Wilson Matthew R, Eyre Toby A, Kirkwood Amy A, Wong Doo Nicole, Soussain Carole, Choquet Sylvain, Martinez-Calle Nicolás, Preston Gavin, Ahearne Matthew, Schorb Elisabeth, Moles-Moreau Marie-Pierre, Ku Matthew, Rusconi Chiara, Khwaja Jahanzaib, Narkhede Mayur, Lewis Katharine L, Calimeri Teresa, Durot Eric, Renaud Loïc, Øvlisen Andreas Kiesbye, McIlroy Graham, Ebsworth Timothy J, Elliot Johnathan, Santarsieri Anna, Ricard Laure, Shah Nimish, Liu Qin, Zayac Adam S, Vassallo Francesco, Lebras Laure, Roulin Louise, Lombion Naelle, Manos Kate, Fernandez Ruben, Hamad Nada, Lopez-Garcia Alberto, O'Mahony Deirdre, Gounder Praveen, Forgeard Nathalie, Lees Charlotte, Agbetiafa Kossi, Strüßmann Tim, Htut Thura Win, Clavert Aline, Scott Hamish, Guidetti Anna, Barlow Brett R, Tchernonog Emmanuelle, Smith Jeffery, Miall Fiona, Fox Christopher P, Cheah Chan Y, El Galaly Tarec Christoffer, Ferreri Andrés J M, Cwynarski Kate, McKay Pamela
Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
Oxford University Hospitals NHS Trust, Churchill Cancer Center, Oxford, United Kingdom.
Blood. 2022 Apr 21;139(16):2499-2511. doi: 10.1182/blood.2021014506.
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.
预防性大剂量甲氨蝶呤（HD-MTX）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，尽管证明其疗效或最佳给药方式的证据有限。我们对1384例接受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，这些患者在R-CHOP/R-CHOP样治疗期间（i-HD-MTX）（n = 749）或结束时（n = 635）接受HD-MTX预防。有78例CNS复发（3年复发率5.7%），i-HD-MTX组和治疗结束时给药组（EOT）之间无差异：5.7%对5.8%，P = 0.98；3年差异：0.04%（-2.0%至3.1%）。在调整基线预后因素或进行6个月的标志性分析（n = 1253）后，结论不变。在中枢神经系统国际预后指数高的患者（n = 600）中，3年CNS复发率为9.1%，i-HD-MTX组和EOT组之间无差异。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。鞘内同时预防与CNS复发减少无关。与EOT相比，i-HD-MTX组R-CHOP延迟≥7天的情况显著增加，1573例i-HD-MTX治疗中有308例（19.6%）导致后续R-CHOP延迟（中位延迟8天）。当给药时间晚于R-CHOP周期的第10天时，老年患者延迟风险增加。总之，我们没有发现证据表明与i-HD-MTX相比，EOT给药会增加CNS复发风险。高危亚组的结果没有变化。在这个接受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。如果仍考虑对某些高危患者使用HD-MTX，给药可推迟至R-CHOP完成后。
