A Prospective Study of Methotrexate in Combination with Ibrutinib and Temozolomide (MIT) in Newly Diagnosed Primary CNS Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin lymphoma ,High-dose methotrexate (HD-MTX) systemic chemotherapy is considered as the first-line standard therapy for PCNSL, but the ORR of HD-MTX-based chemotherapy was 60%~70%.The activation of the B-cell receptor pathway has been identified as a key mechanism of PCNSL and BTK inhibitor is a promising agent. Here we aimed to investigate the safety and efficacy of induction treatment, high-dose methotrexate in combination with ibrutinib and temozolomide (MIT) in newly diagnosed PCNSL.

Methods: This open-label， single-arm, multi-center phase II prospective study(NCT04514393) was designed to enroll 33 patients , and 25 patients have response (approx 75%), the MIT treatment would be considered effective. Eligible patients were ≥18 and ≤75 years of age with adequate organ function, with at least one measurable lesion. The MIT induction treatment included six cycles of high-dose methotrexate (HD-MTX, 3.5 g/m², every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m² d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients < 65 yr) and daily ibrutinib (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of the induction MIT treatment. The primary endpoint was the overall response rate (ORR) of the 6 cycles of MIT induction treatment for PCNSL evaluated by investigator. The safety of the treatment were also investigated. Baseline and sequential CSF/plasma samples were collected and underwent targeted next-generation sequencing (NGS).

Results: Between July 2021 and July 2022, thirty-one newly diagnosed PCNSL patients with no prior therapy were enrolled and 28 patients accepted at least 2 cycles of MIT treatment. The median age of the patients was 53 yr (range: 27-75) and15/28 (53.6%) were male. By data cutoff, 12/28 (42.9%) patients had completed six cycles of treatment, 9/28 had completed 4 cycles of treatment, and 7/28 had completed 2 cycles of treatment. The ORR was 92.9% (26/28), and CR rate was 67.9% (19/28).

Among 12 patients had completed 6 cycles of treatment, 11/12 (91.7%) patients achieved CR, 1 patient achived PR. Among 9 patients had completed 4 cycles of treatment, 4 (44.4%) achived CR, 3/9 (33.3%) achived PR. Among 7 patients had completed 2 cycles of treatment, 4 (57.1%) patients achieved CR and 3 (42.8%) pateints achived PR.

The mutation profiles of dynamic CFS and plasma ctDNA were collected and analyzed. The most commonly mutated genes in CSF were PIM1, MYD88, BTG2, CD79B, IRF4, and ETS1. The Cerebrospinal fluid protein (CSF-TP) and CSF cfDNA concentration (ng/ml), ctDNA MAF, and ctDNA concentration (hGe/ml), MAF,and hGe/ml were positively correlated. We compared gene profiles of patients in response and no response. KMT2D gene mutations were more commonly detected in patients with progression disease compared to patients responding to treatment (P=0.03). Interestingly, detectable baseline plasma ctDNA and post-treatment CSF ctDNA were significant associated with progression disease (P=0.03, P=0.004, respectively). This clinical trial is still on going.

Conclusions: The MIT induction treatment could achieve higher responses compared with HD-MTX-based chemotherapy in newly diagnosed PCNSL patients and the adverse events are manageable.

No relevant conflicts of interest to declare.

Ibrutinib: The activation of B-cell receptor pathway has been identified as a key mechanism of PCNSL and BTK inhibitor is a promising agent.