Pure red cell aplasia: The second hundred years.

Pure red cell aplasia (PRCA) is a rare hematologic syndrome, characterized by an isolated normocytic anemia with severe reticulocytopenia, and defined by absence or near absence of erythroid precursors in the bone marrow. First described in 1922, PRCA may be a primary autoimmune or clonal myeloid or lymphoid disorder, but may also be secondary to other disorders of immune dysregulation/autoimmunity, to infections, to neoplasms, or to drugs. Insights from the study of PRCA have helped illuminate the understanding of the regulation of erythropoiesis. This review summarizes the classification, diagnostic, and therapeutic approach to PRCA as it begins its second century, with a particular focus on opportunities and challenges provided by new developments in the role of T-cells and T-cell regulatory mutations; the role of clonal hematopoiesis; and new developments in therapy for refractory PRCA and PRCA associated with ABO incompatible stem cell transplantation.

Hematologic Manifestations of Parvovirus B19 Infection.

Parvovirus B19 virus infection is widespread among humans because of its highly infectious and obstinate nature, with up to 80% of the population testing positive for IgG antibodies against the virus. Pronormoblasts observed in biopsy are the hallmarks of PVB19 infection. In addition, PVB19 affects the skin, heart, brain, joints, and liver and can be diagnosed through antibody detection or DNA detection via PCR. Due to its capsid proteins' high affinity for bone marrow receptors, its main presentation is the suppression of bone marrow functions. It has been shown to affect patients with hemolytic anemia and patients with hematological malignancies, presenting with pure red cell aplasia. The main available effective treatment option is IV immunoglobulins; however, the risk of recurrence remains high after treatment.

Successful treatment of a pure red cell aplasia patient following ABO-mismatched hematopoietic stem cell transplantation from a sibling donor with multiple sclerosis.

Despite the importance of blood group compatibility in solid organ transplantation, the role of ABO antigens is less critical in hematopoietic stem cell transplantation (HSCT). However, ABO-mismatch HSCT can present specific conditions and challenges for the recipient. One of the possible consequences of ABO-mismatch HSCT is pure red cell aplasia (PRCA). Although there are different treatment strategies to manage PRCA, each may carry its own risk. Here, we report a patient who developed PRCA after ABO-mismatch allogeneic HSCT from her sibling with multiple sclerosis history. PRCA improved with tapering immunosuppressive agents. Although the patient developed manageable graft versus host disease (GVHD), she eventually recovered from both PRCA and GVHD.

Successful treatment of pure red cell aplasia using therapeutic plasma exchange after ABO-incompatible hematopoietic stem cell transplant.

Hematopoietic stem cell transplants (HSCTs) are widely used in the treatment of hematologic malignancies and bone marrow failure syndromes. ABO compatibility is typically of secondary importance, and up to 50% of HSCT are performed in ABO-incompatible pairings. In the literature, pure red cell aplasia (PRCA) occurs in 1% to 50% of all major/bidirectional ABO-incompatible stem cell transplants, but treatment of PRCA remains heterogeneous. Here, we report two cases in which patients with transfusion-dependent PRCA following HSCT were successfully treated with therapeutic plasma exchange (TPE). Case 1: A 52-year-old type O-positive male with acute myeloid leukemia underwent HSCT using apheresis-derived HSCs from a fully human leukocyte antigen (HLA)-matched, related type A-positive male donor. He developed PRCA that was refractory to multiple therapies, so a series of 10 TPE was performed over 3 weeks. Case 2: A 21-year-old type A-positive male with aplastic anemia underwent HSCT using bone marrow-derived HSCs from a fully HLA-matched related type B-positive female donor. He developed PRCA that was refractory to multiple therapies, so a series of 5 TPE was performed over 2 weeks. Case 1: The patient has been transfusion independent since TPE #7, and type A red blood cells (RBCs) were seen on the ABO type after TPE #9. Case 2: The patient has been transfusion independent since after TPE #1, and type B RBCs were seen on the ABO type after TPE #5. TPE was successful in treating two patients with PRCA after ABO-incompatible HSCT transplants. Isoagglutinin titers decreased below the level of detection for both our patients. Ultimately both patients became transfusion independent and showed evidence of erythroid cell recovery.

[Pure red cell aplasia: Diagnosis, classification and treatment]. / L'érythroblastopénie : diagnostic, classification, traitement.

