Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Xavier Mariette, Connie Chen, Pinaki Biswas, Kenneth Kwok, Mary G Boy, Xavier Mariette, Connie Chen, Pinaki Biswas, Kenneth Kwok, Mary G Boy

Abstract

Objective: Tofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). We characterized lymphoma events in the tofacitinib RA clinical development program.

Methods: Lymphoma events (up to March 2015) were identified from 19 tofacitinib studies (2 phase I, 9 phase II, 6 phase III, and 2 long-term extension) of patients with moderate to severe RA. Patients in these studies received tofacitinib dosed at 1-30 mg twice daily or 20 mg once daily, as monotherapy or with conventional synthetic disease-modifying antirheumatic drugs. Lymphoma incidence rates (IRs; number of patients with events/100 patient-years) and standardized incidence ratios (SIRs) were calculated. A descriptive case-matched control analysis (1:4) was performed to identify potential risk factors for lymphoma.

Results: A total of 6,194 patients received tofacitinib (19,406 patient-years of exposure, 3.4 years median treatment duration). Nineteen lymphomas occurred (IR 0.10 [95% confidence interval (95% CI) 0.06-0.15]), with no increase observed with time of exposure. The age- and sex-adjusted SIR of lymphoma was 2.62 (95% CI 1.58-4.09) (Surveillance, Epidemiology, and End Results [SEER] program database). The clinical characteristics of the 19 lymphomas were typical for the RA population. Three lymphomas were positive for Epstein-Barr virus, 8 were negative, 2 were equivocal, and 6 were untested. Numerically, more lymphoma cases had a history of Sjögren's syndrome and were positive for anti-cyclic citrullinated protein and rheumatoid factor at baseline versus matched controls. The mean corticosteroid dose was higher for lymphoma cases versus controls.

Conclusion: In the tofacitinib RA clinical development program, lymphoma rates were stable over time and there were minimal differences in the baseline characteristics of patients with and without lymphoma.

Trial registration: ClinicalTrials.gov NCT00147498 NCT00413699 NCT00413660 NCT00960440 NCT00550446 NCT00603512.

© 2017 The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1
Figure 1
Incidence rates of lymphoma in the tofacitinib clinical program by 6‐month time intervals. Exposure and incidence rates are shown for each discrete 6‐month time period. a = The final reporting period (>54 months) was expanded such that there were at least 1,000 patient‐years of exposure for this period. The final interval included patients with >54 to 96 months of exposure. Since this analysis was performed, a further data cut including exposure up to 105 months has become available. During this time, no additional lymphoma events have occurred. 95% CI = 95% confidence interval.
Figure 2
Figure 2
Standardized incidence ratios of lymphoma with tofacitinib clinical trials compared with published clinical trials data for biologic disease‐modifying antirheumatic drugs used to treat rheumatoid arthritis. Clinical trials data for tofacitinib, adalimumab 32, certolizumab pegol 33, etanercept 37, infliximab 34, abatacept 35, and golimumab 36 are standardized against the Surveillance, Epidemiology, and End Results (SEER) program database 25. For golimumab, combined data for 50‐mg and 100‐mg dose groups are shown. Data for tofacitinib are adjusted for age and sex. The broken horizontal line represents standardized incidence ratio = 1.0, i.e., no difference in lymphoma rate versus the US general population. 95% CI = 95% confidence interval; FDA = Food and Drug Administration.
Figure 3
Figure 3
Tofacitinib dose history for patients with lymphoma events in the tofacitinib rheumatoid arthritis clinical development program. Case numbers correspond to those given in the first column of Table 1. Periods during which patients stopped tofacitinib treatment are included within the prior dose. The longest no‐dose period was 16 days. BID = twice daily.

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