Rituximab, Acalabrutinib, and Durvalumab for Primary Central Nervous System Lymphoma: A Single-Arm, Phase Ib, Multicenter Study

PURPOSE: Primary central nervous system lymphoma (PCNSL) has a poor prognosis and limited treatment options. This phase Ib study evaluates the combination therapy of rituximab, acalabrutinib, and durvalumab (RAD) in relapsed/refractory PCNSL. PATIENTS AND METHODS: The study was conducted with dose escalation (3 + 3 design) and expansion phases. Acalabrutinib (100 mg) was administered once or twice daily for dose determination; rituximab (375 mg/m2) and durvalumab (1,500 mg) were administered every 4 weeks for up to eight cycles. Primary endpoints assessed safety, tolerability, and the recommended phase II dose; secondary endpoints evaluated treatment responses and survival outcomes. RESULTS: Seventeen patients, including 15 with relapsed/refractory diseases, were enrolled between February 2021 and April 2024. One patient was unevaluable. No dose-limiting toxicities were observed in the 4-week observation period for 6 evaluable patients at dose levels 1 and 2. In the expansion cohort, 10 additional patients received dose level 2. Treatment-related adverse events occurred in 14 patients (82%), with 59% experiencing grade 3/4 events, mainly including neutropenia, skin reactions, and transaminitis. Among 16 evaluable patients, the overall response rate was 62.5%, whereas the complete response rate was 12.5%. All responders received dose level 2. Median overall survival (OS) and progression-free survival (PFS) were 11.9 and 4.3 months, respectively. Improved outcomes were observed for responders versus nonresponders (OS, 20.6 vs. 10.2 months; PFS, 5.2 vs. 2.1 months). CONCLUSIONS: The RAD regimen is feasible for treating patients with PCNSL and shows potential as a therapeutic option. Further large-scale trials are needed to confirm its clinical efficacy.