Putting Rituximab in Its Place

 Rituximab in Auto-Immune Hemolytic Anemia

 NCT01181154

 Assistance Publique-Hôpitaux de ParisCollaborator: Hoffmann-La Roche

 Henri Mondor University Hospital, Créteil, France

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 This is a phase III, double-blind, randomized, placebo-controlled trial. Patients with newly diagnosed, primary (not associated with lymphoid neoplasm, lupus erythematosus, etc.) warm autoantibody-mediated, autoimmune hemolytic anemia (AIHA) within six weeks of diagnosis, who are being treated with prednisone 1 mg/kg body weight per day, will be randomized 1:1 to receive either 1,000 mg of rituximab or placebo on days 1 and 15. Prednisone will be tapered based on evidence of response. Patients will participate in the study for three years. The primary endpoint is remission rate (complete + partial) at one year. Secondary outcomes include comparisons between the two groups for two-year remission rates, cumulative prednisone doses, red blood cell transfusions, and requirement for splenectomy, or immunosuppressive therapy.

 Retrospective clinical data suggests that the remission rate at one year will be greater in the rituximab arm (80%) than in the placebo arm (20%). Rituximab, a bioengineered chimeric mouse/human monoclonal antibody that binds CD20, an antigen expressed on B lymphocytes, has been extensively studied and used in the treatment of human lymphoid neoplasms as a single agent and, more commonly, as part of standard chemotherapy regimens. B lymphocytes mediate autoimmune diseases through several actions including antibody production, antigen presentation, and enhancement of T-cell function and dendritic cell differentiation. Therefore, rituximab has been used to treat a variety of autoimmune hematologic disorders including immune thrombocytopenia purpura (ITP), acquired hemophilia A, thrombotic thrombocytopenic purpura, and Evans syndrome, as well as AIHA, both warm-antibody and cold-agglutinin types (Dierickx D et al. Am J Hematol. 2011;86:278-291 and Barcellini W et al. Eur J Intern Med. 2011;22:220-229).

 Until the advent of the use of rituximab, treatment of warm-antibody AIHA followed a familiar algorithm: a corticosteroid, usually prednisone, was first-line treatment, splenectomy was second-line therapy, and an immunosuppressive medication such as azathioprine, cyclophosphamide, or cyclosporine constituted the third line of treatment. About 20 percent of patients who achieve remission with corticosteroids can be tapered off steroids successfully. Among the remaining 80 percent, 20 percent are primarily unresponsive and 60 percent fail the steroid taper. Splenectomy is successful in the majority of patients who are refractory or who require unacceptably high doses of steroids to maintain an adequate response, but relapse is common among splenectomized patients. Because third-line therapy is often unsuccessful and associated with significant adverse effects, rituximab found a place in the clinician’s treatment armamentarium for this difficult-to-manage group. And due to the requirement for an operative procedure and concerns about long-term sequelea associated with splenectomy, rituximab soon became an alternative second-line modality.

Results, emanating from small, uncontrolled studies of high remission rates in patients with AIHA treated with rituximab after failing corticosteroids, have led to its use in combination with steroids as both primary and secondary therapy. However, controlled studies such as NCT01181154 are required to establish the place of rituximab in the hierarchy of AIHA therapy. Rituximab is not entirely benign therapy as it can worsen chronic viral infections such as hepatitis C, CMV, and Herpes zoster. Progressive multifocal leukoencephalopathy is a rare but potentially fatal viral illness associated with rituximab therapy. Further, many patients successfully treated with rituximab for autoimmune diseases have subsequent relapses at lengths of time varying from months to years. Some patients with such relapses respond to additional courses of rituximab, but splenectomy may offer a more durable long-term remission. In light of these observations, the secondary endpoints of remission status at two years and frequency of splenectomy will be of particular interest. Notably, an abstract presented at the recent ASH annual meeting reported that patients with ITP who received rituxan in conjunction with corticosteroids after failing monotherapy with corticosteroids had a higher complete response rate at 24 weeks compared with patients in the placebo control arm, but no difference was observed between the two groups either in the rate of splenectomy or in the number of subjects reaching the criteria for splenectomy by week 78 of the study (Ghanima W et al. Blood. 2013;122:449). The current AIHA trial will likely be one of multiple controlled trials required to put rituximab in its place in the treatment hierarchy of warm-antibody AIHA.