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Guideline 3.15 – Monitoring of ESA Treatment – Evaluation for ESA Induced Pure Red Cell Aplasia

Guideline 3.15 – Monitoring of ESA Treatment – Evaluation for ESA Induced Pure Red Cell Aplasia

We recommend that a diagnosis of ESA induced pure red cell aplasia (PRCA) should be considered whenever a person receiving long term ESA therapy (>8 weeks) develops all the following (1A):

  • A sudden decrease in Hb concentration at the rate of 5 to 10 g/L per week or requirement of transfusions at the rate of approximately 1 to 2 per week
  • Normal platelet and white cell counts
  • Absolute reticulocyte count less than 10,000/μl
  • High serum ferritin

Guideline 3.15.1

We recommend that all ESA therapy should be stopped in people who develop ESA induced PRCA. (1A)

Guideline 3.15.2 We recommend that individuals who remain transfusion dependent after withdrawing ESA therapy should be treated with immunosuppressant medications guided by the level of anti EPO antibodies. (1B)

Guideline 3.15.3 We do not recommend routine screening for anti-erythropoietin antibodies among people with CKD regularly treated with erythropoiesis stimulating agents. (1B)

Rationale

Anti-erythropoietin antibody associated pure red cell aplasia (PRCA) is a very rare cause of resistance characterised by

  • transfusion dependency
  • low reticulocyte count (<1%)
  • lack of proerythroid progenitor cells in the bone marrow
  • neutralising anti-erythropoietin antibodies (1).

ESA induced PRCA is a very rare condition, with the overall incidence of reported cases between 1989 and June 2004 was 1.6 per 10,000 patient-years of subcutaneous exposure (2), and 0.02 per 10,000 patient-years of intravenous exposure (3). Nevertheless, most reported cases of anti-erythropoietin antibody-associated PRCA have occurred in people with CKD who have received the drug subcutaneously (4,5,6).

Pure red cell aplasia (PRCA) due to anti-erythropoietin (EPO) antibodies should be suspected in an individual who has previously responded to EPO if the haemoglobin (Hb) level declines by >20 g/L per month or the reticulocyte count is <20,000 /uL (5). PRCA is specifically characterized by the following clinical features (6):

  • A drop in Hb level of >7 to 10 g/L per week without transfusions or transfusion requirement of at least one unit per week to maintain adequate Hb, despite continued use of ESA at high doses.
  • Markedly reduced reticulocyte count (<10,000 /uL).
  • Normal platelet and white blood cell count.
  • Elevated serum transferrin saturation and serum ferritin.
  • Rarely, allergic urticarial skin reactions at sites of earlier subcutaneous EPO injections have been described (7).

The diagnosis of PRCA is established by:

  • Bone marrow examination: which confirms severe hypoplasia of erythroid precursors (<5%).
  • The presence of anti-erythropoietin antibodies:
    • There are several available tests to detect antibodies to erythropoietin, with varying sensitivities and specificities (8).
    • People with suspected ESA induced PRCA who test positive using binding antibodies should have the diagnosis confirmed with the definitive testing for neutralising antibodies (9).

There are several tests that can be used. These include:

  • radioimmunoprecipitation assay
  • electrochemiluminescence bridging enzyme-linked immunosorbent assay
  • surface plasmon resonance-based immunoassay.

The most validated test is the radioimmunoprecipitation assay. This test is very sensitive and can detect the presence of high-affinity anti-EPO IgG at concentrations as low as 10 ng/ml. This test is not currently available within NHS but can be organised with the industry as a part of post-marketing pharmacovigilance arrangement with the PRCA Rare Disease Group.

ESA induced PRCA is an immune mediated process. While spontaneous remissions after cessation of EPO therapy have been reported, immunosuppressive therapy is usually needed in most cases (10). One study evaluated 170 CKD patients who developed epoetin-associated PRCA (11). Of the 34 people who received epoetin after the onset of PRCA, 56% recovered epoetin responsiveness; the highest rate of epoetin responsiveness was observed among those who had no detectable anti-erythropoietin antibodies at the time of epoetin administration (89%). The study also reported that the highest recovery rates were among those treated with immunosuppressive therapy, particularly a combination of cyclophosphamide and prednisone (11). Other options such as rituximab, danazol or even plasma exchange may be considered.

Verhelst et al (12) compared various immunosuppressive agents in 37 people with antibody mediated PRCA compared to 10 with no treatment and found benefit with cyclophosphamide, plasma exchange and ciclosporin and also transplantation.

Given these data, it is advisable that retreatment with ESA may be considered in people with a history of PRCA only if anti-EPO antibody level is no longer detectable. In addition, if epoetin therapy is to be reconsidered for these people, only the intravenous rather than the subcutaneous route should be considered for drug administration.

ESA induced PRCA is now part of RaDaR, the UKKA’s National Registry of Rare Kidney Diseases. (13).

References

  1. Peschle C, Marmont AM, Marone G, et al. Pure red cell aplasia: studies on an IgG serum inhibitor neutralizing erythropoietin. Br J Haematol 1975; 30:411.
  2. Boven K, Stryker S, Knight J, et al. The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes. Kidney Int 2005; 67:2346.
  3. Cournoyer D, Toffelmire EB, Wells GA, et al. Anti-erythropoietin antibody-mediated pure red cell aplasia after treatment with recombinant erythropoietin products: recommendations for minimization of risk. J Am Soc Nephrol 2004; 15:2728.
  4. Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346:469.
  5. Rossert J, Casadevall N, Eckardt KU. Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc Nephrol 2004; 15:398.
  6. Eckardt KU, Casadevall N. Pure red-cell aplasia due to anti-erythropoietin antibodies. Nephrol Dial Transplant 2003; 18:865.
  7. Weber G, Gross J, Kromminga A, et al. Allergic skin and systemic reactions in a patient with pure red cell aplasia and anti-erythropoietin antibodies challenged with different epoetins. J Am Soc Nephrol 2002; 13:2381.
  8. Pollock C, Johnson DW, Hörl WH, et al. Pure red cell aplasia induced by erythropoiesis-stimulating agents. Clin J Am Soc Nephrol 2008; 3:193.
  9. Casadevall N, Cournoyer D, Marsh J, et al. Recommendations on haematological criteria for the diagnosis of epoetin-induced pure red cell aplasia. Eur J Haematol 2004; 73:389.
  10. Rossert J, Macdougall I, Casadevall N. Antibody-mediated pure red cell aplasia (PRCA) treatment and retreatment: multiple options. Nephrol Dial Transplant 2005; 20 Suppl 4:iv23.
  11. Bennett CL, Cournoyer D, Carson KR, et al. Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project. Blood 2005; 106:3343.
  12. Verhelst D, Rossert J, Casadevall N, et al. Treatment of erythropoietin-induced pure red cell aplasia: a retrospective study. Lancet. 2004 May 29;363(9423):1768-71.
  13. http://rarerenal.org/rare-disease-groups/pure-red-cell-aplasia-rdg/ (accessed 15/06/2017).