CFTR modulator drug desensitization: Preserving the hope
of long term improvement
Kelsey Leonhardt PharmD1 | Elizabeth B. Autry PharmD, BCPPS1,2 |
Robert J. Kuhn PharmD1,2 | Mark A. Wurth MD, PhD3
1
Department of Pharmacy Services,
University of Kentucky HealthCare,
Lexington, Kentucky, USA
2
Department of Pharmacy Practice and
Sciences, University of Kentucky College of
Pharmacy, Lexington, Kentucky, USA
3
Department of Pediatrics, University of
Kentucky College of Medicine, Lexington,
Kentucky, USA
Correspondence
Kelsey Leonhardt, PharmD, Department of
Pharmacy, University of Kentucky
HealthCare, 800 Rose Street, Room H110,
Lexington, KY 40536, USA,
Email: [email protected]
Abstract
The development of modulator therapy has, for the first time, allowed direct tar￾geting of the underlying cause of cystic fibrosis (CF), the cystic fibrosis transmem￾brane 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 re￾actions to CFTR modulators results in discontinuation of therapy, which can be
devastating to our patients. We describe our approach to two cases, not previously
reported, of rash to elexacaftor/tezacaftor/ivacaftor in patients with a previous
history of cutaneous adverse reactions to dual modulator therapy that had been
addressed by desensitization. Case 1 was able to tolerate elexacaftor/tezacaftor/
ivacaftor after desensitization to the triple combination therapy, while in Case 2
tolerance was obtained by treating through the reaction. The loss of tolerance in
these patients was unexpected, and may be a common finding in patients with
history of cutaneous adverse reactions to these drugs. We hope reporting our ex￾perience, including our desensitization protocol, may benefit CF patients for whom
these drug reactions may be limiting access to powerful disease altering therapies.
KEYWORDS
CFTR modulator, cystic fibrosis, desensitization
1 | INTRODUCTION
Cystic fibrosis (CF) is a chronic, progressive disease that results from
a genetic defect in the cystic fibrosis transmembrane conductance
regulator (CFTR). Loss of CFTR function alters salt and water
transport across epithelial surfaces in the airways of patients with CF
resulting in respiratory disease characterized by thick mucus, re￾current infection, chronic inflammation, and airway obstruction.
Over time, these constellation of symptoms leads to irreversible lung
damage. Approximately 2000 mutations of the CFTR gene have been
reported and are classified into six classes based on their known
functional consequences.1 Traditionally CF therapy was focused on
intervening on the downstream effects of CFTR dysfunction. With
the development of CFTR modulators, this allowed, for the first time,
a direct restoration of CFTR function in patients with CF.
Currently approved CFTR modulators fall into two different
drug classes, potentiators (ivacaftor) and correctors (lumacaftor,
tezacaftor, and elexacaftor). Over the last 5 years, various combi￾nations of these agents have been approved for use in select pa￾tients. In clinical studies, these therapies demonstrated an
improvement in lung function and decreased incidence of exacer￾bation.2–7 With the approval of the triple combination of elexacaftor/
tezacaftor/ivacaftor in October 2019, targeted therapy is now
available for nearly 90% of CF patients. CFTR modulators have
revolutionized the care of CF patients, with most patients having a
therapy to target the underlying cause, with hopes of slowing disease
progression. In the age of highly effective modulator therapy, nearly
all patients are encouraged to initiate therapy and the hope that this
therapy brings is palpable in the CF patient population. Adverse
reactions to this new breakthrough therapy is understandably de￾vastating to our patients.
Safety data for the CFTR modulators show that therapy is well‐
tolerated. Rash has been documented as an adverse reaction in less
than 5% of cases in clinical trials for ivacaftor, lumacaftor/ivacaftor,
and tezacaftor/ivacaftor.8 The Phase 3 clinical studies for elex￾acaftor/tezacaftor/ivacaftor reported an incidence of rash ranging
from 4% to 10.9%, requiring discontinuation in one patient, and
appeared to be more common in female patients and in those who
use hormonal contraception.6,7 The severity of a skin reaction could
hinder the ability for a patient to continue modulator therapy and
may require the use of adjunct medications to treat the reaction or
drug desensitization.
Drug desensitization can be an effective procedure that can be
trialed with trained personnel to induce temporary drug tolerance. It
was originally described for immediate‐type reactions mediated my
immunoglobulin E (IgE) antibodies with a success rate near 100%.
