YoshikoAtsuta,1Ritsuro Suzuki,1Tokiko Nagamura-Inoue,2Shuichi Taniguchi,3Satoshi Takahashi,4Shunro Kai,5
Hisashi Sakamaki,6Yasushi Kouzai,7Masaharu Kasai,8Takahiro Fukuda,9HiroshiAzuma,10Minoko Takanashi,11
Shinichiro Okamoto,12Masahiro Tsuchida,13Keisei Kawa,14Yasuo Morishima,15Yoshihisa Kodera,16and
Shunichi Kato,17for the Japan Marrow Donor Program and the Japan Cord Blood Bank Network
1Department of Hematopoietic Stem Cell Transplantation Data Management, Nagoya University School of Medicine, Nagoya;2Department of Cell Processing &
Transfusion, Research Hospital, Institute of Medical Science, University of Tokyo, and Tokyo Cord Blood Bank, Tokyo;3Department of Hematology, Toranomon
Hospital, Tokyo;4Department of Molecular Therapy, Institute of Medical Science, University of Tokyo, Tokyo;5Department of Transfusion Medicine, Hyogo
College of Medicine, Nishinomiya;6Division of Hematology, Tokyo Metropolitan Komagome Hospital, Tokyo;7Department of Transfusion Medicine, Tokyo
Metropolitan Fuchu Hospital, Tokyo;8Department of Hematology, Sapporo Hokuyu Hospital, Sapporo;9Hematopoietic Stem Cell Transplantation Unit, National
Cancer Center Hospital, Tokyo;10Hokkaido Red Cross Blood Center, Sapporo;11Japanese Red Cross Tokyo Blood Center, Tokyo;12Division of Hematology,
Department of Medicine, Keio University School of Medicine, Tokyo;13Ibaraki Children’s Hospital, Mito;14Osaka Medical Center and Research Institute for
Maternal and Child Health, Izumi;15Aichi Cancer Center Hospital, Nagoya;16BMT Center, Japanese Red Cross Nagoya First Hospital, Nagoya; and
17Department of Cell Transplantation & Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan
We made a disease-specific comparison
of unrelated cord blood (CB) recipients
and human leukocyte antigen allele–
matched unrelated bone marrow (BM) re-
cipients among 484 patients with acute
myeloid leukemia (AML; 173 CB and
311 BM) and 336 patients with acute lym-
phoblastic leukemia (ALL; 114 CB and
222 BM) who received myeloablative
transplantations. In multivariate analy-
ses, among AML cases, lower overall
survival(hazardratio[HR] ? 1.5;95%con-
fidenceinterval[CI],1.0-2.0,P ? .028)and
leukemia-free survival (HR ? 1.5; 95% CI,
1.1-2.0, P ? .012) were observed in CB
recipients. The relapse rate did not differ
between the 2 groups of AML (HR ? 1.2;
95% CI, 0.8-1.9, P ? .38); however, the
treatment-related mortality rate showed
higher trend in CB recipients (HR ? 1.5;
95% CI, 1.0-2.3, P ? .085). In ALL, there
was no significant difference between the
groups for relapse (HR ? 1.4, 95% CI,
0.8-2.4, P ? .19) and treatment-related
mortality (HR ? 1.0; 95% CI, 0.6-1.7,
P ? .98), which contributed to similar
overallsurvival(HR ? 1.1;95%CI,0.7-1.6,
P ? .78)andleukemia-free
(HR ? 1.2; 95% CI, 0.9-1.8, P ? .28).
Matched or mismatched single-unit CB is
a favorable alternative stem cell source
for patients without a human leukocyte
antigen–matched related or unrelated do-
nor. For patients with AML, decreasing
mortality, especially in the early phase of
transplantation, is required to improve
the outcome for CB recipients. (Blood.
Allogeneic hematopoietic stem cell transplantation (HSCT) with
bone marrow (BM) or peripheral blood, the curative treatment of
choice for acute leukemia, is limited by the inadequate supply of
human leukocyte antigen (HLA)–identical related donors. Bone
marrow from HLA-matched unrelated donors has been a major
alternative graft source.1-3Umbilical cord blood (CB), an alterna-
tive stem cell source to BM or peripheral blood stem cells, has been
used primarily in children,4-10but its use in adults is increasing.11,12
Clinical comparison studies of cord blood transplantation
(CBT) and bone marrow transplantation (BMT) for leukemia from
unrelated donors in adult recipients showed comparable out-
comes.11-13Recipients of CBT showed delayed neutrophil recovery
Overall treatment-related mortality (TRM) was reported to be
similar12or higher11compared with HLA-matched BM. Acute
myeloid leukemia (AML) and acute lymphoblastic leukemia
(ALL) are different disease entities that require different chemo-
therapy regimens for treatment. However, previous comparison
studies have included both diseases because of limitation in the
number of CBTs given to adults.
