THESIS SAM VOSSEN 6052401

THE CLINICAL IMPACT OF AN ABO-MISMATCH ON THE OUTCOME OF HEMATOPOIETIC
STEM CELL TRANSPLANTS: A SYSTEMATIC REVIEW.
July 3, 2016
Sam Vossen
University of Amsterdam AMC
06052401 – s.vossen@amc.uva.nl
06-57575870
Dr. S.S. Zeerleder MD PhD
Internist-hematologist
s.s.zeerleder@amc.uva.nl

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TABLE OF CONTENTS
ABSTRACT 3
INTRODUCTION 3
METHODS 5
Study Inclusion Criteria 6
Study Exclusion Criteria 6
RESULTS 7
1. Overall survival 7
2. Treatment related mortality 10
3. Acute graft versus host disease 11
4. Chronic graft versus disease 14
5. Relapse 15
6. Engraftment 17
7. Transfusion requirements 19
8. Pure Red Cell Aplasia 21
DISCUSSION 22
Strength and limitations 23
Future work 24
REFERENCES 25

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ABSTRACT
Introduction: At the moment an ABO-mismatch is not considered a contraindication in
HSCTs and to have little effect on the success of the treatment. However, conflicting evidence
suggest that an ABO-mismatch might have a bigger impact than initially assumed. To resolve the
origin of these contradicting results, a more comprehensive analysis is needed. Methods: A
systematic review was therefore conducted of the literature obtained from the PubMed database
through a strategically designed search query. 22 articles were selected, out of a total of 265
search results, using a set of inclusion and exclusion criteria. The data was extracted using a
standardized data-extraction form in order to structure the heterogeneous information of the
studies. Results: The analysis of the studies resulted in a total of 27 tables, covering the impact of
an ABO-mismatched HSCT, consisting of three types of stem cell sources, on seven clinical
outcomes. This review shows that the majority of studies did not find a significant effect of an
ABO-mismatched HSCT on the investigated outcomes. However, there is a non-negligible
amount of studies that do report a significant adverse effect of an ABO-mismatched HSCT on
certain outcomes. Efforts to reduce the transfusion of incompatible plasma are therefore justified
until a better understanding of the mechanism of the adverse effect is attained.
INTRODUCTION
Hematopoietic Stem-Cell Transplantation (HSCT) is a potentially curative treatment for
malignant and non-malignant diseases. Hematopoietic progenitor cells from bone marrow,
peripheral blood and umbilical cord blood are used to reconstitute the bone marrow after it has
been ablated. Worldwide, 40.000 HSCTs are performed each year. Over the years, there has been
improvement in transplant outcomes due to numerous developments, such as refinement in
human leukocyte antigen matching, introduction of reduced toxicity conditioning regimens,
improvement of graft vs host prophylaxis, prevention and treatment of post-transplant infections
and improved supportive care1-3
. Survivors of HSCT still have high mortality rates compared to
the general population, facing challenges that affect their health and wellbeing. Relapse of
primary disease and chronic Graft Versus Host Disease (GVHD) are the leading causes of
premature death4,5
. Moreover, even for patients that survived for at least 5 years after an HSCT
without relapse of the original disease, the life expectancy is still not the same as that of healthy
people. In order, the leading causes of deaths were second malignancies and recurrent disease,
followed by infections, chronic GVHD, respiratory diseases and cardiovascular diseases.
Immediate survival is no longer the sole problem after an HSCT. The aim of an HSCT is
to cure a patient from their primary disease and to contribute to long-term survival while
maintaining normal health6-10
. However, undergoing HSCT exposes the patient to a toxic and
high-risk therapy resulting in potentially numerous complications and life-time patient hood.
Before patients receive an HSCT, they undergo a conditioning regimen, typically chemotherapy

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and/or irradiation immediately prior to a transplant to help eradicate the patient's disease and to
suppress immune reactions. There are two types of conditioning regimen; myeloablative and non-
myeloablative (also known as reduced intensity conditioning (RIC)). Myeloablative is based on
the complete ablation of the patient's bone marrow while keeping the radiation/chemo dose as
low as possible to reduce damage to other tissues11
. The positive effects of this approach are a
complete eradication of tumor cells and low rejection risks. Negative effects are a deficient
immune system causing a higher risk of infections and a higher mortality due to the severity of
the treatment12,13
. A non-myeloablative regimen uses a dose of chemo/radiation that is too low to
eradicate all the host’s bone marrow cells14
. This regimen relies more on the graft-vs-tumor effect
to lower the risk of cancer relapse despite remaining tumor cells. Furthermore, it leads to a lower
risk of infections due to (partial) preservation of the immune system. Overall it can be considered
as a less severe treatment with less transplant related mortality15-17
.
After conditioning the graft is administered. There are three types of stem cell sources
available: 1) bone marrow, 2) peripheral blood stem cells and 3) umbilical cord blood. In the case
of bone marrow, the HSC are removed from a large bone of the donor. Peripheral blood stem
cells are collected from the blood through apheresis. This is now the most common source of
stem cells for HSCT. As a third option, umbilical cord blood is obtained when a mother donates
her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSC
than is normally found in adult blood. However, the small quantity of blood obtained makes it
less suitable for transplantation into adults than into small children. HSCTs can be performed
across blood group barrier. In case of successful engraftment, the recipient will carry the blood
type of the donor regardless of incompatibility. In contrast, solid organ transplantation requires a
matching ABO-transplant since incompatibility may result in (hyper)-acute rejection of the
transplant.
Among the various blood type systems, incompatibilities in ABO blood type between
donor and recipient may lead to (delayed) hemolytic transfusion reactions. This is mainly due to
natural anti-A and anti-B antibodies of IgM isotype, which are efficient activators of the classical
pathway of complement. There are three different types of donor-recipient ABO
incompatibilities: major ABO-mismatch, minor ABO-mismatch, bidirectional mismatch. A major
ABO incompatibility occurs in the presence of recipient’s isoagglutinins directed against A or B
antigens on the donor’s red blood cells. For example, a type-A, AB, or B donor to a type-O
recipient or between AB donors and A or B recipients. The recipients isoagglutinins can bind to
the corresponding donor RBC antigens, which can cause acute hemolysis, delayed red blood cell
engraftment and pure red cell aplasia18-21
. A minor ABO-incompatible HSCT occurs in the
presence of donor isoagglutinins directed against A or B antigens on the recipient’s red blood
cells. This is the case between a type O donor and type A, B or AB recipient or between type A or
B donor and type AB recipient. The isoagglutinins on the donor’s progenitor cells can result in

