Transplants of Umbilical-Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia
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《新英格兰医药杂志》
ABSTRACT
Background Promising results of cord-blood transplants from unrelated donors have been reported in adults.
Methods We compared outcomes in 682 adults with acute leukemia who received a hematopoietic stem-cell transplant from an unrelated donor: 98 received cord blood and 584 received bone marrow. The transplantations were performed from 1998 through 2002 and reported to Eurocord and the European Blood and Marrow Transplant Group.
Results Recipients of cord blood were younger than recipients of bone marrow (median, 24.5 vs. 32 years of age; P<0.001), weighed less (median, 58 vs. 68 kg; P<0.001), and had more advanced disease at the time of transplantation (52 percent vs. 33 percent, P<0.001). All marrow transplants were HLA matched, whereas 94 percent of cord-blood grafts were HLA mismatched (P<0.001). The median number of nucleated cells that were infused was 0.23x108 per kilogram of the recipient's body weight for cord blood and 2.9x108 per kilogram for bone marrow (P<0.001). Multivariate analysis showed lower risks of grade II, III, or IV acute graft-versus-host disease (GVHD) after cord-blood transplantation (relative risk, 0.57; 95 percent confidence interval, 0.37 to 0.87; P=0.01), but neutrophil recovery was significantly delayed (relative risk, 0.49; 95 percent confidence interval, 0.41 to 0.58; P<0.001). The incidence of chronic GVHD, transplantation-related mortality, relapse rate, and leukemia-free survival were not significantly different in the two groups.
Conclusions Cord blood from an unrelated donor is an alternative source of hematopoietic stem cells for adults with acute leukemia who lack an HLA-matched bone marrow donor.
Umbilical-cord blood is considered an alternative to bone marrow as a source of hematopoietic stem cells for transplantation,1 and its use in adults with hematologic cancers is increasing.2 There is considerable evidence that cord blood is a promising option for patients who lack an HLA-matched bone marrow donor.3,4,5,6,7,8,9 The advantages of cord blood are the immediate availability of cells, the absence of risk to the donor, and a lower need for HLA compatibility between the donor and the recipient.8,9,10,11 A limiting factor is the low number of hematopoietic stem cells in a unit of cord blood. For this reason, cord blood has been transplanted into few adults until recently, when cord-blood banks began a policy of selecting units with high numbers of nucleated and CD34+ cells.12,13,14,15,16,17
Methods
Collection of Data
Eurocord and the European Blood and Marrow Transplant Group (EBMT) provided data on cord-blood and bone marrow recipients. Eurocord is an international registry that operates on behalf of EBMT. Participation is open to both European and non-European centers that conduct cord-blood transplantation. The EBMT registry includes more than 450 transplantation centers, which are required to file an annual report of all consecutive stem-cell transplants, with follow-up by Eurocord and EBMT physicians. Eurocord and EBMT databases were checked to verify compliance and detect overlapping reports. Centers not associated with EBMT were asked to report their cord-blood transplants if cord-blood units came from Netcord banks. Eurocord is in charge of the clinical evaluation of cord-blood units provided by Netcord. Netcord is an international organization of cord-blood banks, which are listed in the Appendix.
Inclusion Criteria
Our study evaluated outcomes in patients who were at least 15 years of age at the time of transplantation; who had primary acute leukemia; who received a single cord-blood unit or HLA-matched bone marrow that had not been depleted of T cells; who underwent transplantation between January 1, 1998, and December 31, 2002; who underwent a myeloablative regimen before transplantation; and for whom there were adequate data on outcomes. Seventy-two patients who received bone marrow and 8 who received cord blood were excluded owing to missing data; a total of 98 recipients of a cord-blood transplant and 584 recipients of a bone marrow transplant at 145 transplantation centers met the criteria.
End Points
The probability of neutrophil recovery was defined as the estimated time from transplantation to the first of three consecutive days with an absolute neutrophil count of at least 500 per cubic millimeter. Data on patients who received a second transplant because of nonengraftment of the first were censored at the time of the second transplant. Graft failure was defined as no sign of neutrophil recovery 60 days after transplantation.
The end point of acute graft-versus-host disease (GVHD) was diagnosed and graded according to published criteria18; patients were evaluated one day or more after transplantation. Chronic GVHD was diagnosed according to standard criteria19; patients who survived at least 100 days with sustained engraftment were evaluated.
Transplantation-related mortality was defined as death related to transplantation and not to relapse. Relapse was defined on the basis of morphologic evidence of leukemia in bone marrow or other sites. Survival was calculated from transplantation to death from any cause, and leukemia-free survival was defined as the time from transplantation to either first relapse or death in complete remission.
