Sustained response (ORR4) as an on-treatment prognostic marker in mogamulizumab-treated mycosis fungoides and Sézary syndrome: the FIL-MOGA study

Abstract Background Conventional response endpoints do not adequately capture durable clinical benefit in mycosis fungoides (MF) and Sézary syndrome (SS). Overall response lasting ≥ 4 months (ORR4) has been proposed as a clinically meaningful endpoint in clinical trials, but its prognostic value in real-world mogamulizumab-treated patients remains unknown. Objectives To evaluate the effectiveness and safety of mogamulizumab in routine clinical practice and investigate the prognostic relevance of ORR4 in patients with MF/SS. Methods FIL-MOGA was a nationwide, multicenter, retrospective study including 98 patients with MF/SS treated with mogamulizumab between January 2021 and December 2023 across 18 centers of the Italian Lymphoma Foundation (FIL). The primary endpoint was ORR4. Survival outcomes were assessed using Kaplan–Meier estimates, 4-month landmark analyses, and Cox proportional hazards models treating ORR4 as a time-varying covariate (TVC). Results After a median follow-up of 35 months, ORR4 was achieved in 44 of 93 (47.3%) evaluable patients. Best overall response increased from 29.4% at 1 month to 38.0% at 4 months and 58.1% during follow-up. ORR4 varied significantly according to baseline disease stage (p=0.022), ranging from 10.0% in stage IIB to 70.8% in stage IVA1 disease. In landmark analyses, ORR4 was associated with improved 24-month OS (76% vs 60%; p=0.006), PFS (58% vs 35%; p=0.001), and TTNT (76% vs 47%; p=0.002). These findings were confirmed in time-dependent analyses (OS HR 2.53, p=0.008; PFS HR 2.70, p=0.001; TTNT HR 3.04, p=0.003). In multivariable models, lack of ORR4 remained independently associated with worse OS (HR 3.18, p=0.002), PFS (HR 2.67, p=0.002), and earlier initiation of subsequent systemic therapy (HR 4.27, p=0.001). Skin adverse events were associated with higher ORR4 rates (70% vs 40%, p=0.017) but not independently with survival outcomes. Thirteen patients (13%) underwent allogeneic hematopoietic stem cell transplantation after mogamulizumab. Conclusions This large real-world study confirms the effectiveness of mogamulizumab and identifies ORR4 as a robust on-treatment prognostic marker independently associated with OS, PFS and TTNT. These findings support the incorporation of ORR4 as a clinically meaningful endpoint in real-world studies and routine management of MF/SS.