\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Long-term Neurocognitive and Quality of Life Outcomes in Survivors of
Pediatric Hematopoietic Cell Transplant}



\author[1]{Natalie Wu}%
\author[2]{Kevin Krull}%
\author[3]{Kara Cushing-Haugen}%
\author[4]{Nicole Ullrich}%
\author[5]{Nina Kadan-Lottick}%
\author[3]{Stephanie Lee}%
\author[3]{Eric Chow}%
\affil[1]{Seattle Children's Hospital}%
\affil[2]{St Jude Children's Research Hospital}%
\affil[3]{Fred Hutchinson Cancer Research Center}%
\affil[4]{Children's Hospital Boston}%
\affil[5]{Yale University School of Medicine}%


\vspace{-1em}



  
  \date{May 04, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Pediatric patients who undergo hematopoietic cell transplant
(HCT) are at risk for neurocognitive impairments; however, long-term
studies are lacking. Procedure: Eligible survivors (HCT at age
\textless{}21y and [?]1y post-HCT) completed a 60-question survey of
neurocognitive function and quality of life, which included the
Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ)
and the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL).
Baseline demographic and transplant characteristics were retrieved from
the institutional research database. Analyses of risk factors included
univariate comparisons and multivariable logistic regression. Results:
Participants (n=199, 50.3\% female, 53.3\% acute leukemia, 87.9\%
allogeneic transplants) were surveyed at median age of 37.8 years (range
18-61) at survey and median 27.6 years (range 1-46) from transplant. On
the CCSS-NCQ, 18.9-32.5\% of survivors reported impairments (Z-score
\textgreater{}1.28) in task efficiency, memory, emotional regulation, or
organization, compared with expected 10\% in the general population (all
p\textless{}0.01). Certain co-morbidities were associated with impaired
CCSS-NCQ scores. However, survivors reported average Neuro-QoL (T-score
49.6\selectlanguage{ngerman}±0.7) compared with population normative value of 50 (p=0.52). In
multivariable regression, impaired Neuro-QoL (T-score \textless{}40) was
independently associated with hearing issues (OR 4.79, 95\% CI
1.91-12.0), history of stroke or seizure (OR 5.22, 95\% CI 1.73-15.7),
and sleep disturbances (OR 6.90, 95\% CI 2.53-18.9). Conclusions:
Although long-term survivors of pediatric HCT reported higher rates of
impairment in specific neurocognitive domains, cognitive quality of life
was perceived as similar to the general population. Subsets of survivors
with certain co-morbidities had substantially worse neurocognitive
outcomes.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

Hematopoietic cell transplant (HCT) is increasingly performed as a
potentially curative treatment for both malignant and non-malignant
disorders. However, survivors are at higher risk for developing chronic
health conditions, which contributes to increased morbidity and
mortality compared with non-HCT cancer survivors and the general
population.\textsuperscript{1,2} Neurocognitive function is a broad
category which encompasses memory, attention, concentration, planning,
organization, and problem solving, among other abilities. Impairments in
cognition can complicate the post-HCT course with substantial effects on
both specific cognitive abilities as well as overall quality of
life.\textsuperscript{3} Survivors of pediatric HCT are at greater risk
for neurocognitive toxicity due to treatment exposures during a
developmentally vulnerable period. Despite this fact, few studies have
described the late neurocognitive outcomes in pediatric HCT survivors.

In studies of pediatric cancer survivors regardless of transplant
history, long-term survivors reported greater neurocognitive impairments
at an average of 2 decades following diagnosis compared with healthy
siblings,\textsuperscript{4,5} with more impairments noted in survivors
of central nervous system (CNS) tumors and acute lymphoblastic leukemia
(ALL) following direct CNS treatment or
prophylaxis.\textsuperscript{6,7} In these patients, survivors with
neurocognitive deficits were less likely to attain educational
milestones\textsuperscript{8} or follow recommendations for general
care.\textsuperscript{9} Therefore, further studies of long-term
neurocognitive function are needed specifically in pediatric HCT
survivors to identify potential areas for intervention with the goal of
improving patient function and quality of life.

