Incidence Of Pure Red Cell Aplasia Research Articles

HLA-B*46:01:01:01 and HLA-DRB1*09:01:02:01 are associated with anti-rHuEPO-induced pure red cell aplasia

Treatment of anemia in patients with chronic kidney disease (CKD) with recombinant human erythropoietin (rHuEPO) can be disrupted by a severe complication, anti-rHuEPO-induced pure red cell aplasia (PRCA). Specific HLA genotypes may have played a role in the high incidence of PRCA in Thai patients (1.7/1,000 patient years vs. 0.03/10,000 patient years in Caucasians). We conducted a case–control study in 157 CKD patients with anti-rHuEPO-induced PRCA and 56 controls. The HLA typing was determined by sequencing using a highly accurate multiplex single-molecule, real-time, long-read sequencing platform. Four analytical models were deployed: Model 1 (additive: accounts for the number of alleles), Model 2 (dominant: accounts for only the presence or absence of alleles), Model 3 (adjusted additive with rHuEPO types) and Model 4 (adjusted dominant with rHuEPO types). HLA-B*46:01:01:01 and DRB1*09:01:02:01 were found to be independent risk markers for anti-rHuEPO-induced PRCA in all models [OR (95%CI), p-values for B*46:01:01:01: 4.58 (1.55–13.51), 0.006; 4.63 (1.56–13.75), 0.006; 5.72 (1.67–19.67), 0.006; and 5.81 (1.68–20.09), 0.005; for DRB1*09:01:02:01: 3.99 (1.28–12.49), 0.017, 4.50 (1.32–15.40), 0.016, 3.42 (1.09–10.74), 0.035, and 3.75 (1.08–13.07), 0.038, in Models 1–4, respectively. HLA-B*46:01:01:01 and DRB1*09:01:02:01 are susceptible alleles for anti-rHuEPO-induced PRCA. These findings support the role of HLA genotyping in helping to monitor patients receiving rHuEPO treatment.

Incidence of acquired pure red cell aplasia: a nationwide epidemiologic analysis with 2 registry databases in Japan

AbstractAcquired pure red cell aplasia (PRCA) is a rare syndrome characterized by anemia with reticulocytopenia and a marked reduction in erythroid precursors. Given its rarity, the true incidence is largely unknown, and epidemiological data representing the general population, with a description of the full spectrum of etiologies, are scarce. An epidemiological study on PRCA in Japan conducted 30 years ago estimated the annual incidence as 0.3 per million. To update the data and investigate the incidence and demographics of PRCA, we conducted a nationwide epidemiological study using the Japanese Society of Hematology (JSH) Hematologic Disease Registry, a hematologic disease registration database managed by the JSH and the Diagnosis Procedure Combination (DPC) study data available at a website of the Ministry of Health, Labor, and Welfare (MHLW) of Japan. A total of 1055 patients with newly diagnosed acquired PRCA were identified between 2012 and 2019, and the average annual incidence was calculated at 1.06 (95% confidence interval [CI], 0.83-1.28) per million. The median age was 73 (range, 18-99) years. The female-to-male ratio was 1.5:1, and the female predominance was most prominent in the child-bearing age group. Sixty-nine percent of acquired PRCA was idiopathic. The incidence of PRCA was approximately 20% of that of aplastic anemia (AA) during the same period. Approximately 0.98 patients per million per year (95% CI, 0.89-1.07) required hospitalization for the treatment of PRCA. These results are expected to contribute to the discussion of resource allocation for PRCA in the aging population in many countries, including Japan.

Donor-type fresh frozen plasma is effective in preventing hemolytic reaction in major ABO incompatible allogeneic stem cell transplant.

