Adverse events linked with the use of chimeric and humanized anti-CD20 antibodies in children with idiopathic nephrotic syndrome

Abstract

Aims: Anti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions.

Methods: We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid-dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9 years).

Results: Infusion reactions were mainly absent in children with steroid-dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed.

Conclusion: Overall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS.

Keywords: nephrotic syndrome; ofatumumab; rituximab; side effects.

Figure 1

Overall treatment distribution. Schematic view of cumulative treatments, divided into the number of administered doses. In the rituximab group, 44 patients received a single dose, while 86 patients received multiple doses (two doses, n = 30; three doses, n = 20; four doses, n = 18; more than four doses, up to a maximum of seven, n = 18). In the ofatumumab group, 19 patients received a single dose, while 18 patients received multiple doses (two doses, n = 11; three doses, n = 5; four doses, n = 2). OFA, ofatumumab; RTX, rituximab

Figure 2

Percentage of adverse events correlated with rituximab (A) and ofatumumab (B) infusion. Events are shown for each infusion, divided into infusion reactions, early adverse events and late adverse events. In (A), ordinate axis values go up to 20% instead of 100% for a better graphical representation, in view of the low number of events. In both the rituximab and ofatumumab groups, subsequent doses of anti‐CD20 were not associated with an increased number of side effects. OFA, ofatumumab; n, number of events; RTX, rituximab

Figure 3

B‐cell (CD19+) recovery (A) and the trend in immunoglobulin (Ig) G values (B) in a subgroup of 26 patients treated with rituximab (19 patients) or ofatumumab (seven patients), and with a relapse‐free period of at least 12 months. CD19+ cells were depleted after treatment with both rituximab and ofatumumab (A). In the rituximab group, B‐cell recovery (CD19+ cells >2.5% lymphocytes) was seen in 17% of patients tested at 3 months, 64% at 6 months, 65% at 9 months and 100% of patients after 12 months. In the ofatumumab group, B‐cell recovery was seen in 4% of patients tested at 3 months, 56% at 6 months, 40% at 9 months and 79% at 12 months; however, at 12 months point, the B‐cell count was lower than in the rituximab group. IgG plasma levels, reduced at baseline compared with those of the general population, showed no significant decrease during the 12‐month follow‐up (B). OFA, ofatumumab; RTX, rituximab

Figure 4

Analysis of variations in antitetanus (A) and antihepatitis B virus (B) immunization in two subgroups of patients affected by multidrug‐dependent nephrotic syndrome. (A) Antitetanus immunization was present at baseline in six out of 21 patients in the rituximab subgroup and in two out of 24 patients in the ofatumumab group, and was no longer detectable after rituximab and ofatumumab administration in one and two patients, respectively. (B) Antihepatitis B virus immunization was present at baseline in four out of 10 patients in the rituximab subgroup and six out of 17 patients in the ofatumumab group, and was no longer detectable after ofatumumab administration in one patient, while remaining unchanged in the rituximab subgroup. Analyses were performed at baseline (T0) and at a follow‐up from a minimum of 3 months to a maximum of 12 months (T1). OFA, ofatumumab; RTX, rituximab