ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation

Download as pdf or txt
Download as pdf or txt
You are on page 1of 10

Review Article

Transfus Med Hemother 2016;43:3–12 Received: March 16, 2015


DOI: 10.1159/000441507 Accepted: July 6, 2015
Published online: October 29, 2015

ABO-Mismatched Allogeneic Hematopoietic Stem Cell


Transplantation
Nina Worel

Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria

Keywords Introduction
ABO-incompatible · Hematopoietic stem cells ·
Transplantation Allogeneic hematopoietic stem cell transplantation (HSCT) is
widely used to treat patients with malignant and non-malignant
Summary hematological and congenital diseases [1]. A prerequisite for a suc-
Allogeneic hematopoietic stem cell transplantation cessful HSCT is the availability of a human leukocyte antigen
(HSCT) is a curative option for a variety of malignant and (HLA) identical stem cell donor, which is different to solid-organ
non-malignant hematological and congenital diseases. transplantation where ABO compatibility between the donor and
Due to the fact that the human leukocyte antigen system recipient is critical [2].
is inherited independently of the blood group system, Due to the fact that the HLA system is inherited independently
approximately 40–50% of all HSCTs are performed of the blood group system, approximately 40–50% of all HSCTs
across the ABO blood group barrier. The expected im- are performed across the ABO blood group barrier [3, 4]. Al-
mune-hematological consequences after transplantation though the transplantation of an ABO-mismatched graft is feasi-
of an ABO-mismatched stem cell graft are immediate ble immune-hematological problems have to be considered, and
and delayed hemolytic complications due to presence of special precautions should be taken in order to allow a safe HSCT.
isohemagglutinins or passenger lymphocyte syndrome. The clinical impact of ABO-disparate transplantations in terms of
The risks of these complications can partially be pre- neutrophil or platelet engraftment, incidence of acute and chronic
vented by graft manipulation and appropriate transfu- graft-versus-host disease (GVHD), non-relapse mortality (NRM),
sion support. Dependent on the kind of ABO mismatch, disease-free survival and overall survival is uncertain [4–8]. More-
different effects on engraftment have been observed, over, besides bone marrow (BM) grafts which have been used
e.g. delayed red blood cell recovery and pure red cell since more than two decades other hematopoietic stem cell
aplasia. Data on incidence of acute graft-versus-host dis- sources like peripheral blood stem cells (PBSC) and cord blood
ease (GVHD), non-relapse mortality, relapse, and overall (CB) are currently available [9, 10] and non-myeloablative (NMA)
survival are inconsistent as most studies include limited or reduced-intensity conditioning (RIC) regimens have been in-
patient numbers, various graft sources, and different troduced for stem cell transplantation [11]. ABO-mismatched
conditioning and GVHD prophylaxis regimens. This transplantation may have different effects if G-CSF-primed PBSC
makes it difficult to detect a consistent effect of ABO- or CB grafts or new conditioning regimens are used [11]. Besides
mismatched transplantation in the literature. However, the ABO blood group system, Rhesus (Rh) antigens, especially
knowledge of expectable complications and close moni- the D antigen, are clinically the most significant factors for allo-
toring of patients helps to detect problems early and to immunization that usually occur after exposure of RhD-negative
treat patients efficiently, thus reducing the number of individuals to RhD-positive blood components [12]. Studies in
fatal or life-threatening events caused by ABO-mis- HSCT recipients have shown an incidence of 10% of anti-D allo-
matched HSCT. immunization in RhD-positive patients with a RhD-negative
© 2015 S. Karger GmbH, Freiburg donor [13, 14].

© 2016 S. Karger GmbH, Freiburg Prof. Dr. Nina Worel


1660–3796/16/0431–0003$39.50/0 Department of Blood Group Serology and Transfusion Medicine
Fax +49 761 4 52 07 14 Medical University of Vienna
[email protected] Accessible online at: Währinger Gürtel 18–20, 1090 Vienna, Austria
www.karger.com www.karger.com/tmh [email protected]
Table 1. Standard
ABO mismatch PBSC/BM graft manipulation Therapeutic apheresis
procedures for ABO-
mismatched trans- Major PBSC: plasma exchange with AB plasma or
plants Recipient anti-donor <20 ml RBC: no manipulation; albumin/sodium [26]
isohemagglutinins ≥20 ml RBC: RBC depletion
≥1:32 BM:
RBC depletion

Major PBSC: plasma exchange with AB plasma or


Recipient anti-donor no manipulation albumin/sodium
isohemagglutinins BM:
≤1:16 infusion without modification possible [11];
to be on the safe side: RBC depletion

Minor PBSC + BM: experimental: RBC exchange with group O


Donor anti-recipient plasma depletion RBCs [17]
isohemagglutinins
≥1:256

Minor PBSC: experimental: RBC exchange with group O


Donor anti-recipient no manipulation RBCs [17]
isohemagglutinins BM:
≤1:128 infusion without modification possible [11];
to be on the safe side: plasma depletion

Bi-directional RBC depletion and plasma depletion (when


anti-recipient isohemagglutinins are >1:128)

