Efficacy and Safety of Orelabrutinib-Containing Regime (TORM) As First-Line Therapy in Primary Central Nervous System Lymphoma (PCNSL): A Retrospective Analysis

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extranodal lymphoma with poor prognosis. Currently there is no standard therapeutic strategy for PCNSL, and high-dose methotrexate-based regimens remain the first option (Siegal et al. Acta Haematologica 2019). Recently, studies have shown that Bruton's tyrosine kinase (BTK) plays a crucial part in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in PCNSL (Shen et al. Front Oncol. 2022). BTK inhibitor has been proven effective in treating chronic lymphocytic leukemia and other B-cell lymphomas (Yoshitaka et al. Neuro-Oncology 2021). Orelabrutinib is a novel and highly selective BTK inhibitor with high cerebrospinal fluid (CSF) concentration, which has demonstrated efficacy and safety in PCNSL (Wu et al. Invest New Drugs. 2022). Thus, we conducted a retrospective study to evaluate the efficacy and safety of the orelabrutinib-containing regimens as first-line therapy for patients (pts) with PCNSL.

Methods: This isa retrospective analysis of pts with PCNSL who received TORM regimens (temozolomide 150 mg/m ² day 2-5; orelabrutinib 150 mg qd day 2-21; rituximab 375 mg/m ² day 1; methotrexate 3.5 g/m ² day 2; 3 weeks per cycle) as first-line induction therapy between June 2021 and April 2023. It was proposed to receive autologous stem cells transplantation (ASCT) as consolidation therapy or orelabrutinib monotherapy as maintenance after TORM therapy when deemed necessary. The primary endpoint was overall response rate (ORR) according to the International PCNSL Collaborative Group (IPCG) criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Results: Twelve pts (8 males) with PCNSL were included, with a median age of 63.5 years (range, 40-77). All pts had a histologically confirmed diffuse large B-cell lymphoma and a history of deep intracranial lesions. 8 pts (66.7%) had non-germinal center B-cell-like subtypes. 5 pts (41.7%) had an Eastern Cooperative Oncology Group performance status of ≥2, and 10 pts (83.3%) had International Extranodal Lymphoma Study Group scores ≥2. 4 pts (33.3%) underwent ASCT after induction therapy and 4 pts (33.3%) received orelabrutinib maintenance monotherapy. As of the cut-off date (July 1, 2023), the median follow-up was 11.7 (range, 1.9-23.0) months, and median treatment cycle was 6 cycles (range, 2-9). All 12 pts were evaluated for the treatment response. An interim evaluation after 3/4 cycles was available for 12 pts, showing complete remission (CR) rate of 83.3% (10/12), partial response (PR) rate of 16.7% (2/12), giving an ORR of 100.0% (12/12, Table 1). At data cutoff, of all 12 evaluable pts, the best ORR was 100.0% (12/12), with all pts achieved CR ( Table 1). The median time to response was 1.7 (range, 0.7-2.4) months. Of 12 responders, 9 had an ongoing response, 2 developed progressive disease, and 1 died of covid-19 infection ( Figure 1). Median PFS was 22.6 months, with a 95% CI of 10.4-not reached (NR). Based one OS event, median OS was 22.6 months (95% CI, NR-NR). The most common AEs were anemia. Reported AEs were generally manageable and resolved soon after supportive treatment. AEs associated with off-target activities such as atrial fibrillation, diarrhea, and major hemorrhage were not reported.

Conclusions: TORM regimens demonstrated encouraging efficacy and well-tolerated safety profile among pts with PCNSL in this retrospective study. This orelabrutinib-containing regimens may provide a potential treatment strategy for pts with PCNSL.