Pure red cell aplasia (PRCA) is a rare anemia characterised by profound reticulocytopenia caused by a marked reduction in bone marrow erythroblasts, without abnormalities in other blood lineages. Blackfan-Diamond anemia is an inherited ribosomopathy responsible for a hereditary form of PRCA. Acquired PRCA are separated in primary and secondary forms, including Parvovirus B19 infection, thymoma, lymphoproliferative disorders, autoimmune diseases (lupus) and drug-induced PRCA. The pathophysiology of PRCA is not fully understood and involves both humoral and T lymphocyte autoreactive cells. In Parvovirus B19-related PRCA, treatment is based on polyvalent immunoglobulins. Thymectomy for thymoma is mandatory but results in prolonged remission in a limited number of cases. The therapeutic strategy is based on expert opinion: corticosteroids in monotherapy provide few sustained responses. The choice of an additional immunosuppressant drug is guided by the presence of an underlying disease. In most cases, cyclosporine A is the first choice providing the best response rate but requires a concentration monitoring (150 to 250 ng/mL). The second choice is cyclophosphamide in large granular lymphocyte leukaemia. Sirolimus (mTOR inhibitor) seems to be a promising option especially in refractory cases. Transfusion independence is the main objective. If the patient receives numerous red blood cell transfusions (> 20 packs), iron overload assessment is crucial to initiate an iron chelation. A retrospective and prospective national cohort (EPIC-F) has been set up and is now available to include each case of PRCA to improve the knowledge of this disease and to optimize the therapeutic strategy.

Adult pure red cell aplasia at Universitas Academic Hospital, Bloemfontein, South Africa: A 9-year review.

BACKGROUND: Pure red cell aplasia (PRCA) is characterised by severe normochromic, normocytic anaemia and partial or complete absence of reticulocytes from the peripheral blood. With bone marrow of normal cellularity, an almost complete absence of erythroblasts but preservation of other cell lines is observed. It may be congenital or acquired, with the latter presenting as a primary haematological disorder or secondary to various contributing factors. Management focuses on treatment of the underlying cause and supportive transfusions. Occasionally, immunosuppression or intravenous immunoglobulin (IVIG) is required. OBJECTIVES: To describe the clinical characteristics, treatment and outcomes of adult patients diagnosed with PRCA at Universitas Academic Hospital (UAH) in Bloemfontein, South Africa, from 2010 to 2018. METHODS: A retrospective descriptive file review was performed. All adult patients diagnosed with PRCA and treated in the Division of Clinical Haematology at UAH during the study period were included. Variables recorded included demographic information, clinical details of the PRCA diagnosis, classification of the PRCA, HIV and parvovirus B19 test results, results of special investigations, medical and drug history, treatment and response to treatment. RESULTS: Twenty-seven patients' files were included, with a female predominance (n=22; 81.5%). The median age at diagnosis was 35 years (range 20 - 62). The median number of days from onset of symptoms to date of diagnosis was 61 days (range 27 - 114). Approximately half (n=13; 48.2%) of the patients presented with a haemoglobin concentration of 1 - 3 g/dL. Most patients (n=26; 96.3%) were infected with HIV, with 76.9% (n=20) having a suppressed viral load. Parvovirus B19 infection accounted for 44.4% of cases (n=12), and all these patients were HIV positive. Lamivudine was a probable cause of PRCA in 18.5% of cases, although the true causal relationship was uncertain. Corticosteroids and IVIG were first-line therapy in 44.4% (n=12) and 37.0% (n=10) of cases, respectively. Thirteen patients (48.2%) achieved a complete response and 7 (25.9%) a partial response, while 2 (7.4%) showed no response, with continued transfusion dependence. CONCLUSION: In this population, women were disproportionately affected by PRCA. HIV was the single most important cause of acquired PRCA, which was independent of virological control. Parvovirus B19 and drugs were also important causes of acquired PRCA and played a critical part in the evaluation and work-up of PRCA. Nearly half of the patients achieved a complete response to therapy, which was sustained over 24 months.

Acquired pure red cell aplasia after severe acute respiratory syndrome corona virus 2 infection: a case report.

BACKGROUND: Coronavirus disease 2019, caused by severe acute respiratory coronavirus 2, has been responsible, since December 2019, for a severe pandemic resulting in millions of deaths worldwide, and the number is still increasing. Although coronavirus disease 2019 is mostly a respiratory syndrome, it is considered a multisystemic disease and shows clinical diversity with a wide range of manifestations including hematological features. CASE PRESENTATION: We present the case of an Arab male, 77 years old, who developed severe anemia 8 weeks after acute infection with severe acute respiratory coronavirus 2. The investigations revealed acquired pure red cell aplasia. Workup for an associated underlying disorder was negative, ruling out secondary causes. The patient received corticosteroids as the standard treatment of primary acquired pure red cell aplasia, and he had a good response to treatment. CONCLUSION: This case illustrates that acquired pure red cell aplasia might occur weeks after severe acute respiratory coronavirus 2 infection, suggesting that it might be considered a delayed complication of coronavirus disease 2019. The most relevant hypothesis of the pathogenesis of acquired pure red cell aplasia, in this case, is an immune mechanism triggered by infection with severe acute respiratory coronavirus 2 resulting in interruption of normal erythroid differentiation. We highlight the importance of follow-up care after the acute phase of coronavirus disease 2019 to spot late complications in order to successfully manage the secondary burden of the pandemic.

