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Sleep Disruption in Hematopoietic Cell
Transplantation Recipients: Prevalence,
Severity, and Clinical Management
ASBMT
American Society for Blood
and Marrow Transplantation
Heather S.L. Jim 1, *, Bryan Evans 1, Jiyeon M. Jeong 2,
Brian D. Gonzalez 1, Laura Johnston 2, Ashley M. Nelson 3,
Shelli Kesler 2, Kristin M. Phillips 2, Anna Barata 1, 4,
Joseph Pidala 1, Oxana Palesh 2
1
Moffitt Cancer Center, Tampa, Florida
Stanford School of Medicine, Stanford Cancer Institute, Stanford, California
University of South Florida, Tampa, Florida
4
Psychiatry and Legal Medicine PhD Program, Universitat Autònoma de Barcelona, Barcelona, Spain
2
3
Article history:
Received 27 December 2013
Accepted 9 April 2014
Key Words:
Sleep disruption
Hematopoietic cell transplant
Management of sleep
disruption
a b s t r a c t
Sleep disruption is common among hematopoietic cell transplantation (HCT) recipients, with over 50% of
patients experiencing sleep disruption pretransplantation, up to 82% experiencing moderate to severe sleep
disruption during hospitalization for transplant, and up to 43% in the post-transplantation period. These rates
of sleep disruption are substantially higher than the general population. Although sleep disruption can be
distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits.
The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT to facilitate
patient education, intervention, and research. The review opens with a discussion of sleep disruption measurement and clinical diagnosis of sleep disorders. An overview of the prevalence, severity, and chronicity of
sleep disruption and disorders in patients receiving HCT follows. Current evidence regarding sociodemographic and clinical predictors of sleep disruption and disorders is summarized. The review concludes with
suggestions for behavioral and pharmacologic management of sleep disruption and disorders as well as directions for future research.
Ó 2014 American Society for Blood and Marrow Transplantation.
INTRODUCTION
The number of both autologous and allogeneic hematopoietic cell transplants (HCTs) has increased dramatically in
recent years, with more than 50,000 performed worldwide
each year [1]. This increase in HCT is due to a greater number
of indications for its use as well as advances in therapy,
including more frequent use of peripheral blood stem cells,
reduced-intensity conditioning regimens, greater use of cells
from unrelated and alternative donors, improvements in
supportive care, and advances in histocompatibility typing.
Survival has generally improved as well [1], resulting in a
growing number of patients living with the short- and longterm side effects of HCT.
Sleep disruption is frequently overlooked as a side effect
of HCT. Sleep disruption includes difficulty falling asleep,
staying asleep, awakening earlier than intended, and/or
nonrestorative sleep [2]. It can occur without a clinical
diagnosis of a sleep disorder, although a clinical diagnosis
may be warranted if sleep disruption is chronic and impairs
daily functioning. Sleep disruption is common after HCT,
distressing to patients [3], and associated with greater fatigue and reduced quality of life [3,4]. Nevertheless, sleep
disruption is seldom the focus of patienteprovider communication. A survey of 180 HCT physicians found that only 17%
Financial disclosure: See Acknowledgments on page 18.
* Correspondence and reprint requests: Heather S. L. Jim, PhD, Department of Health Outcomes and Behavior, Moffitt Cancer Center, MRC-PSY,
12902 Magnolia Drive, Tampa, FL 33612.
E-mail address: heather.jim@moffitt.org (H.S.L. Jim).
discussed sleep with their patients during at least half of
clinical visits [5].
The goal of the current review is to draw attention to
sleep disruption as a clinical problem in HCT and to provide
clinicians and researchers with an overview of current evidence to facilitate diagnosis, patient education, intervention,
and research. The review begins with a brief discussion of the
assessment and clinical diagnosis of sleep disruption and
common sleep disorders (ie, insomnia, obstructive sleep
apnea [OSA], and restless legs syndrome [RLS]). We then
synthesize and critically review evidence regarding the
prevalence, severity, and chronicity of sleep disruption and
disorders in patients before HCT, during the acute transplantation phase, and early, middle, and long-term survivorship. This review focuses on HCT studies published in the
past decade to ensure greater relevance to current transplant
practices. Sociodemographic and clinical risk factors are
described, with an emphasis on those relevant to HCT. We
conclude with recommendations for management of sleep
disruption and disorders in the transplant setting as well as
directions for future research.
ASSESSMENT OF SLEEP DISRUPTION
Objective and self-report measures of sleep disruption
have been developed to facilitate differential diagnosis and
to monitor sleep over time. The gold standard for objective
measurement is polysomnography, which measures multiple biologic processes of sleep, including electrical activity in
the brain and heart, limb movement, and eye movements. In
addition to collecting essential data for diagnosing sleep
disorders, polysomnography allows the additional advantage
1083-8791/$ e see front matter Ó 2014 American Society for Blood and Marrow Transplantation.
http://dx.doi.org/10.1016/j.bbmt.2014.04.010
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of monitoring the progression of sleep stages (eg, rapid eye
movement sleep or dreaming) and brain arousal during
sleep, which can elucidate the occurrence of sleep interruptions. It is typically conducted in a sleep lab or hospital,
although home-based polysomnography is increasingly used
because of its lower cost.