Hemolysis at the time of graft infusion is one of the immediate complications in major ABO-incompatible allogeneic hematopoietic stem cell transplants (HSCTs). We conducted a retrospective analysis to evaluate the efficacy of donor-type fresh frozen plasma (FFP) in reducing isohemagglutinin titer and preventing hemolysis, as well as its effect on delayed red cell engraftment. This is a single-center study on a series of 380 allogeneic HSCT between 2005 and 2015; of which 99 were either major (n = 74) or bidirectional (n = 25) ABO mismatched. Pre-transplant infusion of FFP, post-transplant complications and transfusion requirements were determined by retrospective review of individual medical records. Laboratory results were also reviewed for evidence of hemolysis and pure red cell aplasia (PRCA). Clinical manifestation of hemolysis attributable to ABO mismatch was present in one recipient of major ABO-incompatible peripheral blood stem cell (PBSC) with a titer of 64. Another recipient of major ABO-incompatible PBSC with a titer of 64 showed biochemical evidence of hemolysis. Both patients recovered with supportive treatment. Hemolysis did not occur in any patients with titer of 32 or less at the time of stem cell infusion. We were unable to demonstrate the influence of any variables on the incidence of PRCA. Our experience demonstrated that donor-type FFP is safe and effective in preventing acute hemolysis in major ABO-mismatched HSCT. We have also established the titer of 64 as the threshold that may cause hemolysis and therefore efforts should be made to reduce titer to below this level.

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

BackgroundSubcutaneous 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).MethodsPRIMS 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.ResultsOf 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.ConclusionThis 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®.

Incidence and natural history of pure red cell aplasia in major ABO‐mismatched haematopoietic cell transplantation

Major ABO mismatching is not considered a contraindication to allogeneic haematopoietic stem cell transplantation (HSCT). Modern reduced-intensity conditioning and reduced-toxicity regimens cause much less myeloablation than conventional myeloablative regimens, such as cyclophosphamide with busulfan or total body irradiation, which may affect the incidence of pure red cell aplasia (PRCA). We estimated the incidence and described the natural history of PRCA in patients with major ABO-mismatched donor stem cells. Between 2007 and 2008, 161 (27% of all patients undergoing HSCT) underwent allogeneic HSCT with major ABO-mismatched stem cells and 12 (7·5%) of these patients developed PRCA. Thirty and ninety day T-cell and myeloid cell chimerism and neutrophil and platelet engraftment did not differ between patients who developed PRCA and those who did not. The only risk factor associated with PRCA was the use of a fludarabine/busulfan conditioning regimen. All patients with PRCA needed red cell transfusion for several months after HSCT resulting in significant iron overload. Pure red cell aplasia resolved spontaneously in the majority (seven patients) but only resolved after stopping tacrolimus in three patients. Hence, after major ABO-mismatched HSCT, the incidence of PRCA was 7·5% and it resolved spontaneously or after withdrawal of immunosuppression in the majority of patients.

T-cell large granular lymphocyte leukemia: an Asian perspective

To characterize T-cell large granular leukemia in Asia, 22 Chinese patients from a single institute were reported, together with an analysis of 88 Asian and 272 Western patients identified from the literature. In our cohort, anemia due to pure red cell aplasia (PRCA) occurred in 15/22 (68%) of cases, being the most common indication for treatment. Neutropenia was only found in 8/22 (36%) cases, and recurrent infections, the most important clinical problem in Western patients, were not observed. None of our cases presented with rheumatoid arthritis. These clinical features were consistently observed when compared with the 88 other Asian patients. Combined data from our cohort and other Asian cases showed that Asian patients, compared with Western patients, had more frequent anemia (66/110, 60% versus 113/240, 47%; p = 0.044), attributable to a much higher incidence of PRCA (52/110, 47% versus 6/143, 4%; p < 0.001). However, Western patients presented more frequently than Asian patients with neutropenia (146/235, 62% versus 33/110, 30%; p < 0.001) and splenomegaly (99/246, 40% versus 16/110, 15%; p < 0.001). Notably, Western patients were about eight to ten times more likely than Asian patients to have rheumatoid arthritis (73/272, 27% versus 4/106, 4%; p < 0.001) and recurrent infections (81/272, 30% versus 3/107, 3%; p < 0.001). These clinicopathologic differences have important implications on disease pathogenesis and treatment.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-009-0895-3) contains supplementary material, which is available to authorized users.