Slow oral desensitization to various antimicrobials and anti￾retrovirals has also been described for delayed‐type hypersensitivity
reactions with lower success rates.9 CF patients require antibiotics
throughout their lifetime for the management of pulmonary ex￾acerbations and is not uncommon for drug allergies to occur within
this population. Desensitization for delayed type reactions to anti￾biotics in CF patients have been successful in the literature, however,
there is limited data regarding desensitization with another critical
component of CF therapy, the CFTR modulators. Herein, we present
two cases of patients with prior history of drug rash with tezacaftor/
ivacaftor who had undergone desensitization, and had recurrence of
their rash upon transition to elexacaftor/tezacaftor/ivacaftor and our
management of those adverse reactions.
1.1 | Case 1
This is a 20 year‐old female with CF (Phe508del/Phe508del), mild
lung disease (forced expiratory volume in 1 second [FEV1] 79%
predicted), and a prior history of morbiliform drug eruption to iva￾caftor. Her home medication regimen consisted of sodium chloride
7% inhalation solution, dornase alfa, albuterol, budesonide/for￾moterol, tobramycin inhalation solution, pancrelipase, vitamins,
montelukast, levocetirizine, and hormonal contraception. She was
transitioned to elexacaftor/tezacaftor/ivacaftor per package labeling
from tezacaftor/ivacaftor directly without interruption in therapy.
Her previous reaction included the development of a mildly pruritic,
nonconfluent, red, papular rash, 7 days after initiation of lumacaftor/
ivacaftor. Lumacaftor/ivacaftor therapy was discontinued after two
attempts of rechallenging, at full and half dose. With each re￾challenge, a similar rash appeared 3–7 days after drug therapy was
resumed. She was initiated on tezacaftor/ivacaftor after Food and
Drug Administration (FDA) approval and developed a rash consistent
with her previous drug rashes. She successfully completed a 10‐day
desensitization protocol to ivacaftor and was able to transition to
tezacaftor/ivacaftor combination therapy without report of any ad￾verse reaction.10 Upon initiation of elexacaftor/tezacaftor/ivacaftor,
she developed a diffuse, red rash with small papules that began on
her trunk and spread outwards, 7 days after initiation. Treatment
was discontinued and due to severity of rash, patient was seen at a
local urgent treatment center for management. The patient received
a methylprednisolone injection and started on a prednisone taper
over a week. In addition, a prescription for triamcinolone topical
cream was provided. The rash persisted for approximately 2 weeks
following the interventions listed.
The rash that developed after the initiation of elexacaftor/te￾zacaftor/ivacaftor was similar to the rash that developed following
lumacaftor/ivacaftor and tezacaftor/ivacaftor. At no time during
these drug introductions was there fever, signs of mucous membrane
involvement, eosinophilia, or abnormal transaminases. Based on the
clinical history of self‐limited maculopapular rash developing
3–8 days after drug initiation, the diagnosis of morbiliform drug
eruption was made. While off medication therapy, the patient ex￾perienced a decline in lung function with a fall in FEV1 to 70%
predicted from her baseline of 80% and developed a sinus infection.
She required treatment with a course of oral steroids and
sulfamethoxazole‐trimethoprim. Since a response was seen pre￾viously through desensitization and due to the decline in lung func￾tion while off CFTR modulator therapy, a decision was made to
repeat desensitization with elexacaftor/tezacaftor/ivacaftor.
A desensitization protocol developed for elexacaftor/tezacaftor/
ivacaftor is outlined in Table 1. Aliquot dilutions of 1:1000 and 1:200
were prepared by using crushed tablets of elexacaftor/tezacaftor/
ivacaftor in a glass mortar mixed with cornstarch. Additional doses of
ivacaftor were weighed from a crushed tablet. Doses were weighed
on a Mettler Toledo Precision Balance with readability of 1 mg.
Doses were transferred to prescription vials with appropriate la￾beling. The patient was instructed to mix each dose in soft, fat
containing food immediately before administration. Doses were es￾calated over the course of 13 days until a target dose of elexacaftor
200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and
ivacaftor 150 mg in the evening. She developed a rash on her legs,
11 days after therapy initiation, which disappeared on the following
day. On Day 13, the rash reappeared on the abdomen, legs, and face
that was mildly pruritic. She remained on oral contraception
throughout the desensitization. Elexacaftor/tezacaftor/ivacaftor was
discontinued and the rash resolved. While off therapy, spirometry
continued to drop and her FEV1 eventually fell to 58% predicted.
