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The Role of Ivacaftor in Severe Cystic Fibrosis in a Patient With the R117H MutationIvacaftor in Severe CF With R117H Mutation FREE TO VIEW

Nicola J. Ronan, MBBCh; Claire Fleming, BSc; Grace O’Callaghan, PhD; Michael M. Maher, MBBCh, MD; Desmond M. Murphy, MBBCh, PhD, FCCP; Barry J. Plant, MBBCh, MD
Author and Funding Information

From the Cork Adult Cystic Fibrosis Centre (Drs Ronan, O’Callaghan, Murphy, and Plant and Ms Fleming), and the Department of Radiology (Dr Maher), University College Cork, Cork University Hospital, Wilton; and the Health Research Board Clinical Research Facility (Drs Ronan, O’Callaghan, Murphy, and Plant), University College Cork, Cork, Ireland.

CORRESPONDENCE TO: Barry J. Plant, MBBCh, MD, Cork Adult Cystic Fibrosis Centre, University College Cork, Cork University Hospital, Wilton, Cork, Ireland; e-mail: b.plant@ucc.ie


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):e72-e75. doi:10.1378/chest.14-3215
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Cystic fibrosis (CF) conductance transmembrane regulator functions as a chloride (Cl) channel in multiple organs, including the lungs. More than 1,800 disease-associated mutations have been identified, which can be divided into six classes. In patients with CF due to class III gating mutations, ivacaftor produces significant improvement in lung function, weight, reduction in sweat chloride level, and pulmonary exacerbations by enhancing the probability of chloride channel opening (gating). Although the benefit of ivacaftor in CF due to gating mutations is established, its potential role in patients with CF due to class IV conductance mutations is emerging. We report 6 months’ prospective stability of lung function, improved BMI, reduced pulmonary exacerbations, and reduction in sweat chloride level in a patient with severe CF and the class IV R117H mutation. High-resolution CT scan also improved, thus highlighting the potential usefulness of ivacaftor in patients with severe CF due to class IV mutations.

Figures in this Article

Cystic fibrosis (CF) is due to a mutation in the CF conductance transmembrane regulator (CFTR) gene, which codes for the CFTR protein. CFTR regulates chloride transport in multiple organs, including the lungs. To date, more than 1,800 mutations have been identified, which can be divided into six classes. Class III (gating) mutations result in a chloride channel that is correctly localized at the cell surface but fails to open and close correctly. Ivacaftor increases channel open probability (gating) of class III mutations and, in clinical trials, produced significant increases in FEV1 (> 10% absolute) and weight as well as reductions in sweat chloride level and pulmonary exacerbations in patients aged ≥ 6 years with one of nine gating mutations.1,2 It is licensed for treating patients with CF with nine gating mutations (G551D, G551S, G1349D, G1244E, G970R, G178R, S549N, S549R, S1251N, and S1255P) and in December 2014 was approved by the US Food and Drug Administration for patients with the R117H mutation.3 The R117H mutation is a class IV (conductance) mutation in which CFTR is correctly localized at the cell surface but conducts chloride abnormally. Preliminary trial data suggest ivacaftor produces a 5% absolute increase in FEV1 in patients aged ≥ 18 years who carry the R117H mutation.4,5 However, this study excluded patients with severe disease (FEV1 < 40% predicted). Although data demonstrate the usefulness of ivacaftor in patients with severe CF who have gating mutation,6-8 its use in severe CF with class IV mutations has thus far not been described.

We report the case of a 56-year-old woman with severe CF (F508del/R117H), with a baseline FEV1 of 28% predicted and a high exacerbation rate. She was considered an unsuitable candidate for lung transplantation because of a combination of her microbiology—pan-resistant Stenotrophomonas maltophilia—and chest wall deformity due to extensive and disproportionate left lung bronchiectatic destruction.

In February 2014 she started ivacaftor on a named patient basis (compassionate use program). Baseline spirometry, weight, sweat test, and Cystic Fibrosis Questionnaire Revised (CFQ-R)9 were recorded before commencing ivacaftor. High-resolution CT (HRCT) scan of the thorax was performed using an ultra-low-dose protocol10 at baseline and after 3 and 6 months of treatment (mean effective radiation dose, 0.08 mSv). Blood samples were obtained at baseline and after 3 and 6 months of treatment and analyzed for circulating cytokines using a Mesoscale Discovery platform.11,12Table 1 summarizes treatment response.