Pure Red-Cell Aplasia “Epidemic”—Mystery Completely Revealed?

Starting in 1998, the number of pure red-cell aplasia (PRCA) cases in patients treated with recombinant human erythropoietin (rHuEPO) increased dramatically. Most cases were observed in patients treated with epoetin alfa produced outside the United States. The peak was observed in 2002; since then, the PRCA incidence has declined. Many factors are likely to have contributed to this up-surge. The molecular structure of the various epoetins and patient characteristics do not seem to play a major role. The route of administration holds some importance, because most PRCA patients received rHuEPO subcutaneously. The peak of PRCA cases overlapped with the removal of human serum albumin from the Eprex formulation (Janssen-Pharmaceutica NV, Beerse, Belgium), for which polysorbate 80 and glycine were substituted. Polysorbate 80 may have increased the immunogenicity of Eprex by eliciting the formation of epoetin-containing micelles or by interacting with leachates released by the uncoated rubber stoppers of prefilled syringes. Compared with the previous formulation, the polysorbate 80 formulation has lower stability, making it more susceptible to stress conditions such as insufficient attention to the cold chain. This situation could facilitate protein denaturation or aggregate formation. Uncoated rubber stoppers were replaced with coated stoppers, and the cold chain was reinforced; the Eprex formulation has remained unchanged. Even though the incidence of PRCA returned to very low levels, discriminating the cause-effect relationship of a single action is difficult, given that all occurred with a similar chronology, and that PRCA develops after a relatively long exposure period. Careful observation of future trends of new PRCA cases is thus mandatory.

Clinical Features and Risk Factors of Pure Red Cell Aplasia Following Major ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation.

Objective: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).Method: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.Results:1. 11 out of the 42 patients developed PRCA (26.1%); 2. 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). 3. The following factors were associated with an increased risk of PRCA:(1) blood group O recipient;(2) blood group A donor;(3) blood group O/A in recipient/donor pair;4. Only blood group O/A in recipient/donor pair was identified as being significantly associated with the occurrence of PRCA by multivariate analysis (P=0.006); 5. 6 patients who received donor-type plasma exchange did not develop PRCA, and among them, 5 cases were the O blood group recipients. 8 patients obtained spontaneous remission and in the remaining 3 patients, 2 patients 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.Conclusions:The incidence of PRCA in this series of patients was 26.1%. Only 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 is an effective approach for the treatment and prophylaxis of PRCA. Anti-CD20 monoclonal antibody is indicated for patients who are not response to conventional therapy.

Reduced-Intensity Transplants - Red Cell Antigens, Antibodies, and Blood Product Usage.