In addition, the study periods of previous studies encompass the
pioneering period of CBT, when the general practice was to use
these grafts in patients in whom there were no other curative
options and when the relevance of cell dose and HLAmatching had
not yet been recognized.6,7,14
Accumulation of a larger number of CBT results enabled us to
make a controlled comparison with unrelated BMTs. To avoid the
inclusion of the pioneering period of CBT, the subjects were lim-
ited to those who received transplantations in and after 2000.
Collection of data and data source
The recipients’ clinical data were provided by the Japan Cord Blood Bank
Network (JCBBN) and the Japan Marrow Donor Program (JMDP).15
Submitted March 21, 2008; accepted November 14, 2008. Prepublished online
as Blood First Edition paper, December 22, 2008; DOI 10.1182/blood-2008-03-
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
© 2009 by TheAmerican Society of Hematology
1631BLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
Peripheral blood stem cell donation from unrelated donors is not permitted
in Japan. All 11 CB banks in Japan are affiliated to JCBBN. Both JCBBN
tation. Patients’ information on survival, disease status, and long-term
complications, including chronic GVHD and second malignancies, are
renewed annually by follow-up forms. This study was approved by the data
management committees of JMDPand JCBBN.
Between January 2000 and December 2005, a total of 1690 adult patients at
least 16 years of age with acute leukemia (999 AML, 261 CB and 738 BM;
and 691 ALL, 178 CB and 513 BM) received first HSCT with myeloabla-
tive conditioning either CB or BM from unrelated donors. Of these, patients
who received a single CB unit with 0 to 2 HLAmismatches, or HLA-A, -B,
-C, and DRB1 allele-matched BM from unrelated donors were analyzed.
HLAmatching of CB was performed using low-resolution molecular typing
methods for HLA-A and -B, and high-resolution molecular typing for
HLA-DRB1. Of 1023 BM recipients with complete HLA high-resolution
data, the following recipients with HLA HLA-A, -B, -C, and DRB1 allele
mismatches were excluded: 306 recipients with 1 of 8 mismatches (39 for
HLA-A, 6 for HLA-B, 137 for HLA-C, and 124 for HLA-DRB1),
150 recipients with 2 of 8 mismatches (36 for 2 class I antigens, and 114 for
class I and class II antigens), 33 recipients with 3 of 8 mismatches, and
1 recipient with 4 of 8 mismatches. Of 390 recipients of CB with complete
HLA data, 95 recipients with 3 mismatches and 8 patients with 4 mis-
matches were excluded. A total of 484 patients with AML (173 CBTs and
311 BMTs) and 336 patients withALL(114 CBTs and 222 BMTs) were the
subjects for the analyses. Eighty-five centers performed 287 CBTs analyzed
in this study, and 114 centers performed 533 BMTs.
Neutrophil recovery was defined by an absolute neutrophil count of at least
500 cells/mm3for 3 consecutive points; platelet recovery was defined by a
count of at least 50 000 platelets/mm3without transfusion support. Diagno-
sis and clinical grading of acute GVHD were performed according to the
established criteria.16Relapse was defined as a recurrence of underlying
hematologic malignant diseases. Treatment-related death was defined as
death during a continuous remission. Leukemia-free survival (LFS) was
defined as survival in a state of continuous remission.
analysis was performed to assess patient baseline characteristics, diagnosis,
disease classification, disease status at conditioning, donor-patient ABO
mismatches, preparative regimen, and GVHD prophylaxis. The 2-sided ?2
test was used for categorical variables, and the 2-sided Wilcoxon rank sum
test was used for continuous variables. Cumulative incidence curves were
used in a competing-risks setting to calculate the probability of neutrophil
and platelet recovery, acute and chronic GVHD, relapse, and TRM.17For
neutrophil and platelet recovery, death before neutrophil or platelet
recovery was the competing event; for GVHD, death without GVHD and
relapse were the competing events; for relapse, death without relapse was
the competing event; and, for TRM, relapse was the competing event. Gray
test was used for group comparison of cumulative incidence.18Overall
survival (OS) and LFS were calculated using the Kaplan-Meier method.
