Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen.
Karolinska University Hospital, Heart Centre, Stockholm.
Haematologica. 2024 Oct 1;109(10):3327-3337. doi: 10.3324/haematol.2023.284281.
Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) carries a dismal prognosis and most clinical guidelines recommend CNS prophylaxis to patients deemed at high risk of CNS relapse. However, results from observational studies investigating the effect of CNS prophylaxis have yielded conflicting results. The aims of this study were to evaluate: (i) whether addition of prophylactic intravenous high-dose methotrexate (HD-MTX) reduces the risk of CNS relapse in high-risk DLBCL patients treated with R-CHOP or similar, and (ii) whether HD-MTX prophylaxis confers an overall survival benefit, irrespective of CNS relapse. We performed a systematic search of MEDLINE/PubMed and EMBASE for data on DLBCL patients at high risk of CNS relapse treated with R-CHOP or similar who received HD-MTX as an intervention and a comparator arm of patients who did not receive prophylaxis and/or intrathecal prophylaxis. A risk of bias was estimated using the ROBINS-I tool and the quality of the evidence was assessed by the GRADE approach. Finally, a meta- analysis based on the systematic review was conducted. A total of 1,812 studies were screened. No randomized controlled trials were identified. Seven observational studies comprising 1,661 patients met the inclusion criteria. We found a statistically non-significant relative risk of 0.54 (95% confidence interval: 0.27-1.07) of CNS relapse for patients receiving HD-MTX versus controls. The meta-analysis investigating mortality demonstrated a relative risk of death of 0.70 (95% confidence interval: 0.44-1.11) for patients treated with HD-MTX versus controls. The overall risk of bias was adjudged as "serious" and the quality of the evidence was rated as "low". In conclusion, our data indicate that HD-MTX does not prevent or, at best, only slightly reduces the risk of CNS relapse and confers no survival benefit.
中枢神经系统（CNS）复发是弥漫性大 B 细胞淋巴瘤（DLBCL）患者预后不良的原因，大多数临床指南建议对有 CNS 复发高风险的患者进行 CNS 预防。然而，观察性研究调查 CNS 预防效果的结果产生了相互矛盾的结果。本研究的目的是评估：（i）在接受 R-CHOP 或类似治疗的高危 DLBCL 患者中，预防性静脉注射大剂量甲氨蝶呤（HD-MTX）的加入是否降低 CNS 复发的风险，以及（ii）HD-MTX 预防是否无论 CNS 复发如何都具有总生存获益。我们对 MEDLINE/PubMed 和 EMBASE 进行了系统检索，以获取接受 R-CHOP 或类似治疗且接受 HD-MTX 作为干预措施的高危 CNS 复发 DLBCL 患者的数据，以及未接受预防和/或鞘内预防的患者的对照组数据。使用 ROBINS-I 工具评估偏倚风险，并使用 GRADE 方法评估证据质量。最后，根据系统评价进行荟萃分析。共筛选出 1812 项研究。未确定随机对照试验。符合纳入标准的 7 项观察性研究共纳入 1661 例患者。我们发现，接受 HD-MTX 的患者与对照组相比，CNS 复发的相对风险为 0.54（95%置信区间：0.27-1.07），具有统计学意义但无显著性。荟萃分析表明，接受 HD-MTX 治疗的患者与对照组相比，死亡的相对风险为 0.70（95%置信区间：0.44-1.11）。总体偏倚风险被判定为“严重”，证据质量评为“低”。总之，我们的数据表明，HD-MTX 不能预防或最多只能轻微降低 CNS 复发的风险，并且没有生存获益。
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