Statistical Analysis
The duration of follow-up was the time to the last assessment for survivors. Before 2002, 95 marrow recipients and 4 cord-blood recipients were lost to follow-up. With the use of the chi-square statistic for categorical variables and the Mann–Whitney test for continuous variables, we compared variables that were related to the patients, the underlying diseases, and the transplantation procedure. Cumulative incidence curves were used in a competing-risks setting, with death treated as a competing event, to calculate the probability of neutrophil recovery, acute GVHD, chronic GVHD, transplantation-related mortality, and relapse.20 Probabilities of leukemia-free survival and overall survival were estimated by the Kaplan–Meier method; the log-rank test was used for univariate comparisons. The associations of the type of graft with outcomes were evaluated in multivariate analyses, with the use of Cox proportional-hazards regression to adjust for leukemia-free survival and overall survival and with the use of Fine and Gray's proportional-hazards model for subdistribution of a competing risk for other outcomes.21
The variables considered were the age (median) and sex of the recipient and the donor; HLA compatibility, in the case of cord blood; the recipient's serologic status (positive or negative) with respect to cytomegalovirus; the characteristics of the disease (acute lymphoblastic leukemia according to phenotype and cytogenetics, or acute myeloid leukemia according to French–American–British classification and cytogenetics); the status of the disease at the time of transplantation (e.g., first or second complete remission or more advanced disease); and the characteristics of transplantation, including the year of transplantation, receipt of a previous autologous transplant, the conditioning regimen, the type of prophylaxis against GVHD (cyclosporine, cyclosporine and corticosteroids, or cyclosporine and methotrexate), and the dose of nucleated cells infused. Only factors differing in distribution between the two groups (P<0.10) and factors known to influence outcomes (such as type of leukemia) were included in the final models.
All P values are two-sided, with a type I error rate fixed at 0.05. Statistical analyses were performed with SPSS and S-Plus (MathSoft) software.
Results
Patients
Table 1 shows the characteristics of the 98 adults who underwent cord-blood transplantation, their donors, and the grafts. The median times from diagnosis to transplantation for patients who received transplants in first and second complete remission were 18 months (range, 8 to 35) and 51 months (range, 19 to 182), respectively. The median period of follow-up was 27 months (range, 3 to 66).
Table 1. Characteristics of the Recipients of Cord-Blood or Bone Marrow Transplants from Unrelated Donors.
Table 1 also shows the characteristics of the 584 adults who received a bone marrow transplant. The median times from diagnosis to transplantation for patients in first and second complete remission were 18 months (range, 6 to 79) and 59 months (range, 11 to 354), respectively. The median period of follow-up was 24 months (range, 1 to 76).
Cord-blood recipients were younger (P<0.001) and weighed less (P<0.001) than marrow recipients. The proportions of patients with acute myeloid leukemia and acute lymphoblastic leukemia were similar in the two groups (P=0.12). Cord blood was transplanted into patients in a more advanced phase of leukemia than was bone marrow (P=0.002), and more recipients of cord blood had previously received an autologous transplant (P<0.001).
Transplantation
All bone marrow transplants were HLA matched, whereas 94 percent of the recipients of cord blood were given an HLA-incompatible graft (P<0.001). The median number of nucleated cells infused in recipients of cord blood was 0.23x108 per kilogram of the recipient's body weight (range, 0.09x108 to 0.6x108 per kilogram), about 1/10 the number in bone marrow grafts, in which the median number was 2.9x108 per kilogram (range, <1.0x108 to 9.0x108 per kilogram; P<0.001). The median number of CD34+ cells in the cord-blood grafts was 1.1x105 per kilogram (range, 0.08x105 to 8.8x105 per kilogram).
Neutrophil Recovery
In the univariate analysis, neutrophil recovery was significantly delayed after cord-blood transplantation as compared with bone marrow transplantation. The median number of days required for the neutrophil count to reach at least 500 per cubic millimeter after cord-blood transplantation was 26 (range, 14 to 80), as compared with 19 (range, 5 to 72) after bone marrow transplantation (P<0.001). The cumulative incidence of neutrophil recovery 60 days after transplantation was 75 percent (95 percent confidence interval, 66 to 84 percent) after cord-blood transplantation and 89 percent (95 percent confidence interval, 87 to 91 percent) after bone marrow transplantation (P<0.001) (Figure 1A).
Figure 1. Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia.
The unadjusted cumulative incidence of neutrophil recovery (Panel A), chronic graft-versus-host disease (Panel B), transplant-related mortality (Panel C), and relapse (Panel D) is shown after cord-blood or bone marrow transplantation from unrelated donors in adults with acute leukemia.