Definition of ABO Mismatch content of RBCs (approximately 8–15 ml) and plasma (approxi-
mately 200–500 ml) in PBSC grafts, it is usually not necessary to
Three groups of ABO mismatch can be defined. Minor ABO mis- manipulate these products in case of ABO mismatch (table 1) [3].
match (20–25% of transplants) is characterized by the ability of With the introduction of RIC regimens an increased incidence
donor B lymphocytes to produce anti-recipient antibodies (e.g. group of severe delayed immune hemolysis in minor ABO-mismatched
O donor to a group A recipient). In major ABO mismatch cases (20– HSCT (up to 30%) has been observed, which typically presents 7–14
25% of transplants) anti-donor ABO antibodies are present in the days after transplantation [5, 8, 18]. The reason for this complica-
recipient (e.g. group A donor to a group O recipient). Bi-directional tion is thought to be on the one hand a higher amount of remaining
ABO mismatch (up to 5% of transplants) occurs if both donor and recipient RBCs due to the reduced dose of chemo-/radiotherapy
recipient have antibodies directed against ABO blood group antigens and the enhanced isohemagglutinin production by donor B lym-
of each other (e.g. group A donor to a group B recipient). phocytes (passenger lymphocyte syndrome), especially if PBSC
grafts are used. In addition, the post-grafting immunosuppression
which comprises of a calcineurin inhibitor (CNI) and an antime-
Immune-Hematologic Consequences of ABO- tabolite is different after RIC compared to myeloablative regimens.
Mismatched HSCT The majority of GVHD protocols for myeloablative transplant con-
sist of CNI and methotrexate (MTX), whereas in RIC protocols
Immediate and Delayed Hemolysis CNI and mycophenolate mofetil (MMF) are used. Antimetabolites
Due to the immunological incompatibility between donor and like MTX or MMF inhibit proliferation of T and B lymphocytes and
recipient, hemolytic transfusion reactions can appear. According to also antibody production. In contrast to MTX, the circulating half-
the time of occurrence a distinction can be made between immedi- life of MMF is only 3.6 h, and the bond to inosine monophosphate
ate (during graft infusion) and delayed (during engraftment) im- dehydrogenase is rapidly reversible. This may permit antigen-
mune hemolysis. Immediate hemolysis is commonly seen when primed B cells to escape T-cell control and to produce high num-
bone marrow grafts are used as they contain more red blood cells bers of anti-recipient RBC antibodies leading to immune hemolytic
(RBCs; approximately 200–450 ml) and plasma (up to 1,000 ml or complications especially in the RIC setting [17]. Laboratory signs of
more) compared to PBSC grafts [3]. Therefore, in ABO-mis- intravascular hemolysis (e.g. drop in hematocrit and haptoglobin;
matched bone marrow transplant (BMT) it is clinical routine either elevated levels of free hemoglobin and lactate dehydrogenase)
to remove isohemagglutinins (in case of minor ABO mismatch) or should be monitored in patients at risk, and patients should be
incompatible RBCs (in case of major ABO mismatch) from the screened for occurrence of anti-recipient RBC antibodies. In most
graft or to reduce anti-donor RBC antibodies or residual RBCs in cases, laboratory test results on a direct antiglobulin test will remain
the recipient by various techniques (table 1) [15–17]. Due to a lesser positive unless all antibody-bound RBCs have been lysed [8, 19].

4 Transfus Med Hemother 2016;43:3–12 Worel


Rhesus Mismatch mismatch with regard to leukocyte and platelet recovery has been
Besides immunological reactions due to an ABO mismatch in found [33, 34]. Although registry studies of the Japan Marrow
rare cases, a de novo anti-D immunization can occur. In case of a Donor Program (JMDP; 5,549 patients included) and the Société
RhD-positive patient receiving a RhD-negative graft, donor lym- Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-
phocytes are exposed to antigen-bearing recipient RBCs possibly TC; 1,108 patients included) found a correlation of slower neutro-
leading to de novo D immunization in the post-transplantation pe- phil engraftment with major ABO mismatch, a study of the Na-
riod. The development of anti-D normally does not impair the tional Marrow Donor Program (NMDP; 6,978 patients included)
transplant outcome and is not of clinical relevance in the post- could not observe any difference in engraftment with respect to
transplant course of adults. Since RIC has also been demonstrated a ABO match [6, 35, 36] (table 2).
feasible and safe procedure in children, the development of D anti- In terms of platelet engraftment a meta-analysis of 7 cohort
bodies after D-mismatched HSCT may become of clinical impor- studies, the report for the JMDP, and other studies showed a delay
tance in the childbearing age of these individuals [20]. So far, data in recovery for recipients of major ABO-incompatible grafts [6, 37,
on the risk of de novo D immunization after RIC HSCT in children 38]. This phenomenon has previously been reported by other au-
and adolescents are lacking. Thus, antibody screening in young pa- thors to be limited to major ABO-incompatible transplantation,
tients after HSCT seems advisable to avoid complications during who speculated that anti-donor isohemagglutinins bind to A or B
pregnancy. If signs of extravascular hemolysis occur in the post- antigens absorbed on the surface of neutrophils, platelets, or their
transplant course after D-mismatched HSCT, one should consider precursors [32].
de novo D immunization and apply supportive care accordingly.

