Major ABO-incompatible Allogeneic Stem Cell Research Articles

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

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

Successful Treatment of Pure Red Cell Aplasia after Major ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia with Repeated Doses of the Single-Agent Rituximab: A Case Report.

Background: ABO incompatibility occurs in up to 20–40% of HLA matched allogeneic hematopoietic stem cell transplantation (HSCT). Pure red cell aplasia (PRCA) following ABO-incompatible allogeneic HSCT is a rare complication associated with interaction of recipient anti-A or anti-B isoagglutinins, produced by residual B cells, with donor erythrocytes precursors expressing A and/or B antigens. The best treatment approach for PRCA is not established. Plasma exchange and immunoadsorption are regarded as a first-line treatment strategies. Other therapeutic approaches include: erythropoietn (EPO), donor-derived leukocyte infusion (DLI), steroids or induction of graft versus host disease (GVHD) by immunosuppression withdraw. Moreover, recovery or erythropoiesis is often incomplete and may induce futher complications. Recent reports describe successful treatment of PRCA and others cytopenias after HSCT using Rituximab (Mabthera®; Roche; Switzerland). This drug is a chimeric IgG1 monoclonal antibody directed against the CD20 surface antigen expressed by most human B lymphocytes. Its exact mechanism of action is not known.Case Report: We treat a 47-year-old woman with PRCA after a major ABO-mismatched (Donor A Rh-; Recipient O Rh-) allogeneic HSCT after a second remission of a acute myeloid leukemia. Allogeneic HSCT was performed in November 2005, from a HLA-matched older sister, using bone marrow graft (Mn cell dose 1,72x108/kg) following a myeloablative conditioning with busulfan (16mg/kg) and melfalan (140mg/m2). GVHD prophylaxis included cyclosporine A and methotrexate. Baseline anti-A isoagglutinin IgM titers of the paient before transplantation was 1:128 and after immunoadsorption with plasma A for 48 hours decreased to 1:32. One plasmapheresis session was performed to remove ABO antibodies from the patient and her anti-A IgM titer dropped to 1:4 before bone marrow infusion. We also removed red blood cells from the donor's marrow product to prevent risk of hemolysis. After bone marrow transplantation, the patient developed a severe anemia that required weekly red blood cells transfusion over six months. Reticulocyte counts were extremely low during this period, bone marrow aspirate was normal, except for decreased erythrocyte precursors (only 1% of total cells). In August 2006, the diagnosis of PRCA was set after exclusion of red blood cells alloantibodies, hemolysis and viral or bacterial infection. Donor chimerism (STR) was totally completed and the recipient anti-A IgM titer was 1:16 and the patient showed no evidence of GVHD. In October 2006, she was treated with rituximab 375mg/m2 administered once weekly for four weeks. In the next two months, after the treatment with rituximab, her hemoglobin (Hb) increased from 5.5g/dl to 12g/dl. Up to her last medical avaluation (July 2006), she was in PRCA remission, her Hb was 12g/dl and she had no detectable anti-A titer. Conclusion: Rituximab can be a very effective treatment to PRCA secondary to major ABO-incompatible allogeneic stem cell transplantation. The best dose schedule and long term effects must be establish.

The Feasibility and Clinical Efficacy of In Vivo Adsorption of Isohemagglutinins with Fresh Frozen Plasma (FFP) Infusion in Major ABO-incompatible Allogeneic Stem Cell Transplantation

Background: We evaluated the efficacy and feasibility of performing prolonged donor type fresh frozen plasma (FFP) infusion for the in vivo adsorption of isohemagglutinins (IHGs) in major ABO-incompatible allogeneic stem cell transplantation. Methods: Forty-five patients underwent allogeneic stem cell transplantation. Major ABO incompa- tibility was observed in 23 patients. 18 patients of these 23 patients had IHGs directed towards the donor ABO antigens and they received donor type FFP; in 5 patients, the bone marrow grafts were minor incompatible; in 17 patients, the grafts were compatible. Results: The engraftment times of the granulocytes and platelets and the transfusion requirements for red blood cells in the FFP-transfused recipients of the major ABO-incompatible allografts were not different from those of therecipients of ABO-compatible allografts (P >0.1) and these factors were not different from those for the FFP-treated recipients of the major ABO-incompatible allografts. The median duration of FFP infusion and the number of FFP units were 23.5 days (range 8~39) and 47 units (range 16~78), respectively. The median IgG titers decreased from 1: 64 to 1:4 over a median of 22.5 days (range 8~36) in the FFP-treated groups, compared with a median of 61 days (range 19~116) in the non-FFP-treated groups. Conclusion: The infusion of donor-type FFP with red cell depletion represents a more feasible, effective alternative strategy to achieve in vivo immunoadsorption of IHGs and to prevent late immunohematologic complications. (Korean J Hematol 2005;40:254-260.)