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Cardiac function in children and young adults treated with MEK inhibitors: a retrospective cohort study of routinely collected health data

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Cardiac function in children and young adults treated with MEK inhibitors: a retrospective cohort study of routinely collected health data

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Cardiac Function in Children and Young Adults Treated with MEK Inhibitors:
A Retrospective Cohort Study of Routinely Collected Health Data.

Nathan John Robison, M.D

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
In Clinical Biomedical and Translational Investigations

December 2021

ii
Dedication

To Ada

“all I have in this world
is more than a king could ever wish for…”

Thanks for putting up with my side-hustle.

And to Mateo and Isabel

“for the leaves were full of children,
Hidden excitedly, containing laughter…”

iii

Acknowledgements
The following individuals contributed as co-authors to the manuscript, and were involved in
concept inception, data collection and analysis, and drafting the manuscript: Jennifer A. Su,
Melody J. Fang, Jemily Malvar, Jondavid Menteer.
MJF was a participant in the University of Southern California/CHLA Summer Oncology
Research Fellowship (SORF) Program, which is directed by Dr. Anat Erdreich-Epstein.
The authors would like to thank Ashley S. Margol, Tom Belle Davidson, Anat Erdreich-
Epstein, Kasey Rangan, Kaaren Waters, and Kimberly Bira for their intellectual contributions and
assistance with data collection.
The authors would also like to extend a special thanks Cecilia Patino-Sutton, Todd Alonzo,
Yueh-Yun Chi, and Shahab Asgharzadeh for their critical review of the manuscript drafts.

iv
Table of Contents

Dedication ....................................................................................................................................... ii
Acknowledgements ........................................................................................................................ iii
List of Tables .................................................................................................................................. v
List of Figures ................................................................................................................................ vi
Abbreviations ................................................................................................................................ vii
Abstract ........................................................................................................................................ viii
Introduction ..................................................................................................................................... 1
Methods........................................................................................................................................... 2
Results ............................................................................................................................................. 4
Table 1. Patient characteristics ................................................................................................... 6
Figure 1. ...................................................................................................................................... 7
Figure 2. ...................................................................................................................................... 8
Discussion ....................................................................................................................................... 9
Conflicts of interest ....................................................................................................................... 11
References ..................................................................................................................................... 12
Appendix: Supplementary Tables ................................................................................................. 15

v
List of Tables

Table 1: Patient characteristics
vi
List of Figures
Figure 1: Case examples of patients with borderline or decreased cardiac function.

Figure 2: Freedom from borderline and overt cardiac dysfunction.
vii
Abbreviations
BRAFi BRAF inhibitor
CHLA Children’s Hospital Los Angeles
EF Ejection fraction
FS Fractional shortening
LV Left ventricular
MEKi MEK inhibitors
NF1 Neurofibromatosis type 1

viii
Abstract
Introduction: MEK inhibitors (MEKi), which have shown efficacy among children with several
pediatric tumor types, have been associated with the incidence of acute cardiac dysfunction in
adults. Cardiac consequences of MEK inhibitors among children are unknown.
Methods: We performed a retrospective cohort study evaluating cardiac function by
echocardiography (echo) in children and young adults <21 years receiving MEKi between October
2013 and May 2018 at a single pediatric center (Children’s Hospital Los Angeles). Demographic,
disease, and treatment data were extracted from the medical record. Blinded assessment of left
ventricular function by fractional shortening (FS) and ejection fraction (EF) was performed on all
available echocardiograms performed before, during, and following therapy, as well as after re-
initiation of therapy.
Results: Twenty-six patients underwent MEKi therapy with echo follow-up during the study
period. Twenty-four of these had complete pre- and post-therapy echocardiography data. Median
follow-up was 12 months. Borderline EF (EF 53-57.9%) occurred in 12 (50%) patients; and 3
(12.5%) progressed to abnormal EF (EF <53%). Cardiac dysfunction, when it occurred, was mild
in 100% of observations (lowest documented EF was 45%, and lowest FS was 24.4%). EF
abnormalities typically fluctuated during therapy, resolved off therapy, and recurred with MEKi
re-initiation. No clinical or demographic differences were detected between those who maintained
normal cardiac function and those who developed borderline or overt cardiac dysfunction.
Symptomatic heart failure did not occur.
Conclusions: In this cohort of children and young adults treated at a large metropolitan quaternary
pediatric medical center in Southern California, MEKi use was associated with a high (50%)
ix
incidence of borderline or mildly decreased left ventricular function. There was no evidence of
permanent cardiac dysfunction. Further evaluation in larger prospective trials is needed
1
Introduction
The RAS-RAF-MEK-ERK pathway is one of the most commonly activated signal transduction
pathways in cancer; and is known to be a primary driver of pediatric low grade gliomas, both
sporadic and neurofibromatosis type 1 (NF1)-associated, as well as of other NF1-associated
tumors.
1,2
MEK inhibitors (MEKi), a relatively new class of small molecule agents, have
demonstrated efficacy in both pediatric low-grade gliomas and NF1-associated plexiform
neurofibromas.
3–6
Recently, MEKi selumetinib became the first drug approved in the United
States for treatment of NF1-associated plexiform neurofibromas in children.
7