Table Graphic Jump Location
TABLE 1 ]  Change in Clinical Parameters

CFQ-R = Cystic Fibrosis Questionnaire Revised; Sao2 = arterial oxygen saturation.

At 6 months, FEV1 remained stable, weight increased by 5.8 kg, and sweat chloride level fell by 28 mmol/L. In the 6 months after commencement of ivacaftor, she had one course of IV antibiotics (0 inpatient days) in contrast to four courses of IV antibiotics (19 inpatient days) in the corresponding 6-month period in the previous year. Subjectively, she discontinued her home oxygen for routine activities after 3 weeks of treatment.

Quality of life improved across all domains of her CFQ-R after 3 and 6 months of ivacaftor (Table 1). HRCT scan demonstrated a reduction in mucus plugging and in bronchial wall thickening in the functional right lung after 6 months of treatment (Fig 1). Figure 2 demonstrates the change in circulating cytokine profile at baseline and after 3 and 6 months of ivacaftor, with an increase in IL-6 and IL-8.

Figure Jump LinkFigure 1 –  A, Baseline axial high-resolution CT (HRCT) scan shows bronchiectasis with bronchial wall thickening in focal areas, throughout the right lung. Severe volume loss with bronchiectasis and parenchymal lung destruction is shown on the left side. B, Axial HRCT scan after 3 mo of ivacaftor shows interval improvement in bronchial wall thickening in all the focal areas of bronchiectasis seen on pretreatment studies. No change was found in the left hemithorax. C, Axial HRCT scan after 6 mo of ivacaftor shows stable appearances when compared with the 3-mo study. Once again, no change was found in the left hemithorax.Grahic Jump Location
Figure Jump LinkFigure 2 –  Change in circulating cytokine profile at baseline and after 3-6 mo of ivacaftor with an increase in IL-6 and IL-8. IFN = interferon; TNF = tumor necrosis factor.Grahic Jump Location

This is the first case, to our knowledge, to demonstrate the usefulness of ivacaftor in a patient with severe CF and the R117H mutation. Improvement in FEV1 is frequently a primary end point in clinical trials assessing new therapies in CF. On the basis of change in FEV1, this woman would be considered a treatment failure; however, her quality of life, weight, exacerbation rate, and imaging all improved, thus highlighting that in severe disease, traditional markers of treatment response may not be a true reflection of therapeutic benefit.

Recurrent pulmonary exacerbations are associated with more rapid decline in FEV1.13,14 Her pulmonary exacerbation frequency decreased on ivacaftor. Given that she is not a candidate for lung transplantation, prevention of exacerbations and resultant decline in FEV1 could be important in ongoing management. Thus, ivacaftor may have a role in deferring the need for transplantation or as an alternative therapy in patients who are not suitable for transplantation in this cohort.

An increase in all domains of her CFQ-R was observed, which has not been observed in studies of ivacaftor in patients with gating mutations and, therefore, may be unique to the R117H mutation. The increase could also reflect further benefit in the setting of severe CF or be partially due to ascertainment bias (due to lack of blinding). Paradoxically, proinflammatory cytokines increased after commencing ivacaftor during a period of time when she had fewer pulmonary exacerbations. This change may represent a diminution of immunoparesis15,16 or be related to her increased exercise.17 The radiologic changes mirror those seen following ivacaftor administration in other gating mutations.18,19

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Murphy has received honoraria from Bayer AG; Boehringer Ingelheim GmbH; Gilead; GlaxoSmithKline; The Menarini Group; Merck Sharp and Dohme, Corp; Novartis Corporation; and Pfizer Inc. Dr Plant was a PI on the Strive Study and has received speaker fees/honoraria from Gilead, Novartis Corporation, and Vertex Pharmaceuticals Incorporated. Drs Ronan, O’Callaghan, and Maher, and Ms Fleming have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

CF

cystic fibrosis

CFQ-R

Cystic Fibrosis Questionnaire Revised

CFTR

cystic fibrosis conductance transmembrane regulator

HRCT

high-resolution CT

De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551Dgating mutation. J Cyst Fibros. 2014;13(6):674-680. [CrossRef] [PubMed]
 
Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and theG551Dmutation. N Engl J Med. 2011;365(18):1663-1672. [CrossRef] [PubMed]
 
U.S. Food and Drug Administration approves KALYDECO®(ivacaftor) for use in people with cystic fibrosis ages 6 and older who have the R117H mutation. Vertex Pharmaceuticals Incorporated website. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=889027. Accessed January 22, 2015.
 