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acute hemolysis22
. This risk is increased with high-titers donor isoagglutinins and/or small
recipient plasma volume in comparison to the infused volume. Therefore, a minor incompatible
HSCT is usually manipulated with plasma reduction to remove most of the antibodies present,
reducing the risk of acute hemolysis. A minor incompatible HSCT can also result in delayed
hemolysis23
. A bidirectional ABO-incompatible HSCT is a combination of both a major and
minor ABO incompatibility. This occurs only between a type A donor and a type B recipient and
vice versa. A bidirectional ABO-incompatible HSCT poses both the risks of a minor and major
incompatibility.
As stated in multiple studies, ABO incompatibility does not directly influence outcome in
terms of overall survival or mortality24-26
. Nevertheless, various studies report contradicting
results for ABO-mismatched HSCTs with respect to certain outcomes (TRM, relapse,
engraftment etc.) and HSCT related complications (GVHD, PRCA etc.). To resolve the origin of
these contradicting results, a more comprehensive analysis of the characteristics of each of these
studies is needed. Therefore, the purpose of this systematic review is to gather, catalog, assess
and evaluate the available evidence on the effects of an ABO-mismatched hematopoietic
transplant on numerous outcomes. Preferably, this review presents available evidence of studies
comparing the effects of different types of transplants (BM, HSCT, PF, CB) and types of
mismatch (mi, ma, bid).
The review provides insights into various characteristics of the studies that might explain
the contradicting results. The information gathered here can serve to guide future research and
inform the development of evidence-based clinical practice guideline recommendations.
METHODS
In order to obtain sufficient data on the subject we narrowed down our search to a
combination of the ABO blood group system, blood group incompatibility and the 3 forms of
transplants which are of interest; bone marrow transplants, hematopoietic stem cell transplants
and peripheral blood stem cell transplants. With these domains, a literature search in PubMed was
conducted using the terms detailed in appendix B.

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The search did not include the outcome of the studies because an exploratory search was required.
Instead, the outcomes that were reported frequently enough were included in the review. The
purpose of this review was to identify all studies that examined the relationship between an ABO-
mismatched HSCT and certain clinical outcomes. To determine what articles could be used a
number of in- and exclusion criteria were used that are described below. The process of selecting
articles using these criteria is described in the flow chart (Figure 1).
Figure 1. Flow chart overviewing the selection process.
Study Inclusion Criteria
All study designs were eligible with the exception of case reports. However due to the
nature of the treatment the result will mostly consist of retrospective cohort studies. Studies were
included only if they reported on patients receiving an allogenic HSCT from any of the 3
commonly used sources. Another criterion was any form of analyses on the effect of an ABO-
mismatch on certain outcomes. This could be about all the possible mismatches or only one. Only
English studies were included and no date limit was imposed.
Study Exclusion Criteria
To control the feasibility of the review the sample size was set to a minimum of 40
patients. As will be discussed later, studies below this point are not eligible for this review due to
the fragmentation of the sample size. Case reports were excluded from the pool because of the
same reason. Studies that did not report on the predefined outcomes were also excluded to
prevent ending up with a lot of studies reporting on a lot of different outcomes.

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This resulted in a final number of 22 studies, selected out of a total of 265 search results,
to be reviewed and analyzed with respect to the seven different outcomes described in more detail
below. These seven outcomes are to be compared with three types of ABO-mismatches and three
types of different stem cell sources. To create an intelligible overview a separate table was made
for each stem cell source per outcome, further differentiated for each ABO-mismatch.
RESULTS
To review the evidence available on the impact of an ABO-mismatch on the clinical
outcome, relapse, treatment-related mortality and the overall survival in patients receiving an
allogenic hematopoietic stem cell transplant, a review with a systematic approach is best suited.
The purpose of the systematic review is to obtain insight in the multitude of clinical aspects and
the methodological quality of the studies. Due to the complexity of the clinical process and the
variety of observed results, comparing the different studies is necessarily limited to a selection of
major outcomes and complications that are relevant when researching HSCT. There are seven
different outcomes: overall survival (OS), treatment related mortality (TRM), acute graft-versus-
host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse, engraftment and
transfusion requirements. Within each of these outcomes different studies either report three types
of HSCT: BMT, PBSCT, CBT, or they did not differentiate and generalized patients receiving
any type of HSCT. A further division was made in terms of univariate (ABO-mismatched) and
multivariate analyses (major, minor and bidirectional mismatch) of the results. The multivariate
analysis was used to reveal effects within a specific type of mismatch only. For each mismatch,
we list the studies with significant and non-significant results with their p-value.
Next, the results for the different outcomes will be discussed in separate subsections.
1. Overall survival
Table 1.1 shows the overview of eight studies reporting on the overall survival for
patients receiving an HSCT. Two studies27,28
report a significant decrease in overall survival after
a univariate analysis with a sample size of 201 and 119 patients respectively, whereas seven
studies29-35
report no significant decrease in overall survival, with sample sizes ranging from 19 to
414 patients. The majority of studies27,30-33
report no significant decrease in overall survival after
a multivariate analysis with a median sample size of 32.5 patients (12-98). Only one study33
reports a significant decrease in overall survival for minor mismatched AB0-HSCTs. Two
studies27,30
report a significant decrease in overall survival for patients receiving a bidirectional
mismatched transplant.

