ML-21 Tirabrutinib Monotherapy for Relapsed/refractory Primary Central Nervous System Lymphoma

Abstract Backgrounds & purpose: Prognosis of patients with primary central nervous system lymphoma (PCNSL) remains poor despite multiagent immunochemotherapy, and standard of care for relapsed or refractory (r/r) PCNSL has not been established. Recent progresses on molecular genetics and biology of PCNSL have led to development of novel molecular targeted therapies, especially targeting Bruton’s tyrosine kinase (BTK), located in the B-cell receptor and Toll-like receptor signaling pathways. Tirabrutinb, a second generation BTK inhibitor, was approved for r/rPCNSL in March 2020 in Japan. Methods: Patients with r/rPCNSL treated with tirabrutinib since December 2017 were eligible for this retrospective study. Tirabrutinib was given orally at doses 320–480 mg/day daily until progression or unacceptable toxicity. Results: A total of 7 patients were enrolled (6 relapses, 1 refractory), 4 males, median age was 73 (range, 54–80 years), and median KPS was 70 (70–90). Three patients had received prior whole brain radiotherapy. Median number of prior therapies was 1 (1–2). Best overall response rate was 57.1%; 42.9% with a complete response (CR/CRu), 14.3% with a partial response (PR), while there were 3 PDs (42.9%). Four patients experienced PD and estimated median progression-free survival (mPFS) was 29.6 months. All patients were alive at the data cutoff with median follow up of 21.4 months (2–30.4). Common adverse events (AEs) include grade 4 neutropenia (n=1), grade 3 lymphopenia (n=3), and hepatic dysfunction (n=1). Toxic rash was observed in four patients (grade 3 in one, grade 2 in three) leading to discontinuation of tirabrutinib in two patients, while others continued on TIR with dose reduction and steroid use. The median time to rash presentation was 28 days (12–28). Conclusions: Tirabrutinib was well tolerated with frequent minor to moderate skin rash emerging within one month and active for r/rPCNSL. Long-term efficacy and safety profile need to be determined with a larger cohort.