Clinical Use of Umbilical Cord Blood Hematopoietic Stem Cells

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Biology of Blood and Marrow Transplantation 12:34-41 (2006) 䊚 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1201-0107$32.00/0 doi:10.1016/j.bbmt.2005.09.006

Clinical Use of Umbilical Cord Blood Hematopoietic Stem Cells Vanderson Rocha, Eliane Gluckman, Eurocord and European Blood and Marrow Transplant Group Eurocord Office Bone Marrow Transplant Hematology Department, Hôpital Saint Louis, Paris, France Correspondence and reprint requests: Vanderson Rocha, MD, PhD, Hôpital Saint Louis, Université de Paris 7, 1 Av Claude Vellefaux, 75010, Paris, France (e-mail: [email protected]). Received September 8, 2005; accepted September 23, 2005

ABSTRACT Umbilical cord blood hematopoietic stem cells coming from related or unrelated donors are an alternative source of hematopoietic stem cells for patients undergoing transplantation for a wide variety of diseases. In the unrelated donor transplant setting, shorter time to transplant, which is particularly relevant to patients requiring urgent transplantation, and tolerance of 1–2 human leukocyte antigen mismatch, which increases the chance of finding a suitable donor, are evident advantages over bone marrow transplantation. The speed of engraftment is slower after cord blood transplantation but it is counterbalanced by a lower incidence of severe graft-versus-host disease. Cell dose and human leukocyte antigen are major factors influencing outcome after umbilical cord blood transplantation. Retrospective comparisons of clinical outcomes between unrelated cord blood and unrelated bone transplantation in children and adults have shown similar results, showing the value of this source of hematopoietic stem cell for transplantation. This review describes the recent clinical results and discusses developing research strategies aimed at optimizing the results of cord blood transplantation. © 2006 American Society for Blood and Marrow Transplantation

KEY WORDS Umbilical cord blood transplantation

INTRODUCTION Umbilical cord blood transplantation (UCBT) has extended the availability of allogeneic hematopoietic stem cell transplantation (HSCT) to patients who would otherwise not be eligible for this curative approach. Since the first successful UCBT from an HLA-identical sibling in a child with severe Fanconi anemia reported by Gluckman et al. [1] in 1989, the number of UCBTs from siblings and unrelated donors has increased dramatically, and we estimate that more than 5000 patients have undergone UCBT from unrelated donors thus far. A recent survey of the International Bone Marrow Transplant Registry (IBMTR) estimates that after 1998, 20% of stem cell transplantations performed in young patients (⬍20 years old) have been cord blood transplantations. In Japan, nowadays approximately 50% of HSCTs from unrelated donors are being performed with cord blood cells (T. Takahashi, Medical Director, Tokyo Cord Blood Bank, personal communication, 2005). The inventory of Netcord, the cooperative network of large 34

Related donor

Unrelated donor

experienced umbilical cord blood (UCB) banks, currently has more than 100 000 cryopreserved UCB units ready for clinical use, and a reasonably accurate worldwide estimate would be 250 000 cord blood units. In comparison with other sources of allogeneic HSCT, UCB offers substantial logistic and clinical advantages, such as (1) significantly faster availability of banked cryopreserved UCB units, with patients receiving UCBTs a median of 25 to 36 days earlier than those receiving bone marrow (BM) [2,3]; (2) expansion of the donor pool, because sufficiently large UCB units mismatched for 1 or 2 HLA-A, -B, and -DR antigens seem tolerated for survival; (3) a lower incidence and severity of acute graft-versus-host disease (GVHD); (4) a lower risk of transmitting infections by latent viruses, such as cytomegalovirus and EpsteinBarr virus; (5) reduced donor attrition, because cords can likely be stored longer than an average living donor remains available in a registry; and (6) easier targeting of ethnic minorities and an increased pool of rare haplotypes [4]. The disadvantages of UCBT are (1) the low number of hematopoietic progenitor

