(207) Repeat Fecal Elastase Testing in Pediatric Patients on CFTR Modulator Therapy

Background: Exocrine pancreatic insufficiency (PI) is a common feature of cystic fibrosis, occurring in roughly 85% of the CF population. CF Foundation guidelines recommend screening all infants with CF under two years of age for pancreatic insufficiency via fecal elastase-1 (FE-1). The development of highly effective CFTR modulators has begun to challenge the assumption that pancreatic insufficiency is irreversible, but at present there is no formal guidance as to when repeat fecal elastase testing may be indicated to confirm continued PI. There are several documented examples of improvement in pancreatic function, including in the KIWI, KLIMB, and ARRIVAL trials with ivacaftor as well as limited published case reports of patients taking ivacaftor and lumacaftor/ivacaftor. Additionally, our center has previously identified four patients who have had return of pancreatic function after time on CFTR modulator therapy, all four of whom have discontinued pancreatic enzyme replacement therapy (PERT). As other highly effective modulator therapies (e.g. elexacaftor/tezacaftor/ivacaftor) have demonstrated similar improvements in other CF symptoms, it is reasonable to consider that these may confer similar benefits in pancreatic function.

Methods: We developed a protocol of repeat FE-1 testing in children < 12 years of age six months after initiation of CFTR modulator therapy, as well as at any point during treatment in patients of any age with any clinical signs or symptoms suggesting return of pancreatic function.

Results: To date, 21 patients (9 male, 12 female) have been screened with repeat FE-1. Figure 1 shows the baseline and most recent FE-1 for each patient, omitting baseline in the six patients for whom that was unable to be obtained. Patients had an average improvement in FE-1 of 61.4 + 101.9 mcg/g from baseline at an average of 19.4 + 12 months from start of current modulator and 28.8 + 26.8 months from start of initial modulator therapy.

Of these patients, four had repeat FE-1 greater than 200 mcg/g (range 208-294 mcg/g), indicating pancreatic sufficiency, despite all having previously had documented FE-1 indicating severe pancreatic insufficiency (range 15-56 mcg/g). These four patients had been on modulator therapy for a total of 19.9-91.8 months, with two on lumacaftor/ivacaftor only and two initially on ivacaftor who transitioned to elexacaftor/tezacaftor/ivacaftor when eligible. One of these patients has discontinued pancreatic enzyme replacement therapy (PERT), while the other three remain on PERT at an average dose of 2027 units lipase/kg/meal.

Conclusions: While early in its implementation, this protocol has identified improvement in pancreatic function in a number of patients with CF on CFTR modulator therapy. Continued investigation is warranted, but this shows promising long term improvements for patients on these therapies beyond the lung function improvements demonstrated in initial clinical trials.

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