Phase II Trial of an Orelabrutinib-Based Combination Therapy in Newly Diagnosed Primary Central Nervous System...

Primary central nervous system lymphoma (PCNSL) is a rare, yet highly aggressive non-Hodgkin lymphoma confined to the central nervous system (CNS). High-dose methotrexate (HD-MTX) remains the baseline chemotherapy for newly-diagnosed PCNSL. Intensive chemotherapies combined with HD-MTX have improved patient outcomes. However, the substantial toxicities limited their applicability, especially among elderly patients with poor physical status. Optimal composition of induction and consolidation treatment are still warranted.

In this prospective single-arm phase II trial (ChiCTR2200061485), we evaluated the efficacy and safety of HD-MTX combined with rituximab and orelabrutinib, a second-generation BTK inhibitor with high CNS penetration, as induction therapy in newly diagnosed PCNSL. Twenty-two patients received up to six cycles of the combined induction therapy. Patients who achieved remission proceeded to non-randomized consolidation therapies with ASCT (autologous hematopoietic stem cell transplantation), WBRT (whole-brain radiotherapy), or orelabrutinib maintenance, based on patient eligibility and physician discretion. The primary endpoint was the centrally assessed response post-induction. Secondary endpoints included progression free survival (PFS), overall survival (OS), and safety.

Among the 22 enrolled patients, the overall response rate (ORR) at the end of induction therapy was 91.0%, including 9 patients (41.0%) with complete remissions (CRs), and 11 patients (50.0%) with partial remissions (PRs). With a median follow-up of 22.3 months (range 2.3-42.4 months), the 1-year and 2-year PFS rates were 66.6% and 59.2%, respectively; OS rates were 81.8% and 66.3%, respectively. Consolidation was performed in 15 patients: 5 underwent ASCT, 4 received WBRT, and 6 received maintenance orelabrutinib. The most common adverse effects were grade 1 anemia (45.5%). Grade ≥ 3 events included neutropenia (13.6%) and pneumonia (9.0%).

The combination of HD-MTX, rituximab, and orelabrutinib demonstrates high response rates and manageable toxicity in newly diagnosed PCNSL, supporting further evaluation in randomized trials.