Background
Phase III, multicenter, open-label RCT. 64 adults with newly diagnosed warm-antibody autoimmune hemolytic anemia (WAIHA) randomized 1:1 to rituximab combined with prednisolone versus prednisolone monotherapy. All patients received prednisolone 1 mg/kg/day as the backbone. This was the first randomized trial of rituximab in first-line WAIHA; prior evidence was limited to retrospective series and single-arm studies.
Interventions and follow up
Arm A: Rituximab 375 mg/m² IV weekly × 4 doses + prednisolone 1 mg/kg/day (with taper)
Arm B: Prednisolone 1 mg/kg/day (with taper) alone
Primary endpoint: Satisfactory response (complete or partial) at 12 month
mFollow up: 36 month
Arm B: Prednisolone 1 mg/kg/day (with taper) alone
Primary endpoint: Satisfactory response (complete or partial) at 12 month
mFollow up: 36 month
Results
Response at 12 months: 75% vs 36%, P=.003
Relapse-free survival: Significantly better with rituximab + prednisolone, P=.02
Remission at 36 months: ~70% (rituximab) vs ~45% (prednisolone) still in remission
Relapse-free survival: Significantly better with rituximab + prednisolone, P=.02
Remission at 36 months: ~70% (rituximab) vs ~45% (prednisolone) still in remission
Adverse events
Serious adverse events: Equally distributed between groups; no allergic reactions to rituximab
Main adverse events: Grade 3–4 adverse events similar between arms. No anaphylaxis to rituximab. Pneumonia and other infections reported in both groups at comparable rates. Infusion-related reactions to rituximab were mild. Corticosteroid-related toxicities (hyperglycemia, weight gain) in both arms.
Main adverse events: Grade 3–4 adverse events similar between arms. No anaphylaxis to rituximab. Pneumonia and other infections reported in both groups at comparable rates. Infusion-related reactions to rituximab were mild. Corticosteroid-related toxicities (hyperglycemia, weight gain) in both arms.
Conclusions
Adding rituximab to prednisolone as first-line therapy for warm AIHA significantly increased the rate and duration of hematologic response compared to prednisolone alone, supporting the combination as a preferred first-line approach.
Key Limitations
Key Limitations: Open-label design introduces performance and detection bias; the rituximab arm received additional nursing contact and infusion visits which may affect assessment. Small sample size (n=64) limits power for subgroup and safety analyses. Prednisolone monotherapy comparison may underestimate response with more aggressive steroid dosing or prolonged courses. Heterogeneous patient population (primary vs secondary WAIHA not fully stratified). No QoL or patient-reported outcome data reported.
Clinical Context
This trial, together with the RAIHA study (Michel 2017, Am J Hematol), forms the primary randomized evidence base for rituximab in first-line warm AIHA. Rituximab is now recommended by ASH and EHA guidelines as first-line treatment combined with steroids in patients who require treatment. The 70% durable remission rate at 36 months with rituximab contrasts with the high relapse rate of steroids alone. For relapsed/refractory WAIHA, fostamatinib, danicopan (factor D inhibitor), and novel BTK inhibitors are under investigation.
References
References: Birgens H et al, Br J Haematol 2013 (primary)