Pure Red Cell Aplasia Graft Failure


Pure red cell aplasia (PRCA) is a complication after major ABO-
mismatched HSCT and occurs in up to 29% of patients with a Remberger et al. [39] observed an increased risk of graft failure
major ABO-mismatched donor [21, 22]. It is more frequently ob- after major ABO-mismatched transplantation (7.5 vs. 0.6%) in an
served in the constellation of group A donors in group O recipients analysis of 224 patients. In this study, 6 patients with graft failure
and results from the presence of recipient-derived residual B lym- were detected, including 4 of 67 major ABO mismatch and 2 of 16
phocytes or plasma cells which produce isohemagglutinins di- bi-directional ABO mismatch cases. However, in this analysis,
rected against donor RBCs. The risk of PRCA increases with the HLA-A, HLA-B, HLA-DR allele level mismatch was also a factor
use of RIC [22], sibling donors [23], and presence of high anti-A significantly associated with graft failure. Five of 6 patients with
isohemagglutinins [24, 25]. Pre-transplant reduction of host anti- graft failure had at least one HLA allele-mismatched donor, mak-
donor isohemagglutinins either by plasma exchange or immu- ing it difficult to precisely ascribe the definitive role of ABO mis-
noadsorption, or application of donor type packed RBCs, is re- match in this setting. In the report of the JMDP an increased risk
ported to reduce the risk of PRCA [16, 26]. Since the incidence of for secondary graft failure was observed in univariate analysis for
PRCA is relatively low and spontaneous remissions are observed in patients receiving any kind of ABO-mismatched graft but these
a number of patients, a post-transplant prophylactic treatment of findings could not be confirmed in multivariate analysis [6]. In
all major ABO-mismatched allogeneic HSCT recipients is not rec- contrast to the results above, other studies have not found a higher
ommended [27]. If anti-donor isohemagglutinins persist for more risk of secondary graft failure in combination with ABO-mis-
than 60 days after HSCT, the probability of spontaneous clearance matched transplantation, leading to the assumption that additional
is low. In such cases various treatment modalities to remove per- factors may have an influence on sustained engraftment [40–42].
sisting isohemagglutinins have been described [28]. Those may in-
clude erythropoietin [29], plasma exchange or immunoadsorption
[21], taper of immunosuppressive drugs, or administration of Graft-versus-Host Disease
donor leukocyte infusions (DLI) [22, 30]. In addition, the use of
rituximab, a monoclonal antibody directed against CD20-positive As ABO antigens are not only expressed on blood cells but also
B cells, has been shown to be effective in some case reports [31]. on non-hematopoietic structures and tissue (e.g. endothelial and
epithelial cells, von Willebrand factor) donor ABO-type isohemag-
glutinins can also bind to those host cells, and some authors raise
Engraftment the question whether ABO antigens and isohemagglutinins are also
involved in the pathogenesis of GVHD [7]. However, results of
Several registry and cohort studies demonstrate that the pres- published studies are conflicting (table 2).
ence of anti-donor isohemagglutinins (e.g. in major ABO mis- Kimura et al. [6] reported a higher incidence of acute GVHD
match) can delay RBC recovery and increase post-transplant RBC grade III–IV in both the major and minor ABO mismatch but not
transfusion requirements [6, 21, 23, 32]. in the bi-directional ABO-incompatible group. Interestingly, the in-
Despite it is known that ABO blood group antigens are also ex- cidence of liver GVHD was higher in minor ABO-mismatched
pressed on lymphocytes and platelets, no clear influence of ABO transplantation. Their hypothesis is that epithelial cells of the large

ABO-Mismatched Allogeneic Hematopoietic Transfus Med Hemother 2016;43:3–12 5


Stem Cell Transplantation
6
Table 2. Studies focusing on clinical outcomes after ABO-mismatched stem cell transplantationa,b

Author ABO match (N) Donor Conditioning regimen Graft Engraftment Acute GVHD Chronic Relapse NRM OS
Identical GVHD prophylaxis source ANC Grade II–IV GVHD
Minor
Major Platelets Grade III+IV
Bi-directional

Bacigalupo 124 RD MA BM no data 0.003 (higher no data no data no data no data


et al. [43] 27 minor)
23 CNI or MTX or CNI + no data
excluded MoAb no data

Benjamin 153 RD, URD MA BM NS no data no data no data no data 0.003 (lower major)
et al. [50] 55 0.05 (lower minor)
62 CNI + MTX ± steroids NS no data (AML only)
22

Blin et al. [52] 395 RD, URD MA + RIC BM NS 0.05 PBSC NS NS No data NS
0 PBSC only
337 CNI+MTX or MMF cord blood NS no data

Transfus Med Hemother 2016;43:3–12


77

Canals et al. [37] 52 RD RIC PBSC NS NS NS NS NS NS


15
8 CNI + MTX 0.005 (major slower) NS
2

Erker et al. [48] 79 RD, URD MA + RIC BM NS NS NS 0.002 (higher no data 0.006 (higher minor/
32 PBSC minor/bid) bid)
21 CNI+MTX NS NS
11

Gutiérrez-Aguirre 88 RD RIC PBSC NS NS (higher NS no data NS NS


et al. [46] 20 minor)
13 CNI + MTX NS

Worel
0 NS

Kanda et al. [38] 697 RD, URD MA + RIC BM RD: NS no data no data no data GVHD-related RD: NS
Meta-analysis 228 PBSC URD: 0.01 (minor 0.001
202 CNI + others slower) 0.012 (higher bid) URD:
81 (bid slower) lower minor/bid

Keever-Taylor 266 RD, URD MA BM no data 0.001 (higher NS no data no data NS


et al. [44] 96 minor)
90 CNI + MP ± ATG no data
29 no data

Table 2. continued on next page


Table 2. Continued

Author ABO match (N) Donor Conditioning regimen Graft Engraftment Acute GVHD Chronic Relapse NRM OS
Identical GVHD prophylaxis source ANC Grade II–IV GVHD
Minor
Major Platelets Grade III+IV

Stem Cell Transplantation


Bi-directional

Kim et al. [41] 49 RD MA + RIC PBSC NS NS NS NS NS NS


15
20 CNI ± MTX or MMF NS no data
5

ABO-Mismatched Allogeneic Hematopoietic


Kimura et al. [6] 2,820 URD MA + RIC BM 0.004 (major slower) no data no data no data 0.0001 (major 0.016 (major lower)
Registry study 1,202 higher)
JMDP 1,384 CNI + MTX 0.001 (major slower) 0.001 (major or 0.009 (minor
143 minor higher) higher)

Kollman et al. [35] 2,860 URD MA + RIC BM NS no data NS NS NS NS


Registry study 1,802
NMDP 1,670 various no data NS
587

Mehta et al. [47] 76 RD MA BM no data NS NS 0.039 0.048 (lower 0.004 (higher


27 minor/bid (lower ABO-mm) ABO-mm) ABO-mm)
16 major CNI ± MTX no data no data no data

Michallet et al. [36] 716 RD, URD RIC BM no data NS NS no data 0.01 (minor 0.001 (lower
Registry study 205 Cord blood higher) minor vs. id)
(SFGM-TC) 187 CNI ± MTX/MMF + PBSC no data no data NS for major
not stated other agents NS for major

