Pure red cell aplasia associated with hemolytic anemia refractory to standard measures and resolved by rituximab in an elderly patient

Excerpt

Acquired pure red cell aplasia (PRCA) simultaneously associated with autoimmune hemolytic anemia (AIHA) has been very rarely described so far [1, 2]. We describe the case of an elderly woman, who was diagnosed as having idiopathic PRCA associated with AIHA which was unresponsive to two lines of immunosuppressive treatment and was then resolved by rituximab given as salvage therapy. A 68-year-old woman kept under our attention because of severe malaise, pallor and fatigue. Her past medical history was unremarkable; in particular, she denied any personal or familiar history of hereditary hemolytic anemia or autoimmune diseases. A past blood count had shown normal hemoglobin. Physical examination at admission was unremarkable, with the exception of pallor and mild jaundice; the patient did not present either spleen or liver enlargement. A comprehensive laboratory evaluation revealed no abnormalities other than those related to anemia and hemolysis. Indeed, severe normochromic and normocytic anemia (hemoglobin, Hb = 2.7 g/dl) was revealed. Reticulocytes were not detectable; white blood cell and platelet counts were normal. Increased indirect serum bilirubin, urinary urobilinogen and serum lactate dehydrogenase were present; serum haptoglobin was undetectable. Direct and indirect Coombs tests were positive. A warm-reactive antibody of the IgG isotype was eluted from the red blood cells (RBC). Serologic tests for parvovirus B19, HIV, Hepatitis virus, human cytomegalovirus, and Epstein-Barr virus were negative. Moreover, no clinical and/or laboratory signs of associated autoimmune disease were detected. Chest X-ray and total body CT scan showed normal findings. On the blood film, spherocytes and polychromasia were found. A bone marrow (BM) aspirate and a trephine biopsy demonstrated normal representation of myeloid and megakaryocytic precursors, but nearly absent erythroid precursors. Based on these findings, a diagnosis of AIHA combined to PRCA was made. Given the symptomatic anemia and the very low Hb levels, the patient received repeated administration of RBC concentrates. Methylprednisolone 2 mg/kg was given for 4 weeks without any benefit; equally ineffective was the concomitant treatment with cyclosporine-A (CSA) during the following 4 weeks. Therefore, in the light of reported experiences concerning the treatment of AIHA [3] and PRCA [2], the patient was offered rituximab as salvage therapy for which she gave her informed consent. Rituximab was administered intravenously at the dose of 375 mg/m² as a 4-h infusion, once weekly for a total of four doses, without any adverse reaction or side effects (July 2007). Progressive increase of Hb levels and achievement of transfusion independence followed the rise in reticulocytes after the fourth dose of rituximab. Serum hemolytic parameters normalized, as well as the serologic finding of an auto-antibody also disappeared. A BM aspirate demonstrated no abnormal findings and, in particular, the full recovery of the erythroid matrix. The patient, 10 months after rituximab therapy, shows normal Hb and reticulocyte levels, and she is no longer received immunosuppressive therapy. Treatment of PRCA and of AIHA usually employs immunosuppressive drugs, mainly steroids and CSA, or immunomodulating agents [1]. However, conventional immunosuppressive treatments are often unsatisfactory for which rituximab has been successfully used as salvage therapy in the pediatric setting [2]. Our report concerns the case of a combined AIHA/PRCA, which has been very exceptionally observed as primary and idiopathic condition in the elderly, in which the treatment with rituximab has not be reported so far. In our experience, the patient was refractory to steroids and CSA before receiving Rituximab; this finding was probably a reflection of the humoral rather than cellular pathophysiology of disease in our cases, as indirectly confirmed by the lack to response to CSA. After rituximab, the patient achieved a late hematological response that was accompanied by a change in the serological profile, outlining this finding no early effects by this agent, for which it should be attributable to the B-cells ablation induced by the anti-CD20 therapy. Although we did not perform any in vitro BM cultural study revealing the putative anti-erythroid activity and the growth of BFU-E/CFU-E before and after the anti-CD20 therapy, the course of response gave indirect evidence of the immunomediated origin of the two associated disorders resolved by rituximab. Although our case presented a favorable response to rituximab, some controversies about the use of this agent to treat PRCA and AIHA have been raised and should be discussed. Indeed, in a recently published report, all three patients with PRCA treated with rituximab did not respond [4]. Moreover, Campath-1H has been reported as an effective alternative therapeutic option for severe, refractory autoimmune cytopenias, including AIHA and PRCA [5]. Taken together, these findings support the hypothesis that different humoral and/or T-cell mediated mechanisms may be probably responsible for PRCA and AIHA. Therefore, the possibility of a different pathophysiology of PRCA and AIHA in some instance should be taken into account in the management of these patients. …