Introduction Reduced-intensity conditioning (RIC) transplants currently comprise 25–30% of allogeneic transplants in Europe. Previously reported data suggested delayed donor erythroid engraftment and isohaemaglutinin disappearance in RIC transplants, Additionally, reduced blood product usage has been reported. We prospectively studiedthe kinetics of donor red cell engraftment;kinetics of recipient- and donor-type isohaemaglutinnins, andusage of blood products, in 100 consecutive patients undergoing haemopoietic cell transplantation (HCT) for haematological malignancy at a single centre:Material and Methods 59 patients had RIC conditioning (37 FB8C (Fludarabine Busulphan 8mg/kg Campath1H), 22 FMC, Melphalan 140mg/m2), and 41 standard (Std) conditioning (13, TBI 14.4Gy BuCyCampath, 4 BuCy200, 16 BEAM-Campath1H, 8 FB16C, Busulphan 16mg/kg). Emergence of donor red cells and isohaemaglutinine titres were detected by Diamed columns (sensitivity approx. 5%). Bone marrow samples on days 28, 56, and 100 post transplant were used for semisolid culture of erythroid progenitors (BFU-E).Results. In 50/100 patients (26 RIC and 24 Std) emergence of donor red cell antigens was detectable by serology (19 major and 8 bidirectional ABO mismatches; 22 patients were informative due to a Rh antigen mismatch (10 D, 8 E, 2 C, and 2 c); One had a M-mismatch). Median time for the appearance of donor red cells was 66 days for Std conditioning and 56 days for RIC (not significant). Within the RIC group, there was no significant difference between ABO vs. Rh - mismatched transplants. Similarly, the kinetics of disappearance of recipient-type isohaemaglutinin was not different between RIC vs. Std conditioning (median 82 days for RIC and 69 days for Std). Appearance of donor-type isohaemaglutinin, followed in patients with minor or bidirectional ABO mismatch, was delayed regardless of the conditioning regime: only 3/24 patients had detectable donor-derived anti-A/B after a median of 336 days post transplant.Patients receiving a RIC regime required significantly less platelet transfusions: 14.4 vs 7.8 units (P= 0.02). There was a trend toward a higher number of RBC units transfused to patients receiving Std than RIC regimes: 14 vs 9 units (P= 0.06), but with substantial variation between different standard regimes.BFU counts showed a linear increase but the mean count was still subnormal by day 100. within the RIC group, BFU-E counts were not significantly different between ABO identical vs. non-ABO identical transplants. DNA from BFU-E colonies from 87 patient- points has been stored, to be compared with serology and blood lymphoid/myeloid chimerism data.There were no cases of Pure Red Cell Aplasia (PRCA) in the RIC patients with major ABO mismatch. Only one case of autoimmune haemolytic anaemia was identified in the entire study group, after a median follow up of 345 days.Conclusions Donor red cell emergence and disappearance of recipient-type anti-A/B are not delayed wit RIC regimes that we use. In keeping with this is the low incidence of post-transplant PRCA. Donor-type anti-A/B production is suppressed, probably due to the effect of Campath 1H, accounting for the absence of severe “passenger lymphocyte” haemolysis. Red cell and platelet usage are markedly decreased in RIC transplants due to reduced myelosuppression.

Safety and impact of donor‐type red blood cell transfusion before allogeneic peripheral blood progenitor cell transplantation with major ABO mismatch

Changes within the ABO system are regularly observed phenomena in allogeneic bone marrow transplantation (BMT) and peripheral blood progenitor cell transplantation (PBPCT). Major ABO mismatch can lead to different clinical problems including acute hemolysis after infusion of the allograft, delay of red blood cell (RBC) engraftment, or even manifestation of pure red cell aplasia (PRCA). This retrospective study demonstrates the safety and the impact of donor-type RBC transfusion before allogeneic PBPCT in major ABO settings as routinely performed at our transplantation unit. This study reports on transfusion of mismatched RBCs at the end of the conditioning period in 35 patients who underwent allogeneic PBPCT, which led to a decrease in isoagglutinin titers in most cases. A decrease of isoagglutinin titer after donor-type RBC transfusion can significantly reduce the demand of RBC transfusion between transplantation and Day +30 (p = 0.003). Interestingly, patients who developed PRCA were not observed, a complication being regularly documented by other groups. A decrease of isoagglutinin titers by in vivo immunoadsorption before allogeneic PBPCT does not only lack severe complication but also leads to a reduction in demand of RBC transfusion after engraftment and may reduce the incidence of PRCA in these patients.

Incidence of recombinant erythropoietin (EPO) hyporesponse, EPO-associated antibodies, and pure red cell aplasia in dialysis patients

Since 1998, an increase of anti-erythropoietin (anti-EPO) antibody-induced pure red cell aplasia (PRCA) has been reported. As data up to now consisted mostly of spontaneously reported cases the question arose about the frequency of this increase in EPO-induced PRCA. The objectives of this study were to determine the incidence and causes of recombinant EPO hyporesponse, of antibodies to EPO in patients on dialysis, and to relate the detection of anti-EPO antibodies to the presence of PRCA. This multicenter cohort study used existing patient data and serum samples collected at 6-month intervals from 1677 patients with incident end-stage renal disease (ESRD) participating in The Netherlands Cooperative Study on the Adequacy of Dialysis-2 (NECOSAD-2). Fifty-seven patients had an inadequate EPO response, which resulted in an incidence of 16.7 per 1000 patient-years on EPO while on dialysis. All available sera specimens (N = 232) of these patients were screened for anti-EPO antibodies. The sera specimens of two of these 57 patients tested positive. Of the 57 patients with inadequate EPO response, one had clinical PRCA (incidence 0.29 per 1000 patient-years on EPO and on dialysis). Of the 1346 patients without symptoms of inadequate EPO response, one patient tested borderline positive for anti-EPO antibodies. In total, three patients developed EPO antibodies during follow-up, leading to an estimated incidence of 1.27/1000 (95% CI 0.3 to 3.7/1000) patient-years since the start of dialysis. The incidence of inadequate EPO response in our population of dialysis patients is in concordance with tentative calculations found in the literature. Furthermore, we found the incidence of EPO-induced PRCA and EPO antibodies to be low.

