Very low doses of rituximab in autoimmune hemolytic anemia-an open-label, phase II pilot trial.

Introduction: Although rituximab is approved for several autoimmune diseases, no formal dose finding studies have been conducted. The amount of CD20+ cells differs significantly between autoimmune diseases and B-cell malignancies. Hence, dose requirements of anti-CD20 therapies may differ accordingly.

Methods: We conducted a phase II pilot trial investigating the effects and safety of very low doses of rituximab, i.e., 5 mg/m every 3 weeks, 20 mg every 4 weeks, 50 mg every 3 months ( = 3 each) and 100 mg every 3 months ( = 1) in patients with autoimmune hemolytic anemia (AIHA) to effectively suppress CD20 cell counts. Doses were increased if circulating CD20 cell depletion was insufficient (i.e., <95% reduction from baseline) in a dose group. Plasma rituximab concentrations were quantified by enzyme-linked immunosorbent assay, CD20 cell counts were determined by flow cytometry.

Results: Ten patients were included in the final analysis (7 with cold agglutinin disease, 2 with warm AIHA, 1 with mixed-type AIHA). The first infusion depleted ≥95% of CD20 cells in all but one of the included patients. However, the dosing regimens were found ineffective, because a sustained CD20 cell depletion was not achieved, and CD20 cells recovered with a high interindividual variability. CD20 lymphocytes were below the detection limit if rituximab plasma concentrations exceeded 0.4 μg/mL. One endokarditis occured.

Conclusion: Rituximab doses as low as 5 mg/m transiently depleted CD20 cells in almost all patients, but the tested low-dose regimens failed to permanently suppress CD20 cells. The empirically identified EC95% of 0.4 μg/mL rituximab may guide future studies using low-doses of rituximab.

Clinical Trial Registration: https://clinicaltrials.gov/, identifier [EudraCT 2016-002478-11].