MEKi are associated with increased number of cardiovascular toxicities in adult patients,
including arterial hypertension, pulmonary embolism, cardiomyopathy, and decreased ejection
fraction.
8–10
Despite the increasingly wide-spread clinical use of MEKi in children, the incidence
of cardiac abnormalities in children and adolescents treated with MEKi has, to our knowledge, not
yet been described.
The primary objective of this single institution retrospective cohort study was to describe the
incidence of cardiac dysfunction in children and young adults less than 21 years old treated with
MEKi. Exploratory objectives included assessment of association of cardiac changes with age,
diagnosis, and clinical features. We also assessed the reversibility and recovery of cardiac function
after MEKi discontinuation in children with MEKi-associated cardiac dysfunction.

2
Methods
The Children’s Hospital Los Angeles (CHLA) Institutional Review Board approved this
retrospective cohort study. Patients who were followed at CHLA, treated with MEKi before their
twenty-first birthday, and followed with serial echocardiography (echo) were eligible. We
included all patients with at least 2 echocardiograms performed at CHLA before May 1, 2018 and
available for review, at least one of which was obtained after initiation of MEKi therapy. Patients
without echocardiograms, or with echocardiograms obtained at outside institutions and not
available for direct imaging review, were excluded. Clinical data, including demographic
characteristics, diagnosis, age at MEKi treatment, duration of treatment, MEKi drug and dose,
prior tumor-directed treatment (including prior radiation or anthracycline therapy), and
concomitant medications, was extracted by the investigators (MJF and NJR) directly from patients’
electronic medical records and entered into a study database. Cardiac functional measurements
were recorded as described below.
Echocardiography. Transthoracic echocardiographic evaluation was performed using a
cardiac ultrasound imaging system (Philips Medical Systems, Andover, MA). All studies were
clinically indicated and by protocol included measurement of left ventricular (LV) dimensions via
M-mode measurements, systolic shortening, ejection fraction (EF), and diastolic parameters. M-
mode measurements included LV end-diastolic and end-systolic dimensions (LVIDd and LVIDs),
used for calculation of fractional shortening (FS).
Two cardiologists with expertise in echocardiographic interpretation (JDM and JAS) jointly
interpreted the studies using the original DICOM images of all studies and calculated the FS and
EF using Philips IntelliSpace software. The cardiologists were blinded to each patient’s identity
and clinical status during the image analysis. FS ≥ 29% was considered normal, FS < 27% was
3
considered abnormal, and FS ≥ 27 and < 29% was considered “borderline.” Systolic function was
assessed by EF as calculated via the Biplane Simpson’s Method. EF ≥ 58% was considered
normal, EF < 53% was considered overtly abnormal, and EF ≥ 53 and < 58% was considered
“borderline.”
11
Left ventricular measurements were considered normal if they fell within two
standard deviations (SD) of their mean for body surface area (Boston Z-score within ±2). Diastolic
measurements were inconsistently recorded, mostly including mitral inflow E and A wave peaks;
therefore we did not analyze this data. Borderline and/or cardiac dysfunction status was assessed
using all available imaging after the patient initiated MEKi therapy.
Statistical analysis. In a planned exploratory analysis, T-tests, χ
2
, or Fisher’s exact tests were
utilized to compare the distribution of demographics across patients with and without borderline
or cardiac dysfunction. Time to borderline EF and/or FS was defined as the minimum time between
the start of MEKi treatment and date of subsequent ECHO resulting in borderline EF and/or FS.
Patients with normal cardiac function throughout follow up were censored at the last available
imaging. Kaplan-Meier survival curves were provided for each borderline and abnormal EF and/or
FS status with the 2-year survival estimates. The survival estimates included 95% point wide
confidence intervals which were calculated using the log-log transformation and Greenwood’s
formula. All analyses utilized two-sided tests, with significance level set at p<0.05 and were
completed using Stata Statistical Software: Release 14 (StataCorp LP, College Station, TX).