The log-rank test was used for group comparisons.Adjusted comparison of
the stem cell source on OS and LFS was performed with the use of the Cox
proportional-hazards regression model. For other outcomes, the Fine and
Gray proportional-hazards model for subdistribution of a competing risk
was used.19Adjusted probabilities of OS and DFS were estimated using the
Cox proportional-hazards regression model, with consideration of other
significant clinical variables in the final multivariate models. The variables
considered were the patient’s age at transplantation, patient’s sex, donor-
patient sex mismatch, donor-patient ABO mismatch, disease status at
conditioning, and t(9;22) chromosome abnormality or others for ALL,
cytogenetic information and French-American-British (FAB) classification
of M5/M6/M7 or others forAML, the conditioning regimen, and the type of
prophylaxis against GVHD. Factors differing in distribution between CB
and BM recipients (P ? .10) and factors known to influence outcomes
(such as patient age at transplantation and chromosome abnormalities and
FAB classification of leukemia) were included in the final models.Variables
with more than 2 categories were dichotomized for the final multivariate
model. The cutoff points of the variables were chosen to make optimal use
of the information, with the proviso that smaller groups contain at least 20%
of the patients. Variables were dichotomized as follows: patient age greater
or younger than 45 years at transplantation, female donor to male recipient
donor-recipient sex mismatch versus others for donor-recipient sex match-
ing, donor-recipientABO major mismatch versus others forABO matching,
M5/M6/M7 FAB classification versus others for classification of AML,
chromosome abnormality other than favorable abnormalities for cytogenet-
ics ofAML, cyclophosphamide and total body irradiation (TBI) or busulfan
and cyclophosphamide or others for conditioning regimen of AML,
cyclophospohamide and TBI, or others for conditioning regimen of ALL,
Disease status at transplantation was categorized as first complete remission
(1CR), second or later complete remission (2CR), or more advanced
disease; which was included in the final model using dichotomized dummy
variables.All P values were 2-sided.
The statistical power to detect hazard ratios (HRs) of 2.0 and 1.5 (a
regression coefficient equal to 0.6931 and 0.4055, respectively) on Cox
regression of the log hazard ratio at a .05 significance level adjusted for
event rate were 99% and 78%, respectively, for 484 patients withAML and
97% and 60%, respectively, for 336 patients with ALL. The levels of
statistical power for subgroup analyses were as follows: 54% and 22% for
1CR, 51% and 21% for 2CR, 96% and 58% for more advanced in AML
patients, 62% and 26% for 1CR, 47% and 20% for 2CR, and 67% and 29%
for more advanced inALLpatients.20
The characteristics of the patients are shown in Table 1. There was
no significant difference in recipients’ age at transplantation in
AML (median age, CB vs BM ? 38 vs 38 years, P ? .61) and in
ALL (median age, CB vs BM ? 34 vs 32 years, P ? .29). The
female/male ratio was higher (CB vs BM ? 54% vs 38% in AML
patients, and CB vs BM ? 54% vs 38% inALL patients, P ? .001
and P ? .005, respectively) in CB recipients, resulting in the lower
donor-patient sex match rate (CB vs BM ? 48% vs 69% in AML
patients, and CB vs BM ? 46% vs 65% inALL patients, P ? .001
and P ? .002, respectively) in CB recipients. The proportion of
ALL patients with Philadelphia chromosome abnormality was
higher (CB vs BM ? 38% vs 23%) in CB recipients. CB recipients
were likely to have more advanced disease status at transplantation
(relapse or induction failure, CB vs BM ? 47% vs 31% in AML
patients, and CB vs BM ? 26% vs 19% in ALL patients), and the
difference was significant in AML (P ? .003). HLA-A, -B (low-
resolution typing), and -DRB1 (high-resolution typing) was mis-
matched in 93% of both AML and ALL among CB recipients,
whereas HLA -A, -B, -C, and -DRB1 were all genotypically
matched for BM recipients. The ABO-matched donor-patient pair
proportion was consistently lower for CB (CB vs BM ? 34% vs
59% in AML patients and CB vs BM ? 32% vs 58% in ALL
almost all patients, and cytosine arabinoside was supplemented for CB
recipients withAML (36%) in addition to TBI and cyclophosphamide.