Despite known or suspected risk factors, neurocognitive dysfunction may
not become apparent until decades after HCT. The existing literature is
limited by inconsistent definitions, heterogeneous testing methods, and
short follow-up time.\textsuperscript{3,10-13} Specifically among
pediatric HCT survivors, there is a particular lack of data describing
neurocognitive outcomes and functional impact beyond 5 years
post-HCT.\textsuperscript{14} Overall, the limited understanding of the
incidence and characterization of neurocognitive dysfunction following
HCT has been recognized as an important area deserving of further
research.\textsuperscript{15,16} In this study, we aim to address this
gap in knowledge by characterizing the late neurocognitive outcomes in a
cohort of long-term pediatric HCT survivors. We also examine the
association between treatment variables and medical co-morbidities and
neurocognitive dysfunction in this patient population.

\textbf{Methods}

\textbf{Participants}

This study was approved by the Fred Hutchinson Cancer Research Center
(FHCRC) Institutional Review Board. FHCRC maintains continuous follow-up
of HCT survivors who consent to long-term follow-up via an annual
patient-reported health survey, with the earliest transplant performed
in 1971.\textsuperscript{17,18} Patients underwent HCT for both
malignant and non-malignant conditions, including immunodeficiencies and
benign hematologic disorders. The following HCT survivors were eligible
for this study: alive [?]1 year after HCT at FHCRC, age \textless{}21
years at time of transplant, current age [?]18 years at the time of
survey, and available current mailing address. Baseline demographic
characteristics (including age, sex, race and ethnicity, underlying
diagnosis) and HCT details (including conditioning regimen, donor type,
chronic graft versus host disease (cGVHD) status) were retrieved from
the FHCRC research database. Additionally, pre-HCT cranial irradiation
exposure was abstracted from the medical record.

\textbf{Survey Instrument}

All FHCRC HCT survivors consenting to long-term follow-up receive an
annual survey consisting of 236 questions mailed on their transplant
anniversary. The annual survey includes standardized questions on
interval changes in health and presence of cGVHD or other health
conditions. For this study, a 60-question supplementary module was added
to the annual survey to collect information on neurocognitive function
and perceived cognitive quality of life. This supplementary module
included items from several validated self-reported survey measures. The
Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ)
is validated for use in adult survivors of childhood cancer and consists
of 33 questions divided into 4 domains of emotional regulation, task
efficiency, memory, and organization.\textsuperscript{19} The factors of
emotional regulation and organization are primarily measures of
executive function, while task efficiency and memory address attention,
processing speed, and both working and long-term
memory.\textsuperscript{20} The Neuro-Quality of Life Cognitive Function
Short Form (Neuro-QoL) Version 2.0 is an 8-question self-reported
measure addressing perceived difficulties in cognitive abilities, as
well as application of these abilities to daily tasks reflecting
cognitive quality of life.\textsuperscript{21} The Patient-Reported
Outcomes Measure Information System (PROMIS) Sleep Disturbance Short
Form 4a is a 4-question survey to assess perception of sleep quality and
restfulness.\textsuperscript{22} An additional 3 questions were adapted
from the National Health and Nutrition Examination Survey (NHANES) 2011
Audiometry Questionnaire to screen for hearing issues (6-point Likert
scale), need for hearing aid, or presence of tinnitus (5-point Likert
scale).\textsuperscript{23} Finally, 6 questions were included to assess
for neurologic conditions predicted to impact neurocognitive function,
including previous stroke or transient ischemic attack and epilepsy or
seizures. For this analysis, we used responses from surveys distributed
from July 2018 to June 2019 with all results collected by November 2019.
During this time, initial non-responders were sent 2 follow-up survey
requests for a total of 3 mailings.

