Zanubrutinib, Lenalidomide, Rituximab, Temozolomide and Methotrexate (RLZT±MTX) As First-Line Treatment for Newly Diagnosed PCNSL: A Prospective, Open-Lable, Multicenter Clinical Trial

Backgroud：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 disappointing with poor prognosis.

Aim: This study aims to evaluate the clinical efficacy and safety of Zanubrutinib combined with Lenalidomide, Temozolomide and Rituximab monoclonal antibody ±Methotrexate (RLZT±MTX) as first-line treatment for primary central nervous system lymphoma, especially in elderly patients who cannot tolerance to intensive chemotherapy.

Methods: The prospective, multicenter, open-label study planned to enroll 40 patients(Registration number:ChiCTR2000039485). Group A (RLZT+MTX) :eligible 20 young patients were ≤65 years, with normal kidney function. Patients in arm A were treated with regimen 1 and 2 alternately, each 3 courses, A total of 6 courses; Group B (RLZT) :eligible 20 elderly patients were >65 years or ≤65 years frail patients or patients with kidney dysfunction, regimen 2 was used for a total of 6 courses. Regimen 1: high-dose MTX (3.5g/m2) every 28 days; Regimen 2: RLZT (Rituximab 375mg/m2 IV D1, Lenalidomide 15mg/m2 D1-21, Zanubrutinib 160mg bid D1-21, Temozolomide 150mg/m2 Po D1-5) every 28 days. Note: 1. In group A, if patients who did not have a CR or PR after 6 cycles of the above regimen then the whole-brain radiotherapy (WBRT) was recommended; If patients achieved a CR or PR, auto-HSCT consolidation therapy was feasible; If the patient is not willing to transplant, enter single-agent oral Zanubrutinib to maintain until disease progression or intolerance.2. In group B, if patients who did not have a CR or PR after 6 cycles RLZT then the whole-brain radiotherapy (WBRT) was recommended, if patients achieved a CR or PR, maintain Zanubrutinib until diseaseprogression or intolerance.

Results: The data cut-off date was June 30, 2022, totally 24 patients enrolled in this clinical trial，both groups had 12 patients(Table 1). The ORR in the 24 PCNSL pts was 79.2%, with 9 (37.5%) complete responses (CR) and 10 (41.7%) partial responses (PR), in addition, 2 (8.3%) stable disease (SD) and 3 (12.5%) progressive disease (PD) were observed. The ORR was 66.7% (CR:16.7%, PR 50%) in the RLZT+MTX group and 91.7% (CR:58.3%, PR 33.3%) in the RLZT group. The median PFS and OS were not achieved in total patients，and the estimated 18-months OS and PFS were 95.8% and 78.2%, respectively. Similarly, The median PFS and OS were not achieved in both groups，estimated 18-months OS was 91.7% in the RLZT+MTX group and 100% in the RLZT group. The estimated 18-months PFS was 81.5% in the RLZT+MTX group and 80% in the RLZT group (Figure1).

Overall, 50%patients had experienced hematologic toxicity. Only 1 patient had grade ≥3 thrombocytopenia event and 1 patient had grade ≥3 leukopenia event. The overall incidence of non-hematologic toxicity was 50%, including gastrointestinal reactions, rash, liver and kidney damage, but only one patient had≥3 grade AE (rash). In addition, pneumonia was reported in 16.7% (4/24) of the patients, but no deaths were due to adverse events (Table 2).

Conclusions: This study showed that RLZT+MTX was an effective and safety 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.

Keywords:Primary central nervous system lymphoma, Zanubrutinib, first-line treatment