4
Results
Twenty-six children and young adults who initiated MEKi treatment at age < 21 years in our
institution between October 2013 and May 2018 were identified. Two patients did not have echos
available for review and were excluded, leaving 24 subjects for inclusion in this study. The median
age at first MEKi exposure was 10.1+/-4.86 years (range 3-20 years). Patient characteristics are
shown in Table 1. Six patients were treated on dose escalation studies at doses less than the current
recommended pediatric phase II dose; the remaining 18 patients were treated at current standard
pediatric starting doses. Duration of primary treatment course (defined as time from MEKi
initiation to last dose, time to treatment interruption if drug held for > 1 month, or time to last
follow-up if still on drug) was 0.9 to 24.4 months (mean 13, median 12 months). Seven patients
underwent a second course of MEKi; this includes patients who resumed therapy after treatment
interruption > 1 month. M follow-up, defined as time from MEKi initiation to last echo, was 15.4
months (SD 13.2, range 0.8 to 52.4 months). No patients in this cohort received craniospinal
radiation, thoracic radiation, or radiation with scatter to the thorax. One patient with juvenile
xanthogranuloma and a previous history of acute lymphoblastic leukemia had received previous
anthracycline therapy as per CCG-1961 five to six years prior to MEKi initiation; this patient’s
cumulative doxorubicin isotoxic dose was 175mg/m
2
, and the cardiac function was normal at the
time of MEKi initiation.
Borderline EF, but not FS, was seen in 6 patients (25%) on baseline echo prior to therapy
initiation. During treatment, borderline EF was seen in 12 patients (50%) and borderline FS in 6
patients (25%) on at least one echo. Three patients progressed to both abnormal EF and FS, none
of whom had borderline findings at pre-treatment baseline. Abnormal cardiac function resolved
without dose interruption or reduction in 2 of these patients, one of whom had recurrence of
5
dysfunction during a subsequent course of therapy and received ACE inhibition (lisinopril) (Fig.
1a). Follow-up echo after initial development of abnormal cardiac function was not available for
the third patient. MEKi therapy was interrupted in one patient for borderline cardiac dysfunction
that subsequently resolved; this patient again developed borderline cardiac dysfunction upon re-
initiation of therapy (Fig. 1b). The lowest measured EF in any patient was 45%, and lowest FS
was 24.4%. Symptomatic heart failure did not occur, and no patient required inotropic therapy or
hospital admission for cardiac failure.
Kaplan-Meier estimates of freedom from borderline and abnormal cardiac function are shown
in Figure 2. No clinical or demographic differences were detected between those who maintained
normal cardiac function, and those who developed borderline or overt cardiac dysfunction in
response to MEKi (Supplementary Tables). Notably, the one patient with prior anthracycline
exposure had a transiently borderline ejection fraction but did not experience overt cardiac
dysfunction during 12 months of MEKi therapy.

6
TABLE 1. Patient characteristics

Variable Median (Range)
Age at first MEK inhibitor treatment (years) 10.1 (1.7, 20.5)
Duration of follow up (months) 12.0 (0.9, 52.4)
Number (%)
n=24
Female 12 (50)
Race/Ethnicity
White/Non-Hispanic 12 (50)
Hispanic 9 (38)
Other 3 (13)
Diagnosis
Low-grade Glioma 16 (67)
High-grade glioma 1 (4)
Other brain tumors 3 (13)
Plexiform neurofibroma 3 (13)
Juvenile xanthogranuloma 1 (4)
Neurofibromatosis type 1 4 (17)
MEK inhibitor received
Binimetinib 8 (33)
Selumetinib 7 (29)
Trametinib 9 (38)
Concurrent BRAF inhibitor
None 19 (79)
Dabrafenib 3 (13)
Vemurafenib 2 (8)

7

FIGURE 1. Case examples of patients with borderline or decreased cardiac function.
(A) A 19-year-old female with tectal glioma, undergoing treatment with a single agent MEK
inhibitor, experienced asymptomatic decrease in left ventricular function during the first 7
months of treatment. This resolved without dose interruption or modification. Decreased left
ventricular function reoccurred two and a half years later; lisinopril was prescribed. (B) A 12-
year-old male with BRAF V600E-mutated anaplastic astroblastoma, treated with dual agent
MEK and BRAF inhibitors, experienced asymptomatic decrease in left ventricular shortening
fraction after one month of therapy. MEKi treatment was interrupted and then resumed at the
same dose. BRAF inhibitor was continued without interruption.
Grey dotted and dashed lines represent lower limits of normal and lower limits of borderline
values, respectively, for both EF and FS.
M, MEK inhibitor therapy. EF, left ventricular ejection fraction. FS, left ventricular fractional
shortening.
8

