T cell clonal expansion and STAT3 mutations: a characteristic feature of acquired chronic T cell-mediated pure red cell aplasia.

Acquired chronic pure red cell aplasia (PRCA) develops idiopathically or in association with other medical conditions, including T cell large granular lymphocytic leukemia (T-LGLL) and thymoma. T cell dysregulation is considered a cardinal pathogenesis of PRCA, but genetic-phenotypic associations in T cell abnormalities are largely unclear. We evaluated an extended cohort of 90 patients with acquired PRCA, including 26 with idiopathic, 36 with T-LGLL-associated and 15 with thymoma-associated PRCA, for their T cell immuno-phenotypes, clonalities and STAT3 mutations. TCR repertoire skewing of CD8+ T cells was detected in 37.5% of idiopathic, 66.7% of T-LGLL-associated and 25% of thymoma-associated PRCA patients, and restriction to Vß1 was most prominent (41%). Clonalities of TCRß or γ chain and STAT3 mutational status were statistically associated (P = 0.0398), and they were detected in all three subtypes. The overall response rate to cyclosporin A was 73.9%, without significant difference by subtypes nor STAT3 mutational status. The T cell dysregulations, such as TCR repertoire skewing with predominant Vß1 usage, clonality and STAT3 mutations, were frequently found across the subtypes, and the close associations between them suggest that these T cell derangements reflect a common pathophysiological mechanism among these PRCA subtypes.

Alemtuzumab-induced red cell aplasia and other immune cytopenias: not so 'pure'.

We report on the presentation and outcome of a 28-year-old female who developed red cell aplasia following alemtuzumab therapy for relapsing remitting multiple sclerosis. The patient also developed synchronous immune thrombocytopenia and immune neutropenia, but not aplastic anemia. This patient received high dose steroids, intravenous immunoglobulin (iv.Ig), rituximab, red cell transfusions, vincristine, G-CSF, cyclosporin and mycophenolate to treat the combination of cytopenias over a period of 6 months with subsequent improvement in bone marrow function. While alemtuzumab has several recognized autoimmune complications, little is known about the potential hematological side effects. The combination of red cell aplasia, immune thrombocytic purpura and autoimmune neutropenia has not previously been described in the literature following alemtuzumab immunotherapy and highlights the importance of monthly blood monitoring post alemtuzumab administration.

Lay abstract We report a case of 28-year-old women with relapsing remitting multiple sclerosis who was treated with alemtuzumab and subsequently developed a series of autoimmune complications. Several months after completing her second course of alemtuzumab the patient became breathless and noticed bruising on her legs. On investigation she was found to be anemic and had a low platelet level (which predisposed her to bruising). In addition, her immune system was also impaired meaning she was more prone to developing opportunistic infections. The patient was treated with a variety of different medications and required blood transfusions for several months before she recovered. Despite the multiple complications the patient developed from alemtuzumab her multiple sclerosis remains stable with no new relapses 3 years following treatment.

Selective ABO immunoadsorption in hematopoietic stem cell transplantation with major ABO incompatibility.

OBJECTIVE: ABO mismatch between donor and recipient occurs in 40% of allogeneic hematopoietic stem cell transplantations (HCT). Different strategies have been described to reduce isohemagglutinins (IHA) before HCT. We describe the effect of selective ABO immunoadsorption (ABO IA) on erythrocyte transfusion rate and the development of post-transplant pure red cell aplasia (ptPRCA). METHODS: 63 patients with major ABO incompatibility were retrospectively analyzed. Nine patients with major ABO incompatibility and high-IHA titer were treated by ABO IA before HCT. We analyzed the need for transfusion and the occurrence of ptPRCA. We compared the outcome with patients treated by other methods to reduce IHA. RESULTS: In all nine patients treated by ABO IA, IHA decreased in a median four times. PtPRCA occurred in one patient. The median number of transfusions was 8 (range: 0-36) between d0 and d100. In 25 patients with high-IHA titer without treatment or treated by other methods to reduce IHA, the need for transfusions was comparable. No difference in the incidence of ptPRCA was observed. CONCLUSIONS: Selective ABO IA is a feasible, safe, and effective method to reduce IHA before HCT in major ABO incompatibility. No effect on transfusion rate or ptPRCA compared to other strategies could be observed.

Modified recombinant human erythropoietin with potentially reduced immunogenicity.

Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of pure red cell aplasia (PRCA). The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB1*09 gene, which is reported to be entrenched in the Thai population. In this study, we used computational design to screen for immunogenic hotspots recognized by HLA-DRB1*09, and predicted seventeen mutants having anywhere between one through four mutations that reduce affinity for the allele, without disrupting the structural integrity and bioactivity. Five out of seventeen mutants were less immunogenic in vitro while retaining similar or slightly reduced bioactivity than rHuEPO. These engineered proteins could be the potential candidates to treat patients who are rHuEpo-dependent and express the HLA-DRB1*09 allele.

