Severe hemolysis flare of refractory warm hemolytic anemia with positive complement component C3d responsive to iptacopan with cyclophosphamide and prednisone

Abstract Purpose: Warm autoimmune hemolytic anemia (wAIHA) is defined as the enhanced destruction of erythrocytes through autoimmune processes, predominantly mediated by autoantibodies that target erythrocyte surface antigens. The pathogenesis of wAIHA is complex, and prednisolone is recommended as first-line therapy. Refractory wAIHA often shows no response to multi-line therapies, including steroids, intravenous immune globulin (IVIG), and rituximab. Currently, there is a lack of an effective treatment regimen for severe hemolytic episodes in refractory wAIHA patients, especially for those with positive complement component C3d. Methods: From June 2024 to June 2025, fifteen refractory wAIHA patients were treated with iptacopan plus cyclophosphamide and prednisone (CPI regimen) during severe hemolytic episodes. The CPI regimen consisted of cyclophosphamide 100 mg daily, prednisone 1 mg/kg daily, and iptacopan 200 mg twice daily. All patients had received at least two prior therapies, including but not limited to steroids, IVIG, rituximab, tacrolimus and azathioprine without achieving a good response. The study protocol for hemolytic anemia was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (2023-SR-650). Results: Fifteen wAIHA patients were enrolled in the study. The median age of all patients was 59.0 years (range: 34–81), with a median time of 44 days from diagnosis to CPI treatment. Among them, seven were diagnosed with primary AIHA, and four had Evans syndrome. One patient had concurrent systemic lupus erythematosus, and three were diagnosed with lymphoma. Eight patients had received two or more lines of previous therapies. All patients had received glucocorticoid treatment. Three patients (20.0%) had been administered rituximab, and one patient (6.67%) had been given tacrolimus. In addition, two patients (13.33%) had a history of bortezomib treatment, and another two patients (13.33%) had received azathioprine therapy. Direct antiglobulin tests (DATs) in all patients were positive for both IgG and complement component C3d. Thirteen (86.67%) patients achieved hematologic responses (hemoglobin increase >20 g/L and transfusion independence) after treatment with iptacopan combined with cyclophosphamide and prednisone, with a median response time of 29 days (range: 7–152 days). Two patients responded as early as one-week post-treatment. The overall response rate (ORR) was 73.3% at one month and 80.0% at two months. C3d turned negative or its titer decreased in 86.67% of patients. Within 8 weeks of treatment, only 2/15 (13.33%) patients required blood transfusion support. Conclusion: Refractory wAIHA patients achieved good therapeutic efficacy after treatment with Iptacopan combined with cyclophosphamide and prednisone. Our clinical practice will provide a new potential approach to the treatment of refractory wAIHA.