An alternative to polysomnography is actigraphic monitoring in which a small, nonintrusive piezoelectric monitor
similar to a wristwatch is worn on the nondominant wrist to
detect and record motion. Specialized software is used to
determine sleep versus waking using algorithms validated
against polysomnography. Actigraphy data, in combination
with patients’ self-reports of bedtime and rising time, have
been found to be a reliable and valid measure of circadian
sleep patterns [6]. Parameters assessed include time in bed
asleep, time until sleep onset, number and length of nighttime awakenings, number and length of daytime naps, and
circadian variation in sleep and activity. Periodic limb
movement can also be assessed. Actigraphs are relatively
inexpensive and can be worn at home or in the hospital for
several days or weeks, enabling the naturalistic study of
sleep disruption over time. Actigraphy is typically used for
research rather than diagnostic purposes.
Despite the widespread availability of polysomnography
and actigraphy, to our knowledge only 1 study in HCT patients has been published using these measures to assess
sleep [7]. Thus, objective sleep patterns of HCT patients are
largely unknown.
Regarding self-report measures of sleep, several have
been validated in cancer patients [8,9]. The most common
are the Insomnia Severity Index [10] and the Pittsburgh Sleep
Quality Index [11]. These measures typically ask patients to
estimate how long it takes them to fall asleep, how many
hours they sleep each night, their use of sleep medications,
and their perceptions of sleep quality. Additional measures
used include the Epworth Sleepiness Scale [12] to evaluate
daytime sleepiness and the International Restless Legs Syndrome Study Group rating scale to evaluate RLS symptomatology [13].
In addition to self-report measures, sleep diaries can play
an important role in research and clinical diagnosis. Patients
are typically asked to fill out the diary on a daily basis for
several days or weeks. Requested information includes
bedtime and rising times as well as duration of sleep, sleep
quality, difficulty initiating and maintaining sleep, daytime
napping, medications taken, and other details [14,15]. Diaries
can be particularly useful in both the research and clinical
settings for obtaining detailed information regarding patterns of disruption, contributing factors, and targets of
intervention.
CLINICAL DIAGNOSIS OF SLEEP DISORDERS
Guidelines for clinical evaluation of sleep disorders
depend on the disorder under consideration. Regarding
insomnia, diagnosis is based on a detailed sleep, medical,
substance, and psychiatric history in addition to a physical
and mental status examination. Sleep diaries are often used
as well. The goal is to establish the type and evolution of
insomnia, perpetuating factors, extent of daytime dysfunction, and identification of comorbid medical, substance, and/
or psychiatric conditions [16].
Diagnostic criteria for insomnia include (1) difficulty
initiating sleep, maintaining sleep, and/or early morning
awakening with the inability to return to sleep; (2) significant distress and/or impairment in functioning; (3) sleep
difficulty that occurs at least 3 nights a week for at least
3 months; (4) sleep difficulty that occurs despite adequate
opportunity to sleep; and (5) symptoms that cannot be
explained by another mental or medical disorder [2].
Regarding OSA, a sleep history and physical exam
including symptoms and risk factors (eg, snoring, gasping/
choking at night, daytime sleepiness, obesity, type 2 diabetes, congestive heart failure, treatment-refractory hypertension) are indicated [17]. Patients deemed to be at high risk
should then be evaluated using polysomnography or homebased monitoring for definitive diagnosis [17]. Criteria for
diagnosis are (1) evidence by polysomnography of at least 5
apneas or hypopneas per hour of sleep (ie, snoring, snorting/
gasping, breathing pauses); (2) daytime sleepiness, fatigue,
or unrefreshing sleep despite sufficient opportunity for
sleep; (3) symptoms are not better explained by another
mental or sleep disorder or medical condition; or (4) evidence by polysomnography of 15 or more obstructive apneas
and/or hypopneas per hour of sleep regardless of accompanying symptoms [2].
Regarding RLS, diagnosis is based primarily on self-report,
although polysomnography and actigraphy can be used [18].
Diagnostic criteria for RLS are (1) an urge to move the legs
accompanied by or in response to uncomfortable and unpleasant sensations in the legs; (2) the urge begins or
worsens during periods of rest or inactivity, is partially or
totally relieved by movement, and is worse or occurs only in
the evening or at night; (3) symptoms occur at least 3 times a
week for 3 months; (4) symptoms are accompanied by significant distress and/or impairment in functioning; and (5)
symptoms are not attributable to another mental or medical
disorder [2].
SLEEP DISRUPTION AND DISORDERS BEFORE
TRANSPLANT
Research on sleep disorders before HCT is limited to case
studies of lymphomas presenting as OSA (eg, [19]). In addition, a study of polysomnography in 12 multiple myeloma
patients receiving high-dose chemotherapy [7] reported
greater respiratory events and lower-than-normal levels of
arterial oxygen saturation, on average. Periodic limb movements in the sample were high and increased during the
course of chemotherapy. No studies have reported on the
incidence or prevalence of pretransplant sleep disorders.
Numerous precipitating factors can contribute to sleep
disruption in patients before transplant, however. Patients
typically undergo several rounds of standard-dose chemotherapy that is associated with short- and long-term sleep
disruption [20]. Side effects of chemotherapy, such as peripheral neuropathy, may also contribute to sleep disruption [20]. Among cancer patients treated with standarddose chemotherapy, the prevalence of RLS was 18% (ie,
double that of the general population), with longer
chemotherapy associated with greater risk of RLS [21]. In
addition, many patients have elevated levels of anxiety and
depressive symptomatology [22]; anxiety can contribute to
sleep disruption, whereas both insomnia and hypersomnia
are symptoms of depression and share some common etiology [2].
