Restoration of erythropoiesis by rituximab in an adult patient with primary acquired pure red cell aplasia refractory to conventional treatment (2002)

Primary acquired pure red cell aplasia (PRCA) is characterized by the inability of erythroid progenitors to differentiate into erythroblasts, which is considered to result from the presence of a soluble inhibitory factor in the patient's serum. This inhibitor has been localized to the immunoglobulin (Ig) G fraction and targets hitherto undefined molecules on erythroid cells at any stage of differentiation between erythrocyte burst-forming units and erythroblasts. Therapeutic options include immunosuppressing or immunomodulating agents as well as plasmapheresis or splenectomy. However, these treatments may be associated with significant toxicity and only about half of patients respond (Charles et al, 1996; Dessypris, 2000). Recently, autoimmune haemolytic anaemia with concomitant PRCA in a child refractory to cyclosporin A was successfully treated with the anti-CD20 monoclonal antibody rituximab (Zecca et al, 2001), which effectively depletes B cells in vivo and has been introduced for the treatment of B-cell lymphomas (McLaughlin et al, 1998). We should like to report on an adult patient with primary acquired PRCA relapsing after treatment with cyclosporin A and refractory to antithymocyte globulin (ATG), in whom rituximab rapidly restored erythropoiesis. A 68-year old Caucasian man presented with severe normochromic-normocytic anaemia. The patient had been diagnosed with chronic renal failure of unknown aetiology 5 years previously, and treatment with recombinant human erythropoietin over the past 2 years had resulted in normal haemoglobin levels. Upon presentation, physical examination showed pallor but was otherwise unremarkable. A prosthetic heart sound was heard as the patient had received a non-biological mitral valve 5 years previously. Full blood count showed normochromic-normocytic anaemia (haemoglobin 7·8 g/dl), reticulocytopenia (absolute reticulocyte count 3 × 109/l) and normal white blood cell and platelet counts. Serum creatinine was 168 µmol/l and serum haptoglobin was undetectable. Lactate dehydrogenase and bilirubin levels were normal, and both direct and indirect Coombs tests were negative. No erythrocyte fragments were detectable upon examination of the blood film. There were no signs of active infection, and serological tests for parvovirus B19, Epstein–Barr virus and hepatitis B or C were negative. Extensive diagnostic evaluation of the patient did not reveal any evidence of neoplastic or autoimmune diseases. A bone marrow biopsy demonstrated slightly reduced overall cellularity, with normal granulopoiesis and megakaryopoiesis but almost complete absence of erythropoietic precursors. Upon immunohistochemistry, no reactivity with antibodies against glycophorin A and C and CD71 could be detected. Therefore, PRCA was diagnosed. The patient required multiple transfusions with packed red cells and treatment with prednisone in combination with cyclosporin A at conventional doses was initiated. During the following weeks, reticulocyte counts and haemoglobin levels gradually increased and 3 months after the beginning of immunosuppressive therapy the haemoglobin level had returned to normal despite tapering of prednisone. However, 2 months later reticulocyte counts and haemoglobin level began to decrease again and rapidly dropped to pretreatment values despite continued treatment with cyclosporin A. Again, bone marrow biopsy demonstrated an almost complete absence of erythropoiesis (Fig 1A). Recombinant human erythropoietin was stopped and treatment with horse antithymocyte globulin (ATG) at a dose of 15 mg/kg/d for 5 d in combination with prednisone 2 mg/kg/d with subsequent tapering was initiated, but did not result in any improvement of either haemoglobin level or reticulocyte counts. Eight weeks after treatment with ATG, the patient was still transfusion dependent and had an absolute reticulocyte count of 1·6 × 109/l. Treatment with rituximab was started at a dose of 375 mg/m2, administered weekly for a total of three doses and was well tolerated. Reticulocyte counts were 72·5 × 109/l 7 d after the first infusion and reached a maximum of 216 × 109/l on d 16. A bone marrow biopsy obtained after the third infusion of rituximab showed complete restoration of normal erythropoiesis (Fig 1B). Three months after completion of therapy the reticulocyte count was 89 × 109/l and the haemoglobin had reached 12·8 g/dl without any further red cell transfusion. Bone marrow biopsy (Giemsa, ×600) demonstrating absence of erythropoietic cells after conventional treatment for PRCA (A) and complete restoration of erythropoiesis after therapy with rituximab (B). This report suggests that treatment with the anti-CD20 monoclonal antibody rituximab may effectively restore erythropoiesis in adults with PRCA, even if immunosuppressive therapies have failed. The rapid increase in reticulocyte counts only a few days after the first infusion of the drug was paralleled by an almost complete disappearance of CD19+ B cells from the peripheral blood and is consistent with the observations made by Zecca et al (2001) in an 18-month-old girl. Our data and the results reported by Zecca et al (2001), who gave rituximab only twice, suggest that lower doses of rituximab than those needed for the treatment of lymphomas may be highly effective in eliminating the erythropoietic inhibitor from the patient's serum. As B-cell regeneration after treatment with rituximab usually occurs after 6–12 months (McLaughlin et al, 1998), erythropoietic failure might recur after that time. However, it seems justifiable to speculate that repeated administrations of low doses of rituximab could result in long-term remissions. Therefore, prospective trials of anti-CD20 therapy for PRCA would, in particular, have to address questions of duration of remission, optimal dosing and toxicities resulting from continued in vivo B-cell depletion, notably infectious complications.