A Retrospective, Longitudinal Registry Study on the Long-Term Durability of Ivacaftor Treatment in People with Cystic Fibrosis.

INTRODUCTION: Ivacaftor (IVA) has been shown to change the trajectory of cystic fibrosis (CF) disease progression by slowing the rate of lung function decline in clinical studies. Long-term real-world data help to confirm the durability of this response. METHODS: This non-interventional, longitudinal study used data from the US CF Foundation Patient Registry to describe the annualized rate of change in lung function in people with CF receiving IVA. The IVA-treated cohort included people with CF aged ≥ 6 years who had ≥ 1 CF transmembrane conductance regulator (CFTR)-gating mutation and initiated IVA between 31 January 2012 and 31 December 2018. An age-matched comparator cohort included people with CF heterozygous for the F508del-CFTR mutation and a minimal function mutation (R117H excluded) and had not received CFTR modulator therapy. Baseline characteristics were balanced using standardized mortality ratio (SMR) weights computed from estimated propensity scores. The annualized rate of change in percent predicted forced expiratory volume in 1 s (ppFEV1) was estimated over 5 years and used to calculate the relative annualized rate of change in lung function in the IVA-treated versus comparator cohorts. RESULTS: In the 5-year follow-up period, 548 people were in the IVA-treated and 541 in the comparator cohorts after SMR weighting. The annualized rate of change in ppFEV1 over 5 years was -1.23 (95% CI -1.45, -1.03) and -2.03 (-2.16, -1.90) percentage points in the IVA-treated and comparator cohorts, respectively. There was a 39% reduction (95% CI: 28, 50) in the rate of lung function decline in the IVA-treated versus comparator cohort over 5 years. Findings were generally consistent with those of shorter follow-up periods. CONCLUSION: IVA showed a durable clinical benefit by slowing the rate of lung function decline over 5 years. Results support a sustained and consistent impact of IVA on lung function trajectory in people with CF. Word count: 300 (limit: 300 words).

Cystic fibrosis patient characteristics and healthcare resource utilization in Finland using linked registries.

Background: Knowledge of prevalence and epidemiology of cystic fibrosis (CF) and healthcare resource use among Finnish people with CF is incomplete. Methods: We conducted a population-based matched cohort study using retrospective real-world data from linked Finnish national registries. Electronic healthcare data and drug purchases of 102 people with CF were analyzed between January 2015 and December 2019 (follow-up). A 5-fold control population was matched by sex, age, and place of residence. Comorbidities and medication use that occurred at any time during follow-up were assessed; annual rates of hospital service use were adjusted for follow-up. Results: The prevalence of CF in Finland was 1.85 per 100,000. Median age at diagnosis was 1 year, with 60 % diagnosed at age <2 years and 80 % at age <10 years. Median age at death in people with CF was 31.4 years (n < 5); no controls died. The most common comorbidities included chronic sinusitis (39.2 %), pneumonia (38.2 %), diabetes (20.6 %), and nasal polyps (18.6 %). The most purchased medications were antibiotics (99.0 %) and pancreatic enzymes (84.3 %). The annualized rate of hospital visits was higher in people with CF vs controls (outpatient: mean [SD], 17.4 [14.5] vs 0.9 [3.3]; median, 13.6 vs 0.4, respectively; inpatient: mean [SD], 1.0 [1.66] vs 0.03 [0.14]; median, 0.34 vs 0, respectively). Conclusions: The prevalence of CF in Finland is remarkably low, likely reflecting unique population characteristics and, in part, delayed diagnosis. Antibiotic use is frequent among Finnish people with CF. Inpatient hospital visits are >30 times higher in people with CF than matched controls.

Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of long-term outcomes with this treatment. This retrospective, longitudinal cohort study investigated the impact of IVA on mortality rate and health outcomes among people with CF in the US. METHODS: Data from the US CF Foundation Patient Registry from January 2010 to December 2019 were analysed. The IVA-treated cohort included people with a CF transmembrane conductance regulator (CFTR) gating mutation (excluding R117H); age-matched comparator cohort included people with a F508del and a minimal function CFTR mutation who had no prior CFTR modulator treatment. Baseline characteristics were balanced between cohorts using standardised mortality ratio weighting generated from propensity scores. Outcomes of interest were overall survival, lung transplant, percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), outpatient visits and hospitalisations. FINDINGS: Over a maximum follow-up of 7.9 years, the IVA-treated cohort (N=736) had lower rates of mortality (hazard ratio [HR] (95% CI): 0.22 (0.09 to 0.45)), lung transplant (HR: 0.11 (95% CI 0.02 to 0.28)), PEx (rate ratio: 0.49 (95% CI 0.42 to 0.55)) and all-cause hospitalisations (rate ratio: 0.50 (95% CI 0.43 to 0.56)) as well as better lung function (mean difference in ppFEV1: 8.46 (95% CI 7.34 to 9.75)) and higher BMI/BMI z-scores (mean difference 1.20 (95% CI 0.92 to 1.71) kg/m2 and 0.27 (95% CI 0.25 to 0.40), respectively) than the comparator cohort (N=733). INTERPRETATION: Our analysis suggests that IVA provides sustained clinical benefits in people with CF over a follow-up period of approximately 8 years. These findings reinforce the existing real-world evidence that IVA can slow disease progression and decrease the healthcare burden of CF over the long term.

Clinical, economic, and societal burden of cystic fibrosis and the impact of the CFTR modulator, lumacaftor/ivacaftor: an assessment using linked registry data in Sweden.

AIMS: We aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems. MATERIAL AND METHODS: This retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation. RESULTS: People with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9). CONCLUSION: CF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.

Cystic fibrosis (CF) is a disease caused by a single faulty gene called CFTR, which affects the lungs, pancreas, and other organs. Medications known as CFTR modulators help improve the function of this faulty gene and have shown benefits for people with CF. In Sweden, two such medicines, lumacaftor and ivacaftor (LUM/IVA), have been available since July 2018 for treating CF. This study looks at the impact of CF on patients, caregivers, and the healthcare system, as well as the benefits of CFTR modulators. Using data from Swedish national healthcare and social insurance registries, the study compared 743 people with CF in 2019 to about 7400 people without CF, matched by sex, birth year, and location. The findings show that people with CF had 24 times higher direct healthcare costs, including outpatient visits, hospitalizations, and CF-related medications, totaling 23,233 Euros. Indirect costs, such as work absences for those over 18 with CF anssd caregivers' absences to care for sick children, were 9,629 Euros, which is five times higher than the general population. Those over 6 years old treated with LUM/IVA showed improved lung health, reduced hospitalizations (though not significantly), and needed fewer antibiotics. Caregivers' work absences decreased, but there was no change in work absences for adults with CF. Overall, treatment with LUM/IVA improved clinical outcomes and reduced the burden on caregivers and society.

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied. METHODS: We conducted an observational cohort study of people in the US CF Foundation Patient Registry aged ≥6 years with ≥1 CF transmembrane conductance regulator-gating mutation to compare the effects of initiating IVA at earlier ages on per cent predicted forced expiratory volume in 1 s (ppFEV1) and pulmonary exacerbation (PEx) outcomes. People with CF were grouped by age at IVA initiation (ages 6-10, 11-15, 16-20 and 21-25 years) to perform three analyses of younger versus older IVA initiation (6-10 vs 11-15, 11-15 vs 16-20 and 16-20 vs 21-25 years). For each analysis, baseline characteristics assessed over 1-year periods at the same age prior to IVA initiation were balanced by standardised mortality/morbidity ratio (SMR) weighting. For each analysis, outcomes were compared over a 5-year outcome assessment period when both groups were in the same age range and receiving IVA. FINDINGS: Baseline characteristics were well balanced between younger and older IVA initiator groups after SMR weighting. In the outcome assessment period, younger IVA initiators had significantly higher mean ppFEV1 than older initiators across all comparisons, and those initiating IVA between ages 6-10 and 11-15 years had significantly lower PEx rates. INTERPRETATION: Study findings showed the importance of early IVA initiation in people with CF.

Psychometric performance of the CFQ-R-8D compared to the EQ-5D-3L and SF-6D in people with cystic fibrosis.