Mielcarek et al.[23] 960 RD, URD MA BM NS NS no data no data no data NS


299
314 CNI + MTX NS no data

Transfus Med Hemother 2016;43:3–12


103

Ozkurt et al. [53] 80 RD, URD MA + RIC BM NS NS NS NS 0.01 (higher 0.02 (lower minor)
30 PBSC minor)
25 NS 0.04 (higher
12 minor)

Resnick et al. [49] 127 RD, URD RIC BM NS NS NS NS 0.045 (minor NS


38 PBSC higher)
56 major/bid CNI NS NS 0.023 (major
higher)

7
Table 2. continued on next page
8
Table 2. Continued

Author ABO match (N) Donor Conditioning regimen Graft Engraftment Acute GVHD Chronic Relapse NRM OS
Identical GVHD prophylaxis source ANC Grade II–IV GVHD
Minor
Major Platelets Grade III+IV
Bi-directional

Seebach et al. [32] 2,108 RD MA BM 0.001 (major slower) NS NS NS NS NS


Registry study 451
(CIBMTR) 430 CNI + MTX no data 0.006 (bid only)

Transfus Med Hemother 2016;43:3–12


114

Stussi et al. [7] 361 RD, URD MA + RIC BM NS NS no data NS no data 0.0009 (lower bid)
98 PBSC NS (major or minor)
86 NS no data
17

Worel et al. [42] 21 RD, URD RIC PBSC NS NS NS 0.056 (lower for 0.05 (higher for NS
9 ABO-mm) ABO-mm)
8 CNI + MMF NS no data
2

ABO-mm = ABO-mismatched; AML = acute myelogenous leukemia; ANC = absolute neutrophil cells; ATG = antithymocyte globulin; bid = bidirectional; BM = bone marrow; CIBMTR = Center of International
Blood and Marrow Transplant Research; CNI = calcineurin inhibitors; id = identical; JMDP= Japan Marrow Donor Program; MA = myeloablative; MMF = mycophenolate mofetil; MoAB = monoclonal antibodies;
MP = methylprednisolone; MTX = methotrexate; N = number; NMDP = National Marrow Donor Program; NRM = non relapse mortality; NS = not significant; OS = overall survival; PBSC = peripheral blood stem cells;

Worel
RD = related donor; RIC = reduced intensity conditioning; SFGM-TC = Société Francaise de Greffe de Moelle et Thérapie Cellulaire; URD = unrelated donor.
aAdapted from Rowley et al. [11].
bP value is given where a significant correlation was found.
bile tract expressing ABO blood group antigens may be injured by findings compared to myeloablative treatment protocols [11, 42]
donor-derived isohemagglutinins, thereby possibly increasing the (table 2).
incidence and severity of liver GVHD. On the contrary Seebach et
al. [32] observed severe acute GVHD (grade III–IV) of the liver lim-
ited to recipients of bi-directional ABO-incompatible grafts. In a Non-Relapse Mortality
study of Bacigalupo et al. [43], 174 patients receiving an HLA-iden-
tical allogeneic BMT were analyzed for factors associated with acute As already discussed, the transplantation of ABO-mismatched
GVHD. In this study, minor ABO mismatch was associated with a grafts can cause severe immediate or delayed immune hemolytic
significantly higher risk of severe acute GVHD when compared reactions, leading to the death of the patient in the worst case. Be-
with ABO-matched and major ABO-mismatched pairs. Besides the sides this complication which can be avoided by prophylactic ac-
ABO match, donors of group O, older recipients, rapid engraft- tions in nearly all cases, no other consistent effect on transplant-
ment, and older donors were also associated with a higher risk of related mortality has been found (table 2). After the introduction
GVHD. The cumulative incidence of GVHD ˰ grade II was 39% for of RIC regimens, some authors found an increased mortality for
ABO-matched, 54% for major ABO-mismatched, and 82% for patients receiving ABO-mismatched grafts [6, 36, 42, 49]. One pos-
minor ABO-mismatched pairs. Keever-Taylor et al. [44] analyzed sible reason is that myeloablative conditioning could obscure such
risk factors for the development of GVHD in 481 recipients of T- an effect due to the higher toxicity [11]. However, results of cohort
cell-depleted marrow allografts. The results showed an increased and registry studies are conflicting. Two registry studies found a
relative risk of acute GVHD for patients with a ˰ 2 HLA antigen- higher risk for NRM in the RIC cohort, one of those also for major
mismatched donor and for recipients of minor but not of major or ABO-mismatched cases if myeloablative conditioning was applied
bi-directional ABO-mismatched grafts compared to ABO-identical [6, 36], whereas some cohort studies observed an increased risk for
pairs. Ludajic et al. [45] observed that a minor ABO-mismatch rep- patients after minor, major or bi-directional ABO-mismatched
resents a significant risk factor for acute GVHD (grade II–IV) with transplants [4, 8, 46] (table 2).
an estimated risk increase of almost 3-fold, and even 4-fold for se-
vere acute GVHD (grade III–IV). Recently, Gutiérrez-Aguirre et al.
[46] analyzed a cohort of patients exclusively receiving RIC and Overall Survival
found the highest rate of acute GVHD in minor ABO-mismatched
transplant recipients (25%) compared with ABO-identical (20.5%) As overall survival reflects the observations for non-relapse mor-
and major ABO-mismatched cases (15.4%). Other publications did tality especially in the early post-transplantation period, it is not
not observe any influence of ABO mismatch on the incidence of amazing that some authors found ABO mismatch as a cause for de-
clinically significant acute GVHD [8, 23, 37]. creased survival rates. Kimura et al. [6] observed a shorter overall
All but one of the studies reporting on the incidence of GVHD survival for patients receiving a major ABO-mismatched graft com-
showed no influence of ABO-mismatched transplantation on de- pared to minor or bi-directional ABO-mismatched transplantation,
velopment or severity of chronic GVHD. Gutiérrez-Aguirre et al. whereas Michallet et al. [36] found a lower survival rate for minor
[46] observed a higher incidence of chronic GVHD in the context ABO-mismatched versus ABO-matched cases. Besides these large
of minor ABO mismatch (35%), in contrast to ABO-identical registry reports, various cohort studies including lower numbers of
(30.8%) and major ABO-mismatched transplants. patients reported on conflicting results. The majority of authors did
not observe an influence of ABO mismatch on survival. Benjamin et
al. [50] revealed a significantly decreased survival in ABO-mis-
Risk of Relapse matched BM graft recipients in the first 100 days after transplanta-
tion. Multivariate analyses showed that the effect was significant for
None of the four large register studies which included RIC cases both minor and major ABO mismatches only in patients with acute
reported an effect of ABO mismatch on risk of malignant disease myelogenous leukemia and myelodysplastic syndrome. Stussi et al.
relapse [6, 32, 35, 36]. In two of these studies data regarding relapse [7] showed a lower overall survival only for bi-directional ABO-
were even not reported as did most of the cohort studies (table 2). mismatched cases. In contrast, Mehta et al. [47] found that ABO-
Three studies showed an influence but with conflicting results. mismatch was associated with superior overall and disease-free
Mehta et al. [47] found that donor-recipient ABO match in his pa- survival as did Erker et al. [48] for patients receiving minor and
tient cohort of myeloablatively treated patients was the only factor bi-directional ABO-mismatched grafts (table 2).
independently associated with a higher risk of relapse as it was
found in the study of Worel et al. [42]. The latter study included
only RIC cases. In contrast Erker et al. [48] who analyzed myeloab- Standard Procedures and Transfusion Strategy for
lative and RIC cases showed that the risk for relapse was higher in ABO-Mismatched HSCT
minor and bi-directional ABO-mismatched cases.
Some authors assume that by using RIC regimens, any graft- To avoid immediate or delayed complications of ABO-mis-
versus-tumor effect may be more evident, resulting in different matched stem cell grafts several manipulation steps have been de-

