ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation
ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation
ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation
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].
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].
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
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
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
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
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
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
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)
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
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-
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
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.