The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes

The incidence of pure red cell aplasia (PRCA) in chronic kidney disease patients treated with epoetins increased substantially in 1998, was shown to be antibody mediated, and was associated predominantly with subcutaneous administration of Eprex. A technical investigation identified organic compounds leached from uncoated rubber stoppers in prefilled syringes containing polysorbate 80 as the most probable cause of the increased immunogenicity. This study investigated whether the incidence of PRCA was higher for exposure to the product form containing leachates than for leachate-free product forms. Antibody-mediated PRCA cases were classified according to indication, product form, and route of administration. Exposure estimates were obtained by country, indication, route of administration, and product form. For 2001 to 2003, the PRCA incidence rate for patients with subcutaneous exposure to Eprex in prefilled syringes with polysorbate 80 and uncoated rubber stoppers (leachates present) was 4.61/10,000 patient years (95% CI 3.88-5.43) versus 0.26/10,000 patient years (95% CI 0.007-1.44) for syringes with coated stoppers (leachates absent). The rate difference was 4.35/10,000 patient years (95% CI 3.44-5.26; P < 0.0001); the rate ratio was 17 (95% CI 3.14-707). A substantial rate difference remained in sensitivity analyses that adjusted for exposure to multiple product forms. The epidemiologic data, together with the chemical and immunologic data, support the hypothesis that leachates from uncoated rubber syringe stoppers caused the increased incidence of PRCA associated with Eprex. Currently, all Eprex prefilled syringes contain fluoro-resin coated stoppers, which has contributed to decreased incidence of PRCA with continued surveillance.

Acquired red cell aplasia in association with the use of recombinant erythropoietin in chronic renal failure

Acquired pure red cell aplasia (PRCA) is a rare condition. Traditionally it has been described in association with various etiologies such as parvovirus B19 infection, auto-immune disorders and drugs. Immunologically mediated PRCA is by far the commonest cause in adults, particularly since 1998, when a marked increased incidence of PRCA was noted in chronic renal failure patients receiving subcutaneous (SC) recombinant erythropoietin (rEpo). Typically these patients had been given erythropoietin for correction of anemia of renal failure and subsequently present with severe transfusion dependent anemia. Most cases were associated with SC administration of human serum albumin (HSA) free erythropoieitin alfa product (Eprex). Early recognition and withdrawal of erythropoietin therapy is essential. Treatment with immunosuppressive therapy, particularly in conjunction with renal transplant results in good response with resolution in the majority of cases. The pathogenesis is related to interaction of multiple factors such as formulation change and improper storage leading to increased immunogenicity of the recombinant product. The incidence peaked in 2001 and 2002, subsequently dropping considerably from 2003. This can be explained by the institution of measures such as more stringent handling and storage conditions, improvements in formulation of HSA free Eprex and switch to intravenous (IV) administration for Eprex in dialysis patients. The evidence to date on this condition is summarized in this review.

Pre-transplant reduction of isohaemagglutinin titres by donor group plasma infusion does not reduce the incidence of pure red cell aplasia in major ABO-mismatched transplants

Major ABO incompatibility in stem cell transplant recipients has been associated with pure red cell aplasia (PRCA). Reduction of incompatible isohaemagglutinin titres pre-transplant by various methods has been thought to reduce the incidence of PRCA. Our data suggest that pre-transplant reduction of incompatible isohaemagglutinin titres by donor group plasma infusion does not reduce the incidence of PRCA. We also failed to find any relationship between pre-transplant ABO isohaemagglutinin titre and the risk of developing PRCA.