Related and Unrelated Cord Blood Transplantation

cells and hematopoietic stem cells in UCB compared with BM or mobilized peripheral blood (this translates into an increased risk of graft failure and delayed hematopoietic engraftment); (2) increased resource utilization in hospitalization days and blood and platelet transfusions; and (3) the impossibility of using donor lymphocyte transfusion for immunotherapy.

who received UCB from HLA-identical siblings with that of 2052 children who underwent HLA-identical sibling BM transplantation (BMT). UCBT recipients had slower recovery of neutrophils and platelets and a lower risk of acute and chronic GVHD. It is interesting to note that relapse-related deaths, the mortality rate at 100 days after transplantation, and overall survival were not significantly different between the 2 groups [6]. Although longer follow-up is required, these findings suggest that in the HLA-identical sibling setting, UCBT is as useful as BMT in children. On the basis of these results, we recommend collecting and freezing cord blood units in families in which a sibling child is affected with genetic or hematologic diseases.


Related UCBT has been performed almost exclusively in children [5]. In an update of the Eurocord experience with a median follow-up of 41 months after related UCBT for children, the survival estimate at 3 years was 47% ⫾ 5% in patients with malignancies (n ⫽ 96), 82% ⫾ 7% in patients with BM failure (n ⫽ 33), 100% in patients with hemoglobinopathies (n ⫽ 52), of which 90% had a donor graft, and 70% ⫾ 15% (n ⫽ 10) in patients with inborn errors of metabolism or primary immunodeficiencies (Eurocord, unpublished data). For children with malignancies, the 3-year overall survival was 71% ⫾ 12% for those in the early phase of the disease (first complete remission of leukemia), 45% ⫾ 7% for those in the intermediate phase of the disease (second complete remission), and 24% ⫾ 7% for those with an advanced phase of the disease. A joint study by Eurocord and the IBMTR [6] compared the outcome of 113 children

UCBT from Unrelated Donors in Children

Multicenter [4-8], single-institution [3,9,10], and consortium [11,12] studies have shown that unrelated donor UCBT in children was able to reconstitute hematopoiesis and achieve sustained engraftment in most cases, was associated with a low incidence of GVHD, and did not result in a higher relapse risk. Almost all pediatric series on UCBT from unrelated donors have demonstrated the profound effect of cell dose—measured as total nucleated cells, colony-forming cells, and CD34⫹ cells— on engraftment, adverse transplant-related events, and survival [5,7-9,13]. Although the prognostic importance of HLA disparity

Table 1. Patient Disease and Transplant Characteristics and Outcomes of 323 Children with ALL Receiving an Unrelated UCBT According to Disease Status at Transplantation Characteristic

CR1 (n ⴝ 76)

CR2 (n ⴝ 136)

Advanced Phase (n ⴝ 111)

Median age (y) Immunophenotype (pre-B/B/T/null or biphenoptypic) Previous autologous transplantation, (n) Caryotype, (n) Not available Normal Abnormal Good and intermediate Poor risk Median time from diagnosis to UCBT (mo) HLA disparities (6/6), (n) 0 1 2 3-4 Nucleated cell dose infused, median (ⴛ 107/kg) TBI-based regimen Median follow-up, mo (range) Outcomes Neutrophil recovery at day 60 Acute GVHD (II-IV) at day 100 Chronic GVHD at 2 y TRM at day 100 Relapse at 2 y LFS at 2 y

4 18%/47%/17%/15% 1 (1%)

6 17%/57%/17%/8% 5 (4%)

8 10%/67%/12%/5% 20 (18%)