Regarding the prevalence of sleep disruption outside the
context of a diagnosable sleep disorder, 16 studies have
examined sleep before transplantation (Table 1). Of these, 9
studies did not provide estimates of prevalence of sleep
disruption or comparisons with individuals not receiving
HCT [7,23-30]. The remaining 7 studies are heterogeneous in
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Table 1
Observational Studies of Sleep in HCT Recipients
Sample
Demographics
Time Frame
Sleep Measures
Statistical Analyses
Main Relevant Findings
Anderson et al.
(2007) [31]
Auto-HCT (N ¼ 100)
Included both disease-free and
relapsed patients
NHL (34%), MM (66%)
Age:
Mean ¼ 53.6 (9.7)
Range ¼ 24-75
Gender:
M ¼ 60%
F ¼ 40%
Race:
Caucasian ¼ 81%
African American ¼ 12%
Hispanic ¼ 5%
Other ¼ 2%
Longitudinal; 5
assessments: pre-HCT, 3rd4th day of conditioning, day
0, nadir, day 30
MDASI-BMT (a singleitem measure of sleep
disruption)
Repeated measures
ANOVA
Andrykowski et al.
(2005) [48]
HCT survivors (N ¼ 662) and
age- and sex-matched healthy
control subjects (N ¼ 158)
Allo (41%), auto (59%),
missing (1%)
AML (29%), CML (19%), ALL (7%),
Breast cancer (23%), lymphoma
(20%), other (1%)
Allo-HCT (N ¼ 76)
RIC (54%), myeloablative (46%)
Included patients in remission
and with progressive disease
Acute leukemia (17%), chronic
leukemia (38%), lymphoma or
MM (29%), MDS (12%),
nonhematologic malignancy
(4%)
Mean age: 50.1 (14.2)
Gender:
M ¼ 30%
Race:
White ¼ 95%
Cross-sectional; mean of
7 yr (84 mo) post-HCT
(inclusion criteria: >12 mo
post-HCT)
MOS-Sleep
MANOVA (univariate
analyses)
The percentage of patients
reporting disturbed sleep at
moderate or severe levels at
each time point were as
follows: 8% at baseline, 34%
at conditioning, 39% at
nadir, 14% at day 30.
8% reported sleep
disruption at baseline, 34%
at conditioning, 26% at
transplant, 39% at nadir,
and 14% at day 30.
Sleep disruption was one of
most severe symptoms at
nadir, returned to pre-HCT
levels by day 30 post-HCT
Sleep disruption was
significantly worse for NHL
than MM patients (P ¼ .024)
HCT survivor group
reported more sleep
problems than healthy
control group (effect size ¼
.39, P < .001).
Mean age: 40.2 (13.5)
Gender:
M ¼ 67%
F ¼ 33%
Race:
White ¼ 46%
Hispanic ¼ 30%
Asian ¼ 9%
Black ¼ 7%
Other ¼ 8%
Longitudinal; baseline
(before transplant
conditioning), day 0, day
30, day 100
Symptom Distress Scale
Univariate descriptive
analyses
Age:
Median ¼ 34
Range ¼ 14-65
Gender:
M ¼ 79
F ¼ 45
Cross-sectional; median of
7.3 yr post-HCT
EORTC QLQ-C30
Descriptive statistics,
t-test
Bevans et al.
(2008) [3]
Bieri et al. (2008)
[49,50]
Allo-HCT (N ¼ 124)
AML (n ¼ 40), ALL (n ¼ 20), CML
(n ¼ 31), CLL (n ¼ 1), MDS
(n ¼ 8), lymphoma (n ¼ 14),
MM (n ¼ 1), MPS (n ¼ 3), AA
(n ¼ 6)
At baseline, approximately
55% of patients reported
insomnia, 86% had
insomnia at day 0, nearly
70% had insomnia at day 30,
and at day 100 insomnia
levels went down to
baseline levels.
Insomnia was the most
distressing symptom at day
0 (reported by 32% of
participants).
Significantly higher sleep
disruption among HCT
patients compared with
Norwegian population
norms. Unclear where
normative data came from.
Difference of .33 SD.
Univariate analysis
indicated that employment
status was associated with
sleep disruption.
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Table 1
(continued )
Sample
Demographics
Time Frame
Sleep Measures
Statistical Analyses
Main Relevant Findings
Bishop et al.
(2007) [50]
HCT (N ¼ 177), partners (N ¼
177), control subjects (N ¼ 133)
Allogeneic ¼ 78 (44%),
Autologous ¼ 99 (56%)
AML or ALL (39%), CML (22%),
breast cancer (18%), lymphoma
(21%)
Mean age: 50 (10)
Gender:
F ¼ 50%
Race:
White ¼ 94%
Cross-sectional; mean of
7 yr (84 mo) post-HCT
(inclusion criteria: >12 mo
post-HCT)
MOS-Sleep
Mixed Effect
Linear Models
Boland et al.
(2013) [60]
Auto-HCT (n ¼ 29), allo-HCT
(n ¼ 3), tandem HCT (n ¼ 10)
MM (100%)
MEL (n ¼ 29), maintenance
lenalidomide (n ¼ 3),
maintenance interferon-a
(n ¼ 1)
Hospitalized HCT (N ¼ 69)
Allo (n ¼ 46), auto (n ¼ 23)
Disease sites not reported
Age:
Median: 60
Range: 41-71
Gender:
M ¼ 17
F ¼ 15
Cross-sectional: mean
5.5 yr post-diagnosis
(range, 2-12)
EORTC QLQ C-30
Spearman’s correlations
Patients showed
significantly higher rates of
sleep problems than control
subjects (ES ¼ .39).