FIGURE 2. Freedom from borderline and overt cardiac dysfunction. Shown are Kaplan-Meier
estimates of the likelihood of developing (a) borderline cardiac dysfunction, defined as left
ventricular shortening fraction <29% or ejection fraction <58%, and (b) abnormal cardiac
function, defined as shortening fraction <27% or ejection fraction < 53%. Abnormal shortening
fraction and ejection fraction always occurred synchronously in this cohort, thus only a single
abnormal-free survival curve is shown in (b).
EF, left ventricular ejection fraction. MEKi, MEK inhibitor. SF, left ventricular shortening
fraction.

9
Discussion
MEKi treatment has been associated with a number of cardiac effects in adults, including
decreased LV EF, as well blood pressure elevation and decreased heart rate.
12–14
We note in our
pediatric population that MEKi is associated with a high (50%) incidence of borderline cardiac
dysfunction (by EF and/or FS). Importantly, these events were mild and self-resolved even with
continued therapy in most cases. Symptomatic heart failure was not seen, nor did patients suffer
morbidity of cardiac dysfunction.
The Ras-Raf-MEK-ERK pathway plays a key role in cell proliferation, differentiation,
survival, and death; its specific role within the heart is complex, and perhaps not fully
understood.
15–17
There is evidence that the pathway plays a cytoprotective role within the heart,
including protecting cardiac myocytes from apoptotic death and oxidative stress, and maintaining
cardiac progenitor cells.
9,18–22
On the other hand, inhibition of the MEK-ERK axis has been shown
to be cardioprotective in pressure overload-induced cardiac hypertrophy in human cardiac tissue
samples and murine models.
16,23–25
How and whether these preclinical findings relate to the
changes in cardiac function shown in our study is unclear. Assuming a causal relationship, the
rapid recovery seen in affected subjects may argue against a cardiac progenitor cell-mediated
effect, and instead suggests a possible metabolic/energy depletion etiology.
Several patients in this cohort received dual therapy with a MEKi and a first-generation BRAF
inhibitor (BRAFi). Decreased toxicity with combined MEKi and BRAFi compared to
monotherapy with either drug alone has been described, putatively due to mutually cancelling
effects of pathway inhibition and paradoxical pathway activation in non-tumor cells by MEKi and
BRAFi, respectively.
12,26,27
While the sample size precludes an adequately powered comparison
between dual and single agent therapy in this cohort, it is noteworthy that borderline EF and FS
10
were seen in dual therapy patients. This is similar to findings in adult studies, and suggests that
dual therapy may not be protective against MEKi-induced cardiac effects.
10

The population included in this study was diverse, and reflects the ethnic and racial diversity
represented in patients treated at our institution. Similarly, the range of diagnoses, including
patients with and without brain tumors, and with and without NF1, reflects the diversity of children
likely to be treated with MEKi.
Our study has several important limitations. Although the experience reported is large for a
single pediatric center, the relatively small sample size precludes evaluation of rare events, or a
well-powered assessment of association between patient characteristics and cardiac risks.
Similarly, the relatively small sample size precludes adequate assessment of potential confounders
or effect modifiers, including prior therapy. An adequately powered prospective study is needed
to identify potential risk factors for MEKi-associated cardiac function. A minority of patients in
the cohort were treated at starting dose less than the standard or recommended phase 2 pediatric
doses, which could result in an underestimate of a dose-related cardiac effect. As a retrospective
study, we also are confined to existing clinically ordered echocardiographic data, which was often
limited in advanced heart function assessments in this population of patients without clinically
significant heart dysfunction. This would be better addressed in a prospective, protocolized study.
Perhaps most importantly, since MEKi have only recently been introduced into pediatric use and
long-term follow-up is not yet available, the study did not evaluate possible long-term or late-onset
cardiac effects of MEKi therapy in childhood.
It is perhaps unconventional to use both EF and FS as endpoints for systolic function analysis,
and to delineate a borderline function category for each. However, the authors felt that this
11
description of the data best illuminated the mild nature of the cardiac function changes seen in this
data set.
This study is unique because it describes specific cardiac effects of MEKi in children. We
have demonstrated that MEKi treatment is associated with varying degrees of left ventricular
dysfunction in children, seemingly comparable to that in older adults. This confirms the
importance of cardiac monitoring for children treated with MEKi, whether in a research or clinical
practice setting. Findings were reassuring, however, in that borderline or mildly decreased left
ventricular function in this cohort was not a harbinger of more serious or progressive acute cardiac
dysfunction, and in that no patient developed symptomatic or irreversible heart failure.
In conclusion, we report that minor cardiac dysfunction was common in young patients
receiving MEKi. Dose adjustment or treatment interruption was rarely required, and abnormalities
self-resolved without treatment interruption in many cases. Heart failure was not seen, and there
was no evidence of permanent cardiac systolic dysfunction. Overall, our findings are reassuring,
and preliminarily suggest that children with minor MEKi-associated cardiac dysfunction may be
able to safely continue MEKi therapy. However, prospective evaluation in larger cohorts with
long-term follow-up is needed.