A second desensitization protocol developed for elexacaftor/
tezacaftor/ivacaftor is outlined in Table 2. Aliquot dilutions of 1:1000
and 1:200 were prepared in the same manner as previously de￾scribed. Doses were again transferred to prescription vials with ap￾propriate labeling and the patient received appropriate counseling.
Doses were escalated over the course of 17 days until a target dose
2 | LEONHARDT ET AL.
TABLE 1 Elexacaftor/tezacaftor/ivacaftor desensitization plan
Day 1 2 3 4 5
Dose# 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Dose 5 mcg 10 mcg 15 mcg 20 mcg 25 mcg 30 mcg 35 mcg 40 mcg 45 mcg 50 mcg 75 mcg 100 mcg 150 mcg 200 mcg 400 mcg
Day 6 7 8 9 10
Dose# 16 17 18 19 20 21 22 23 24 25 26 27 28
Dose 600 mcg 800 mcg 1 mg 2 mg 4 mg 8 mg 16 mg 24 mg 32 mg 50 mg 75 mg 100 mg Ivacaftor 75 mg
Day 11 12 13
Dose# 29 30 31 32 33 34
Dose 125 mg Ivacaftor 93.75 mg 150 mg Ivacaftor 112.5 mg 200 mg Ivacaftor 150 mg
Note: Doses were provided at an 8‐h interval of 0700, 1500, and 2300 on Days 1 through 8. Starting on Day 9, doses were provided at 0700 and 1900.
TABLE 2 Elexacaftor/tezacaftor/ivacaftor second desensitization plan
Day 1 2 3 4 5
Dose# 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Dose 5 mcg 10 mcg 20 mcg 30mcg 40 mcg 50 mcg 75 mcg 100 mcg 150 mcg 200 mcg 400 mcg 600 mcg 800 mcg 1 mg 2 mg
Day 6 7 8 9 10
Dose# 16 17 18 19 20 21 22 23 24 25
Dose 4 mg 8 mg 12 mg 20 mg 30 mg Ivacaftor 22.5 mg 40 mg Ivacaftor 30 mg 50 mg Ivacaftor 37.5 mg
Day 11 12 13 14 15
Dose# 26 27 28 29 30 31 32 33 34 35
Dose 65 mg Ivacaftor 48.75 mg 80 mg Ivacaftor 60 mg 100 mg Ivacaftor 75 mg 125 mg Ivacaftor 93.75 mg 150 mg Ivacaftor 112.5 mg
Day 16 17
Dose# 36 37 38 39
Dose 175 mg Ivacaftor 131.25 mg 200 mg Ivacaftor 150 mg
Note: Doses were provided at an 8‐h interval of 0700, 1500, and 2300 on Days 1 through 5. Starting on Day 6, doses were provided at 0700 and 1900.
LEONHARDT ET AL
.
|
3
of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the
morning and ivacaftor 150 mg in the evening. Oral contraception was
discontinued 1 month before the second desensitization attempt and
restarted 1 month after the completion of the protocol. We elected
to pursue the 1 month washout period due to the higher incidence of
rash reported in the literature in women who are taking hormonal
contraception. She has currently been on therapy for 8 months
without report of any adverse reaction and with a new baseline best
FEV1 of 93% predicted.
1.2
| Case 2
A 47 year
‐old female with CF (Phe508del/3849+10kbC
‐T), moderate
lung disease (FEV1 53% predicted), and a drug therapy regimen of
sodium chloride 7% inhalation solution, dornase alfa, fluticasone
propionate/salmeterol, and albuterol was initiated on tezacaftor/
ivacaftor per package labeling. She developed red, pruritic spots
9 days after initiation of tezacaftor/ivacaftor with attempts to treat
through the reaction with prednisone and loratadine. The rash con￾tinued to worsen over the next 3 days and spread throughout the
body ultimately requiring discontinuation of therapy due to intoler￾able pruritus. The pruritus persisted for 5 days and the rash persisted
for 1 month following medication discontinuation. At no time during
this drug reaction were other symptoms noted and the reaction was
limited to the skin.
