Efficacy and safety of bmetl regimen (Orelabrutinib plus Semustine, Temozolomide and Lenalidomide) with subsequent maintenance treatment in elderly/frail patients with CNSL

Abstract Introduction: Central nervous system lymphoma (CNSL) is an aggressive lymphoma (Radke J et al. Nat Commun. 2022), including primary CNSL (PCNSL) and secondary CNSL (SCNSL). Although high-dose methotrexate-based regimens like MATRix (always 6 cycles with 3.5mg/m2 methotrexate) constitute the main therapeutic strategies, severe toxicities and poor tolerability in elderly and frail patients underscore the urgency for low-toxicity and well-tolerance strategies without compromising efficacy (Dasgupta et al. Leuk Lymphoma. 2018; Sacks et al. Int J Stroke. 2018). Studies have shown that Bruton tyrosine kinase inhibitors (BTKis) are effective for CNSL by regulating the B cell receptor pathway (Zhang Y et al. Cancers. 2024). Orelabrutinib, a potent, irreversible, and highly selective BTKi, combined with lenalidomide and other treatments has shown synergistic activity and well-tolerance in CNSL patients (Yang C et al. Front Oncol. 2022). This study evaluated the efficacy and safety of the oral orelabrutinib plus semustine, temozolomide and lenalidomide (called BMeTL) regimen with sequential maintenance in elderly/frail patients with CNSL. Methods: This multicenter, open-label, observational clinical study enrolled adult patients with histopathologically or cytologically confirmed PCNSL or SCNSL. Eligible patients received 4-cycle induction therapy with BMeTL (orelabrutinib 150 mg, once daily; semustine 75 mg/m2, day 1; temozolomide 100 mg/m2, days 1-5; lenalidomide 15 mg, days 1-14) in a 21-day cycle. After induction therapy, patients with objective response received sequential MT regimen (methotrexate 3 mg/m2, day 1; thiotepa 20 mg/m2, day 2) in a 21-day cycle for 2-4 cycles. Responders after MT regimen were recommended for autologous stem cell transplantation (ASCT) or whole-brain radiotherapy (WBRT) according to their performance status and age. The primary endpoint was the objective response rate (ORR) before ASCT or WBRT as per Lugano 2014 criteria. Secondary endpoints were complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Adverse events (AEs) were assessed according to the NCI-CTCAE v 5.0. Results: Forty patients with (23 [57.5%] males; 7 [17.5%] SCNSL) were enrolled, with a median age of 65 years (range: 56-87). Most patients had an ECOG performance status of ≥2 (77.5%) and concomitant disease (70%). Of 40 patients evaluated for induction (BMeTL) efficacy, ORR was 80%, with 14 (35%) CR and 18 (45%) partial responses (PR). As of the cut-off date (May 31, 2025), twenty-four responders sequentially received MT regimen, among whom 10 (41.7%) achieved CR, 5 (20.8%) achieved very good PR (VGPR), and 6 (25%) achieved PR. And the median follow-up time was 13.5 months. With 13 PFS events, median PFS was not reached; 12- and 24-month PFS rates were 70.9% and 61.4%. With 13 death events (2 died of COVID-19), median OS has yet reached, with 2- and 24-months OS rates of 67.6% and 62.4%, respectively. Among 33 PCNSL patients, ORR was 81.8% (8 CR and 19 PR) after BMeTL regimen; of 20 patients received MT maintenance, ORR was 90% (18/20; 9 CR, 5 VGPR, and 4 PR). The 12- and 24-month PFS rates were 73.8% and 66.4%, 12- and 24-month OS rates were 69.5% and 69.5%, respectively. Grade 3-4 AEs occurred in 35 (87.5%) patients, including granulocytopenia (n=24, 60%), thrombocytopenia (n=18, 45%), and anemia (n=10, 25%), infectious AEs (n=6, 15%) with antifungal prophylaxis.Conclusions: BMeTL regimen with subsequent maintenance treatment is effective and well-tolerated for elderly/frail patients with CNSL. This study provides a potential novel strategy for this elderly/frail population.