\textbf{Statistical Analysis}

Patient-reported surveys were scored according to the scoring guides of
the individual test developers, including methods for handling any
missing data. The CCSS-NCQ was scored by calculating a total raw score
for each of the 4 domains, then converted to a Z-score using a healthy
comparison group as reference, with higher Z-scores corresponding to
worse neurocognitive scores.\textsuperscript{19} Responses for the
Neuro-QoL were summed as total raw scores and converted to standardized
T-scores with a mean score of 50 and a standard deviation of 10 using
the general U.S. population as reference, with lower T-scores suggesting
lower cognitive quality of life.\textsuperscript{21} The PROMIS Sleep
Short Form 4a was summed as a total raw score and then translated into a
T-score with a mean of 50 and a standard deviation of 10 based on the
general population, with higher T-scores signifying worse sleep
quality.\textsuperscript{22} Hearing issues were defined as
self-reported moderate/severe hearing trouble or deafness, current use
of hearing aid, or moderate/severe tinnitus.

Descriptive statistics including frequency distributions and medians and
IQR (interquartile range) were calculated for demographic and treatment
variables. Primary outcome variables, including individual CCSS-NCQ
domain and Neuro-QoL scores, were further dichotomized into 2 groups
based on perceived clinical impairment. Consistent with previous
studies, impairment was defined as Z-score \textgreater{}1.28 for the
CCSS-NCQ (corresponding to the worst 10\textsuperscript{th} percentile
of scores based on healthy control age-adjusted
norms)\textsuperscript{19} and T-score \textless{}40 for the Neuro-QoL
(corresponding to 1 SD below the standardized
mean).\textsuperscript{24}Scores were compared using chi-squared test
for categorical variables and analysis of variance or t-tests as
appropriate for continuous variables. To assess the potential influence
of non-responders on the reported group averages, we also applied
inverse probability sampling weights accounting for sex, age at HCT, and
current age of the entire eligible population. Finally, the strength of
the associations between certain clinical features and impairment on the
CCSS-NCQ or Neuro-QoL were examined using multivariable logistic
regression and reported as odds ratios (OR) with 95\% confidence
intervals (95\% CI). The models for risk of neurocognitive impairment
included dichotomized co-variates, defined as presence or absence of age
\textless{}10 years at HCT, hearing issues, stroke/seizures, and sleep
impairment adjusted for each other, as well as sex and current age.
Other potential co-variates were examined but ultimately not included in
the multivariable models. All analyses were completed using Stata
(Version 16, StataCorp, College Station, TX).

\textbf{Results}

Of 626 eligible pediatric HCT survivors surveyed, 199 participated
(50.3\% female) at a median age of 37.8 years (range 18-61) at survey
and median 27.6 years (range 1-46) from transplant (Table 1). Of note,
59 (29.6\%) of participants underwent transplant at age \textless{}10
years and 21 (10.6\%) were transplanted at age \textless{}3 years. The
majority underwent transplantation for malignant conditions, including
106 patients with acute leukemia (53.3\%) and 20 with chronic leukemia
(10.1\%). Among non-malignant conditions, 44 patients (22.1\%) received
transplants for hematologic conditions, most commonly aplastic anemia.
Nine patients (4.5\%) received transplants for immunodeficiencies,
histiocytic disorders, or other indications. Most (175/199 patients)
initially received allogeneic transplants (87.9\%) and a subset of 20
patients (10.1\%) received multiple transplants. Across all transplants,
132 patients (66.3\%) underwent conditioning with total body irradiation
(TBI), with 123 (61.8\%) receiving [?]1000cGy. Eighteen (9.0\%) also
received additional cranial irradiation prior to TBI (median 1200cGy,
range 480-5400); 1 additional patient received cranial irradiation alone
without TBI. The prevalence of moderate/severe hearing issues and
history of stroke/seizures was 40/198 (20.2\%) and 21/197 (10.7\%),
respectively. Compared with non-participants, participants were more
likely to be female, currently older, and transplanted at an earlier
age, but did not differ across other demographic or clinical
characteristics (Supplemental Table S1).