OBJECTIVE: This study aimed to compare the psychometric performance of the Cystic Fibrosis Questionnaire-Revised-8 Dimensions (CFQ-R-8D), a new, condition-specific, preference-based measure, with that of generic preference-based measures EQ-5D-3L and Short Form 6 dimensions (SF-6D). METHODS: Data from three trials of participants with CF aged ≥ 14 years who completed the CFQ-R and EQ-5D-3L or SF-6D were used. Analyses were undertaken to evaluate convergent validity based on correlations with CFQ-R domain scores. Known-group validity was assessed based on percent predicted forced expiratory volume in one second and pulmonary exacerbations. Responsiveness was based on correlation of change and sensitivity to change based on change in symptom severity. Effect sizes and standardized response means were estimated. RESULTS: CFQ-R-8D utilities and dimensions were strongly correlated with most of the overlapping CFQ-R domain scores (ρ > 0.5); EQ-5D-3L and SF-6D utilities and dimensions had moderate (ρ > 0.3) to strong correlations in dimensions capturing similar concepts. All measures showed evidence of known-group validity (P < 0.05). Change correlations were strong for CFQ-R-8D utilities and dimensions and CFQ-R, but they were moderate for SF-6D and mostly weak ((ρ > 0.1) for EQ-5D-3L. The SF-6D had the largest mean change over time and effect sizes, followed by CFQ-R-8D and then EQ-5D-3L. Neither CFQ-R-8D or SF-6D utility scores had ceiling effects (< 9% responses in full health) compared with those of EQ-5D-3L (61-62%). In participants classified as being in full health by EQ-5D-3L, CFQ-R-8D captured CF-specific health problems, particularly cough, abdominal pain, and breathing difficulty. CONCLUSIONS: The CFQ-R-8D reflected known-group differences and changes over time with stronger evidence of good psychometric performance than EQ-5D-3L and similar evidence as SF-6D. Additionally, the CFQ-R-8D captured more condition-specific symptoms than EQ-5D-3L or SF-6D, which are important determinants of health-related quality of life for people with CF.

Impact of Elexacaftor/Tezacaftor/Ivacaftor on Healthcare Resource Utilization and Associated Costs Among People With Cystic Fibrosis in the US: A Retrospective Claims Analysis.

INTRODUCTION: Cystic fibrosis (CF) is a life-limiting genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a CFTR modulator (CFTRm) that targets the underlying cause of CF. Based on safety and efficacy demonstrated in clinical trials, ELX/TEZ/IVA is approved in the US for the treatment of CF in people aged ≥ 2 years who have ≥ 1 F508del-CFTR mutation or a CFTR mutation that is responsive to ELX/TEZ/IVA based on in vitro data. While ELX/TEZ/IVA demonstrated unprecedented improvements in lung function and dramatic reductions in pulmonary exacerbations (PEx) and associated hospitalizations in clinical trials, a limited number of studies have examined the impact of ELX/TEZ/IVA on healthcare resource utilization (HCRU) and associated costs in a real-world setting. The aim of this retrospective study was to evaluate changes in PEx, HCRU, and associated non-CFTRm healthcare costs following initiation of ELX/TEZ/IVA among people with CF aged ≥ 12 years in the US. METHODS: We evaluated the rates of PEx, HCRU, and associated costs before and after initiation of ELX/TEZ/IVA in people with CF aged ≥ 12 years using data from the Merative MarketScan® Commercial Claims and Encounters Database and the Merative Multi-State Medicaid Database from April 21, 2019 to December 31, 2020. Because the study period included time following the onset of the COVID-19 pandemic, we limited our primary analysis to the period prior to the pandemic (October 21, 2019 to March 12, 2020). Outcomes following the onset of the pandemic (March 13 to December 31, 2020) were examined in an exploratory analysis. RESULTS: In both commercially insured and Medicaid-insured people with CF, ELX/TEZ/IVA was associated with reductions in PEx, hospitalizations, and associated costs prior to the COVID-19 pandemic, and these reductions were maintained following the onset of the pandemic. CONCLUSIONS: These findings suggest that ELX/TEZ/IVA reduces the burden and costs associated with PEx and hospitalizations in people with CF.