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Table 1.2 shows the overview of six studies29,36-40
reporting on overall survival in patients
receiving a BMT. Four studies29,37-39
found no significant effect of ABO-mismatched transplant
on the overall survival of patients and therefore found no evidence for decreased probability of
survival due to mismatch. The sample size of these studies ranges from 43 to 995 patients with a
median of 246.5. Adversely, two studies36,40
, with a sample size of 2729 and 61 patients
respectively, report that there is a significant effect and a decrease in overall survival due to
mismatch. Only three36,38,40
made a multivariate analysis but they show contradicting results. One
study states that a major and minor mismatch negatively influence overall survival whereas two
other studies38,40
find no significant difference. Moreover, two studies38,41
measure no significant
effect with a bidirectional mismatch while there is one study40
that does measure a significant
effect.
Table 1.2
Summary of included studies reporting on the overall survival in patients receiving a bone marrow transplant
Significant Nonsignificant
Matching type Study P Follow-up (years) Study P Follow-up (years)
ABO-mismatch Kimura, F.36
(N=2729) .0003 1 Blin, N.29
(N=414) .07 5
Stussi, G.40
(N=61) .004 5 Mehta, J.37
(N=43) .18 5
Rozman, P.38
(N=79) .61
Seebach, J.D.39
(N=995) .294 5
ABO-major Kimura, F.36
(n=1384) <.0001 1 Rozman, P.38
(n=34) .76
Stussi, G.40
(n=25) .85 5
ABO-minor Kimura, F.36
(n=1202) .0051 1 Rozman, P.38
(n=32) .22
Stussi, G.40
(n=30) .37 5
Table 1.1
Summary of included studies reporting on the overall survival in patients receiving a hematopoietic stem cell transplant
ABO-mismatch Stussi, G.27
(N=201) .006 Blin, N.29
(N=414) .06 5
Worel, N.28
(N=119) <.05 Goldman, J.30
(N=69) NS
Klumpp, T.R.31
(N=92) .73 5
Ludajic, K.32
(N=96) .3 3
Ozkurt, Z.N.33
(N=67) NS
Wang, Z.34
(N=211) .17 3
Worel, N.35
(N=19) .89 3
ABO-major Goldman, J.30
(n=35) NS
Klumpp, T.R.31
(n=39) .34 5
Ludajic, K.32
(n=30) .471 3
Ozkurt, Z.N.33
(n=25) NS
Stussi, G.27
(n=98) .18
ABO-minor Ozkurt, Z.N.33
(n=30) <.05 Goldman, J.30
(n=29) NS
Klumpp, T.R.31
(n=40) .3 5
Ludajic, K.32
(n=44) .47 3
Stussi, G.27
(n=86) .27
ABO-bidirectional Goldman, J.30
(n=5) .05 Klumpp, T.R.31
(n=13) .47 5
Stussi, G.27
(n=17) .0009 Ludajic, K.32
(n=22) .67 3
Ozkurt, Z.N.33
(n=12) NS
Note. N = total number of patients in the sample of the study, n = number of patients in a subgroup of the sample of a study, NS = nonsignificant, P = p-
value as described in the study

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ABO-bidirectional Stussi, G.40
(n=6) .0004 5 Kimura, F.36
(n=143) .1884 1
Rozman, P.38
(n=13) .26
Note. N = total number of patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, P = p-value as described in the
study
Table 1.3 shows the overview of five studies29,42-45
reporting on the effect of an ABO-
mismatched transplant in patients receiving a PBSCT. Of these five, one study43
reports a
statistically significant decrease in the overall survival of mismatched patients, whereas four
studies29,42,44,45
report no significant effects. Only one study44
reports no significant effect for the
multivariate analysis of major and minor mismatch. Again, the majority of studies reports no
significant effects. The one study43
reporting a significant difference has a sample sizes of 43. The
other four studies29,42,44,45
have sample sizes ranging from 13 to 414 with a median of 36.5
patients.
Table 1.3
Summary of included studies reporting on the overall survival in patients receiving a peripheral blood stem cell transplant
ABO-mismatch Worel, N.43
(N=43) <.05 1 Blin, N.29
(N=414) .055 5
Canals, C.42
(N=25) .54 1
Guitierrez-Aguirre, C.H.44
(N=33) .45 5
Kim, J.G.45
(N=40) .8652 3
ABO-major Guitierrez-Aguirre, C.H.44
(n=13) .83 5
ABO-minor Guitierrez-Aguirre, C.H.44
(n=20) .21 5
Note N = total number of patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, P = p-value as described in the
study
Table 1.4 shows the overview of only two studies29,41
reporting on the effect of an ABO-
mismatched transplant in patients receiving a CBT. One study41
reports a significant effect in a
decreased overall survival in a group of 136 patients, while the other study29
reports no significant
effect for 414 patients. Remarkably, the former study41
reports no significant effects on the
multivariate analysis while reporting a significant decrease in overall survival in a univariate
analysis.
Table 1.4
Summary of included studies reporting on the overall survival in patients receiving a cord blood transplant
ABO-mismatch Konuma, T.41
(N=136) .03 5 Blin, N.29
(N=414) .35 5
ABO-major Konuma, T.41
(n=47) .62 5
ABO-minor Konuma, T.41
(n=58) .41 5
ABO-bidirectional Konuma, T.41
(n=31) .14 5
Note. N = total number of patients in the sample of the study, P = p-value as described in the study
Overall, 38 analyses, multivariate and univariate combined, found no significant decrease
in overall survival regardless of the source and regardless of the type of mismatch. However, the
median sample size of these studies (median of 39.5, range (12-414)) is much lower than the

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median sample size of 14 analyses that do report a significant decrease in overall survival with a
median sample size of 127.5 patients, (range 5-2729).
2. Treatment related mortality
Table 2.1 shows the overview of three studies reporting on the treatment related mortality
in patients receiving an HSCT. All three studies31-33
report no increased treatment related
mortality caused by an ABO-mismatched transplant. A multivariate analysis performed by 2
studies32,33
, also shows no significant increase in treatment related mortality.
Table 2.1
Summary of included studies reporting on the treatment related mortality in patients receiving a hematopoietic stem cell transplant
Matching type Study P Study P
ABO-mismatch Klumpp, T.R.31
(N=92) .21
Ludajic, K.32
(N=96) .53
Ozkurt, Z.N.33
(N=67) NS
ABO-major Ludajic, K.32
(n=30) .61
Ozkurt, Z.N.33
(n=25) NS
(n=30) <.01 Ludajic, K.32
(n=44) .61
ABO-bidirectional Ludajic, K.32
(n=22) .63
Ozkurt, Z.N.33
(n=12) NS
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, NS = nonsignificant, P =
p-value as described in the study
Table 2.2 shows the overview of three studies36,37,39
reporting on the treatment related
mortality in patients receiving a BMT. Two studies37,39
report no significant effect for their
univariate analysis, implying that an ABO-mismatched BMT does not increase the probability of
treatment related mortality. They did not conduct a multivariate analysis. Kimura36
reports
multivariate results with significantly higher treatment related mortality in major and minor
ABO-mismatches but no significant increase in a bidirectional ABO-mismatch.
Table 2.2
Summary of included studies reporting on the treatment related mortality in patients receiving a bone marrow transplant
ABO-mismatch Mehta, J.37
(N=43) .35
Seebach, J.D.39
(N=995) NS
(n=1384) <.001
(n=1202) .009
ABO-bidirectional Kimura, F.36
(n=143) .344
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample under study, NS = nonsignificant, P =
Table 2.3 shows the overview of two studies42,43
reporting on the treatment related
mortality in patients receiving a PBSCT. One study42
shows no effect of an ABO-mismatched
PBSCTs on an increased probability of treatment related mortality. The other study43
reports that

