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1735 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

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphomas, Clinical Research, B Cell lymphoma, Diseases, Aggressive lymphoma, Lymphoid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Lijuan Deng1*, Tianheng He2*, Yongjing Tang3*, Lan Mi4*, Changyu Lu5*, Hanxiao Liu2*, Shupeng Zhong1*, Jin Chai1*, Jun Luo, MD6*, Liling Zhang7*, Shujuan Wen8*, Xiaopei Wang1*, Jun Zhu, PhD9 and Yuqin Song10*

1Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
2Department of lymphoma, Peking University International Hospital, Beijing, China
3Department of lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China
5Department of neurosurgery, Peking University International Hospital, Beijing, China
6Department of Haematology, THE FIRST AFFILIATED HOSPITAL OF GUANGXI MEDICAL UNIVERSITY, Nanning, China
7Department of lymphoma, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
8Department of lymphoma, The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
9Department of Lymphoma, Peking University Cancer Hospital, Beijing, Beijing, China
10Department of Lymphoma,, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China

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.

Disclosures: No relevant conflicts of interest to declare.

OffLabel Disclosure: B-cell receptor-mediated signaling plays a pivotal role in the development of B-cell tumors. Zanubritinib is a second-generation oral Bruton tyrosin kinase (BTK) inhibitor. This study aims to evaluate the efficacy and safety of R-MTX-Zebrutinib in patients with relapsed or refractory central nervous system lymphoma (SCNSL) and provide evidence for the combination therapy regimen with Zebrutinib.

*signifies non-member of ASH