CFTR modulator drug desensitization: Preserving the hope of long term improvement

Abstract

The development of modulator therapy has, for the first time, allowed direct targeting of the underlying cause of cystic fibrosis (CF), the cystic fibrosis transmembrane conductance regulator (CFTR). Patients treated with CFTR modulators have improvement in lung function and decreased rates of pulmonary exacerbations. In 2019, elexacaftor/tezacaftor/ivacaftor was approved for use in the United States, opening these therapies to 90% of patients with CF. Intolerable adverse drug reactions to CFTR modulators results in discontinuation of therapy, which can be devastating to our patients. We describe our approach to two cases, not previously

T‐cell‐mediated hypersensitivity to lumacaftor and ivacaftor in cystic fibrosis

“…With the increased use of CFTR modulators, there are emerging reports of T-cell-mediated reactions. [4][5][6] To our knowledge, this is the first reported case of delayed-type, T-cell-mediated hypersensitivity to multiple CFTR modulators described in the literature. Our findings suggest possible cross-reactivity between CFTR modulators or multiple sensitizations, which should be taken into account in similar cases.…”

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

“…Skin-related adverse effects are commonly reported by PwCF after the start of ETI therapy. Several case reports have already reported rash, Malassezia folliculitis , and acne as common manifestations [ 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ] ( Table 8 ). Indeed, up to 10% of PwCF receiving ETI therapy were reported to present skin manifestations in clinical trials [ 17 , 18 ].…”

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

“…Rash appeared to be more common in female patients and in those who use hormonal contraception. Meanwhile numerous adverse skin reactions have been observed in the real-life setting ranging from skin rash, drug-induced acne, eruptive melanocytic naevi to toxic epidermal necrolysis ( Goldberg et al, 2021 ; Leonhardt et al, 2021 ; Atkinson et al, 2022 ; Bhaskaran and Bateman, 2022 ; Cheng et al, 2022 ; Diseroad et al, 2022 ; Hu et al, 2022 ; Hudson et al, 2022 ; Loyd et al, 2022 ; Mederos-Luis et al, 2022 ; Muirhead et al, 2022 ; Okroglic et al, 2023 ). Desensitization protocols were often successful, but etiology has not been examined, the exception being a case report of LUM-responsive CD4 + T-cell clones in non-immediate allergy ( Roehmel et al, 2021 ).…”