Pure red cell aplasia due to follow-on epoetin

Abstract

A 57-year-old man with end-stage renal disease secondary to chronic interstitial nephritis was initiated on hemodialysis in February 2006 for uremic symptoms. In April 2006, his hemoglobin (Hgb) was 10.7 g/dl and transferrin saturation was 12.7%. He was started on subcutaneous follow-on epoetin-alfa, Wepox (Wockhardt Limited India, Mumbai, India) and 10 weekly doses of 100 mg each of iron sucrose administered intravenously. His Hgb increased to 12.3 g/dl within 2 months after the initiation of epoetin. He then underwent coronary artery bypass graft surgery for triple vessel coronary artery disease. He received two units of packed cells during the post-operative period because of a decrease in the Hgb level to 8.2 g/dl. He was continued on epoetin at the same dose. Three months later the Hgb level later was 6.6 g/dl (Figure 1). Two units of red blood cell transfusion and intravenous iron were administered, and Wepox was continued. In December 2006, his Hgb decreased further to 4.9 g/dl. Further work up of his anemia revealed that a stool sample for occult blood was negative, an upper gastrointestinal endoscopy showed an antral ulcer, and gastric biopsy for Helicobacter pylori was positive. He was treated with ampicillin, tinidazole, and omeprazole for 10 days. A repeat endoscopy, 1 month later, revealed a healed duodenal ulcer. A peripheral smear showed reduced reticulocytes (0.8%) with normal platelet and myelocyte series. His serum transferrin saturation was 97.8%. lactate dehydrogenase was 385 U/l. Parvovirus B19 serology was negative (IgM level was 9.3 U/ml (negative if less than 17 U/ml)).He received, on an average, 4 units of packed red cells per month. A bone marrow trephine (Figure 2a) and aspirate (Figure 2b) showed a selective depletion of erythroblast precursors with normal granulopoiesis and megakaryopoiesis suggestive of pure red cell aplasia (PRCA). Wepox was withheld. His serum erythropoietin level was 558 mU/ml (normal range 10-30 mU/ml). The serum anti-erythropoietin antibody assay was positive (0.9% c.p.m. at 1:100 dilution and 4.3% c.p.m. at 1:20 dilution by radioimmunoprecipitation assay (RIPA)).

Regulatory considerations in oncologic biosimilar drug development

“…Reports of safety issues with some of these products, such as recombinant erythropoietins, have raised concerns about the quality of these biologics. [45][46][47][48] For example, increased rates of pure red-cell aplasia were observed in patients with chronic kidney disease who received subcutaneous administration of recombinant human erythropoietin compared with the reference product. Such adverse reaction appeared associated with an increased immunogenicity of the biologic product, with induction of anti-erythropoietin antibodies and pure red-cell aplasia in treated patients.…”

Terminology for biosimilars–a confusing minefield

“…It has been shown that the quality of different non-innovator/copy products can vary signifi cantly and even different batches of what appears to be the same product can differ, with implications for both effi cacy and safety [10,18,19,20]. It is therefore imperative that clear terminology is used to accurately describe the nature and particularly the regulatory procedure used for particular biologicals.…”

“…A case of pure red cell aplasia (PRCA) in an end-stage renal disease patient associated with induction of antibodies to administered erythropoietin (EPO) was described in India [10]. The patient had received the EPO product Wepox (Wockhardt Limited, India) which is referred to as a 'follow-on' product.…”

Erythropoiesis-Stimulating Agents in Renal Medicine

“…However, the EU leaves a broad margin of discretion to each member state concerning substitution. The introduction of biosimilars into clinical practice may affect patient safety, as can be seen from the fact that a small change in the manufacture of epoetin alfa in the late 1990s led to an upsurge in the number of cases of pure red cell aplasia (PRCA) [12], and other cases have also been described in patients receiving s.c. copies of epoetin alfa manufactured outside the EU [13,14]. Given these concerns, the EMA requires registration studies of s.c. biosimilars before approving this route of administration; however, one such study of HX575 was halted for safety reasons following one case of PRCA and one case of anti-rHuEPO antibody positivity [15].…”