35 (26%) 53 (39%) 48 (35%) 32 (57%) 16 (33%) 28

31 (28%) 37 (33%) 43 (39%) 25 (58%) 18 (42%) 33

14 61 47 4

10 47 40 4

5 14 57 6 51

(7%) (18%) (75%) (11%) (89%) 6

10 29 27 3

(14%) (42%) (39%) (4%) 5.3 39 (51%) 17 (3-60) 75 46 15 22 34 42

ⴞ ⴞ ⴞ ⴞ ⴞ ⴞ

5% 6% 4% 5% 8% 6%

(11%) (48%) (37%) (3%) 3.7 107 (79%) 29 (3-93) 85 43 16 25 37 41

ⴞ ⴞ ⴞ ⴞ ⴞ ⴞ

3% 4% 3% 4% 5% 4%

(10%) (47%) (39%) (4%) 3.4 68 (61%) 23 (3-96) 65 36 12 34 48 24

ⴞ ⴞ ⴞ ⴞ ⴞ ⴞ

5% 5% 3% 5% 7% 4%

CR indicates complete remission; TBI, total body irradiation.



V. Rocha and E. Gluckman

was not clearly recognized in earlier series, it became apparent in recent updates [8,9,13]. Recently, results of unrelated UCBT in children with specific diseases have been published in myeloblastic leukemia (AML) [7], Hurler syndrome [11], and Krabbe disease [12]. The Eurocord group has recently performed 2 studies (unpublished data) on the outcomes of unrelated UCBT for childhood acute lymphoblastic leukemia (ALL) and for children with primary immunodeficiencies. We have analyzed a total of 323 children with ALL who received a UCBT from 1994 to 2004 in 24 countries, mostly in Europe. The median age was 6.5 years, the median cell dose infused was 4.1 ⫻ 107/kg, and the median follow-up time was 22 months (range, 3-96 months). Overall, the 2-year leukemia-free survival (LFS) was 36% ⫾ 3%. In a multivariate analysis, only first or second complete remission was associated with better LFS (hazard ratio [HR], 1.8; P ⬍ .0001). Therefore, a separate analysis was performed according to the disease status. Disease and patient characteristics and outcomes are listed in Table 1. All children received myeloablative conditioning regimens, and most (67%) received cyclosporin A (CsA) and corticoids as GVHD prophylaxis. We have also analyzed the results of 82 unrelated UCBTs in children with severe primary immune deficiencies reported to the Eurocord by 40 centers (J. Ortega on behalf of Eurocord, unpublished data). The median age was 0.9 years (range, 0-26 years), and the median weight was 8 kg (range, 3-39 kg). There were 29 severe combined immunodeficiency diseases, 19 Wiskott-Aldrich syndromes, and 34 other immunodeficiencies (chronic granulomatous disease, X-linked lymphoproliferative syndrome, Chediak-Higashi syndrome, bare lymphocyte syndrome, Di George anomaly, common variable immunodeficiency, and so on). Considering HLA typing at the serologic level for HLA-A and -B and high-resolution DNA for -DRB1, donor and recipient were matched in 16 cases and had 1 difference in 32 cases, 2 differences in 25, and 3 in only 2. The median number of nucleated cells infused was 8.3 ⫻ 107/kg (range, 0.1-94), and the median number of CD34⫹ cells was 3.4 ⫻ 105/kg (range, 0.4-33). The conditioning regimen more commonly used was busulfan ⫹ cyclophosphamide (n ⫽ 43) and busulfan ⫾ others (n ⫽ 17). Ten patients had no conditioning; total body irradiation (TBI) was administered in 4 cases, and total lymphatic irradiation, in 2. Anti-T serotherapy (antithymocyte globulin [ATG], antilymphocytic globulin, or monoclonal antibody) was given in 59 patients before transplantation. GVHD prophylaxis consisted of CsA plus steroids (n ⫽ 42), CsA alone (n ⫽ 16), CsA ⫹ methotrexate (n ⫽ 9), and others (n ⫽ 15). The cumulative incidence of neutrophil recovery (⬎500/mm3) at day 60 was 78%, and the incidence of platelet engraftment 36