For GVHD prophylaxis, tacrolimus (CB vs BM?29% vs 56% in
AML patients, and CB vs BM?37% vs 53% in ALL patients) and
1632ATSUTAet alBLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
Table 1. Characteristics of recipients of cord blood or bone marrow from unrelated donors in 484 patients with acute myeloid leukemia and
336 patients with acute lymphoblastic leukemia
Acute myeloid leukemiaAcute lymphoblastic leukemia
No. of transplantations
Median patient age at transplantation, y (range)
Patient sex, n (%)
Sex matching, n (%)
Male to female
Female to male
Second or after CR
0 mismatched loci
1 mismatched locus
2 mismatched loci
Nucleated cells infused per 107/kg, median (range)
CY ? TBI
CY ? CA ? TBI
CY ? BU ? TBI
Other TBI regimen
BU ? CY
Other non-TBI regimen
Cyclosporine A ? sMTX
Cyclosporine A ? other
Tacrolimus ? sMTX
Tacrolimus ? other
38 (16-69)38 (16-60).6134 (16-58) 32 (16-59).29
? .001 52 (46)
? .001 .002
U-CBT, indicates unrelated cord blood transplantation; U-BMT, unrelated bone marrow transplantation; CR, complete remission; HLA, human leukocyte antigen; CY,
cyclophosphamide; CA, cytarabine; BU, oral busulfan; TBI, total body irradiation; and sMTX, short-term methotrexate.
*Favorable abnormal karyotypes are defined as t(8;21), inv16,or t(15;17).
†Number of mismatches was counted among HLA-A, -B (low-resolution typing), and DRB1 (high-resolution typing).
CORD BLOOD TRANSPLANTATION INADULTACUTE LEUKEMIA1633 BLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
short-term methotrexate (CB vs BM?80% vs 96% in AML patients,
and CB vs BM?80% vs 93% in ALL patients) were used preferen-
tially in BM recipients. The median follow-up period for survivors
was 1.9 years (range, 0.1-6.2 years) for CB recipients and 1.4 years
OS. For patients with AML, the unadjusted probabilities of OS
were lower for CB recipients at 1 year (51% vs 69%) and 2 years
(43% vs 60%) compared with BM recipients (P ? .001). For
patients with ALL, there were no significant differences between
the 2 groups (CB vs BM ? 66% vs 66% at 1 year, 49% vs 57% at
2 years, P ? .40).
Among patients with AML, the use of CB remained a signifi-
cant risk factor for overall mortality after adjustment for other
factors(HR ? 1.5;95%confidenceinterval[CI],1.0-2.0;P ? .028;
Table 2). However, in patients with ALL, the use of CB was not a
significant factor for overall mortality on multivariate analysis
(HR ? 1.1; 95% CI, 0.7-1.6; P ? .78). The adjusted probability of
OS was significantly lower for CB recipients (57% vs 69% at
1 year, and 48% vs 59% at 2 years, P ? .010; Figure 1A) compared
with BM recipients for patients with AML, whereas the adjusted
probability of OS was similar (69% vs 64% at 1 year, and 52% vs
53% at 2 years, P ? .99; Figure 1B) between the groups for
Results of the subgroup analyses showed that the difference in
ing1CRattransplantation(RR ? 2.9,95%CI ? 1.4-6.2,P ? .005;
LFS. For patients with AML, the unadjusted probabilities of
LFS were significantly lower for CB recipients at 1 year (43% vs
62%) and 2 years (36% vs 54%) compared with BM recipients
(P ? .001). For patients with ALL, the unadjusted probabilities of
LFS were lower with marginal significance for CB recipients at
1 year (52% vs 58%) and 2 years (45% vs 51%) compared with BM
recipients (P ? .06).
