Polatuzumab vedotin retains potent activity against CD79B mutations: Preclinical and clinical efficacy in diffuse large B-cell lymphoma

Abstract Background Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug conjugate delivering monomethyl auristatin E (MMAE), is approved for diffuse large B-cell lymphoma (DLBCL). CD79B mutations are recurrent in DLBCL, particularly in patients with multiple extranodal diseases and MCD subtype, and associate with inferior prognosis following standard immunochemotherapy. Whether these mutations confer resistance to Pola remains clinically significant yet undetermined. Methods In vitro, CD79B-null K562 and 293T cell lines were transduced to express CD79B Y196H mutant variant, while endogenous CD79B in TMD8 cell line was modified to generate homozygous mutations using CRISPR-Cas9 gene editing. Cells were exposed to Pola (5 μg/mL, 72 hours), and cytotoxicity was evaluated by trypan blue exclusion assay. Clinically, 20 treatment-naïve DLBCL patients with CD79B Y196 mutation received either R-CHOP (n=10) or Pola-based regimens (Pola-R-CHP: n=9; Pola-R2: n=1) for six cycles. Treatment responses (ORR, CRR) and progression-free survival (PFS) were compared between cohorts. Results Pola demonstrated potent cytotoxicity against CD79B-mutated cells in vitro. Viability plummeted to 6.39% ± 1.71% (vs. 81.27% ± 2.25% in controls, p<0.001) in mutant K562 cells, 2.29% ± 0.90% (vs. 88.22% ± 1.82%, p<0.001) in 293T transfectants, and 6.57% ± 0.69% (vs. 82.47% ± 1.37%, p<0.001) in homozygous mutant TMD8 cells. Clinically, Pola-based regimens achieved superior best overall response rates (ORR 100% vs. 90%; CRR 80% vs. 60%) and end-of-treatment responses (Cycle 6 ORR 100% vs. 80%; CRR 88.9% vs. 60%) compared to R-CHOP. At median 6-month follow-up, PFS rates were 100% for Pola-based therapy versus 90.0% for R-CHOP (log-rank p=0.705). Conclusions Pola retains potent activity against CD79B-mutant DLBCL models and demonstrates clinically meaningful efficacy in treatment-naïve patients, achieving 100% response rates despite this historically adverse biomarker. These findings position Pola-based regimens as a promising therapeutic strategy for CD79B-mutated DLBCL.