End point surrogacy in first-line chronic lymphocytic leukemia
PURPOSE Surrogate end points are commonly used to estimate treatment efficacy in clinical studies of chronic lymphocytic leukemia (CLL). This patient- and trial-level analysis describes the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
August 30, 2024
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| In: |
Journal of clinical oncology
Year: 2025, Volume: 43, Issue: 4, Pages: 381-391 |
| ISSN: | 1527-7755 |
| DOI: | 10.1200/JCO.24.01192 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1200/JCO.24.01192 Verlag, kostenfrei, Volltext: https://ascopubs.org/doi/10.1200/JCO.24.01192 
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| Author Notes: | Florian Simon, MD, Rudy Ligtvoet, PhD, Sandra Robrecht, PhD, Paula Cramer, MD, Nadine Kutsch, MD, Moritz Fürstenau, MD, Valentin Goede, MD, Julia von Tresckow, MD, Petra Langerbeins, MD, Anna-Maria Fink, MD, Henriette Huber, MD, Eugen Tausch, MD, Christof Schneider, MD, Clemens M. Wendtner, MD, Matthias Ritgen, MD, Martin Dreyling, MD, Lothar Müller, MD, Lutz Jacobasch, MD, Werner J. Heinz, MD, Ursula Vehling-Kaiser, MD, Liliya Sivcheva, MD, Sebastian Böttcher, MD, Peter Dreger, MD, Thomas Illmer, MD, Michael Gregor, MD, Philipp B. Staber, MD, Stephan Stilgenbauer, MD, Carsten U. Niemann, MD, Arnon P. Kater, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD, Michael Hallek, MD, and Othman Al-Sawaf, MD |
| Summary: | PURPOSE Surrogate end points are commonly used to estimate treatment efficacy in clinical studies of chronic lymphocytic leukemia (CLL). This patient- and trial-level analysis describes the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (OS) in first-line trials for CLL. PATIENTS AND METHODS First, patient-level correlation was confirmed using source data from 12 frontline German CLL Study Group (GCLLSG)-trials. Additionally, a joint-frailty copula model was fitted to validate correlation in the setting of targeted therapies (TT). Second, a meta-analysis of first-line phase III trials in CLL from 2008 to 2024 was performed. Treatment effect correlation was quantified from seven GCLLSG and nine published trials, using hazard ratios (HRs) for time-to-event and odds ratios for binary end points. RESULTS The GCLLSG analysis set comprised 4,237 patients. Patient-level correlation for PFS/OS was strong with Spearman Rho >0.9. The joint-frailty copula indicated a weak correlation for chemotherapy/chemoimmunotherapy (C/CIT) with a tau of 0.52 (95% CI, 0.49 to 0.55) while the correlation was strong for TT (tau, 0.91 [95% CI, 0.89 to 0.93). The meta-analysis set contained a total of 8,065 patients including 5,198 (64%) patients treated with C/CIT and 2,867 (36%) treated with TT. Treatment-effect correlation of the HRs for PFS and OS was R 5 0.75 (95% CI, 0.74 to 0.76, R2 5 0.56) while correlation of end-of-treatment MRD with PFS and OS was R 5 0.88 (95% CI, –0.87 to 0.89; R2 5 0.78) and 0.71 (95% CI, 0.69 to 0.73; R2 5 0.5), respectively. CONCLUSION Patient-level correlation was confirmed in the setting of TTs while treatment-effect correlation between PFS and OS remains uncertain. MRD response status showed a high treatment-effect correlation with PFS but not OS, with the caveat of a limited number of randomized trials with available MRD data. |
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| Item Description: | Gesehen am 30.09.2025 |
| Physical Description: | Online Resource |
| ISSN: | 1527-7755 |
| DOI: | 10.1200/JCO.24.01192 |