Graft failure occurred in 43 patients (7 percent) in the marrow group and 20 patients (20 percent) in the cord-blood group. In the marrow group, 3 of 43 patients who had autologous reconstitution were alive at 3, 18, and 23 months after transplantation, respectively; 4 patients who received a second transplant died. In the cord-blood group, 4 of 20 patients with graft failure survived, 1 after a second transplant 17 months after the first cord-blood transplant, 1 after a second transplant at 40 months, and 2 with autologous reconstitution at 13 and 31 months, respectively. Secondary graft failure occurred in 4 of 528 marrow recipients and 1 of 77 cord-blood recipients. In the multivariate analysis, the relative risk of neutrophil recovery was significantly lower after cord-blood transplantation than after marrow transplantation (relative risk, 0.49; 95 percent confidence interval, 0.41 to 0.58; P<0.001) (Table 2).
Table 2. Results of Multivariate Analyses in Which Outcomes Were Compared between Recipients of Unrelated Cord-Blood Transplants and Recipients of Unrelated Bone Marrow Transplants.
Acute and Chronic GVHD
The cumulative incidence of grades II, III, and IV acute GVHD 100 days after transplantation was 26 percent (95 percent confidence interval, 14 to 38 percent) after cord-blood transplantation, which was significantly lower than that after bone marrow transplantation (39 percent; 95 percent confidence interval, 31 to 47 percent; P=0.008). Severe acute GVHD (grades III and IV) occurred in 13 percent of cord-blood recipients and in 19 percent of marrow recipients (P=0.26). In a multivariate analysis, the risk of acute GVHD was significantly lower after transplantation of cord blood than after transplantation of bone marrow (Table 2).
Among patients who survived more than 100 days, chronic GVHD affected proportionally fewer cord-blood recipients (18 of 61) than marrow recipients (94 of 203). The two-year cumulative incidence of chronic GVHD was 30 percent (95 percent confidence interval, 20 to 40 percent) after transplantation of cord blood and 46 percent (95 percent confidence interval, 44 to 48 percent) after transplantation of marrow (P=0.07) (Figure 1B). In the multivariate analysis, the risk of chronic GVHD was not significantly different between the two groups.
Transplantation-Related Mortality
In the univariate and multivariate analyses, there was no significant difference in transplantation-related mortality between the two groups (two-year cumulative incidence, 44 percent with cord blood vs. 38 percent with bone marrow; P=0.13) (Figure 1C and Table 2).
Relapse
The cumulative incidence of relapse was not significantly different between the two groups (23 percent with cord blood vs. 23 percent with bone marrow, P=0.71) (Figure 1D). In a multivariate analysis, the risk for relapse was similar in the two groups; only advanced disease was associated with an increased risk of relapse (Table 2).
Overall Survival and Leukemia-free Survival
The unadjusted two-year probabilities of overall survival and leukemia-free survival were similar in the two groups (36 percent in recipients of cord blood and 42 percent in recipients of bone marrow, P=0.08 ; and 33 percent in recipients of cord blood and 38 percent in recipients of bone marrow, P=0.06 ), and a multivariate analysis showed no significant difference in overall survival or leukemia-free survival between the groups (Table 2). Table 3 lists the unadjusted two-year probability of leukemia-free survival in recipients of cord blood and recipients of bone marrow according to the type of leukemia and disease status at the time of the transplantation.
Figure 2. Kaplan–Meier Estimates of Overall Survival (Panel A) and Leukemia-free Survival (Panel B) after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia.
Table 3. Unadjusted Two-Year Probability of Leukemia-free Survival after Transplantation of Unrelated Umbilical-Cord Blood or Unrelated Bone Marrow in Adults with Acute Leukemia.
Causes of Death
Sixty-two of 98 recipients of cord-blood transplants (63 percent) and 320 of 584 recipients of bone marrow transplants (55 percent) died. Persistent or recurrent leukemia caused 19 (31 percent) of the deaths in the recipients of cord-blood and 118 (37 percent) of those in the recipients of bone marrow transplants. Table 4 lists the causes of death related to transplantation. Deaths related to toxicity were significantly more common in the cord-blood group (P<0.001), whereas deaths related to GVHD were significantly more common in the bone marrow group (P=0.02).
Table 4. Causes of Death after Transplantation of Unrelated Cord Blood or Unrelated Bone Marrow.
