Combination therapy with methotrexate, ifosfamide, cytarabine, dexamethasone and rituximab (R-MIAD) improves clinical outcomes in primary central nervous system lymphoma: A monocentric retrospective observational study

Abstract Background: High-dose methotrexate (HD-MTX) based combination chemotherapy is the first-line induction regimen for the treatment of primary central nervous system lymphoma (PCNSL). Various combinations have been reported by a bunch of clinical investigations. However, up to date, there is no consensus on the optimal combination regimens by international guidelines, largely due to the crucial issue of balancing efficacy and safety with HD-MTX-based chemotherapy in clinical practice. In this retrospective study, we described our institutional experience with R-MIAD regimen (rituximab, methotrexate, ifosfamide, cytarabine, dexamethasone) for patients with newly diagnosed PCNSL. Patients and methods We retrospectively analyzed PCNSL patients treated with R-MIAD regimen at Beijing Tiantan Hospital, Capital Medical University from November, 2019 to November, 2024. The R-MIAD regimen was planned as: rituximab 375 mg/m² d0, MTX 3.5 g/m² d1 [for those >65 years old, partially discretionary to 3g/m2 depending on the general condition of the patient], ifosfamide (IFO) 1.5 g/m² d2, cytarabine (HD-AraC) 2 g/m² d3, dexamethasone (DEX) 10 mg d1-3, every 21 days as 1 cycle. Calcium folinate salvage was started every 6 h for a total of 8 doses after 24 h of MTX administration every 6 h for a total of 8 times, while with regular monitoring of the blood MTX concentration of MTX. During ifosfamide administration, 300 mg/m² of mesna was administered simultaneously at time 0, 4 hours, and 8 hours for urinary tract protection. ORR was defined as the sum of partial response (PR) and CR. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 of the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. The This study was approved by the institutional ethics committee of Beijing Tiantan Hospital, Capital Medical University. Informed consent was obtained from all patients. All research procedures adhered to the Declaration of Helsinki. Results A total of 63 immunocompetent newly diagnosed PCNSL patients received the R-MIAD regimen, including 26 males (41.3%) and 37 females (58.7%). The median age was 60 (18-79) years with 34 patients (54%) aged 60 years or older. At onset, 10 patients underwent neurosurgical resection, 52 underwent stereotactic biopsy, and 1 underwent cerebrospinal fluid (CSF) examination. Pathological confirmation revealed that 59 cases were diffuse large B-cell lymphoma (DLBCL), of which 8 cases had a germinal center B-cell (GCB) phenotype (CD10+ BCL-6+/- MUM1+/-), 43 cases had an activated B-cell (ABC) phenotype (CD10- BCL-6+/- MUM1+ or CD10- BCL-6- MUM1-), and 8 cases were classified as DLBCL-NOS. All patients were followed up from the date of diagnosis until March 1, 2025, and none were lost to follow-up. The median follow-up time was 17.5 (3-64) months. Among the 63 patients, 45(71.4%) patients achieved complete remission, 13(20.6%) achieved partial remission, 2(3.2%) had stable disease and 3(4.8%) had progression of disease. The objective response rate (ORR) was 92%. %. The with median progression-free survival (PFS) was 19.8 months and the median overall survival (OS) was not achieved. The 1-year PFS and OS rates were 53% and 96.3%, respectively. The adverse events (AEs) of chemotherapy were mainly bone marrow suppression, with the incidence of grade 3-4 neutropenia, anemia, and thrombocytopenia being 46%, 3.2%, and 17.5%, respectively. All AEs were manageable; with no grade 4 non-hematologic AEs were observed. Only 7(11.1%) cases were observed with grade 3 non-hematological adverse reactions, and recovered well after treatment. No treatment related deaths occurred. Conclusion Our results suggest that R-MIAD regimen is a feasible, safety-manageable, and effective combination therapy for patients with newly diagnosed PCNSL. Prospective clinical trials are still needed for further verification of R-MIAD regimen in first-line treatment of PCNSL.