Pola-R-edch shows high response rates in high-risk aggressive B-cell lymphomas or PMBCL: A phase 2 study

Abstract Background Polatuzumab vedotin (Pola), an anti-CD79b monoclonal antibody-drug conjugate, has been approved for first-line treatment of diffuse large B-cell lymphoma (DLBCL) based on results from the POLARIX phase III trial. This study demonstrated that Pola-R-CHP significantly improved progression-free survival (PFS) compared to R-CHOP in patients with LBCL and IPI scores of 2-5 (Tilly et al., 2022). Meanwhile, R-DA-EPOCH has shown superior PFS to R-CHOP in DLBCL patients with IPI 3-5 (Bartlett et al., 2019) and is the preferred regimen for primary mediastinal large B-cell lymphoma (PMBCL) or high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements. However, the safety and efficacy of incorporating Pola into modified R-EDCH (with vincristine omission and dexamethasone substitution) remains unknown. To investigate this novel combination, we conducted a prospective phase 2 study evaluating R-EDCH plus Pola in high-risk aggressive non-Hodgkin's lymphoma or PMBCL. Methods This study enrolled patients aged 18-65 years with newly diagnosed aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma not otherwise specified (HGBL-NOS), and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH). Non-PMBCL DLBCL patients were required to have high-risk disease, defined as an International Prognostic Index (IPI) score ≥3 or age-adjusted IPI (aaIPI) score ≥2. All participants received six 21-day cycles of Pola-R-EDCH, consisting of polatuzumab vedotin (1.8 mg/kg IV, day 1), rituximab (375 mg/m² IV, day 0), etoposide (50 mg/m²/day continuous IV infusion, days 1-4), liposomal doxorubicin (30-40 mg/m² IV, day 1), cyclophosphamide (750 mg/m² IV, day 5), and dexamethasone (30 mg IV, days 1-5). The study protocol was approved by the Institutional Review Board/Ethics Committee of Blood Diseases Hospital, Chinese Academy of Medical Sciences. Results From July 2023 to April 2025, 16 patients were included in the study, with a median age of 41.5 years (range: 18-63 years). Among them, 4 patients (25%) were diagnosed with PMBCL, while the remaining 12 patients (75%) had DLBCL. Key clinical characteristics showed that 81.3% of patients had non-GCB subtype, 75% had elevated LDH levels, 37.5% presented with extranodal involvement, and 25% were classified as double-expressor lymphoma. Cytogenetic and molecular analysis revealed TP53 depletion/mutation in 5 patients (31.3%), CDKN2A depletion in 5 patients (31.3%), and concurrent TP53 and CDKN2A abnormalities in 3 patients (18.8%). No MYC rearrangements were detected in any patient. As of July 26, 2025, all 16 patients had undergone at least one efficacy evaluation. The best overall response rate was 100%, with a complete response rate of 81.3%. After a median follow-up of 10.1 months, disease progression occurred in 4 patients. Three of these progressing patients (75%) harbored TP53 depletion/mutation, and 2 (50%) had both TP53 depletion/mutation and CDKN2A depletion. The estimated 1-year progression-free survival (PFS) rate was 62.5%, while the 1-year overall survival (OS) rate was 87.5%.Treatment-related adverse events included grade ≥3 neutropenia in 15 patients (93.8%) and grade ≥3 thrombocytopenia in 5 patients (31.3%). Febrile neutropenia was reported in 43.8% of cases. Peripheral neuropathy occurred in 50% of patients, all of which were grade 1 or 2. Conclusions The Pola-R-EDCH regimen demonstrated high response rates in patients with PMBCL or high-risk LBCL. The addition of polatuzumab vedotin did not result in unexpected toxicities. Patients with TP53 abnormalities, with or without CDKN2A depletion, showed an increased risk of disease progression.