Conflicts of interest
The authors have no conflicts of interest to disclose.

12
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The quotes in the dedication are from “Kiss your feet” by Martin Smith and Jonathan Thatcher,
and from “Burnt Norton” by T.S. Eliot.

15
Appendix: Supplementary Tables

Supplementary Table 1 Patient demographics: Borderline EF status (n = 24 patients)
Variable Borderline EF status p-value
No (n = 12) Yes (n = 12) Total (n = 24)
Age at first MEKi treatment (years)
1
8.09 (4.45) 12.08 (4.58) 10.08 (4.86) 0.041
2

Age at first MEKi treatment (years)
3
8.29 (1.7, 16.1) 11.94 (3.8, 20.5) 10.14 (1.7, 20.5) 0.043
4

Sex
5
Male 7 (58%) 5 (42%) 12 (50%) 0.684
6

Female 5 (42%) 7 (58%) 12 (50%)
Race/ethnicity
5
White/Non-Hispanic 4 (33%) 8 (67%) 12 (50%) 0.149
6

Hispanic 5 (42%) 4 (33%) 9 (38%)
Other 3 (25%) 0 (0%) 3 (13%)
Diagnosis
5
Low-grade Glioma 8 (67%) 8 (67%) 16 (67%) 0.385
6
High-grade glioma 0 (0%) 1 (8%) 1 (4%)
Juvenile xanthogranuloma 0 (0%) 1 (8%) 1 (4%)
Plexiform neurofibroma 3 (25%) 0 (0%) 3 (13%)
Other brain tumors 1 (8%) 2 (17%) 3 (13%)
NF1
5
No 9 (75%) 11 (92%) 20 (83%) 0.590
6

Yes 3 (25%) 1 (8%) 4 (17%)
Number of MEKi
courses
5

1 10 (83%) 7 (58%) 17 (71%) 0.371
6

2 2 (17%) 5 (42%) 7 (29%)
BRAFi drug received
5
None 11 (92%) 8 (67%) 19 (79%) 0.217
6

Dabrafenib 0 (0%) 3 (25%) 3 (13%)
Vemurafenib 1 (8%) 1 (8%) 2 (8%)
Maximum Echo follow up time (in months)
1
11.51 (9.43) 19.21 (15.63) 15.36 (13.23) 0.158
2

Maximum Echo follow up time (in months)
3
12.04 (0.9, 31.7) 14.13 (1.8, 52.4) 12.04 (0.9, 52.4) 0.299
4

Borderline EF status at
last ECHO
5

No 12 (100%) 8 (67%) 20 (83%)

Yes 0 (0%) 4 (33%) 4 (17%)

1: Arithmetic Mean (SD)
2: t-test
3: Median (Range)
4: Wilcoxon Rank Sum test
5: n (column percentage)
6: Fisher's exact test
Note:
Patients with borderline EF: 1, 4, 5, 6, 8, 10, 11, 12, 17, 19, 20, and 21
Patient with borderline EF at last ECHO: 4, 17, 19 and 20
- Patient 4 reached abnormal EF and FS at last ECHO without further follow up imaging
- Patient 8 reached EF borderline levels at last ECHO
- Patient 17 reached abnormal EF and FS on second MEKi therapy, and both EF and FS recovered by end of 3
rd
MEKi therapy
- Patient 19 reach abnormal EF and FS in first course of MEKi and recovered. But sustained additional cardiac dysfunction in
second course of MEKi, and this dysfunction went unresolved. The last ECHO showed cardiac dysfunction, by both criteria, in
last 2 ECHO imaging.
- Patient 20 reached borderline EF (but normal FS) at last ECHO without further follow up imaging
16

Supplementary Table 2 Patient demographics: Borderline FS status (n = 24 patients)
Variable Borderline FS status p-value
No (n = 18) Yes (n = 6) Total (n = 24)
Age at first MEKi treatment (years)
1
9.81 (4.94) 10.92 (4.97) 10.08 (4.86) 0.640
2