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there is an increased treatment related mortality in the ABO-minor and bidirectional group. These
are also the only studies who report on the effect of an ABO-mismatched PBSCT on the TRM.
Table 2.3
Summary of included studies reporting on the treatment related mortality in patients receiving a peripheral stem cell transplant
ABO-mismatch Canals, C. (N=25) .27
ABO-major
ABO-minor Worel, N. (n=21) <.01
ABO-bidirectional Worel, N. (n=4) <.01
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, P = p-value as described
in the study
Table 2.4 shows the overview of one study41
reporting on the treatment related mortality
in patients receiving a CBT. This study41
reports no effect of AB0-incompatibility on an increased
TRM. However, multivariate analysis shows that a major AB0-incompatibility gives an increased
probability of TRM. Both minor and bidirectional ABO-mismatched transplants do not have an
effect on TRM.
Table 2.4
Summary of included studies reporting on the treatment related mortality in patients receiving a cord blood transplant
(N=136) .19
(n=47) .05
(n=58) .67
(n=31) .33
Overall, 15 analyses, multivariate and univariate combined, report that there is no
increased treatment related mortality caused by an ABO-mismatched transplant. They have a
median sample size of 44 patients ranging from 12 to 995. However, six analyses report an
increased treatment related mortality in patients receiving an ABO-mismatched BMT, CBT or
HSCT with a median sample size of 38.5 patients ranging from 4 to 1384.
3. Acute graft versus host disease
Some studies apply different analyses to different severities of GVHD, varying between 1
and 4. For example study41
makes a grouping into grade 2 to 4 aGVHD and into grade 3 and 4
aGVHD. Other studies, e.g. study27
, try to contrast mild cases (grade 1) with moderate (grade 2)
and very severe cases (grade 3 and 4). In Tables 3.1-3.4, the references to the studies have
therefore been extended with the type of grading for which a significant or no significant effect
was detected.

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As shown in Table 3.1, seven studies27,29,31-35
report on the incidence of aGVHD among
patients receiving a HSCT in relation to the type of mismatch. In ABO-mismatched HSCTs, two
studies27,32
report an increased incidence of aGVHD while four studies29,31,34,35
report no
significant impact of ABO-mismatched HSCTs on aGVHD incidence. Further multivariate
analyses conducted by 3 studies27,32,33
show no increased aGVHD, with severities >=1,2 incidence
in both the major and the bidirectional ABO-mismatched HSCTs. However, among patients
receiving HSCTs with a minor AB0-incompatibility, 3 studies27,32,33
do show a significantly
increased incidence in aGVHD. One study27
reports no effects on aGVHD>=2 but an increased
incidence in of aGVHD with a severity of >=1, while another study33
reports an increased
incidence of aGVHD with a severity of >=3 and no higher incidence in aGVHD with a severity of
>=1. The third study32
shows an increased incidence of aGVHD with a grade of >=2 among
patients receiving a minor ABO-mismatched HSCT.
Table 3.1
Summary of included studies reporting on acute graft-versus-host disease in patients receiving a hematopoietic stem cell transplant
Matching type Study P Grade Study P Grade
ABO-mismatch Ludajic, K.32
(N=96) .032 >=2 Blin, N.29
(N=414) .06 >=2
Stussi, G. (N=201) .02 >=1 Klumpp, T.R.31
(N=92) .44 >=2
Wang, Z. (N=211) .72 >=2
Worel, N. (N=19) NS
ABO-major Ludajic, K.32
(n=30) .23 >=2
Ozkurt, Z.N. (n=25) NS >=1
Stussi, G. (n=98) .37 >=2
ABO-minor Ludajic, K.32
(n=44) .003 >=2 Ozkurt, Z.N. (n=30) NS >=1
Stussi, G. (n=86) .009 >=1 Stussi, G. (n=86) .42 >=2
Ozkurt, Z.N. (n=30) <.05 >=3
ABO-
bidirectional
Ludajic, K.32
(n=22) .48 >=2
Ozkurt, Z.N. (n=12) NS >=1
Stussi, G. (n=17) .54 >=2
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, NS = nonsignificant, P = p-
value as described in the study, grade = the range of severity for which aGVHD was determined
Table 3.2 gives an overview of six studies29,36-40
reporting on the incidence of aGVHD
among patients receiving BMTs in relation to the type of mismatch. Of these studies, four
studies29,37-39
report there is no significant relation between a ABO-blood-group mismatch and the
incidence of aGVHD. After multivariate analysis, which was performed by three of those
studies36,38,40
, only one36
found an increased incidence of aGVHD with a severity of >=3 as a
result of both a major and minor ABO-mismatched BMT. This is the only study that shows
significant results for an increased incidence of aGVHD that also has a high sample size. The
studies36,38,40
reporting no significant increase in incidence of aGVHD have a median sample size
of 34 ranging from 6-995. The studies29,39
at the higher end of this range report no significantly
increased incidence of grade >=2 aGVHD.

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Table 3.2
Summary of included studies reporting on acute graft-versus-host disease in patients receiving a bone marrow transplant
ABO-mismatch Stussi, G.40
(N=61) .02 >=2 Blin, N.29
(N=414) .19 >=2
Mehta, J.37
(N=43) .25 >=1
Rozman, P.38
(N=79) .53 >=2
Seebach, J.D.39
(N=995) .74 >=2
(n=1384) <.001 >=3 Rozman, P.38
(n=34) .91 >=2
Stussi, G.40
(n=25) .16 >=2
(n=1202) .004 >=3 Rozman, P.38
(n=32) .11 >=2
Stussi, G.40
(n=30) .19 >=2
ABO-bidirectional Kimura, F.36
(n=143) .77 >=3
Rozman, P.38
(n=13) .26 >=2
Stussi, G.40
(n=6) .85 >=2
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, P = p-value as described in the
study, grade = the range of severity for which aGVHD was determined
In Table 3.3, five studies29,42-45
report on the incidence of aGVHD among patients
receiving PBSCTs in relation to the type of mismatch. Only one study29
found a significant
relation between ABO-mismatched PBSCTs and an increased incidence aGVHD grade >=2. The
other four studies42-45
report no significant outcome, neither in the patients with aGVHD grade
>=3 nor in grades >=1. These four are all relatively small studies ranging from 25 to 43 patients.
The study29
that did find an increased incidence of aGVHD analyzed 414 patients.
Table 3.3
Summary of included studies reporting on acute graft-versus-host disease in patients receiving a peripheral stem cell transplant
ABO-mismatch Blin, N.29
(N=414) .01 >=2 Canals, C.42
(N=25) NS >=3
Gutierrez-Aguirre, C.H.44
(N=33) .79 >=1
Kim, J.G.45
(N=40) NS >=1
Worel, N.43
(N=43) NS
Note. N = total number patients in the sample of the study, NS = nonsignificant, P = p-value as described in the study, grade = the range of severity for which
aGVHD was determined
As shown in Table 3.4, only two studies29,41
report on the incidence of aGVHD among
patients receiving CBTs in relation to the type of mismatch. Only one study41
reports a significant
increase between ABO-mismatched CBTs and the incidence of aGVHD grade >=3 but no
significant relation for aGVHD grade >=2, which is confirmed by one other study29
. The
multivariate analysis41
performed shows no significant increase in incidence for both stages of
aGVHD (>=2, >=3) in relation to a major, minor and bidirectional ABO-mismatched CBT.
Table 3.4
Summary of included studies reporting on acute graft-versus-host disease in patients receiving a cord blood transplant
(N=136) .02 >=3 Blin, N.29
(414) .15 >=2
Konuma, T.41
(N=136) .91 >=2
(n=47) .81 >=2