On the CCSS-NCQ, 32.5\% of survivors reported problems with task
efficiency, 25.4\% with memory, 21.8\% with emotional regulation, and
18.9\% with organization compared with an expected 10\% in the general
population (Table 2; all \emph{p\textless{}0.01} ). Results were similar
after application of inverse probability weights, with 33.0\% reporting
impairment with task efficiency, 27.6\% with memory, 22.6\% with
emotional regulation, and 18.4\% with organization (Supplemental Table
S2). In unweighted analysis, female survivors reported more issues with
emotional regulation and memory relative to males. Race/ethnicity,
current age, underlying diagnosis, year of transplant, number of
transplants, or history of cGVHD were not associated with a significant
difference in CCSS-NCQ scores. Characteristics associated with
impairments in most or all CCSS-NCQ domains included hearing issues,
history of stroke or seizure, and self-reported sleep disturbances.
Survivors \textgreater{}25 years of age with less educational
achievement also reported significantly worse scores in all domains
(all\emph{p\textless{}0.05} ). Survivors who received cranial
irradiation were more likely to report impaired scores in task
efficiency and organization compared with survivors who did not receive
any radiation or those treated with TBI alone (\emph{p\textless{}0.05}
). In multivariable regression analysis adjusted for sex and current
age, hearing issues were independently associated with impaired task
efficiency (OR 2.71, 95\% CI 1.19-6.17) and organization (OR 3.39, 95\%
CI 1.38-8.32), while history of stroke or seizure was independently
associated with impaired emotional regulation (OR 4.78, 95\% CI
1.81-12.6) and memory (OR 3.98, 95\% CI 1.46-10.8; Figure 1 and
Supplemental Table S3). Sleep disturbances were associated with
impairments across all CCSS-NCQ domains. Younger age at transplant was
generally associated with increased risk of impairments in CCSS-NCQ
domains, although estimates were not statistically significant in
adjusted models. Additionally, results were essentially unchanged if
models were further adjusted by radiation exposure.

Respondents reported average Neuro-QoL (49.6\selectlanguage{ngerman}±0.7) compared with an
expected mean score of 50 in the general population (\emph{p=0.52} ;
Table 3). The proportion with impaired cognitive quality of life with
T-score \textless{}40 was 19.1\% compared with 16\% expected in the
general population sample (\emph{p=0.23} ).\textsuperscript{21} These
values were similar after accounting for inverse probability weights,
with mean Neuro-QoL score of 49.2±0.7 and 20.5\% impairment
(Supplemental Table S2). In unweighted analysis, characteristics
associated with lower Neuro-QoL scores included younger age
(\textless{}10 years) at HCT, prior cranial irradiation, hearing issues,
history of stroke or seizure, and sleep disturbances
(all\emph{p\textless{}0.05} ). Sex, race/ethnicity, current age,
underlying diagnosis, year of transplant, number of transplants, or
history of cGVHD were not associated with a significant difference in
Neuro-QoL scores. In survivors \textgreater{}25 years old, lower
Neuro-QoL scores were associated with less educational achievement,
defined as less than college completion (\emph{p\textless{}0.01} ). In
multivariable regression analysis adjusted for sex and current age,
impaired Neuro-QoL was independently associated with hearing issues (OR
4.79, 95\% CI 1.91-12.0), history of stroke or seizure (OR 5.22, 95\% CI
1.73-15.7), and sleep disturbances (OR 6.90, 95\% CI 2.53-18.9; Figure 1
and Supplemental Table S3). Younger age (\textless{}10 years) at time of
transplant was not significantly associated with impaired Neuro-QoL in
multivariable analysis compared with age \selectlanguage{english}[?] 10 years (OR 1.63, 95\% CI
0.64-4.16).