Age at first MEKi treatment (years)
3
10.14 (1.7, 20.5) 10.49 (4.8, 19.2) 10.14 (1.7, 20.5) 0.790
4

Sex
5
Male 9 (50%) 3 (50%) 12 (50%) 1.000
6

Female 9 (50%) 3 (50%) 12 (50%)
Race/ethnicity
5
White/Non-Hispanic 9 (50%) 3 (50%) 12 (50%) 1.000
6

Hispanic 7 (39%) 2 (33%) 9 (38%)
Other 2 (11%) 1 (17%) 3 (13%)
Diagnosis
5
Low-grade Glioma 13 (72%) 3 (50%) 16 (67%) 0.381
6

High-grade glioma 1 (6%) 0 (0%) 1 (4%)
Juvenile xanthogranuloma 1 (6%) 0 (0%) 1 (4%)
Plexiform neurofibroma 2 (11%) 1 (17%) 3 (13%)
Other brain tumors 1 (6%) 2 (33%) 3 (13%)
NF1
5
No 15 (83%) 5 (83%) 20 (83%) 1.000
6

Yes 3 (17%) 1 (17%) 4 (17%)
Number of MEKi courses
5
1 14 (78%) 3 (50%) 17 (71%) 0.307
6

2 4 (22%) 3 (50%) 7 (29%)
BRAFi drug received
5
None 15 (83%) 4 (67%) 19 (79%) 0.539
6

Dabrafenib 2 (11%) 1 (17%) 3 (13%)
Vemurafenib 1 (6%) 1 (17%) 2 (8%)
Maximum Echo follow up time (in months)
1
13.02 (9.66) 22.37 (20.22) 15.36 (13.23) 0.137
2

Maximum Echo follow up time (in months)
3
11.33 (0.9, 34.5) 16.33 (1.8, 52.4) 12.04 (0.9, 52.4) 0.317
4

Borderline FS at last ECHO
5
No 18 (100%) 3 (50%) 21 (88%)

Yes 0 (0%) 3 (50%) 3 (13%)

1: Arithmetic Mean (SD)
2: t-test
3: Median (Range)
4: Wilcoxon Rank Sum test
5: n (column percentage)
6: Fisher's exact test

Note:
Patient with borderline FS: 4, 5, 11, 17, 19, and 22
Patient with borderline FS at last ECHO: 4, 11, and 19
- Patient 4 reached abnormal EF and FS at last ECHO without further follow up imaging
- Patient 11 with borderline remained with borderline cardiac dysfunction
- Patient 17 reached abnormal EF and FS on second MEKi therapy, and both EF and FS recovered by end of 3
rd

MEKi therapy
- Patient 19 reach abnormal EF and FS in first course of MEKi and recovered. But sustained additional cardiac
dysfunction in second course of MEKi, and this dysfunction went unresolved. The last ECHO showed cardiac
dysfunction, by both criteria, in last 2 ECHO imaging.
17

Supplementary Table 3 Patient demographics: Borderline EF and FS status (n = 24 patients)
Variable Borderline EF and FS status p-value
No (n = 21) Yes (n = 3) Total (n = 24)
Age at first MEKi treatment (years)
1
9.80 (4.76) 12.06 (6.23) 10.08 (4.86) 0.464
2

Age at first MEKi treatment (years)
3
10.75 (1.7, 20.5) 9.21 (7.8, 19.2) 10.14 (1.7, 20.5) 0.827
4

Sex
5
Male 11 (52%) 1 (33%) 12 (50%) 1.000
6

Female 10 (48%) 2 (67%) 12 (50%)
Race/ethnicity
5
White/Non-Hispanic 11 (52%) 1 (33%) 12 (50%) 0.707
6

Hispanic 7 (33%) 2 (67%) 9 (38%)
Other 3 (14%) 0 (0%) 3 (13%)
Diagnosis
5
Low-grade Glioma 14 (67%) 2 (67%) 16 (67%) 0.723
6

High-grade glioma 1 (5%) 0 (0%) 1 (4%)
Juvenile xanthogranuloma 1 (5%) 0 (0%) 1 (4%)
Plexiform neurofibroma 3 (14%) 0 (0%) 3 (13%)
Other brain tumors 2 (10%) 1 (33%) 3 (13%)
NF1
5
No 17 (81%) 3 (100%) 20 (83%) 1.000
6

Yes 4 (19%) 0 (0%) 4 (17%)
Number of MEKi courses
5
1 16 (76%) 1 (33%) 17 (71%) 0.194
6

2 5 (24%) 2 (67%) 7 (29%)
BRAFi drug received
5
None 17 (81%) 2 (67%) 19 (79%) 0.268
6

