Transplant Immunology 21 (2009) 234–239

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Transplant Immunology
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t r i m

Meta-analysis of HLA matching and the outcome of unrelated umbilical cord blood
transplantation (CBT)
Xu Shi-xia a,⁎, Tang Xian-hua a, Xu Hai-qin a, Feng Bo a, Chen Hai-qing a, Tang Xiang-Feng b
a
Department of Medical Information, Navy General Hospital, Beijing, 100037, China
b
Department of Pediatrics, Navy General Hospital, Beijing, 100037, China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The aim of this meta-analysis is to compare the HLA disparities and the outcome of UCBT, i.e. the disease-
Received 12 March 2009 free survival (DFS), engraftment, graft-versus-host disease, (GVHD), and transplantation related mortality (TRM).
Received in revised form 10 May 2009 Methods: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE,
Accepted 14 May 2009 Pubmed, IBMTR and critically appraised all relevant articles (1989.01–2008.12). Comparative studies are carried
on HLA typing and cord blood transplantation with research on stem cells engraftment, GVHD, TRM, and DFS. A
Keywords: meta-analysis is performed using Review Manager 5.0 software and adopted funnel plot regression assessed the
HLA typing
publication bias.
Transplant
Meta-analysis
Results: We got 882 records, and 10 trials totaling 1589 patients assessed. Pooled comparisons of studies of
Cord blood outcomes found that the incidence of neutrophil and platelet engraftment failure increased with HLA-
Outcome mismatched antigen increased, ≥2-Ag mismatched group had a higher risk of ≥II degree GVHD and a lower DFS
rate than the HLA matched group.
Conclusions: Our meta-analysis confirmed that with the HLA-mismatched antigen increased, the rate of graft
failure, severe GVHD and TRM increased, and the DFS decreased. We cannot fully exclude the possibility of center
biases in treatment and selection of patients and well-designed trials need to carry out.
© 2009 Published by Elsevier B.V.

Umbilical Cord blood (UCB) is increasingly used as a source of

haematopoietic stem cells in both related and unrelated recipients
[1–4] and preliminary data indicate that they may have some
immunological advantages over bone marrow [5]. Hematopoietic
stem cells in UCB from an HLA identical donor were first used to
transplant a patient with Fanconi's anemia in 1988 by Gluckman et al
[6]. The successful use of partially HLA-mismatched unrelated UCB
donor as a source of hematopoietic stem cells was first reported by
Kurtzberg et al [7] in 1996. Since then, the number of UCBT has
increased very quickly and, to date, preliminary multicenter analyses
show encouraging results in hematologic patients receiving related or
unrelated CBT. Compared with unrelated donor bone marrow, major
advantages of UCB include the speed of availability and less stringent
requirements of HLA typing between the donor and recipient because
of a low risk of severe GVHD [8,9]. The accepted level of mismatching
in cord blood transplant is generally 4/6 or better, so the role of HLA
is difficult to ascertain if everyone has the same degree of mismatch
because of the limited number of patients. Relationships between
CBT outcome and HLA disparities have not clearly identified. The aim

⁎ Corresponding author. Tel.: +86 10 13381207353.

E-mail address: shixia@rocketmail.com (X. Shi-xia). Fig. 1. Flow chart of study inclusion process.

0966-3274/$ – see front matter © 2009 Published by Elsevier B.V.

doi:10.1016/j.trim.2009.05.004
 X. Shi-xia et al. / Transplant Immunology 21 (2009) 234–239 235

