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\begin{document}

\title{CLINICAL EVIDENCE OF PANCREATIC RECOVERY IN CHILDREN WITH CYSTIC
FIBROSIS ON IVACAFTOR}



\author[1]{Corinne Muirhead}%
\author[1]{Sydney Walker}%
\author[1]{Sarah Dykes}%
\author[1]{Kristen Wright}%
\affil[1]{Oregon Health \& Science University Doernbecher Children's Hospital}%


\vspace{-1em}



  
  \date{May 25, 2024}


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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 (\textgreater{}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 \textgreater{}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 (\textgreater{}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 \textgreater{}200 ug/g. Six of the
seven pancreatic insufficient patients presented as newly pancreatic
sufficient as evidenced by a FE result of \textgreater{}200 ug/g
compared to previous result of \textless{}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).\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Patient\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Current Age (years)\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Ivacaftor Initiation\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Age of Initiation (years)\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Ivacaftor Duration (years)\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Initial FE Result (ug/g)*\^{}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Repeat FE Result (ug/g)\selectlanguage{ngerman}¥\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Repeat FE Result (ug/g) \selectlanguage{ngerman}¥\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
Repeat FE Result 2023 (ug/g)\^{}\selectlanguage{greek}Δ\selectlanguage{english}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
A\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4.5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8/2019\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3.4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{}15\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
392\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
B\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6/2019\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3.9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textgreater{}800\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
C\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.7\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3/2018\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
95\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
453\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
D\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2.3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
7/2021\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.9\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
58\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textgreater{}800\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
E\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2/2019\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.1\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4.3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
212\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{}15\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
21\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8.3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3/2017\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
6.3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{}50\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
98\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
G\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3.3\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
8/2020\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.5\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
2.8\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
151\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
375\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
H\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4.0\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1/2020\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
3.4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
43\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textgreater{}500\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
I\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
5.6\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4/2019\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
1.4\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
4.2\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
485\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
488\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
243\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
606\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Figure 1. Individual Fecal Elastase results

FE=Fecal elastase

*Initial FE result (testing completed shortly after birth),
\selectlanguage{ngerman}\textbf{¥}repeat FE results if available, \selectlanguage{greek}Δ \selectlanguage{english}testing completed
05/2023-06/2023 and prior to ETI initiation if applicable

for upper and lower limits are different

Shaded boxes represent pediatric patients who appear newly pancreatic
sufficient based on FE result \textgreater{}200ug/g (6) and clinical
assessment of symptoms.\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Result} & \textbf{Interpretation}\tabularnewline
\midrule
\endhead
Less than 100 ug/g & Severe insufficiency\tabularnewline
100-199 ug/g & Moderate insufficiency\tabularnewline
200 ug/g or greater & Normal\tabularnewline
\bottomrule
\end{longtable}

Figure 2. Reference range for Pancreatic Fecal Elastase by Immunoassay
(6)

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics,
  and pharmacodynamics of ivacaftor in patients aged 2-5 years with
  cystic fibrosis and a CFTR gating mutation (KIWI): an open-label,
  single-arm study. \emph{Lancet Respir Med} . 2016; \textbf{4} (2):
  107- 115.
\item
  Rosenfeld M, Cunningham S, Harris WT, et al. An open-label extension
  study of ivacaftor in children with CF and CFTR gating mutation
  initiating treatment at age 2-5 years (KLIMB\emph{)} . \emph{J Cyst
  Fibros} . 2019; \textbf{18} (6): 838- 843.
\item
  Rosenfeld M, Wainwright C.E., Higgins M, et al. Ivacaftor treatment of
  cystic fibrosis in children aged 12 to \textless{}24 months and with a
  CFTR gating mutation (ARRIVAL): a phase 3 single-arm
  study.\emph{Lancet Respir Med} . 2018; \textbf{6} (7): 545- 553.
\item
  Berman H.B., ''Binomial Probability Distribution'', {[}online{]}
  Available
  at:~https://stattrek.com/probability-distributions/Binomial~URL
  {[}Accessed Date: 9/22/2023{]}.
\item
  Kimberly G. Stephenson et al., Journal of Cystic Fibrosis,
  https://doi.org/10.1016/j.jcf.2023.09.005 {[}Article in Press{]}
\item
  Phillips I J, Rowel D J, Dewar P, and Connett G J. Faecal elastase 1:
  a marker of exocrine pancreatic insufficiency in cystic fibrosis. Ann
  Clin Biochem 1999; 36: 739-742
\end{enumerate}

\textbf{Authors}

Sydney Walker, BSN, RN, CPN

Sarah Dykes, DNP, CPNP-PC, PMHS

Kristen Wright, MS, RDN, LD

Corinne Muirhead PharmD, BCPPS, CPP

Doernbecher Children's Hospital

Pediatric Cystic Fibrosis Center

Portland, Oregon

\selectlanguage{english}
\FloatBarrier
\end{document}