Partners showed
significantly higher rates of
sleep problems than control
subjects (ES ¼ .22).
Sleep disruption
significantly correlated
with serum IL-6 levels (P ¼
.02)
Gender:
Male ¼ 41
Female ¼ 26
Cross-sectional; day 14
post-HCT (reflective of
2-week period)
ISI
Descriptives and
chi-square tests
Mean age: 45
Range ¼ 19-74
Gender:
M ¼ 56%
F ¼ 44%
Race:
Black ¼ 15%
Latino ¼ 23%
White ¼ 62%
Mean age: 48.65 (23-64)
Gender:
M ¼ 45%
F ¼ 55%
Race:
White ¼ 35%, Black ¼ 40%,
Latino ¼ 15%, Asian ¼ 5%,
Other ¼ 5%
Longitudinal; 8
assessments: pre-HCT to
day 100 post-HCT
MDASI
Longitudinal linear mixed
models, correlations
Longitudinal; pre-HCT and
5 and 8 d post-HCT
EORTC QLQ-C30
t-tests
Boonstra et al.
(2011) [37]
Cohen et al.
(2012) [28]
Diverse HCT (N ¼ 164)
Allo (62%), auto (38%)
Disease sites not reported
HD (n ¼ 24), NHL (n ¼ 21), AML
(n ¼ 11)
38 Chemotherapy, 20
radiochemotherapy
Danaher et al.
(2006) [24]
HCT (N ¼ 20 at baseline; N ¼ 17
post-HCT)
Auto ¼ 10 (59%), allo ¼ 7 (41%)
Lymphoma (23%), CML (6%),
AML (18%), ALL (6%), MM (29%),
myelofibrosis (12%), plasma cell
leukemia (6%)
No insomnia ¼ 26%,
subthreshold insomnia ¼
48%, clinically significant
insomnia (moderate) ¼
23%, clinically significant
insomnia (severe) ¼ 3%.
Female and allo patients
were more likely to report
insomnia (no observed
differences in age).
Toileting (85%), staff
interruptions (80%),
physical symptoms (41%),
anxiety-self (39%), anxietyothers (35%), and noise
(24%) most common
reasons for sleep
disruption.
Sleep disruption was 1 of
the 5 worst reported
symptoms; associated with
myeloablative regimens
and worse functional
status.
Sleep disruption
significantly worse postHCT.
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De Souza et al.
(2002) [77]
Diez-Campelo et al.
(2004) [39]
Faulhaber et al.
(2010) [44]
Allo-HCT (N ¼ 61)
CML (37.7%), severe AA (21.3%),
AML (14.7), ALL (8.1%), NHL
(6.5%), HD (4.9%), Other (6.5%)
BU/CY (65.6%), RIC (18%), Cy
(9.8%), TBI/CY (6.6%)
Frick et al.
(2006) [23]
HCT (N ¼ 282)
Allo (35%), auto (62%)
AML/MDS (11.7%), ALL (5%),
CML (16%), HD (4.3%), NHL
(29.9%), MM (29.5%), Other
(3.6%); (97% hematologic
malignancies)
Age:
Range ¼ 19-61
Gender:
M ¼ 14
F ¼ 12
Age range, 16-70
Age:
Mean ¼ 61
Range ¼ 48-72
Gender:
M ¼ 10
F¼2
Race:
White ¼ 10
African American ¼ 2
Mean age: 36.5 (12.3)
Gender:
M ¼ 54.1%
F ¼ 45.9%
Age:
Median ¼ 48.5
SD ¼ 11.9
Gender:
F ¼ 39%
Cross-sectional; mean of
1248 d post-HCT
WHOQOL-100: singleitem assessment: “Do
you have difficulties
with sleeping?”
Wilcoxon rank sum,
Kruskal-Wallis tests
No differences in sleep
between patients receiving
BM versus PBSC.
Longitudinal; 6
assessments:
days þ7, þ14, þ21, þ90,
þ270, þ360 post-HCT
FACT sleep disruption
item: “I am sleeping
well”
Descriptives
14.3% of allo-RIC and 26.3%
of auto patients had
problems sleeping at 1 yr
post-transplant (P ¼ .29).
Cross-sectional; pre-HCT (1
assessment before, 1
assessment after chemo
cycle)
Polysomnography
Descriptives
Cross-sectional; 1-10 yr
post-HCT
DSM-IV-TR criteria for
sleep disorders
Multivariate analysis
Cross-sectional; pre-HCT
EORTC QLQ-C30
Pearson’s correlation
coefficient
Patients had a short sleep
time, excessive time spent
awake after sleep onset,
poor sleep efficiency, more
time in non-REM sleep, low
arterial oxygen saturation,
elevated periodic limb
movements as measured by
polysomnography.
The prevalence of sleep
disorders was 26.2%.
Multivariate analysis
indicated that busulfancyclophosphamide was an
independent risk factor for
sleep disorders (included
sex and age).
Compared patients with
sample of German
populationd36.6 patients
versus 16.4 population (no
SDs or SEs given).
Sleep disruption was
positively correlated with
problematic social support
(.183)
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Enderlin et al.