14
(n=58) .66 >=2
(n=31) .37 >=2
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, P = p-value as described in the
study, grade = the range of severity for which aGVHD was determined
Overall 10 analyses, multivariate and univariate combined, report a statistically
significant effect of an ABO-mismatched transplant increasing the incidence of aGVHD. In
general, this results in an increased risk of developing grade >=2 aGVHD. For the multivariate
analysis, only 4 studies27,32,33,36
reported a significant effect of a minor ABO-mismatch on the
occurrence of aGVHD. The median sample size of the 10 analyses is 116 patients with a range of
30-1384. 32 analyses, multivariate and univariate combined, report that there is no significant
effect of an ABO-mismatched transplant on the occurrence of aGVHD which have a median
sample size of 37 patients ranging from 6-995.
4. Chronic graft versus disease
Table 4.1 to 4.4 shows the overview results for chronic GVHD from 11 studies. All 11
studies report that there is no significant impact of an ABO-mismatched transplant on the
incidence of cGVHD, regardless of the donor source. The sample size of the combined 16
analyses has a median of 41.5 patients ranging from 12-995.
Table 4.1
Summary of included studies reporting on the chronic graft-versus-host disease in patients receiving a hematopoietic stem cell transplant
ABO-mismatch Klumpp, T.R.31
(N=92) .53
Wang, Z.34
(N=211) .57
Worel, N.35
(N=19) NS
ABO-major Ozkurt, Z.N.33
(n=25) NS
(n=30) NS
ABO-bidirectional Ozkurt, Z.N.33
(n=12) NS
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, NS = nonsignificant, P = p-value
as described in the study
Table 4.2
Summary of included studies reporting on the chronic graft-versus-host disease in patients receiving a bone marrow transplant
(N=43) .39
Seebach, J.D.39
(N=995) .779
Note. N = total number patients in the sample of the study, P = p-value as described in the study
Table 4.3
Summary of included studies reporting on the chronic graft-versus-host disease in patients receiving a peripheral stem cell transplant
ABO-mismatch Canals, C.42
(N=25) .74
Guitierrez-Aguirre, C.H.44
(N=33) .45
Kim, J.G.45
(N=40) NS
Worel, N.43
(N=43) NS

15
Note. N = total number patients in the sample of the study, NS = nonsignificant, P = p-value as described in the study
Table 4.4
Summary of included studies reporting on the chronic graft-versus-host disease in patients receiving a cord blood transplant
(N=136) .86
(n=47) .65
(n=58) .58
(n=31) .3
in the study
5. Relapse
Table 5.1 shows the overview of 6 studies reporting on the relapse for patients receiving
an HSCT. One study29
shows an increased relapse risk in patients receiving an ABO-mismatched
HSCT. Four studies27,32-34
report no increased risk among patients receiving ABO-mismatched
HSCTs. Applying multivariate analysis, two studies27,32
report no increased risk of relapse after a
major, minor or bidirectional HSCT. The four studies reporting no increased risk have a median
sample size of 76.5 patients with a range of 17-211. The one study that does report a higher
relapse rate has a sample size of 414 patients.
Table 5.1
Summary of included studies reporting on relapse in patients receiving a hematopoietic stem cell transplant
(N=414) .04 Ludajic, K.32
(N=96) .53
Ozkurt, Z.N.33
(N=67) NS
Stussi, G.27
(N=201) .78
Wang, Z.34
(N=211) .36
ABO-major Ludajic K.32
(n=30) .83
Stussi, G.27
(n=86) .51
ABO-minor Ludajic K.32
(n=44) .33
Stussi, G.27
(n=98) .67
ABO-bidirectional Ludajic K.32
(n=22) .56
Stussi, G.27
(n=17) .4
As seen in Table 5.2, four studies29,37-39
report on the relapse risk for ABO-mismatched
BMT, of which one study37
reports a significant increase. Only one study38
carried out a
multivariate analysis; reporting no significant effects for major, minor and bidirectional
mismatched BMTs. Out of the 3 studies reporting no significant effect, there are 2 relatively
larger studies (N=414 and N=995) and 1 smaller one (N=79). The study that does report a
statistically significantly increased relapse risk consists of 43 patients.

16
Table 5.2
Summary of included studies reporting on relapse in patients receiving a bone marrow transplant
(N=43) .028 Blin, N.29
(N=414) .065
Rozman, P.38
(N=79) .8
Seebach, J.D.39
(N=995) .685
ABO-major Rozman, P.38
(n=34) .34
ABO-minor Rozman, P.38
(n=32) .92
ABO-bidirectional Rozman, P.38
(n=13) .18
in the study
Table 5.3 shows the overview of three studies29,42,45
reporting on ABO-mismatched
PBSCTs, of which none found an increased relapse risk. No multivariate analyses have been
performed.
Table 5.3
Summary of included studies reporting on relapse in patients receiving a peripheral stem cell transplant
(N=414) .055
Canals, C.42
(N=25) .91
Kim, J.G.45
(N=40) .4272
Note. N = total number patients in the sample of the study, P = p-value as described in the study
Two studies29,41
report no increased risk of relapse rate among patients with an ABO-
mismatched CBT which can be seen in Table 5.4. Multivariate analysis performed by one study41
also shows no relation between major, minor and bidirectional mismatched CBTs and an
increased relapse risk.
Table 5.4
Summary of included studies reporting on relapse in patients receiving a cord blood transplant
(N=414) NS
Konuma, T.41
(N=136) .09
(n=74) .21
(n=58) .18
(n=31) .86
Overall, 2 analyses report a significant relation between a mismatch and an increased
relapse rate. One study29
analyzed HSCTs in general while the other study37
investigated BMTs.
These analyses have a sample size of 414 and 43 patients respectively. 25 analyses, multivariate
and univariate combined, report no significant increase in the relapse rate and have a median
sample size of 67 with a range of 13-995.