Calibration and validation of modeled 5-year survival predictions among people with cystic fibrosis treated with the cystic fibrosis transmembrane conductance regulator modulator ivacaftor using United States registry data.

OBJECTIVES: Cystic fibrosis (CF) is a rare genetic disease characterized by life-shortening lung function decline. Ivacaftor, a CF transmembrane conductance regulator modulator (CFTRm), was approved in 2012 for people with CF with specific gene mutations. We used real-world evidence of 5-year mortality impacts of ivacaftor in a US registry population to validate a CF disease-progression model that estimates the impact of ivacaftor on survival. METHODS: The model projects the impact of ivacaftor vs. standard care in people with CF aged ≥6 years with CFTR gating mutations by combining parametric equations fitted to historical registry survival data, with mortality hazards adjusted for fixed and time-varying person-level characteristics. Disease progression with standard care was derived from published registry studies and the expected impact of ivacaftor on clinical characteristics was derived from clinical trials. Individual-level baseline characteristics of the registry ivacaftor-treated population were entered into the model; 5-year model-projected mortality with credible intervals (CrIs) was compared with registry mortality to evaluate the model's validity. RESULTS: Post-calibration 5-year mortality projections closely approximated registry mortality in populations treated with standard care (6.4% modeled [95% CrI: 5.3% to 7.6%] vs. 6.0% observed) and ivacaftor (3.4% modeled [95% CrI: 2.7% to 4.4%] vs. 3.1% observed). The model accurately predicted 5-year relative risk of mortality (0.53 modeled [0.47 to 0.60] vs. 0.51 observed) in people treated with ivacaftor vs. standard care. CONCLUSIONS: Modeled 5-year survival projections for people with CF initiating ivacaftor vs. standard care align closely with real-world registry data. Findings support the validity of modeling CF to predict long-term survival and estimate clinical and economic outcomes of CFTRm.

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1 second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.

Development of the Cystic Fibrosis Questionnaire-Revised-8 Dimensions: Estimating Utilities From the Cystic Fibrosis Questionnaire-Revised.

OBJECTIVES: Cystic fibrosis (CF) limits survival and negatively affects health-related quality of life (HRQOL). Cost-effectiveness analysis (CEA) may be used to make reimbursement decisions for new CF treatments; nevertheless, generic utility measures used in CEA, such as EQ-5D, are insensitive to meaningful changes in lung function and HRQOL in CF. Here we develop a new, CF disease-specific, preference-based utility measure based on the adolescent/adult version of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a widely used, CF-specific, patient-reported measure of HRQOL. METHODS: Blinded CFQ-R data from 4 clinical trials (NCT02347657, NCT02392234, NCT01807923, and NCT01807949) were used to identify discriminating items for a classification system using psychometric (eg, factor and Rasch) analyses. Thirty-two health states were selected for a time trade-off (TTO) exercise with a representative sample of the UK general population. TTO utilities were used to estimate a preference-based scoring algorithm by regression analysis (tobit models with robust standard errors clustered on participants with censoring at -1). RESULTS: A classification system with 8 dimensions (CFQ-R-8 dimensions; physical functioning, vitality, emotion, role functioning, breathing difficulty, cough, abdominal pain, and body image) was generated. TTO was completed by 400 participants (mean age, 47.3 years; 49.8% female). Among the regression models evaluated, the tobit heteroscedastic-ordered model was preferred, with a predicted utility range from 0.236 to 1, no logical inconsistencies, and a mean absolute error of 0.032. CONCLUSION: The CFQ-R-8 dimensions is the first disease-specific, preference-based scoring algorithm for CF, enabling estimation of disease-specific utilities for CEA based on the well-validated and widely used CFQ-R.

Healthcare resource utilization and costs among children with cystic fibrosis in the United States.

