CNS Prophylaxis With High-Dose Methotrexate in High-Risk Aggressive B-Cell Lymphoma

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In a retrospective study reported in the Journal of Clinical Oncology, Lewis et al found that prophylactic high-dose methotrexate did not appear to offer a clinically meaningful reduction in risk of central nervous system (CNS) disease progression in patients with high-risk aggressive B-cell lymphoma.

Study Details

The study involved data collected between 2000 and 2020 at 23 sites in Australia, Asia, North America, and Europe from patients aged 18 to 80 years diagnosed with aggressive B-cell lymphoma who were at high risk of CNS progression. Patients received curative-intent anti–CD20-based chemoimmunotherapy. Effects of high-dose methotrexate on CNS progression were analyzed in all patients and in the cohort of patients in complete response at completion of chemoimmunotherapy.

Key Findings

A total of 2,418 patients were included in the analysis, including 425 who received high-dose methotrexate. Among these, 1,616 were in the complete response cohort, including 356 who received high-dose methotrexate. The CNS International Prognostic Index was 4 to 6 in 83.4% of all patients. Median follow-up was 68 months.

Among all patients, those receiving high-dose methotrexate had a lower risk of CNS progression vs those who did not receive high-dose methotrexate (adjusted hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.38–0.90, P = .014). However, there was only a 1.6% absolute reduction (95% CI = –1.1% to 4.4%) in 5-year risk—6.9% vs 8.5%. The adjusted 5-year risk difference corresponded to a number needed to treat of 63 patients to prevent one CNS relapse. The 2-year risk of CNS progression was 5.2% vs 7.6%

Among patients in the complete response cohort, the reduction in risk of CNS progression with high-dose methotrexate was not significant (adjusted HR = 0.74, 95% CI = 0.42–1.30, P = .29). The 5-year adjusted risk was 5.2% vs 6.3%, an absolute reduction of 1.4% (95% CI = –1.5% to 4.1%). The 2-year risk of CNS progression was 3.9% vs 5.2%.

Although subgroups were underpowered to support conclusions regarding the impact of high-dose methotrexate in individual high-risk clinical settings, no clear reduction in risk of CNS progression with high-dose methotrexate was observed in any high-risk subgroup.

The investigators concluded, “In this retrospective study of 2,418 relatively uniformly treated patients with aggressive B-cell lymphoma at high risk of CNS progression, high-dose methotrexate was not associated with clinically meaningful reduction in the risk of CNS progression. With an absolute risk reduction of 1.6% with high-dose methotrexate, 63 patients would need to be treated to prevent one CNS progression event over 5 years.”

Chan Y. Cheah, MD, of Sir Charles Gairdner Hospital, Nedlands, Australia, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Swedish Cancer Society, Janssen Pharmaceuticals NV, U.S. National Cancer Institute, Ministry of Health of the Czech Republic, and others. For full disclosures of the study authors, visit

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