Asymptomatic patients with synchronous leptomeningeal involvement on baseline cerebrospinal fluid (CSF) examination are at elevated risk of further central nervous system (CNS) disease events and poor survival compared to patients without CSF involvement, according to a study published in the American Journal of Hematology.

The study retrospectively identified adult patients with diffuse large B cell lymphoma (DLBCL) with a high risk of CNS involvement. Patients with high-risk criteria, including the involvement of extra-nodal sites of special interest, were included in the study. Moreover, the study evaluated the efficacy of high-dose methotrexate (HD-MTX) prophylaxis for patients at high risk of CNS disease events who received at least 4 cycles of curative intent chemoimmunotherapy.

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In addition, the study’s primary endpoint was the 5-year cumulative incidence of CNS disease events, while the secondary endpoints included median progression-free survival (PFS) and overall survival (OS). Furthermore, the researchers used multiparametric flow cytometry analysis for CNS disease detection and CSF analysis of survival outcomes in patients with synchronous leptomeningeal involvement (CNSinv) and noCNS group.

Study results showed no significant difference in 5-year CNS relapse incidence after performing HD-MTX prophylaxis compared to no prophylaxis (6.2% vs. 5.6% CNS-IPI risk). Moreover, of the CNSinv patients, 93.3% had at least 1 extra-nodal site, with elevated CNS relapse/progression risk and poor PFS and OS compared to all noCNS patients. Furthermore, the CNSinv group had superior OS compared with noCNS patients who later experienced CNS relapse.

The study findings also suggest that HD-MTX prophylaxis did not reduce the risk of CNS relapse in high-risk DLBCL without leptomeningeal involvement by CSF analysis at diagnosis, suggesting that patients with synchronous leptomeningeal involvement may have a higher risk of CNS relapse/progression and inferior survival than those without it.

“We demonstrated that the use of HD-MTX CNS prophylaxis in high-risk DLBCL patients does not significantly reduce the incidence of CNS relapse when compared to patients with no CNS prophylaxis,” the study authors wrote.

“These findings are consistent with several recent retrospective studies which have directly or indirectly compared HD-MTX with no or alternative CNS prophylaxis strategies.”

Further studies might be required to evaluate the value of HD-MTX prophylaxis in patients with DLBCL with high-risk diseases not identified by baseline CSF analysis, the researchers concluded.

CNS involvement is a devastating demonstration of DLBCL with historically discouraging outcomes. Screening high-risk asymptomatic patients for leptomeningeal involvement at diagnosis is critical given the susceptibility of occult cases to appear with early CNS relapse with high mortality risk.

It is uncertain whether CNS prophylaxis strategies, including HD-MTX, lead to a statistically significant reduction in CNS relapse incidence. Until now, studies have generated conflicting outcomes and have been confounded using multimodality CNS prophylaxes.


Bennett R, Ruskova A, Coomarasamy C, et al. Diffuse large B-cell lymphoma at risk of secondary CNS involvement: the inefficacy of intravenous high-dose methotrexate CNS prophylaxis and the importance of baseline cerebrospinal fluid analysis. Am J Hematol. Published online May 10, 2023. doi:10.1002/ajh.26953.