Bruton's Tyrosine Kinase (BTK) Inhibitors Plus RM (rituximab and methotrexate) for the First-Line Treatment of Primary Central Nervous System Lymphoma (PCNSL)

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare invasive non Hodgkin's lymphoma (NHL), with the vast majority being diffuse large B-cell lymphoma. Due to its invasive biological behavior, the median survival time is only 2-3 months without therapy. Currently, the standard regimen for newly diagnosed (ND) PCNSL was high dose methotrexate (HD-MTX) combined with rituximab (R), and more effective regimens also have been explored since its poor prognosis. Genomic studies in PCNSL demonstrated that recurrent and CDKN2A deletions, MYD88 and CD79B mutations, and mutations that activate BCR signaling. BTK mediates downstream signaling of MYD88 and, and is an important regulator of the BCR signaling pathway. To date, three BTKs, Ibrutinib (I), Zebutinib (Z), and Obutinib (O) are approved for clinical using in China and have shown promising anti-tumor activity in NHL, and PCNSL in particular. So we analyze the efficacy and safety of BTKs combined with RM for ND PCNSL.

Methods: ND PCNSL patients who received BTKi-RM (I 420mg po qd (1 patient) , Z 160mg po bid (4 patients) or O 150mg po qd (17 patients), rituximab 375 mg/m2 iv day 0, MTX 3.5 g/m2 iv day1, 21 days per cycle) regimens in our center between March 2021 and February 2024 were included.Tumor evaluation was performed usually every two cycles during the induction therapy, at end of treatment and every 3 to 6 months after that by MRI or PET/CT, PET/MR.The overall remission rate (ORR), complete remission (CR) rate, progression-free survival (PFS), and overall survival (OS) were described.

Results:Twenty patients (11 males), with a median age of 61 (rang, 44-74) years were included, the median number of treatment was 6 (rang, 3-8). Eleven and six patients were considered moderate and high risk respectively according IELSG scores. Eleven patients were non-GCB subtype, and 14 were double-expression. Twelve samples were performed genetic analysis and classified by LymphGen algorithm, 9 (75%) were MCD genetic subtype, 2 were non-subtyped and the other was assigned to BN2.Ten patients underwent ASCT and 15 patients received maintenance therapy (BTKi or Lenalidomide) after induction therapy. After median follow-up of 16.3 months, a CR rate of 60% (12/20 patients) and a ORR of 95% (19/20 patients) was achieved, and 1-year PFS and OS were 71.5% (95% CI 53.1%-96.3%) and 94.7% (95% CI 85.2%-100%), respectively. All patients had response to O-RM (ORR 100%, CR rate 66.7%) in the O-RM cohort, and 8 patients (88.9%) achieved CR in MCD subgroup. There were no treatment-related deaths occurred.Conclusion: This real-word analysis demonstrates that BTKi-RM regimen is effective and safe for the treatment of patients with ND PCNSL.

No relevant conflicts of interest to declare.