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.

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.

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.

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.

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.

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.

Pure Red Cell Aplasia Associated with Monoclonal Gammopathy of Undetermined Significance and Literature Review.

BACKGROUND: Pure red cell aplasia (PRCA) is an uncommon disease which involves an almost complete absence of the erythroid lineage in bone marrow (BM) and causes severe anemia. Cases due to monoclonal gammopathy occurring in plasma cell disorder have been infrequently reported. Here we report a case of PRCA associated plasma cell disorder, especially monoclonal gammopathy of undetermined significance (MGUS). METHODS: A 55-year-old male visited the ER due to general weakness. At his initial visit he exhibited severe anemia. Mild intravascular hemolysis was suspected. For anemia evaluation, BM examination was performed. In BM aspiration, almost no erythroid precursor cells were observed. Also, plasma cells were relatively elevated, at 7.2%. Serum electrophoresis and immunofixation revealed paraproteinemia of 5.1 g/L (IgG and lambda). No hypercalcemia, renal insufficiency or lytic bone lesions were found. This unusual case showed MGUS accompanied by PCRA. We were also able to assume the erythroid cell-specific restriction due to paraprotein, because we ruled out possible causes of PRCA. RESULTS: We discovered several reported cases associated with plasma cell dyscrasia. However, most of these cases involved plasma cell myeloma, characterized by high immunoglobulin burden. Our case demonstrates that PRCA is also observed in cases with MGUS, where immunoglobulin burden is low. CONCLUSIONS: It is not yet accurately known, what parts of erythroid precursors are targeted by M-protein nor what the mechanism is. Therefore, additional research into this matter is necessary.

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia.

Most patients with acquired pure red cell aplasia (PRCA) and some with acquired aplastic anemia (AA) respond well to cyclosporine (CsA), but thereafter often show CsA dependency. The mechanism underlying this dependency remains unknown. We established a reliable method for measuring the regulatory T cell (Treg) count using FoxP3 and Helios expression as markers and determined the balance between Tregs and other helper T cell subsets in 16 PRCA and 29 AA patients. The ratios of interferon-γ-producing CD4(+) (Th1) T cells to Tregs in untreated patients and CsA-dependent patients were significantly higher (PRCA 5.77 ± 1.47 and 7.38 ± 2.58; AA 6.18 ± 2.35 and 8.94 ± 4.06) than in healthy volunteers (HVs; 3.33 ± 0.90) due to the profound decrease in the percentage of Tregs. In contrast, the ratios were comparable to HVs in convalescent CsA-treated AA patients (4.74 ± 2.10) and AA patients in remission after the cessation of CsA treatment (4.24 ± 1.67). Low-dose CsA (100 ng/ml) inhibited the proliferation of conventional T cells (Tconv) to a similar degree to the inhibition by Tregs in a co-culture with a 1:1 Treg/Tconv ratio. The data suggest that CsA may reverse the hematopoietic suppression in PRCA and AA patients by compensating for the inadequate immune regulatory function that occurs due to a profound decrease in the Treg count.

Bone marrow transplantation for CVID-like humoral immune deficiency associated with red cell aplasia.

Patients with common variable immunodeficiency (CVID) have a higher incidence of autoimmune disease, which may mark the disease onset; however, anemia secondary to pure red cell aplasia is an uncommon presenting feature. Here, we describe a case of CVID-like humoral immune deficiency in a child who initially presented with red cell aplasia and ultimately developed progressive bone marrow failure. Although bone marrow transplantation (BMT) has been associated with high mortality in CVID, our patient was successfully treated with a matched sibling BMT and engrafted with >98% donor chimerism and the development of normal antibody titers to diphtheria and tetanus toxoids.

[Significance of clonal TCR gene rearrangement in acquired pure red cell aplastic anemia].