\textbf{Discussion}

Our study demonstrated that pediatric HCT survivors reported higher
impairments in specific CCSS-NCQ neurocognitive domains of emotional
regulation, task efficiency, memory, and organization but average
cognitive quality of life compared with general population norms at a
median of 27 years post-transplant. Despite reported problems with
specific cognitive abilities, reassuringly these problems were not
perceived to have significant consequences on daily life as reflected on
the Neuro-QoL. This could represent adaption to cognitive difficulties
over time or an adjustment in expectations. These results reflect the
long-term follow-up period of our patient population, in contrast with a
shorter-term study in pediatric HCT survivors that described largely
stable intelligence and academic achievement through 5 years
post-HCT.\textsuperscript{12} Given the limited studies of late
neurocognitive effects among pediatric HCT survivors, some comparisons
can be drawn from CCSS studies of childhood cancer survivors at a
similar follow-up interval.\textsuperscript{4,9,25} In a report from the
CCSS featuring over 6,000 survivors (mean age 32 years), a lower
percentage (12.5-22.4\%) reported impairments in the CCSS-NCQ
domains.\textsuperscript{9} Although not directly comparable, this
suggests that pediatric HCT survivors may be more likely to report
neurocognitive impairments compared with general pediatric cancer
survivors.

Various treatment characteristics and exposures have been explored in
terms of their association with neurocognitive dysfunction. Previous
literature has suggested that younger age at time of cancer diagnosis or
HCT is a risk factor for worse neurocognitive
function.\textsuperscript{4,14,15} While a cohort study of pediatric HCT
survivors initially demonstrated overall stability in cognitive
functioning at 5 years post-HCT,\textsuperscript{12} a follow-up study
with an expanded cohort showed that patients \textless{}3 years at time
of transplant may be particularly susceptible to the cognitive impact of
TBI, with lower IQ (16 points on average) at 5 years post-HCT compared
with those who did not receive TBI.\textsuperscript{26} In our study,
younger age \textless{}10 years at time of HCT was suggestive of worse
outcomes after multivariable analysis, although the study may have been
underpowered to detect a statistically significant association.
Additionally, the sample size was too small to draw any conclusions in
the cohort \textless{}3 years at time of HCT. As above, radiation
exposures such as TBI and cranial irradiation have been associated with
neurocognitive dysfunction.\textsuperscript{3,11} While we did not find
a difference between non-irradiated survivors versus those who underwent
TBI only, those who received pre-HCT cranial irradiation were more
likely to report worse neurocognitive function. In our cohort, survivors
treated with cranial irradiation reported impairments in the CCSS-NCQ
domains comparable to childhood CNS tumor
survivors,\textsuperscript{8,27,28} as well as pediatric ALL survivors
treated with cranial irradiation, with significant late cognitive
deficits detected at a median follow-up of 28.5 years after
treatment.\textsuperscript{29}

Subsets of pediatric HCT survivors were more likely to have impaired
neurocognitive function, including those with hearing conditions
(moderate to severe hearing loss or more bothersome tinnitus), history
of stroke or seizures, or sleep disturbances. The association of poor
long-term neurocognitive outcomes in survivors with a higher burden of
chronic health conditions is unsurprising, given previous
studies.\textsuperscript{25} Specifically for long-term pediatric cancer
survivors, hearing and visual deficits have been associated with
impaired emotional regulation and organization,\textsuperscript{4} while
history of stroke is associated with worse health-related quality of
life and neurocognitive function, particularly task efficiency and
memory.\textsuperscript{30} Lastly, we found that self-reported sleep
disturbances were significantly associated with greater impairments in
all CCSS-NCQ domains and worse cognitive quality of life. Given the
cross-sectional nature of our study, we were unable to determine if
sleep issues had a causal effect on neurocognitive function. However,
pediatric cancer survivors who reported greater fatigue and poorer sleep
quality have also exhibited greater impairments in all CCSS-NCQ
domains.\textsuperscript{31} Studies of pediatric cancer survivors have
reported a greater burden of sleep disturbances and fatigue compared
with non-cancer controls.\textsuperscript{6,32} Additional research to
better characterize the sleep disorders experienced by our patients may
help determine specific targets for intervention.