BACKGROUND: Adverse health impacts of cystic fibrosis (CF) can be present in children before respiratory complications are observed. Children with CF show progressive health decline, with increasing lung function decline in adolescence. This study aims to quantify the healthcare resource utilization (HCRU) and costs attributable to CF by comparing children with CF with the general pediatric population. METHODS: This retrospective, cross-sectional, observational study compared HCRU and costs among children with CF in the US with demographically similar children without CF (comparison group) over a 12-month period using administrative claims data spanning 2010-2017. Analyses were conducted by insurance type (commercially insured [COM] and Medicaid insured [MED]) and stratified by age (<2 years, 2 to <6 years, 6 to <12 years, and 12-17 years). RESULTS: Children with CF (2831 COM and 1896 MED) were matched to children in the comparison group (8493 COM and 5688 MED). Higher prevalence of comorbidities was seen in children with CF versus the comparison group across all ages. Across all ages, HCRU attributable to CF was substantial (higher hospitalization rates, more outpatient and emergency room visits, and greater use of prescription medications), and there were higher associated costs (all p values < .05), in COM and MED populations. HCRU and costs attributable to CF were highest for children aged 12-17 years. CONCLUSIONS: Substantial HCRU and costs are evident among children with CF across all ages, starting as young as infancy, with highest HCRU and costs among adolescents. Effective treatments from an early age are needed for children with CF.

Real-World Outcomes of Ivacaftor Treatment in People with Cystic Fibrosis: A Systematic Review.

Cystic fibrosis (CF) is a rare, progressive, multi-organ genetic disease. Ivacaftor, a small-molecule CF transmembrane conductance regulator modulator, was the first medication to treat the underlying cause of CF. Since its approval, real-world clinical experience on the use of ivacaftor has been documented in large registries and smaller studies. Here, we systematically review data from real-world observational studies of ivacaftor treatment in people with CF (pwCF). Searches of MEDLINE and Embase identified 368 publications reporting real-world studies that enrolled six or more pwCF treated with ivacaftor published between January 2012 and September 2019. Overall, 75 publications providing data from 57 unique studies met inclusion criteria and were reviewed. Studies reporting within-group change for pwCF treated with ivacaftor consistently showed improvements in lung function, nutritional parameters, and patient-reported respiratory and sino-nasal symptoms. Benefits were evident as early as 1 month following ivacaftor initiation and were sustained over long-term follow-up. Decreases in pulmonary exacerbations, Pseudomonas aeruginosa prevalence, and healthcare resource utilization also were reported for up to 66 months following ivacaftor initiation. In studies comparing ivacaftor treatment to modulator untreated comparator groups, clinical benefits similarly were reported as were decreases in mortality, organ-transplantation, and CF-related complications. The safety profile of ivacaftor observed in these real-world studies was consistent with the well-established safety profile based on clinical trial data. Our systematic review of real-world studies shows ivacaftor treatment in pwCF results in highly consistent and sustained clinical benefit in both pulmonary and non-pulmonary outcomes across various geographies, study designs, patient characteristics, and follow-up durations, confirming and expanding upon evidence from clinical trials.

Long-Term Impact of Ivacaftor on Healthcare Resource Utilization Among People with Cystic Fibrosis in the United States.

INTRODUCTION: Ivacaftor was first approved in 2012 for the treatment of a select population of individuals with cystic fibrosis (CF), a rare, life-shortening genetic disease. Reductions in healthcare resource utilization (HCRU) associated with ivacaftor have been observed during limited follow-up and for selected outcomes in real-world studies. This study aimed to further describe the long-term impact of ivacaftor treatment on multiple measures of HCRU among people with CF (pwCF). METHODS: This retrospective study used US commercial and Medicaid claims data from 2011-2018. We included pwCF ≥ 6 years of age with ≥ 1 claim for ivacaftor and 12 months of continuous health plan enrollment before ivacaftor initiation ("pre-ivacaftor" period) who also had 36 months of continuous enrollment and persistent ivacaftor use (i.e., no gap ≥ 90 days between refills) following initiation ("post-ivacaftor" period). We compared comorbidities occurring pre-ivacaftor versus the last 12 months post-ivacaftor. HCRU outcomes included medication use, inpatient admissions, and outpatient office visits. We compared medication use pre-ivacaftor versus the last 12 months post-ivacaftor and inpatient admissions and outpatient office visits pre-ivacaftor versus the post-ivacaftor period annualized across 36 months. RESULTS: Seventy-nine pwCF met all criteria, including persistent ivacaftor use during the post-ivacaftor period. Ivacaftor treatment was associated with a significant reduction in pneumonia prevalence (10.1% vs. 26.6%; p < 0.001) and significantly fewer mean [SD] antibiotics claims (8.0 [7.3] vs. 12.3 [11.1]; p < 0.001) in the last 12 months post-ivacaftor versus pre-ivacaftor. In comparing the 36-month post-ivacaftor period to the pre-ivacaftor period, we also observed fewer mean [SD] annual inpatient admissions (0.2 [0.4] vs. 0.4 [0.7]), CF-related inpatient admissions (0.1 [0.2] vs. 0.2 [0.5]), and outpatient office visits (8.8 [4.9] vs. 9.9 [5.4]) (all, p < 0.05). CONCLUSION: Long-term ivacaftor treatment reduced HCRU, consistent with trends observed in prior real-world studies. Our results support the sustained, long-term value of ivacaftor treatment in reducing CF burden.

