Pure red blood cell aplasia: patient management pitfalls in major ABO-incompatible haematopoietic cell transplantation.

Abstract

In this issue of British Journal of Haematology, Longval and colleagues report on the successes and pitfalls of prediction, diagnosis and management of pure red blood cell aplasia (PRCA) after major ABO-incompatible allogeneic stem cell transplantation.1 Their data confirm prior reports indicating a paucity of cases of PRCA after umbilical cord blood transplantation.2 Among the remaining 587 patients receiving major ABO-incompatible donor grafts, 66 cases of PRCA were identified. In this series, high pre-transplant isohaemagglutinin titre was the only pre-transplant variable associated with subsequent development of PRCA. Despite the various methodologies for performing isohaemagglutinin titre assays,4, 5 this observation highlights the need for pre-transplant quantitation of isohaemagglutinin titre in instances of major ABO mismatch in order to identify patients at highest risk. Furthermore, at some centres pre-conditioning therapeutic plasma exchange is considered for patients with high titres.6 In some patients, residual recipient plasma cells may secrete sufficient quantities of antibody to prevent nascent erythroblast precursors from achieving timely maturation,3 forming a rationale for consideration of plasma cell-directed therapy in patients with persistently high isohaemagglutinin titres. Interestingly, several low titre isohaemagglutinin recipient–donor pairs resulting in post-transplant PRCA were identified, pointing to the need to identify additional predictors of PRCA. This work also exposes a gap in knowledge within the transplant field, namely when can we be sure that red blood cell engraftment has transpired? To date, no universal standard for red blood cell engraftment exists, and across institutions several working definitions exist including red cell transfusion independence, ABO blood type conversion, and absence of reticulocytopenia. Advantages and disadvantages of various case definitions are outlined in Table I. Standard diagnostic assessments for profound anaemia, reticulocytopenia, and absence of red blood cell precursors in the bone marrow are certainly essential when patients display prolonged red cell transfusion dependence,7 but in the absence of alternative causes, the presumptive diagnosis in this setting is PRCA due to ABO incompatibility, and persistence of some level of the corresponding isohaemagglutinin is typical. In this series, over 10% of patients receiving transplants from donors with a major ABO incompatibility developed PRCA, but this immunologic insult did not significantly affect overall survival, which is in line with results of previous studies.8, 9 As such, any therapeutic intervention must be considered in the context of the inherent risk of the intervention itself. Introduction of rituximab,10 donor lymphocyte infusions,11 tapering of immunosuppressive medications, or use of a proteasome inhibitor12 all carry risk–benefit calculations, and to date have demonstrated mixed results in treating post-transplant PRCA. Anecdotal reports of the successful use of the anti-CD38 monoclonal antibody daratumumab for management of post-transplant PRCA13, 14 deserve mention, particularly given that the physiology of prolonged PRCA after transplant is presumably a reflection of residual host plasma cell clones producing the isohaemagglutinin. In the current study, no particular intervention was associated with more rapid resolution of PRCA, although no patients in this series received daratumumab and only a handful received a proteasome inhibitor. Management of patients undergoing major ABO-incompatible allogeneic stem cell transplantation requires close collaboration with the blood bank to identify patients at greatest risk prior to transplantation, and to optimize transfusion strategies during the post-transplant period. This may include pre-transplant minor red blood cell antigen typing to reduce the likelihood of alloimmunization,15 and consideration of pre-transplant plasma exchange for patients with very high isohaemagglutinin titres. It is fair to say that there is no ‘gold standard’ for treatment of active post-transplant PRCA, and this study does not inform us regarding how best to manage these patients. Fortunately, the situation typically resolves over time, but further studies to establish effective treatment strategies are sorely needed given the significant morbidity and symptom burden associated with this not so rare complication. As a final thought, we might speculate two distinct (but not mutually exclusive) mechanisms for what we call ‘PRCA’ in this setting: residual host isohaemagglutinin levels that simply take time to dissipate because of high pre-transplant titres versus persistence of host isohaemagglutinin-producing plasma cells. We have the molecular and blood banking tools to systematically study these post-transplant events, which could better elucidate management approaches most appropriate for individual patients. Variability in RBC products Complicated by suspected transfusion reactions Provider/institutional variability for transfusion thresholds Time to independence is not a universal definition (e.g,, 30 days without transfusion versus 60 days) Inter-observer variability in scoring of agglutination Interference between residual transfused isohaemagglutinins from platelets/plasma No established grading system for mixed field observations Interference from intravenous immune-globulin treatment Results often not reported in patient’s medical record Difficulty in interpretation for non-transfusion medicine personnel Monoclonal antibodies for minor RBC antigens are licensed Low cost and quick turn-around time Only viable if minor antigen discrepancy exists between donor/recipient. If patient has positive Direct Coombs’ test, results could be invalid based on reagent used