Cutaneous Lymphoma International Prognostic Index and Risk Stratification in Advanced Mycosis Fungoides and Sézary Syndrome

Importance Risk stratification in advanced mycosis fungoides and Sézary syndrome (MF/SS) remains suboptimal given that current TNMB (tumor, node, metastasis, blood) staging has limited prognostic value for clinically relevant outcomes. Objective To determine whether the Cutaneous Lymphoma International Prognostic Index (CLIPI) may be used to predict progression-free survival (PFS) and best objective response (BOR) in patients with advanced MF/SS. Design, Setting, and Participants This international prospective cohort study included patients with stage IIB to IVB MF/SS from the PROCLIPI trial which ran from July 1, 2015, to May 1, 2025, across 46 referral centers. Median follow-up was 4.75 (95% CI, 4.04-5.13) years; eligible participants had complete data on CLIPI, PFS, and BOR. Data were analyzed from September 1 to December 1, 2025. Exposure CLIPI score at diagnosis, based on age (>60 years), elevated serum lactate dehydrogenase, N3 nodal status, and large-cell transformation in the skin. Patients were classified as having low (0 or 1 factor), intermediate (2 factors), or high risk (3 or 4 factors). Main Outcomes and Measures PFS (defined as diagnosis to disease progression or death) and BOR (complete response, partial response, stable disease, or progressive disease) during follow-up. Exploratory analyses evaluated treatment effects before progression using inverse probability weighting. Results Among 277 patients (median [IQR] age at diagnosis, 66 [23-89] years; 183 male individuals [65.7%]), 144 (52.0%) were classified as having low risk, 93 (33.6%) intermediate risk, and 40 (14.4%) high risk. They had a median PFS of 4.64 years (95% CI, 3.50-5.76), 2.72 years (95% CI, 1.81-4.56), and 0.89 years (95% CI, 0.65-1.14), respectively (log-rank P < .001). Patients in the intermediate-risk (hazard ratio [HR], 1.45; 95% CI, 1.01-2.08) and high-risk (HR, 3.84; 95% CI, 2.21-6.66) CLIPI groups displayed higher hazards of progression or death than those at low risk. Inclusion of CLIPI improved PFS discrimination over a model with baseline stage alone. Each 1-point increase in CLIPI was associated with approximately 38% lower odds of observing a better response during follow-up (odds ratio, 0.62; 95% CI, 0.43-0.89). Conclusions and Relevance In this international prospective cohort of patients with advanced MF/SS, CLIPI scores were associated with risk of disease progression and likelihood of response beyond clinical stage. These findings indicate that CLIPI may help to refine risk stratification and support its integration into clinical decision-making and future trial design.