Single‐dose rituximab plus glucocorticoid versus cyclophosphamide plus glucocorticoid in patients with newly diagnosed acquired hemophilia A: A multicenter, open‐label, randomized noninferiority trial

Abstract

Acquired hemophilia A (AHA) is a rare but serious bleeding disorder. Randomized controlled trial (RCT) comparing the efficacy of immunosuppression therapy for AHA lacks. We conducted the first multicenter RCT aiming to establish whether the single‐dose rituximab combination regimen was noninferior to the cyclophosphamide combination regimen. From 2017 to 2022, 63 patients with newly diagnosed AHA from five centers 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/m2; n = 31) or plus cyclophosphamide (2 mg/kg per day until inhibitor becomes negative, for a maximum of 5 weeks; n = 32). The primary outcome was complete remission (CR, defined as FVIII activity ≥50 IU/dL, FVIII inhibitor undetectable, immunosuppression tapered and no bleeding for 24 h without bypassing agents) rate measured within 8 weeks. The noninferiority margin was an absolute difference of 20%. Twenty‐four (77.4%) patients in the rituximab group and 22 (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%; Pnoninferiority = 0.005). No difference was found in the incidence of treatment‐related adverse events. Single‐dose rituximab plus glucocorticoid regimen showed similar efficacy and safety, 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. This trial was registered at ClinicalTrials.gov as #NCT03384277.

Genetics and Epigenetics in Acquired Hemophilia A: From Bench to Bedside

“…Rituximab has been used as an immunosuppressant in various benign and malignant hematological disorders [ 102 , 103 , 104 ] as cytotoxic agents’ cyclophosphamide (PO, 1.5–2 mg/kg/day, for a maximum of 6 weeks) or mycophenolate mofetil (1 g/day for 1 week, and after 2 g/day). In a randomized controlled study comparing corticosteroids plus rituximab with corticosteroids plus cyclophosphamide in patients with AHA, similar efficacy and safety were reported between the two drug combinations [ 105 ]. During treatment with cytotoxic agents, patients should be watched closely for the development of cytopenias or infections [ 106 , 107 , 108 , 109 , 110 ].…”

“…Plasma-deprived FVIIa/FX has been also evaluated in patients with AHA, with favorable outcomes without an increase in the thrombotic risk [103]. Emicizumab, a monoclonal antibody restoring the function of missing FVIII by connecting FIXa and FX, has been used off-label in AHA [104][105][106][107][108]. Figure 2 presents the initial clinical administration of the patient with AHA in the emergency room department.…”