Lymphoma in the Tofacitinib Rheumatoid Arthritis Clinical Development Program

Abstract

ObjectiveTofacitinib is an oral JAK inhibitor indicated for the treatment of rheumatoid arthritis (RA). We characterized lymphoma events in the tofacitinib RA clinical development program.MethodsLymphoma 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.ResultsA 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.ConclusionIn 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.

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…EBV‐associated post‐transplant lymphoproliferative disorder was observed at an increased rate in renal transplant patients treated with tofacitinib, but these patients also received additional, concomitant immunosuppressive medications . So far, the RA patients treated with tofacitinib or baricitinib seem to have a similar risk of cancer to those treated with other biological therapies, although long‐term follow‐up studies are certainly missing to assess whether blockade of the JAK–STAT pathway is associated with increased risk of cancer …”

“…155 So far, the RA patients treated with tofacitinib or baricitinib seem to have a similar risk of cancer to those treated with other biological therapies, although long-term follow-up studies are certainly missing to assess whether blockade of the JAK-STAT pathway is associated with increased risk of cancer. 156,157…”

Singapore Chapter of Rheumatologists updated consensus statement on the eligibility for government subsidization of biologic and targeted‐synthetic therapy for the treatment of rheumatoid arthritis

“…In keeping with recommendations from major rheumatology societies and reimbursement guidelines, with recent studies of tsDMARD efficacy and safety, all TFP members voted for the use of all other options (bDMARD/ tsDMARD) as second‐line after failure of non‐TNFi. This leaves the treating rheumatologist with significant discretion in deciding on a second‐line agent.…”

“…25 However, use of any bDMARD or tsDMARD in the instance of failing a first-line non-TNFi is supported by the two most recently published best practice guidelines in 2016 (EULAR and Thai Rheumatism Association) and Australia's Medicare and NICE reimbursement guidelines. [17][18][19][20]22,25,27,57 In keeping with recommendations from major rheumatology societies and reimbursement guidelines, with recent studies of tsD-MARD efficacy and safety, 58,59 all TFP members voted for the use of all other options (bDMARD/ tsDMARD) as second-line after failure of non-TNFi. This leaves the treating rheumatologist with significant discretion in deciding on a second-line agent.…”

Tofacitinib y la necesidad de vigilancia de potenciales efectos adversos en pacientes con artritis reumatoide

“…[8] En el caso de estos pacientes con AR, que recibieron tofacitinib y desarrollaron linfoma, la mayoría tenían sín-drome de Sjögren secundario asociado, siendo seropositivos y ACPA (+) al inicio del estudio, frente a los controles emparejados.…”