(⬎20,000/mm3) at day 180 was 63%. Nineteen patients did not engraft; 2 of them engrafted after a second UCBT. During the first 3 months, 48% of patients showed full and 20% showed mixed chimerism; 8% had autologous reconstitution, and the data were not available in 24% (not reported, 13%; early death, 11%). The cumulative incidence of acute GVHD grade II to IV was 43%, and that of chronic GVHD was 13%. Data on immunologic reconstitution after transplantation was reported in 45 patients. At 2 years, the estimated overall survival was 70% ⫾ 6% for severe combined immunodeficiency disease and other immunodeficiencies and 67% ⫾ 11% for Wiskott-Aldrich syndrome. Twenty-six patients died (acute GVHD, n ⫽ 8; infections, n ⫽ 10; toxicity, n ⫽ 6; rejection, n ⫽ 1; and secondary malignancies, n ⫽ 1). In summary, these results show that UCBT can be considered as a source of allogeneic stem cells for transplantation for children with genetic metabolic diseases and malignant disorders who need an HSCT and who lack an HLA-identical sibling HSCT. UCBT Compared with BM from Unrelated Donors in Children

The comparison of the results of UCBT and BMT from unrelated donors in children is of paramount relevance, because for many patients the search process will identify both UCB units and unrelated bone marrow (UBM) donors. Unfortunately, no randomized clinical trial has been conducted to compare unrelated cord blood transplantation and unrelated BMT. Three published studies—2 single-center studies and a Eurocord registry series— have reported retrospective analyses comparing outcomes after UCBT and unrelated bone marrow transplantation (UBMT) in children [3,14,15]. The Eurocord group has compared the outcomes of 99 children with acute leukemia receiving an unrelated cord blood transplant (UCBT) with those of 442 children receiving either a nonmanipulated UBMT (n ⫽ 262) or a T cell– depleted UBMT (T-UBMT) (n ⫽ 180). Patients underwent transplantation from 1994 to 1998. Comparisons were performed after adjustment for patient, disease, and transplant variables. The major difference among the 3 groups was the higher number in the UCBT group of HLA mismatches (defined by serology for class I and molecular typing for DRB1). The donor was HLA mismatched in 92% of UCBTs, in 18% of UBMTs, and in 43% of T-UBMT (P ⬍ .001). Other significant differences were observed in pretransplantation disease characteristics, preparative regimens, GVHD prophylaxis, and the number of cells infused. Nonadjusted estimates of 2-year survival and eventfree survival rates for patients surviving more than 100 days were 49% and 43%, respectively, in the UBMT group; 41% and 37% in the T-UBMT group; and

Related and Unrelated Cord Blood Transplantation

35% and 31% in the cord blood transplant group. After adjustment, differences in outcomes appeared in the first 100 days after transplantation. Compared with UBMT, UCBT recipients had delayed hematopoietic recovery (P ⬍ .001), increased 100day transplant-related mortality (P ⬍ .01), and decreased acute GVHD (P ⬍ .001). T-UBMT recipients had decreased acute GVHD (P ⬍ .0001) and increased relapse (P ⫽ .02). After day 100 after transplantation, the 3 groups achieved a similar relapse incidence. Chronic GVHD was decreased after T-UBMT (P ⬍ .0001) and UCBT (P ⫽ .002), and there was a trend of higher overall mortality after T-UBMT (P ⬍ .07). The Minnesota [14] and Montreal [3] groups have analyzed a smaller group of patients with malignant and nonmalignant disorders. As with the Eurocord analysis, they have shown that recipients of UCBT underwent transplantation in a shorter time compared with children given a UBMT, that neutrophil and platelet recovery were delayed, that the acute GVHD incidence was similar or decreased, and that overall survival was not significantly different after UCBT compared with UBMT. These data gathered together strongly suggest that UCB is an acceptable alternative to matched unrelated BM in children and support the start of a simultaneous search for BM and UCB unrelated donors. The final selection of unrelated donor BM versus UCB should be based on the urgency of the transplantation and the characteristics of the BM and UCB unrelated donor, such as cell dose and HLA compatibility. For children who require an urgent transplantation, UCB is advantageous for faster procurement. UCBT from Unrelated Donors in Adults

