Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic)

Abstract

Background: Lupus animal model has shown that arsenic trioxide (ATO), a treatment of acute promyelocytic leukaemia, could be effective in SLE. This is the first clinical study to determine the safety and efficacy of a short course of intravenous ATO in patients with active SLE.

Methods: This phase IIa, open-label, dose-escalating study enrolled 11 adult SLE patients with a non-organ threatening disease, clinically active despite conventional therapy. Patients received 10 IV infusions of ATO within 24 days. The first group received 0.10 mg/kg per injection, with dose-escalating to 0.15 mg/kg in a second group, and to 0.20 mg/kg in a third group. The primary endpoint was the occurrence of adverse events (AEs) and secondary endpoints were the number of SLE Responder Index 4 (SRI-4) responders at week 24 and reduction of corticosteroid dosage. In an exploratory analysis, we collected long-term data for safety and attainment of lupus low disease activity state (LLDAS).

Results: Four serious AEs occurred (grade 3 neutropenia, osteitis, neuropathy), 2 of which were attributable to ATO (neutropenia in the 2 patients treated with mycophenolate). Two patients suffered a severe flare during the last 4 weeks of the trial. At W24, five patients among 10 were SRI-4 responders. Overall, mean corticosteroid dosage decreased from 11.25 mg/day at baseline to 6 mg/day at W24 (P < 0.01). In the long term, 6 patients attained LLDAS at W52, which continued at last follow-up (median LLDAS duration 3 years, range 2-4).

Conclusions: A short course of ATO has an acceptable safety profile in SLE patients and encouraging efficacy.

Trial registration: ClinicalTrials.gov, NCT01738360 registered 30 November 2012.

Keywords: Arsenic trioxide; Autoimmune diseases; Phase II clinical trial; Systemic lupus erythematosus; Treatment.

Conflict of interest statement

François Rieger is currently an employee of MEDSENIC.

Figures

Fig. 1

Clinical efficacy outcomes of ATO. Efficacy results after ATO infusion. Treatment was given over 21 days and changes in a SLEDAI score, b corticosteroid dose and c PGA score were recorded every 4 weeks over 24 weeks thereafter. Histograms depict the median. *P < 0.05, **P < 0.01, ***P < 0.001 (mixed model for repeated measurements). d Median Health-Related Quality of Life (HRQoL) scores for the 8 dimensions of the SF36 for the patients at D0, D90 and D180 and the score of a gender- and age-matched sample of individuals drawn from the general French population. We noted a marked increase between D0 and D90/D180 for all the dimensions of the HRQoL and globally stable scores between D90 and D180, which remained inferior to those of the general population. ATO, arsenic trioxide; Eq., equivalent; PGA, Physician Global Assessment; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index

Fig. 2

Immunological effects of ATO. Changes in a anti-ds-DNA, b immunoglobulin G, c complement factor 3 and d complement factor 4 levels over 24 weeks after ATO infusion. Each dot represents an individual measurement. Changes in anti-dsDNA level are represented as variation from baseline in 6 patients with detectable anti-dsDNA at baseline. Dotted lines represent the lower limit of normal complement level

Fig. 3

ATO pharmacokinetics. Plasma arsenic concentrations (mean +/− SD) in the three groups of ATO dosage before (a) or at the end of the perfusion (b). White circle indicates 0.10 mg/kg, white square indicates 0.15 mg/kg, and black triangle indicates 0.20 mg/kg