Efficacy and safety of orelabrutinib plus R-CDOP as first-line therapy in diffuse large B-cell lymphoma with high-risk CNS-IPI: a prospective, multicenter, single-arm, phase II study.

Background: Diffuse large B-cell lymphoma (DLBCL) patients central nervous system international prognostic index (CNS-IPI) ≥4 have a high risk of central nervous system (CNS) relapse and poor prognosis. Orelabrutinib, a next-generation Bruton's tyrosine kinase (BTK) inhibitor with excellent blood-brain barrier (BBB) penetration. This study evaluated orelabrutinib plus R-CDOP as first-line therapy in this high-risk population. Methods: This prospective, multicenter, single-arm, phase II trial (ClinicalTrials.gov: NCT06290817) enrolled untreated DLBCL patients with CNS-IPI ≥4. Patients received six 21-day cycles of orelabrutinib (150 mg orally once daily) plus R-CDOP. The primary endpoint was objective response rate (ORR) at the end of the induction; secondary endpoints included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), cumulative incidence of CNS relapse, and safety. Results: Between March 2021 and September 2024, 44 patients were enrolled and constituted the intention-to-treat (ITT) population. Median age was 63 years, 64.9% had double-expressor lymphoma. In the ITT population, the ORR at the end of induction was 70.5% (31/44, 95% confidence interval [CI]: 55.3-82.1), with a CR rate of 50.0% (22/44, 95% CI: 35.1-64.9). In the per-protocol population of 37 evaluable patients, the ORR and CR rate at the end of induction were 75.7% (28/37, 95% CI: 59.9-86.9) and 59.5% (22/37, 95% CI: 43.4-73.9), respectively. At a median follow-up of 22.6 months, median PFS was not reached. The 1- and 2-year PFS rates were 77.6% (95% CI: 64.5-90.7) and 57.4% (95% CI: 40.9-73.9). Median OS was 38.1 months, with 1- and 2-year OS rates of 93.8% (95% CI: 86.2-100) and 90.2% (95% CI: 80.4-100). The 1- and 2-year cumulative incidences of CNS relapse were 0% and 9.3%, respectively. All patients had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurring in 67.6%, mainly neutropenia (59.5%), anemia (24.3%), and thrombocytopenia (16.2%). No unexpected toxicities or treatment-related deaths were observed. Conclusion: In previously untreated DLBCL patients with high-risk CNS-IPI, orelabrutinib plus R-CDOP demonstrated promising antitumor activity and a low observed rate of CNS relapse. Hematologic toxicity was frequent, but was clinically manageable with standard supportive care. These findings should be considered hypothesis-generating and warrant validation in randomized controlled trials. Clinical trial registration: ClinicalTrials.gov, identifier NCT06290817.