The Cystic Fibrosis Impact Questionnaire: qualitative development and cognitive evaluation of a new patient-reported outcome instrument to assess the life impacts of cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) experience significant disease burden, including progressive pulmonary decline and reduced survival. This multicenter qualitative study was conducted to develop a new patient-reported outcome (PRO) measure to assess the impact of CF on patients' quality of life: the Cystic Fibrosis Impact Questionnaire (CF-IQ). Semi-structured qualitative concept elicitation (CE) interviews with patients and caregivers documented CF-related symptoms, impacts, and treatment experiences. Coded interview data were considered alongside existing PROs, published literature, and expert opinion to develop an initial scale. Three rounds of cognitive interviews evaluated respondent comprehension and facilitated refinement of the CF-IQ. RESULTS: Adult (N = 20) and pediatric (N = 22) patients with CF and their parents/caregivers (N = 22) completed CE interviews at 7 US clinics. The sample included patients aged 6-58 years, 57% females, and represented a broad range of disease severity (forced expiratory volume in 1 s range: 22%-127% predicted). Interviews identified 59 unique CF-related impact concepts in domains, including activity limitations (physical, social, leisure), functional limitations (school, work), vulnerability/lack of control, emotional impact, treatment burden, and future outlook. Concept saturation was achieved, and a draft questionnaire was developed. Findings from the cognitive interviews (n = 18) confirmed that instructions, items, and response scales were relevant and clear, and interpreted as intended by patients. CONCLUSION: The CF-IQ is a 40-item novel PRO scale assessing a comprehensive set of patient-relevant concepts to characterize the multifaceted nature of CF. Qualitative interview data support the content validity of the CF-IQ, which is currently undergoing additional psychometric evaluation in patients with CF.

Cost Effectiveness of the Third-Generation Tyrosine Kinase Inhibitor (TKI) Ponatinib, vs. Second-Generation TKIs or Stem Cell Transplant, as Third-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVES: Third-line treatment options for patients with chronic-phase chronic myeloid leukemia include tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (alloHSCT). The objective of this study was to develop a Markov model with a lifetime time horizon to assess the cost effectiveness of ponatinib for third-line chronic-phase chronic myeloid leukemia vs. second-generation tyrosine kinase inhibitors (dasatinib, nilotinib, bosutinib) or alloHSCT from the public healthcare system perspective in Germany, Sweden, and Canada. METHODS: Clinical outcomes were derived from the literature, and from patient-level data (phase II PACE trial) for ponatinib. Resource use included drugs, alloHSCT, monitoring and follow-up, adverse events, and end-of-life care; costs were based on national tariffs. Quality-adjusted life-years (QALYs) were calculated using chronic myeloid leukemia health-state utilities from an international time-trade-off study. Costs and benefits were discounted at 3% per annum for Germany and Sweden, and 5% for Canada. RESULTS: Ponatinib yielded more discounted QALYs than any second-generation tyrosine kinase inhibitor/alloHSCT in all three countries, mainly owing to better response rates and longer durations of response. Incremental cost-effectiveness ratios for ponatinib vs. second-generation tyrosine kinase inhibitors were US$21,543-37,755/QALY in Germany, $24,018-38,227/QALY in Sweden, and $43,001-58,515/QALY in Canada. Ponatinib was dominant over alloHSCT in Germany, while incremental cost-effectiveness ratios for ponatinib vs. alloHSCT in Sweden and Canada were $715/QALY and $31,534/QALY, respectively. CONCLUSIONS: Ponatinib may improve outcomes (mainly because of higher response rates and longer response durations) at an acceptable cost level compared with other third-line treatment options for chronic-phase chronic myeloid leukemia in Germany, Sweden, and Canada; however, the lack of an indirect comparison is a limitation of our study.

Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison.

OBJECTIVE: Comparing the benefit-risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit-risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects' baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation. METHODS: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial. RESULTS: Responses were more frequent and durable with ponatinib (n = 70 MAIC-adjusted) than with bosutinib (n = 119) - complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan-Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n = 97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events. CONCLUSIONS: Based on these surrogate measures of patient benefit-risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.

Efficacy of Ponatinib Versus Earlier Generation Tyrosine Kinase Inhibitors for Front-line Treatment of Newly Diagnosed Philadelphia-positive Acute Lymphoblastic Leukemia.

INTRODUCTION: Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who had undergone front-line combination chemotherapy plus ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). PATIENTS AND METHODS: We identified 26 Ph+ ALL studies: 25 of earlier generation TKIs and 1 of ponatinib. The outcomes from studies of combination chemotherapy plus earlier generation TKIs were summarized using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the results from the single-arm combination chemotherapy plus ponatinib trial. Adjusted logistic meta-regression analyses were used to compare the outcomes between the TKI groups. RESULTS: The percentage of patients achieving a CMR was greater with combination chemotherapy plus ponatinib (79%) than the pooled percentage of patients achieving a CMR with combination chemotherapy plus earlier generation TKIs (34%). Greater OS was observed with ponatinib compared with the pooled OS for earlier generation TKIs (2-year, 83% vs. 58%; 3-year, 79% vs. 50%). Odds ratios for ponatinib versus earlier generation TKIs were 6.09 (95% CI, 1.16-31.90; P = .034) for CMR, 3.70 (95% CI, 0.93-14.73; P = .062) for 2-year OS, and 4.49 (95% CI, 1.00-20.13; P = .050) for 3-year OS. CONCLUSION: Ponatinib plus chemotherapy might be associated with better outcomes than chemotherapy with earlier generation TKIs in patients with newly diagnosed Ph+ ALL.

Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation.

BACKGROUND: Effective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with ponatinib versus allogeneic stem cell transplantation (allo-SCT). METHODS: A post hoc, retrospective, indirect comparison of OS among patients who received single-agent ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo-SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted. Kaplan-Meier survival curves and multivariate Cox proportional-hazards models were used to compare OS between intervention groups, adjusting for time from diagnosis to intervention, age, sex, and geographic region; 24-month and 48-month OS rates and median OS were reported. RESULTS: After adjustment for potential confounders, 24-month and 48-month OS rates were significantly higher in patients with chronic-phase CML (CP-CML) who received ponatinib compared with those who underwent allo-SCT (24 months: 84% vs 60.5%, respectively; P = .004; 48 months: 72.7% vs 55.8%, respectively; P = .013), with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.16-0.84; P = .017). In patients who had accelerated-phase CML, OS rates were not significantly different between the groups (HR, 0.90; 95% CI, 0.20-4.10; P = .889). In patients who had blast-crisis CML and those with Ph+ ALL, ponatinib was associated with shorter OS compared with allo-SCT (blast-crisis CML: HR, 2.29 [95% CI, 1.08-4.82; P = .030]; Ph+ ALL: HR, 2.77 [95% CI, 0.73-10.56; P = .146]). CONCLUSIONS: Although allo-SCT remains an important treatment option for patients with T315I-positive advanced CML and Ph+ ALL, ponatinib represents a valuable alternative for patients with T315I-positive CP-CML. Cancer 2017;123:2875-80. © 2017 American Cancer Society.

