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

Abstract

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(®).

Keywords: chronic kidney disease; darbepoetin alfa; epoetin alfa; epoetin beta; pure red cell aplasia.

FIGURE 1:

Distribution of (a) the 751 sites from Europe and Australia that participated in the registry and (b) patients enrolled per country.

FIGURE 2:

K/DOQI CKD stage (a) and dialysis status (b) at enrolment. CKD, chronic kidney disease; K/DOQI, Kidney Disease Outcomes Quality Initiative.

FIGURE 3:

Outcomes of investigations of LOE reports. Ab, antibody; ICAC, Independent Case Adjudication Committee; EPO, erythropoietin; LOE, loss or lack of effect. ^aCause of LOE could not be confirmed by available laboratory data from the time of LOE for two cases with iron deficiency (one Ab testing not performed, one Ab-negative) and the Ab-negative case with folate deficiency reported as the cause of LOE. ^bBone marrow investigation was not suggestive of PRCA. ^cPRCA was excluded based on short duration of LOE (n = 3) or high reticulocyte count at time of LOE (n = 1). ^dPatient tested negative for anti-EPO Abs ∼6 months after LOE onset. ^eScreening failure. ^fBone marrow suggestive of PRCA in four cases; no bone marrow test for one case.