Discussion
In this registry-based retrospective analysis, we found that adults with acute leukemia who underwent cord-blood transplantation had delayed neutrophil recovery and a lower incidence of acute GVHD, but other outcomes were similar to those in adults who underwent bone marrow transplantation. The main differences between the cord-blood group and the bone marrow group were the number of nucleated cells in the graft and HLA compatibility. A major factor that limits the use of cord blood is the number of nucleated cells and CD34+ cells in the graft. There is a consensus that a unit of cord blood should have at least 2.0x10 nucleated cells per kilogram at the time of freezing and no more than two disparities in the matching for HLA-A, B, or DRB1, alone or in combination, with the recipient.11,22,23 The delayed neutrophil recovery and the decreased incidence of acute GVHD in adult cord-blood recipients are similar to these outcomes in children8,9,24 and probably reflect the properties of the hematopoietic and lymphocytic components of cord blood.25,26,27,28,29 The relatively low incidence of GVHD after cord-blood transplantation, despite HLA incompatibility, is notable.30,31,32 However, the role of HLA mismatches is difficult to analyze, since typing for class I HLA alleles is not routine with cord-blood transplants. The number of HLA disparities, found with low-resolution typing, has been associated with neutrophil and platelet recovery, grades III and IV GVHD, and relapse, but not with survival.22
In our study, we included all cord-blood transplantations performed from 1998 through 2002, regardless of the number of HLA disparities, because during this period transplanting cord blood with as many as three HLA mismatches was a common practice. We have previously shown that transplant-related mortality at 100 days was higher after transplantation of cord blood than after transplantation of bone marrow in children with acute leukemia, because of delayed neutrophil recovery and a higher incidence of infections. In the present study, the risk of transplantation-related mortality was similar in the two groups, perhaps because transplantation centers have improved their criteria for selecting patients and units of cord blood. We expected more deaths related to infections in the cord-blood group owing to delayed neutrophil recovery and probably delayed immune recovery.14,33 However, causes of death were more frequently related to the toxicity of treatment, since cord-blood recipients underwent transplantation in a more advanced phase of leukemia than did recipients of bone marrow.
In conclusion, we believe that cord blood should be considered an alternative to bone marrow for transplantation in adults with acute leukemia. The choice of the source of hematopoietic stem cells will depend on the available number of cord-blood cells, on HLA compatibility, and on the urgency of the need for the transplant.
Supported by a grant from the European Commission (QLK3-CT-1999-00380, to Eurocord) and by grants from Programma Nazionale sulle Cellule Staminali 2003 and Progetto CARIGE Cellule Staminali (to Dr. Frassoni).
We are indebted to Dr. I. Ionescu and Dr. F. Garnier for collecting and validating clinical data from Eurocord, to Professor S. Chevret of the Biostatistical Medical Department of H?pital Saint-Louis, to Mrs. Emmanuelle Polge for collecting data from the Acute Leukemia Working Party of European Blood and Marrow Transplant Group, and to the data managers from all the Eurocord–European Blood and Marrow Transplant Group centers.
* Other members of the Eurocord–Netcord Registry and the Acute Leukemia Working Party of European Blood and Marrow Transplant Group Registry are listed in the Appendix.
Source Information
From H?pital Saint-Louis (V.R., E.G.), and H?pital Saint Antoine (M. Labopin), Assistance Publique des H?pitaux de Paris and Paris University, Paris; Hospital Universitario La Fe, Valencia, Spain (G.S.); Università Tor Vergata, Rome (W.A.); Deutsche Klinik für Diagnostik, Wiesbaden, Germany (R.S.); Ospedale di Careggi, Florence, Italy (A.B.); University Hospital for Internal Medicine, Rigshospitalet, Copenhagen (N.J.); Helsinki University Central Hospital, Helsinki (T.R.); M.D. Anderson Cancer Center, Houston (M. de Lima); University of Freiburg, Freiburg, Germany (J.F.); and Ospedale San Martino, Genoa, Italy (F.F.).
Address reprint requests to Dr. Gluckman at H?pital Saint-Louis, Hematology Bone Marrow Transplant Department, 1 Ave. Claude Vellefaux, 75475 Paris CEDEX 10, France, or at eliane.gluckman@sls.ap-hop-paris.fr.
References
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Netcord inventory and use Sept. 2004. (Accessed October 29, 2004, at https://www.netcord.org/inventory.gif.)
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Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. N Engl J Med 1997;337:373-381.
Cairo MS, Wagner JE. Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. Blood 1997;90:4665-4678.
Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 1998;339:1565-1577.
Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Exp Hematol 2000;28:1197-1205.
Rocha V, Wagner JE, Sobocinski KA, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. N Engl J Med 2000;342:1846-1854.
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Sanz GF, Saavedra S, Planelles D, et al. Standardized, unrelated donor cord blood transplantation in adults with hematological malignancies. Blood 2001;98:2332-2338.
Long GD, Laughlin M, Madan B, et al. Unrelated umbilical cord blood transplantation in adult patients. Biol Blood Marrow Transplant 2003;9:772-780.