For pediatric HCT survivors over the age of 25 years at the time of
survey completion, greater impairments in all CCSS-NCQ domains and worse
Neuro-QoL scores were associated with less educational achievement
(defined as less than college education). Our findings are similar to
other studies showing that childhood cancer survivors with
neurocognitive deficits are less likely to attain educational
milestones, obtain employment, or live
independently.\textsuperscript{3,4} These results may be time-dependent,
as differences in educational achievement may not be fully appreciated
until an extended time interval after HCT. This highlights the
importance of early referrals for resources or interventions to
potentially mitigate HCT treatment effects. The Children's Oncology
Group's Long-Term Follow-Up guidelines recommends routine formal
neuropsychological evaluation for patients at risk for late
neurocognitive deficits, including those who receive any cranial
irradiation (including TBI) or specific chemotherapy agents commonly
used during HCT, including intrathecal methotrexate, high-dose
intravenous methotrexate and/or cytarabine.\textsuperscript{33} While
previous pediatric HCT reviews\textsuperscript{3,15} have suggested the
implementation of similar routine screening, further studies will be
needed to study if earlier testing and intervention improves long-term
outcomes.

Our study benefited from a very long average follow-up duration, greatly
exceeding that of other studies of neurocognitive outcomes among
pediatric HCT survivors. Additionally, our study also featured one of
the largest samples examining neurocognitive outcomes in this patient
population. However, there were several limitations to this study. Our
study was conducted at a single center and limited by lower response
rate; thus, our results may not be fully representative of the overall
population of pediatric HCT survivors. Non-responders were more likely
to be younger and male; however, when inverse probability weighting was
applied to represent the entire cohort, we did not find a meaningful
difference in our results. It is unclear how potential response bias
would have influenced these results, as those with lower function or
quality of life may have been both less likely to respond or possibly
more likely to participate given the nature of the survey. Lastly, while
our study was based on self-reported measures with no objective
neurocognitive testing, many components of cognition can only be
captured by patient self-report and we relied on well-validated surveys
which enabled comparisons with the general population.

\textbf{Conclusion}

Our study found that pediatric HCT survivors surveyed at a median of 27
years post-transplant reported higher frequencies of impairments in the
domains of emotional regulation, task efficiency, memory, and
organization but similar cognitive quality of life compared with the
general population. Subsets of survivors with certain neurologic
co-morbidities were at higher risk for worse neurocognitive outcomes,
which may influence monitoring and counseling for post-HCT survivorship
care. Sleep intervention and early referral for educational and
rehabilitation services may offer possible avenues to mitigate
HCT-related treatment effects on later life achievements.

\textbf{Conflict of Interest Statement}

None of the authors have conflicts of interest to declare.

\textbf{Acknowledgements}

Funded in part by NIH grant CA15704, CA018029.

\textbf{Data Availability Statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{Author Contributions}

All of the authors have contributed to the manuscript in significant
ways and have reviewed and agreed upon its content.

\textbf{References}

1. Chow EJ, Anderson L, Baker KS, et al. Late effects surveillance
recommendations among survivors of childhood hematopoietic cell
transplantation: a Children's Oncology Group report. \emph{Biology of
Blood and Marrow Transplantation.} 2016;22(5):782-795.

2. Yen H-J, Eissa H, Bhatt NS, et al. Patient-Reported Outcomes in
Survivors of Childhood Hematologic Malignancies with Hematopoietic Stem
Cell Transplant. \emph{Blood Journal.} 2020:blood. 2019003858.

3. Buchbinder D, Kelly DL, Duarte RF, et al. Neurocognitive dysfunction
in hematopoietic cell transplant recipients: expert review from the late
effects and Quality of Life Working Committee of the CIBMTR and
complications and Quality of Life Working Party of the EBMT. \emph{Bone
marrow transplantation.} 2018;53(5):535-555.

4. Kadan-Lottick NS, Zeltzer LK, Liu Q, et al. Neurocognitive
functioning in adult survivors of childhood non-central nervous system
cancers. \emph{JNCI: Journal of the National Cancer
Institute.}2010;102(12):881-893.

5. Ellenberg L, Liu Q, Gioia G, et al. Neurocognitive status in
long-term survivors of childhood CNS malignancies: a report from the
Childhood Cancer Survivor Study. \emph{Neuropsychology.} 2009;23(6):705.

