Golidocitinib-based therapy in relapsed/refractory mycosis fungoides and Sézary syndrome: A real-world retrospective analysis

Abstract

Abstract Cutaneous T-cell lymphoma (CTCL) is an incurable malignancy of skin-tropic malignant CD4+ T cells, with mycosis fungoides (MF; indolent cutaneous plaques/tumors) and Sézary syndrome (SS) as predominant subtypes. Current stage-guided therapies exhibit limited efficacy, while chemotherapy yields transient responses. Patients with refractory/transformed disease face dismal outcomes, highlighting critical unmet needs. Somatic JAK1/3 pseudokinase domain mutations drive constitutive JAK/STAT activation in CTCL, promoting oncogenesis and treatment resistance. Golidocitinib (Go), a potent and selective JAK1 inhibitor, has shown promising anti-tumor activity with favorable safety profile in relapsed/refractory (r/r) Peripheral T-cell lymphoma （PTCL）and has been granted conditional approval in China for the treatment of r/r PTCL. Herein, this study evaluates the clinical benefit of golidocitinib monotherapy as well as combination therapy for the treatment of R/R MF/SS in real-world setting. As data cutoff on July 22, 2025, a total of 10 patients received at least one cycle of Go-based therapy. The treatment protocol consisted of golidocitinib 150 mg QD (initial dose) with optional dose reduction to 150 mg QOD based on physician assessment. Combination strategies predominated (n=9, 90%), with all combination regimens incorporating brentuximab vedotin (BV; 1.8 mg/kg IV q3wk). The median age was 57.4 years (range 26-76), 5 patients were male. Most patients had advanced and/or more aggressive disease, including large cell transformation (LCT), high CLIPI and/or elevated LDH level. The median modified Severity Weighted Assessment Tool score at baseline was 64 (range, 12-108). The median prior line of systemic therapies was 2 (range 1-3). One multi-agents pretreated patient received golidocitinib monotherapy as subsequent-line intervention. All patients were evaluable for efficacy, Both the best overall and skin response rates were 80% (8/10). Eight patients achieved partial response (PR); one patient developed progression disease (PD) after 1.5 months of Go+BV treatment and one patient maintained stable disease (SD). Notably, 4 patients have previously relapsed or failed to respond to BV. The median time to response was 31.5 days. Intriguingly, despite golidocitinib's JAK1 inhibition suppressing IFN-γ production and T-cell proliferation/differentiation, responding patients demonstrated significant post-treatment elevation of IFN-γ levels. This paradoxical immune reconstitution suggests Go-based therapy may reverse tumor-driven immunosuppression, favoring Th1 polarization and functional recovery of antitumor immunity. Treatment-related adverse events (TRAE) were observed in 6 patients, consisting of cytomegalovirus infection (CMV) reaction (50%) and thrombocytopenia (30%). Grade 3 TRAEs occurred in 2 patients (CMV infection, thrombocytopenia), with others being Grade 1. Two patients developed treatment-related serious adverse events (SAEs), both presenting as CMV infections. This pioneering real-world study demonstrates the favorable clinical efficacy and safety of Go-based regimens in pretreated MF/SS patients. Subsequent prospective trials are warranted to further explore combination strategies.