Cytokine signatures predict response, progression, and immune-related toxicity in Sézary syndrome patients treated with mogamulizumab

Abstract Introduction Sézary syndrome is a rare, aggressive cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy, and malignant T-cells in peripheral blood. Mogamulizumab, a humanized anti-CCR4 monoclonal antibody, has demonstrated clinical efficacy in this setting. However, the immunologic mechanisms driving treatment response, disease progression, and immune-mediated adverse events (MAR) remain unclear. This study investigates longitudinal cytokine profiles in Sézary patients treated with mogamulizumab to identify biomarkers predictive of therapeutic response and toxicity. Methods In a prospective multicenter study conducted at the Hematology Clinic of AOU Marche (Ancona, Italy), we enrolled 10 consecutive patients with Sézary syndrome treated with mogamulizumab between May 2021 and May 2024. Serum cytokine levels (IL-2R, IL-1β, IL-6, IL-8, IL-10, TNF-α) were measured at baseline, and after 3, 6, and 12 months of therapy. Data on treatment response, disease progression, and MAR (mogamulizumab-associated rash) were collected longitudinally. Cytokine levels were analyzed in relation to clinical outcomes using non-parametric statistical methods. Results The median patient age was 71 years; 60% were female. Mogamulizumab was administered as third-line therapy (range 2–8), with a median of 16.5 cycles (range 13–33). At follow-up, 30% of patients were non-responders, and 20% progressed on treatment. MAR occurred in 5 patients, with a median onset at cycle 7 (range 6–12). Patients who achieved clinical response had significantly lower baseline IL-2R levels (median 906.5 vs 2815 U/mL, p = 0.0039), lower IL-6 at 3 months (3.59 vs 7.25 pg/mL, p = 0.0057), and reduced TNF-α at 6 months (11.5 vs 436 pg/mL, p = 0.0210) compared to non-responders. Conversely, patients who progressed showed higher IL-2R at both baseline (7137 vs 921 U/mL, p = 0.0356) and 6 months (3757 vs 975 U/mL, p = 0.0134), and lower IL-1β at baseline (4 vs 14.65 pg/mL, p = 0.0346) and 3 months (4 vs 19.2 pg/mL, p = 0.0210). TNF-α at 6 months was also significantly higher in progressors (436 vs 11.5 pg/mL, p = 0.0211). Patients who developed MAR had significantly lower IL-8 at baseline (14.8 vs 25.1 pg/mL, p = 0.0210) and higher IL-1β at 6 months (20.5 vs 4 pg/mL, p = 0.0245) compared to those without rash. Conclusions This study highlights distinct cytokine signatures associated with clinical response, disease progression, and immune-related toxicity in Sézary syndrome patients treated with mogamulizumab. Lower levels of IL-2R, IL-6, and TNF-α were linked to treatment response, while elevated IL-2R and TNF-α and decreased IL-1β were associated with progression. MAR correlated with low IL-8 and elevated IL-1β. These findings support the potential utility of serial cytokine profiling to inform prognosis and personalize therapy in this rare lymphoma subtype.