TITLE: CLINICAL EVIDENCE OF PANCREATIC RECOVERY IN CHILDREN WITH CYSTIC
FIBROSIS ON IVACAFTOR
To the Editor,
Pediatric research has shown that young children with cystic fibrosis
(CF) and treated with ivacaftor have seen improvements in pancreatic
function. KIWI was a 24-week safety and efficacy trial of ivacaftor in
children aged 2-5 years with CF (1). KLIMB was an 84-week open label
extension of KIWI (2). Patients enrolled in KIWI revealed an average
increase of 99.8 ug/g in fecal elastase (FE). Before beginning
ivacaftor, 26 of 27 patients were pancreatic insufficient. After
24 weeks, 25% of these 26
patients had FE results demonstrating pancreatic sufficiency
(>200 ug/g) (1). These improvements in FE were maintained
during the 84-week KLIMB extension (2).
In the ARRIVAL Study, a younger population was studied. Infants aged
12-24 months previously diagnosed
with pancreatic insufficiency were assessed (3). After
24 weeks post ivacaftor
initiation, six of nine, or 67%, of the infants had repeat FE values of
>200 ug/g, consistent with pancreatic sufficiency, as well
as evidence of decreased pancreatic inflammation noted with reduction in
immunoreactive trypsinogen.
Based on this data we instituted a new protocol for repeat FE monitoring
in all patients with pancreatic insufficiency who started on ivacaftor
by the age of two years. If FE is normal (>200 ug/g),
discontinuation of pancreatic enzyme replacement therapy (PERT) is
considered along with ongoing monitoring of clinical symptoms and
adjustments to vitamin and diet recommendations as indicated.
Below is a review of our cohort of pediatric patients who were
currently, had been consistently treated with ivacaftor, and were
assessed for current pancreatic function by repeat FE testing. All FE
values were collected prior to initiation of
elexacaftor/tezacaftor/ivacaftor (ETI) in those newly eligible. Nine
patients at our CF center who were on PERT have started ivacaftor in the
last 6 years with a mean current age of 4.9 years (SD 1.7). The median
age of ivacaftor initiation was 1.1 years (range 0.4 - 2). The mean
duration of treatment is 3.9 years (SD 1.3).
Seven patients had a repeat FE result >200 ug/g. Six of the
seven pancreatic insufficient patients presented as newly pancreatic
sufficient as evidenced by a FE result of >200 ug/g
compared to previous result of <200 ug/g. Patient I was
included in this cohort as he was treated with PERT for clinical
symptoms of pancreatic insufficiency even though his baseline FE values
were above 200 ug/g.
The six newly pancreatic sufficient patients started ivacaftor between
0.4 and 1.1 years of age. Our recovery data of 75% is close to the rate
seen in the ARRIVAL study. We calculated binomial probability for
pancreatic recovery in this small case control series using 0.67 factor
based on previous data in ARRIVAL (4). This resulted in a 28%
favorability of success.
Unsurprisingly, the rate of recovery was higher in the younger age of
initiation of ivacaftor than that seen in the older 2–5 year-old cohort
in KIWI. A correlation between pancreatic recovery and younger age of
initiation was also noted in a recently published multi-center
retrospective study of all available CFTR modulators and PE recovery
(5). In this study, of the 15 patients with FE results of 200 or
greater, 10 had been treated with ivacaftor as their initial modulator
therapy. Based on the demographic data, 62.5% of those treated with
ivacaftor had pancreatic recovery, which is similar to our cohort data.
We urge CF Centers to institute clinical protocols to recheck pancreatic
elastase to assess for restoration of pancreatic function in all
pediatric patients treated with PERT on ivacaftor. Subsequently, CF
Centers should establish processes for discontinuing PERT, monitoring
fat soluble vitamins, and adjusting diet as indicated. Resulting
medication adjustments will significantly impact the treatment burden
and cost for these children and their families. Those with pancreatic
restoration should be monitored for symptoms of pancreatic insufficiency
as well as growth trends at routine intervals and pursue repeat FE as
indicated based on clinical assessment.
This study was approved by the Oregon Health and Science University
Institutional Review Board (IRB#26442).