Clinical features and risk factors of pure red cell aplasia following major ABO-incompatible allogeneic hematopoietic stem cell transplantation

The objective of this paper was to study the incidence, risk factors, clinical outcome, management and prevention of pure red cell aplasia (PRCA) following major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed 11 cases of PRCA from a series of 42 patients undergoing major ABO-incompatible allo-HSCT from April 1997 to December 2005. Eleven out of the 42 patients developed PRCA (26.1%). All the 11 cases of PRCA were in blood group O recipients of grafts from blood group A donor (n = 9) or blood group B donor (n = 2). The following factors were associated with an increased risk of PRCA: (1) blood group O recipient; (2) blood group A donor; and (3) blood group O/A in recipient/donor pair. Only blood group a/A in recipient/donor pair was identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Six patients who received donor-type plasma exchange did not develop PRCA and among them 5 cases were the blood group O recipients. Eight patients obtained spontaneous remission and in the remaining 3 patients 2 with long-lasting PRCA were successfully treated with plasma exchange with donor-type plasma replacement and the other one who was also complicated by EBV-associated lymphoproliferative disorder (EBV-PTLD) responded rapidly to anti-CD20 monoclonal antibody and achieved complete resolution of clinical finding and symptom of both EBV-PTLD and PRCA. We conclude that blood group A/O in donor/recipient pair is identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Donor-type plasma exchange and anti-CD20 monoclonal antibody is an effective approach for the treatment of PRCA. PRCA could be prevented by plasma exchange prior to transplantation.     

Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation

Delayed donor red cell engraftment and pure red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible hematopoietic stem cell transplantation (SCT) performed by means of myeloablative conditioning. To evaluate these events following reduced-intensity nonmyeloablative SCT (NST), consecutive series of patients with major ABO incompatibility undergoing either NST (fludarabine/cyclophosphamide conditioning) or myeloablative SCT (cyclophosphamide/high-dose total body irradiation) were compared. Donor red blood cell (RBC) chimerism (initial detection of donor RBCs in peripheral blood) was markedly delayed following NST versus myeloablative SCT (median, 114 versus 40 days; P <.0001) and strongly correlated with decreasing host antidonor isohemagglutinin levels. Antidonor isohemagglutinins declined to clinically insignificant levels more slowly following NST than myeloablative SCT (median, 83 versus 44 days; P =.03). Donor RBC chimerism was delayed more than 100 days in 9 of 14 (64%) and PRCA occurred in 4 of 14 (29%) patients following NST, while neither event occurred in 12 patients following myeloablative SCT. Conversion to full donor myeloid chimerism following NST occurred significantly sooner in cases with, compared with cases without, PRCA (30 versus 98 days; P =.008). Cyclosporine withdrawal appeared to induce graft-mediated immune effects against recipient isohemagglutinin-producing cells, resulting in decreased antidonor isohemagglutinin levels and resolution of PRCA following NST. These data indicate that significantly delayed donor erythropoiesis is (1) common following major ABO-incompatible NST and (2) associated with prolonged persistence of host antidonor isohemagglutinins. The clinical manifestations of these events are affected by the degree and duration of residual host hematopoiesis.     

Successful treatment of pure red cell aplasia with high-dose dexamethasone after ABO-incompatible allogeneic hematopoietic stem cell transplantation

The literature reports an incidence of Pure Red Cell Aplasia (PRCA) ranging from 6-30% of all cases of ABO-incompatible HSCT. Although most patients resolve spontaneously after withdrawal immunosuppression, some of them require more aggressive treatment to manage this condition.     