6. Krull KR, Hardy KK, Kahalley LS, Schuitema I, Kesler SR.
Neurocognitive outcomes and interventions in long-term survivors of
childhood cancer. \emph{Journal of Clinical Oncology.} 2018;36(21):2181.

7. Iyer NS, Balsamo LM, Bracken MB, Kadan-Lottick NS. Chemotherapy-only
treatment effects on long-term neurocognitive functioning in childhood
ALL survivors: a review and meta-analysis.
\emph{Blood.}2015;126(3):346-353.

8. Brinkman TM, Krasin MJ, Liu W, et al. Long-term neurocognitive
functioning and social attainment in adult survivors of pediatric CNS
tumors: results from the St Jude Lifetime Cohort Study. \emph{Journal of
Clinical Oncology.} 2016;34(12):1358.

9. Krull KR, Annett RD, Pan Z, et al. Neurocognitive functioning and
health-related behaviours in adult survivors of childhood cancer: a
report from the Childhood Cancer Survivor Study. \emph{European Journal
of Cancer.} 2011;47(9):1380-1388.

10. Barrera M, Atenafu E. Cognitive, educational, psychosocial
adjustment and quality of life of children who survive hematopoietic SCT
and their siblings. \emph{Bone marrow transplantation.}2008;42(1):15-21.

11. Harder H, Cornelissen JJ, Van Gool AR, Duivenvoorden HJ, Eijkenboom
WM, van den Bent MJ. Cognitive functioning and quality of life in
long\selectlanguage{english}-term adult survivors of bone marrow transplantation.
\emph{Cancer.}2002;95(1):183-192.

12. Phipps S, Rai SN, Leung W-H, Lensing S, Dunavant M. Cognitive and
academic consequences of stem-cell transplantation in
children.\emph{Journal of clinical oncology.} 2008;26(12):2027-2033.

13. Syrjala KL, Artherholt SB, Kurland BF, et al. Prospective
neurocognitive function over 5 years after allogeneic hematopoietic cell
transplantation for cancer survivors compared with matched controls at 5
years. \emph{Journal of clinical oncology.} 2011;29(17):2397.

14. Parsons SK, Phipps S, Sung L, Baker KS, Pulsipher MA, Ness KK. NCI,
NHLBI/PBMTC First International Conference on Late Effects after
Pediatric Hematopoietic Cell Transplantation: health-related quality of
life, functional, and neurocognitive outcomes. \emph{Biology of Blood
and Marrow Transplantation.} 2012;18(2):162-171.

15. Kelly DL, Buchbinder D, Duarte RF, et al. Neurocognitive dysfunction
in hematopoietic cell transplant recipients: expert review from the Late
Effects and Quality of Life Working Committee of the Center for
International Blood and Marrow Transplant Research and Complications and
Quality of Life Working Party of the European Society for Blood and
Marrow Transplantation. \emph{Biology of Blood and Marrow
Transplantation.} 2018;24(2):228-241.

16. Baker KS, Bhatia S, Bunin N, et al. NCI, NHLBI first international
consensus conference on late effects after pediatric hematopoietic cell
transplantation: state of the science, future directions. \emph{Biology
of Blood and Marrow Transplantation.} 2011;17(10):1424-1427.

17. Lee SJ, Onstad L, Chow EJ, et al. Patient-reported outcomes and
health status associated with chronic graft-versus-host
disease.\emph{haematologica.} 2018;103(9):1535-1541.

18. Khera N, Chow EJ, Leisenring WM, et al. Factors associated with
adherence to preventive care practices among hematopoietic cell
transplantation survivors. \emph{Biology of blood and marrow
transplantation.} 2011;17(7):995-1003.

19. Kenzik KM, Huang I, Brinkman TM, et al. The Childhood Cancer
Survivor Study--Neurocognitive Questionnaire (CCSS-NCQ) Revised: Item
response analysis and concurrent validity.
\emph{Neuropsychology.}2015;29(1):31.