OBJECTIVE: To evaluate the significance of T-cell antigen receptor (TCR) gene rearrangement among patients with acquired pure red cell aplastic anemia (A-PRCA). METHODS: For 16 patients with A-PRCA, an immunosuppressive regimen based on cyclosporin A (CsA) was applied. Rearrangement of the TCR gene was detected by PCR, and T lymphocyte subsets in peripheral blood specimens was detected with flow cytometry. RESULTS: Five patients had presented with TCR clonal rearrangement and were positive for both TCR γ and TCR δ. The blood of 13 patients have returned to normal with the treatment, which included 3 cases with bone marrow returning to normal. In 7 cases, the red cell hyperplasia of bone marrow is still down, but has increased with the treatment. Three patients were close to cure, 7 showed remission, 3 were improved, but 3 were ineffective. The rate of effective treatment in those with TCR rearrangement (2/5) was significantly lower than that those without (11/11, chi-square=8.123, P < 0.05). Compared with those without the TCR gene rearrangement, the Th cells and proportion of Th/Ts were significantly lower, while the Ts cell (CD3+CD8+) were significantly higher in those with the rearrangement (P < 0.05). CONCLUSION: TCR gene rearrangement may play a role in the pathogenesis of A-PRCA. CsA is effective for the treatment of A-PRCA, but patients presenting clonal TCR gene rearrangement may response poorly to the treatment.

Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS).

BACKGROUND: Subcutaneous administration of Eprex(®) (epoetin alfa) in patients with chronic kidney disease (CKD) was contraindicated in the European Union between 2002 and 2006 after increased reports of anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA). The Prospective Immunogenicity Surveillance Registry (PRIMS) was conducted to estimate the incidence of antibody-mediated PRCA with subcutaneous administration of a new coated-stopper syringe presentation of Eprex(®) and to compare this with the PRCA incidence with subcutaneous NeoRecormon(®) (epoetin beta) and Aranesp(®) (darbepoetin alfa). METHODS: PRIMS was a multicentre, multinational, non-interventional, parallel-group, immunogenicity surveillance registry. Adults with CKD receiving or about to initiate subcutaneous Eprex(®), NeoRecormon(®) or Aranesp(®) for anaemia were enrolled and followed for up to 3 years. Unexplained loss or lack of effect (LOE), including suspected PRCA, was reported, with antibody testing for confirmation of PRCA. RESULTS: Of the 15 333 patients enrolled, 5948 received Eprex(®) (8377 patient-years) and 9356 received NeoRecormon(®)/Aranesp(®) (14 286 patient-years). No treatment data were available for 29 patients. Among 23 patients with LOE, five cases of PRCA were confirmed (Eprex(®), n = 3; NeoRecormon(®), n = 1; Aranesp(®), n = 1). Based on exposed time, PRCA incidence was 35.8/100 000 patient-years (95% CI 7.4-104.7) for Eprex(®) versus 14.0/100 000 patient-years (95% CI 1.7-50.6) for NeoRecormon(®)/Aranesp(®). The incidence of PRCA with Eprex(®) was not significantly different versus comparator ESAs (rate ratio: 2.56; 95% CI 0.43-15.31). An analysis based on observed time produced similar findings. CONCLUSION: This large, prospective registry demonstrates that PRCA is rare with subcutaneous administration of either the new coated-stopper syringe presentation of Eprex(®), or NeoRecormon(®) or Aranesp(®).

Risk of pure red cell aplasia in patients with hepatitis C receiving antiviral therapy and an erythropoiesis-stimulating agent.

Antibody-mediated pure red cell aplasia (PRCA) has been primarily observed in patients with chronic kidney disease treated with an erythropoiesis-stimulating agent (ESA); only a few anecdotal cases have been reported in other patient populations. We searched the Amgen Global Safety Adverse Event Database and identified 14 patients with hepatitis C who developed severe anemia, anti-erythropoietin antibodies, and bone marrow biopsy-proven PRCA, while receiving interferon therapy (with or without ribavirin) and an ESA. During the follow-up period and after ESA treatment stopped, 11 patients no longer required transfusions and 3 did. Analysis of antibody isotypes showed that, contrary to reports of patients with chronic kidney disease, immunoglobulin G1 was the predominant isotype rather than immunoglobulin G4 (immunoglobulin G4 was detected in only 1 of 6 patients). Epitope mapping showed the anti-erythropoietin antibodies bound domains required for receptor binding. Therefore, the potential benefits of ESA therapy must be weighed against the risk for PRCA in patients with hepatitis C who are receiving treatment with interferon and ribavirin.

A simple screening test for the detection of erythropoietin antibodies.