ABO-Mismatched Allogeneic Hematopoietic Transfus Med Hemother 2016;43:3–12 9


Stem Cell Transplantation
Table 3. Transfusion
ABO mismatch Recipient Donor RBC support from start of Plateletsb and plasma
strategy
conditioning regimen

Major O A Oa A, AB
O B Oa B, AB
O AB Oa AB
A AB A, Oa AB
B AB B, Oa AB

Minor A O O A, AB
B O O B, AB
AB O O AB
AB A A, O AB
AB B B, O AB

Bi-directional A B Oa AB
B A Oa AB

Rhesus D mismatch Recipient Donor RBC and platelet support from RBC and platelet
start of conditioning regimen support after HSCT

Rh D positive negative positive negative


negative positive negative positive
a
Group O RBC until anti-donor isohemagglutinins are undetectable, additionally RBCs of donor type blood group should be present
while signs of relapse or graft failure are absent, then switch to donor blood group.
b
First choice for platelet support given. Platelets stored in additive solution reduce the volume of incompatible plasma.
Otherwise ABO-incompatible platelet components should be plasma reduced.

scribed. It is either possible to remove incompatible cells or isohem- velopment of acute GVHD, risk for relapse, NRM, and overall sur-
agglutinins from the graft by various techniques or to remove or vival. However, outcome of patients after ABO-mismatched HSCT
adsorb incompatible cells or isohemagglutinins from the recipient reported in the literature are not consistent, and several other fac-
by apheresis devices [3, 15–17] (table 1). tors, e.g. kind of conditioning regimen, donor and graft source and
The transfusion strategy in ABO-mismatched cases must consider GVHD prophylaxis, have to be taken into account to be able to
both the blood group systems of the recipient and the donor [11, 19]. compare the studies properly. Recently, major ABO mismatch in
In case of major or bi-directional ABO-mismatched transplants, CB transplantations has been described to be associated with de-
transfusions of blood group O RBCs and blood group AB platelets or creased survival and disease free survival rates and higher trans-
plasma are necessary. The decision when to switch to donor type plant-related mortality in adults with hematological malignancies.
blood group varies from center to center. We would recommend Therefore when several CB units are available, the use of a unit that
transfusing blood group O RBCs until anti-donor isohemagglutinins is ABO-identical or with minor ABO mismatch should be taken
are undetectable in two consecutive blood samples of the recipient; into consideration [51].
additionally, RBCs of donor type blood group should be present To implement standard procedures and transfusion strategy for
while signs of relapse or graft failure are absent (table  3). As ABO ABO-mismatched transplants, besides conditioning regimen,
blood group antigens are also expressed on the surface of platelets, donor and graft source, also the availability of different technolo-
not only the blood group of the product which is considered to be gies (graft manipulation, apheresis techniques) and the compe-
transfused but also the natural blood group antibodies of the recipi- tence of the staff should be considered before a decision is made.
ent and stem cell donor have to be taken into account. Especially in Despite advances in knowledge, development of new technolo-
group O patients with high anti-A isohemagglutinins, platelets of gies, and closed monitoring of patients at risk, complications after
group A1 donors should be avoided. If platelet components stored in ABO-mismatched stem cell transplantation may still occur. But
additive solution are used, the remaining donor plasma concentra- knowledge of these complications and close monitoring of patients
tion is only 35%. Therefore, transfusion of minor ABO-mismatched can help to detect problems early and to treat the patient efficiently,
platelets can be performed without further plasma removal [19]. thus reducing the number of fatal or life-threatening events.

Conclusion Disclosure Statement

The author declares no conflict of interest.


