Antibody-Mediated Pure Red-Cell Aplasia in Patients Treated with Recombinant Erythropoietin
March 1, 2002 4 minutes read
Antibody-Mediated Pure Red-Cell Aplasia in Patients Treated with Recombinant Erythropoietin
Abstract & Commentary
Synopsis: Pure red-cell aplasia developed in 13 renal failure patients who had been treated with recombinant erythropoietin. The serum of these patients inhibited bone marrow erythroid colony formation and was shown to contain antibody to the recombinant erythropoietin molecule. Discontinuation of erythropoietin treatment and immunosuppressive therapy (with or without renal allograft) partially corrected the red cell aplasia in most of the evaluable patients. The development of antibody to erythropoietin may account for the acquired refractoriness to erythropoietin treatment in previous responders, such as observed occasionally in medical oncology clinics.
Source: Casadevall N, et al. N Engl J Med. 2002;346: 469-475.
Over a period of 3 years, 13 patients (12 from France, 1 from Great Britain), who developed pure red-cell aplasia (PRCA) while receiving recombinant human erythropoietin (rHuEPO) to improve the anemia associated with chronic renal failure, were found to become refractory to treatment. All but 2 were receiving hemodialysis, and all received their rHuEPO by subcutaneous injection (from 3 to 67 months before refractoriness was apparent). Pure red-cell aplasia was diagnosed on the basis of absence of differentiating red cells in the marrow (in 12 patients) and the absence of circulating reticulocytes in 1 patient. All patients were screened for virus infection (B19, HIV, EBV, hepatitis and CMV) and were evaluated by CT to rule out thymoma. Serum erythropoietin levels were undetectable in 10 patients and within the normal range (but not high) in the other 3.
Normal bone marrow was obtained from nonanemic hip replacement patients and erythroid colony assays were performed. Serum from all 13 PRCA patients inhibited colony formation. The inhibition was reversed by added rHuEPO. The presence of antierythropoietin antibodies was identified by means of binding assays with the use of 125I-labled rHuEPO. All 13 patients had detectable antibody that reacted with epitopes on the intact rHuEPO molecule but binding was lost in 12 of the 13 patients when the rHuEPO molecule was denatured. Thus, the developed antibodies were likely to be reacting with conformational epitopes only.
Therapy with rHuEPO was discontinued in all patients and 6 of the 13 recovered some erythropoietic function after receiving immunosuppressive therapy or renal allograft. Two patients remain transfusion dependent and the remaining patients had been followed an inadequate period of time to assess response to therapy or duration of PRCA.
Casadevall and colleagues recommend that physicians who care for patients receiving rHuEPO consider immunological mechanisms if refractory anemia develops while receiving, or after treatment. Assessment of anti-erythropoietin antibodies is recommended and, if found, erythropoietin treatment discontinued immediately. Challenging with other recombinant erythropoietin products was not recommended because the antibodies have been shown to cross react with all commercially available recombinant erythropoietic products, including darbepoetin alfa (Amgen).
Comment by William B. Ershler, MD
Recombinant erythropoietin is now commonly used in oncology practices, particularly for chemotherapy-induced anemia. Its use has been shown to raise the hemoglobin level in the majority of patients,1 and more importantly, improve quality of life for those who respond.2 In addition to its efficacy, what is remarkable has been the paucity of serious adverse events. However, in this recently published report from France, 13 renal failure patients were shown to develop pure red-cell aplasia after treatment with recombinant erythropoietin. Although all were renal failure patients, it is possible, even likely, that similar immunologic processes are occurring in other rHuEPO treated patients. However, there is a small chance that because of the dose and schedule differences, and the length of treatment (often several years), renal failure patients might be particularly susceptible to this complication. Furthermore, patients receiving cytotoxic chemotherapy might be sufficiently immune suppressed to not mount a response to the recombinant erythropoietin molecule.
Oncologists, however, not uncommonly experience patients who have initially responded to rHuEPO treatment only to become refractory after some period of time. This may have been attributed to a progression of their underlying malignancy or damage to marrow progenitor cells with continued cytoreductive therapy. The information presented in this report raises the alternative suggestion that immunological mechanisms are responsible. Hopefully, additional research by this, or another group will test to see if this mechanism is relevant to other (nonrenal) patients.
Until these data are available, the common practice of escalating doses in patients who become refractory to standard dose rHuEPO might be the wrong thing to do and should be done with caution. Unfortunately, commercial laboratories do not currently offer an anti-erythropoietin antibody assay, although it is likely that such will be available before long. Short of that, bone marrow aspirate and biopsy might be useful in patients who become refractory to rHuEPO treatment and if PRCA is observed, treatment immediately discontinued, and possibly immunosuppressive therapy offered under certain specific clinical circumstances.
References
1. Glaspy J, et al. J Clin Oncol. 1997;15:1218-1234.
2. Demetri GD, et al. J Clin Oncol. 1998;16:3412-3425.
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