Ooi J, Iseki T, Nagayama H, et al. Unrelated cord blood transplantation for adult patients with myelodysplastic syndrome-related secondary acute myeloid leukaemia. Br J Haematol 2001;114:834-836.
Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia. Blood 2004;103:489-491.
Sanz G, Rocha V. Umbilical cord blood transplantation: current status and future directions. Curr Opin Organ Transplant 2003;8:109-17.
Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974;18:295-304.
Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-217.
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Gluckman E, Rocha V, Arcese W, et al. Factors associated with outcome of unrelated cord blood transplant: guidelines for donor choice. Exp Hematol 2004;32:397-407.
Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002;100:1611-1618.
Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis. Blood 2001;97:2957-2961.
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Petersdorf EW, Gooley TA, Anasetti C, et al. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and the recipient. Blood 1998;92:3515-3520.
Sasazuki T, Juji T, Morishima Y, et al. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. N Engl J Med 1998;339:1177-1185.
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Background Promising results of cord-blood transplants from unrelated donors have been reported in adults.
Methods We compared outcomes in 682 adults with acute leukemia who received a hematopoietic stem-cell transplant from an unrelated donor: 98 received cord blood and 584 received bone marrow. The transplantations were performed from 1998 through 2002 and reported to Eurocord and the European Blood and Marrow Transplant Group.
Results Recipients of cord blood were younger than recipients of bone marrow (median, 24.5 vs. 32 years of age; P<0.001), weighed less (median, 58 vs. 68 kg; P<0.001), and had more advanced disease at the time of transplantation (52 percent vs. 33 percent, P<0.001). All marrow transplants were HLA matched, whereas 94 percent of cord-blood grafts were HLA mismatched (P<0.001). The median number of nucleated cells that were infused was 0.23x108 per kilogram of the recipient's body weight for cord blood and 2.9x108 per kilogram for bone marrow (P<0.001). Multivariate analysis showed lower risks of grade II, III, or IV acute graft-versus-host disease (GVHD) after cord-blood transplantation (relative risk, 0.57; 95 percent confidence interval, 0.37 to 0.87; P=0.01), but neutrophil recovery was significantly delayed (relative risk, 0.49; 95 percent confidence interval, 0.41 to 0.58; P<0.001). The incidence of chronic GVHD, transplantation-related mortality, relapse rate, and leukemia-free survival were not significantly different in the two groups.
Conclusions Cord blood from an unrelated donor is an alternative source of hematopoietic stem cells for adults with acute leukemia who lack an HLA-matched bone marrow donor.
Umbilical-cord blood is considered an alternative to bone marrow as a source of hematopoietic stem cells for transplantation,1 and its use in adults with hematologic cancers is increasing.2 There is considerable evidence that cord blood is a promising option for patients who lack an HLA-matched bone marrow donor.3,4,5,6,7,8,9 The advantages of cord blood are the immediate availability of cells, the absence of risk to the donor, and a lower need for HLA compatibility between the donor and the recipient.8,9,10,11 A limiting factor is the low number of hematopoietic stem cells in a unit of cord blood. For this reason, cord blood has been transplanted into few adults until recently, when cord-blood banks began a policy of selecting units with high numbers of nucleated and CD34+ cells.12,13,14,15,16,17
Methods
Collection of Data
Eurocord and the European Blood and Marrow Transplant Group (EBMT) provided data on cord-blood and bone marrow recipients. Eurocord is an international registry that operates on behalf of EBMT. Participation is open to both European and non-European centers that conduct cord-blood transplantation. The EBMT registry includes more than 450 transplantation centers, which are required to file an annual report of all consecutive stem-cell transplants, with follow-up by Eurocord and EBMT physicians. Eurocord and EBMT databases were checked to verify compliance and detect overlapping reports. Centers not associated with EBMT were asked to report their cord-blood transplants if cord-blood units came from Netcord banks. Eurocord is in charge of the clinical evaluation of cord-blood units provided by Netcord. Netcord is an international organization of cord-blood banks, which are listed in the Appendix.
Inclusion Criteria
Our study evaluated outcomes in patients who were at least 15 years of age at the time of transplantation; who had primary acute leukemia; who received a single cord-blood unit or HLA-matched bone marrow that had not been depleted of T cells; who underwent transplantation between January 1, 1998, and December 31, 2002; who underwent a myeloablative regimen before transplantation; and for whom there were adequate data on outcomes. Seventy-two patients who received bone marrow and 8 who received cord blood were excluded owing to missing data; a total of 98 recipients of a cord-blood transplant and 584 recipients of a bone marrow transplant at 145 transplantation centers met the criteria.
