Chemotherapy-Free Salvage Therapy with Rituximab, Lenalidomide, and Poseltinib in Relapsed or Refractory Primary Central Nervous System Lymphoma: A Multi-Center, Phase II Study.

A multicenter, real-world analysis of primary central nervous system lymphoma in those with and without human immunodeficiency virus.

Nivolumab and Ibrutinib for Treatment of Patients with Refractory or Relapsed Central Nervous System Lymphoma

Real-World Efficacy and Safety of Rituximab, Lenalidomide and İbrutinib Combination in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

Orelabrutinib, Rituximab, and High-Dose Methotrexate (HD-MTX) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Retrospective Analysis on Efficacy, Safety, and Biomarker

30 Background: Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis. Ibrutinib-based regimens revealed promising efficacy but showed off-target effects and drug resistance in some cases. Here, we conducted a retrospective study to evaluate the efficacy and safety of regimens based on second-generation bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in R/R PCNSL. Methods: We respectively reviewed 23 patients with R/R PCNSL treated with zanubrutinib in our center from Apr. 2021 to Jan. 2024. The primary end points were overall response rate (ORR) and progression-free survival (PFS). Secondary end points included complete response rate (CRR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Response was assessed according to International Primary CNS Lymphoma Collaborative Group criteria. The severity of AEs was graded using the NCI Common Toxicity Criteria, version 5.0. Validated next-generation sequencing (NGS) panels were used to analyze the mutational status of the BCR pathway genes or other solid tumor-related genes. Results: The median follow-up at the cutoff date (15 Jan 2024) was 17.0 months (range, 2-33 months). The ORR, CRR and DCR were 78.3%, 39.1% and 91.3%. The median PFS was 31.0 months, but the median OS was not reached. Compared to germinal center B-cell like (GCB) group, non-GCB group showed a better ORR (76.9% vs 66.7%) and CRR (46.2% VS 33.3%). Multivariate analysis revealed that overall response (vs. no response, HR=0.20, P=0.027), long duration of zanubrutinib (≥6months vs. 2-5 months, HR=0.07, P=0.009) and refractory disease status (vs. relapse disease status, HR=0.12, P=0.014) were independent factors for longer PFS. The most commonly mutated genes are MYD88(15/17,88.2%), PIM1(9/17 52.9%), CD79B (8/17,47.1%), ETV6(7/17,41.2%), BTG1(5/17,29.4%) and GNA13(5/17,29.41%). The mutational status of MYD88/CD79B did not lead to any difference in PFS and OS. We obtained the Tumor Mutational Burden (TMB) information from 11 patients. The median TMB was 15.96 (range: 3.82-28.11) muts/Mb. Kaplan-Meier analysis demonstrated that PFS was significantly longer in patients with higher TMB (≥15.96 muts/Mb) after zanubrutinib-based treatment(P=0.005). Grade ≥3 and serious treatment-emergent AEs (TEAEs) were not found. The most commonly TEAEs were hematologic toxicity (8/23,34.8%) and skin rash (5/23,21.7%). Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the prolonged administration of zanubrutinib to maintain treatment response. Patients with higher TMB derive greater benefits from zanubrutinib-based regimens.

Long Term Outcomes of Rituximab, Temozolamide, and High-Dose Methotrexate for Lymphoma Involving the Central Nervous System

Orelabrutinib, sintilimab, and temozolomide (OST) in relapsed/refractory primary central nervous system lymphoma

A Pilot Study of Axicabtagene Ciloleucel (axi-cel) for the Treatment of Relapsed/Refractory Primary and Secondary Central Nervous System Lymphoma (CNSL)

Efficacy and safety of bmetl regimen (Orelabrutinib plus Semustine, Temozolomide and Lenalidomide) with subsequent maintenance treatment in elderly/frail patients with CNSL

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

2019 Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of non-Hodgkin lymphoma localized to the brain, cerebrospinal fluid, or eyes. For patients with PCNSL, treatment options are limited, standard of care is not well established, and prognosis is poor, particularly in the relapsed or refractory (r/r) setting. Tirabrutinib, a highly potent selective second-generation Bruton’s tyrosine kinase inhibitor, is approved in Japan, Taiwan, and South Korea based on a phase I/II study that demonstrated clinical activity in Japanese patients with r/r PCNSL. There are no currently approved drug therapies for PCNSL in the US or Europe. Here we report results from the PROSPECT study (NCT04947319) conducted in the US. Methods: In this open-label phase II study, patients with r/r PCNSL received oral tirabrutinib 480 mg as monotherapy once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by Independent Review Committee. Secondary endpoints included duration of response (DOR), time to response (TTR), best overall response (BOR), and safety. Overall survival (OS) and progression-free survival (PFS) were exploratory endpoints. Results: Forty-eight patients were enrolled. Median age was 65.5 y (range, 34-87). With a median follow-up of 11.2 mo as of November 1, 2024 (data cut-off), ORR was 66.7% (n = 32), with a complete response rate (CRR), confirmed (CR) + unconfirmed (CRu), of 43.8% (n = 21) and a partial response rate of 22.9% (n = 11). Median DOR was 9.3 mo (range, 0.0-23.5), and median TTR was 0.95 mo (range, 0.9-3.7). Median OS was not reached (range, 1.0-33.0); median PFS was 6.0 mo (range, 0.0-26.0). Overall incidence of any-grade treatment-emergent adverse events (TEAEs) was 97.9% (n = 47) and grade ≥3 was 56.3% (n = 27). Any-grade treatment-related adverse events (TRAEs) were experienced by 75.0% (n = 36), most frequently anemia (18.8%), fatigue (14.6%), neutrophil count decreased (14.6%), pruritus (14.6%), rash (14.6%), and maculo-papular rash (14.6%). Grade ≥3 TRAEs were experienced by 27.1% (n = 13), most frequently neutrophil count decreased (8.3%) and rash maculo-papular (4.2%). Deaths related to TEAEs occurred in 2 (4.2%) patients: 1 patient died from seizure and pneumonia, and the other from a fall; these grade 5 TEAEs were considered unrelated to study treatment. At data cutoff, 27.1% (n = 13) of patients remain on tirabrutinib treatment. Main reasons for discontinuation were disease progression (54.2%, n = 26) and death (8.3%, n = 4), and 1 (2.1%) patient discontinued due to an AE; deaths included the 2 patients with grade 5 TEAEs. Conclusions: With an ORR of 66.7%, CR/CRu rate of 43.8%, median DOR of 9.3 mo, and a manageable safety profile, the PROSPECT trial supports tirabrutinib monotherapy as a potentially effective treatment option for patients with r/r PCNSL. Clinical trial information: NCT04947319 .

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Trial in progress: A phase 3, multi-regional, open-label, randomized study of tirabrutinib vs rituximab and temozolomide in participants with Relapsed/Refractory primary central nervous system lymphoma

A Multicenter, Real World Analysis of Primary Central Nervous System Lymphoma in Those with and without Human Immunodeficiency Virus

Preliminary Exploration of Ibrutinib Combined with Methotrexate, Ifosfamide, Liposomal Doxorubicin and Methylprednisolone in the Treatment of Relapsed/Refractory Primary CNS Lymphoma