Daratumumab for pure red cell aplasia post ABO incompatible allogeneic hematopoietic stem cell transplant for aplastic anemia.

Pure red cell aplasia is a known complication after ABO incompatible stem cell transplant. Due to rarity of disease, no established treatment guidelines are available for PRCA. Daratumumab is a monoclonal antibody against CD38 expressed by plasma cells. In this report we present our experience of successfully managing a patient of post-transplant PRCA with daratumumab. Our patient had failed multiple lines of therapy prior to receiving daratumumab. Response was seen after the 3rd weekly dose of daratumumab.

Antibody-mediated pure red cell aplasia related with epoetin-beta pegol (C.E.R.A.) as an erythropoietic agent: case report of a dialysis patient.

BACKGROUND: Erythropoietin-stimulating agents (ESAs) are used to treat anemia in patients with chronic kidney disease, enabling maintenance of stable hemoglobin levels and eliminating the need for multiple transfusions. Epoetin-beta pegol (C.E.R.A.) is a continuous erythropoietin receptor activator created by integrating a large methoxy-polyethylene-glycol-polymer chain into the erythropoietin molecule, which provides it with a longer half-life. On rare occasions, cases of antibody-mediated pure red cell aplasia (PRCA) related to ESAs are reported. They are characterized by abrupt onset of severe transfusion-dependent anemia, despite ESA therapy. We herein report a case of antibody-mediated PRCA in a dialysis patient receiving C.E.R.A. CASE PRESENTATION: A 44-year-old man with end-stage renal failure had been receiving continuous ambulatory peritoneal dialysis for 2 years. C.E.R.A. was administered subcutaneously as a sole ESA once a month at the hospital since 4 years ago for the treatment of renal anemia and his hemoglobin level was well controlled at 12 g/dl. From 10 months before diagnosis, however, his hemoglobin level suddenly declined, necessitating frequent transfusions. Based on the results of a bone marrow examination and detection of anti-C.E.R.A. antibodies, the patient was diagnosed with antibody-mediated PRCA. After successful elimination of the antibodies using oral prednisolone plus cyclosporine, the patient was re-administrated C.E.R.A. intravenously, as there are few reports of antibody-mediated PRCA related to ESA using that administration route. He responded to the C.E.R.A., and his anemia dramatically improved, eliminating the need for blood transfusions. CONCLUSIONS: This is the first reported case of recovery from an antibody-mediated PRCA with C.E.R.A. after its re-administration following a reversal of the antibody. It has been suggested that the additional large pegylation chain makes C.E.R.A. less likely to trigger antibody generation than other ESAs. Following successful treatment of antibody-mediated PRCA using immunosuppressive therapy, C.E.R.A. can be re-administered intravenously to treat renal anemia.

Pure Red Cell Aplasia and Antibody-Mediated Rejection: Double Trouble in 1 Kidney Transplant Recipient Solved by Intravenous Immunoglobulin Infusion: A Case Report.

Acquired pure red cell aplasia (PRCA) is characterized by severe normocytic (rarely macrocytic) and normochromic anemia, a low reticulocytes count in peripheral blood, and near absence of erythroid precursors in the bone marrow, with a normal level of erythropoietin. We describe a case of the kidney transplant recipient, diagnosed with PRCA induced with parvovirus B19 infection. Our case demonstrates that although this complication is rare, it should be considered in a differential diagnosis of anemia diagnostics in immunocompromised patients. In our case reduced immune response resulted from post-transplant immunosuppressive therapy. In our patient, apart from infection by parvovirus B19, graft dysfunction due to polyomavirus BK virus infection was also detected together with histologic and serologic features of antibody-mediated renal graft rejection. Considering the entire clinical picture, intravenous immunoglobulin therapy (IVIg) was successfully introduced.

A tale of autoimmunity: thymoma, thymectomy, and systemic lupus erythematosus.

The thymus plays an integral role in immune system regulation, modulating the development, diversity, and selection of T lymphocytes, a critical feature for the prevention of T cell-mediated autoimmunity. Thymoma is a rare tumor of the thymus. Autoimmune diseases and paraneoplastic syndromes such as myasthenia gravis, pure red blood cell aplasia, and systemic lupus erythematosus, although relatively uncommon, have been described in association with thymomas. Rare cases of post-thymectomy autoimmune related diseases, including systemic lupus erythematosus and pure red cell aplasia, have been reported in the literature. Here, we present the case of a 65-year-old male who developed systemic lupus erythematosus 2 years after thymectomy in the setting of thymoma-associated pure red cell aplasia.

