Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

中文翻译：

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DLBCL 中大剂量甲氨蝶呤 CNS 预防的时机：对 1384 名患者的多中心国际分析。

预防性大剂量甲氨蝶呤 (HD-MTX) 通常用于中枢神经系统 (CNS) 复发风险高的弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者，尽管证明疗效或最佳给药方法的证据有限。我们对 1384 名接受 HD-MTX 中枢神经系统预防的患者进行了一项回顾性国际分析，无论是插入 (i-HD-MTX) (n = 749) 还是在 R-CHOP/R-CHOP 样治疗结束时 (n = 635) （EOT）。有 78 例 CNS 复发（3 年复发率为 5.7%），i-HD-MTX 和 EOT 之间没有差异：5.7% vs 5.8%，P = .98；3 年差异：0.04%（-2.0% 至 3.1%）。调整基线预后因素或 6 个月标志性分析 (n = 1253) 得出的结论没有变化。在具有高 CNS 国际预后指数的患者（n = 600）中，3 年 CNS 复发率为 9.1%，i-HD-MTX 和 EOT 没有区别。在多变量分析中，年龄增加和肾脏/肾上腺受累是 CNS 复发的唯一独立危险因素。同时进行的鞘内预防与 CNS 复发的减少无关。i-HD-MTX 与 EOT 相比，R-CHOP 延迟≥7 天显着增加，1573 次 i-HD-MTX 治疗中有 308 次（19.6%）导致后续 R-CHOP 延迟（中位数 8 天）。当分娩晚于 R-CHOP 周期的第 10 天时，老年患者的延迟风险增加。总之，与 i-HD-MTX 相比，我们没有发现 EOT 给药增加 CNS 复发风险的证据。高风险亚组的结果没有变化。在这个 HD-MTX 治疗的队列中，CNS 复发率与接受不频繁 CNS 预防的可比队列相似。