A Multi-Centre Randomized and Double-Blind Controlled Trial of Rituximab for Warm Autoimune Hemolytic Anemia in Adults

Introduction: Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease that can be life threatening especially in elderly patients. Rituximab has shown very promising efficacy in several uncontrolled studies and in one controlled trial for treating adult’ wAIHA and it is commonly used off-label as a second-line treatment and as a corticosteroid-sparing agent.  

Methods: This phase 3 multicentre randomized (1/1 ratio) and double-blind controlled trial aimed to assess the efficacy and safety of rituximab compared to placebo for the treatment of adults with newly diagnosed wAIHA treated with prednisone.  Inclusion criteria were: age ≥ 18 years with a confirmed diagnosis of wAIHA (hemoglobin level ≤ 10g/dL with hemolysis and a positive direct antiglobulin test with an anti-IgG ± anti-C3d pattern in the absence of any other cause of hereditary or acquired hemolytic anemia). Only patients previously treated with corticosteroids for less than 6 weeks could be included. Patients with secondary wAIHA (except for stage A chronic lymphocytic leukemia) were excluded.  At time of inclusion, all patients were given prednisone at a daily dose of 1 mg/kg for 2 weeks and then tapered every 10 days according to a standardized procedure and stopped within 3 months in case of response. Eligible patients received in combination with prednisone (double-blind) 2 infusions of either rituximab (arm A) or placebo (arm B) at a fixed dose of 1,000 mg 2 weeks apart (on days 1 and 15 after randomization). The primary endpoint was the overall response rate (CR + PR) at 1 year in both arms. Complete remission (CR) was defined by a hemoglobin (Hb) level ≥11 g/dL (women) or 12 g/dL (men) without hemolysis (including a normal haptoglobin level) in the absence of any ongoing treatment for wAIHA, on 2 different occasions 4 weeks apart in the absence of recent transfusion. Partial remission (PR) was defined by a Hb level ≥ 10g/dL with at least a 2g increase from baseline in the absence of any other treatment than prednisone given at a daily dose ≤ 10 mg or recent transfusion. A non-response (NR) was defined by the need of receiving prednisone at a daily dose > 10mg to maintain a PR and/or any other treatment potentially active in wAIHA (i.e., splenectomy, immunosuppressors). The hypothesis for the calculation of the sample size (n = 32 patients, 16 in each arm) was, based on previous data from the literature, an 80% overall response rate (CR + PR) at 1 year in the RTX arm versus 20% in the placebo arm with an a risk of 5% and a b risk of 10%.

Results: A total of 32 patients, 17 females (53%), with a mean age at inclusion of 71 (SD: 16) years were enrolled and randomized. The patients main characteristics (mean age, sex ratio, Hb and LDH levels, number of packed red cells transfused at diagnosis) were comparable in both arms. Twenty-eight patients were followed for at least 1 year and were evaluable for response. Three patients aged of 90, 84 and 87 from the placebo arm prematurely died versus none in the rituximab arm (p=0.073) and 1 patient from the placebo arm was prematurely withdrawn at Week 28 for severe anemia. At 1 year, in intention to treat, the overall response rate (CR + PR) was 75% (11 CR and 1 PR) in the rituximab arm versus 31% (5 CR) in the placebo arm (p value=0.032).  Among the non-responders in the placebo arm, 6 patients were given azathioprine and 2 patients underwent splenectomy. There was no difference in the mean gammaglobulin level at 1 year between the 2 arms (8.1 ±2.2 g/l versus 7.7 ±1.5 g/l, p value 0.499). A total of 7 severe infections occurred during the first year of follow-up, 5 in the placebo group and 2 in the RTX group (p=0.39) including 2 cases of pneumocystosis (1 in each treatment arm) and 1 bilateral pneumonia due to Streptococcus pneumonia in the placebo arm. One severe pulmonary embolism occurred on day 15 in a 84-year-old woman in the placebo arm.

Conclusion: Compared to placebo, rituximab given in combination with prednisone is an effective and safe option for treating adult patients with newly-diagnosed wAIHA leading to an overall response of 75% at one year.