Moss R, Flume P, Elborn J, et al. WS23. 6 Ivacaftor treatment in patients with cystic fibrosis who have anR117H-CFTRmutation, the KONDUCT study. J Cyst Fibros. 2014;13(suppl 2):S44. [CrossRef]
 
Moss R, Flume PA, Elborn JS, et al. Effects of Ivacaftor in CF Patients withR117H-CFTR[abstract]. Pediatr Pulmonol. 2014;49(S38):S221.
 
Barry PJ, Plant BJ, Nair A, et al. Effects of ivacaftor in cystic fibrosis patients carrying the G551D mutation with severe lung disease. Chest. 2014;146(1):152-158. [CrossRef] [PubMed]
 
Harrison MJ, Murphy DM, Plant BJ. Ivacaftor in a G551D homozygote with cystic fibrosis. N Engl J Med. 2013;369(13):1280-1282. [CrossRef] [PubMed]
 
McGarry ME, Nielson DW. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013;144(4):1376-1378. [CrossRef] [PubMed]
 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128(4):2347-2354. [CrossRef] [PubMed]
 
O’Connor OJ, Vandeleur M, McGarrigle AM, et al. Development of low-dose protocols for thin-section CT assessment of cystic fibrosis in pediatric patients. Radiology. 2010;257(3):820-829. [CrossRef] [PubMed]
 
Breen EC, Reynolds SM, Cox C, et al. Multisite comparison of high-sensitivity multiplex cytokine assays. Clin Vaccine Immunol. 2011;18(8):1229-1242. [CrossRef] [PubMed]
 
Chowdhury F, Williams A, Johnson P. Validation and comparison of two multiplex technologies, Luminex and Mesoscale Discovery, for human cytokine profiling. J Immunol Methods. 2009;340(1):55-64. [CrossRef] [PubMed]
 
Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010;182(5):627-632. [CrossRef] [PubMed]
 
Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol. 2011;46(4):393-400. [CrossRef] [PubMed]
 
Pohl K, Hayes E, Keenan J, et al. A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood. 2014;124(7):999-1009. [CrossRef] [PubMed]
 
Sabroe I, Jones EC, Whyte MK, Dower SK. Regulation of human neutrophil chemokine receptor expression and function by activation of Toll-like receptors 2 and 4. Immunology. 2005;115(1):90-98. [CrossRef] [PubMed]
 
Tirakitsoontorn P, Nussbaum E, Moser C, Hill M, Cooper DM. Fitness, acute exercise, and anabolic and catabolic mediators in cystic fibrosis. Am J Respir Crit Care Med. 2001;164(8 pt 1):1432-1437. [CrossRef] [PubMed]
 
Sheikh SI, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. J Cyst Fibros. 2015;14(1):84-89. [CrossRef] [PubMed]
 
Hoare S, McEvoy S, McCarthy CJ, et al. Ivacaftor imaging response in cystic fibrosis. Am J Respir Crit Care Med. 2014;189(4):484. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  A, Baseline axial high-resolution CT (HRCT) scan shows bronchiectasis with bronchial wall thickening in focal areas, throughout the right lung. Severe volume loss with bronchiectasis and parenchymal lung destruction is shown on the left side. B, Axial HRCT scan after 3 mo of ivacaftor shows interval improvement in bronchial wall thickening in all the focal areas of bronchiectasis seen on pretreatment studies. No change was found in the left hemithorax. C, Axial HRCT scan after 6 mo of ivacaftor shows stable appearances when compared with the 3-mo study. Once again, no change was found in the left hemithorax.Grahic Jump Location
Figure Jump LinkFigure 2 –  Change in circulating cytokine profile at baseline and after 3-6 mo of ivacaftor with an increase in IL-6 and IL-8. IFN = interferon; TNF = tumor necrosis factor.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Change in Clinical Parameters

CFQ-R = Cystic Fibrosis Questionnaire Revised; Sao2 = arterial oxygen saturation.

