Zanubrutinib in Combination with R-MTX for Newly Diagnosed Primary Central Nervous System Lymphoma
Authors: Xiao Xibin , Chen Panpan , Jiang Huawei , Li Xian , Xie Jing , Qian Wenbin 
Published: December 2024

Background:

Primary Central Nervous System Lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma (NHL) restricted to the brain, meninges, spinal cord, and eyes and is histopathologically predominantly classified as diffuse large B-cell lymphoma (DLBCL) (90%). Traditional first-line treatment for PCNSL, based on high-dose methotrexate regimens, has demonstrated disappointingly low cure rates, falling below 40%, and unfortunately, these treatments are also prone to late recurrences. Recent studies revealed that BTK inhibitors (BTKi) play a role in various B cell lymphomas, including DLBCL, and have also shown promising efficacy in PCNSL. We hypothesized that BTK inhibitors (BTKi) combined with R-MTX (rituximab plus methotrexate ) might be a favorable option for PCNSL patients. Here, we present preliminary data from the pilot of Zanubrutinib combined with R-MTX in PCNSL patients.

Methods:

Patients were eligible to participate in the study if they were aged 18 years or older, had a diagnosis of Primary Central Nervous System Lymphoma (PCNSL), and possessed an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 4. The induction treatment was performed with four cycles of Zanubrutinib (160 mg twice daily,orally ), rituximab (375 mg/m2, intravenously IV, d0), and methotrexate (3.5 g/m2, IV, d1) every 3 weeks. Patients achieving partial remission (PR) or complete remission (CR) after induction therapy proceeded to receive two cycles of ZR-MTX followed by either ASCT or Zanubrutinib maintenance therapy for consolidation, tailored to the patient's fitness and preference. Patients who did not achieve PR or CR were to receive subsequent anti-tumor therapies, as determined by the investigator. Treatment response was determined by central neuroradiology review with contrast-enhanced brain magnetic resonance imaging every two cycles.

The primary endpoint was the objective response rate (ORR) at the end of induction therapy. Secondary endpoints were best ORR recorded during induction therapy, progression-free survival (PFS), OS, and safety. Adverse events (AEs) were assessed complying with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

Results:

At data cutoff (Jul 24, 2024), 15 patients were enrolled. Median age was 63 years (range 21-78), 8 (53.3%) patients were male, 12 (80.0%) had an Eastern Cooperative Oncology Group score 1-2. Thirteen patients (86.7%) had an International Prognostic Index (IPI) score of 2 or higher.

At the end of induction therapy, 6 (40.0%) patients achieved CR, and 4 (26.7%) patients achieved PR, indicating an ORR of 66.7%. At the end of second cycle, The ORR was 73.3% with one patient achieving CR and 10 patients achieving PR. The best ORR during induction therapy was 86.7%. The median follow-up time was 20.2 (range 8.8 - 44.2) months. the median PFS was 7.9（range:5.2-35.1）months, and the median OS was not reached. The estimated 2-year PFS rate was 38.9% and the estimated 2-year OS rate was OS 67.5%.

Overall, 15(100%) patients had at least one TEAE and Only 4 (26.7%) patients experienced Grade 3 TEAE, all the other TEAEs were not higher than grade 2. No patient reported grade 4-5 AEs. The most common (≥30%) all-grade TEAEs were neutropenia (100.0%), followed by hemorrhage (80%), anemia (73.3%), nausea (60%), poor appetite (53.3%), platelet count decreased (46.7%), Vomiting (40%), Fatigue (40%), Constipation (40%), Oral mucositis (40%). The most common (≥15%) TEAEs of Grade ≥3 were neutropenia (20%). No treatment discontinuation occurred due to AE. No unexpected toxicities were observed.

Conclusions:

Zanubrutinib combined with H-MTX showed promising efficacy and acceptable safety in Primary Central Nervous System Lymphoma (PCNSL).