WS03.05 Multicenter validation of the cystic fibrosis-ABLE score as a predictor of outcome and therapeutic response in cystic fibrosis

Objectives: The CF-ABLE score is an easy-to-use weighted prognostic scoring system previously validated in a large cohort from the national CF Registry of Ireland. The score ranges from 0–7 and predicts risk of poor outcome, defined as death or requirement for lung transplantation, over time. This study aimed to evaluate real-world clinical performance of the CF-ABLE score as a clinical predictor in CF and its response to CFTR modulator therapy. Methods: PWCF (n = 872) were recruited from 4 large specialist CF centers in the US and Ireland between 2013 and 2015 and followed clinically for 4 years. In a parallel cross-sectional analysis of 65 PWCF chosen at random from the total cohort, the relationship between sputum inflammatory mediators and CF-ABLE score was evaluated. Changes in CF-ABLE scores over time in PWCF who subsequently commenced CFTR modulators were also recorded prospectively. Results: In clinical practice, the CF-ABLE score performed substantially better than it did in its original derivation study, and outperformed FEV1 alone as a predictor of outcome. A cutoff score of 5 distinguished PWCF who went on to poor outcome from those who did not. Approximately half of PWCF with a score ≥5 died or were transplanted within 4 years. In contrast, poor outcome at 4 years was observed in less than 5% of PWCF with a score <5. The score correlated with sputum neutrophil elastase activity, MMP activity, and levels of IL-1β, IL-6, IL-8 and IL-10. Elexacaftor/tezacaftor/ivacaftor resulted in marked decreases in CF-ABLE score within 3 months, returning PWCF with baseline scores ≥5 to the low-risk range. Conclusion: The CF-ABLE score robustly identifies PWCF at increased risk of poor outcome, correlates with airway inflammation, and detects a probable effect on mortality in response to CFTR modulators early in treatment – an endpoint that has proven elusive in prospective clinical trials and served as an obstacle in drug reimbursement negotiations with policymakers.