Orelabrutinib combined with R-CDOP regimen for first-line treatment of diffuse large B-cell lymphoma with high-risk CNS-IPI

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) relapse in the central nervous system (CNS) is a highly destructive complication with a poor prognosis; the typical median overall survival is less than six months. The CNS-IPI has clear predictive value for CNS relapse, and patients with a high-risk CNS-IPI score have a CNS relapse rate exceeding 10 % (Schmitz N et al., J Clin Oncol 2016). Orelabrutinib, a next-generation BTK inhibitor with enhanced BTK kinase inhibitory activity, can penetrate the blood–brain barrier and may therefore benefit patients at high risk of CNS relapse. The novel anthracycline liposomal doxorubicin is virtually devoid of cardiotoxicity. Consequently, the combination of orelabrutinib with the R-CDOP regimen is expected to improve the poor prognosis of DLBCL patients with high-risk features for CNS relapse. Methods This was a single-arm, prospective study (NCT06290817) that enrolled untreated patients with DLBCL and a high-risk CNS-IPI score. Patients received orelabrutinib combined with an R-CDOP regimen: orelabrutinib 150 mg orally once daily; rituximab 375 mg/m²; cyclophosphamide 750 mg/m²; liposomal doxorubicin 30 mg/m²; vinorelbine 25 mg/m² on day 1; and prednisone 100 mg daily on days 1–5. Treatment was given in 21-day cycles for a total of six cycles. Patients eligible for autologous stem-cell transplantation (ASCT) could undergo stem-cell collection after 3–4 cycles. For cyclophosphamide and liposomal doxorubicin, doses were adjusted according to age: patients aged 70–80 years received 70–80 % of the standard dose, and patients > 80 years received 50–60 % of the standard dose. Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The primary endpoint was the objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results From March 2021 to September 2024, 37 patients with high-risk CNS-IPI DLBCL were enrolled. The median age was 63 years (range, 41–89), and 24 (64.9 %) were male. Most patients had an Eastern Cooperative Oncology Group performance-status score of 0–2 (78.4 %). Immunohistochemistry showed double expression of BCL-2 and MYC in 64.9 % (24/37) of cases. The median follow-up was 22.6 months (range, 1.6–50.9). After two cycles, the ORR was 83.8 % (31/37), with a CR rate of 13.5 % (5/37). After four cycles, the ORR was 78.4 % (29/37), with a CR rate of 48.6 % (18/37) . Among the 37 patients who completed all six induction cycles, the ORR was 75.7 % (28/37), and the CR rate increased to 59.5 % (22/37). There were seven CR patients underwent ASCT and maintained CR. During the median follow-up of 19.1 months, CNS relapse occurred in 2 (5.4%) patients, the 1-year and 2-year cumulative incidence of CNS relapse was 0 and 9.3%. Median PFS was not reached, with 1- and 2-year PFS rates of 77.6 % and 57.4 %, respectively. Median OS was 38.1 months, 1- and 2-year OS rates were 93.8 % and 90.2 %, respectively. During the study, all patients experienced grade 1-2 adverse reactions, with grade 3-4 adverse reactions occurring in 67.6% (25/37). The most common grade 3-4 adverse events were neutropenia (59.5%), anemia (24.3%) and thrombocytopenia (16.2%). Conclusion In treatment-naïve, high-risk CNS-IPI DLBCL, the orelabrutinib plus R-CDOP regimen achieves early, deep, and durable responses with low CNS relapse rates (0% at 1 year and 9.3% at 2 years), which are significantly lower than the relapse rates with MTX plus R-CHOP prophylaxis (12.4% at 2 years), and an acceptable safety profile.