A Pilot Study Of Rituximab In Patients With Moderate Aplastic Anemia, Diamond-Blackfan Anemia and Pure Red Cell Aplasia

Background Pure red cell aplasia (PRCA), Diamond-Blackfan anemia (DBA) and moderate aplastic anemia (MAA) are all bone marrow failure syndromes that are immune-mediated or may respond to immunosuppressive therapies (IST). Anti-thymocyte globulin, cyclosporine and corticosteroids have been used with some success but have significant toxicities. The humanized monoclonal antibody to the interleukin-2 receptor on T cells, daclizumab, showed efficacy in MAA and PRCA patients with some patients achieving transfusion independence (Sloand et al, Haematologica 2010). However, this agent has since been withdrawn from the market. It is increasing recognized that the anti-CD20 chimeric monoclonal antibody, rituximab, may modulate T cell immunity in addition to its known depletion of B cells (Staci, Seminars in Hematology 2010). There are anecdotal case reports of rituximab, showing benefit in PRCA. Here, we summarize our experience using rituximab in PRCA, DBA and MAA. Design and Methods We enrolled 11 patients with PRCA (n = 7), DBA (n = 1), and MAA (n = 3) who had failed at least one prior immunosuppressive regimen to receive rituximab 375 mg/m2intravenous infusions weekly times 4 doses ([NCT00229619][1]). Responses were evaluated at 3, 6 and 12 months. Patients with MAA, DBA or PRCA were eligible for trial participation. MAA was defined as a hypocellular marrow without evidence of an underlying disease process and depression of at least two of three cell lines (an absolute neutrophil count (ANC) ≤ 1200/µL, a platelet count ≤ 70,000/µL, and a hemoglobin ≤ 8.5 g/dL or absolute reticulocyte count (ARC) ≤ 60, 000/µL in transfusion-dependent patients) but who do not fulfill criteria for severe aplastic anemia (i.e. bone marrow cellularity < 30% and depression of two of the three peripheral counts: ANC < 500/µL, a platelet count < 20,000/µL and an ARC < 60,000/µL). DBA and PRCA were defined as anemia, reticulocytopenia (ARC ≤ 50, 000/µL) and absent or decreased marrow erythroid precursors. Patients with Fanconi’s anemia, other congenital bone marrow failure syndromes, cytologic abnormalities indicating myelodysplasia or recent/ongoing parvovirus infection were excluded. Complete response (CR) was defined as return of blood counts to normal. Partial response (PR) for MAA was defined as improvement in two of the three depressed blood counts that qualified patient for participation. PR for DBA/PRCA was defined as an increase in hemoglobin by 1.5 g/dl of blood and or ARC ≥ 50,000/µL but not meeting criteria for normal counts. Results Overall, 5/11 (45%) patients responded to rituximab, all achieving PR. At 3 months, one patient with PRCA had responded. At 6 months, two additional patients responded (one with PRCA, one with MAA). At 12 months, an additional two responses were confirmed (one PRCA, one MAA). One PRCA patient lost his response between the 6 and 12 month endpoint. Among the three responding PRCA patients, the mean reticulocyte count at study initiation was 4400/µL; this increased to 54,000/µL at 6 months and further increased to 61,000/µL at 12 months (including patient who lost his response). The study was terminated early for poor accrual; many eligible patients received alternate treatments at home. Due to early study termination, the duration of responses for majority of the patients is unknown. Given the reports of daclizumab efficacy in these diseases, 90% of our patients were previously treated with daclizumab. Notably, 3 of the patients responding to rituximab had previously not responded to daclizumab. Safety The most common toxicity of rituximab observed was an infusion related reaction affecting (8/11) 73% of patients with the first infusion of rituximab. One patient developed serum sickness after the third cycle which precluded the administration of the last dose. An expected decrease in quantitative immunoglobulin levels was observed; at the 6 month evaluation there was an 11% decrease in IgG and IgA; a greater decrease (48%) was observed in IgM. Conclusions Rituximab is a viable treatment option in the armamentarium for patients with PRCA and MAA. Rituximab is safe, effective, and easily administered. Responses can be delayed to beyond 6 months therefore we suggest observation for at least 6 months after rituximab administration. Disclosures: Off Label Use: Rituximab is not FDA approved for the treatment of Pure Red Cell Aplasia, Diamond-Blackfan Anemia or Moderate Aplastic Anemia. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00229619&atom=%2Fbloodjournal%2F122%2F21%2F2479.atom