Abstract
To investigate progression-free survival (PFS) and event-free survival (EFS) as early efficacy endpoints in diffuse large B-cell lymphoma (DLBCL), this systematic review included phase III randomized controlled trials (RCTs), phase II trials, and retrospective studies in newly diagnosed DLBCL receiving rituximab-containing chemotherapy through databases search up to 2019. Quality control was performed, where studies with high risk of bias were excluded. Prediction models were first established using the RCTs, and then externally validated in the phase II and retrospective populations. Trial-level surrogacy analysis was conducted by correlating the logarithmic (log) hazard ratio (HR) for PFS or EFS and log HR for OS. Correlation analysis at treatment arm-level was performed between 1-, 2-, 3-, and 5-year PFS or EFS rates and 5-year OS. The correlation was evaluated using the Pearson correlation coefficient r in weighted linear regression, with weight equal to patient size. Sensitivity analyses were performed to assess the consistency of predictive model by leaving one subgroup of trials out at a time. Twenty-six phase III RCTs, 4 phase II trials and 47 retrospective studies were included. In trial-level surrogacy, PFS (r, 0.772; 95% confidence interval [CI], 0.471–0.913) or EFS (r, 0.838; 95% CI, 0.625–0.938) were associated with OS. For rituximab immunochemotherapy treatment arms in RCTs, there was a linear correlation between 1 and 5-year PFS (r, 0.813–0.873) or EFS (r, 0.853–0.931) and 5-year OS. Sensitivity analysis demonstrated reasonable overall consistency. The correlation between PFS and OS was externally validated using independent phase II, and retrospective data (r, 0.795–0.897). We recommend PFS and EFS as earlier efficacy endpoints in patients with DLBCL primarily treated with rituximab-containing immunochemotherapy.
Highlights
These authors contributed : Jie Zhu, Yong Yang
The predicted 5-year Overall survival (OS) rate correlated significantly with the actual 5-year OS rate, with the correlation coefficient r ranging from 0.795 to 0.897 (Fig. 6a–d). This finding validates the premise that progression-free survival (PFS) is predictive of OS. This is a large-scale, comprehensive study combining data from high-quality phase III randomized controlled trials (RCTs), phase II trials, and retrospective studies to assess the association between the early efficacy endpoints of PFS or event-free survival (EFS) with OS in patients with diffuse large Bcell lymphoma (DLBCL) primarily treated with immunochemotherapy
Consistent with previous findings [9,10,11,12], analyses of the 26 qualified RCTs showed that improved PFS or EFS
Summary
Trial- and individual-level studies have demonstrated that 24-month PFS and EFS may be considered the early efficacy endpoints for OS in DLBCL [9,10,11,12]. These studies may not be comprehensive because they only included available 13 RCTs willing to disclose individual patient data and were based on a subset of all potentially eligible trials [1,2,3,4, 12,13,14,15,16,17,18,19,20,21]. The correlation between PFS and OS was validated in independent cohort studies to confirm its significant role in guiding clinical practice
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