Table 1 treatment of children with malignant disorders, results from inde-

Characteristics of included studies. pendent and comparable studies are integrated to increase statistical
Author Publication Age diseases No Follow-up power. The primary outcome of interest for our analysis is survival,
year (year) patients and the secondary outcomes studied included engraftment, GVHD,
Eapen [14] 2007 0–16 Leukemia 503 5 years and TRM incidence.
Liao C [15] 2007 1.2–34 Malignant 65 6 years
non-malignant
1.1. Search strategy
Kögler [16] 2005 0.3–48.4 Malignant 122 2 years
non-malignant
Gluckman [17] 2004 4.5–21.2 Malignant 550 3 years Following established guidelines, we performed a literature search
non-malignant using the databases were Medline (1989.01–2008.12), CENTRAL,
Nishihira [18] 2003 0–56 malignant 216 2 years Pubmed, and IBMTR. The search terms used were “cord blood”,
Abu-Ghosh [19] 1999 1.25–21 Malignant 11 0.3year
non-malignant
“transplantation”, and “HLA typing”. For limited publications to
Gluckman [20] 1997 0.3–45 Malignant 65 1 year randomized controlled trials, we expanded our search criteria to
non-malignant include all listed clinical trials. Full text papers were obtained to
Elia [21] 1999 2–16 AML, ALL, CML 14 3 years extract the data for this analysis. References of retrieved articles were
Wagner [9] 1996 0.1–21.3 Malignant 18 0.5 year
also checked for any relevant trials.
non-malignant
Kurtzberg [7] 1996 0.8–23.5 Malignant 25 1 year According the HLA typing based on HLA-A and HLA-B low-
non-malignant resolution typing and HLA-DRB1 high resolution typing, the patients
divided into 3 groups, i.e: the HLA matched group, 1-Ag (antigen)
mismatched group and ≥2-Ag mismatched group. Selection Criteria:
of this meta-analysis is to compare the HLA disparities and the out- (1) All studies on CBT and HLA typing selected. (2) Patients requiring
come of CBT, i.e. the DFS, engraftment, GVHD, and TRM. CBT mainly to treat for malignant disorders (3).The articles should be
published in English journals. Studies published in languages other
1. Methods than English were also translated and included. (4). Data for any of the
outcome such as neutrophil and platelet engraftment, TRM, GVHD,
Unrelated donor search between 1989.01 and 2008.12 were overall or event-free survival is available. Two independent reviewers
eligible for analysis on HLA matching and UCBT outcome. We (T XH, X HQ) examined the titles and the articles of all identified trials
systematically reviewed all data on CBT and HLA typing in which to confirm that they fulfilled the inclusion criteria. They examined and
survival was the key outcome measure. To obtain reliable evidence on recorded the trial characteristics and outcomes independently, using a
the relative effect of different conditioning regimens in the primary predesigned data abstraction form. This abstraction form was used to

Fig. 2. The rate of neutrophil engraft in HLA matched group compared with the 1-Ag mismatched or 2-Ag mismatched CBT group. CI indicates confidence interval. Each study is
shown by the point estimate of the odds ratio (square proportional to the weight of each study) and 95% confidence interval for the risk ratio (extending lines), the summary risk ratio
and 95% confidence interval by fixed-effects calculations are shown by diamonds. For all figures, odds ratio values higher than one indicate that HLA mismatch has a risk effect.
236 X. Shi-xia et al. / Transplant Immunology 21 (2009) 234–239

Fig. 3. Meta-analysis of the rates of platelet engraftment in HLA matched and mismatched CBT group. CI indicates confidence interval. Each study is shown by the point estimate of the
odds ratio (square proportional to the weight of each study) and 95% confidence interval for the risk ratio (extending lines), the summary risk ratio and 95% confidence interval by
fixed-effects calculations are shown by diamonds. For all figures, odds ratio values higher than one indicate that HLA mismatch has a risk effect.

record information regarding the quality of the trial such as allocation (1) Studies without comparable patient demographics between the 3
concealment, randomization method, blinding of treatment, and comparative groups were excluded. (2).All review papers reiterating
inclusion and exclusion criteria. Any disagreements between the two previous data were excluded. (3).The trials with case report, poor
independent reviewers were resolved by consensus. Exclusion criteria: quality, and little information should be also excluded.

Fig. 4. Meta-analysis of the rates of grade ≥II aGVHD in HLA matched and mismatched CBT group. CI indicates confidence interval. Each study is shown by the point estimate of the
odds ratio (square proportional to the weight of each study) and 95% confidence interval for the risk ratio (extending lines).the summary risk ratio and 95% confidence interval by
fixed-effects calculations are shown by diamonds. For all figures, odds ratio values higher than one indicate that HLA mismatch has a risk effect.
 X. Shi-xia et al. / Transplant Immunology 21 (2009) 234–239 237

Fig. 5. Meta-analysis of the rates of TRM in HLA matched and mismatched CBT group. CI indicates confidence interval. Each study is shown by the point estimate of the odds ratio
(square proportional to the weight of each study) and 95% confidence interval for the risk ratio (extending lines), the summary risk ratio and 95% confidence interval by random-
effects calculations are shown by diamonds. For all figures, odds ratio values higher than one indicate that HLA mismatch has a risk effect.