End Points
The probability of neutrophil recovery was defined as the estimated time from transplantation to the first of three consecutive days with an absolute neutrophil count of at least 500 per cubic millimeter. Data on patients who received a second transplant because of nonengraftment of the first were censored at the time of the second transplant. Graft failure was defined as no sign of neutrophil recovery 60 days after transplantation.
The end point of acute graft-versus-host disease (GVHD) was diagnosed and graded according to published criteria18; patients were evaluated one day or more after transplantation. Chronic GVHD was diagnosed according to standard criteria19; patients who survived at least 100 days with sustained engraftment were evaluated.
Transplantation-related mortality was defined as death related to transplantation and not to relapse. Relapse was defined on the basis of morphologic evidence of leukemia in bone marrow or other sites. Survival was calculated from transplantation to death from any cause, and leukemia-free survival was defined as the time from transplantation to either first relapse or death in complete remission.
Statistical Analysis
The duration of follow-up was the time to the last assessment for survivors. Before 2002, 95 marrow recipients and 4 cord-blood recipients were lost to follow-up. With the use of the chi-square statistic for categorical variables and the Mann–Whitney test for continuous variables, we compared variables that were related to the patients, the underlying diseases, and the transplantation procedure. Cumulative incidence curves were used in a competing-risks setting, with death treated as a competing event, to calculate the probability of neutrophil recovery, acute GVHD, chronic GVHD, transplantation-related mortality, and relapse.20 Probabilities of leukemia-free survival and overall survival were estimated by the Kaplan–Meier method; the log-rank test was used for univariate comparisons. The associations of the type of graft with outcomes were evaluated in multivariate analyses, with the use of Cox proportional-hazards regression to adjust for leukemia-free survival and overall survival and with the use of Fine and Gray's proportional-hazards model for subdistribution of a competing risk for other outcomes.21
The variables considered were the age (median) and sex of the recipient and the donor; HLA compatibility, in the case of cord blood; the recipient's serologic status (positive or negative) with respect to cytomegalovirus; the characteristics of the disease (acute lymphoblastic leukemia according to phenotype and cytogenetics, or acute myeloid leukemia according to French–American–British classification and cytogenetics); the status of the disease at the time of transplantation (e.g., first or second complete remission or more advanced disease); and the characteristics of transplantation, including the year of transplantation, receipt of a previous autologous transplant, the conditioning regimen, the type of prophylaxis against GVHD (cyclosporine, cyclosporine and corticosteroids, or cyclosporine and methotrexate), and the dose of nucleated cells infused. Only factors differing in distribution between the two groups (P<0.10) and factors known to influence outcomes (such as type of leukemia) were included in the final models.
All P values are two-sided, with a type I error rate fixed at 0.05. Statistical analyses were performed with SPSS and S-Plus (MathSoft) software.
Results
Patients
Table 1 shows the characteristics of the 98 adults who underwent cord-blood transplantation, their donors, and the grafts. The median times from diagnosis to transplantation for patients who received transplants in first and second complete remission were 18 months (range, 8 to 35) and 51 months (range, 19 to 182), respectively. The median period of follow-up was 27 months (range, 3 to 66).
Table 1. Characteristics of the Recipients of Cord-Blood or Bone Marrow Transplants from Unrelated Donors.
Table 1 also shows the characteristics of the 584 adults who received a bone marrow transplant. The median times from diagnosis to transplantation for patients in first and second complete remission were 18 months (range, 6 to 79) and 59 months (range, 11 to 354), respectively. The median period of follow-up was 24 months (range, 1 to 76).
Cord-blood recipients were younger (P<0.001) and weighed less (P<0.001) than marrow recipients. The proportions of patients with acute myeloid leukemia and acute lymphoblastic leukemia were similar in the two groups (P=0.12). Cord blood was transplanted into patients in a more advanced phase of leukemia than was bone marrow (P=0.002), and more recipients of cord blood had previously received an autologous transplant (P<0.001).
Transplantation
All bone marrow transplants were HLA matched, whereas 94 percent of the recipients of cord blood were given an HLA-incompatible graft (P<0.001). The median number of nucleated cells infused in recipients of cord blood was 0.23x108 per kilogram of the recipient's body weight (range, 0.09x108 to 0.6x108 per kilogram), about 1/10 the number in bone marrow grafts, in which the median number was 2.9x108 per kilogram (range, <1.0x108 to 9.0x108 per kilogram; P<0.001). The median number of CD34+ cells in the cord-blood grafts was 1.1x105 per kilogram (range, 0.08x105 to 8.8x105 per kilogram).