20. Krull KR, Gioia G, Ness KK, et al. Reliability and validity of the
childhood cancer survivor study neurocognitive
questionnaire.\emph{Cancer.} 2008;113(8):2188-2197.

21. National Institute of Neurological Disorders and Stroke
(NINDS).\emph{User Manual for the Quality of Life in Neurological
Disorders (Neuro-QoL) Measures, Version 2.0.} 2015.

22. Yu L, Buysse DJ, Germain A, et al. Development of short forms from
the PROMIS\selectlanguage{english} sleep disturbance and sleep-related impairment item
banks.\emph{Behavioral sleep medicine.} 2012;10(1):6-24.

23. National Health and Nutrition Examination Survey. Audiometry.
https://wwwn.cdc.gov/nchs/data/nhanes/2011-2012/questionnaires/auq.pdf.
Published 2011. Accessed 06/01/2020.

24. Gabel N, Altshuler DB, Brezzell A, et al. Health related quality of
life in adult low and high-grade glioma patients using the national
institutes of health patient reported outcomes measurement information
system (PROMIS) and neuro-QOL assessments. \emph{Frontiers in
neurology.} 2019;10:212.

25. Cheung YT, Brinkman TM, Li C, et al. Chronic health conditions and
neurocognitive function in aging survivors of childhood cancer: A report
from the Childhood Cancer Survivor Study. \emph{JNCI: Journal of the
National Cancer Institute.} 2018;110(4):411-419.

26. Willard VW, Leung W, Huang Q, Zhang H, Phipps S. Cognitive outcome
after pediatric stem-cell transplantation: impact of age and total-body
irradiation. \emph{Journal of Clinical Oncology.} 2014;32(35):3982.

27. Armstrong GT, Jain N, Liu W, et al. Region-specific radiotherapy and
neuropsychological outcomes in adult survivors of childhood CNS
malignancies. \emph{Neuro-oncology.} 2010;12(11):1173-1186.

28. Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes among adult
survivors of childhood central nervous system malignancies in the
Childhood Cancer Survivor Study. \emph{JNCI: Journal of the National
Cancer Institute.} 2009;101(13):946-958.

29. Krull KR, Zhang N, Santucci A, et al. Long-term decline in
intelligence among adult survivors of childhood acute lymphoblastic
leukemia treated with cranial radiation. \emph{Blood, The Journal of the
American Society of Hematology.} 2013;122(4):550-553.

30. Mueller S, Kline CN, Buerki RA, et al. Stroke impact on mortality
and psychologic morbidity within the Childhood Cancer Survivor
Study.\emph{Cancer.} 2020;126(5):1051-1059.

31. Clanton NR, Klosky JL, Li C, et al. Fatigue, vitality, sleep, and
neurocognitive functioning in adult survivors of childhood cancer: a
report from the Childhood Cancer Survivor Study.
\emph{Cancer.}2011;117(11):2559-2568.

32. Mulrooney DA, Ness KK, Neglia JP, et al. Fatigue and sleep
disturbance in adult survivors of childhood cancer: a report from the
childhood cancer survivor study (CCSS). \emph{Sleep.}2008;31(2):271-281.

33. Children's Oncology Group. \emph{Long-term follow-up guidelines for
survivors of childhood, adolescent and young adult cancers. .}Children's
Oncology Group;2018.

\textbf{Figure Legend}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`PBC Table 1.docx`  available at \url{https://authorea.com/users/355324/articles/478619-long-term-neurocognitive-and-quality-of-life-outcomes-in-survivors-of-pediatric-hematopoietic-cell-transplant}

\textbf{Hosted file}

\verb`PBC Table 2.docx`  available at \url{https://authorea.com/users/355324/articles/478619-long-term-neurocognitive-and-quality-of-life-outcomes-in-survivors-of-pediatric-hematopoietic-cell-transplant}

\textbf{Hosted file}

\verb`PBC Table 3.docx`  available at \url{https://authorea.com/users/355324/articles/478619-long-term-neurocognitive-and-quality-of-life-outcomes-in-survivors-of-pediatric-hematopoietic-cell-transplant}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

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

