Ibrutinib, Rituximab, and High-Dose Methotrexate in Newly Diagnosed Primary Diffuse Large B-Cell Lymphoma of the CNS: A Prospective, Phase II, Single-Arm, Single-Center Study

Background and Significance: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of extranodal non-Hodgkin lymphoma with an increasing incidence, particularly among the elderly. The optimal treatment strategies for newly diagnosed PCNSL remain elusive. The Bruton's tyrosine kinase (BTK) inhibitor-ibrutinib, has shown promise in recurrent/refractory CNS lymphoma due to its efficacy and ability to penetrate the blood-brain barrier. This prospective study explored the combination of ibrutinib, rituximab, and HD-MTX ( IRM regimen) as a novel therapeutic approach for newly diagnosed PCNSL, aiming to improve response rates and minimize toxicity.

Study Population: Thirty-two patients with newly diagnosed PCNSL were enrolled between January 1, 2020, and May 2024.The median age of the participants was 59 years, with a Karnofsky Performance Status (KPS) score ranging from 20 to 40.

Location of Participating Centers: This single-center study was conducted at the Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Inclusion Criteria: Newly diagnosed patients with PCNSL confirmed by brain biopsy; aged 18-80 years; signed informed consent; at least one measurable lesion; ECOG 0-4; leucocytes ≥5x10^9/L, hemoglobin ≥80 g/L, platelets ≥75x10^9/L, bilirubin ≤1.5 ULN, AST ≤2.5 ULN, ALT ≤2.5 ULN, creatinine ≤1.5 ULN; LEVF ≥50%; effective contraception for men or women of childbearing age; expected survival time of at least 6 months.

Exclusion Criteria: Participated in other clinical trials within 3 months before enrollment. Patients who participated in non-intervention studies were eligible to participate in this study; Received blood transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment within 14 days before enrollment; Patients who are planned to be vaccinated with live virus, or patients who have been vaccinated within 28 days (or 5 half-life of the vaccine) before enrollment; History of gastrointestinal perforation and/or fistula within 6 months before enrollment; Those who have contraindications to any of the components in the Ibutinib-R-HD-MTX scheme; The patient had previously received treatment for lymphoma, including: chemotherapy, immunotherapy, local radiotherapy for lymphoma, surgical treatment (except tumor or pathological tissue biopsy and surgical removal not for lymphoma) and any BTK inhibitor treatment before enrollment.

History of other malignancies that may affect the compliance of the research protocol or the analysis of the results (there are cured skin cells that have cured and have not relapsed within 3 years before enrollment, or skin melanoma or cervical Patients with a history of carcinoma in situ can be enrolled);Severe non-malignant tumor diseases that can affect compliance with the study protocol, such as severe cardiovascular disease (such as New York Heart Association Class III or IV heart disease, myocardial infarction or unstable type within the last 6 months)，arrhythmia or unstable angina), uncontrolled diabetes and hypertension;

Known uncontrolled active infectious disease or any major infection event requiring intravenous antibiotic treatment or hospitalization (excluding tumor fever) within 4 weeks before enrollment; Human immunodeficiency virus (HIV) antibody is positive;

Hepatitis C virus (HCV) antigens or antibodies were positive; Hepatitis B virus (HBV) surface antigen positive, and HBV-DNA> 10^3 copy number; Researchers consider whether anyone is unsuitable for enrollment.

Endpoints: Primary endpoint: ORR. Secondary endpoints: PFS, OS and safety profile.

Current Status: As of June 30, 2024, the median follow-up was 25.1 months. Of the 32 enrolled patients, 8 patients were withdrawn due to drug allergies and dropout (loss to follow-up and disease progression). Among the remaining 24 patients, 13 completed consolidation therapy and entered maintenance therapy. Five patients just completed 4 cycles of induction therapy, and six are still undergoing induction therapy. No severe adverse reactions, such as atrial fibrillation or pulmonary fungal infections, were reported. Further detailed results will be available upon study completion.

No relevant conflicts of interest to declare.

In this study, we utilized ibrutinib and the IRM regimen in a manner not specifically approved by regulatory authorities. Specifically, ibrutinib was used for recurrent/refractory primary central nervous system lymphoma based on multiple high-level published studies suggesting potential efficacy and safety. This off-label use was chosen due to the lack of alternative approved therapies and the potential benefits to patients. Informed consent was obtained from all patients or their legal representatives before treatment initiation. The risks and benefits of off-label use were thoroughly discussed with the patients. All participants were closely monitored for adverse events, and established protocols were followed to manage potential risks associated with off-label use.