ABO-mismatched HSCT has specific effects on transplant-asso-
ciated morbidity, mostly due to immune hematologic events, de-

10 Transfus Med Hemother 2016;43:3–12 Worel


References
1 Passweg JR, Baldomero H, Bregni M, Cesaro S, Dreger 15 Larghero J, Rea D, Esperou H, Biscay N, Maurer MN, 27 Benjamin RJ, Connors JM, McGurk S, Churchill WH,
P, Duarte RF, Falkenburg JH, Kroger N, Farge-Bancel Lacassagne MN, Ternaux B, Traineau R, Yakouben K, Antin JH: Prolonged erythroid aplasia after major
D, Gaspar HB, Marsh J, Mohty M, Peters C, Sureda A, Dosquet C, Socie G, Gluckman E, Benbunan M, ABO-mismatched transplantation for chronic myelog-
Velardi A, Ruiz de Elvira C, Madrigal A; European Marolleau JP: ABO-mismatched marrow processing enous leukemia. Biol Blood Marrow Transplant 1998;
Group for Bone Marrow Transplantation: Hematopoi- for transplantation: results of 114 procedures and anal- 4: 151–156.
etic SCT in Europe: data and trends in 2011. Bone ysis of immediate adverse events and hematopoietic 28 Helbig G, Stella-Holowiecka B, Wojnar J, Krawczyk M,
Marrow Transplant 2013; 48: 1161–1167. recovery. Transfusion 2006; 46: 398–402. Krzemien S, Wojciechowska-Sadus M, Markiewicz M,
2 Rydberg L: ABO-incompatibility in solid organ trans- 16 Nussbaumer W, Schwaighofer H, Gratwohl A, Kilga S, Wylezol I, Kopera M, Holowiecki J: Pure red-cell apla-
plantation. Transfus Med 2001; 11: 325–342. Schonitzer D, Nachbaur D, Niederwieser D: Trans- sia following major and bi-directional ABO-incompat-
3 Rowley SD: Hematopoietic stem cell transplantation fusion of donor-type red cells as a single preparative ible allogeneic stem-cell transplantation: recovery of
between red cell incompatible donor-recipient pairs. treatment for bone marrow transplants with major donor-derived erythropoiesis after long-term treat-
Bone Marrow Transplant 2001; 28: 315–321. ABO incompatibility. Transfusion 1995; 35: 592–595. ment using different therapeutic strategies. Ann He-
4 Worel N, Kalhs P: AB0-incompatible allogeneic he- 17 Worel N, Greinix HT, Supper V, Leitner G, Mitter- matol 2007; 86: 677–683.
matopoietic stem cell transplantation. Haematologica bauer M, Rabitsch W, Fischer G, Rosenmayr A, 29 Santamaria A, Sureda A, Martino R, Domingo-Albos A,
2008; 93: 1605–1607. Hocker P, Kalhs P: Prophylactic red blood cell ex- Muniz-Diaz E, Brunet S: Successful treatment of pure
5 Bolan CD, Childs RW, Procter JL, Barrett AJ, Leitman change for prevention of severe immune hemolysis in red cell aplasia after major ABO-incompatible T cell-
SF: Massive immune haemolysis after allogeneic pe- minor ABO-mismatched allogeneic peripheral blood depleted bone marrow transplantation with erythropoi-
ripheral blood stem cell transplantation with minor progenitor cell transplantation after reduced-intensity etin. Bone Marrow Transplant 1997; 20: 1105–1107.
ABO incompatibility. Br J Haematol 2001;112:787–795. conditioning. Transfusion 2007; 47: 1494–1502. 30 Verholen F, Stalder M, Helg C, Chalandon Y: Resistant
6 Kimura F, Sato K, Kobayashi S, Ikeda T, Sao H, Oka- 18 Bornhauser M, Ordemann R, Paaz U, Schuler U, pure red cell aplasia after allogeneic stem cell trans-
moto S, Miyamura K, Mori S, Akiyama H, Hirokawa Kompf J, Holig K, Ehninger G: Rapid engraftment plantation with major ABO mismatch treated by esca-
M, Ohto H, Ashida H, Motoyoshi K, Japan Marrow after allogeneic ABO-incompatible peripheral blood lating dose donor leukocyte infusion. Eur J Haematol
Donor P: Impact of AB0-blood group incompatibility progenitor cell transplantation complicated by severe 2004; 73: 441–446.
on the outcome of recipients of bone marrow trans- hemolysis. Bone Marrow Transplant 1997; 19: 295–297. 31 Helbig G, Stella-Holowiecka B, Krawczyk-Kulis M,
plants from unrelated donors in the Japan Marrow 19 Cohn CS: Transfusion support issues in hematopoietic Wojnar J, Markiewicz M, Wojciechowska-Sadus M,
Donor Program. Haematologica 2008; 93: 1686–1693. stem cell transplantation. Cancer Control 2015; 22: 52– Kopera M, Kruzel T, Najda J, Nowak K, Holowiecki J:
7 Stussi G, Muntwyler J, Passweg JR, Seebach L, Schanz 59. Successful treatment of pure red cell aplasia with re-
U, Gmur J, Gratwohl A, Seebach JD: Consequences of 20 Pulsipher MA, Boucher KM, Wall D, Frangoul H, peated, low doses of rituximab in two patients after
ABO incompatibility in allogeneic hematopoietic stem Duval M, Goyal RK, Shaw PJ, Haight AE, Grimley M, ABO-incompatible allogeneic haematopoietic stem cell
cell transplantation. Bone Marrow Transplant 2002; 30: Grupp SA, Kletzel M, Kadota R: Reduced-intensity al- transplantation for acute myeloid leukaemia. Haema-
87–93. logeneic transplantation in pediatric patients ineligible tologica 2005; 90(suppl):ECR33.
8 Worel N, Greinix HT, Keil F, Mitterbauer M, Lechner K, for myeloablative therapy: results of the Pediatric 32 Seebach JD, Stussi G, Passweg JR, Loberiza FR, Gajew-
Fischer G, Mayr W, Hocker P, Kalhs P: Severe immune Blood and Marrow Transplant Consortium Study ski JL, Keating A, Goerner M, Rowlings PA, Tiberghien
hemolysis after minor ABO-mismatched allogeneic pe- ONC0313. Blood 2009; 114: 1429–1436. P, Elfenbein GJ, Gale RP, van Rood JJ, Reddy V, Gluck-