17
6. Engraftment
Section six shows the overview of studies reporting on the effect of an ABO-mismatched
transplant for the success of engraftment. Engraftment is in most studies examined by measuring
either the ANC (absolute neutrophil count), PLT (platelet count) or RTC (reticulocyte count).
Engraftment is deemed successful if ANC >0.5x10^9, PLT >50x10^9 and RTC >1% either
combined or individually; in other words, the graft has successfully replaced the host's
hematopoietic stem cells and is functioning accordingly.
As shown in Table 6.1 two studies30,33
report on the effects of ABO-mismatched HSCTs
on engraftment. One study30
only performs a univariate analysis and shows no significant effect
of an ABO-mismatch on engraftment in terms of a delayed ANC>0.5x10^9 and PLT>50x10^9.
The second study33
did not find any significant relation between an ABO-mismatched HSCT and
a delayed engraftment in terms of ANC>0.5x10^9, PLT>050x10^9 and RTC>1% in most forms
of mismatch, with the exception of an ABO-major mismatch for which they found a significant
delay in patients reaching a RTC>1%. Both studies have a small sample size of 69 and 67
respectively.
Table 6.1
Summary of included studies reporting on the engraftment in patients receiving a hematopoietic stem cell transplant
Matching type Study P Engraftment
criteria
Study P Engraftment
criteria
ABO-mismatch Goldman, J. (N=69) NS
NS
ANC
PLT
Ozkurt, Z.N. (N=67) NS
NS
NS
ANC
PLT
RTC
ABO-major Ozkurt, Z.N. (n=25) <.01 RTC Ozkurt, Z.N. (n=25) NS
NS
ANC
PLT
ABO-minor Ozkurt, Z.N. (n=30) NS
NS
NS
ANC
PLT
RTC
ABO-
bidirectional
Ozkurt, Z.N. (n=12) NS
NS
NS
ANC
PLT
RTC
p-value as described in the study, ANC = absolute neutrophil count >0.5x10^9, PLT = platelet count >50x10^9, RTC = reticulocyte count >1%
Table 6.2 shows the overview of five studies28,36,38,39,46
reporting on a delayed
engraftment due to ABO-mismatched BMT. One study36
, having the largest sample size
(N=2729), shows a statistically significant result for a delayed ANC>0.5x10^9, PLT>50x10^9
and RTC>1%, while a second study38
only shows a significant delay in ANC>0.5x10^9 and no
delay in PLT reaching >50x10^9. After applying multivariate analyses, there is one study36
that
finds a significant delay in engraftment on all fronts (ANC, PLT, RTC) in patients receiving a
major ABO-mismatched BMT. Two other studies28,46
only measured RTC and a third study39
only the ANC, for which they all found a significant delay of engraftment caused by an ABO-

18
major mismatched BMT. These 4 studies have a median sample size of 247 ranging from 29-
1384. One study46
, with a sample size of 16 patients, also finds a significant effect in ABO-
bidirectional mismatched transplants, delaying reaching RTC>1%. Four studies28,36,38,46
report that
an ABO-mismatch has no significant effect on engraftment. The median sample size of these four
studies is 46.5, ranging between 16-1202.
Table 6.2
Summary of included studies reporting on the engraftment in patients receiving a bone marrow transplant
criteria
Study P Engraftment
criteria
ABO-mismatch Kimura, F.36
(N=2729) <.001
<.001
<.001
ANC
PLT
RTC
Rozman, P.38
(N=79) NS PLT
Rozman, P.38
(N=79) <.037 ANC
ABO-major Benjamin, R.J.46
(n=29) <.005 RTC Benjamin, R.J.46
(n=29) NS ANC
Kimura, F.36
(n=1384) <.004
<.001
<.001
ANC
PLT
RTC
Worel, N.28
(n=43) NS
NS
ANC
PLT
Seebach, J.D.39
(n=451) <.001 ANC
Worel, N.28
(n=43) <.05 RTC
(n=1202) .711
.211
.603
ANC
PLT
RTC
Benjamin, R.J.46
(n=29) NS
NS
ANC
RTC
Worel, N.28
(n=50) NS
NS
NS
ANC
PLT
RTC
ABO-
bidirectional
Benjamin, R.J.46
(n=16) <.05 RTC Benjamin, R.J.46
(n=16) NS ANC
Kimura, F.36
(n=143) .22
.42
.781
ANC
PLT
RTC
as described in the study, ANC = absolute neutrophil count >0.5x10^9, PLT = platelet count >50x10^9, RTC = reticulocyte count >1%
Table 6.3 shows the overview of three42,44,45
studies reporting on a delayed engraftment
due to an ABO-mismatched peripheral stem cell transplant. Two studies44,45
show no significant
delay in engraftment. Only one study42
, with a low sample size (n=8), finds a significant delay in
PLT count reaching >50x10^9 in patients receiving an ABO-major mismatched PBSCT. This
same study finds no significant effect in patients reaching ANC>0.5x10^9.
Table 6.3
Summary of included studies reporting on the engraftment in patients receiving a peripheral stem cell transplant
criteria
Study P Engraftment
criteria
ABO-mismatch Guitierrez-Aguirre, C.H.44
(N=33) .73
.54
ANC
PLT
Kim, J.G.45
(N=40) NS ANC
PLT

19
NS
NS
RTC
ABO-major Canals, C.42
(n=8) <.01 PLT Canals, C.42
(n=8) .73
.36
ANC
RTC
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample of the study, NS = nonsignificant, P = p-value as
described in the study, ANC = absolute neutrophil count >0.5x10^9, PLT = platelet count >50x10^9, RTC = reticulocyte count >1%
As shown in Table 6.4 only one study41
reports on the effects of an ABO-mismatch in
CBTs. Their multivariate analysis showed a significant effect of an ABO-major mismatch on a
delayed PLT>50x10^9 with a sample size of 74 patients. For the univariate ABO-mismatch and
multivariate ABO-minor/bidirectional mismatch no significant delayed engraftment was reported.
Table 6.4
Summary of included studies reporting on the engraftment in patients receiving a cord blood transplant
criteria
Study P Engraftment
criteria
(N=136)
.73
.3
ANC
PLT
(n=74) .01 PLT Konuma, T.41
(n=74) .33 ANC
(n=58) .59
.64
ANC
PLT
ABO-
bidirectional
Konuma, T.41
(n=31) .8
.37
ANC
PLT
in the study, ANC = absolute neutrophil count >0.5x10^9, PLT = platelet count >50x10^9, RTC = reticulocyte count >1%
Overall, 11 studies report about the effect of an ABO-mismatched transplant on the rate
of success and delay of engraftment. This is measured by examining ANC, PLT and RTC. Ten
analyses, multivariate and univariate combined, report a significant effect, of which the majority
of studies find this in the ABO-major group with a negative effect on engraftment. The median
sample size of these analyses is 58.5 with a range of 8-2729. 20 analyses, multivariate and
univariate combined, report no significant effect of an ABO-mismatched transplant on a delayed
engraftment. The median sample size of these analyses is 41.5 with a range of 8-1202.
7. Transfusion requirements
Section 7 shows the overview of studies reporting on the effect of an ABO-mismatched
transplant on the transfusion requirements. The transfusion requirements are generally described
by the median number of red blood cell transfusion units needed and the median number of days
a patient would need a transfusion.
As shown in Table 7.1 there are 3 studies33-35
reporting on the transfusion requirements in
patients receiving HSCTs. Two studies33,35
report that there is no significant relation between an
ABO-mismatch and the number of units required. One of these studies33
also reports that the
amount of days needed is not affected by the ABO-compatibility. Both studies have a sample size