A recent review focusing on the clinical results of unrelated donor UCBT in adults has been published [16]. To date, more than 1400 UCBTs have been performed in adults with a unit coming from the Netcord organization (; however, the available information in this setting is still limited to small series of patients. Six major reports of unrelated donor UCBT in adults [17-22] have been published. As expected from retrospective studies and multicenter studies, the series were heterogeneous in terms of recipients and disease-related characteristics, such as the type and status of the disease at transplantation [17,21,22]. However, single centers report more homogenous series of patients and diseases with standard conditioning regimens and GVHD prophylaxis [18-20]. For example, in the Japanese series [19,20], the analyses are from a single center, reporting patients with myelodysplastic syndrome or AML with a homogenous conditioning regimen (without


ATG) and with the use of methotrexate in combination with CsA as GVHD prophylaxis. Another important difference is that in 4 of the 6 series, the median number of nucleated cells infused was ⬍2 ⫻ 107/kg, and several patients received ⬍1.5 ⫻ 107/kg—figures that are below recent recommendations [9,13]. However, in the Japanese series, very few patients received a cord blood cell dose inferior to 2⫻107/kg. Granulocyte colony-stimulating factor was commonly used after UCBT in all series. The myeloid engraftment rate at 60 days has ranged from 80% to 100%, and the probability of platelet engraftment at 180 days was 65% to 90%. The median time to achieve a neutrophil count ⬎0.5 ⫻ 109/L varied from 22 to 32 days. The incidence of acute and chronic GVHD has widely ranged in adults undergoing unrelated UCBT, as has transplant-related mortality (TRM) at 100 days (0%54%) and disease-free survival (15%-76%). It is difficult to explain the reason for such differences, because factors such as patient and cord blood graft selection, disease and disease status, center effect, and period of transplantation may be involved. Moreover, studies of prognostic factors with larger series of adults given a UCBT are still missing, and any attempt to explain the different outcomes among these series is still premature. Results of Unrelated Cord Blood Transplantations Compared with Unrelated BMTs in Adults with Hematologic Malignancies

Three retrospective studies comparing the results of UCBT and UBMT in adults [23-25] have been recently published. Investigators from a single center in Japan have compared the outcomes of 113 adult patients with hematologic malignancies who received unrelated UBMT (n ⫽ 45) or unrelated UCBT (n ⫽ 68). In this single-center analysis, the time from donor search to transplantation was significantly shorter between UCBT recipients (median, 2 months) and UBMT recipients (11 months). Neutrophil and platelet recovery were delayed in UCBT recipients. UCBT recipients experienced a faster tapering of immunosuppressants after transplantation, and treatment of acute GVHD with steroids was less frequent. Moreover, no UCBT recipient died of GVHD, despite the high HLA mismatch. TRM was decreased, and disease-free survival was superior after UCBT when compared with UBMT. In this study, all but 4 patients received a cord blood cell dose ⬎2 ⫻ 107/kg [23]. Eurocord and the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation have performed a retrospective registrybased comparative study of 98 UCBTs with 584 UBMTs from unrelated donors in adults with acute leukemia [24]. The transplantations were performed between 1998 and 2002. Recipients of cord blood were younger (median, 24.5 versus 32 years; P ⬍ 37