Epoetin-associated pure red cell aplasia in patients with chronic kidney disease: solving the mystery

A substantial increase in the incidence of pure red cell aplasia (PRCA) associated with recombinant human erythropoietin (epoetin) treatment occurred in 1998. The upsurge of antibody-mediated PRCA was almost exclusively associated with chronic kidney disease patients who received subcutaneous epoetin therapy and the formulation of epoetin-alpha distributed outside the USA (EPREX/ERYPO). A systematic programme of technical, immunological and epidemiological investigations was initiated to identify the possible causes. The potential causes were evaluated on the basis of the following criteria: temporal correlation with the increase in incidence of PRCA, significant difference between EPREX/ERYPO and other epoetin products, sufficient concentration in the product to elicit a weak immune response, evidence of immunogenic activity in animals supportive, and consistent with available clinical data. Organic compounds that were leached from rubber stoppers through the action of polysorbate 80 were detected in pre-filled syringes with uncoated rubber stoppers containing polysorbate 80-formulated EPREX/ERYPO (introduced outside the USA in 1998). The leachates were not present when the stoppers were coated, in the product formulated with human serum albumin or in other epoetin products. The adjuvant activity of the leachates was demonstrated in mice. The incidence of PRCA was significantly higher in patients exposed to the polysorbate 80 formulation of epoetin-alpha delivered from pre-filled syringes with uncoated rubber stoppers, which were recalled in 2003, than in patients exposed to the same formulation from syringes with coated rubber stoppers. In conclusion, these data strongly suggest that leachates were the critical contributory factor in the increased incidence of antibody-mediated PRCA attributed to EPREX/ERYPO.

Pure red-cell aplasia and epoetin therapy.

Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France--12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States. We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon. The numbers of case reports and estimates of exposure-adjusted incidence were analyzed according to the product, the cause of anemia, the route of administration, the country in which pure red-cell aplasia was identified, and the date on which pure red-cell aplasia was reported. Between January 1998 and April 2004, 175 cases of epoetin-associated pure red-cell aplasia were reported for Eprex, 11 cases for Neorecormon, and 5 cases for Epogen. Over half these cases had occurred in France, Canada, the United Kingdom, and Spain. Between 2001 and 2003, the estimated exposure-adjusted incidence was 18 cases per 100,000 patient-years for the Eprex formulation without human serum albumin, 6 per 100,000 patient-years for the Eprex formulation with human serum albumin, 1 case per 100,000 patient-years for Neorecormon, and 0.2 case per 100,000 patient-years for Epogen. After procedures were adopted to ensure appropriate storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83 percent worldwide. After the peak incidence of Eprex-associated pure red-cell aplasia was reached in 2001, interventions designed in response to drug-monitoring programs worldwide resulted in a reduction of more than 80 percent in the incidence of pure red-cell aplasia due to Eprex.

Epoetins: differences and their relevance to immunogenicity

SUMMARYRecombinant human erythropoietin (epoetin) is a highly active molecule and as such is used at very low therapeutic concentrations that requirestabilisation. Commercially available epoetins differ in the stabilisers used in their formulations, which result in variations between epoetin preparations in storage and handling requirements. The stability and solubility of the epoetins are also affected by differences in the carbohydrate moieties that exist between them. However, it is the difference in stabilising agents that is thought to be the major cause of the upsurge in pure red cell aplasia (PRCA) cases observed predominantly with one epoetin alfa formulation, Eprex (Johnson & Johnson). In 1998 the European formulation of Eprex was changed with the replacement of human serum albumin (HSA), by polysorbate 80 and glycine. This formulation change coincided with an increased incidence of PRCA. In contrast, the incidence of PRCA has remained low with other HSA-containing epoetin alfa products and with epoetin beta. Therefore, it appears that the change in Eprex formulation has resulted in reduced protein stability and increased immunogenicity.