As AB0 blood group system genes are inherited independently from human leukocyte antigens, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed across the AB0 blood group barrier.1 Approximately about 30-50% of HLA-matched allogeneic SCTs are performed with AB0 mismatch, which can be further classified as major, minor, or bidirectional.2,3 In case of major AB0 mismatch (MM), the recipient expresses isoagglutinins (IA) directed against donor red blood cells (RBCs). Major AB0 MM is known to be a risk factor for acute hemolysis of donor RBCs during graft infusion, and delayed RBC engraftment, as well as for pure red cell aplasia (PRCA) due to IA production by recipient B lymphocytes that survived the conditioning regimen.
Minor AB0 MM can result in an increased risk of delayed immune hemolysis due to the transfer of donor B lymphocytes present in the stem cell graft (“passenger lymphocytes”) which may produce IAs against recipient RBCs. In case of bidirectional AB0 mismatch, potential consequences of both incompatibilities must be considered.
Donor-recipient AB0 mismatch is not considered a barrier to successful allogeneic HSCT, however the published data on its impact on overall survival (OS), non-relapse mortality (NRM), Graft versus Host Disease (GvHD), relapse rate and engraftment are severely conflicting.4–7 Moreover, most data are based on adult study populations as well as in the setting of HSCT for malignancy.
The impact of AB0 MM in pediatric HSCT for hemoglobinopathies has not yet been analyzed in a systematic manner. A retrospective study evaluating AB0 MM as a risk factor for allogeneic HSCT in pediatric thalassemic patients found a significantly longer time to RBC transfusion independency in major AB0-incompatible patients when compared to the group receiving an AB0-compatible graft.8 This is particularly crucial as the indication for HSCT in thalassemia is transfusion dependency, and the aim of the transplantation should be transfusion independency in those patients where most of them present with important iron overload.
However, also in the adult studies, the impact of AB0 incompatibility cannot be ignored: In a large cohort of 1737 patients who underwent allogeneic HSCT at Stanford University between 1986 and 2011, OS was inferior in minor MM when compared to AB0 matched grafts.9 AB0 minor MM was associated with an increase in early NRM. The same results have been shown in an CIBMTR analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts (PBSC).9 Moreover, in the Stanford analysis, in recipients of AB0 minor MM bone marrow grafts, an increased risk of GvHD was observed; an effect which was not seen in case of PBSC.9 A German study demonstrated that minor AB0 MM appeared as an independent risk factor for TRM after allogeneic HSCT with PBSC, while major AB0 MM was found to be significantly associated with increased RBC and platelet transfusion requirements as well as delayed platelet engraftment.10 The impact on a prolonged median time to RBC transfusion independency was shown also by Blin et al. with a relevant effect on RBC engraftment after bone marrow transplantation.11 The impact on the occurrence and/or severity grading of GvHD could not yet been established in a reliable manner, however some data show a possible impact of AB0 incompatibility and GvHD incidence.11,12 A large Italian retrospective study from 2017 found that major AB0 incompatibility was clearly associated with inferior day +100 engraftment rate whereas multivariate analyses showed that bidirectional mismatching was associated with increased risk of grade II-IV acute GvHD.13
Considering these data, the impact of AB0 incompatibility should receive critical attention in the setting of hemoglobinopathies because
- There is an increasing attention and a rise in transplant frequency in these indications, in particular in sickle cell disease (SCD)
- In contrast to adult patients with malignant diseases, the transfusion frequency in primarily immunocompetent mostly pediatric patients might have an additional impact on the above-mentioned outcome parameter
- With the rise of haploidentical HSCT in this patient population T cell depletion might in combination with AB0 incompatibility impact more prominently on outcome parameter such as rejection.
So that, in particular in the haploidentical setting, where the luxury of several donor options might allow the donor selection algorithm to receive a prioritization of the ABO setup in order to improve outcome.
For a systematic analysis of the impact of AB0 incompatibility in pediatric patients with hemoglobinopathies, we propose to conduct a retrospective, multicenter study analyzing data available in the EBMT registry.