20
of 67 and 19 respectively. When multivariate analysis is performed a third study34
shows an
increase in both the amount of days and number of units required for ABO-major, minor and
bidirectional transplants. Another study33
only reports an increased number of units needed for
the ABO-major mismatched group while reporting no significant increase for the amount of days
in the ABO-major mismatched group. This study33
also reports no increase in the amount of days
and number of units required for both the ABO-minor and bidirectional group. The median
sample size of the studies reporting a significant result is 61.5 patients with a range of 20-102.
The median sample size of the studies reporting no significant results is 25 with a range of 12-67.
Table 7.1
Summary of included studies reporting on the transfusion requirements in patients receiving a hematopoietic stem cell transplant
Matching type Study P Units and/or days Study P Units and/or days
AB0-mismatch Ozkurt, Z.N.33
(N=67)
NS
NS
Units
Days
Worel, N.35
(N=19) NS Units
AB0-major Ozkurt, Z.N.33
(n=25) <.05 Units Ozkurt, Z.N.33
(n=25) NS Days
Wang, Z.34
(n=98) <.05
<.05
Units
Days
AB0-minor Wang, Z.34
(n=102) .0095
.026
Units
Days
Ozkurt, Z.N.33
(n=30) NS
NS
Units
Days
AB0-bidirectional Wang, Z.34
(n=20) <.05
<.05
Units
Days
Ozkurt, Z.N.33
(n=12) NS
NS
Units
Days
Note. N = total number patients in the sample of the study, n = number of patients in a subgroup of the sample under study, NS = nonsignificant, P = p-
value as described in the study, units = the units of transfusions required, days = the amount of days a transfusion is required
Table 7.2 shows the overview of four studies29,38,39,46
reporting on transfusion
requirements in patients receiving ABO-mismatched BMTs. One study29
reports an increased
required number of days for patients with an ABO-mismatched transplant. Two other studies38,39
report that there is no significant relation between an ABO-mismatch and the amount of days.
One of those studies38
also reports that the number of units needed is not affected by the ABO-
compatibility. Both studies have a sample size of 79 and 995 patients respectively. When
multivariate analysis is performed, the two studies39,46
show an increased amount of required
transfusion days in the ABO-major mismatched transplants. One of those studies46
also shows an
increased number of units required and also reports an increased amount of transfusion days and
number of units required in the ABO-bidirectional mismatched group. The median sample size of
the studies reporting a significant result is 238 patients with a range of 22-451. The median
sample size of the studies reporting no significant results is 114 patients with a range of 55-995.
Table 7.2
Summary of included studies reporting on the transfusion requirements in patients receiving a bone marrow transplant
AB0-mismatch Blin, N.29
(N=414) .001 Days Rozman, P.38
(N=79) .87
.49
Units
Days
Seebach, J.D.39
(N=995) NS Days

21
AB0-major Benjamin, R.J.46
(n=62) <.005
<.05
Units
Days
Seebach, J.D.39
(n=451) .001 Days
AB0-minor Benjamin, R.J.46
(n=55) NS
NS
Units
Days
Seebach, J.D.39
(n=430) NS Days
AB0-bidirectional Benjamin, R.J.46
(n=22) <.05
<.05
Units
Days
Seebach, J.D.39
(n=114) NS Days
as described in the study, units = the units of transfusions required, days = the amount of days a transfusion is required
As shown in Table 7.3 two42,45
studies report on transfusion requirements in patients receiving a
ABO-mismatched PBSCT. Both report no significant increase in either the number of units or
amount of days.
Table 7.3
Summary of included studies reporting on the transfusion requirements in patients receiving a peripheral stem cell transplant
AB0-mismatch Canals, C.42
(N=25) .16
.15
Units
Days
Kim. J.G.45
(N=40) NS Units
Note. N = total number patients in the sample of the study, NS = nonsignificant, P = p-value as described in the study, units = the units of transfusions
required, days = the amount of days a transfusion is required
There are no studies reporting on the transfusion requirements in patients receiving
CBTs.
Overall, nine studies report on the effect of an ABO-mismatched transplant on the
transfusion requirements. Eight analyses, multivariate and univariate combined, report a
significant increase in transfusion requirements, having a median sample size of 80 patients with
a range of 20-451. 12 analyses, multivariate and univariate combined, report no increase in
transfusion requirements due to an ABO-mismatched transplant, having a median sample size of
47.2 patients with a range of 12-995.
8. Pure Red Cell Aplasia
Only three studies33,42,45
actually report on PRCA. One study42
reports on 1 patient
developing PRCA 8 months after allogeneic PBSCT without giving further details. The second
study45
reports that no patients developed PRCA at all. There is only one study33
that reports a
significant increased risk of developing PRCA after receiving a major mismatched HSCT.
The reason for the low amount of evidence about the incidence of PRCA is likely due to
the fact that the prevalence of PRCA is low. A retrospective study47
shows that in a population of
596 major ABO-mismatched HSCTs 7,5% of the population developed PRCA. A second
retrospective study48
shows again that with a group of 707 patients undergoing major ABO-
mismatched HSCTs 11.7% developed PRCA. When we translate this to the sample sizes of the

