Long-term safety data from extended follow-up and repeat use of Rituximab in Rheumatoid Arthritis - OP0119
Authors: R. van Vollenhoven, P. Emery, C. Bingham, E. Keystone, M. Greenwald, L.W. Moreland, M. Sweetser, K. Rowe, B. Wagner, F. Magrini
Disclaimer: Dr. Bingham is an author on this presentation
Background:
Ritxuimab (RTX) is a targeted B-cell depleting agent that is approved in the US for the treatment of patients with RA who are refractory to TNF antagonists. This medication may result in sustained reductions in signs and symptoms after a single course but the effects begin to wane over time requiring readministration. This study reports the long-term safety of single and multiple courses of rituximab in patients with RA. Similar results have been presented in the past, but the numbers of patients exposed to further courses increases providing additional important data.
Methods:
This is an analysis of patients exposed to RTX in the ongoing clinical program with data on all patients receiving up to 4 treatment courses.
Results:
As of September 2006, a total of 1053 RA pts had been exposed to RTX in the clinical program; with a total duration of exposure of 2438 pt-years, with 700 pts followed-up for >2 yrs and 120 pts for >3 yrs, receiving up to 7 treatment courses. In this abstract, safety information for Courses 1–4 (C1–4) is reported wherein 684, 400 and 142 pts received ≥2, ≥3 and ≥4 courses of RTX, respectively. Overall, the incidence of adverse events (AEs) decreased from 88% (931/1053) of RTX pts after Course 1 to 81%, 72% and 65% following Course 2, Course 3 and Course 4, respectively (Table). Serious AEs (SAEs) also followed a similar pattern (Table). Acute infusion reactions upon first infusion of each course decreased from 23% in the first course to 11% in the fourth course, and the incidence with the second infusion of each course decreased from 7% in the first course to 2% in the second. A total of 702 pts (67%) experienced ≥1 infection. The most common infections were upper respiratory tract infections, including nasopharyngitis (32%), and urinary tract infections (11%). The proportion of pts with IgM and IgG levels below the lower limit of normal increased with further treatment courses. Additional analyses are ongoing evaluating the potential relationship between the immunoglobulin levels and non-serious/serious infections. In this series, opportunistic infections, viral reactivations or tuberculosis were not reported. A total of 36 high- and low-grade malignancies (18 in course 1, 13 in course 2, 4 in course 3 and 1 in course 4) occurred in 32 pts (3%), of which 4 had a fatal outcome (duodenal cancer, adenocarcinoma, pancreatic cancer, myelodysplastic syndrome). No lymphoproliferative malignancies and no increased risk of malignancy with additional courses of treatment were observed.
|
1st course (n=1053) |
2nd course (n=684) |
3rd course (n=400) |
4th course (n=142) |
Any AE n (%) |
931 (88) |
553 (81) |
228 (72) |
93 (65) |
Serious AE n (%) |
187 (18) |
105 (15) |
39 (10) |
4 (3) |
No. of infections |
1083 |
608 |
260 |
75 |
Infections/100 pt-yrs (CI) |
79.46 (74.87–84.34) |
84.76 (78.28–91.77) |
96.97 (85.87–109.50) |
101.4 (80.86–127.15) |
No. of serious infections |
73 |
33 |
17 |
4 |
Serious infections /100 pt-yrs (CI) |
5.36 (4.26-6.74) |
4.6 (3.27-6.47) |
6.34 (3.94-10.20) |
5.41 (2.03-14.41) |
CI=confidence interval.
Conclusion:
This further update on the long-term follow-up (2438 pt-yrs) of RA pts receiving RTX showed a safety profile consistent with that reported previously. After 4 courses, a slight upward trend was observed in the rate of infections; however, the rate of serious infections remained stable with repeated treatment.
Editorial Comment:
Evaluating the long term safety of new compounds used to treat RA is very important. In earlier clinical trials of Rituximab, patients received a single course of treatment while in clinical practice repeat infusions are used as efficacy wanes. Ongoing data is very important in understanding longer term safety consequences of repeat courses of therapy. The data presented does indicate a slight increase in overall numbers of infections per 100 patient-years of exposure with additional courses of treatment, however the confidence intervals are somewhat overlapping. Data presented on the poster showed that the numbers of patients who had IgG and IgM levels below the lower limit of normal also increased with subsequent courses. As pointed out in the abstract, additional analyses to investigate the relationship between the lower levels of IgG and IgM will be important in understanding the possible clinical consequences of low levels. Close follow up with larger number of patients treated with repetitive courses of Rituximab will be critical in understanding if there is any clinically significant selective immunoglobulin deficiency that develops with B cell continuous or repetitive B cell depletion.