Background: The management of AIHA, based mainly on empirical data and uncontrolled studies, relies principally on corticosteroids as a first-line therapy. Patients who are refractory or intolerant to these therapies (approximately 5–10% of the cases) constitute an important therapeutic challenge. The most frequent second-line options are splenectomy or immunosuppressive agents. Rituximab (R), an anti-CD20 chimeric monoclonal antibody being increasingly used in autoimmune disorders. Transfusion in patients with autoimmune hemolytic anemia generally is unwise, because the autoantibody in the serum usually reacts with the RBCs of all potential donors, making a satisfactory cross match impossible. Moreover, the erythroid response, can be inappropriately low, and several reports or senies’ have highlighted cases that have been associated with reticulocytopenia. Aim of this study is to test if the introduction of Rh-Epo in the refractory AIHA treatment may reduce the blood transfusion need and related risks
Methods: 14 pts (M 7, F 7) median age 59.2 yr (range, 18–82) and AIHA resistant to standard treatment were treated with a schedule containing Rituximab, rh-EPO and prednisone (R-EP) 6 pts were idiopathic and the remaining 8 were associated with chronic lymphoproliferative syndromes (3), connective tissue diseases (2), primary antiphospholipid syndrome (APS)(1) and ulcerative colitis (2). mean Hb value and Ht at presentation were 6.3 g/dL ± 1.2, and 24 mL/dL, Median reticulocyte percentage was 9%, and median reticulocyte production index was 2.8 times basal. 24 % of cases had an initial reticulocyte count less than 4%, and 40% had an initial reticulocyte production index less than 2.0 times basal. These reticulocytopenic patients were prevalent in secondary cases. Serum erythropoietin level at baseline was (14 +/− 11 mU/mL)) Pts had altered hemolysis markers and direct antiglobulin test (DAT) was positive for both complement and IgG (IgA 1 pts). All cases had a bone marrow examination during hospitalization Erythroid hypoplasia was seen only in CLL pts.14/14 pts had serial reticulocyte measurements, Rituximab was administered intravenously at a dose of 375mg/m2 weekly for 4 weeks; prednisone 1 mg/Kg/day /for 30 days ; rh-EPO 30.000U/weekly for 4 weeks.
Results: All pts completed treatment. No major infusion related side effects to R-EP were observed. Response criteria to R-EP were defined as follows: Complete Response (CR): Hb >10 g/dl or Hb increase >1.5 g/dl, resolution of symptoms of anemia, transfusion independent; Partial Response (PR): Hb > 9 g/dl or Hb increase of 1–1.5 g/dl. improvement in symptoms of anemia, transfusion independent; NR (failure to meet CR/PR). 100% were eligible for response. Responses were seen in 14/14 pts. CR in 13/14 and PR in 1/14, median follow up of 25.8 months (range 5–66 months). At the end of treatment DAT became negative in 12/14 pts, concentration of lactic dehydrogenase, total bilirubin and indirect bilirubin began to decrease at 12 days after the first dose of rituximab, and decreased to normal range after 22 days.. Three patients required packed red cell transfusions before starting R-EP and all became transfusion-free. A moderate hemolysis still persisted only in one patient. In the cases that were initially reticulocytopenic, reticulocyte production index rapidly increased, indicating a marrow erythropoietic response to REP
Conclusion: Our experience demonstrates that R-EP is an effective and safe alternative for the treatment of refractory autoimmune hemolytic anemia. Awareness of the frequency of an initial reticulocytopenia in cases of autoimmune hemolysis may be important in initial diagnosis and treatment, because low reticulocyte production index may represent a lag in marrow responsiveness to hemolytic stress. Striking, the introduction of rh-Epo clearly avoids blood transfusions and overcame inappropriately low erythroid response in reticulocytopenic patients