Neutrophil Recovery
In the univariate analysis, neutrophil recovery was significantly delayed after cord-blood transplantation as compared with bone marrow transplantation. The median number of days required for the neutrophil count to reach at least 500 per cubic millimeter after cord-blood transplantation was 26 (range, 14 to 80), as compared with 19 (range, 5 to 72) after bone marrow transplantation (P<0.001). The cumulative incidence of neutrophil recovery 60 days after transplantation was 75 percent (95 percent confidence interval, 66 to 84 percent) after cord-blood transplantation and 89 percent (95 percent confidence interval, 87 to 91 percent) after bone marrow transplantation (P<0.001) (Figure 1A).
Figure 1. Outcomes after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia.
The unadjusted cumulative incidence of neutrophil recovery (Panel A), chronic graft-versus-host disease (Panel B), transplant-related mortality (Panel C), and relapse (Panel D) is shown after cord-blood or bone marrow transplantation from unrelated donors in adults with acute leukemia.
Graft failure occurred in 43 patients (7 percent) in the marrow group and 20 patients (20 percent) in the cord-blood group. In the marrow group, 3 of 43 patients who had autologous reconstitution were alive at 3, 18, and 23 months after transplantation, respectively; 4 patients who received a second transplant died. In the cord-blood group, 4 of 20 patients with graft failure survived, 1 after a second transplant 17 months after the first cord-blood transplant, 1 after a second transplant at 40 months, and 2 with autologous reconstitution at 13 and 31 months, respectively. Secondary graft failure occurred in 4 of 528 marrow recipients and 1 of 77 cord-blood recipients. In the multivariate analysis, the relative risk of neutrophil recovery was significantly lower after cord-blood transplantation than after marrow transplantation (relative risk, 0.49; 95 percent confidence interval, 0.41 to 0.58; P<0.001) (Table 2).
Table 2. Results of Multivariate Analyses in Which Outcomes Were Compared between Recipients of Unrelated Cord-Blood Transplants and Recipients of Unrelated Bone Marrow Transplants.
Acute and Chronic GVHD
The cumulative incidence of grades II, III, and IV acute GVHD 100 days after transplantation was 26 percent (95 percent confidence interval, 14 to 38 percent) after cord-blood transplantation, which was significantly lower than that after bone marrow transplantation (39 percent; 95 percent confidence interval, 31 to 47 percent; P=0.008). Severe acute GVHD (grades III and IV) occurred in 13 percent of cord-blood recipients and in 19 percent of marrow recipients (P=0.26). In a multivariate analysis, the risk of acute GVHD was significantly lower after transplantation of cord blood than after transplantation of bone marrow (Table 2).
Among patients who survived more than 100 days, chronic GVHD affected proportionally fewer cord-blood recipients (18 of 61) than marrow recipients (94 of 203). The two-year cumulative incidence of chronic GVHD was 30 percent (95 percent confidence interval, 20 to 40 percent) after transplantation of cord blood and 46 percent (95 percent confidence interval, 44 to 48 percent) after transplantation of marrow (P=0.07) (Figure 1B). In the multivariate analysis, the risk of chronic GVHD was not significantly different between the two groups.
Transplantation-Related Mortality
In the univariate and multivariate analyses, there was no significant difference in transplantation-related mortality between the two groups (two-year cumulative incidence, 44 percent with cord blood vs. 38 percent with bone marrow; P=0.13) (Figure 1C and Table 2).
Relapse
The cumulative incidence of relapse was not significantly different between the two groups (23 percent with cord blood vs. 23 percent with bone marrow, P=0.71) (Figure 1D). In a multivariate analysis, the risk for relapse was similar in the two groups; only advanced disease was associated with an increased risk of relapse (Table 2).
Overall Survival and Leukemia-free Survival
The unadjusted two-year probabilities of overall survival and leukemia-free survival were similar in the two groups (36 percent in recipients of cord blood and 42 percent in recipients of bone marrow, P=0.08 ; and 33 percent in recipients of cord blood and 38 percent in recipients of bone marrow, P=0.06 ), and a multivariate analysis showed no significant difference in overall survival or leukemia-free survival between the groups (Table 2). Table 3 lists the unadjusted two-year probability of leukemia-free survival in recipients of cord blood and recipients of bone marrow according to the type of leukemia and disease status at the time of the transplantation.
Figure 2. Kaplan–Meier Estimates of Overall Survival (Panel A) and Leukemia-free Survival (Panel B) after Transplantation of Cord Blood or Bone Marrow from Unrelated Donors in Adults with Acute Leukemia.
Table 3. Unadjusted Two-Year Probability of Leukemia-free Survival after Transplantation of Unrelated Umbilical-Cord Blood or Unrelated Bone Marrow in Adults with Acute Leukemia.
