INSERM U1153, Epidemiology and Clinical Statistics for Trials & Real-world Evidence Research Team, Saint-Louis Hospital, Paris, France.
Université Paris Cité, Paris, France.
Blood. 2024 Feb 1;143(5):422-428. doi: 10.1182/blood.2023020984.
Extranodal marginal zone lymphoma (EMZL) has a very indolent course, and the validation of surrogate markers could accelerate novel therapies. Although prognostic markers do exist, no surrogate markers have been validated in EMZL. We hypothesized that time to complete response within 24 months (TTCR24) and complete response (CR) at 24 months (CR24) could be valid surrogate markers of progression-free survival (PFS). The International Extranodal Lymphoma Study Group 19 phase 3 trial showed the advantage of double therapy (rituximab + chlorambucil) over single therapy (rituximab or chlorambucil) on PFS. We used 2 recently published single-trial approaches to assess whether TTCR24 and CR24 were good surrogate markers of 8-year PFS (8y-PFS). Among the 401 patients, 264 (66%) reached a CR in the first 24 months, of which 222 (84%) remained in CR at month 24. The cumulative incidence of CR over time was significantly higher in patients under double therapy (hazard ratio, 1.75; P < .001). The double therapy arm was associated with a higher CR24 rate, a shorter TTCR24, and a longer 8y-PFS. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% confidence interval [CI], 0.27-1.87). CR24 was also a strong surrogate marker because it mediated 90% (95% CI, 0.51-2.22) of the treatment effect on PFS and its natural indirect effect was significant throughout the follow-up. We found that TTCR24 predicted 95% and that CR24 mediated 90% of the treatment effect on long-term PFS. Therefore, TTCR24 and CR24 could be used in clinical trials as informative and valid early indicators of treatment effect on PFS. This trial was registered at www.clinicaltrials.gov as #NCT00210353.
结外黏膜边缘区淋巴瘤（EMZL）具有非常惰性的病程，验证替代标志物可以加速新疗法的发展。尽管已经存在预后标志物，但尚无替代标志物在 EMZL 中得到验证。我们假设，24 个月内完全缓解的时间（TTCR24）和 24 个月时的完全缓解（CR24）可能是无进展生存期（PFS）的有效替代标志物。国际结外淋巴瘤研究组 19 项 3 期试验表明，双药治疗（利妥昔单抗+苯丁酸氮芥）优于单药治疗（利妥昔单抗或苯丁酸氮芥）在 PFS 方面的优势。我们使用最近发表的两种单试验方法来评估 TTCR24 和 CR24 是否是 8 年 PFS（8y-PFS）的良好替代标志物。在 401 例患者中，264 例（66%）在头 24 个月达到完全缓解，其中 222 例（84%）在第 24 个月时仍处于完全缓解状态。随着时间的推移，双药治疗组患者的 CR 累积发生率显著更高（风险比，1.75；P<.001）。双药治疗组与更高的 CR24 率、更短的 TTCR24 和更长的 8y-PFS 相关。TTCR24 对 8y-PFS 的治疗效果的估计比例为 95%（95%置信区间[CI]，0.27-1.87）。CR24 也是一个强有力的替代标志物，因为它介导了 PFS 上 90%（95%CI，0.51-2.22）的治疗效果，并且在整个随访过程中其自然间接效应是显著的。我们发现 TTCR24 预测了 95%的治疗效果，而 CR24 介导了 90%的治疗效果。因此，TTCR24 和 CR24 可在临床试验中用作对 PFS 的治疗效果有意义且有效的早期指标。该试验在 www.clinicaltrials.gov 上注册为 #NCT00210353。
