Anti-CD20 monoclonal antibody therapy for autoimmune hemolytic anemia following T cell-depleted, haplo-identical stem cell transplantation.

Immune-mediated hemolytic anemia is relatively common following allogeneic bone marrow transplantation (BMT) but is generally related to either ABO or minor red blood cell incompatibilities between donor and recipient (alloimmune).1,2 Autoimmune hemolytic anemia (AIHA) has been described by several investigators following allogeneic BMT,3,4,5,6 and may be associated with other cytopenias as well.2 Dysregulated immune reconstitution of B and T cells post transplant may allow for the emergence of polyclonal proliferations of B lymphocytes that produce antibodies with activity against red cells, as has been demonstrated in a mouse model.7 The time frame that AIHA occurs post transplant is frequently related to the type of antibody causing the hemolysis, since IgM levels normalize earlier than IgG levels.8 Chen et al5 presented nine cases of patients with AIHA following allogeneic BMT, in which hemolysis occurred either early (2–8 months post BMT; associated with a cold antibody) or late (6–18 months post transplant; associated with warm antibodies). While the majority of patients responded to immunosuppressive therapy, two of nine patients had hemolysis refractory to corticosteroid therapy. Horn et al4 reported an incidence of 19.5% of AIHA in 41 patients with severe combined immunodeficiency syndrome who underwent a T cell-depleted haplo-identical transplant. Of these eight patients, only one was alive and off medications, and four of the eight died from infectious complications or their AIHA. Drobyski et al6 reported a 5% incidence of AIHA in patients receiving a T cell-depleted graft, and half of the patients in this series died due to infectious complications or disseminated intravascular coagulation secondary to cold-agglutinin disease. In the setting of T cell-depleted BMT, the treatment of AIHA with immunosuppressive therapy could complicate already existing immune deficiency and render these patients at risk for infectious complications. Considering the exceptionally poor prognosis of AIHA in recipients of haplo-identical T cell-depleted transplants,4,6 alternate therapies beside systemic immunosuppression would be of benefit. Rituxan (IDEC Pharmaceuticals Corp., San Diego, CA, USA) is an IgG kappa chimeric mouse/human antibody that binds to the CD20 antigen, which is found on the surface of most normal and malignant B cells. The antibody successfully depletes B cells from the peripheral blood, lymph nodes, and bone marrow.9 Rituxan has been previously demonstrated to be useful in a non-transplant setting for cold agglutinin disease.10 Considering the very poor prognosis of T cell-depleted, haplo-identical stem cell transplant patients who develop this complication, we have applied this intervention to one such patient. A 7 year-old CMV sero-positive male with Wiskott-Aldrich syndrome received a stem cell transplant from his HLA haplo-identical, CMV sero-negative father. Prior to transplant he received a conditioning regimen consisting of 235 cGy total body irradiation in twice daily doses for 3 days (total dose 1410 cGy), cytarabine 3 g/m2 i.v. twice daily for 3 days, cyclophosphamide 50 mg/kg i.v. once daily for 2 days, and equine anti-thymocyte globulin (Pharmacia and Upjohn Co., Kalamazoo, MI, USA) 10 mg/kg daily for 3 days pre-transplant and for 12 days post transplant. He received a CD34-selected peripheral blood stem cell transplant, and had tri-lineage hematopoietic reconstitution by day 16. The patient received cyclosporine and a brief course of corticosteroids for graft- versus-host disease prophylaxis. CMV reactivation occurred on day +21, and the patient was persistently CMV antigen positive for 6 weeks despite the use of ganciclovir and later foscavir. The patient developed CMV retinitis, requiring 6 weeks of foscavir and a rapid taper of cyclosporine. He did not develop any evidence of GVHD and his retinitis resolved. Forty-two days post transplant the patient developed fever and was noted to have a cavitary lesion of the right lung by CT imaging, which was resected and identified as Aspergillus. The patient was treated with i.v. Ambisome (Fujisawa Healthcare, Deerfield, IL, USA) for 7 weeks, and maintained on oral itraconazole. Seven months post transplant the patient’s hemoglobin fell to 6.7 g/dl and he required weekly red blood cell transfusions to maintain a hemoglobin of 8 g/dl. His platelet count, which has previously been stable at >300 000/mm3, fell to 119 000/mm3. An anti-platelet antibody and a warm red cell autoantibody were detected. The patient received immunoglobulin 500 mg/kg daily for 4 days and then weekly for 4 weeks, with no improvement in his hemolysis or red cell transfusion requirements but stabilization of his platelet count. Due to his past history of Aspergillus and CMV infection, immunosuppressive therapy was not considered a desirable option, and the patient received Rituxan 375 mg/m2 i.v. weekly for four doses. This patient received his last blood transfusion 1 week prior to the final dose of Rituxan, with the hemoglobin level stabilizing at 11 g/dl and the platelet count increasing to previous levels. He is now 1 year following treatment and has not had a recurrence of his hemolytic anemia or autoimmune thrombocytopenia. Immunosuppressive therapy with cyclosporine and steroids has been effective in the treatment of many patients with AIHA,4 but subjects already immunocompromised patients to an increased risk of infection. This is especially relevant in patients who receive T cell-depleted haplo-identical stem cell transplants, who have been reported to have delayed immune reconstitution.11 The patient discussed in the report would have been at high risk for infectious complications considering his past history of CMV and Aspergillus infections. From this experience we conclude that Rituxan is a viable first line option for treating autoimmune cytopenias in recipients of allogeneic stem cell transplants.