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, 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.

FIG 1.

Flow chart of patient and trial selection. (A) Flow chart of patient and trial selection for patient-level correlation analyses. (B) Flow chart of patient and treatment comparisons for trial-level correlation analyses. EOIT, end of induction therapy; GCLLSG, German CLL Study Group; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.

FIG 2.

Patient-level surrogacy and correlation analyses. (A) Trial-level results for estimated PFS rate at 24 months (x axis) and OS rate at 60 months (y axis) are shown. The size of each dot corresponds with the number of included patients (n = 4,237). (B) PFS according to MRD status and type of treatment. MRD measured in peripheral blood via flow cytometry or ASO-PCR with a sensitivity of 10⁻⁴. Undetectable MRD: <10⁻⁴. Detectable MRD: ≥10⁻⁴. (C) OS according to MRD status and type of treatment. MRD measured in peripheral blood via flow cytometry or ASO-PCR with a sensitivity of 10⁻⁴. Undetectable MRD: <10⁻⁴. Detectable MRD: ≥10⁻⁴. (D) OS since EO(I)T by CR and MRD for chemoimmunotherapy. (E) OS since EO(I)T by CR and MRD for targeted agents. ASO-PCR, allele specific oligonucleotide-polymerase chain reaction; CIT, chemoimmunotherapy; CR, complete response; EOIT, end of induction therapy; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.

FIG 3.

Trial-level surrogacy and correlation analysis. (A) Scatterplot of HR for PFS and OS. Each circle represents a different trial/trial comparison. Sizes of the circles correspond with the number of included patients. (B) Scatterplot of ORs for undetectable MRD and HR PFS. Each circle represents a different trial/trial comparison. Sizes of the circles correspond with the number of included patients. (C) Scatterplot of OR for undetectable MRD and HR OS. Each circle represents a different trial/trial comparison. Sizes of the circles correspond with the number of included patients. HR, hazard ratio; MRD, minimal residual disease; OR, odds ratio; OS, overall survival; PFS, progression-free survival.