A Case Report of Pulmonary Exacerbation after Initiation of Lumacaftor/Ivacaftor Therapy in a CF Female with Complicated Lung Disease

Abstract

Novel targeted treatments for Cystic Fibrosis give rise to new hope for an ever-growing number of CF patients with various mutations. However, very little evidence and guidelines exist to steer clinical decisions regarding patients whose illness takes an unexpected course. In such cases, the benefits and risks of discontinuing these treatments must be carefully and individually weighed, since their long-term effects remain mainly uncharted territory. In this report we document the case of a homozygous F508del CF patient with severe lung disease who presented with a pulmonary exacerbation shortly after the beginning of treatment with lumacaftor/ivacaftor and the complicated initial phase of therapy, which was followed by significant improvements.

Use of CFTR modulators in special populations, part 2: Severe lung disease

“…Popowicz et al did note a transient yet significant decline in pulmonary function soon after initiation of full‐dose LUM/IVA that persisted for 24 hours; however, at 1 month, lung function returned to baseline for all pwCF 16 . Likewise, respiratory events and treatment discontinuations were reported by Hubert et al as well as Hatziagorou et al; however, improvement in lung function was observed with continued treatment 17,18 . Taylor‐Cousar et al also reported respiratory events (e.g., infective pulmonary exacerbations, dyspnea, cough) requiring CFTR modulator treatment modification and/or discontinuation 19 .…”

“…There were no major safety concerns for pwCF and severe lung disease reported with use of IVA, TEZ/IVA, or ELE/TEZ/IVA. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Popowicz et al did note a transient yet significant decline in pulmonary function soon after initiation of full-dose LUM/IVA that persisted for 24 hours; however, at 1 month, lung function returned to baseline for all pwCF. 16 Likewise, respiratory events and treatment discontinuations were reported by Hubert et al as well as Hatziagorou et al; however, improvement in lung function was observed with continued treatment.…”

“…There were no major safety concerns for pwCF and severe lung disease reported with use of IVA, TEZ/IVA, or ELE/TEZ/IVA 10–29 . Popowicz et al did note a transient yet significant decline in pulmonary function soon after initiation of full‐dose LUM/IVA that persisted for 24 hours; however, at 1 month, lung function returned to baseline for all pwCF 16 .…”

“…16 Likewise, respiratory events and treatment discontinuations were reported by Hubert et al as well as Hatziagorou et al; however, improvement in lung function was observed with continued treatment. 17,18 Taylor-Cousar et al also reported respiratory events (e.g., infective pulmonary exacerbations, dyspnea, cough) requiring CFTR modulator treatment modification and/or discontinuation. 19 The authors did note less frequent respiratory events with shorter duration and no treatment-related discontinuations when half the dose of LUM/IVA was used.…”

“…years • Respiratory adverse events were reported by 27/51 patients and 16 discontinued treatment • Discontinuation rate was greater than reported in clinical trials Improvement in FEV 1 was observed with continued treatment compared to what was observed in pivotal trials Hatziagorou et al18 2018 years • Common adverse events included infective pulmonary exacerbations, abnormal respiration, cough, and dyspnea• Patients initiating LUM/IVA at half the dose experienced less frequent respiratory events (56% vs. 71%) of shorter median duration (4 vs. 9 days); these patients did not require dose modifications or discontinuation due to adverse respiratory events and were increased to full dose over 2 weeks• CF patients with ppFEV1 < 40% might benefit from initiation at a lower dose and close monitoring before increasing to the full doseWark et al years • Statistically significant improvement in 6MWT at 4 weeks and maintained at 52 weeks, and FEV 1 at 24 weeks and maintained at 52 weeks Tong et al 21 2020 LUM/IVA F508del homozygous LUM/IVA, 72; controls, 33 Mean 31 (SD: 11.6) years • Statistically significant reduction in pulmonary exacerbations requiring IV antibiotics, prolonged time to first exacerbation, and reduced rate of decline in ppFEV 1 over 12 months • Chest tightness and dyspnea were experienced by 55% of patients and 32% ceased treatment over the 12 month observation period Ejiofor et aland 3rd quartile) 33.0 (23−40) years • Statistically significant improvement in ppFEV 1 after 3, 6, 9, and 12 months (in comparison to baseline), cardiopulmonary exercise test, and health-6 (SD: 8.6) years • Statistically significant reduction in the number of pulmonary exacerbations requiring hospitalization, hospitalization days, IV antibiotic usage days, increase in FEV 1, and body weight Martin et al 24 2021 ELE/TEZ/IVA F508del homozygous (N = 39), F508del/other (N = 61), Unreported (N = 1) 101 28−41 years • Patients reported significant impact on respiratory symptoms, quality, general well-being, physical selfesteem, and reduction in treatment burden after initiation of ELE/TEZ/IVA O'Shea et al 25 2021 ELE/TEZ/IVA F508del homozygous (N = 8), chloride concentrations, and infective exacerbations requiring hospitalization • No therapy related significant adverse effects were observed Carnovale et al 26 2021 ELE/TEZ/IVA F508del/minimal function mutation 46 17−52.6 years • Statistically significant improvement in mean sweat chloride concentrations, ppFEV 1 after 1 and 6 months of therapy, BMI, and quality of life • No adverse effects were observed Burgel et al 27 2021 ELE/TEZ/IVA At least one F508del mutation 245 24−38 years • Statistically significant improvement in mean ppFEV 1 , BMI, long-term oxygen, noninvasive ventilation, and/or enteral tube feeding • Twofold decrease in the number of lung transplantations over a 2 year period primarily due to the rapid disease modification effects of ELE/TEZ/IVA Kos et al 28 2022 ELE/TEZ/IVA F508del heterozygous (N = 8), Statistically significant improvement in ppFEV1 and BMI • ELE/TEZ/IVA was well tolerated with mild side effects and led to a self-reported improvement in quality of life as well as reduction in pulmonary exacerbations and hospitalizations • Pulmonary and extrapulmonary benefits were maintained for 12 months McCoy et al 29 2023 ELE/TEZ/IVA F508del homozygous (N = 8), F508del heterozygous (N = 10) 18 15−49 years • Over a period of 2 years, statistically significant improvement in ppFEV1, body weight, BMI, and sweat chloride concentrations were observed • Treatment was well tolerated by all patients with no treatment discontinuations, deaths, or need for lung transplant after 2 years publication separated outcomes by age (pediatric vs. adult), likely due to the small proportion (e.g., 1 of 13 pwCF) of the total population. 15,28 The data regarding safety and efficacy outcomes of CFTR modulators in pwCF and severe lung disease is limited.…”