Tzm Regimen: A Promising Therapeutic Approach for Primary Central Nervous System Diffuse Large B Cell Lymphoma

Background:

Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare subtype of non-Hodgkin lymphoma that specifically affects the brain, spinal cord, or cerebrospinal fluid, without involving other body parts. Currently, multi-drug chemotherapy, including high-dose methotrexate therapy, is the preferred first-line treatment for PCNS-DLBCL, regardless of age. However, treatment-associated adverse events are a significant concern that cannot be ignored.

Aims:

To reduce the incidence of treatment-associated adverse events in PCNS-DLBCL patients, we developed a regimen combining tislelizumab, zanubrutinib, and high-dose methotrexate (TZM). This study aims to assess the clinical efficacy and therapeutic tolerance of the TZM regimen in PCNS-DLBCL patients by systematically analyzing the response rates and adverse events in thirty-three patients treated with the TZM regimen.

Methods:

Newly diagnosed PCNS-DLBCL patients aged 18 to 90 years were enrolled from multiple centers in China between May 2022 and May 2024. Clinical information, objective response rates, and adverse events were collected. The TZM regimen details are as follows: Tislelizumab (200 mg) and high-dose methotrexate (3.5 g/m²) were administered intravenously on the first and second day of each 21-day cycle, respectively. Zanubrutinib (160 mg) was taken orally twice a day until two years after the sixth cycle of TZM treatment. All patients signed an informed consent form before participating in the clinical trial.

Results:

Thirty-three newly diagnosed PCNS-DLBCL patients, with a median age of 68 years (range 42-82 years), were enrolled. The male-to-female ratio was 2:1. Based on the IELSG risk score, 36.4% were assigned to the low-risk group, while 63.6% were in the intermediate or high-risk groups. The white blood cell, hemoglobin, and platelet counts were normal in all patients at enrollment. Most patients had normal levels of lactic dehydrogenase and β2 microglobulin, with only six and four patients showing abnormal results, respectively. The MYD88L265P gene mutation was detected in 81.8% of patients, and 90.9% were classified as non-GCB based on the Hans algorithm. Additionally, 45.5% of patients were diagnosed with double-expressor lymphoma, and 42.4% had a TP53 gene mutation. Among the patients, 32 completed at least two cycles of the TZM regimen, with an objective response rate (ORR) of 100% and a complete response rate (CRR) of 9.1% after two cycles. Twenty-two patients completed six cycles, achieving an ORR of 100% and a CRR of 81.8%. As of July 2024, the median follow-up time was 13 months (range 2-26 months). All patients were alive except for a 73-year-old male who died one week after the second cycle due to severe infection. Adverse events were generally mild, with six patients experiencing grade 3 or greater toxicities (four cases of acute renal failure, one case of rash, and one case of autoimmune liver dysfunction).

Conclusion:

The combination of tislelizumab, zanubrutinib, and methotrexate (TZM) shows promise as a treatment for PCNS-DLBCL, demonstrating high response rates and good tolerability, despite the limited sample size. This clinical trial is ongoing to further validate these findings (Clinical Trials No. ChiCTR2300071346).

No relevant conflicts of interest to declare.