and 200 cGy TBI on day À1), we protracted T-cell effector mechanism along with a observed comparable outcomes for recipients of either single (n = 17) or double (n = 93) UCB units (JEW et al., effect promotes and mediates the rapid engraftment of Interestingly, sustained hematopoiesis after double Nauta et al. [] have reported increased engraftment in UCBT is usually derived from a single donor. In our NOD/SCID mice transplanted with human haemato- initial report of 21 patients who received double UCBT poietic progenitor cells derived from two unrelated using myeloablative conditioning [], single donor UCB units. Mice were transplanted with CD34+ cells accounted for hematopoiesis in 76% and 100% of evalu- derived from single UCB units (1 Â 105), with a combina- able patients at days 21 and 100 post-transplant, respec- tion of two UCB units (1 Â 105 each), or with a single tively. The relative percent viability, the infused TNC UCB unit that had a cell dose equivalent to that of the and CD34+ cell dose, and the donor–recipient HLA- double unit group (2 Â 105). Engraftment of a single UCB disparity were not helpful in predicting which of the unit was significantly enhanced with the cotransplanta- two UCB units would predominate. Although early data tion of a second UCB unit. This was comparable to the suggested that the dominant unit had a higher median engraftment achieved by a single UCB unit that had the infused CD3+ cell dose, this observation has not persisted same number of cells as the double UCBT group with investigation of a larger cohort of patients. Order of Current Opinion in Immunology 2006, 18:571–575 Double umbilical cord blood transplantation Majhail, Brunstein and Wagner Clinical experience with double UCBT.
Reduced-intensity conditioningUniversity of Abbreviations: ANC, absolute neutrophil count; Ara-C, cytosine arabinoside; Cy, cyclophosphamide; DFS, disease-free survival; Flu, fludarabine;GVHD, graft-versus-host disease; Mel, melphalan; PFS, progression-free survival; Pr graft fail, primary graft failure; TBI, total body irradiation; TNC,total nucleated cell; TRM, transplant related mortality; UCBT, umbilical cord blood transplantation.
a Includes studies with more than 10 patients.
b Includes unpublished data.
c Method of CD34+ cell analysis not known.
infusion, location of HLA mismatch, ABO blood group or Transplantation of two cord blood units can potentially sex mismatch also did not have a predictive effect on augment the graft-versus-leukemia (GVL) effect. We reported recently a reduced risk of relapse in patientswith acute leukemia who received double unit UCBT In another analysis of 93 patients who received double ]. We compared the outcome of patients with acute UCBT using reduced-intensity conditioning the leukemia who received myeloablative UCBT using predominant unit and nonsustained units had similar either one (n = 67) or two (n = 29) UCB units that had median infused TNC dose (1.8 Â 107 cells/kg versus similar HLA disparity. Adjusting for factors potentially 1.7 Â 107 cells/kg, p = 0.10), CD34+ cell dose (2.6 Â 105 influencing outcome, double unit UCBT was associated cells/kg versus 2 Â 105 cells/kg, p = 0.22) and CD3+ cell with a reduced chance of relapse (relative risk 0.3, p = 0.03) in Cox regression. This effect was most promi- p = 0.06). The predominant unit, however, had a higher nent in patients undergoing transplantation in their first or median granulocyte-macrophage colony-forming unit con- second complete clinical remission; the overall risk of tent (2.2 Â 104 cells/kg versus 2.0 Â 104 cells/kg, p = 0.02).
relapse was 11% (95% cumulative incidence [CI], 0–25%) Haspel et al. ] have also reported the presence of single in recipients of two UCB units compared with 54% (95% unit predominance in 21 patients who received double CI, 23–85%) in those receiving one unit (p < 0.01). It is UCBT with non-myeloablative conditioning. In contrast not known whether this enhanced GVL effect is mainly to our practice of infusing the two UCB units simulta- the result of increased HLA disparity from the use of two neously, they infused them sequentially 1–6 h apart. The mismatched units or if it is owing to the presence of first infused unit predominated in 76% of the transplants.
additional graft–graft or graft–patient immune effects.
