A Prospective, Open-Label, Multicenter, Randomized Controlled Study Comparing the Efficacy and Safety of Polatuzumab Vedotin, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone Combined with Orelabrutinib/Chidamide/Venetoclax/Lenalidomide/Penpulimab (Pola-RCHP-X) Versus RCHOP-X and Pola-Rchp in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma

Background and Significance

In recent years, most phase III clinical trials exploring first-line treatments for diffuse large B-cell lymphoma (DLBCL) have ended in failure, with the notable exception of the POLARIX study. This may be primarily due to the heterogeneity of DLBCL. Currently, the Pola-R-CHP regimen has emerged as one of the new standard first-line treatments for DLBCL. Given the heterogeneity of DLBCL, combining different therapeutic agents tailored to specific genetic subtypes may be a strategy to further improve first-line treatment efficacy. Therefore, we are planning to conduct a prospective, multicenter, randomized controlled trial to comparing the efficacy and safety of Pola-RCHP-X versus R-CHOP-X or Pola-R-CHP (NCT06516978).

Study Design and Methods:

This study aims to enroll 528 patients aged 18-80 years with an International Prognostic Index (IPI) score of 2-5, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, diagnosed with CD20+ DLBCL, and who have not received prior systemic treatment. Eligible patients will be randomly assigned in a 1:1:1 ratio to one of the following three arms: Pola-RCHP-X, R-CHOP-X, or Pola-R-CHP.

Patients in the Pola-RCHP-X and R-CHOP-X arms will first receive one cycle of Pola-R-CHP or R-CHOP while undergoing genetic subtyping. From cycles 2 to 6, patients with MCD, BN2, or N1 subtypes will receive Pola-RCHP-orelabrutinib/ R-CHOP-orelabrutinib; those with the EZB-MYC+ subtype will receive Pola-RCHP-venetoclax/ R-CHOP-venetoclax; those with the EZB-MYC− subtype will receive Pola-RCHP-chidamide/R-CHOP-chidamide; those with TP53 mutations will receive Pola-RCHP-penpulimab/R-CHOP-penpulimab; and those with the ST2 subtype or NOS will receive Pola-RCHP-lenalidomide/R-CHOP-lenalidomide. This will be followed by two cycles of Rituximab monotherapy. Patients in the Pola-R-CHP arm will receive the standard 6 cycles of Pola-R-CHP followed by 2 cycles of Rituximab.

The primary endpoint of the study is progression-free survival at 24 months (PFS24) as assessed by the investigators. Secondary endpoints include investigator-assessed complete response (CR) rate, overall response rate (ORR), event-free survival (EFS), overall survival (OS), and safety.

No relevant conflicts of interest to declare.