ripheral blood progenitor cell transplantation occurs 21 Worel N, Greinix HT, Schneider B, Kurz M, Rabitsch man E, Bolwell BJ, Klumpp TR, Horowitz MM,
more frequently after nonmyeloablative than myeloabla- W, Knobl P, Reiter E, Derfler K, Fischer G, Hinter- Ringden O, Barrett AJ; GVHD Working Committee of
tive conditioning. Transfusion 2002; 42: 1293–1301. berger W, Hocker P, Kalhs P: Regeneration of erythro- Center for International Blood and Marrow Transplant
9 Baldomero H, Gratwohl M, Gratwohl A, Tichelli A, poiesis after related- and unrelated-donor BMT or pe- Research: ABO blood group barrier in allogeneic bone
Niederwieser D, Madrigal A, Frauendorfer K; Euro- ripheral blood HPC transplantation: a major ABO mis- marrow transplantation revisited. Biol Blood Marrow
pean Group for Bone Marrow Transplantation EBMT: match means problems. Transfusion 2000; 40: 543–550. Transplant 2005; 11: 1006–1013.
The ebmt activity survey 2009:Trends over the past 5 22 Bolan CD, Leitman SF, Griffith LM, Wesley RA, 33 Dunstan RA: Status of major red cell blood group anti-
years. Bone Marrow Transplant 2011; 46: 485–501. Procter JL, Stroncek DF, Barrett AJ, Childs RW: De- gens on neutrophils, lymphocytes and monocytes. Br J
10 Gratwohl A, Baldomero H, Aljurf M, Pasquini MC, layed donor red cell chimerism and pure red cell apla- Haematol 1986; 62: 301–309.
Bouzas LF, Yoshimi A, Szer J, Lipton J, Schwendener sia following major ABO-incompatible nonmyeloabla- 34 Cooling LLW, Kelly K, Barton J, Hwang D, Koerner
A, Gratwohl M, Frauendorfer K, Niederwieser D, tive hematopoietic stem cell transplantation. Blood TAW, Olson JD: Determinants of ABH expression on
Horowitz M, Kodera Y, Worldwide Network of Bone 2001; 98: 1687–1694. human blood platelets. Blood 2005; 105: 3356–3364.
Marrow Transplantation: Hematopoietic stem cell 23 Mielcarek M, Leisenring W, Torok-Storb B, Storb R: 35 Kollman C, Howe CWS, Anasetti C, Antin JH, Davies
transplantation: a global perspective. JAMA 2010; 303: Graft-versus-host disease and donor-directed hemag- SM, Filipovich AH, Hegland J, Kamani N, Kernan NA,
1617–1624. glutinin titers after ABO-mismatched related and un- King R, Ratanatharathorn V, Weisdorf D, Confer DL:
11 Rowley SD, Donato ML, Bhattacharyya P: Red blood related marrow allografts: evidence for a graft-versus- Donor characteristics as risk factors in recipients after
cell-incompatible allogeneic hematopoietic progenitor plasma cell effect. Blood 2000; 96: 1150–1156. transplantation of bone marrow from unrelated do-
cell transplantation. Bone Marrow Transplant 2011; 46: 24 Lee JH, Lee KH, Kim S, Lee JS, Kim SH, Kwon SW, nors: the effect of donor age. Blood 2001; 98:2043–2051.
1167–1185. Kim WK: Anti-A isoagglutinin as a risk factor for the 36 Michallet M, Le QH, Mohty M, Prebet T, Nicolini F,
12 Gonzalez-Porras JR, Graciani IE, Perez-Simon JA, development of pure red cell aplasia after major ABO- Boiron JM, Esperou H, Attal M, Milpied N, Lioure B,
Martin-Sanchez J, Encinas C, Conde MP, Nieto MJ, incompatible allogeneic bone marrow transplantation. Bordigoni P, Yakoub-Agha I, Bourhis JH, Rio B,
Corral M: Prospective evaluation of a transfusion pol- Bone Marrow Transplant 2000; 25: 179–184. Deconinck E, Renaud M, Chir Z, Blaise D: Predictive
icy of D+ red blood cells into D– patients. Transfusion 25 Schetelig J, Breitschaft A, Kroger N, Zabelina T, Ebell factors for outcomes after reduced intensity condition-
2008; 48: 1318–1324. W, Bornhauser M, Haack A, Ehninger G, Salama A, ing hematopoietic stem cell transplantation for hema-
13 Cid J, Lozano M, Fernandez-Aviles F, Carreras E, Siegert W, Cooperative Transplantations Study Group: tological malignancies: a 10-year retrospective analysis
Pereira A, Mazzara R, Ordinas A: Anti-D alloimmuni- After major ABO-mismatched allogeneic hematopoietic from the Société Française de Greffe de Moelle et de
zation after D-mismatched allogeneic hematopoietic progenitor cell transplantation, erythroid engraftment Thérapie Cellulaire. Exp Hematol 2008; 36: 535–544.
stem cell transplantation in patients with hematologic occurs later in patients with donor blood group A than 37 Canals C, Muniz-Diaz E, Martinez C, Martino R,
diseases. Transfusion 2006; 46: 169–173. donor blood group B. Transfusion 2005; 45: 779–787. Moreno I, Ramos A, Arilla M, Boto N, Pastoret C,
14 Worel N, Bohm A, Rabitsch W, Leitner G, Mitterbauer 26 Stussi G, Halter J, Bucheli E, Valli PV, Seebach L, Remacha A, Sierra J, Madoz P: Impact of ABO incom-
M, Kalhs P, Mayr WR, Schwartz D, Greinix HT: Fre- Gmur J, Gratwohl A, Schanz U, Passweg JR, Seebach patibility on allogeneic peripheral blood progenitor
quency and prognostic value of D alloantibodies after JD: Prevention of pure red cell aplasia after major or cell transplantation after reduced intensity condition-
D-mismatched allogeneic hematopoietic stem cell bidirectional ABO blood group incompatible hemat- ing. Transfusion 2004; 44: 1603–1611.
transplantation after reduced-intensity conditioning. opoietic stem cell transplantation by pretransplant re-
Transfusion 2012; 52: 1348–1353. duction of host anti-donor isoagglutinins. Haemato-
logica 2009; 94: 239–248.