While off medication therapy, the patient experienced a decline
in lung function to an FEV1 of less than 30% predicted and devel￾oped bronchial pneumonia requiring inpatient hospitalization with
2 weeks of intravenous (IV) antibiotics for exacerbation manage￾ment. This was the first exacerbation requiring IV antibiotics the
patient had experienced in 7 years. After management of this ex￾acerbation, her FEV1 recovered to 46% predicted, but was still be￾low her baseline that was reported while on a CFTR modulator. Due
to the significant decline in lung function, the unsuccessful attempt
to treat through the reaction, and since the rash was self
‐limited to
the skin without any other systemic involvement, a decision was
made to attempt desensitization.
A desensitization protocol for tezacaftor/ivacaftor is out￾lined in Table 3. After several months off therapy, an in￾dependent pharmacy agreed to participate in the desensitization
and compounding of the medication dilutions. The protocol de￾veloped was based on a protocol previously reported in the lit￾erature for ivacaftor.10 Dilutions of tezacaftor/ivacaftor were
prepared using crushed tablets mixed with a fixed oil, which
consisted of almond oil with silica gel. The patient was instructed
to take each dose with whole milk and high fat food. Both iva￾caftor and tezacaftor doses were gradually escalated over
10 days to reach a target dose of tezacaftor 100 mg/ivacaftor
150 mg. The patient was desensitized to both medication com￾ponents due to uncertainty of which medication was causing the
reaction. She remained on therapy for 4 months without any
further report of adverse reactions to tezacaftor/ivacaftor.
TABLE 3 Tezacaftor/ivacaftor desensitization plan
Day 1 2 3 4 5
Dose# 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Ivacaftor Dose 5 mcg 10 mcg 15 mcg 20 mcg 25 mcg 30 mcg 35 mcg 40 mcg 45 mcg 50 mcg 75 mcg 100 mcg 150 mcg 200 mcg 400 mcg
Tezacaftor Dose 3.3 mcg 6.7 mcg 10 mcg 13.3 mcg 16.66 mcg 20 mcg 25 mcg 26.6 mcg 30 mcg 33.3 mcg 50 mcg 66.66 mcg 100 mcg 133.3 mcg 266.6 mcg
Day 6 7 8 9 10
Dose# 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Ivacaftor Dose 600 mcg 800 mcg 1000 mcg 2 mg 4 mg 8 mg 16 mg 24 mg 32 mg 50 mg 75 mg 100 mg 125 mg – 150 mg
Tezacaftor Dose 400 mcg 433.3 mcg 666.6 mcg 1.33 mg 2.66 mg 5.33 mg 10.66 mg 16 mg 21.3 mg 33.3 mg 50 mg – 83.3 mg – –
Note: Four different oil suspensions were compounded: one tezacaftor/ivacaftor tablet QS to 600 ml with fixed oil, one tezacaftor/ivacaftor tablet QS to 30 ml with fixed oil, three tezacaftor/ivacaftor tablets
QS to 30 ml with fixed oil, one ivacaftor tablet QS to 10 ml with fixed oil.
4
| LEONHARDT ET AL
.
She was transitioned without interruption to elexacaftor/teza￾caftor/ivacaftor after FDA approval per package labeling. Upon in￾itiation of elexacaftor/tezacaftor/ivacaftor, she developed a rash
similar to her previous drug reaction but with less pruritus and
better tolerability. The rash developed 9 days after initiation and was
described as red, diffuse spots located everywhere except the face.
The reaction was treated with a course of prednisone and fex￾ofenadine. The rash peaked approximately 10 days after it appeared
and then began to fade. A second rash developed 4 days after
completion of the prednisone taper and 1 day after the last dose of
fexofenadine. The second rash was characterized by small, faint
spots, mild, with minimal pruritus, and was localized only to the
stomach, chest, neck, and back. This reaction was treated by a longer
prednisone taper of 5 weeks with rash clearance approximately
1 month after finishing steroid therapy. She has currently been on
elexacaftor/tezacaftor/ivacaftor for 8 months with no further ad￾verse reactions reported. Patient has reported an improvement in
sinus congestion, endurance, and quality of life.