Immunosuppressive therapy for elderly-acquired pure red cell aplasia: cyclosporine A may be more effective.

This current study retrospectively analyzed the clinical characteristics of 69 adult patients with acquired pure red cell aplasia (PRCA) including 40 elderly and 29 non-elderly patients from September 2009 to June 2019. The remission induction therapy regimens included cyclosporine A (CsA), corticosteroids (CS), or other immunosuppressive agents. The overall response rate was 55% (22/40) in the elderly group compared with 75.9% (22/29) in non-elderly patients (P = 0.075). In elderly patients, the best remission was achieved in the group treated with CsA than those treated with CS or other immunosuppressive agents (83.3% vs 26.7% vs 42.9%%, P = 0.004). However, outcomes of remission were similar among different treatment groups (P = 0.458) in non-elderly patients. CS induced a higher response rate in the non-elderly than that in the elderly (88.9% vs 26.7%, P = 0.009). By univariate and multivariate analysis, the clinical efficacy of elderly patients with acquired PRCA was closely associated with an induction regimen of CsA (P = 0.009; P = 0.017). In conclusion, CsA might produce higher response rate than CS and other drugs in elderly patients with acquired PRCA.

Recurrence of Pure Red Cell Aplasia in a Kidney Transplant Recipient Due to Reactivation of Parvovirus B19 Infection Despite Two Cycles of Intravenous Immunoglobulin Therapy.

Parvovirus B19 is a single-stranded DNA virus that typically has an affinity for erythroid progenitor cells in bone marrow and leads to pure red cell aplasia. This is a common pathogen in humans, and the expression of the infection depends on the host's hematologic and immunologic status. Here, we report a female patient who developed severe and persistent anemia after kidney transplant while being on immunosuppressive therapy. The parvovirus B19 immunoglobulin M test was positive, and the virus was detected by polymerase chain reaction as parvovirus B19 (23.5 million copies/mL) in the blood sample. Bone marrow examination revealed giant pronormoblasts. She responded well to intravenous immunoglobulin without adverse event. Hemoglobin levels gradually increased, and normal levels were achieved at 3 months posttreatment. Although her renal function did not deteriorate, severe anemia (with hemoglobin level 5 g/dL) recurred 3 times during 12 months posttransplant.

Progressive peripheral CD8+ T lymphocytosis complicated by pure red cell aplasia following immunosuppressive therapy for thymoma-associated myasthenia gravis.

We herein report a unique case of type B2 thymoma-associated myasthenia gravis which was ameliorated by immunosuppressive therapy in combination with chemotherapy. However, the patient subsequently developed pure red cell aplasia and marked lymphocytosis after additional chemotherapy aimed at improvement of thymoma. While a separate immunosuppressive regimen was effective for anemia, lymphocytosis was exacerbated. The biopsied thymoma specimen contained CD4+, CD8+, and CD4+/CD8+ T cells, some of which were CD3-, suggesting immature thymocytes. In contrast, majority of the peripheral lymphocytes were polyclonal CD3+/CD8+/T cell receptor (TCR)αß+ T cells. The CD4/CD8 ratio in the present patient might be affected by immunosuppressive agents, resulting in CD8+ T cell expansion associated with pure red cell aplasia. Although several cases of thymoma accompanied by peripheral T cell lymphocytosis were reported, marked CD8+ T cell proliferation is extremely rare.

Successful treatment of refractory/relapsed acquired pure red cell aplasia with sirolimus.

Acquired pure red cell aplasia (aPRCA) is a kind of anemia characterized by severe reticulocytopenia and obvious bone marrow erythroblastic cells decreased. Some patients are refractory or intolerant to the first-line therapy (cyclosporine A with/without steroids). The effects of the second-line therapy are not satisfactory and sometimes not available. In this study, we analyzed the efficacy and side effect of sirolimus on refractory/relapsed aPRCA and investigated the possible mechanism of sirolimus on immune regulation. Twenty-one patients with refractory/relapsed aPRCA were enrolled in this study and were administered with sirolimus. Totally, 76.2% of patients responded to the sirolimus with 42.9% complete response during the experimental period. The median time for reaction was 4 months. Side effects were tolerable including infections; mild oral mucositis; sinus tachycardia, the increase of creatinine, transaminase, triglyceride, or cholesterol; and thrombocytopenia. Most patients stayed in remission or remained stable during the follow-up period. Early drug withdrawal may lead to quick relapse. Compared with healthy control, Treg levels in patients with aPRCA reduced significantly before sirolimus but recovered after successful treatment. Level of Treg cells correlated with hemoglobin level after effective sirolimus treatment. Thus, sirolimus was effective and tolerable for refractory/relapsed aPRCA. Effective sirolimus treatment may lead to the upregulation of Treg cells which may partly explain the underlying mechanism.

