CD20-negativity at the start of second-line therapy predicts a shorter overall survival in B-cell lymphomas

- CD20 negativity was observed in 12.2% B-cell lymphomas before second-line therapy and independently associated with poor overall survival - CD20 expression should be reassessed before initiating second-line therapy and considered when choosing subsequent therapies CD20 expression is a hallmark of B-cell lymphomas and the target of anti-CD20 monoclonal antibodies. Although CD20 negativity at second-line therapy initiation has been reported, its prevalence and prognostic impact in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) remain uncertain. We assessed prevalence of CD20 negativity at second-line initiation and its association with overall survival (OS) in a nationwide cohort. We included consecutive Danish adults with DLBCL, FL, or MCL who received rituximab-based first-line therapy and were diagnosed between 2005 and 2023, for whom CD20 expression was evaluated at second-line initiation. The primary endpoint was OS from second-line therapy, stratified by CD20 status. Multivariable Cox regression analysis was adjusted for age, sex, and subtype-specific international prognostic indices. Among the 1,375 patients (814 DLBCL, 339 FL, 222 MCL), 168 (12.2%) were CD20-negative at second-line initiation. Patients who were CD20-negative had lower complete remission rates to first-line therapy (61.5% vs 72.9%, p <0.001) and shorter time to second-line therapy compared with CD20-positive patients (25.4 vs 35.2 months, respectively; p <0.001). Median OS from second-line therapy was 0.9 years for CD20-negative patients and 3.1 years for CD20-positive patients. CD20 negativity was independently associated with shorter OS from second-line therapy in multivariable analysis (hazard ratio 1.44, 95% confidence interval 1.18-1.74, p <0.001). In conclusion, CD20 negativity is observed in one in eight patients with B-cell lymphomas at second-line initiation and independently associates with poorer OS from second-line therapy. This underscores an unmet need for therapies targeting non-CD20-dependent antigens.