(2013) [7]
Allo-HCT (N ¼ 26)
All in complete remission
BM (n ¼ 13), PBSC (n ¼ 13)
CML (n ¼ 21), AML (n ¼ 3), MDS
(n ¼ 1), ALL (n ¼ 1)
RIC allo-HCT (n ¼ 47), auto-HCT
(n ¼ 70)
AML (n ¼ 15), ALL (n ¼ 3), CML
(n ¼ 5), MDS (n ¼ 7), NHL (n ¼
3), HD (n ¼ 11), breast cancer
(n ¼ 6), MM (n ¼ 29), CLL (n ¼
4), amyloidosis (n ¼ 1)
FLU/MEL or FLU/BU (n ¼ 47),
BEAM (n ¼ 37), BU/MEL (n ¼ 8),
CY/carboplatin/thiotepa (n ¼ 6),
MEL (n ¼ 11), BU/CY (n ¼ 7), CY/
TBI (n ¼ 1)
Auto-HCT (N ¼ 12)
MM only
All participants on the Total
Therapy 3 protocol
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707
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6
Table 1
(continued )
Sample
Demographics
Time Frame
Sleep Measures
Statistical Analyses
Main Relevant Findings
Frodin et al.
(2011) [25]
Auto-HCT (N ¼ 111)
MM (n ¼ 56), lymphoma (n ¼
32), testicular cancer (n ¼ 3),
AML (n ¼ 2), multiple sclerosis
(n ¼ 1)
Conditioning: MEL (n ¼ 56),
BEAM (n ¼ 33), CEC (n ¼ 3), BU/
MEL (n ¼ 2), ZAM (Aavados,
ARA-C, melphalan) (n ¼ 2)
Based on 96 patients:
Age:
Mean ¼ 54 (12)
Gender:
M ¼ 62
F ¼ 34
Longitudinal; baseline,
week 1, week 2, week 3,
week 4, month 2, month 3,
month 6, year 1, year 1.5,
year 2, year 2.5, and year 3
EORTC QLQ-C30
The results are presented
using descriptive statistics,
means adjusted for gender
and age
Gallardo et al.
(2009) [61]
Allogeneic BMT (N ¼ 820; N ¼
150 QOL assessed)
Peripheral blood group (N ¼
410): AML (25.9%), ALL (24.1%),
CML (30.7%), MM (2.7%), NHL
(7.3%), HD (0.5%), MDS (7.8%),
Other (1%)
Bone marrow group (N ¼ 410):
AML (25.9%), ALL (24.1%), CML
(30.7%), MM (2.7%), NHL (7.3%),
HD (0.5%), MDS (7.8%), Other
(1%)
Peripheral blood group:
conditioning regimen with
TBI ¼ 198 (48.3%)
Bone marrow group:
conditioning regimen with
TBI ¼ 200 (48.8%)
HCT (N ¼ 163)
Allo (85%), auto (12%), syngenic
(3%)
Included both disease-free and
relapsed patients
CLL/CML (n ¼ 69), ALL/AML (n ¼
58), Other (n ¼ 36)
Quantitative review of 33
papers reporting EORTC scores
in HCT and covering 2800
patients
Range of participants (15-415),
total N ¼ 2804
Allo ¼ 52.6%
Auto ¼ 48.4%
Acute leukemia (28%), CML
(15.3%), other hematologic
diseases (42.1%), solid tumors
(14.8%)
Peripheral blood group
(N ¼ 410):
Age:
Median ¼ 35
Range ¼ 15-59
Gender:
M ¼ 58.9%
F ¼ 41.1%
Bone marrow group
(N ¼ 410):
Age:
Median ¼ 35
Range ¼ 15-59
Gender:
M ¼ 62.3%
F ¼ 37.7%
Retrospective;
follow up for alive patients:
median 43.8 mo for
patients receiving
peripheral blood, median
46.6 mo for patients
receiving bone marrow.
EORTC QLQ-C30,
Spanish Version
Chi-square, t tests
Worst sleep disruption at 2
weeks post-HCT.
Sleep returned to baseline
levels by 2 mo post-HCT,
and remained relatively
stable thereafter through
the 3-year follow up.
Increase of 1.1 SD from preHCT baseline to 2 wk follow
up.
Sleep disruption did not
differ between myeloma
and lymphoma patients.
There were no significant
differences in sleep
difficulties reported
between patients who
received bone marrow (n ¼
73, M ¼ 15.9, SD ¼ 26.7)
versus peripheral blood
(n ¼ 77, M ¼ 18.2, SD ¼
26.2).
Age at BMT:
Median ¼ 34 (9.2)
Gender:
M ¼ 62.6%
F ¼ 37.4%
Cross-sectional; within
16 yr post-HCT; (inclusion
criteria: 2 yr post-HCT,
transplanted b/w 19791996)
SF-36, EORTC QLQ-C30,
SIP, Herschbach Stress
in Cancer Patients
Mann-Whitney analysis,
correlations
Unemployed, divorced, and
distressed patients
reported significantly
greater sleep problems.
Age Range (14-70)
Gender:
M ¼ 50.1%
Longitudinal; pre-HCT,
during hospitalization, at
discharge, up to 6 mo,
7-12 mo, 1-3 yr, >3 yr
EORTC QLQ-C30
Categorized data by time of
assessment, unweighted
arithmetic means.
Sleep problems increase
during inpatient stay then
return to baseline levels
after discharge (change of
25 points).
Sleep problems described
by authors as “persistent”
and at a “high level.”
Gruber et al.
(2003) [29]
Grulke et al.