Among patients with AML, the use of CB remained as a
significant risk factor for treatment failure (ie, relapse or death)
after adjustment for other factors (HR ? 1.5; 95% CI, 1.1-2.0;
P ? .012; Table 2). However, in patients with ALL, the use of CB
was not a significant factor for treatment failure by multivariate
analysis (HR ? 1.2; 95% CI, 0.9-1.8; P ? .28). The adjusted
probability of LFS was significantly lower for CB recipients (51%
vs 62% at 1 year, and 42% vs 54% at 2 years, P ? .004; Figure 1C)
compared with BM recipients for patients with AML, whereas the
adjusted probability of LFS was similar (53% vs 53% at 1 year, and
46% vs 44% at 2 years, P ? .41; Figure 1D) between the groups for
On univariate analyses, the cumulative incidence of relapse was
higher for CB recipients with marginal significance in both AML
(27% vs 20% at 1 year, and 31% vs 24% at 2 years) andALL(27%
vs 19% at 1 year, and 31% vs 24% at 2 years) (P ? .067, and .085,
respectively; Figure 2A,B).
On multivariate analyses adjusted by other factors, there was no
significantly higher risk of relapse for CB recipients with either
AML (RR ? 1.2, 95% CI ? 0.8-1.9, P ? .38) or ALL (RR ? 1.4,
95% CI ? 0.8-2.4, P ? .19; Table 2).
For patients with AML, the unadjusted cumulative incidence of
TRM was significantly higher for CB recipients at 1 year (30% vs
19%) and 2 years (33% vs 22%) compared with those for BM
recipients (P ? .004; Figure 2C). For patients with ALL, the
Figure 1. Adjusted OS and LFS of recipients with AML or ALL of CB or BM from unrelated donors. For patients with AML, adjusted probabilities of (A) OS (CB vs
BM ? 48% vs 59% at 2 years, P ? .010) and (C) LFS (CB vs BM ? 42% vs 54% at 2 years, P ? .004) were both lower in CB recipients. For patients with ALL, the adjusted
probabilities of (B) OS (CB vs BM ? 52% vs 53% at 2 years, P ? .99) and (D) LFS (CB vs BM ? 46% vs 44% at 2 years, P ? .41) were similar between CB recipients and BM
1634 ATSUTAet al BLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
cumulative incidence of TRM was similar between the 2 groups
(CB vs BM ? 21% vs 23% at 1 year, 24% vs 25% at 2 years,
P ? .83; Figure 2D).
On multivariate analyses adjusted by other factors, the risk for
TRM was higher for CB recipients compared with that for BM
recipients among patients with AML (RR ? 1.5, 95% CI ? 1.0-
2.3, P ? .085; Table 2) with marginal significance. For patients
with ALL, the risk for TRM was similar between CB and BM
recipients (RR ? 1.0, 95% CI ? 0.6-1.7, P ? .98).
Cause of death
Recurrence of the primary disease was the leading cause of death in
each group (CB vs BM ? 37% vs 33% in patients with AML and
36% vs 41% in patients with ALL). The following causes were
infection and organ failure in all groups (Table 4).
Other outcomes of transplantation
Neutrophil and platelet recovery.
incidence of neutrophil recovery or platelet recovery at day 100
was significantly lower in CB recipients for both AML (77% vs
94%) and ALL (80% vs 97%) compared with that among BM
recipients (P ? .001 for both). On multivariate analyses, neutrophil
recovery was significantly lower among CB recipients for both
AML(RR ? 0.4,95%CI ? 0.3-0.5,P ? .001)andALL(RR ? 0.4,
95% CI ? 0.3-0.5, P ? .001; Table 2).
The unadjusted cumulative
Table 2. Results of multivariate analysis of outcomes in 173 recipients of cord blood and 311 recipients of bone marrow with acute myeloid
leukemia, and 114 recipients of cord blood and 222 recipients of bone marrow with acute lymphoblastic leukemia
Acute myeloid leukemiaAcute lymphoblastic leukemia
RR (95% CI)P RR (95% CI)P
Chronic GVHD, extensive type††
1.06 (0.71-1.57).028 .78
1.22 (0.85-1.76).012 .28
1.42 (0.84-2.41) .38.19
1.01 (0.59-1.73) .085.98
0.61 (0.39-0.95) .23.028
1.08 (0.66-1.77) .79.77
0.58 (0.28-1.20) .004 .14
RR indicates relative risk; CI, confidence interval; BM, bone marrow; CB, cord blood; and GVHD, graft-versus-host disease.
