Surrogate Endpoints in CLL: From Promise and Pitfalls to a Context-Specific Validation Framework

Area of Science:

• Hematology
• Clinical Trials
• Oncology

Background:

• Surrogate endpoints accelerate drug evaluation in chronic lymphocytic leukemia (CLL).
• Their validity in CLL is highly dependent on the specific clinical context.
• Key surrogate endpoints include progression-free survival (PFS), time to next treatment (TTNT), measurable residual disease (MRD), and quality of life (QoL)/patient-reported outcomes (PROs).

Purpose of the Study:

• To review and critically assess the utility of common surrogate endpoints in CLL.
• To propose a framework for selecting appropriate surrogate endpoints based on treatment type and patient characteristics.
• To emphasize the need for context-specific validation of surrogate endpoints in CLL.

Main Methods:

• Literature review of surrogate endpoints used in chronic lymphocytic leukemia (CLL) clinical trials.
• Analysis of the strengths and limitations of PFS, TTNT, MRD, and QoL/PROs.
• Development of a practical framework for endpoint selection.

Main Results:

• PFS is standard but limited by competing risks and patient experience.
• TTNT reflects efficacy and tolerability but is influenced by external factors.
• MRD is predictive in fixed-duration therapies but less so in continuous ones.
• QoL/PROs offer essential patient-centered insights.
• Endpoint selection should be tailored: MRD for fixed-duration, TTNT for continuous therapy, and PROs for vulnerable populations.

Conclusions:

• Surrogate endpoint selection in CLL requires careful consideration of the treatment modality and patient population.
• MRD, TTNT, and PROs have specific roles and limitations that must be understood.
• Setting-specific validation is essential to ensure surrogate endpoints reflect genuine clinical benefit in CLL treatment.