Fig. 6. Meta-analysis of the rates of DFS in HLA matched and mismatched CBT group. CI indicates confidence interval. Each study is shown by the point estimate of the odds ratio
(square proportional to the weight of each study) and 95% confidence interval for the risk ratio (extending lines), the summary risk ratio and 95% confidence interval by fixed-effects
calculations are shown by diamonds. For all figures, odds ratio values higher than one indicate that HLA mismatch has a risk effect.
238 X. Shi-xia et al. / Transplant Immunology 21 (2009) 234–239
1.2. Statistical analysis
To estimate the treatment effects, outcomes were calculated as odd
ratio (OR) and their 95% confidence intervals (CI). The pooled effect
estimates were calculated using the Review Manager 5.0.0 statistical
package (RevMan, The Nordic Cochrane Center, the Cochrane
Collaboration). The I2 statistic was used to assess statistical hetero-
geneity [10] which describes the percentage of total variation across
studies due to heterogeneity rather than chance, and is a derivative of
Cochran's Q [11]. Cochran's Q displays a low power for detection of
inconsistency when the number of studies is low, and a too high
power when the number of studies is high. All analyses were initially
done using a fixed-effects model, and if I2 N50% considered to indicate
significant result heterogeneity and a random effects model was used
to estimate the overall treatment effect [12]. Finally, we adopted
funnel plot graphically [13] to assess the publication bias.
2. Results
2.1. Trial searches and study characteristics
Bibliographic search yielded 882 studies. Of which, 421 were excluded after
removal of duplicates. 49 references appeared to meet our eligibility criteria and were
obtained in full text. Finally 10 of the articles totaling 1589 patients were included
(Fig. 1), and most of the patients are malignant diseases [7,9,14–21]. The Characteristics
of included studies are showed in the Table 1.
2.2. Outcome
2.2.1. Engraftment
Engraftment of neutrophils was defined as achievement of a peripheral neutrophil
count above 500 cells/ml for 3 consecutive days. Engraftment of platelets was defined
as a platelet count above 20000/ml without transfusions for at least 7 days. Seven
studies [7,9,14–16,18,20] (493 cases) reported the rate of neutrophil engraft with
matched, 1-Ag mismatched and ≥ 2-Ag mismatched CBT groups. The outcome is
showed in Fig. 2. The result of the heterogeneity test in 3 groups indicates no evidence
of heterogeneity in these studies, hence the fixed effect model is used. There is no
significant difference in the rate of neutrophil engraft between the matched and 1-Ag
mismatched CBT group [OR 1.03, 95%CI (0.57, 1.85), P = 0.92]. Epen, Liao and Nishihira
reported a trend of lower rate of neutrophil engraft in 1-Ag mismatched, while other 4
studies found a negative effect. As the ≥ 2-Ag mismatched group, all the 7 studies
showed a trend of lower rate of neutrophil engraft compared with the matched group,
and the overall effect is significant [OR 2.28, 95%CI (1.22,4.23), P = 0.009]. Similarly, the
rate of platelet engraft is significantly lower in the 1-Ag or ≥2-Ag mismatched CBT
group compared with the matched group [OR 1.72, 95%CI (1.02, 2.89), P = 0.04 and OR
2.31, 95%CI (1.36, 3.94), P = 0.002 respectively]. This indicates that 1 or ≥ 2-Ag HLA
mismatches results in a reduced rate of platelet engraft (Fig. 3).
2.2.2. Acute GVHD
GVHD was graded according to the Seattle consensus criteria [22]. 6 trials reported
the occurrence of GVHD. There is no significant difference in grade 0–1 acute GVHD
occurrence between the three groups (data not shown), but the occurrence of grade ≥II
GVHD was significantly higher in the ≥ 2-Ag mismatched than the matched group [OR
2.00, 95%CI (1.04, 3.85), P = 0.04] (Fig. 4).
Fig. 7. Funnel plot of the nine trials.
2.2.3. Early transplant related mortality (ETRM)
4 studies [14–16,18] reported the ETRM and the result is showed in Fig. 5. Compared
with the matched group, all the studies in the ≥2-Ag mismatched group found a trend
of higher TRM. Only the Epen's study indicated a significant effect, and the total effect is
significant [OR 3.08, 95%CI (1.15, 8.23), P = 0.02].
2.2.4. DFS
Nine trials [7,9,14–20] reported the DFS between the 3 groups and the result is
showed in Fig. 6. There is no significant difference between the matched and the 1-Ag
mismatched group, but a trend of lower DFS rate in the ≥ 2-Ag mismatched group has
seen in 8 studies except the Gluckman study [20], and the combined effect is also
significant [OR 1.70, 95%CI (1.17, 2.48), P = 0.006].
In order to test for publication bias, we used the funnel plot for visual assessment
(Fig. 7) on graphical representation of publication bias. The dots, each representing one
study are conforming to a triangular form, the funnel plots for DFS and other analyses
show that the distribution of the funnel plot is fairly symmetrical, meaning that
publication bias is low.
3. Discussion
It is known that allele-level disparity between donor and
recipient may impact transplant outcomes in largest studies in adult
unrelated transplant and CML, although the deficiency of data is a
limitation in determining the current role of allele-level HLA matching
in unrelated CBT. At present, most unrelated CBT have performed with
cord blood units that had one or two HLA mismatches by low-
resolution typing. The rate of hematopoietic recovery after unrelated