(2011) [26]
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824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
Auto-HCT (N ¼ 274)
MEL/prednisone only (n ¼ 203),
MM only
Not reported
Longitudinal; pre-HCT, 1
mo, 6 mo, 12 mo, 24 mo,
and 36 mo post-HCT
EORTC QOLQ-C30
Linear regression model
with forward stepwise
selection
Hacker et al.
(2003) [30]
HCT (pre-HCT N ¼ 16, 6 wk
post-discharge N ¼ 8)
Allo (n ¼ 11), auto (n ¼ 5)
Lymphoma (n ¼ 4), CML (n ¼ 3),
AML (n ¼ 3), ALL (n ¼ 1), MM
(n ¼ 3), myelofibrosis (n ¼ 3)
Longitudinal; 4
assessments:
pre-HCT, hospital
discharge, 2 weeks
post-discharge, 6 weeks
post-discharge
EORTC QLQ-C30
One-way repeated
measures ANOVA with
paired samples t-tests
and Bonferroni corrections
Harder et al.
(2002) [78]
HCT (N ¼ 40)
Allo HCT (87.5%); allo MRD ¼
26, allo MUD ¼ 9, auto ¼ 5
ALL (n ¼ 8), AML (n ¼ 10), CML
(n ¼ 6), NHL (n ¼ 6), MDS (n ¼
4), MM (n ¼ 4), AA (n ¼ 2)
All had TBI up to 12 Gy,
intrathecal treatment (n ¼ 11),
conditioning regimen: CY (n ¼
12), ARA-C/CY (n ¼ 19), VP-16/
CY (n ¼ 9)
Sibling allo-HCT (N ¼ 51)
(original sample of 75 HCT
patients)
CY/TBI (32%); BU/CY (68%)
Mean age: 46.56
(11.31)
Gender:
M ¼ 50%
F ¼ 50%
Race:
White ¼ 10
Black ¼ 2
Latino ¼ 2
Native American ¼ 1
Asian ¼ 1
Age at HCT:
Mean ¼ 37.2
Range ¼ 15-55
Gender:
M ¼ 24
F ¼ 16
Cross-sectional; 22-82 mo
post-HCT
EORTC QLQ-C30
Descriptives
Sleep disruption M ¼ 18.3
(SD ¼ 22.6)
Sleep disturbances were
one of the most commonly
reported complaints.
Cross-sectional; median of
98 mo post-HCT
EORTC QLQ-C30
Descriptives
No difference in sleep
disruption between HCT
patients and reference
population.
Reference population not
described.
Longitudinal; mean of 2.5
yr and 4.5 yr post-HCT
EORTC QLQ-C30
Mann-Whitney U test,
correlations
No differences in sleep
disruption over time.
Patients reported more
sleep disruption than
general Norwegian
population.
Physicians tended to
underestimate sleep
problems.
Hayden et al.
(2004) [53]
Hendriks &
Schouten
(2002) [45]
HCT (N ¼ 52 at T1; N ¼ 33 at T2)
Auto (81%), allo (19%) at T1
Relapse free
Lymphoma (40%), breast cancer
(29%), acute leukemia (29%)
Based on 51 patients
alive in 2003:
Age at BMT:
Median ¼ 35
Range ¼ 14-55
Gender:
M ¼ 31
F ¼ 20
Age:
Mean ¼ 41
Gender:
M ¼ 42%
F ¼ 58%
Reference population of
population-based study of
3000 Norwegians aged 1893 yr
Statistically significant
difference between newly
diagnosed multiple
myeloma patients and
population norms, small in
magnitude with worse
scores in patients.
Sleep differences were
found between T1 (M ¼
41.67) and T2 (M ¼ 73.33)
(baseline to immediately
before discharge) and
between T2 and T3 (M ¼
33.33) (immediately before
discharge to 2 wk posthospitalization). T4 M ¼
33.33
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(2004) [32]
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912
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918
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920
921
922
923
924
925
926
927
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
8
Table 1
(continued )
Sample
Demographics
Time Frame
Sleep Measures
Statistical Analyses
Main Relevant Findings
Hjermstad et al.
(2004) [33]
HCT (N ¼ 130), chemotherapy
patients (N ¼ 118)
Allo (n ¼ 61), auto (n ¼ 69)
HCT group: HD (n ¼ 15), highgrade NHL (n ¼ 43), low-grade
NHL (n ¼ 11), CML (n ¼ 31),
AML (n ¼ 19), ALL (n ¼ 11)
Age at baseline:
Median ¼ 35
Range ¼ 17-55
Gender:
M ¼ 56%
F ¼ 44%
Longitudinal; pre-HCT and
3-5 yr post-HCT
EORTC QLQ-C30
Wilcoxontest or
1-way ANOVA as
appropriate. Confidence
intervals for graphic
illustrations
Kiss et al.
(2002) [57]
Allo-HCT (N ¼ 28)
Included both disease-free and
relapsed patients
CML only
CY/TBI/ARA-C (n ¼ 27), BU/CY
(n ¼ 1)
HCT (N ¼ 34) and age- and sexmatched noncancer control
subjects (N ¼ 68)
Allo-HCT (61.8%), auto-HCT
(38.2%)
Chronic leukemia (14.7%), acute
leukemia (47.1%), MM (8.8%),
MDS (5.9%), solid tumor (2.9%),
lymphoma (17.6%), sarcoma
(2.9%)
TBI fractionated (67.6%), TBI
single dose (8.8%), no (23.5%)
Allo-HCT (N ¼ 121) and
chemotherapy (N ¼ 221)
Disease free
AML Only
Age:
Mean ¼ 32.6
Range ¼ 18.2-49.2
Gender:
M ¼ 16
F ¼ 12
Mean age: 44.7 (9.4)
Gender:
M ¼ 50%
F ¼ 50%
Cross-sectional; mean of
13.2 yr post-HCT
Single item from a
symptom checklist
developed at the
hospital
Descriptives
No statistically significant
changes in sleep disruption
from baseline to 3-5 yr in
allo or auto groups, but CT
group reported improved
sleep quality over time.
