Single-Dose Rituximab Plus Glucocorticoid Versus Cyclophosphamide Plus Glucocorticoid in Patients with Newly Diagnosed Acquired Hemophilia a: A Multicenter, Open-Label, Randomized Clinical Trial

Abstract

Introduction Cyclophosphamide plus glucocorticoid is a first-line immunosuppressive therapy for acquired hemophilia A (AHA), a serious bleeding disorder, but brings risks of myelosuppression, secondary tumor, and reproductive toxicity. Rituximab plus glucocorticoid therapy shows comparable efficacy but lacks results from randomized controlled trials. We aimed to establish whether the single-dose rituximab regimen was non-inferior to the cyclophosphamide regimen. Methods This study was the first noninferiority, multicenter, open-label, randomized controlled clinical trial comparing these two combination therapies in AHA patients (ClinicalTrails.gov number, NCT03384277). Adult patients (18-80 years) with newly diagnosed AHA from five centers in China were randomly assigned 1:1 to receive glucocorticoid (methylprednisolone 0.8 mg/kg per day for the first 3 weeks and then tapered) plus single-dose rituximab (375 mg/m 2) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks). The primary outcome was complete remission (CR, defined as FVIII activity ≥ 50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 hours without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. The secondary outcomes included partial remission (PR) rate, time to PR, time to CR, time for inhibitor titer to decrease by 50% of baseline, relapse rate, time to relapse and so on. Safety was assessed in all patients. Results Between December 29, 2017 and June 9, 2022, 67 patients were screened, of whom 63 (33 female and 30 male) were assigned: 31 to single-dose rituximab group and 32 to cyclophosphamide group. The baseline characteristics of these patients were balanced between the single-dose rituximab group and cyclophosphamide group. Twenty-four (77.4%) patients in the rituximab group and twenty-two (68.8%) patients in the cyclophosphamide group achieved CR, which showed the noninferiority of the single-dose rituximab-based regimen (absolute difference=-8.67%, lower limit of the 95% confidence interval=-13.11%; P noninferiority=0.005). PR was observed in 25 (80.6%) of 31 patients in the single-dose rituximab group and 26 (81.3%) of 32 patients in the cyclophosphamide group (P=0.95). The median time to PR was similar between two groups (23.0 days for rituximab group vs. 25.5 days for cyclophosphamide group, P=0.47). The median time to CR was 8 days shorter in the single-dose rituximab group than in the cyclophosphamide group, but with no statistically significant difference (28.0 days vs. 36.0 days, P=0.41). The median time for inhibitor titer to decrease by 50% of baseline also showed a shorter trend in the single-dose rituximab plus glucocorticoid group (8.0 days vs. 11.0 days, P=0.39). Subgroup analysis showed patients with high FVIII inhibitor titer (>20 BU/ml) were less likely and slower to achieve both CR and PR. The percentage of patients who experienced treatment-related adverse events (TRAEs) or grade 3 or 4 TRAEs were comparable between the rituximab and cyclophosphamide groups (58.1% vs. 37.5%, P=0.10 and 12.9% vs. 6.3%, P=0.43 respectively). Conclusion Single-dose rituximab plus glucocorticoid regimen showed similar efficacy and safety in this trial, without a reported risk of secondary malignancies or reproductive toxicity seen in cyclophosphamide, it might be recommended as a first-line therapy for AHA, especially in China where there is a young age trend in AHA patients.