POS0600 IMMUNOGENICITY OF RITUXIMAB BIOSIMILAR GP2013: A RARE EVENT, BUT NOT WITHOUT CONSEQUENCES ...

Abstract

Background: The bioequivalence between rituximab (RTX) originator and its biosimilar GP2013 has been demonstrated in rheumatoid arthritis (RA) (1). A recent randomized controlled trial suggested in a selected population a very low immunogenicity of GP2013 in RA (<1%) (2). Objectives: To study in daily practice the risk of immunogenicity of patients treated with GP2013 for their chronic inflammatory rheumatic disorder. Methods: Prospective routine care study carried out between September 2018 and August 2020 in the Rheumatology department of Cochin Hospital. We consecutively included patients treated with the biosimilar RTX GP2013, systematically used in the department since March 2018. Samples were taken before each infusion in order to detect anti-RTX antibodies (Ab) and RTX residual concentrations by ELISA (Lisa Tracker Duo Rituximab, LTR005, Theradiag). Results: We included 159 consecutive patients treated with GP2013 (124 women, 78%) with a mean age of 59±13 years and a mean disease duration of 18±11 years. Among these 159 patients, 108 (68%) had RA and 51 had another disease (16 systemic sclerosis (SSc), 15 mixed connective tissue disease (MCTD), 5 systemic lupus (SLE), 5 inflammatory myopathies (MI), 5 undifferentiated polyarthritis, 2 juvenile idiopathic arthritis (JIA) and 3 primary Sjogren's syndromes). 137 patients (86%) were receiving associated disease-modifying therapy (DMARD), mainly methotrexate (111/137 patients, 81%). 120 patients (75%) were in maintenance therapy with originator RTX (cumulative dose of RTX: 3.5±6g) before the switch to GP2013 in March 2018. Originator RTX was not re-established during the entire treatment period. The other 39 patients (25%) treated with GP2013 were naive of originator RTX. The analysis of the first sample, performed before the second GP2013 infusion, identified 8 patients (5 RA, 1 SLE, 1 MCTD and 1 SSc) with positive anti-RTX antibodies (prevalence 5%), with rates varying between 6 and >100ng/mL and undetectable residual RTX concentrations. Among these 8 patients, 6 had previously received originator RTX and 2 were RTX-naive patients. There was a trend for higher body mass index in patients with positive anti-RTX antibodies (28±7 vs. 25±6 kg/m2, p=0.12), and no association was observed between anti-RTX immunization and age, disease duration, combination with conventional DMARD, mean interval between infusions or cumulative RTX dose. Among the 8 immunized patients, two groups could be isolated: i) a group of 5 patients (3 RA, 1 SLE, 1 SSc) with low antibody levels (6-22 ng/mL) and no significant clinical consequences (absence of treatment discontinuation and loss of efficacy after 13±4 months of follow-up, only one minor allergic reaction) and ii) a group of 3 patients (2 RA, 1 MCTD) with a high antibody levels (≥100ng/ mL) and meaningful clinical consequences: one severe allergic reaction during the second GP2013 infusion leading to treatment discontinuation, and a loss of efficacy with incomplete B depletion in 2 patients leading to RTX dose escalation from 500 mg to 1 g. Among the 151 patients not immunized at the time of the first sample, no severe allergic reaction and 6 minor allergic reactions were noted under GP2013. Conclusion: The immunogenicity of patients treated with RTX is a rare event with possible clinical and biological consequences, especially in patients with high antibody levels.