References

De Boeck K, Munck A, Walker S, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551Dgating mutation. J Cyst Fibros. 2014;13(6):674-680. [CrossRef] [PubMed]
 
Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and theG551Dmutation. N Engl J Med. 2011;365(18):1663-1672. [CrossRef] [PubMed]
 
U.S. Food and Drug Administration approves KALYDECO®(ivacaftor) for use in people with cystic fibrosis ages 6 and older who have the R117H mutation. Vertex Pharmaceuticals Incorporated website. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=889027. Accessed January 22, 2015.
 
Moss R, Flume P, Elborn J, et al. WS23. 6 Ivacaftor treatment in patients with cystic fibrosis who have anR117H-CFTRmutation, the KONDUCT study. J Cyst Fibros. 2014;13(suppl 2):S44. [CrossRef]
 
Moss R, Flume PA, Elborn JS, et al. Effects of Ivacaftor in CF Patients withR117H-CFTR[abstract]. Pediatr Pulmonol. 2014;49(S38):S221.
 
Barry PJ, Plant BJ, Nair A, et al. Effects of ivacaftor in cystic fibrosis patients carrying the G551D mutation with severe lung disease. Chest. 2014;146(1):152-158. [CrossRef] [PubMed]
 
Harrison MJ, Murphy DM, Plant BJ. Ivacaftor in a G551D homozygote with cystic fibrosis. N Engl J Med. 2013;369(13):1280-1282. [CrossRef] [PubMed]
 
McGarry ME, Nielson DW. Normalization of sweat chloride concentration and clinical improvement with ivacaftor in a patient with cystic fibrosis with mutation S549N. Chest. 2013;144(4):1376-1378. [CrossRef] [PubMed]
 
Quittner AL, Buu A, Messer MA, Modi AC, Watrous M. Development and validation of The Cystic Fibrosis Questionnaire in the United States: a health-related quality-of-life measure for cystic fibrosis. Chest. 2005;128(4):2347-2354. [CrossRef] [PubMed]
 
O’Connor OJ, Vandeleur M, McGarrigle AM, et al. Development of low-dose protocols for thin-section CT assessment of cystic fibrosis in pediatric patients. Radiology. 2010;257(3):820-829. [CrossRef] [PubMed]
 
Breen EC, Reynolds SM, Cox C, et al. Multisite comparison of high-sensitivity multiplex cytokine assays. Clin Vaccine Immunol. 2011;18(8):1229-1242. [CrossRef] [PubMed]
 
Chowdhury F, Williams A, Johnson P. Validation and comparison of two multiplex technologies, Luminex and Mesoscale Discovery, for human cytokine profiling. J Immunol Methods. 2009;340(1):55-64. [CrossRef] [PubMed]
 
Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010;182(5):627-632. [CrossRef] [PubMed]
 
Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol. 2011;46(4):393-400. [CrossRef] [PubMed]
 
Pohl K, Hayes E, Keenan J, et al. A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood. 2014;124(7):999-1009. [CrossRef] [PubMed]
 
Sabroe I, Jones EC, Whyte MK, Dower SK. Regulation of human neutrophil chemokine receptor expression and function by activation of Toll-like receptors 2 and 4. Immunology. 2005;115(1):90-98. [CrossRef] [PubMed]
 
Tirakitsoontorn P, Nussbaum E, Moser C, Hill M, Cooper DM. Fitness, acute exercise, and anabolic and catabolic mediators in cystic fibrosis. Am J Respir Crit Care Med. 2001;164(8 pt 1):1432-1437. [CrossRef] [PubMed]
 
Sheikh SI, Long FR, McCoy KS, Johnson T, Ryan-Wenger NA, Hayes D Jr. Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation. J Cyst Fibros. 2015;14(1):84-89. [CrossRef] [PubMed]
 
Hoare S, McEvoy S, McCarthy CJ, et al. Ivacaftor imaging response in cystic fibrosis. Am J Respir Crit Care Med. 2014;189(4):484. [CrossRef] [PubMed]
 
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