Cell-Of-Origin Subtype Predicts Response to Polatuzumab Vedotin in Large B Cell Lymphoma

Abstract Purpose: Polatuzumab vedotin (polatuzumab) was approved for upfront treatment of diffuse large B-cell lymphoma (DLBCL) in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell-of-origin (COO), polatuzumab appears to have greater efficacy in activated B-cell (ABC) than germinal center B-cell (GCB) subtype. Most studies of polatuzumab used RNA expression to assess COO, whereas, in routine clinical practice the immunohistochemistry-based Hans algorithm is used. Methods: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with LBCL receiving polatuzumab from 2015–2024, split by receipt of polatuzumab in frontline versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL. Results: Of 740 patients, 305 received polatuzumab in the frontline and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% (OR 2.6, 95%CI 1.77–3.84, p<0.0001), with complete response rate (CRR) of 35.7% versus 17.7% (OR 2.6, 95%CI 1.66–4.02, p<0.0001). Progression-free survival (PFS) was longer for patients with non-GCB versus GCB COO (HR 0.64, 95%CI 0.5–0.83, p=0.0006). In the frontline cohort, ORR, CRR, and PFS were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP. Conclusions: Based on these data, COO classification by Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.