Updated Results from a Multicenter, Phase II Study of Zanubrutinib in Combination with Rituximab and Methotrexate, Followed By Zanubrutinib Maintenance in Patients with Secondary Central Nervous System Lymphoma
Authors: Deng Lijuan , He Tianheng , Tang Yongjing , Mi Lan , Lu Changyu , Liu Hanxiao , Zhong Shupeng , Chai Jin , Luo Jun , Zhang Liling , Wen Shujuan , Wang Xiaopei , Zhu Jun , Song Yuqin 
Published: December 2024

BACHGROUND
Secondary central nervous system lymphoma (SCNSL) occurs in approximately 5% of patients with diffuse large B-cell lymphoma (DLBCL) and is associated with a poor prognosis. Previously, at the ASH 2022 conference, we reported that zanubrutinib, a second-generation BTK inhibitor, combined with rituximab and high-dose methotrexate demonstrated favorable efficacy and a good safety profile in a phase II trial for SCNSL (NCT05398224). This report presents updated results with longer follow-up and additional patient enrollment, including subgroup analyses of clinical and molecular characteristics.

METHODS
Patients with DLBCL and secondary CNS involvement are eligible. The treatment regimen consists of zanubrutinib combined with rituximab and methotrexate as induction therapy for six 14-day cycles. For patients aged ≤65, autologous hematopoietic stem cell transplantation (ASCT) will be provided as consolidation treatment. All patients will receive continuous zanubrutinib as maintenance therapy after induction therapy or ASCT until disease progression, intolerable toxicity, or death. The primary outcome measure is 1-year progression-free survival (PFS), while secondary endpoints include response rate, overall survival (OS), and toxicity.Tumor samples were collected at initial diagnosis. Whole-exome sequencing and bulk RNA sequencing were performed on 16 and 14 samples, respectively. The log-rank test was used to compare survival distributions.

RESULTS
As of 28 July 2024, 21 patients have been enrolled. Median age was 62 (range 33-72); 8 were men. Median ECOG was 2 (1: 3, 2: 10, 3: 8). The median time from first diagnosis to CNS relapse was 1.8 year (range 0.2-15.0 years). Thirteen patients were isolated CNS disease and 8 patients had synchronous CNS and systemic disease. Seventeen patients had parenchymal disease, 4 had additional cerebrospinal fluid involvement, and 2 had spinal disease.
After a median follow-up of 15.1 months, 12 patients progressed (6 of them died) and 9 were still on therapy. Fourteen patients had received 6 cycles of induction therapy and 3 of them received ASCT. In total, 19 patients were evaluable. Of 11 patients with isolated CNS disease, 7 achieved CR, 1 achieved PR, and 3 developed CNS PD. Of 8 patients with synchronous CNS and systemic disease, 2 patients developed early CNS PD, 3 achieved CR in both CNS and systemic disease, and 3 had CNS or systemic PR. The combined ORR was documented in 14 patients (73.7%), with CR in 10 (52.6%) and PR in 4 (21.1%) patients. The median PFS was 12.2 months and the median OS has not been reached. The 1-year PFS and OS were 54.3% and 75.0% respectively (Figure 1). Safety was consistent with that previously reported. Grade 3/4 events were only observed in 3 patients (1 grade 4 thrombocytopenia, 1 grade 3 urinary infection, and 1 grade 3 anemia).
COO was identified in 14 patients Using the Lymph2Cx classifier (ABC: 9, GCB: 2, unclassified: 3) and genetic subtype was predicted in 16 patients using the LymphGen tool (MCD: 2, ST2: 3, EZB: 1, BN2: 1, EZB/A53: 1, Other: 8). MYD88 mutation was detected in 9 of 16 patients (L265P: 7, non-L265P: 2). CD79b mutation was detected in 5 of 16 patients. Subgroup analysis of PFS revealed no statistically significant differences across various clinical subgroups (CNS relapsed within 1 year or not, p value =0.16; isolated CNS relapse or with systemic relapse, p value =0.46). No significant differences in PFS were observed within the COO subgroups and the genetic subgroups (p value =0.54 & p value =0.88). The MYD88 and CD79b mutation status showed no association with PFS (p value =0.48 & p value =0.37).

CONCLUSION
These updated results further demonstrated the efficacy and tolerability of R-MTX-zanubrutinib in treating patients with SCNSL. This study also highlighted the genetic heterogeneity of SCNSL and notably, therapeutic efficacy was observed in most subgroups, including GCB subtype and genetic subtypes other than MCD.