Recovery of Pure Red Cell Aplasia Following Hematopoietic Stem Cell Transplantation Associated with Interleukin (IL)-6 Elevation Caused by Odontogenic Infection.

We herein report a case of long-lasting pure red cell aplasia (PRCA) after major ABO-incompatible allogeneic stem cell transplantation (SCT) for acute lymphoblastic leukemia. The patient needed red blood cell (RBC) transfusion every week after SCT. On day 236, he was diagnosed with odontogenic infection, and the serum levels of Interleukin (IL)-6 were elevated to 12.1 pg/mL. After that, the numbers of reticulocyte rapidly began to increase, and RBC support was not needed from day 251. No standard care for PRCA following SCT has been established. The IL-6 elevation caused by the odontogenic infection therefore appears to have been affected by the improvement in PRCA.

Haemolysis, pure red cell aplasia and red cell antibody formation associated with major and bidirectional ABO incompatible haematopoietic stem cell transplantation.

BACKGROUND: Acute and delayed haemolysis, alloimmunisation and pure red cell aplasia (PRCA) are potential complications after ABO incompatible haematopoietic stem cell transplantation (HSCT). The aims of this study were to investigate acute and delayed red blood cell (RBC) antibody-associated complications, including haemolysis, PRCA and alloimmunisation in major and bidirectional ABO incompatible HSCT. MATERIALS AND METHODS: We retrospectively examined the transplant courses of 36 recipients of bone marrow or peripheral blood stem cells from ABO incompatible donors and evaluated the current practice of performing plasmapheresis in patients with higher isoagglutinin titres. We investigated the role of ABO incompatibility in haematopoietic recovery, transfusion requirements, alloimmunisation and PRCA. RESULTS: Laboratory signs of acute haemolysis were noted in five (14%) patients, one (3%) of whom had clinically overt haemolysis. Patients with haemolysis had IgM titres ≥1:8 and received >16 mL of RBC in the HSCT. In patients with higher titres, plasmapheresis performed prior to the transplant prevented acute haemolysis. Delayed haemolysis was not recorded in the follow up. Haematopoietic recovery and transfusion requirements did not differ notably between patients with and without haemolysis. De novo RBC antibodies were detected in two (5.5%) patients after HSCT, and PRCA was noted in one (3%) patient. DISCUSSION: Carried out with adequate graft processing, plasmapheresis and blood component support, haemolysis is not a common complication after HSCT. Our results confirm that the occurrence of haemolysis depends on larger RBC volumes and higher isoagglutinin titres. Despite the reduction of patients' isoagglutinin titres by plasmapheresis, we still noted a critical combination for the development of laboratory signs of haemolysis (IgM titre ≥1:8 and RBC volume >16 mL). De novo immunisation to RBC antigens and PRCA are rare events following ABO incompatible HSCT.

Efficacy and safety of rituximab for systemic lupus erythematosus-associated immune cytopenias: A multicenter retrospective cohort study of 71 adults.

The aim of the study was to assess the efficacy and safety of rituximab (RTX) for treating systemic lupus erythematosus (SLE)-associated immune cytopenias. This multicenter retrospective cohort study of adults from French referral centers and networks for adult immune cytopenias and SLE involved patients ≥18 years old with a definite diagnosis of SLE treated with RTX specifically for SLE-associated immune cytopenia from 2005 to 2015. Response assessment was based on standard definitions. In total, 71 patients, 61 women (85.9%), with median age 36 years [interquartile range 31-48], were included. The median duration of SLE at the time of the first RTX administration was 6.1 years [2.6-11.6] and the reason for using RTX was immune thrombocytopenia (ITP) for 44 patients (62.0%), autoimmune hemolytic anemia (AIHA) for 16 (22.5%), Evans syndrome for 10 (14.1%), and pure red cell aplasia for one patient. Before receiving RTX, patients had received a mean of 3.1 ± 1.3 treatments that included corticosteroids (100%), and hydroxychloroquine (88.5%). The overall initial response rate to RTX was 86% (91% with ITP, 87.5% with AIHA, and 60% with Evans syndrome), including 60.5% with complete response. Median follow-up after the first injection of RTX was 26.4 months [14.3-71.2]. Among 61 initial responders, relapse occurred in 24 (39.3%); for 18, RTX retreatment was successful in 16 (88.8%). Severe infections occurred after RTX in three patients, with no fatal outcome. No cases of RTX-induced neutropenia were observed. In conclusion, RTX seems effective and relatively safe for treating SLE-associated immune cytopenias.