Dabrafenib 3 (14%) 0 (0%) 3 (13%)
Vemurafenib 1 (5%) 1 (33%) 2 (8%)
Maximum Echo follow up time (in months)
1
12.81 (9.31) 33.25 (24.43) 15.36 (13.23) 0.009
2

Maximum Echo follow up time (in months)
3
11.66 (0.9, 34.5) 41.56 (5.7, 52.4) 12.04 (0.9, 52.4) 0.176
4

Borderline EF & FS status at
last ECHO
5

No 21 (100%) 1 (33%) 22 (92%)

Yes 0 (0%) 2 (67%) 2 (8%)

1: Arithmetic Mean (SD)
2: t-test
3: Median (Range)
4: Wilcoxon Rank Sum test
5: n (column percentage)
6: Fisher's exact test

Note:
Patients with borderline EF and FS: 4, 17, and 19
Patient with borderline EF and FS at last ECHO: 4 and 19
- Patient 4 reached abnormal EF and FS at last ECHO without further follow up imaging
- Patient 17 reached abnormal EF and FS on second MEKi therapy, and both EF and FS recovered by end of 3
rd

MEKi therapy
- Patient 19 reach abnormal EF and FS in first course of MEKi and recovered. But sustained additional cardiac
dysfunction in second course of MEKi, and this dysfunction went unresolved. The last ECHO showed cardiac
dysfunction, by both criteria, in last 2 ECHO imaging.

18

Supplementary Table 4 Patient demographics: Borderline EF or FS status (n = 24 patients)
Variable Borderline EF or FS status p-
value No (n = 11) Yes (n = 13) Total (n = 24)
Age at first MEKi treatment (years)
1
8.39 (4.54) 11.52 (4.83) 10.08 (4.86) 0.118
2

Age at first MEKi treatment (years)
3
8.80 (1.7, 16.1) 11.77 (3.8,
20.5)
10.14 (1.7,
20.5)
0.111
4

Sex
5
Male 6 (55%) 6 (46%) 12 (50%) 1.000
6

Female 5 (45%) 7 (54%) 12 (50%)
Race/ethnicity
5
White/Non-Hispanic 4 (36%) 8 (62%) 12 (50%) 0.447
6

Hispanic 5 (45%) 4 (31%) 9 (38%)
Other 2 (18%) 1 (8%) 3 (13%)
Diagnosis
5
Low-grade Glioma 8 (73%) 8 (62%) 16 (67%) 1.000
6

High-grade glioma 0 (0%) 1 (8%) 1 (4%)
Juvenile
xanthogranuloma
0 (0%) 1 (8%) 1 (4%)
Plexiform neurofibroma 2 (18%) 1 (8%) 3 (13%)
Other brain tumors 1 (9%) 2 (15%) 3 (13%)
NF1
5
No 9 (82%) 11 (85%) 20 (83%) 1.000
6

Yes 2 (18%) 2 (15%) 4 (17%)
MEKi drug received
5
None 1 (9%) 1 (8%) 2 (8%) 1.000
6

Binimetinib 3 (27%) 3 (23%) 6 (25%)
Selumetinib 3 (27%) 4 (31%) 7 (29%)
Trametinib 4 (36%) 5 (38%) 9 (38%)
Number of MEKi courses
5
1 9 (82%) 8 (62%) 17 (71%) 0.386
6

2 2 (18%) 5 (38%) 7 (29%)
BRAFi drug received
5
None 10 (91%) 9 (69%) 19 (79%) 0.283
6

Dabrafenib 0 (0%) 3 (23%) 3 (13%)
Vemurafenib 1 (9%) 1 (8%) 2 (8%)
Maximum Echo follow up time (in months)
1
11.15 (9.81) 18.92 (15.00) 15.36 (13.23) 0.156
2

Maximum Echo follow up time (in months)
3
11.66 (0.9,
31.7)
15.41 (1.8,
52.4)
12.04 (0.9,
52.4)
0.213
4

Borderline EF or FS at last ECHO
5

No 11 (100%) 8 (62%) 19 (79%)

Yes 0 (0%) 5 (38%) 5 (21%)

1: Arithmetic Mean (SD)
2: t-test
3: Median (Range)
4: Wilcoxon Rank Sum test
5: n (column percentage)
6: Fisher's exact test