2 | DISCUSSION
The loss of tolerance when transitioning our patients to elexacaftor/
tezacaftor/ivacaftor from an alternative modulator therapy was not
expected since both patients previously went through a successful
desensitization protocol and no pause occurred in therapy during the
drug transition. It was originally hypothesized in Case 1 that iva￾caftor was the contributing medication causing rash since she de￾veloped a rash to both lumacaftor/ivacaftor and tezacaftor/ivacaftor.
Tolerance was developed through desensitization with ivacaftor and
she was able to tolerate tezacaftor/ivacaftor with no addition con￾cerns for adverse drug reactions (ADRs). If ivacaftor was the con￾tributing medication, tolerance should have continued when
transitioning to elexacaftor/tezacaftor/ivacaftor. In Case 2, both
components of tezacaftor/ivacaftor were escalated in a stepwise
fashion since it was unknown, which component was causing the
reaction. Once again tolerance was successfully developed through
desensitization but when transitioning to elexacaftor/tezacaftor/
ivacaftor, a rash appeared. Elexacaftor appears to represent either a
very high rate of co‐occurring drug allergy in patients with hy￾persensitivity to tezacaftor/ivacaftor or through other mechanisms
resulting in loss of tolerance to other modulators upon its
introduction.
A potential mechanism for these types of reactions is described
by Roehmal et al., who reported a T‐cell mediated non‐immediate
allergy in a 20 year‐old CF patient homozygous for the Phe508del
mutation following initiation of lumacaftor/ivacaftor. Drug re￾sponsive T‐cell clones were created, which showed 33 of the 96
lumacaftor lines were drug‐responsive but clones generated from
ivacaftor and tezacaftor were not activated by either drug. Inter￾estingly the T‐cell clones did not demonstrate cross‐reactivity be￾tween lumacaftor and tezacaftor. All lumacaftor‐responsive clones
were CD4+ and their data revealed that lumacaftor binds directly to
HLA Class II molecules to activate T‐cell clones, identifying luma￾caftor as the allergy‐causing compound in this patient. These meth￾odologies may provide significant insight into the underlying
mechanisms and patterns of cross‐reactivity we see in patients
moving forward.11
ADRs are commonly classified as either predictable reactions
(Type A) or unpredictable reactions (Type B). Although infrequent,
Type B reactions are immunologic by nature and can be further
classified into Type I through Type IV reactions according to the Gell
and Coombs’ classification system. Being the most common, Type I
reactions are immediate‐type reactions mediated by IgE antibodies,
while Type III reactions are defined as immune‐complex reactions,
and Type IV reactions are delayed‐type hypersensitivity reactions
mediated by T‐cells.12 Serum sickness is a clinical manifestation of a
Type III reaction, which is characterized by rash, fever, and ar￾thralgia, presenting 5–10 days after drug exposure. While Type IV
reactions can range in severity to include relatively benign reactions
such as morbiliform drug eruption to severe reactions such as
Stevens‐Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)
and Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS). Morbiliform drug eruption typically involves a maculo￾papular rash without evidence of mucus membrane involvement,
fever, or other organ system involvement.
Management of drug allergies typically involves discontinuation
of the medication, avoidance of the medication in the future, and
selection of an alternative agent. When no alternatives exist and
drug therapy is essential, treating through the reaction depending on
severity or drug desensitization may be considered. Brennan et al.,
recently reported a case of serum sickness‐like reaction following
initiation of elexacaftor/tezacaftor/ivacaftor therapy. The 12‐year
old patient required hospitalization, discontinuation of elexacaftor/
tezacaftor/ivacaftor, and treatment with IV fluids and a prednisone
taper which resulted in symptom resolution.13 Similarly, Type IV
reactions may be managed by discontinuing therapy and treating the
reaction. At this time, however, there is no consensus on pharma￾cologic treatment of more severe cases, like SJS/TEN, to halt pro￾gression and reduce mortality. Lehloyna et al., described six patients
who were re‐challenged to antituberculous drugs after a history of
SJS/TEN or DRESS to one of the medications in the standard four‐
drug regimen. At the appearance of a clinically detectable re￾challenge reaction, a single early infusion of methylprednisolone was
given to each patient which resulted in symptom resolution and each
patient was able to tolerate the standard four‐drug regimen for
treatment of tuberculosis to completion.14 However, in specific cases
if treating the reaction is unsuccessful, drug desensitization can be an
effective procedure.
