Brentuximab vedotin in cutaneous T-Cell lymphoma: emerging evidence and therapeutic insights for CD30-negative and CD30-low disease

BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are rare, heterogeneous non-Hodgkin lymphomas primarily involving the skin and are associated with poor outcomes in advanced disease. CD30 expression varies across CTCL subtypes and serves as the therapeutic target for brentuximab vedotin (BV), an antibody-drug conjugate with established efficacy in CD30-positive CTCL. OBJECTIVE: To review the clinical evidence supporting BV use in CTCL, with emphasis on CD30-low (<10%) and CD30-negative disease, and to contextualize its role relative to standard therapies. METHODS: A comprehensive literature review was conducted, including prospective clinical trials, retrospective analyses, and real-world studies. Key areas of focus included BV's mechanism of action, predictors of response, safety profile, and guideline recommendations across levels of CD30 expression, particularly in CD30-negative CTCL. RESULTS: BV demonstrates robust efficacy in CD30-positive CTCL, with the phase III ALCANZA trial showing superior response rates, progression-free survival, and quality-of-life outcomes compared with standard therapies. In contrast, responses among CD30-negative patients included in clinical trials were limited and inconsistent. However, emerging real-world data describe clinically meaningful responses in CD30-negative and CD30-low disease, potentially mediated by bystander cytotoxicity or heterogeneous, low-level CD30 expression, particularly in transformed mycosis fungoides. BV is guideline-endorsed for relapsed or refractory CD30-positive CTCL, and ongoing studies are exploring combination strategies and next-generation antibody-drug conjugates. CONCLUSION: BV is a key therapy for CD30-positive CTCL. While real-world experience suggests potential activity in CD30-negative or low disease, prospective trials are needed to define its role in this challenging subgroup.