Note:
Patients with borderline EF OR FS: 1, 4, 5, 6, 8, 10, 11, 12, 17, 19, 20, 21, and 22
Patient with borderline EF OR FS at last ECHO: 4, 8, 11, 19, and 20
- Patient 4 reached abnormal EF and FS at last ECHO without further follow up imaging
- Patient 8 reached EF borderline levels at last ECHO
- Patient 11 with borderline remained with borderline cardiac dysfunction
- Patient 19 reach abnormal EF and FS in first course of MEKi and recovered. But sustained additional cardiac dysfunction in
second course of MEKi, and this dysfunction went unresolved. The last ECHO showed cardiac dysfunction, by both criteria, in
last 2 ECHO imaging.
- Patient 20 reached borderline EF (but normal FS) at last ECHO without further follow up imaging

19

Supplementary Table 5 Patient demographics: Abnormal EF and FS status (n = 24 patients)
Variable Abnormal EF and FS status p-
value No (n = 21) Yes (n = 3) Total (n = 24)
Age at first MEKi treatment (years)
1
9.80 (4.76) 12.06 (6.23) 10.08 (4.86) 0.464
2

Age at first MEKi treatment (years)
3
10.75 (1.7,
20.5)
9.21 (7.8, 19.2) 10.14 (1.7,
20.5)
0.827
4

Sex
5
Male 11 (52%) 1 (33%) 12 (50%) 1.000
6

Female 10 (48%) 2 (67%) 12 (50%)
Race/ethnicity
5
White/Non-Hispanic 11 (52%) 1 (33%) 12 (50%) 0.707
6

Hispanic 7 (33%) 2 (67%) 9 (38%)
Other 3 (14%) 0 (0%) 3 (13%)
Diagnosis
5
Low-grade Glioma 14 (67%) 2 (67%) 16 (67%) 0.723
6

High-grade glioma 1 (5%) 0 (0%) 1 (4%)
Juvenile
xanthogranuloma
1 (5%) 0 (0%) 1 (4%)
Plexiform neurofibroma 3 (14%) 0 (0%) 3 (13%)
Other brain tumors 2 (10%) 1 (33%) 3 (13%)
NF1
5
No 17 (81%) 3 (100%) 20 (83%) 1.000
6

Yes 4 (19%) 0 (0%) 4 (17%)
Number of MEKi courses
5
1 16 (76%) 1 (33%) 17 (71%) 0.194
6

2 5 (24%) 2 (67%) 7 (29%)
BRAFi drug received
5
None 17 (81%) 2 (67%) 19 (79%) 0.268
6

Dabrafenib 3 (14%) 0 (0%) 3 (13%)
Vemurafenib 1 (5%) 1 (33%) 2 (8%)
Maximum Echo follow up time (in months)
1
12.81 (9.31) 33.25 (24.43) 15.36 (13.23) 0.009
2

Maximum Echo follow up time (in months)
3
11.66 (0.9,
34.5)
41.56 (5.7,
52.4)
12.04 (0.9,
52.4)
0.176
4

Abnormal EF & FS at last ECHO
5

No 21 (100%) 1 (33%) 22 (92%)

Yes 0 (0%) 2 (67%) 2 (8%)

1: Arithmetic Mean (SD)
2: t-test
3: Median (Range)
4: Wilcoxon Rank Sum test
5: n (column percentage)
6: Fisher's exact test

Note:
Abnormal EF and FS were concurrent in all cases.
Patients with abnormal EF and FS: 4, 17, and 19
Patient with abnormal EF and FS at last ECHO: 4 and 19
- Patient 4 reached abnormal EF and FS at last ECHO without further follow up imaging
- Patient 17 reached abnormal EF and FS on second MEKi therapy, and both EF and FS recovered by end of 3
rd

MEKi therapy
- Patient 19 reach abnormal EF and FS in first course of MEKi and recovered. But sustained additional cardiac
dysfunction in second course of MEKi, and this dysfunction went unresolved. The last 2 ECHOs showed cardiac
dysfunction by both criteria.

Abstract (if available)

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Asset Metadata

Creator Robison, Nathan John (author)

Core Title Cardiac function in children and young adults treated with MEK inhibitors: a retrospective cohort study of routinely collected health data

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Degree Conferral Date 2021-12

Publication Date 09/21/2021

Defense Date 09/02/2021

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag echocardiography,low-grade glioma,MEK inhibitor,OAI-PMH Harvest,Pediatrics,ventricular dysfunction

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Alonzo, Todd (committee chair), Asgharzadeh, Shahab (committee member), Chi, Yueh-Yun (committee member), Patino-Sutton, Cecilia (committee member)

Creator Email nrobison@chla.usc.edu,nrobison@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC15921172

Unique identifier UC15921172

Legacy Identifier etd-RobisonNat-10087

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