End Point Surrogacy in First-Line Chronic Lymphocytic Leukemia.
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Simon Florian, Ligtvoet Rudy, Robrecht Sandra, Cramer Paula, Kutsch Nadine, Fürstenau Moritz, Goede Valentin, von Tresckow Julia, Langerbeins Petra, Fink Anna-Maria, Huber Henriette, Tausch Eugen, Schneider Christof, Wendtner Clemens M, Ritgen Matthias, Dreyling Martin, Müller Lothar, Jacobasch Lutz, Heinz Werner J, Vehling-Kaiser Ursula, Sivcheva Liliya, Böttcher Sebastian, Dreger Peter, Illmer Thomas, Gregor Michael, Staber Philipp B, Stilgenbauer Stephan, Niemann Carsten U, Kater Arnon P, Fischer Kirsten, Eichhorst Barbara, Hallek Michael, Al-Sawaf Othman
Аннотация
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, R2 = 0.56) while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 (95% CI, -0.87 to 0.89; R2 = 0.78) and 0.71 (95% CI, 0.69 to 0.73; R2 = 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.