Clinical characteristics and outcomes of 100 adult patients with pure red cell aplasia.

Adult pure red cell aplasia (PRCA) is a rare syndrome characterized by a severe normocytic anemia, reticulocytopenia, and absence of erythroblasts from bone marrow. The standard treatment has not yet been established for PRCA, although cyclosporine (CsA), corticosteroids (CS) showed a response in PRCA. We retrospectively analyzed the clinical data of 60 primary and 40 secondary adult patients with acquired PRCA. The proportion of secondary PRCA is relatively high and commonly associated with large granular lymphocyte leukemia (LGLL) (28 cases, 70.0%). The remission-induced regimens included CS, CsA, or other agents, and the response rate was 66.7%, 71.4%, and 50%, respectively (P = 0.336). When treating with CsA, the response rate of LGLL-associated PRCA was lower than primary PRCA (42.1% vs 85.7%, P = 0.001). Logistic regression analysis showed that ORR was inversely related to LGLL-associated PRCA. LGLL-associated PRCA had poor therapeutic efficacy to CsA.

Immune reconstitution and survival of patients with parvovirus B19 related pure red cell aplasia after haplo-PBSCT.

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.

[Diagnosis and management of pure red cell aplasia].

Pure red cell aplasia (PRCA) is characterized by normocytic anemia with reticulocytopenia and marked reduction of the bone marrow erythroid precursors. PRCA may be congenital (Diamond-Blackfan anemia) or acquired. Acquired PRCA may present in the context of various backgrounds, the most common type in Japan being idiopathic, thymoma-associated, and large granular lymphocyte leukemia. Idiopathic and secondary PRCA that do not respond to the treatment of the underlying disease are generally treated using immunosuppressive agents. A retrospective study PRCA2004/2006 suggests that maintenance therapy and management of infectious complications is crucial for improving the prognosis in patients with PRCA. Recently, allogeneic stem cell transplantation has been considered as a potential option for the treatment of patients with PRCA who are refractory to immunosuppressive therapy. Sirolimus and roxadustat may be effective for relapsed/refractory PRCA with renal insufficiency and anti-erythropoietin antibody-mediated PRCA, respectively. Some gene mutations were detected in certain patients who had acquired PRCA, and the identification of STAT3 mutations may be useful in PRCA management. A prospective cohort study PRCA2016 has been ongoing in Japan, and novel discoveries provide hope for improving the outcome in patients with PRCA.

Pure red cell aplasia in systemic lupus erythematosus, a nationwide retrospective cohort and review of the literature.

OBJECTIVES: To characterize the clinical and biological course, management and response to treatment in SLE-associated pure red cell aplasia (PRCA). METHODS: This was a nationwide, multicentre, retrospective cohort study. From 2006 to 2018, we included adults with a diagnosis of PRCA supported by bone marrow examination and SLE or biologic manifestations of SLE after ruling out parvovirus B19 infection. RESULTS: We enrolled 24 patients (20 women). SLE was diagnosed before PRCA for 14 patients (median delay 81 months). At PRCA diagnosis, mean age, haemoglobin level, and reticulocyte and differential erythroblast count were 39.2 (13.2) years, 62 ( 20) g/l, 9.1 (7.6) × 109/l and 2.8 ( 2.5)%, respectively. Eleven (45%) patients experienced multiple PRCA flares (median 6, range 2-11). CS therapy resulted in only three complete sustained responses, and 19 (79%) patients required immunosuppressive agents with highly variable regimens. After a median follow-up of 76 months (range 13-173), 17 (71%) patients showed complete response for PRCA, 5 (21%) partial response and 2 (8%) treatment failure. In total, 21 (87%) patients required red blood cell transfusion; 5 had a diagnosis of transfusion-related iron overload. Eighteen (75%) patients experienced severe infectious events requiring hospitalization. CONCLUSION: SLE-associated PRCA is a severe condition. Repeated red blood cell transfusions and several lines of immunosuppressant therapy are mostly required, with high risk of severe infectious events and iron overload. Despite sustained response for PRCA and SLE obtained in most patients, the best therapeutic strategy remains to be determined.