主要血型不合骨髓移植后纯红细胞再生障碍性贫血的临床观察

目的　探讨主要血型不合骨髓移植（ＭＩｃ－ ＢＭＴ）后的纯红细胞再生障碍性贫血（ＰＲＣＡ） 的临床及实验室特点。方法　对３ 例ＭＩｃ－ ＢＭＴ 后ＰＲＣＡ 的临床及实验室有关资料进行分析,并与９ 例对照组（８ 例血型相合,１ 例次要血型不合） 进行比较。结果　３ 例ＰＲＣＡ发生于ＭＩｃ－ ＢＭＴ后８ 周内,伴有较高的血型凝集素滴度;未治疗的ＰＲＣＡ 骨髓中幼红细胞比例在０．０５ 左右,网织红细胞计数≤０．００１ ;骨髓植活时间、血小板数、骨髓中粒细胞与巨核细胞在ＭＩｃ－ ＢＭＴ 与对照组间无明显差异。ＭＩｃ－ ＢＭＴ 后８ 周内输血量明显增多。结论　ＭＩｃ－ ＢＭＴ 后ＰＲＣＡ有显著的临床与实验室特点,其发生的主要机理可能为受者血型凝集素对供者红系前体细胞的抑制作用。     

Mesenchymal stem cells for the treatment of refractory pure red cell aplasia after major ABO-incompatible hematopoietic stem cell transplantation

Pure red cell aplasia (PRCA) is a well-known, although infrequent, hematological complication after allogeneic hematopoietic stem cell transplantation (HSCT). PRCA occurs in cases of major ABO mismatch between donor and recipient and is believed to be due to inhibition of donor erythroid progenitors by residual host isohemagglutinins. The purpose of our study was to further evaluate the efficacy of human adipose tissue-derived mesenchymal stem cells (AMSC) as the salvage therapy for refractory PRCA after major ABO-incompatible HSCT. Two patients with refractory pure red cell aplasia received intravenous infusions of AMSC at a dose of 1.5 × 10⁶/kg of the patients’ weight, and rapid recovery from PRCA without any side effects was observed. We conclude that AMSC seems to be a promising therapeutic option in patients with PRCA after ABO-mismatched HSCT, in whom conventional treatment fails.     

Prolonged red cell aplasia after major ABO-incompatible allogeneic hematopoietic stem cell transplantation: removal of persisting isohemagglutinins with Ig-Therasorb immunoadsorption

Delayed donor red cell engraftment and prolonged red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT). There is an intense debate about the impact on outcome, severity of hemolysis, association with graft-versus-host disease and survival after blood group-incompatible stem cell transplantation. Therefore, therapeutic strategies should be considered to avoid these possible complications. We present five patients, who received allogeneic HSCT from human leukocyte antigen-identical donors for hematological malignancies, which were treated with Ig-Therasorb immunoadsorption (five treatments/week) to remove persisting incompatible isohemagglutinins. After a median of 17 treatments (range 9-25), all the patients became transfusion independent with the presentation of donor's blood group. No side effects occurred during treatment. Ig-Therasorb immunoadsorption seems to be a promising therapeutic method for rapid, efficient and safe elimination for persisting isohemagglutinins for patients with PRCA after allogeneic hematological stem cell transplantation.     

Anti-A isoagglutinin as a risk factor for the development of pure red cell aplasia after major ABO-incompatible allogeneic bone marrow transplantation

Delayed erythropoiesis and pure red cell aplasia (PRCA) have been reported after major ABO-incompatible BMT. We attempted to find risk factors for the development of PRCA in 27 patients who underwent major ABO-incompatible BMT. In all patients, the donor marrow was depleted of RBCs before infusion. In 22 patients, isoagglutinins were determined until they disappeared. In eight (29.6%) out of 27 patients, bone marrow examination following BMT showed the findings of PRCA. We analyzed various clinico-pathologic risk factors and isoagglutinin type was the only significant risk factor. Patients with anti-A isoagglutinins against donor RBC developed PRCA more frequently than patients with anti-B (8/17 vs 0/9). Median days to the disappearance of isoagglutinins tended to be longer in patients with PRCA (PRCA vsnon-PRCA, 200 vs 66 days) and in cases with anti-A isoagglutinins (anti-A vsanti-B, 160 vs 51 days). Times to disappearance of isoagglutinins correlated with times to reticulocytes over 1% and initial appearance of donor type RBC (R2 = 0.708 and 0.711). In conclusion, RBC engraftment following major ABO-incompatible BMT was dependent on the disappearance of isoagglutinins against donor RBC, and anti-A isoagglutinin was a risk factor for the development of PRCA after major ABO-incompatible allogeneic BMT. Bone Marrow Transplantation (2000) 25, 179-184.     