*For overall survival, other significant variables forAMLwere patient age more than 45 years at transplantation, more advanced disease status at conditioning, M5/M6/M7
French-American-British classification, and female donor to male recipient donor-recipient sex mismatch; other significant variables for ALL were second or after complete
remission disease status, more advanced disease status, and Philadelphia chromosome abnormality.
†For leukemia-free survival, other significant variables for AML were patient age more than 45 years at transplantation, more advanced disease status at conditioning,
M5/M6/M7 French-American-British classification, and female donor to male recipient donor-recipient sex mismatch; other significant variables for ALL were second or after
complete remission disease status, more advanced disease status, and Philadelphia chromosome abnormality.
‡For relapse, other significant variables forAMLwere more advanced disease status at conditioning, donor-recipientABO major mismatch, chromosome abnormality other
than favorable abnormalities, and cyclophosphamide and total body irradiation or busulfan and cyclophosphamide conditioning regimen; other significant variables for ALL
were second or after complete remission disease status, more advanced disease status, and cyclophosphamide and total body irradiation conditioning.
§For TRM, other significant variables forAML were patient age more than 45 years at transplantation, second or after complete remission disease status, more advanced
disease status, and chromosome abnormality other than favorable abnormalities; other significant variables for ALL were patient age more than 45 years at transplantation,
more advanced disease status at conditioning, and conditioning other than cyclophosphamide and total body irradiation.
?For neutrophil recovery, other significant variables for AML were second or after complete remission disease status and more advanced disease status; other significant
variables forALLwere more advanced disease status at conditioning and cyclosporine-based GVHD prophylaxis.
¶For platelet recovery; other significant variables for AML were second or after complete remission disease status, more advanced disease status, female donor to male
recipient donor-recipient sex mismatch, and tacrolimus-based GVHD prophylaxis; other significant variables for ALL were more advanced disease status at conditioning and
conditioning other than cyclophosphamide and total body irradiation.
#For acute GVHD, no other significant variables were identified for bothAMLandALL.
**For chronic GVHD, other significant variables for AML were more advanced disease status and conditioning other than cyclophosphamide and total body irradiation or
busulfan and cyclophosphamide; there were no other significant variables identified forALL.
††For extensive chronic GVHD, there were no other significant variables identified forAML; another significant variable forALLwas patient male sex.
CORD BLOOD TRANSPLANTATION INADULTACUTE LEUKEMIA 1635BLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
The unadjusted cumulative incidence of platelet recovery
greater than 50 000/?L at 4 months was significantly lower among
CB recipients for bothAML(59% vs 85%) andALL(61% vs 83%)
compared with that of BM recipients (P ? .001 for both). The
difference was also significant on multivariate analyses for both
AML(RR ? 0.3,95%CI ? 0.3-0.4,P ? .001)andALL(RR ? 0.4,
95% CI ? 0.3-0.6, P ? .001; Table 2).
to 4 acute GVHD was lower among CB recipients compared with
that among BM recipients (32% vs 35% in AML, 28% vs 42% in
ALL); the difference was significant in patients withALL(P ? .39
in AML, P ? .008 in ALL). The difference was also significant on
multivariate analyses in ALL (RR ? 0.6, 95% CI ? 0.4-1.0,
P ? .028). There was no significant difference in patients with
AML(RR ? 0.8, 95% CI ? 0.6-1.2, P ? .23; Table 2).
The unadjusted cumulative incidence of
chronic GVHD at 1 year after transplantation did not significantly
differ between CB recipients and BM recipients in bothAML(28%
vs 32%, P ? .46) and ALL (27% vs 30%, P ? .50). The cumula-
tive incidence of extensive-type chronic GVHD was significantly
lower among CB recipients compared with that among BM
recipients in both AML (8% vs 20%, P ? .001) and ALL (10% vs
17%, P ? .034). On multivariate analyses, the risk of developing
chronic GVHD was similar in CB recipients and BM recipients in
both AML (RR ? 0.9, 95% CI ? 0.6-1.4, P ? .79) and ALL
(RR ? 1.1, 95% CI ? 0.7-1.8, P ? .77). The risk of developing
extensive chronic GVHD was lower in CB recipients compared
with BM recipients (RR ? 0.4, 95% CI ? 0.2-0.7, P ? .004 in
AML, and RR ? 0.6, 95% CI, 0.3-1.2, P ? .14 in ALL) and was
significantly different in patients withAML(Table 2).