Allo patients reported
better sleep, auto worse
sleep than general
Norwegian population at
baseline and 3-5 yr postHCT.
21 of 26 patients were
mildly bothered by sleep
disruption, whereas 5 of 26
were moderately or
severely bothered.
Cross-sectional; patients
were at least 5 yr post-HCT
EORTC-QLQ C30
Mann-Whitney U-tests
No significant differences in
sleep between HCT patients
and healthy control
subjects; patients had
worse sleep by .06 SD.
Allogeneic BMT:
Age at diagnosis:
Median ¼ 38
Gender:
F ¼ 52%
Mean age: 49.25 (12.82)
Gender:
M ¼ 51.5%
F ¼ 47.8%
Race:
White ¼ 83.7%, African
American ¼ 5.7%,
Hispanic ¼ 3.9%, West
Indian ¼ 1.5%,
Other ¼ 4.4%
Cross-sectional; HCT
patients were a median of
8 yr post-HCT; chemo
patients were a median of
9 yr post-chemo
Cross-sectional; mean of
21 mo post-HCT
EORTC QLQ-C30
Chi-square, stratified
Mantel-Haenszel, non
parametrics
FACT-BMT
Percentage
No difference in sleep
disruption between allo
HCT patients and
chemotherapy patients (.06
SD).
80% of patients reported
sleeping well.
Kopp et al.
(2005) [51]
Messerer et al.
(2008) [55]
Mosher et al.
(2011) [56]
HCT (N ¼ 406)
Auto (60.3%), allo (29.1%)
Relapse free
NHL (22.4%), HD (6.2%), AML/
CML (11.6%), ALL/CLL (3.4%),
MDS/MPS (8.4%), MM/
amyloidosis (33.7%), Other
(1.5%)
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973
974
975
976
977
978
979
980
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997
998
999
1000
1001
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
1025
1026
1027
1028
1029
1030
1031
1032
1033
1034
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1047
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
1091
1092
1093
1094
1095
1096
1097
1098
1099
1100
1101
Allo-HCT (N ¼ 100)
AML (41%), CML (22%), ALL
(12%), lymphoma (6%), MDS
(6%), MM (4%), AA (4%), MPD
(2%), PNH (2%), CLL (1%)
Age:
Mean ¼ 46.3 (14.7)
Range ¼ 16-76
Gender:
M ¼ 55%
F ¼ 45%
Cross-sectional; mean of
95.4 mo post-HCT
EORTC QLQ-C30
Effect Sizes ¼ Cohen’s d, t-tests,
1-way ANOVA
Rischer et al.
(2009) [4]
HCT (N ¼ 50 at pre-HCT, N ¼ 32
at day 100 post-HCT)
Allo (78%), auto (22%)
AML (36%), MM (22%), NHL
(14%), MDS (10%),
osteomyelofribrosis (10%),
Others (8%)
Mean age: 53.3 (12.6)
Gender:
M ¼ 74%
F ¼ 26%
Longitudinal; 3
assessments: pre-HCT,
during hospital stay, and
day 100 post-HCT
PSQI, sleep diary
Chi-square, McNemar
tests, repeated measures
ANOVA Spearman’s
correlation coefficients
Sherman et al.
(2003) [35]
Pre-BMT (N ¼ 61)
MM (85.3%), MGUS (8.2%),
amyloid (6.6%)
Age:
Mean ¼ 57 (12.3)
Gender:
M ¼ 63.9%
F ¼ 36.1%
Race:
White ¼ 91.8%
Other ¼ 8.2%
Cross-sectional; mean of
7.4 mo post-diagnosis; all
were assessed before BMT
Epworth Sleepiness
Scale
Descriptives, percentages,
and Spearman correlations
No significant association
between sleep disruption
and time since transplant.
Sleep disruption was
greater in patients with
ongoing GVHD compared
with patients with no
GVHD (ES ¼ .31; not
significant).
Difference in sleep
disruption between HCT
patients and the reference
Austrian population (ES ¼
.31).
Prevalence of sleep
disruption 32% before HCT,
77% during hospitalization,
28% at day 100.
During hospitalization:
difficulties maintaining
sleep was the most
reported sleep dimension
(81.8% moderate to severe,
mainly caused by noises
and toileting), then
nonrestorative sleep
(61.4%), difficulties falling
asleep (52.3%), difficulties
falling back asleep (47.7%),
and early a.m. awakenings
(20.5%).
Allo patients had
significantly worse sleep
than auto patients.
Increases in sleep
disruption correlated with
increases in fatigue,
physical functioning,
treatment-specific distress
but not anxiety and
depression
Pilot study
43.33% exceeded the
clinical cut-off of daytime
sleepiness.
Older age associated with
more daytime sleepiness.
Lower hemoglobin levels
associated with more
daytime sleepiness.
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Pallua et al.