V. Rocha and E. Gluckman

.001), weighed less (median, 58 versus 68 kg; P ⬍ .001), and had more advanced disease at the time of transplantation (52% versus 33%; P ⬍ .001). All marrow transplants were HLA matched, whereas 94% of cord blood grafts were HLA incompatible (P ⬍ .001). The median number of infused nucleated cells was 0.23 ⫻ 108/kg for cord blood and 2.9 ⫻ 108/kg for BM (P ⬍ .001). Multivariate analysis demonstrated lower risks of grade II to IV acute GVHD after UCBT (relative risk, 0.57; 95% confidence interval, 0.370.87; P ⫽ .01), but neutrophil recovery was significantly delayed (relative risk, 0.49; 95% confidence interval, 0.41-0.58; P ⬍ .001). Transplantation-related mortality, relapse rate, chronic GVHD, and LFS were not significantly different in the 2 groups. In another registry-based analysis, Laughlin et al. [25], on behalf of IBMTR, found inferior outcomes for patients with leukemia given a UCBT compared with an HLAmatched UBMT; however, similar outcomes were found when UCBT was compared with 1-HLA-mismatched UBMT. The results of these 3 comparative studies gathered together, despite their different results and although definitive conclusions will require larger and homogenous series of patients with longer follow-up, showed that UCBT is feasible in adults when a cord blood unit contains a higher number of cells and should be considered an option as an allogeneic stem cell source for patients lacking a HLA matched BM donor. The results also show that despite increased HLA disparity, UCB from unrelated donors offers promising results in adults with hematologic malignancies, thus leading to the conclusion, as in children, that the donor search process for BM and UCB from unrelated donors should be started simultaneously, especially in patients with acute leukemia, for whom the time factor is crucial. Results of Unrelated Cord Blood Transplantations Compared with Haploidentical Peripheral Blood Stem Cell Transplantation in Adults with Hematologic Malignancies

Haploidentical T cell– depleted peripheral blood stem cell transplantation has emerged as another option for treating patients with high-risk

malignancies, mainly because of the lower risk of relapse in patients with AML who receive a haploidentical HSCT with killer immunoglobulin receptor incompatibilities [26]. We have retrospectively analyzed data from adult patients with ALL or AML who received either UCBT or haploidentical transplantation performed in European Group for Blood and Marrow Transplantation centers from 1998 to 2002 (V. Rocha, unpublished Eurocord data). One hundred forty-four patients had ALL (haploidentical, n ⫽ 75; UCBT, n ⫽ 73), and 220 had de novo AML (haploidentical, n ⫽ 154; UCBT, n ⫽ 66). In the ALL group, UCBT patients were younger and received less TBI than haploidentical recipients. The frequency of patients with an advanced phase of disease at transplantation was 45% in haploidentical and 51% in UCBT (P ⫽ .79). Cytogenetics and the interval from diagnosis to transplantation were not statistically different between groups. In the AML group, UCBT recipients were younger than haploidentical recipients. Many patients underwent transplantation in an advanced phase of disease in both groups (58% of haploidentical recipients and 59% of the UCBT group), and other disease-related factors were not significantly different. Table 2 lists the unadjusted outcomes after haploidentical HSCT and unrelated UCBT in adults according to diagnosis. After statistical adjustment for differences between the 2 groups, in both analyses (ALL and AML), UCBT recipients had delayed neutrophil recovery and a higher incidence of acute GVHD (grade II-IV) compared with haploidentical recipients. In the AML group, relapse incidence, TRM, and LFS were not statistically different after UCBT or haploidentical; however, in the ALL group, LFS was superior and relapse incidence decreased after UCBT compared with haploidentical transplantation. In conclusion, in this registry-based retrospective analysis, UCBT and haploidentical showed similar TRM, relapse, and LFS for adults with AML. However, LFS was superior after UCBT for patients with ALL because of a decreased incidence of relapse.

Table 2. Unadjusted Outcomes after Haploidentical (Haplo) HSCT and UCBT in Adults with Acute Lymphoblastic or Myeloblastic Leukemia

Variable ALL Haplo (n ⴝ 75) UCBT (n ⴝ 73) P value AML Haplo (n ⴝ 154) UCBT (n ⴝ 66) P value


Cumulative Incidence of Acute GVHD

Cumulative Incidence of 2y-RI

Cumulative Incidence of 2-y TRM

Kaplan-Meier Estimate 2-y LFS

8 ⴞ 3 26 ⴞ 5 .004

38 ⴞ 5 23 ⴞ 4 .07

49 ⴞ 6 41 ⴞ 6 .55

13 ⴞ 4 36 ⴞ 6 .01

5 ⴞ 5 23 ⴞ 5

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