According to a study published in Blood, researchers have demonstrated that ruxolitinib appears to be clinically efficacious across a variety of peripheral T-cell lymphoma (PTCL) subtypes, especially T-cell large granular lymphocytic leukemia (T-LGL) and that ruxolitinib activity was enriched among in patients with PTCL with JAK/STAT mutations or active signaling.

“No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed,” wrote Alison J. Moskowitz, MD, of Memorial Sloan-Kettering Cancer Center, New York, NY, and colleagues. “The JAK/STAT pathway is activated in many TCL entities and therefore represents a potential therapeutic target.”

The team conducted a multicenter, investigator-initiated, phase 2 study ( Identifier: NCT02974647) of the JAK1/2 inhibitor ruxolitinib in patients with relapsed/refractory PTCL or mycosis fungoides. Between January 2017 and July 2019, they enrolled patients onto 3 biomarker-defined cohorts: those with activating JAK and/or STAT mutations (n = 21); those with >30% phosphorylated (p) STAT3 expression among tumor cells by immunohistochemistry (n = 15); or those with neither JAK/STAT mutations or >30% pSTAT3 or who had insufficient tissue to assess the biomarkers (n = 17).

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All patients received oral ruxolitinib (20 mg) twice daily until disease progression. The investigators assessed response after cycles 2 and 5 then every 3 cycles. The primary endpoint was clinical benefit rate (CBR), which was defined as the combination of complete response (CR), partial response (PR), and stable disease (SD) lasting at least 6 months.

A total of 53 patients (51% male), with relapsed/refractory PTCL (n = 45) or mycosis fungoides (n = 7) were enrolled on the study. The patients had a median age of 62 years (range, 19-88) and had received a median of 3 prior therapies (range, 0-11). The most common disease subtypes included PTCL-not otherwise specified (n=12), T-cell prolymphocytic leukemia (n = 8); angioimmunoblastic T-cell lymphoma/T follicular helper cell lymphoma (n = 9); and T-LGL (n = 5).

Among 52 patients evaluable for response (1 patient withdrew consent following only 1 week of treatment without progression of disease or toxicity), the investigators reported CR in 3 (6%), PR in 10 (19%), and SD in 5 (10%). The overall response rate (ORR) and CBR were 25% and 35%, respectively.

Of the 7 patients with mycosis fungoides, only 1 had CBR (ongoing PR > 18 months). CBR among the patients with PTCL was 53% in cohort 1 (activating JAK/STAT mutations), 45% in cohort 2 (>30% pSTAT3), and 13% in cohort 3 (cohorts 1 and 2 vs 3, P = .02). The investigators also reported that 8 patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-LGL.

In an exploratory analysis, the team demonstrated that expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in fewer than 25% of tumor cells was associated with response to ruxolitinib (P = .05).

All enrolled patients were evaluable for safety. The investigators reported that the adverse events (AEs) were consistent with the known profile of ruxolitinib. Treatment-related serious AEs included herpes simplex virus-1 stomatitis (n = 1), spontaneous bacterial peritonitis (n = 1), febrile neutropenia (n = 3), anemia (n = 1), and herpes zoster (n = 1).

Limitations of the study included the inability to assess pSTAT3 expression in the peripheral blood (instead of bone marrow) of patients with T-LGL and T-PLL, a limited definition of JAK/STAT activation, and the small sample size.

“[T]his study provides proof of principle that the JAK/STAT pathway is clinically relevant in TCLs,” the authors wrote. “We demonstrate that the readily available oral inhibitor ruxolitinib was active across various subtypes characterized by JAK/STAT pathway activity with acceptable toxicity. Furthermore, in T-LGL, ruxolitinib provided benefit regardless of JAK/STAT mutational status.”

Disclosure: This research was partially funded by Incyte. Please see the original reference for a full list of disclosures.


Moskowitz AJ, Ghione P, Jacobsen E, et al. A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood. 2021;138(26):2828-2837. doi:10.1182/blood.2021013379