Use of ivacaftor in late diagnosed cystic fibrosis monozygotic twins heterozygous for F508del and R117H-7T – a case report

Abstract

Background CFTR modulator therapy with ivacaftor is a treatment option for Cystic Fibrosis (CF) patients with at least one copy of a R117H-7T mutation in the CFTR gene. Desirable effects of this therapy are improvement of lung function, decrease in exacerbation rate, normalization or reduction of sweat chloride and weight gain. Monogenetic CF-twins carry identical genetic information, so therapy response and side effects are expected to be nearly identical under this specific therapy. Case presentation In monozygotic twins, at the age of 55, two pathogenic variants in the CFTR gene (F508del and R117H-7T) were detected. Both patients presented with a borderline sweat test (30–59 mmol / L ) and despite the same genetic information and similar life circumstances the disease proceeds completely different. While one patient has severe pulmonary involvement with chronic P. aeruginosa infection, her twin sister is almost unimpaired. Liver or pancreatic involvement was not seen in either patient. Due to the presence of one copy of a R117H-7T mutation, CFTR modulator therapy with ivacaftor was initiated in both. Response and side effects were significantly different. In the less affected patient, we observed an improvement in lung function and a normalization of sweat chloride. In the severely affected patient, no functional response to treatment was seen, but stabilization of the disease state with a decrease in exacerbation and hospitalization rate and weight gain as well as a normalization of sweat chloride. There was an increase in liver enzymes in the less affected patient, which normalized after halving the dose of ivacaftor, while the therapeutic effect was maintained. Conclusions Despite nearly identical genetic information, as in monogenetic twins, therapy response and onset of side effects of CFTR modulating therapy are very different. In patients with late diagnosis and severe pulmonary involvement, ivacaftor does not seem to improve lung function, whereas in patients with late diagnosis and low disease severity a relevant therapy response was obtained. In addition to lung function, additional clinical parameters such as reduction of exacerbation and hospitalization rate and weight gain should be used to assess therapy response, especially in severely affected patients.

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review

“…Fourteen (26%) of the observational studies focused on patients with severe airflow obstruction, defined as ppFEV 1 < 40%; in 11 of these studies, patients accessed the CFTR modulator via a compassionate access program (also referred to as a “managed access”, “early access’, “expanded access”, or “named patient” program) through the manufacturer [ 25 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Twenty (65%) of the full manuscripts were deemed to have safety as a primary focus or outcome [ 27 , 28 , 29 , 30 , 32 , 33 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…Another study reported increased bronchial and nasal secretions after initiating IVA in a patient with low lung function (baseline ppFEV 1 13.9%) prompting a severe pulmonary exacerbation, and IVA ultimately had to be discontinued due to difficulty clearing “liquefied” secretions despite decreases in dose [ 30 ]. Otherwise, respiratory AE reportedly resolved over time without changes to IVA therapy [ 30 , 46 ].…”

“…In one observational study, transaminitis and a diagnosis of liver cirrhosis resulted in IVA discontinuation in one individual each, and hepatitis warranted interruption of therapy [ 58 ]. One case report indicated a decrease in IVA dose was necessary for normalization of transaminases [ 46 ]. Hepatic AEs were not otherwise reported to require changes in IVA therapy.…”

Therapeutic Drug Monitoring of Ivacaftor, Lumacaftor, Tezacaftor, and Elexacaftor in Cystic Fibrosis: Where Are We Now?

“…The described AE symptoms in cohorts were related to respiratory intolerance (3/20 F508del homozygote CF adult patients with LUM/IVA) [32]; chest tightness (2/29 F508del homozygote adult CF patients with LUM/IVA [33] and 1/14 F508del homozygote pediatric CF patients with LUM/IVA [34]); and undescribed AE (10/116 F508del homozygote CF patients ≥12 years old (yo) with LUM/IVA [35]). Finally, a case report described elevated transaminases with subsequent normalization of symptoms (1 adult CF heterozygous for F508del and R117H-7T with IVA [36]), and in another one, a breast development was reported as a rare dose-dependent AE of treatment with IVA [16]. Alternatively, a case report concerned a CF adult who discontinued LUM/IVA for respiratory dyspnea AE despite having already a half-dose reduction [37].…”