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Can Surrogate Markers Speed Up Clinical Trials in CLL?

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Authored by: Dr. Brian Koffman

Bottom Line:

Both progression free survival (PFS) and measurable (minimal) residual disease (MRD) status were found to strongly correlate with overall survival (OS), suggesting these markers could be safely used as surrogates for OS and thus provide quicker results in clinical trials.

Who Performed the Research and Where Was it Presented:

Florian Simon, MD of the Faculty of Medicine and University Hospital Cologne, and colleagues from the German CLL study presented the results at iwCLL 2023 (international workshop on CLL) in Boston, MA.


Improvement in overall survival or, more simply, living longer should be the primary endpoint for all chronic lymphocytic leukemia (CLL) patients. It is considered the gold standard in cancer trials. However, its practicality and relevancy in CLL is suspect for several reasons:

  1. Many CLL patients are older and have significant comorbidities that may contribute to death unrelated to CLL.
  2. The high efficacy of targeted therapies and the durability of responses demand increasingly long observation periods before the trial can see differences between the groups.
  3. Excellent “salvage” therapies are available, at least for second-line relapsed/refractory disease, which makes measuring OS a longer process. It demands recognizing that OS is dependent on much more than the particular therapy being studied but also the efficacy of any and all subsequent treatment.

Therefore, surrogate endpoints are commonly used in CLL research but are often not accepted by the FDA and other regulatory agencies due to the lack of data demonstrating their tight correlation with OS. Common surrogates include progression-free survival, overall response (OR) complete response rate (CR), or minimal (measurable) residual disease.

Methods and Participants:

The researchers studied approximately 4,000 patients in 12 phase II and phase III trials done by the German CLL Study Group from 1999 to 2022. Only data from patients receiving frontline therapy were included.


  • 4,237 patients were included, with a median observation time of 67 months.
  • The median age was 64 years.
  • 3,159 patients (74.6%) had received chemo/chemoimmunotherapy
  • 1,078 (25.4%) were treated with targeted therapies.
  • There were 2,114 progressive disease events and 1,211 deaths captured within the trial data. 
  • For patients with a confirmed OS event (n=1,211), the correlation between PFS and OS in months was 0.66 for patients receiving chemo/chemoimmunotherapy and 0.88 for patients receiving targeted treatment.
  • The median OS for undetectable and intermediate MRD was not reached, and 60.7 months for high MRD status.
  • In patients ≤65 years of age, median OS was not reached with undetectable or intermediate MRD and 70.5 months in patients with high MRD status. In patients >65 years, median OS was not reached for undetectable MRD and was 75.2 and 58.8 months, respectively, for patients with intermediate or high MRD.


In these 12 CLL trials, there was a strong correlation between PFS and OS, especially among those CLL patients using targeted therapies. This finding supports using PFS as a quicker, faster surrogate outcome in CLL trials, hopefully allowing more “accelerated” drug approvals. MRD status at the end of treatment was associated with OS across all treatment modalities. Its prognostic utility urges its use in planning disease management decisions.

Links and Resources:

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

Surrogate Markers to Speed Up Clinical Trials in CLL

Stay strong. We are all in this together.

Brian Koffman MDCM (retired), MS Ed
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society