Chemotherapy-free induction with pomalidomide, orelabrutinib, and rituximab (POR) followed by high-dose methotrexate,rituximab and orelabrutinin (ROM) in newly diagnosed primary CNS lymphoma: Interim analysis of a phase II study

Abstract

Abstract Background:High-dose methotrexate (HD-MTX) is widely used as front-line treatment in patients with primary central nervous system lymphoma (PCNSL). Both preclinical models and clinical data suggested pomalidmide and orelabrutinib were effective in PCNSL and the combination of them may have synergy in DLBCL. We aimed to evaluate the tolerability and efficacy of pomalidomide, orelabrutinib and rituximab (POR) with the sequential addition of HD-MTX chemotherapy in newly diagnosed PCNSL, especially the efficiency of chemofree regimen (POR) as lead-in treatment in PCNSL.Methods:This is an investigator-initiated, single-arm phase II study, and immunocompetent patients with untreated PCNSL were enrolled. This trial was registered at www.clinicaltrials.gov (#NCT 05390749). Patients were treated with pomalidomide 4mg once per day on days 1-14, orelabrutinib 150 mg once daily continuously, and rituximab 375 mg/m2 intravenous once on day 1 of each 21-day cycle. After four cycles, HD-MTX(3.5g/m2 civ 4h) was sequentially added with rituximab and orelabrutinib(ROM) for two additional cycles. After 4 cycles of POR and 2 cycles of ROM, the patients will be treated with Autologous hematopoietic stem cell transplantation(ASCT) for consolidation or orelabrutinib for maintenance according to the physicians choice. The primary endpoint was overall response rate (ORR) at the end of four cycles of POR. Secondary endpoints were ORR at the end of six cycles, 2-year PFS rate and safety. Therapeutic responses were assessed according to the International Primary CNS Lymphoma Collaborative Group Response Criteria every 2 cycles in the induction phase and every 3 month during the follow-up phase. Results:The data cut-off date was 15th July 2025, 33 patients were enrolled in this study. The median age was 59 years (range, 22-79 years). 11 patients had eye involvement and 2 patient had leptomeninges involvement. 26 patients belonged to IESLG intermittent/high risk group(IESLG score 2-5). One patient discontinued the treatment due to treatment-related adverse events (TRAE) after 1 cycle, two patients withdraw after 2 cycles for disease progression, and eleven patients finished four cycles of POR and were evaluable. The ORR after four cycles of POR was 84.3%(27/32) and the complete response rate was 59.3%(19/32), and 15.6%(5/32) patients had disease progression. After 2 cycles of ROM intensive induction therapy, ORR were 84.3% and CR rate increased to 78% (25/32). 11 patients received ASCT, 4 patients received WBRT as consolidation, and the other 10 patients received orelabrutinib as maintenance. With a median follow-up of 24.3 months, 2-year PFS and OS were 56.2% (95% CI 47.7%-84.2%) and 81.0%,(95%CI 68.3%-96.0%) respectively. Age, sex, IELSG risk group, consolidation therapy and maintenance with BTKi were not related with PFS or OS. All patients were received 1 cycle POR regimen at least and were evaluated for safety analysis of POR regimen. 96.7%(32/33) patients had AE. The most common AEs(≥10%) were neutropenia(60.6%), elevated transaminases(42.4%), leukopenia(36.4%), rash(36.4%), fatigue(30.3%), anemia(27.3%), infecion(18.2%), thrombocytopenia(12.1%), majority of which were grade 1 to 2. Elevated transaminases and skin rashes deserve special attention,there were 3 cases of grade 3-4 elevated transaminases and 2 cases of grade 3-4 skin rashes, respectively.ConclusionThis is the first study to treat newly diagnosed PCNSL with a targeted therapy combination before chemotherapy. POR produced a high ORR with good tolerance. This suggested the potential of noncytotoxic first-line therapies for PCNSL.