The objective of our study was to investigate the outcomes of
HLA-A, -B, low-resolution, and -DRB1 high-resolution 0 to 2
mismatched single-unit unrelated CBT in adult patients with acute
leukemia compared with those of HLA-A, -B, -C, and -DRB1 (8 of
8) allele-matched unrelated BMT. Although AML and ALL are
different diseases, previous comparisons of unrelated BMT and
Figure 2. Cumulative incidence of relapse or TRM of recipients of CB or BM among patients with AML or ALL. For patients with AML, the cumulative incidence of (A)
relapse (CB vs BM ? 31% vs 24% at 2 years, P ? .068) and (C) TRM (CB vs BM ? 33% vs 22% at 2 years, P ? .004) was higher in CB recipients. For patients withALL, the
cumulative incidence of relapse (B) was higher in CB recipients with marginal significance (CB vs BM ? 31% vs 24% at 2 years, P ? .085), but the incidence of TRM (D) was
similar in CB and BM recipients (CB vs BM ? 24% vs 25% at 2 years, P ? .83).
Table 3. Results of multivariate analysis of overall survival according to disease status at transplantation
First complete remissionSecond or after complete remissionMore advanced
n RR (95% CI)Pn RR (95% CI)Pn RR (95% CI)P
1.29 (0.84-1.98) .005.63 .25
0.80 (0.38-1.69).16 .36.57
RR indicates relative risk; CI, confidence interval; UBMT, unrelated bone marrow transplantation; and UCBT, unrelated cord blood transplantation.
1636 ATSUTAet alBLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
unrelated CBT did not separate these 2 diseases. Our report is the
first to show the result of disease-specific analyses with a sufficient
number of patients.
ForAMLpatients, the recipients of CB were more likely to have
advanced leukemia at the time of transplantation, as reported
previously, suggesting that CB was used as an alternative stem cell
source in the later phase of unrelated donor searches, especially in
adults.11,12,14Alarger proportion of CB recipients withALLhad the
aggressive ALL and usually requires urgent transplantation, in
which CB has an advantage over BM.21
Different outcomes of mortality were found between AML and
ALL in a controlled comparison using multivariate analyses.
Whereas significantly lower OS and LFS rates were observed in
CB recipients with AML, rates of overall mortality and treatment
failure were similar between CB and BM recipients withALL. The
relapse rate was not different between CBT and BMT in patients
with both AML and ALL, which was consistent with previous
reports.11-13In adult patients with ALL, a previous report showed
no difference in the outcome of related compared with unrelated
BM or peripheral blood transplantation in 1CR.22Favorable
disease status at transplantation could be a more important factor
affecting outcome rather than the type of stem cell source or donor
type in patients with ALL. It is notable that TRM in HLA
allele-matched unrelated BM recipients withAMLwas quite low in
our study. This is probably associated with the low incidence of
acute and chronic GVHD in the Japanese population, which is
thought to be the result of genetic homogeneity.23-26Among
patients with AML, although the difference was not statistically
significant, a higher trend of TRM observed in CB recipients might
be associated with higher overall and TRM rates in CB recipients.
Reasons for higherTRM could include the graft source and delayed
neutrophil recovery. Better supportive care is required after CBT
for patients going through a prolonged neutropenic period. Devel-
opment of better graft engineering or better conditioning regimens
would help to decrease the TRM rate in CB recipients. Because
relapse was the major cause of death in all groups, any attempt to
decrease TRM should preserve the antileukemia effect to improve
OS and LFS.Another reason for the higher TRM could be a higher
risk patient population, higher risk for both disease status and
comorbid conditions, requiring rapid transplantation. Searching for
unrelated donors earlier and providing transplantation earlier in the
disease course could help to decrease TRM in CB recipients.
Neutrophil and platelet recovery was slower in CB recipients
with either AML or ALL, consistent with the results of previous
reports.11,12,27Multiple studies have reported lower incidence of
acute GVHD in CB recipients.8-10,12,13In our study, particularly in
patients withALL, the risk of developing grade 2 to 4 acute GVHD
in CB recipients was lower compared with BM recipients, which
was reported to be lower compared with the incidence reported
from Western countries.23-25The risk of developing chronic GVHD
was similar between CB and BM recipient with either disease, but
the risk of developing extensive-type chronic GVHD was lower in
CB recipients; the difference was significant in patients withAML.