Mortality and Vascular Events Among Elderly Patients With Chronic Myeloid Leukemia: A Retrospective Analysis of Linked SEER-Medicare Data.

BACKGROUND: Tyrosine-kinase inhibitors (TKIs) can be associated with vascular events (VEs). The expected VE rates in patients with chronic myeloid leukemia (CML) are unknown. The present study examined the event rates and mortality among elderly patients with and without CML. MATERIALS AND METHODS: Linked Surveillance, Epidemiology, and End Results cancer registry and Medicare claims data were used to identify patients aged ≥ 66 years with an incident (index) diagnosis of CML from 2004 to 2009. A comparison cohort of patients without cancer was matched 1:1 to the CML cohort. All patients were followed up from 12 months before the index diagnosis through death or December 31, 2010. The overall survival and rates of myocardial infarction (MI), stroke, pulmonary embolism (PE), and peripheral arterial disease (PAD) were analyzed. RESULTS: A total of 1466 patients with CML (mean age, 78 years; average follow-up period, 25 months) were identified and matched 1:1 to a noncancer cohort (mean age, 78 years; follow-up period, 42 months). Compared with the noncancer patients, those with CML had greater mortality (63% vs. 23% died during the follow-up period; median survival, 23 vs. > 84 months) and greater rates of MI (33.0 vs. 11.9 per 1000 person-years), stroke (83.2 vs. 43.0), PE (6.6 vs. 2.6), and PAD (92.1 vs. 59.3; P < .01 for all). Of the 15% of CML patients with TKI claims, 97% had received imatinib. The event rates were not elevated for TKI-treated patients compared with the overall group of patients with CML. CONCLUSION: Elderly patients with CML had greater mortality and greater rates of MI, stroke, PE, and PAD than did noncancer patients. The event rates were not elevated among the TKI-treated (primary imatinib) patients, suggesting that the VE risk in these patients with CML was driven primarily by the underlying factors associated with CML.

Increasing economic burden of tyrosine kinase inhibitor treatment failure by line of therapy in chronic myeloid leukemia.

OBJECTIVE: To assess the economic burden of tyrosine kinase inhibitor (TKI) treatment failure in chronic myeloid leukemia (CML), by assessing all-cause health care resource use (HCRU) and costs in the year after treatment failure by line of therapy (LOT; 1L/2L/3L) using real-world data. METHODS: Treatment episodes initiating a TKI of interest (index TKI) during June 2008-December 2011 were identified from the IMS PharMetrics Plus Health Plan Claims Database for adult patients with CML diagnosis (ICD-9-CM 205.1x), 120 days pre-index continuous enrollment (CE) and no clinical trial participation. Episodes experiencing treatment failure, defined as switch to a non-index TKI or discontinuation of index TKI (gap of ≥ 60 days), and with 1 year CE post-failure, were analyzed. LOT was determined by number of unique TKIs used in the pre-index. All-cause HCRU and costs (2012 USD) in the 1 year post-failure were assessed by LOT, and the comparisons between 1L and 2L failures were also adjusted using multivariate generalized linear models (GLMs) to control for underlying differences. RESULTS: A total of 706 episodes were identified (518 1L; 180 2L; 8 3L). Unadjusted HCRU over 1 year post-failure increased significantly. This was accompanied by a significant increase in unadjusted mean costs for 2L failures vs. 1L failures ($99,624 vs. $78,667, p = 0.021, Δ$20,957). Following the adjustment using GLMs, adjusted mean costs were 38% higher (95% CI 1.14-1.68), driven primarily by use of medical services. In adjusted analyses, compared to 1L, 2L failures had: 45% more ambulatory visits (mean 31 vs. 21, 95% CI 1.26-1.66), 75% higher risk of hospitalization (33% vs. 23% hospitalized, 95% CI 1.16-2.64), and 73% higher medical costs (95% CI 1.31-2.29). Medical costs comprised a greater proportion of total costs in 2L vs. 1L (55% vs. 44%); pharmacy costs did not increase significantly. CONCLUSIONS: The economic burden over 1 year post TKI failure increased with each sequential line of TKI treatment failure.