Phase II Study of Zanubrutinib in Combination with Rituximab and Methotrexate, Followed By Zanubrutinib Maintenance in Patients with Secondary Central Nervous System Lymphoma

BACHGROUND: Secondary central nervous system lymphoma (SCNSL) occurred in about 5% of patients with diffuse large B-cell lymphoma (DLBCL). The prognosis of SCNSL is very poor. There is no consensus on the treatment of SCNSL and new therapeutic strategies are urgently needed. Zanubrutinib is a new second-generation BTK inhibitor and has showed good efficacy and safety in a variety of B-NHLs. This study attempts to evaluate the efficacy and safety of zanubrutinib combined with rituximab and high-dose methotrexate in the treatment of SCNSL in patients with DLBCL.

METHODS: Patients with DLBCL and secondary CNS involvement are eligible if age≥ 18, ≤75, ECOG≤3, and adequate organ function. Patients must have relapsed after ≥1, ≤4 lines of prior systemic lymphoma directed therapy. Zanubrutinib in combination with rituximab and methotrexate will be given as induction therapy for 6 14-day cycles. Zanubrutinib will be given as 160mg bid orally between days 1 and 14 of each cycle; rituximab will be given at 375mg/m2 intravenously on day 1 of each cycle; methotrexate at 3.5g/m2 for patients ≤65 or 1.5g/m2 for patients >65 (standard hydration/leucovorin support) will be given intravenously on day 2 of each cycle. For patients ≤65, autologous hematopoietic stem cell transplantation (ASCT) with conditioning regimen of thiotepa/carmustine will be given as consolidation treatment after induction therapy. For all patients, zanubrutinib will be given continuously after induction therapy or ASCT as maintenance therapy until disease progression, intolerable toxicity, or death. Primary outcome measure is 1-yaer PFS and secondary end points are response, overall survival, and toxicity.

RESULTS: Nine patients have been enrolled. Median age was 62 (range 33-72); 5 were men. Median ECOG was 2 (1: 1, 2: 4, 3: 4). Eight had newly diagnosed SCNSL and one had recurrent SCNSL. The median time from first diagnosis to CNS relapse was 2.5 year (range 0.5-15 years). Five patients were isolated CNS disease and 4 patients had synchronous CNS and systemic disease. Seven patients had parenchymal disease, one had additional cerebrospinal fluid (CSF) involvement, and one had spinal disease. Two patients developed CNS progression after 1 and 4 cycles of induction therapy respectively and both had stable systemic disease. The other 7 patients all had received 6 cycles of induction therapy and zanubrutinib maintenance therapy. Two of them received ASCT and then zanubrutinib maintenance. At the end of induction therapy, of 5 patients with isolated CNS disease, 4 achieved CR and 1 achieved PR. Of 2 patients with synchronous CNS and systemic disease, both achieved CNS CR and 1 had systemic CR and 1 had systemic PR. The combined ORR was documented in 7 patients (78%), with CR in 5 (56%) and PR in 2 (22%) patients. After a median follow-up of 9 months, 4 patients progressed (1 of them died) and 5 were still in maintenance therapy. The median PFS was 9 months (range 0.5-15 months). The most common adverse events were leukopenia, thrombocytopenia, and hypokalemia. Grade 3/4 events were only observed in 2 patients (1 grade 4 thrombocytopenia and 1 grade 3 urinary infection). Only these two patients temporarily discontinued therapy due to adverse events.

CONCLUSION: Zanubrutinib in combination with rituximab and methotrexate displayed clinical activity in SCNSL in both CNS and systemic disease. The safety and tolerability of this regimen in SCNSL patients were favorable. More clinical data will be updated from this ongoing study (NCT05398224).

No relevant conflicts of interest to declare.

In this trial, we try to use the BTK inhibitor zanubrutinib in secondary central nervous system diffuse large B-cell lymphoma