AB0614 Late-onset neutropenia after rituximab treatment in patients with ANCA-associated systemic vasculitis: a retrospective analysis of a register-based patient cohort

Abstract

BackgroundAnti-B-cell therapy with rituximab (RTX) plays an important role in the induction and maintenance therapy of ANCA- associated vasculitis (AAV). Late-onset neutropenia (LON) has been reported following RTX therapy.ObjectivesBased on a retrospective analysis of the register of AAV patients (pts) treated with RTX, to study the incidence and outcomes of LON.Methods140 AAV pts (median age 52 (20-83) years, 57% women) were treated with RTX between 2009 to 2021: 63 with granulomatosis with polyangiitis (GPA), 45 microscopic polyangiitis (MPA), 24 eosinophilic granulomatosis with polyangiitis (EGPA), and 8 unclassified AAV. The median total dose of RTX was 3.5 (0.5-45) g. As a rule, single 500-mg infusions were used with an interval of 4-6 months for retreatment courses. The duration of follow-up exceeded 6 months after the first dose of RTX. Regular pts monitoring every 3 months included estimation absolute neutrophil count (ANC). LON was defined as unexplained neutropenia occurring 3 weeks after the last RTX infusion.ResultsLON I-IV grade was noted in 16 (11.4%) AAV pts: 6 GPA, 4 MPA, 4 EGPA, and 2 unclassified AAV. In 7 out of 16 cases (43.7%) LON developed after the first course of RTX. Neutropenia grade I was observed in 3 pts (ANC 1.68-2.0x109/l, 2-15.5 months after the last RTX infusion), grade II - in 4 patients (1.1-1.5x109/l, 3-9 months after RTX). Neutropenia grade I-II resolved independently, without adverse reactions. LON grade IV was noted in 9 pts (0.06-0.3x109/l, 1.1-11 months after RTX), 3 of them received leukopoiesis-stimulating drugs with normalization of ANC. In one EGPA pt febrile LON grade IV developed twice (in 2017, 11 months after RTX; in 2019, 4 months after RTX and complicated by uterine bleeding). Fatal outcome occurred in 5 out of 16 cases (31.2%): 1 MPA, 3 GPA, and 1 EGPA. In 3 fatal cases LON was complicated by pneumonia (in 2 with septic shock), in one with acute myocardial infarction and another one with progression of chronic renal failure. According to our registry, the total mortality among 140 AAV pts receiving RTX was 11.4%, while 5 of 16 fatal cases (31.2%) had LON grade IV. Three of the 5 death were noted in 2013-2014, which attributed to the use of cyclophosphamide >2 gm before RTX, as well as insufficient awareness of the risk of LON, which contributed to the delay in control of a full blood count, untimely diagnosis of LON and late treatment. At the beginning, the original drug Mabthera was used, while after 2014 biosimilar Acellbia was mainly used.The disadvantages of this study: the lack of information about the ANC in 4 cases with COVID-19 and fatal outcome.ConclusionLON after RTX therapy can develop in 11.4% of AAV pts, which exceeds the data for rheumatoid arthritis (1,3-3%) [1,2]. Our register data are lower than the rate of LON in AAV, presented by D. Tesfa et al. (23%) [1], which could be affected by the use of low-dose RTX for retreatment courses. LON accounts for a significant part in the structure of deaths of AAV pts (31.2%). It needs to careful monitoring of ANC in pts receiving RTX and awareness of both pts and physicians about the risk of LON.