ABO主血型不合的非清髓性异基因造血干细胞移植2例

目的：观察ABO主血型不合的非清髓性异基因造血于细胞移植(NST)治疗2例慢性髓细胞自血病(CML)患者的耐受性、疗效及其ABO血型转变。方法：采用氟达拉宾、白消安、抗人淋巴细胞球蛋白和骁悉的非清髓性预处理，异基因造血干细胞移植，移植后2周开始供者淋巴细胞输注(DLI)，每例5～6次；应用STR—PCR及染色体核型分析检测供者嵌合体；每半月～1个月监测血型。结果：2例患者移植后造血恢复较快，骨髓细胞混合嵌合体形成分别为 15～ 23d，完全嵌合体形成为 23～ 43d；例1血型为O型，于 388d血型转变为供者血型A型，移植后6个月细胞遗传学水平复发．DLI后Ph染色体转阴，但发生皮肤慢性移植物抗宿主病。例2于 45d血型由A型转变为供者血型AB型，移植后5个月与1年2次出现纯红细胞再生障碍性贫血表现，均用DLI后红系造血恢复，Ph染色体转阴。结论：ABO主血型不合的NST易出现红系造血延迟及纯红细胞再生障碍性贫血，DLI具有促进供者嵌合体形成，防治复发效应。     

Impact of nonmyeloablative conditioning regimens on the occurrence of pure red cell aplasia after ABO-incompatible allogeneic haematopoietic stem cell transplantation

BACKGROUND AND OBJECTIVES: In the setting of major ABO-incompatible allogeneic haematopoietic stem cell transplantation (HSCT), pure red cell aplasia (PRCA) is linked to the persistence of host residual plasma cells secreting antidonor isohaemagglutinins (HA) after transplantation. There are conflicting results regarding the impact of the intensity of conditioning regimen on the occurrence of PRCA after major ABO-mismatched HSCT. MATERIAL AND METHODS: To address this question, we compared two cases occurring after nonmyeloablative (NMA) and myeloablative (MA) HSCT and reviewed previous cases reported in the NMA setting. RESULTS AND CONCLUSIONS: We observed a delayed disappearance of antidonor HAs in the NMA setting, associated to a more prolonged period of red blood cells transfusion dependence than in the MA setting. In our case as in several others, the disappearance of antidonor HAs and resolution of PRCA were observed after reinforcement of the graft-versus-host effect (i.e. immunosuppression removal or donor leukocytes infusion).     

Treatment of pure red cell aplasia after major ABO-incompatible peripheral blood stem cell transplantation by induction of chronic graft-versus-host disease

This report concerns a case of long-lasting pure red cell aplasia (PRCA) with a duration of 178 days after major ABO-incompatible allogeneic peripheral blood stem cell transplantation (PBSCT). The patient needed red blood cell transfusion every week from day 54 following PBSCT. He showed no evidence of GVHD and the dose of cyclosporin A (CsA) was reduced rapidly from day 123, followed by the development of chronic GVHD around day 145. The patient no longer needed transfusions from day 167, the reticulocyte count began to increase on day 179, and antidonor isohemagglutinin titers became undetectable. Chronic GVHD induced by tapering of CsA thus appeared to be related to improvement in PRCA.     

Non-ABO red blood cell alloantibodies following allogeneic hematopoietic stem cell transplantation

Immune-mediated hemolysis is a well-recognized occurrence which complicates the period following a bone marrow transplant (BMT). However, although many studies have investigated the hemolytic anemia following ABO-incompatible BMT, data regarding the occurrence of alloantibodies against red blood cell (RBC) antigens other than ABO in patients undergoing hematopoietic stem cell transplantation are limited. In this review, we briefly analyze the most important non-ABO red blood cell (RBC) antigen systems involved in the development of post-BMT alloimmune hemolytic anemia, paying particular attention to the pathogenic mechanisms and the clinical significance of the alloantibodies involved. Among the non-ABO RBC antigens, RhD antigen is the one most frequently implicated in the development of post-BMT alloimmune hemolytic anemia. Although less frequent than hemolysis following transplants with ABO incompatibility, non-ABO-incompatible allograft hemolysis may severely complicate the post-BMT period creating difficult clinical management issues. For this reason, we advise careful pre-transplant donor and recipient checks for the most important RBC antigen systems and close post-BMT immunohematological monitoring in those patients undergoing allogeneic hematopoietic stem cell transplant with RBC antigen incompatibility.     