Again, the TNC and CD34+ cell dose were not predictors Our observations also need to be investigated and con- of which of the two UCB units would eventually predo- minate, and they did not investigate the impact of CD3+cells. Although the precise biologic mechanisms for single- donor predominance in double UCBT are not understood Our current UCBT protocols at the University of Min- to date, reported studies suggest at least a partial role for nesota select UCB units based on cryopreserved TNC T-cell mediated immune effects. Other putative expla- dose and HLA-A, -B and -DRB1 match using intermedi- nations could be the inclusion of a larger number of ate resolution antigen level typing for A and B and for supporting mesenchymal stem cells and the presence of DRB1 allele level typing. Single unit UCBT is performed a graft-versus-graft alloreactivity.
if a 5–6 out of 6 HLA-matched UCB unit is available that Current Opinion in Immunology 2006, 18:571–575 has an NC dose of >3.0 Â 107 cells/kg, otherwise patients Confer DL: The National Marrow Donor Program. Meetingthe needs of the medically underserved. Cancer 2001, Mayani H, Lansdorp PM: Biology of human umbilical cord As of 2006, the method of unit selection for double UCBT blood-derived hematopoietic stem/progenitor cells.
is complex and there are no currently available data that specifically address their optimal selection. Because it is Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, becoming increasingly clear that HLA match has an Douglas GW, Devergie A, Esperou H, Thierry D, Socie G,Lehn P: Hematopoietic reconstitution in a patient with impact on relapse and that HLA match and cell dose Fanconi’s anemia by means of umbilical-cord blood have an impact on transplant-related mortality, we pre- from an HLA-identical sibling. N Engl J Med 1989,321:1174-1178.
ferentially select a 5–6 out of 6 HLA-matched unit,regardless of the TNC dose as long as it exceeds Brunstein CG, Wagner JE: Umbilical cord blood transplantationand banking. Annu Rev Med 2006, 57:403-417.
2.5 Â 107 cells/kg. Also, because immunological rejection Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, is hypothesized to account for loss of one unit over time, Bosi A, Jacobsen N, Ruutu T, de Lima M, Finke J et al.: our practice has always required partial HLA matching Transplants of umbilical-cord blood or bone marrowfrom unrelated donors in adults with acute leukemia.
between the two units. This requirement often results in the selection of units that are not necessarily the two units Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, that have the greatest cell dose. HLA disparity between Champlin RE, Stevens C, Barker JN, Gale RP, Lazarus HM et al.: each unit and the recipient and between the two units Outcomes after transplantation of cord blood or bone marrowfrom unrelated donors in adults with leukemia. N Engl J Med does not necessarily have to be at the same loci. Each unit is required to have a cryopreserved TNC dose of at least Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, 1.5 Â 107 cells/kg, such that the total graft dose is Wagner JE: Survival after transplantation of unrelated donor 3.0 Â 107 cells/kg or more. We do not use CD34+ cell umbilical cord blood is comparable to that of human leukocyteantigen-matched unrelated donor bone marrow: results of a dose routinely for UCB unit selection, unless two units of matched-pair analysis. Blood 2001, 97:2957-2961.
equal HLA match that have a TNC dose within 0.3 Â 107 10. Barker JN, Scaradavou A, Stevens CE, Rubinstein P: Analysis of cells/kg of each other are available. The unit with larger 608 umbilical cord blood (UCB) transplants: HLA-match is a CD34+ cell dose is then selected for UCBT. It is not critical determinant of transplant-related mortality (TRM) inthe post-engraftment period even in the absence of acute known whether these selection criteria are optimal, but graft-vs-host disease (aGVHD). ASH Annual Meeting Abstracts they represent the practice used at our institution to date.
11. Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, Goldman A, Kersey J, Krivit W, MacMillan ML et al.:Transplantation of unrelated donor umbilical cord blood Double UCBT is a feasible, safe and effective transplan- in 102 patients with malignant and nonmalignant diseases: tation strategy for patients that have life-threatening influence of CD34 cell dose and HLA disparity ontreatment-related mortality and survival haematological disorders who need a haematopoietic stem cell transplant but lack a HLA-matched related or 12. Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, unrelated donor. It is an attractive option, especially for Wagner JE, Gerson SL, Lazarus HM, Cairo M, Stevens CE et al.: adults who are typically not eligible for single UCBT Hematopoietic engraftment and survival in adult recipients ofumbilical-cord blood from unrelated donors. N Engl J Med because of limitations of cell dose. Besides being rapidly available, an acceptable double unit graft can be identi- 13. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, fied for the majority of patients. The rates of engraftment, Pasquini R, Ortega J, Souillet G, Ferreira E, Laporte JP et al.: transplant-related mortality, GVHD and survival are simi- Outcome of cord-blood transplantation from related andunrelated donors. Eurocord Transplant Group and the lar to those seen with single UCBT and unrelated donor European Blood and Marrow Transplantation Group.
bone marrow. Ongoing studies are investigating the more general applicability of double UCBT in a multi-institu- 14. Nauta AJ, Kruisselbrink AB, Lurvink E, Mulder A, Claas FH, Noort WA, Willemze R, Fibbe WE: Enhanced engraftment ofumbilical cord blood-derived stem cells in NOD/SCID miceby cotransplantation of a second unrelated cord blood unit.