It is notable that there was no increase in the incidence of acute or
chronic GVHD in CB recipients among patients with either AML
orALL, despite HLAdisparity.
For differences in outcomes between AML and ALL, one
possibility is a difference of treatment before conditioning therapy.
MostAMLpatients received a more intense treatment for induction
and consolidation therapy compared with that for ALL. There was
no adjustment made for previous treatment, and this could be the
reason for higher mortality in CBT, which requires a longer time
for neutrophil recovery.Another possible cause of the difference in
outcomes is the difference in conditioning regimens. Preparative
regimens were similar between CB and BM recipients amongALL
patients. However, in patients with AML, the proportion of
standard regimens, such as cyclophosphamide and TBI or busulfan
and cyclophosphamide, was smaller among CB recipients. These
differences in the distribution of preparative regimens were also
seen in a previous report.11Although the final model was adjusted
for conditioning regimens, we cannot rule out the possibility of an
effect that larger CB recipients received additional or different
chemotherapeutic agents compared with BM recipients among
patients withAML.Although the difference was small, the median
age of CB recipients with AML was 4 years older than CB
recipients withALL(median age, 38 vs 34 years, P ? .021), which
might have affected the higher mortality rate among CB recipients
with AML. It is also possible that some unknown biologic aspects
have contributed to these differences, and this would require
further evaluation in future studies.
Further subgroup analyses indicated that the superiority of HLA
allele-matched BM versus CB for OS was mostly found in patients
with AML showing 1CR at conditioning. However, because of the
limited numbers of patients in these subgroup analyses and the
possibility of an unidentified bias in stem cell source selection, our
In conclusion, we found different outcomes between patients
with AML and ALL, indicating the importance of disease-specific
analyses in alternative donor studies. HLA-A, -B low-resolution,
and -DRB1 high-resolution 0 to 2 mismatched single-unit CB is a
favorable alternative stem cell source for patients without a suitable
related or 8 of 8 matched unrelated BM donor. In the absence of a
suitable donor, unrelated CBT should be planned promptly to
transplant the patient while in a better disease status and better
clinical condition. For patients with AML, decreasing mortality,
especially in the early phase of transplantation, is required to
improve the outcome for CB recipients.
The authors thank all the staff members of the collaborating
institutes of the Japan Cord Blood Bank Network and Japan
Marrow Donor Program for their assistance and cooperation and
Table 4. Causes of death after transplantation of unrelated cord
blood or unrelated bone marrow among patients with acute myeloid
leukemia or acute lymphoblastic leukemia
Cause of death
Recurrence of disease
Data are presented as n (%).
UCBT indicates unrelated cord blood transplantation; and UBMT, unrelated bone
CORD BLOOD TRANSPLANTATION INADULTACUTE LEUKEMIA 1637BLOOD, 19 FEBRUARY 2009?VOLUME 113, NUMBER 8
Dr Takakazu Kawase for validating human leukocyte antigen data Download full-text
of the Japan Marrow Donor Program.
This work was supported by a Research Grant for Tissue
Engineering (H17-014), a Research Grant forAllergic Disease and
Immunology (H20-015), and a Research Grant for Cancer (H19-1)
from the Japanese Ministry of Health, Labor, and Welfare.
Contribution: Y.A. and R.S. designed the study and wrote the
paper;Y.A. analyzed results and made the figures; S. Kato andY.M.
designed the research; T.-N.I., H.A., and M. Takanashi reviewed
and cleaned the Japan Cord Blood Bank Network data and
reviewed the results; S. Taniguchi, S. Takahashi, S. Kai, H.S.,
Y. Kouzai, M.K., andT.F. submitted and cleaned the data; and S.O.,
M. Tsuchida, K.K., Y.M., and Y. Kodera reviewed and cleaned the
Japan Marrow Donor Program data and reviewed the results.
Conflict-of-interest disclosure: The authors declare no compet-
ing financial interests.
A complete list of members from the Japan Marrow Donor
Program and the Japan Cord Blood Bank Network can be found in
the Supplemental Appendix (available on the Blood website; see
the Supplemental Materials link at the top of the online article).
Correspondence:YoshikoAtsuta, Department of Hematopoietic
Stem Cell Transplantation Data Management, Nagoya University
School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku Nagoya,
461-0047 Japan; e-mail: email@example.com.
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