A UK Cost-Effectiveness Analysis Comparing First Line Treatment with Rituximab in Combination with Fludarabine and Cyclophosphamide Versus Fludarabine and Cyclophosphamide Alone in Chronic Lymphocytic Leukemia (CLL) Patients
Authors: Papadakis Konstantinos , Oscier David , Carr Emma SC , Lewis Gavin , Aultman Rick 
Published: April 2020

Abstract
Introduction: This analysis assesses whether Rituximab added to a Fludarabine Cyclophosphamide regimen (R-FC) is a cost-effective first-line treatment option for previously untreated CLL patients, using evidence from the phase III randomised controlled trial, ML17102 (CLL8) (Hallek et al., ASH 2008). In this trial, R-FC significantly prolonged the primary endpoint of progression–free survival (PFS) compared to FC alone and was well tolerated with no unexpected safety signals.
Methods: A cost-effectiveness model was developed to evaluate the life-time health outcomes and direct costs of R-FC compared to FC as first-line treatment for CLL patients in the UK. Patients were modelled to be in one of three health states; PFS, Progressed or Death. The best parametric fit (Weibull) was used to extrapolate PFS beyond the end of the CLL8 trial follow-up period to a 15 year life-time horizon. The number of patients in each treatment arm that died while in PFS was based on the maximum of either the observed rate of death or background mortality. Because median overall survival had not been reached in CLL-8, a Markov process was used to model the transition from the progressed health state to death. Given the non significant difference in post progression survival by treatment (R-FC or FC), patients transitioning from progression to death were modelled as a single population with mean time to death (Kaplan-Meier) converted to a monthly probability of dying. This approach is conservative in that treatment benefit is exclusively a function of time spent in PFS. This Markovian approach is conservative in that treatment benefit is exclusively a function of time spent in PFS. Predicted time in each health state was weighted using CLL utility scores (Hancock et. al. 2002) to account for patient quality of life and estimate the Quality Adjusted Life Years (QALYs). Drug administration, patient monitoring and pharmacy costs were taken from the NHS schedule of reference costs 2006 and the published literature. Blood transfusions, bone marrow transplants, stem cell therapy and second line CLL treatments collected prospectively in CLL8 were included in monitoring costs. The cost of treatment related grade 3 or 4 infections were not included in the analysis as the incidence between the two treatment arms was comparable (Hallek et al., ASH 2008). Both costs and outcomes were discounted by 3.5%.
RESULTS: R-FC improves mean life expectancy by 1.33 years compared to FC alone. After adjusting for quality of life, the incremental quality-adjusted life expectancy estimated was 1.06 years. Improvements in health outcomes were attributed to an increase in the time R-FC patients spent in the PFS health state (1.17 years).Total direct costs were higher for R-FC by £13,081 per patient, however, this was partially offset by a reduction in medication and monitoring costs incurred in the progressed health state. The incremental cost-effectiveness ratios (ICERs) were estimated to be £9558 per Life Year Gained with R-FC. When health-related quality of life was taken into account, the ICER was £12,387 per QALY gained for R-FC, well below commonly accepted thresholds in the UK. Although there is uncertainty associated with the progression of CLL and relapse treatment costs, the ICER did not exceed £22,458 per QALY despite a wide variation in each parameter value used in the probabilistic sensitivity analysis.
CONCLUSIONS: Based on the significant prolongation of PFS demonstrated in CLL8, first-line R-FC substantially increases quality-adjusted life expectancy for CLL patients and is well within the UK threshold of cost-effectiveness. The sensitivity analysis provides adequate reassurance that the cost-effectiveness of R-FC held under most plausible scenarios.