Treatment for pure red cell aplasia after major ABO-incompatible allogeneic stem cell transplantation: a multicentre study.

Pure red cell aplasia (PRCA) following allogeneic haematopoietic stem cell transplantation (aHSCT) with major ABO incompatibility is responsible for transfusion dependent anaemia, impaired quality of life and iron overload. We conducted a retrospective study, over a 10-year period, which included all consecutive patients who received a major ABO mismatched aHSCT, to assess the impact of specific treatment on PRCA. We did not observe any PRCA in the 57 aHSCT issued from cord blood. Among the remaining 631 patients, cumulative incidence of PRCA was 10·5% [range 8·2-13.0]. The median duration of resolved PRCA was 171 days [IQR 116; 261]. Pre-transplant high isohaemagglutinins titre was associated with an increased risk of PRCA (P < 10-4 ). PRCA did not affect overall survival (P = 0·95). Twenty-two patients (33·3%) received at least one specific treatment. The most commonly used treatments were rituximab (17 patients) and donor lymphocyte infusion (DLI; seven patients). Regarding PRCA resolution, we did not observe a significant difference between treated or untreated subjects (HR = 0·93, 95% confidence interval (CI) 0·48- 1·80; P = 0·82). Similar results were observed with erythropoietin treatment (22 patients, HR = 0·86 95% CI: [0·47-1·57] P = 0·62). Our data do not support the use of erythropoietin, rituximab or DLI for the treatment of PRCA.

How I manage acquired pure red cell aplasia in adults.

Pure red cell aplasia (PRCA) is a rare hematological disorder with multiple etiologies. The multifaceted nature of this disease is emphasized by the variety of concomitant clinical features. Classic idiopathic presentation aside, prompt recognition of pathogenetic clues is important because of their diagnostic and therapeutic implications. As a consequence, treatment of PRCA is diverse and strictly dependent on the presented clinical scenario. Here, we propose a series of clinical vignettes that showcase instructive representative situations derived from our routine clinical practice. Using these illustrative clinical cases, we review the diagnostic workup needed for a precise diagnosis and the currently available therapeutic options, discussing their applications in regard to the various PRCA-associated conditions and individual patients' characteristics. Finally, we propose a treatment algorithm that may offer guidance for personalized therapeutic recommendations.

[Persistent anemia after kidney transplantation in a 36-year-old male patient-an unusual cause]. / Persistierende Anämie nach Nierentransplantation bei einem 36-jährigen Patienten ­ eine ungewöhnliche Ursache.

An allogeneic kidney transplantation (match 1­1­0, cytomegalovirus, CMV, donor, D, +/recipient, R, - high risk) was performed in a 36-year-old patient. The patient was on dialysis due to a tubulointerstitial nephritis confirmed by biopsy 11 years previously. Posttransplantation there was a gradual decrease in the hemoglobin (Hb) level from 11.4 g/dl to 7.3 g/dl during the initial hospitalization period. Initially this was explained by the kidney transplantation and chronic fibrosing antral gastritis with erosions. Despite repeated transfusion of red cell concentrates, a refractory anemia persisted, which is why the patient presented several times at our clinic for further diagnosis and treatment. The presence of giant erythroblasts in the bone marrow and quantitative detection of parvovirus B19 (>900 million IU/ml DNA replications) was consistent with a virus-associated red cell aplasia. Intravenous immunoglobulin administration was established and showed long-term therapeutic success.

Pure red cell aplasia after major or bidirectional ABO incompatible hematopoietic stem cell transplantation: to treat or not to treat, that is the question.

Pure red cell aplasia (PRCA) is a complication related to major or bidirectional ABO mismatched hematopoietic stem cell transplantation. This disorder is characterized by anemia, reticulocytopenia, and the absence or virtual absence of erythroid progenitors, other causes such as infections, hemolysis, disease relapse, or drug toxicity having been excluded. Patients with PRCA may become RBC transfusion dependent for long periods, suffering an important long-term iron overload, alloimmunization, and transfusion reactions. The persistence of recipient isoagglutinins against donor ABO antigens produced by host residual plasmatic cells has been considered as the immunological cause of the prolonged erythroid aplasia. PRCA behaves in many cases as a self-limited condition and resolution may occur spontaneously within weeks, months, and even years. Many different therapeutic approaches have been reported for posttransplant PRCA as plasmapheresis, high doses of erythropoietin, donor lymphocyte infusions, anti-thymocyte globulin, Rituximab and steroids, among others. However, to date there is no standard of care and the question if patients with PRCA should be treated and at which point remains. The objective of this article is to review the natural evolution of PRCA, and the treatments that have been used over time focusing on their suitability and efficacy.