Late onset of autoimmune hemolytic anemia and pure red cell aplasia after allogeneic hematopoietic stem cell transplantation using in vivo alemtuzumab

Hemolytic anemia and pure red cell aplasia (PRCA) after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported to be mainly related to ABO-incompatibility between donor and recipient. Autoimmune hemolytic anemia (AIHA) without ABO-incompatibility has been also reported after allogeneic HSCT, especially with T-cell depletion. However, optimal management of AIHA or PRCA remains unclear. A 54-year-old male with myelodysplastic syndrome (MDS) underwent haploidentical human leukocyte antigen-mismatched HSCT using in vivo alemtuzumab and developed AIHA and PRCA simultaneously 15 months after transplantation, following the administration of cidofovir and probenecid for persistent cytomegalovirus (CMV) antigenemia and retinitis. AIHA was successfully treated with rituximab, and subsequently PRCA with cyclosporine without relapse of MDS or recurrence of CMV infection. The clinical course suggested that AIHA was mainly caused by humoral immune response, while PRCA was mainly caused by cell-mediated immune response in this patient, although these immune responses might be related to each other.     

Persistent parvovirus B19 infection resulting in red cell aplasia after allogeneic hematopoietic stem cell transplantation

Persistent parvovirus B19 (PVB) infection has been reported sporadically in immunocompromised patients including hematopoietic stem cell and solid organ transplant recipients. However, the pathogenesis of persistent infection has yet to be fully elucidated. We report here a patient with multiple myeloma developing red cell aplasia during the hematopoietic recovery after allogeneic hematopoietic stem cell transplantation (HSCT) caused by PVB. The patient had already had PVB viremia before transplantation and remained asymptomatic. The route of PVB transmission was considered to be direct contact with the patient's family member with primary PVB infection 1 month before transplantation. Treatment with intravenous immunoglobulin resulted in prompt resolution of anemia. These findings suggest that monitoring of PVB DNA is recommended for patients undergoing HSCT and having contact with individuals with documented PVB infection, even if they are asymptomatic.     

Resistant pure red cell aplasia after allogeneic stem cell transplantation with major ABO mismatch treated by escalating dose donor leukocyte infusion

We report a case of pure red cell aplasia (PRCA) following allogeneic stem cell transplantation (SCT) with major ABO mismatch which proved resistant to all standard treatment options such as change in immunosuppressive treatment, high-dose erythropoietin (EPO) or plasma exchange. We therefore proceeded to administer five cycles of Rituximab therapy, without success. Finally, escalating doses of donor-derived leukocyte infusion (DLI) resolved the PRCA of our patient 415 d after bone-marrow transplantation (BMT) and 140 d after the first infusion of donor leukocytes. A review of the literature shows the efficacy of various treatments; the role of DLI and other treatment options are discussed. Furthermore, the underlying pathophysiological mechanisms especially with regard to the role of NK cells in alloreactivity after allogeneic SCT are explained.     

Pure red cell aplasia of long duration complicating major ABO-incompatible bone marrow transplantation

In 3 of 15 consecutive patients receiving a human leukocyte antigen (HLA)-identical but major ABO incompatible bone marrow transplant (BMT), pure red cell aplasia (PRA) lasting 5 to 8 months was observed. Titers of the incompatible anti-A agglutinin before infusion of the red blood cell (RBC)-depleted BMT was very high in one, and in the usual range in two patients. Decrease of agglutinin titers during the first 4 weeks after BMT were comparable between PRA patients and those of ABO-incompatible BMT recipients with timely RBC recovery. However, in PRA patients, agglutinin titers rose again and remained elevated for 19 to 28 weeks. RBC engraftment and reticulocyte recovery ultimately occurred spontaneously and coincided with the decrease of agglutinin titers below 16. These observations indicate that PRA is antibody-dependent in this setting. Furthermore, it is conceivable that cyclosporine facilitates recipient-derived antibody synthesis after major ABO-incompatible BMT.