Causes of Death
Sixty-two of 98 recipients of cord-blood transplants (63 percent) and 320 of 584 recipients of bone marrow transplants (55 percent) died. Persistent or recurrent leukemia caused 19 (31 percent) of the deaths in the recipients of cord-blood and 118 (37 percent) of those in the recipients of bone marrow transplants. Table 4 lists the causes of death related to transplantation. Deaths related to toxicity were significantly more common in the cord-blood group (P<0.001), whereas deaths related to GVHD were significantly more common in the bone marrow group (P=0.02).
Table 4. Causes of Death after Transplantation of Unrelated Cord Blood or Unrelated Bone Marrow.
Discussion
In this registry-based retrospective analysis, we found that adults with acute leukemia who underwent cord-blood transplantation had delayed neutrophil recovery and a lower incidence of acute GVHD, but other outcomes were similar to those in adults who underwent bone marrow transplantation. The main differences between the cord-blood group and the bone marrow group were the number of nucleated cells in the graft and HLA compatibility. A major factor that limits the use of cord blood is the number of nucleated cells and CD34+ cells in the graft. There is a consensus that a unit of cord blood should have at least 2.0x10 nucleated cells per kilogram at the time of freezing and no more than two disparities in the matching for HLA-A, B, or DRB1, alone or in combination, with the recipient.11,22,23 The delayed neutrophil recovery and the decreased incidence of acute GVHD in adult cord-blood recipients are similar to these outcomes in children8,9,24 and probably reflect the properties of the hematopoietic and lymphocytic components of cord blood.25,26,27,28,29 The relatively low incidence of GVHD after cord-blood transplantation, despite HLA incompatibility, is notable.30,31,32 However, the role of HLA mismatches is difficult to analyze, since typing for class I HLA alleles is not routine with cord-blood transplants. The number of HLA disparities, found with low-resolution typing, has been associated with neutrophil and platelet recovery, grades III and IV GVHD, and relapse, but not with survival.22
In our study, we included all cord-blood transplantations performed from 1998 through 2002, regardless of the number of HLA disparities, because during this period transplanting cord blood with as many as three HLA mismatches was a common practice. We have previously shown that transplant-related mortality at 100 days was higher after transplantation of cord blood than after transplantation of bone marrow in children with acute leukemia, because of delayed neutrophil recovery and a higher incidence of infections. In the present study, the risk of transplantation-related mortality was similar in the two groups, perhaps because transplantation centers have improved their criteria for selecting patients and units of cord blood. We expected more deaths related to infections in the cord-blood group owing to delayed neutrophil recovery and probably delayed immune recovery.14,33 However, causes of death were more frequently related to the toxicity of treatment, since cord-blood recipients underwent transplantation in a more advanced phase of leukemia than did recipients of bone marrow.
In conclusion, we believe that cord blood should be considered an alternative to bone marrow for transplantation in adults with acute leukemia. The choice of the source of hematopoietic stem cells will depend on the available number of cord-blood cells, on HLA compatibility, and on the urgency of the need for the transplant.
Supported by a grant from the European Commission (QLK3-CT-1999-00380, to Eurocord) and by grants from Programma Nazionale sulle Cellule Staminali 2003 and Progetto CARIGE Cellule Staminali (to Dr. Frassoni).
We are indebted to Dr. I. Ionescu and Dr. F. Garnier for collecting and validating clinical data from Eurocord, to Professor S. Chevret of the Biostatistical Medical Department of H?pital Saint-Louis, to Mrs. Emmanuelle Polge for collecting data from the Acute Leukemia Working Party of European Blood and Marrow Transplant Group, and to the data managers from all the Eurocord–European Blood and Marrow Transplant Group centers.
* Other members of the Eurocord–Netcord Registry and the Acute Leukemia Working Party of European Blood and Marrow Transplant Group Registry are listed in the Appendix.
Source Information
From H?pital Saint-Louis (V.R., E.G.), and H?pital Saint Antoine (M. Labopin), Assistance Publique des H?pitaux de Paris and Paris University, Paris; Hospital Universitario La Fe, Valencia, Spain (G.S.); Università Tor Vergata, Rome (W.A.); Deutsche Klinik für Diagnostik, Wiesbaden, Germany (R.S.); Ospedale di Careggi, Florence, Italy (A.B.); University Hospital for Internal Medicine, Rigshospitalet, Copenhagen (N.J.); Helsinki University Central Hospital, Helsinki (T.R.); M.D. Anderson Cancer Center, Houston (M. de Lima); University of Freiburg, Freiburg, Germany (J.F.); and Ospedale San Martino, Genoa, Italy (F.F.).
Address reprint requests to Dr. Gluckman at H?pital Saint-Louis, Hematology Bone Marrow Transplant Department, 1 Ave. Claude Vellefaux, 75475 Paris CEDEX 10, France, or at eliane.gluckman@sls.ap-hop-paris.fr.
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