The efficacy of systemic high dose methotrexate as central nervous system prophylaxis in patients with high risk diffuse large B-cell lymphoma: A propensity score-matched analysis

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Background: While the outcome of patients with diffuse large B-cell lymphoma (DLBCL) has been improved with the introduction of rituximab, central nervous system (CNS) relapse is still associated with poor prognosis. Although intrathecal methotrexate has been widely used for prophylaxis of such CNS relapse, its role has been questioned and systemic high dose methotrexate (HD-MTX) has been advocated as the preferred method of utilization by a few retrospective studies. With a prospectively collected cohort, we performed multiple analyses with various statistical methods including propensity score (PS)-based analysis to evaluate the efficacy of systemic HD-MTX therapy in CNS prophylaxis in high risk DLBCL patients.
Methods: The registry data set of DLBCL patients, collected from January 2010 through March 2015 at a single institute, Asan Medical Center, was retrospectively reviewed. From July 2013, all consecutive DLBCL patients who were considered at high risk for CNS recurrence received systemic HD-MTX with standard R-CHOP therapy. We analyzed the progression-free survival (PFS), CNS relapse-free survival (CNS-RFS) and overall survival (OS) of the patients receiving CNS prophylaxis and compared them with patients who received R-CHOP only. Multivariate Cox regression and propensity score analysis were used to evaluate the treatment effect of systemic HD-MTX.
Results: A total of 197 patients with DLBCL and CNS risk factors who were treated with standard R-CHOP therapy were identified between January 2010 and March 2015. Among them, 47 patients received systemic HD-MTX as CNS prophylaxis. The actuarial 2-year risk of CNS relapse was 6.9% in patients who received R-CHOP with systemic HD-MTX, while 10.5% of patients received R-CHOP only with no other prophylactic treatment. A trend toward lower incidence of CNS relapse and longer PFS or OS (HR < 1) was seen in patients given systemic HD-MTX as CNS prophylaxis, though there was no statistical significance in multivariate nor propensity score analysis (P values > 0.05).
Conclusions: Systemic HD-MTX prophylaxis for CNS relapse show non-significant trend towards better survival outcome in high risk DLBCL patients. As these results are limited by small cohort size, short follow-up duration and by its retrospective nature, multi-center, prospective randomized studies are necessary to appropriately appraise the efficacy of systemic HD-MTX as a method of CNS prophylaxis in high risk DLBCL patients.
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