Beyond progression-free survival (PFS): time to next treatment (TTNT) as a patient-centered metric of clinical benefit in chronic lymphocytic leukemia (CLL).

[INTRODUCTION] In chronic lymphocytic leukemia (CLL), progression-free survival (PFS) remains a fundamental efficacy endpoint; however, it does not fully capture patient-centric measures such as treatment discontinuation or adherence. Time to next treatment (TTNT) offers a pragmatic alternative, encompassing not only the interval until initiation of subsequent therapy but also reflecting treatment tolerability and compliance.

[AREAS COVERED] A comprehensive literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines identified 40 full-text articles reporting TTNT as an outcome measure. Among these, 30 were retrospective real-world studies, while 10 were prospective phase II or phase III clinical trials involving patients with either treatment-naïve or relapsed/refractory CLL. Meta-analytic evaluation of the prospective trials, each with a minimum follow-up of four years, revealed a strong trial-level correlation between PFS and TTNT, with an r value of 0.7410 ( = 0.0003). Additionally, TTNT demonstrated a statistically significant, though more moderate, correlation with overall survival (OS), yielding an r value of 0.5160 ( = 0.008).

[EXPERT OPINION] The analysis suggests that TTNT enriches the CLL endpoint repertoire by capturing patient-centered outcomes and informing pragmatic clinical decision-making. Nevertheless, regulatory and methodological standards advocate a two-tier validation approach that includes both individual patient-level analyses and trial-level validation. TTNT in CLL should complement, but not substitute for, PFS in evaluating therapeutic benefit and guiding clinical decision-making.