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The Usefulness of Surrogate Markers in Clinical Trials for Chronic Lymphocytic Leukemia (CLL) – ICML 2023

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Authored by Dr. Brian Koffman

The Bottom Line:

Overall response rate (ORR) is a robust surrogate marker for progression-free survival (PFS), especially when chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) is treated with a Bruton tyrosine kinase inhibitor (BTKi) such as ibrutinib, acalabrutinib or zanubrutinib, but is not well correlated with overall survival (OS).

Who Performed the Research and Where Was it Presented:

Nasim Bahar of BeiGene led the team of presenters of this abstract at ICML (International Conference on Malignant Lymphoma) in Lugano, Switzerland, in June of 2023.


What CLL / SLL patients care about most in terms of how well a CLL drug works is whether or not it improves overall survival (OS). That, by definition, means, in a clinical trial, waiting for enough people to die to show that one treatment arm is better than the other. Not only are there obvious ethical concerns about letting participants die in a trial without the option of trying a different therapy to prove one arm is superior, but there is also the problem that CLL tends to be indolent (slow-moving), and many therapies provide excellent long-term disease control, meaning trials can take many years to produce meaningful results. Finding quicker, reliable surrogate markers would speed up trials, lower the cost of drug development, and could be a more ethical way to prove a drug’s efficacy.

Methods and Participants:

A retrospective literature review of randomized controlled trials (RCTs) for CLL published between January 2015 and January 2022 was conducted. RCTs reporting at least two endpoints of interest (ORR, PFS, OS) were included.


A total of 69 RCTs were included: 28, 25, and 29 trials were available for the ORR vs. PFS, ORR vs. OS, and PFS vs. OS comparisons, respectively.

Some definitions:

  • Overall Response Rate (ORR) is how many participants respond to the therapy.
  • Progression-free Free Survival (PFS) is the average time to disease progression for all participants, those who respond and those who do not.
  • Overall Survival (OS) is the average time to death for all participants, those who respond and those who do not.

Based on all trials, significant correlations for ORR vs PFS were found. The correlation observed between ORR and PFS was categorized as moderate in the BTKi trials. No clear correlation between the comparative effect on ORR and OS was observed. A statistically significant association between the comparative effect on PFS and OS was also shown.


The authors found strong evidence that ORR serves as a surrogate for PFS in CLL, especially when evaluating the treatment with BTKis, some evidence of an association between PFS and OS, and no clear evidence of ORR as a surrogate for OS. This is good news, but probably not good enough. ORR is usually a quickly acquired result, and the fact that it would be found to correlate well with how long one survived without the disease progressing was not a foregone conclusion. Therefore, it is comforting for patients and researchers to see the statistically significant link. But we and the FDA want more, a marker that links with overall survival, and that’s looking much harder to prove. PFS might be the answer, but more research will be needed.

Links and Resources:

Watch Dr. Brian Koffman’s monologue on the abstract:


Stay strong; we are all in this together.

Brian Koffman, MDCM (retired), MSEd
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.