From our experience, CF patients have waited with great an￾ticipation for a “breakthrough” drug that targets the underlying
cause of their disease and when discontinuation due to an intolerable
side effect occurs, these patients suffer from mental anguish and
frustration. Beyond the emotional impact of being off therapy, pa￾tients can have a decline in lung function requiring antibiotics for a
pulmonary exacerbation. The patients in our report both subjectively
LEONHARDT ET AL. | 5
reported feeling worse and had objectively worsening lung function
while off CFTR modulator therapy. Since both patients developed
rash to elexacaftor/tezacaftor/ivacaftor when transitioning from te￾zacaftor/ivacaftor per package labeling, we anticipate additional
ADRs in the future in CF patients who are started on elexacaftor/
tezacaftor/ivacaftor with a previous skin reaction to one of the other
modulators. Strategies should be developed to manage these pa￾tients to prevent the development of any ADR including rash and to
allow for tolerability of treatment. To develop strategies, a risk vs
benefit discussion should be held between the patient and the mul￾tidisciplinary team. It is important to create a collaboration between
the CF team, allergy/immunology, and pharmacy to develop an ap￾propriate treatment plan whether that includes treating through the
reaction or developing a desensitization protocol.
Both cases included in our report, highlight the successful
management of ADRs to CFTR modulator therapy. In Case 1, we
elected to proceed with desensitization due to the previous success
of the procedure for a similar rash and after weighing the risks of
rash recurrence and benefits of long‐term use of elexacaftor/teza￾caftor/ivacaftor. The patient tolerated desensitization to elexacaftor/
tezacaftor/ivacaftor after the second attempt without recurrence of
her rash. Our experience has showed that holding oral hormonal
contraception and using a slower dose escalation approach during
repeat desensitization can be successful. In Case 2, the attempt to
treat through the drug reaction with tezacaftor/ivacaftor was un￾successful therefore it was ultimately decided to proceed with de￾sensitization due to previous success in the literature. When this
patient was transitioned to elexacaftor/tezacaftor/ivacaftor from
tezacaftor/ivacaftor, a rash appeared that was less severe than the
first reaction. The reaction to elexacaftor/tezacaftor/ivacaftor was
able to successfully be treated with adjunct medications such as
antihistamines and a prolonged corticosteroid course. These cases
highlight that a combination of desensitization and treating through
the reaction can be successful and that each individual CF patient
may require a unique care plan developed by the multidisciplinary
team to manage ADRs to CFTR modulators.
3 | CONCLUSION
CFTR modulators are an essential component in the treatment of CF.
Patients have been awaiting the availability of these new compounds
with the hope of long‐term improvement and to decrease the in￾cidence of pulmonary exacerbations. We anticipate additional CF
patients will experience ADRs on elexacaftor/tezacaftor/ivacaftor if
they have had a prior skin reaction to another CFTR modulator.
Therefore, it is important to develop strategies to mitigate ADRs
including delayed type hypersensitivity reactions. Strategies will re￾quire a multidisciplinary effort and consideration of the potential
risks of precipitating recurrent ADRs versus the potential long‐term
benefit of modulator therapy. We hope these cases can be used as a
reference to show potential strategies for managing drug allergy to
CFTR modulators.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
AUTHOR CONTRIBUTIONS
Kelsey Leonhardt: conceptualization (supporting); methodology
(supporting); project administration (supporting); resources (equal);
writing original draft (lead); writing review and editing (equal). Eli￾zabeth B Autry: conceptualization (lead); methodology (lead); project
administration (lead); resources (equal); supervision (lead); writing
original draft (supporting); writing review and editing (lead). Robert J
Kuhn: conceptualization (lead); methodology (lead); project admin￾istration (lead); resources (equal); supervision (lead); writing original
draft (supporting); writing review and editing (lead).
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were gen￾erated or analyzed during the current study.
ORCID
Kelsey Leonhardt https://orcid.org/0000-0002-6652-5278
Elizabeth B. Autry https://orcid.org/0000-0002-6022-460X
Robert J. Kuhn https://orcid.org/0000-0001-8267-9683
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How to cite this Ivacaftor article: Leonhardt K, Autry EB, Kuhn RJ,
Wurth MA. CFTR modulator drug desensitization: preserving
the hope of long term improvement. Pediatric Pulmonology.
2021;1‐7. https://doi.org/10.1002/ppul.25437
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