CBT has been associated with the NC and CD34+ cell dose and the
degree of HLA disparity between the donor and recipient. This analysis
indicated that there is a significantly lower rate of neutrophil and
platelet engraft with the number of HLA-antigen mismatch increased.
Engraftment after CBT differs from that seen following either bone
marrow or peripheral blood stem cell transplantation in that there is a
significant delay in the time to engraftment [2,14,23,24]. Studies of
unrelated CBTs have shown that the total nucleated cell dose is a
critical factor that is strongly correlated with hematopoietic engraft-
ment [5,9]. Other studies suggest that the CD34+ cell dose [25] may be
more important determinants of hematopoietic recovery post CBT.
Rubinstein et al [5] have shown that there is a progressive delay in
myeloid engraftment by day 42 with increasing HLA mismatching. In
the COBLT study [26], multivariate analysis showed that a higher
original HLA match (5 or 6/6) correlated with neutrophil recovery
(P b 0.04). Our result confirmed previous findings that the number of
HLA mismatches were the important factor for neutrophil and platelet
engraftment, and the more antigens mismatch, the great risk of graft
failure. These may be related to several factors, such as the lower
nucleated cell and CD34+ cell doses with the UCB grafts compared
with the marrow allografts [27], immaturity of stem cells, which
might need more cell divisions before differentiation to marrow
progenitors, and the lack of subpopulations to facilitate engraftment
[28].
Acute GVHD is an early event after allogeneic bone marrow
transplantation. Because the UCB stem cells are immunologically
naïve, the risk of severe GVHD is much lower [1] than other form
of HSCT, But graft versus leukemia (GVL) should be maintained
because of the presence of precursor T and NK cells. The analysis of
the New York Blood Center's experience [5] showed that there
was a trend suggesting an impact of matching on risk of severe
grade III–IV GVHD. The COBLT study, multivariate analysis showed
that HLA matching impacted grade II–IV risk with a significantly
higher risk of GVHD in recipients of 4/6 matched UCB compared to 5–
6/6 matched UCB [26]. Our result indicates that the occurrence of
≥II degree GVHD was significantly higher in ≥2-Ag mismatched
CBTs group. The TRM significantly increased with the more HLA-
antigen mismatch, perhaps due to the severed GVHD, hematological
reconstruction delayed and the rate of infection increased.
The impact of HLA mismatches on survival is difficult to analyze
because of the small series of patients and their heterogeneity in other
prognostic factors such as age, disease, status of the disease, CMV
 X. Shi-xia et al. / Transplant Immunology 21 (2009) 234–239
serology before transplant, and cell dose. Rubinstein et al [5] found
that event-free survival (EFS) was associated with HLA incompat-
ibility. Multivariable Cox model analysis found a higher risk of these
adverse events in 1-Ag mismatch, and 2-Ag or more mismatches
compared with matched CBT. Wagner et al [29] found an increased
risk of death (RR = 2.4, 95% CI 1.2–4.7) among 44 recipients of
CBT mismatched for 2–3 loci, compared to 58 mismatched for 0–1
locus (multivariable P b 0.01). HLA disparity did impact survival for
patients with nonmalignant diseases [30]. Ohnuma et al [31] reported
that mismatching for 2–4 HLA-A, B, or DRB1 alleles was associated
with decreased survival compared to mismatching for 0–1 alleles. But
Cornetta et al [32] reported no effect of HLA-mismatching at low
resolution on the 1-year survival in a small study of 24 adults. Our
analysis indicates there is a lower rate of DFS in the ≥2-Ag mis-
matched CBT group compared the matched group. Cell dose is a
critical factor influencing engraftment and outcome of UCBT, Eapen
et al [14] comparing outcomes of 503 UCBTs and 282 UBMTs in
children b16 years with acute leukemia to assess the influence of both
cell dose and HLA matching on outcome. A cutoff for cell dose for 1-
antigen mismatched transplants was defined as 3 × 107/kg. It was
found that higher cell doses resulted in a higher probability of both
neutrophil and platelet recovery in 1-antigen mismatched UCBT but
had no effect in 2-antigen mismatched transplants, suggesting that
cell dose may not be able to overcome the adverse impact of
mismatching in the setting of 4 out of 6 matched UCBT.
It is important to emphasize that our comparisons are between
fully matched, 1-Ag mismatched and 2-Ag mismatched UCBT. The
comparisons are not between UBMT and UCBT, where another meta-
analysis has shown that UCBT with up to 2-Ag mismatches has
equivalent outcomes with fully matched UBMT [33]. Thus, our
conclusions, while important in choosing between cord blood units,
should not affect decisions when choosing between bone marrow and
cord blood. The sensitive analysis, in which the fix effect and random
effect used respectively, and the results were similar between each
group. In this meta-analysis, we applied a systematic methodology in
which the studies were selected and analyzed, but blinded or
randomized controlled trials were not available. We cannot fully
exclude the possibility of center biases in treatment and selection of
patients and large sample and well-designed trials need to carry out in
the future.
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