End Point Surrogacy in First-Line Chronic Lymphocytic Leukemia
Abstract
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 = 0.75 (95% CI, 0.74 to 0.76, R 2 = 0.56) while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 (95% CI, –0.87 to 0.89; R 2 = 0.78) and 0.71 (95% CI, 0.69 to 0.73; R 2 = 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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (33)
Florian Simon
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Rudy Ligtvoet
1Department I of Internal Medicine and Center of Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
Sandra Robrecht
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Paula Cramer
18Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German Chronic Lymphocytic Leukemia Study Group, University of Cologne, Cologne, Germany
Nadine Kutsch
1University Hospital Cologne, Department of Internal Medicine I, Cologne, Germany
Moritz Fürstenau
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Valentin Goede
20Department of Oncogeriatrics, St Marien Hospital, Cologne, Germany
Julia von Tresckow
4Department of Hematology, Oncology and Palliative Care, Katholisches Klinikum Bochum, Ruhr University Bochum, Bochum, Germany
Petra Langerbeins
University Hospital, Cologne, Germany
Anna-Maria Fink
University Hospital of Cologne, Cologne, Germany
Henriette Huber
Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
Eugen Tausch
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Christof Schneider
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Clemens M. Wendtner
Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
Matthias Ritgen
Universitaetsklinikum Schleswig-Holstein, Medizinische Klinik II, Kiel, Germany
Martin Dreyling
LMU Hospital, Munich, Germany
Lothar Müller
Studienzentrum UnterEms, Leer, Germany
Lutz Jacobasch
11Praxis of Haematology and Oncology, Dresden, Germany
Werner J. Heinz
Caritas-Krankenhaus Bad Mergentheim, Medizinische Klinik II, Bad Mergentheim, Germany
Ursula Vehling-Kaiser
Day Clinic Hematology Oncology Palliative Care
Liliya Sivcheva
4First Department of Internal Medicine, Hristo Botev Multiprofile Hospital for Active Treatment, Vratsa, Bulgaria
Sebastian Böttcher
Clinic III (Hematology, Oncology, and Palliative Medicine), Rostock University Medical Center, Rostock, Germany
Peter Dreger
Thomas Illmer
Berufsausüebungsgemeinschaft, Gokos, Dresden, Germany
Michael Gregor
Cantonal Hospital of Lucerne, Lucerne, Switzerland
Philipp B. Staber
Medical University Vienna, Vienna, Austria
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Carsten U. Niemann
Rigshospitalet, Copenhagen University Hospital, Copenhagen
Arnon P. Kater
Amsterdam University Medical Center location University of Amsterdam, Department of Hematology
Kirsten Fischer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Barbara Eichhorst
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Michael Hallek
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Othman Al-Sawaf