Phase II Clinical Trial on Chidamide, Rituximab and High-Dose Methotrexate (C-R-HDMTX) in Newly Diagnosed Primary CNS Lymphoma

Abstract

Background:

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma variant confined to the central nervous system. Current treatment primarily uses high-dose methotrexate (MTX) with rituximab, but incomplete responses and relapse are common. Chidamide, an oral histone deacetylase (HDAC) inhibitor, can cross the blood-brain barrier, achieving therapeutic concentrations in cerebrospinal fluid. In addition, it enhances MTX efficacy by promoting its polyglutamylation and regulating key genes. This study investigates the potential of combining chidamide with rituximab and high-dose MTX (C-R-HDMTX) in PCNSL treatment.

Methods:

This single-center, open-label, phase II trial administered C-R-HDMTX every three-week for six courses unless disease progression, death, or intolerable toxicity. The primary endpoint was complete remission (CR) rate. Progression-free survival (PFS) was also assessed. Treatment included chidamide (20 mg orally, twice weekly for two weeks, followed by a one-week break), rituximab (375 mg/m² IV, day 1), and MTX (3.5 g/m² IV, day 2) per 21-day cycle. Responses were evaluated using the international PCNSL collaborative group (IPCG) criteria after 2-4 cycles.

Results:

Between September 7, 2020, and August 26, 2023, ten patients (7 males, 3 females) were enrolled. The median age was 62 years (range, 50-76). Overall, 8 patients had non-germinal center B-cell-like (non-GCB) subtype, 2 patients had GCB subtype. Nine patients were evaluable for efficacy. Six patients exhibited multiple enhancing lesions. The overall response rate at the end of induction was 89%, with a CR rate of 78% (7/9 patients). With a median follow-up of 16.5 months (range 11.0-46.5)，the median PFS was 13 months, with the longest ongoing at 46.5 months. The median OS was not achieved. Grade 3/4 hematologic toxicities included neutropenia and thrombocytopenia (20% each). Common non-hematologic adverse events were mild, including hypocalcemia (80%), hyponatremia and elevated AST (50% each), and increased ALT (30%).

Conclusions:

The C-R-HDMTX regimen demonstrated high efficacy and manageable toxicity in PCNSL patients, warranting further investigation as a potential treatment option for this aggressive lymphoma.

Clinical trial information: NCT04516655

Lv:MSD: Research Funding.

Chidamide. The ability of chidamide to traverse the blood-brain barrier significantly enhances its clinical utility, making it a viable candidate for inclusion in combination therapies aimed at treating PCNSL.