High-Dose Methotrexate Effective in Preventing Isolated CNS Relapse in Diffuse Large B-Cell Lymphoma

Risk of isolated central nervous system (CNS) involvement was found to be significantly lower in patients with diffuse large B-cell lymphoma who received high-dose methotrexate vs RCHOP chemotherapy, although risk of concomitant CNS-systemic relapse rates were similar between both groups.

High-dose methotrexate may reduce risk of isolated central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL), according to study findings published in Blood Cancer Journal.

Occurring in 1% to 14% of patients with DLBCL, CNS relapse is associated with significant risk of mortality, as prognosis for survival ranges from 2 to 5 months. For those at high risk, researchers note that guidelines have recommended systemic high-dose methotrexate as a preventive measure, although evidence has been limited to small retrospective studies, with some studies demonstrating no benefit on curbing CNS involvement.

“Given the potential for high-dose methotrexate to be associated with significant toxicity and delays of RCHOP chemotherapy which may compromise systemic control, further evaluation of the role of HDMTX in mitigating the risk of CNS recurrence is warranted,” noted the study authors.

Seeking to further investigate the preventive efficacy of high-dose methotrexate on CNS relapse in patients with DLBCL, they conducted a retrospective study of 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index score treated with RCHOP.

Participants were evaluated for isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes. A total of 66 patients were administered prophylactic high-dose methotrexate at a dosage of greater than or equal to 3 g/m2 in 81% of cycles, in which this group tended to be younger, have more extranodal involvement, and have lymphoma involving the breast.

Across a median follow-up of 20 months overall (range, 10 months to 8 years), 24 isolated CNS relapses, 10 concomitant CNS-systemic relapses, and 43 systemic relapses were identified.

Compared with patients given standard RCHOP chemotherapy, those administered high-dose methotrexate were associated with significantly lower 3-year risk of isolated CNS relapse (14.6% vs 3.1%; P = .032). Furthermore, among propensity score-matched patients (n = 102), high-dose methotrexate was associated with a significant 94% lower risk of isolated CNS relapse than the control group (HR, 0.06; 95% CI, 0.004–0.946; P = .046).

Conversely, concomitant CNS-systemic relapse rates and systemic relapse rates were not significantly different between both groups. For survival, 3-year progression-free survival (PFS) and overall survival (OS) rates were improved in patients given high-dose methotrexate compared with RCHOP chemotherapy, but multivariable analysis findings were also not significant (PFS: 66% vs 58%; P =.05; OS: 69.1% vs 63.2%; P = .07).

High-dose methotrexate was indicated to be well tolerated with manageable toxicities when given at a dose of 3 g/m2 by day 3 of RCHOP chemotherapy.

“Our study suggests that effective prophylaxis against isolated CNS relapse can be provided with high-dose methotrexate in a high-risk cohort, possibly by treating occult microscopic disease or preventing dissemination during primary therapy,” concluded the study authors. “Further investigation is necessary to better define the group of patients who will benefit from high-dose methotrexate prophylaxis, and the optimal dose and timing, while minimizing potential toxicities.”


Ong SY, Mel SD, Grigoropoulos NF, et al. High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma. Blood Cancer J. Published online August 12, 2021. doi:10.1038/s41408-021-00535-y