Antibody-mediated pure red cell aplasia (PRCA) is a rare complication of erythropoietin (EPO) therapy. Identification and demonstration of functional activity of EPO antibodies required to diagnose this condition is difficult and only performed in selected laboratories worldwide. In this article we report a recent cluster of three cases of antibody-mediated PRCA over a 16-month period in a single center associated with EPREX use. We also describe the use of a simple low-cost inhibitor assay that can be used to screen for PRCA in local laboratories.

[Clinical assessment of CD4/8 ratio of bone marrow lymphocytes in acquired pure red cell aplasia].

We have reviewed 6 patients with acquired PRCA and investigated CD4/8 ratio in the bone marrow lymphocytes prior to treatment with cyclosporin A (CsA). CsA, as a remission induction therapy, produced CR in 3/6 patients, and PR+NR in 3/6 patients. CD4/8 ratio in CR group was high compared to PR+NR group. Moreover, the number of reticulocyte and hemoglobin concentration in CR group was high in comparison with PR+NR group. In acquired PRCA, CD4/8 ratio in the bone marrow lymphocytes may correlate with the disease status and the outcome of CsA treatment.

[Treating aplasia through home hospital care]. / Prise en charge d'une aplasie en hospitalisation à domicile.

Home care is developing for patients suffering from haematological-oncological pathologies. The nurses and the whole team of the home hospitalisation department of the Léon-Bérard Centre in Lyon are prepared to deal with aplasia. Depending on its seriousness, the patient may be hospitalised or treated at home.

Efficacy and long-term outcome of treatment for pure red cell aplasia after allogeneic stem cell transplantation from major ABO-incompatible donors.

No standard of care for pure red cell aplasia (PRCA) after major ABO-incompatible hematopoietic stem cell transplantation (HSCT) has been established. We conducted a retrospective cohort study to learn the efficacy and outcome of treatment for PRCA. One hundred forty-five recipients who showed delayed recovery of erythropoiesis and survived >100 days after transplantation without early disease progression were selected from 2846 records of major ABO-incompatible transplantation in the registry database in Japan, and detailed data of 46 recipients were collected. Treatment of PRCA, such as rapid tapering of calcineurin inhibitors, corticosteroids, or additional immunosuppressants, was given to 22 patients but not to the other 24 patients. The overall response rate of the treatment group was 54.5%. The number of days from diagnosis of PRCA to recovery of reticulocytes >1% and the cumulative number of red blood cell transfusions were not significantly different between the 2 groups. Infections accounted for the death of 7 of 11 patients in the treatment group. Univariate analysis identified 5 variables influencing survival, including graft-versus-host disease, disease progression, and treatment of PRCA; disease progression remained as the only factor negatively affecting survival by multivariate analysis. The present study could not provide supportive evidence for the beneficial effects of treatment for PRCA after major ABO-mismatched HSCT.

Allogeneic Th1 cells home to host bone marrow and spleen and mediate IFNγ-dependent aplasia.

Bone marrow graft failure and poor graft function are frequent complications after hematopoietic stem cell transplantation and result in significant morbidity and mortality. Both conditions are associated with graft-versus-host disease (GVHD), although the mechanism remains undefined. Here we show, in 2 distinct murine models of GVHD (complete MHC- and class II-disparate) that mimic human peripheral blood stem cell transplantation, that Th1 CD4(+) cells induce bone marrow failure in allogeneic recipients. Bone marrow failure after transplantation of allogeneic naïve CD4(+) T cells was associated with increased CD4(+) Th1 cell development within bone marrow and lymphoid tissues. Using IFNγ-reporter mice, we found that Th1 cells generated during GVHD induced bone marrow failure after transfers into secondary recipients. Homing studies demonstrated that transferred Th1 cells express CXCR4, which was associated with accumulation within bone marrow and spleen. Allogeneic Th1 cells were activated by radiation-resistant host bone marrow cells and induced bone marrow failure through an IFNγ-dependent mechanism. Thus, allogeneic Th1 CD4(+) cells generated during GVHD traffic to hematopoietic sites and induce bone marrow failure via IFNγ-mediated toxicity. These results have important implications for prevention and treatment of bone marrow graft failure after hematopoietic stem cell transplantation.