Ruxolitinib is clinically efficacious across various T-cell lymphoma subtypes, especially T-LGL.
Ruxolitinib activity is enriched among PTCL with JAK/STAT mutations or active signaling.
Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, for patients with relapsed/refractory PTCL (n=45) or mycosis fungoides (MF) (n=7). Patients enrolled onto one of three biomarker-defined cohorts: 1) activating JAK and/or STAT mutations; 2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry; or 3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. The primary endpoint was clinical benefit rate (CBR) defined as the combination of complete response (CR), partial response (PR), and stable disease lasting at least 6 months. Only one of 7 patients with MF had CBR (ongoing PR>18 months). CBR among the PTCL cases (n=45) in cohorts 1, 2 and 3 were 53%, 45%, and 13% (cohorts 1&2 vs. 3, p=0.02). Eight patients had CBR>12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6 (pS6), a marker of PI3 kinase or MAP kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (p=0.05). We conclude that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. (Registered at clincialtrials.gov, #NCT02974647).