22
studies included in this review, the amounts of major mismatched transplants could easily be too
low for PRCA to occur at all. The studies that do have a larger sample size unfortunately do not
report on the incidence of PRCA. Another reason for the low amount of evidence might be that
the search strategy is not directly focused on PRCA. Because of the low prevalence of PRCA it is
likely that studies focused their efforts on researching purely the relation between an ABO-major
mismatch and PRCA. This would leave these studies out of the selection process. To further
identify this relation a more focused review would be required.
DISCUSSION
At first sight, this systematic review of 22 studies on HSCT shows that the majority of
studies did not find a significant effect of an ABO-mismatched HSCT on the investigated
outcomes. However, there are also numerous studies that report a significant adverse effect of an
ABO-mismatched HSCT on certain outcomes. On the overall survival and the incidence of
aGVHD there are a few large scale studies that do report an adverse effect of an ABO-mismatch
while the majority (although generally smaller in size) report otherwise. Another outcome such as
the relapse rate is more uniform since only three studies report about an increased relapse rate due
to an ABO-mismatch as opposed to nine studies that report no relation between an ABO-
mismatched transplant and the rate of relapse.
The conflicting evidence makes this review not conclusive, specifically since the studies
that report no effect also tend to have smaller sample sizes. In fact, many of the individual studies
report that the number of patients available is problematic. However, the studies that did find a
significant effect, although a minority, all have a higher median sample size. Furthermore, these
studies consistently report a significant effect across all the outcomes except for relapse.
Because there has not been an active selection on the number of patients in both the
matched and the mismatched group, it is likely that there will be more AB0-matched than
mismatched transplants. This is simply due to the fact that when given a choice, an AB0-matched
transplant will always be preferential. As a result, the ABO-mismatched sample size will often be
significantly smaller than the initial sample size. Furthermore, the biomechanical differences
between the different types of mismatches require to individually analyze the impact of each
mismatch. This will cause the sample size to narrow down even further, with a bidirectional
mismatch becoming the smallest. All in all, the initial sample size needs to be substantial to have
sufficient data to analyses each type of mismatch individually. For example, Kimura, F.36
with an
initial sample size of 5,549 patients has 2,729 mismatched transplants, 1,384 major mismatches,
1,202 minor mismatches and only 143 bidirectional mismatches. In this particular case, the initial
sample size would be sufficient to still provide a large enough sample size to analyze each type of
mismatch. However, the initial sample size of most studies is only a fraction of this magnitude
(with extreme cases: Worel, N.35
(N=40 initial, 19 mismatches, 8 major, 9 minor and 2

23
bidirectional), Canals, C.42
(N=77 initial), Kim, J.G.45
(N=89 initial)), resulting in sample sizes of
the individual types of mismatches becoming far too small.
Another matter to discuss is the heterogeneity of the patient characteristics considered in
the studies included in this review. Because of limited knowledge on available evidence, the
inclusion and exclusion criteria were kept as broad as possible in combination with a more
specific search. This resulted in no patient-characteristic inclusion or exclusion criteria, except for
the fact that they must have had an HSCT. There are 5 major aspects that play a role in the
heterogeneity of the studies.
1. Disease: While the majority of the studies reported mostly on patients with hematologic
malignancies there were also numerous amounts of non-malignant and immunologic
diseases included. These all have a very different pathology which, in return, may affect
certain outcomes.
2. Stem cell source: Each stem cell source has different characteristics. Even though there
are only 3 different types, still not all studies report on all types of sources. This further
complicates comparing the results of these studies.
3. Handling of transplant material: Each hospital has their own transfusion protocol. The
way they prepare and handle the transplant material can vary greatly, among which
processing it or not (i.e. RBC- or plasma-depleted). This likely has an effect on the
severity of the complications and effects on an ABO-mismatched transplantation.
4. Transfusion policy: As with the transplant material, the transfusion policy varies due to
different hospital policies. Such policies differ in, among others: matching AB0-type,
pre- and post-transplant care, washed ABO compatible platelets, and red cells that did not
carry antigen or antibody incompatible with the recipient. This could have an effect on
transplant requirements and recovery.
5. Conditioning regimen: There are a lot of different commonly used conditioning
regimens used in pre-HSCT treatment. These can generally be divided into a
myeloablative regimen (further divided into a conventional, standard and intensified
regimen) and a reduced intensity regimen. Both of these regimens have different
influences on the outcome of an HSCT. An intensified regimen has a reduced relapse rate
but an increased TRM and OS while the RIC has a higher relapse rate and a lower TRM.
The large heterogeneity may explain the wide range of different results of the studies. It also
makes it difficult to compare the results and to come to a clear conclusion for a direction of future
research.
Strength and limitations
This study provides a concise analysis of a heterogeneous collection of research in the
last decades on HSCT. One of the goals was to assess the contradicting results to investigate the
directions of future research. The analysis has clearly shown that the status of the current research

24
is such that no conclusions can be drawn with respect to the significant effects of ABO-
mismatches. The main shortcoming being the initial and distributed sample size of the studies in
the light of the heterogeneity of the cases.
The main limitation of this study is that it was carried out by one person. Assessing the
relevance of studies and controlling for the reported data could benefit from a critical secondary
researcher. Furthermore, the study should be extended with a meta-analysis and more elaborate
data extraction, possibly including the data that was used by the considered studies. Within the
limitation of this study given the available resources, such a more elaborate study was not
feasible.
Future work
As mentioned, the heterogeneity and the low patient sample size is a major shortcoming
in the reliability of studies and could explain the many contradicting outcomes. In the case of
retrospective studies, which is the majority of the studies considered, it is not possible to apply a
power analysis to determine the required sample size. New research on possible ABO-mismatch
effects should therefore use sample sizes on the basis of a power analysis in relation to the
complexity and diversity of the treatment and the possible complications to be able to draw any
conclusions. To propose a solution to this, a meta-analysis of more studies would give much
greater insights in the actual effect of AB0-incompatible transplants, as this solves both the low
sample size and the heterogeneity.
Regardless of the majority of studies that have not been able to find a significant effect,
more recent and larger studies report a more unified effect of an ABO-mismatched transplant.
ABO-incompatibility could therefore be considered a prognostic risk factor in allogeneic HSCTs.
Efforts to reduce the transfusion of incompatible plasma are justified until a better understanding
of the mechanism of the adverse effect is attained.

25
REFERENCES
1 Gooley, T. A. et al. Reduced mortality after allogeneic hematopoietic-cell transplantation.
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28
APPENDIX A: In and Exclusion criteria
APPENDIX B: Literature search in PubMed
Inclusion criteria Exclusion criteria
Patients receiving allogeneic-HSCT Studies without an outcome as an endpoint
Stem cell source: bone marrow, cord blood, and
peripheral
Case-reports
Malignant and non-malignant disease Studies with an initial sample size of n<40
ABO-mismatch/match comparison
All study designs

THESIS SAM VOSSEN 6052401

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