ABO-Mismatched Allogeneic Hematopoietic Transfus Med Hemother 2016;43:3–12 11


Stem Cell Transplantation
38 Kanda J, Ichinohe T, Matsuo K, Benjamin RJ, Klumpp 44 Keever-Taylor CA, Bredeson C, Loberiza FR, Casper JT, 49 Resnick IB, Tsirigotis PD, Shapira MY, Aker M, Bitan
TR, Rozman P, Blumberg N, Mehta J, Sohn SK, Uchiy- Lawton C, Rizzo D, Burns WH, Margolis DA, Vesole M, Samuel S, Abdul-Hai A, Ackerstein A, Or R, Slavin
ama T: Impact of ABO mismatching on the outcomes DH, Horowitz M, Zhang MJ, Juckett M, Drobyski WR: S: ABO incompatibility is associated with increased
of allogeneic related and unrelated blood and marrow Analysis of risk factors for the development of GVHD non-relapse and GVHD related mortality in patients
stem cell transplantations for hematologic malignan- after T cell-depleted allogeneic BMT: effect of HLA dis- with malignancies treated with a reduced intensity
cies: IPD-based meta-analysis of cohort studies. Trans- parity, ABO incompatibility, and method of T-cell de- regimen: a single center experience of 221 patients.
fusion 2009; 49: 624–635. pletion. Biol Blood Marrow Transplant 2001;7:620–630. Biol Blood Marrow Transplant 2008; 14: 409–417.
39 Remberger M, Watz E, Ringden O, Mattsson J, Shan- 45 Ludajic K, Balavarca Y, Bickeböller H, Rosenmayr A, 50 Benjamin RJ, McGurk S, Ralston MS, Churchill WH,
well A, Wikman A: Major ABO blood group mismatch Fischer GF, Faé I, Kalhs P, Pohlreich D, Kouba M, Do- Antin JH: ABO incompatibility as an adverse risk fac-
increases the risk for graft failure after unrelated donor brovolna M, Greinix HT: Minor ABO-mismatches are tor for survival after allogeneic bone marrow trans-
hematopoietic stem cell transplantation. Biol Blood risk factors for acute graft-versus-host disease in he- plantation. Transfusion 1999; 39: 179–187.
Marrow Transplant 2007; 13: 675–682. matopoietic stem cell transplant patients. Biol Blood 51 Rocha V, Gluckman E; Eurocord-Netcord registry and
40 Bensinger WI, Buckner CD, Thomas ED, Clift RA: Marrow Transplant 2009; 15: 1400–1406. European Blood and Marrow Transplant group: Im-
ABO-incompatible marrow transplants. Transplanta- 46 Gutierrez-Aguirre CH, Gomez-De-Leon A, Alatorre- proving outcomes of cord blood transplantation: HLA
tion 1982; 33: 427–429. Ricardo J, Cantu-Rodriguez OG, Gonzalez-Llano O, matching, cell dose and other graft- and transplanta-
41 Kim JG, Sohn SK, Kim DH, Baek JH, Lee KB, Min WS, Jaime-Perez JC, Mancias-Guerra C, Flores-Jimenez JA, tion-related factors. Br J Haematol 2009; 147: 262–274.
Kim CC, Lee MH, Lee JJ, Chung IJ, Kim HJ, Lee JW: Gomez-Almaguer D: Allogeneic peripheral blood stem 52 Blin N, Traineau R, Houssin S, Peffault de Latour R,
Impact of ABO incompatibility on outcome after allo- cell transplantation using reduced-intensity condition- Petropoulou A, Robin M, Larghero J, Ribaud P, Socie
geneic peripheral blood stem cell transplantation. Bone ing in an outpatient setting in ABO-incompatible pa- G: Impact of donor-recipient major ABO mismatch on
Marrow Transplant 2005; 35: 489–495. tients: are survival and graft-versus-host disease differ- allogeneic transplantation outcome according to stem
42 Worel N, Kalhs P, Keil F, Prinz E, Moser K, Schulen- ent? Transfusion 2014; 54: 1269–1277. cell source. Biol Blood Marrow Transplant 2010; 16:
burg A, Mitterbauer M, Mannhalter C, Mayr WR, 47 Mehta J, Powles R, Sirohi B, Treleaven J, Kulkarni S, 1315–1323.
Schwarzinger I, Hocker P, Lechner K, Greinix HT: ABO Saso R, Tait D, Singhal S: Does donor-recipient ABO 53 Ozkurt ZN, Yegin ZA, Yenicesu I, Aki SZ, Yagci M,
mismatch increases transplant-related morbidity and incompatibility protect against relapse after allogeneic Sucak GT: Impact of ABO-incompatible donor on
mortality in patients given nonmyeloablative allogeneic bone marrow transplantation in first remission acute early and late outcome of hematopoietic stem cell
HPC transplantation. Transfusion 2003; 43: 1153–1161. myeloid leukemia? Bone Marrow Transplant 2002; 29: transplantation. Transplant Proc 2009; 41: 3851–3858.
43 Bacigalupo A, Van Lint MT, Occhini D, Margiocco M, 853–859.
Ferrari G, Pittaluga PA, Frassoni F, Peralvo J, Lercari 48 Erker CG, Steins MB, Fischer RJ, Kienast J, Berdel WE,
G, Carubia F, et al: ABO compatibility and acute graft- Sibrowski W, Cassens U: The influence of blood group
versus-host disease following allogeneic bone marrow differences in allogeneic hematopoietic peripheral
transplantation. Transplantation 1988; 45: 1091–1094. blood progenitor cell transplantation. Transfusion
2005; 45: 1382–1390.

You might also like