Papers of particular interest, published within the annual period of 15. Kim DW, Chung YJ, Kim TG, Kim YL, Oh IH: Cotransplantation of third-party mesenchymal stromal cells can alleviate single-donor predominance and increase engraftment from double cord transplantation. Blood 2004, 103:1941-1948.
16. Liu M, Reese JS, Jaroscak JJ, Gerson SL: Progressive emergence of a dominant unit during dual unit umbilical cord Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, blood (UCB) culture. ASH Annual Meeting Abstracts 2005.
Weisdorf DJ: Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord bloodversus bone marrow. Biol Blood Marrow Transplant 2002, 17. Kai S, Misawa M, Iseki T, Takahashi S, Kishi K, Hiraoka A, Kato S, Hara H: Double-unit cord blood transplantation in Japan.
ASH Annual Meeting Abstracts 2004. 104:5166 Grewal SS, Barker JN, Davies SM, Wagner JE: Unrelated donorhematopoietic cell transplantation: marrow or umbilical cord 18. Barker JN, Weisdorf DJ, Wagner JE: Creation of a double chimera after the transplantation of umbilical-cord blood from Current Opinion in Immunology 2006, 18:571–575 Double umbilical cord blood transplantation Majhail, Brunstein and Wagner two partially matched unrelated donors. N Engl J Med 2001, 23. Verneris MR, Brunstein CG, DeFor T, Barker J, Weisdorf DJ, Blazar BR, Miller JS, Wagner JE: Risk of relapse after umbilicalcord blood transplantation in patients with acute leukemia: 19. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, marked reduction in recipients of two units. ASH Annual Miller JS, Verfaillie CM, Wagner JE: Transplantation of 2 partially HLA-matched umbilical cord blood units to enhanceengraftment in adults with hematologic malignancy.
24. Yoo KH, Kang HJ, Lee SH, Jung HL, Sung KW, Koo HH, Shin HY, Ahn HS: Double unit cord blood transplantation in children with This study describes preliminary results of double umbilical cord blood acute leukemia. ASH Annual Meeting Abstracts 2005. 106:2043.
transplantation. This is the first report on the use of partially HLA matchedunits in the literature.
25. Ballen KK, Spitzer TR, Yeap B, Steve M, Dey BR, Attar E, Alyea E, Cutler C, Ho V, Lee S et al.: Excellent disease free survival after 20. Brunstein CG, Barker J, DeFor T, French K, Weisdorf DJ, double cord blood transplantation using a reduced intensity Wagner JE: Non-myeloablative umbilical cord blood chemotherapy only conditioning regimen in a diverse adult transplantation: promising disease-free survival in 95 population. ASH Annual Meeting Abstracts 2005. 106:2048 consecutive patients. ASH Annual Meeting Abstracts 2005.
26. Barker JN, Weisdorf DJ, DeFor TE, Brunstein CG, Wagner JE: Umbilical cord blood (UCB) transplantation after non- 21. Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, myeloablative (NMA) conditioning for advanced follicular Wagner JE: Rapid and complete donor chimerism in lymphoma, mantle cell lymphoma and chronic lymphocytic adult recipients of unrelated donor umbilical cord blood leukemia: low transplant-related mortality and high transplantation after reduced-intensity conditioning.
progression-free survival. ASH Annual Meeting Abstracts 2005.
22. Majhail NS, Weisdorf DJ, Wagner JE, Defor TE, Brunstein CG, 27. Haspel RL, Kao GS, Yeap B, Spitzer TR, Ritz J, Antin JH, Ballen K: Burns LJ: Comparable results of umbilical cord blood and Pre-infusion characteristics of the predominant cord blood HLA-matched sibling donor hematopoietic stem cell unit correlate with hematopoietic engraftment in the setting transplantation after reduced-intensity preparative regimen of non-myeloablative double cord blood transplant (DCBT).
for advanced Hodgkin lymphoma. Blood 2006, 107:3804-3807.
ASH Annual Meeting Abstracts 2005. 106:3027.
Current Opinion in Immunology 2006, 18:571–575



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