Zanubrutinib, Lenalidomide, Rituximab, Temozolomide and Methotrexate (RLZT ± MTX) As First-Line Treatment for Newly Diagnosed PCNSL: A Prospective, Open-Label, Multicenter Clinical Trial
Authors: Fu Rong , Song Jia , Liu Hui , Jiao Zongjiu , Gao Da , Ding Kai , Zhuo Jie , Jiang Huijuan , Gao Shan , Ren Yue , Li Lijuan , Wang Yihao 
Published: December 2024

Background Primary central nervous system lymphoma (PCNSL) represents approximately 2% of all primary central nervous system tumors and 4% to 6% of all extranodal lymphomas. The incidence of PCNSL has been increasing in recent years, and the median age at diagnosis was 65 years old. Most PCNSLs are diffuse large B-cell lymphoma (DLBCL; 90%-95%). PCNSL-DLBCL is a rare and highly aggressive lymphoma, due to its characteristics and special involved sites，previous treatment effect is disappointed with poor prognosis.
Aim: This study aims to evaluate the efficacy and safety of zanubrutinib combined with Lenalidomide, Temozolomide and Rituximab monoclonal antibody ± Methotrexate (RLZT±MTX) as first-line treatment for PCNSL, especially in elderly patients who cannot tolerate the intensive chemotherapy.
Methods: The prospective, multicenter, open-label, two-cohort study planned to enroll 40 patients (Registration number: ChiCTR2000039485). Young PCNSL patients aged ≤65 years and with normal kidney function were enrolled in cohort A and received MTX (high-dose MTX 3.5 g/m2, every 28 days) alternating with RLZT (rituximab 375 mg/m2 IV D1, lenalidomide 15 mg/m2 D1-21, zanubrutinib 160 mg bid D1-21, temozolomide 150 mg/m2 Po D1-5) every 3 cycles (28 days a cycle) for a total of 6 cycles. Elderly patients aged &gt;65 years or ≤65 years frail patients or patients with kidney dysfunction were enrolled in cohort B and received RLZT for 6 cycles (28 days a cycle). For cohort A, if patients who did not achieve a complete response (CR) or partial response (PR) after 6 cycles treatment, the whole-brain radiotherapy (WBRT) was recommended. If patients achieved a CR or PR, auto-HSCT consolidation therapy was feasible. Patients who are not willing to transplant could receive single-agent oral zanubrutinib as maintenance treatment until disease progression or intolerance. For cohort B, if patients who did not achieve a CR or PR after 6 cycles' RLZT, the WBRT was recommended. If patients achieved a CR or PR, zanubrutinib was administered as maintenance therapy until disease progression or intolerance.
Results: As of June 30, 2023, 32 patients were enrolled (15 patients in cohort A and17 patients in cohort B). For total patients, the ORR was 81.2%, with 12 (37.5%) patients achieving CR and 14 (43.7%) PR. In addition, 3 (9.4%) patients were stable disease, 3 (9.4%) of progressive disease (PD), 3 (9.4%) of relapse disease and 4 (12.5%, 3 cases died of PD/ relapse, 1 case died of COVID-19) deaths were observed. The ORR was 86.7% (CR 40%, PR 46.7%) in the RLZT+MTX group and 76.5% (CR 35.3%, PR 41.2%) in the RLZT group. The median progression free survival (PFS) and overall survival (OS) were not reached in total patients，and the estimated 24-months OS and PFS rate were 77.1% and 77%, respectively. Similarly, the median PFS and OS were not reached in both groups and the estimated 24-month OS rate was 83% in the RLZT+MTX group and 70% in the RLZT group (P &gt;0.05). The estimated 24-month PFS rate was 86.7% in the RLZT+MTX group and 70% in the RLZT group (P &gt;0.05).
Overall, 50% of patients experienced hematologic toxicity. Only 4 patients had grade ≥3 hematologic toxicity event. The 40.7% of patients experienced non-hematologic toxicity, including gastrointestinal reactions, rash, liver and kidney damage, and only 3 patients had grade ≥3 adverse events (AE). In addition, pneumonia was reported in 15.7% (5/24) of the patients, but there were no deaths due to AE.
Conclusions: This study showed that RLZT+MTX was effective and safe as first-line treatment for PCNSL patients. It is worth noting that in elderly patients who cannot tolerate high-dose chemoradiotherapy, RLZT shows a promising prospect.