(2010) [47]
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1102
1103
1104
1105
1106
1107
1108
1109
1110
1111
1112
1113
1114
1115
1116
1117
1118
1119
1120
1121
1122
1123
1124
1125
1126
1127
1128
1129
1130
1131
1132
1133
1134
1135
1136
1137
1138
1139
1140
1141
1142
1143
1144
1145
1146
1147
1148
1149
1150
1151
1152
1153
1154
1155
1156
1157
1158
1159
1160
1161
1162
1163
1164
1165
1166
1167
1168
1169
1170
1171
1172
1173
1174
1175
1176
1177
1178
1179
1180
1181
1182
1183
1184
1185
1186
1187
1188
1189
1190
1191
1192
1193
1194
1195
1196
1197
1198
1199
1200
1201
1202
1203
1204
1205
1206
1207
1208
1209
1210
1211
1212
1213
1214
1215
1216
1217
1218
1219
1220
1221
1222
1223
1224
1225
1226
1227
1228
1229
1230
1231
10
Table 1
(continued )
Sample
Demographics
Time Frame
Sleep Measures
Statistical Analyses
Main Relevant Findings
Syrjala et al.
(2005) [52]
HCT survivors (N ¼ 137) and
age- and sex-matched control
subjects from the NHANES
study (N ¼ 4020)
Allo (88%), auto (12%)
CML (chronic phase) (45%), CML
(accelerated or blast crisis) (7%),
acute leukemia in remission
(14%), acute leukemia in relapse
(8%), lymphoma in remission
(10%), lymphoma in relapse
(7%), MDS (7%), Other (4%)
HCT (N ¼ 171) and
chemotherapy (n ¼ 310)
Allo (n ¼ 97), auto (n ¼ 74)
CY (n ¼ 147), BU (n ¼ 26),
mesna (n ¼ 27), MEL (n ¼ 18),
TBI (n ¼ 135)
BMT survivors:
Mean Age: 34.6 (9.0)
Gender:
M ¼ 48%
Race:
White ¼ 95%
non-white,
non-Hispanic ¼ 3%
Hispanic ¼ 2%
Cross-sectional; 10 yr postHCT
Checklist of symptoms
developed for the study
Paired t-tests, McNemar,
Wilcoxon signed ranks tests
Alphas set at .01.
14% of survivors reported
moderate or severe sleep
problems compared with
9% of control subjects;
results were not
statistically significant.
For all groups:
Age:
Median ¼ 39
Range ¼ 15-58
Gender:
M ¼ 45%
F ¼ 55%
Cross-sectional; at least 1 yr
post-HCT
EORTC QLQ-C30
Wilcoxon 2 sample test, t-test,
generalized linear models
Age:
Median ¼ 50
Range ¼ 31-66
Gender:
M ¼ 13
F¼9
Age:
Median ¼ 34
Range ¼ 17-57
Gender:
M ¼ 86
F ¼ 69
Longitudinal; pre-HCT and
1 yr post-HCT
EORTC QLQ-C30
McNemar test, paired t-test
45% of patients reported
sleep disruption.
Sleep disruption more
severe in older patients
than younger patients. No
difference in sleep
disruption between allo,
auto, or chemotherapy
groups. No differences in
sleep disruption between
males and females.
No significant changes in
sleep disruption (ES ¼ .03),
no differences compared
with Swedish population
norms
Cross-sectional; at least 2 yr
post-HCT
EORTC QLQ-C30
Descriptives
Watson et al.
(2004) [59]
Wettergren et al.
(2008) [34]
Auto-HCT (N ¼ 22), compared
with Swedish population
norms
HD (n ¼ 1), NHL (n ¼ 3), AML
(n ¼ 6), MM (n ¼ 12)
Worel et al.
(2002) [46]
Allo or syngeneic HCT (N ¼ 155)
Disease free
ALL/AML (n ¼ 9/43), CML (n ¼
56), MM (n ¼ 5), MDS (n ¼ 7),
NHL (n ¼ 15), AA (n ¼ 19),
testicular cancer (n ¼ 1)
TBI/CY, CY, CY/ATG, BU/CY
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Divided patients 2-5 yr
post-HCT and more than 5
yr post-HCT. Of all patients,
45% had none or slight sleep
disruption, 43% had
moderate sleep disruption,
and 12% had severe sleep
disruption. Percentages
were comparable for
patients 2-5 yr post-HCT
and more than 5 yr postHCT.
AA indicates aplastic anemia; ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; ARA-C, cytarabine; ATG, anti-thymocyte globulin; BEAM, carmustine, etoposide, cytarabine, melphalan; BM, bone marrow; BU,
busulfan; CEC, ; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CY, cyclophosphamide; DSM-IV-TR, Diagnostic and statistical manual of mental disorders, 4th edition, Text Revision; EORTC QLQ-C30,
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; ES, ; FACT-BMT, Functional Assessment of Cancer TherapyeBone Marrow Transplant; FLU, fludarabine; HD, hodgkin disease; ISI, Insomnia Severity Index; MDASI, M.D. Anderson Symptom Inventory; MDS, myelodysplastic syndrome; MEL, melphalan; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MOS,
medical outcomes study; MPS, myeloproliferative syndrome; MRD, matched related donor; MUD, matched unrelated donor; NHL, non-Hodgkin’s lymphoma; PBSC, peripheral blood stem cell; PNH, paroxysmal nocturnal
hemoglobinuria; PSQI, Pittsburgh Sleep Quality Index; REM, rapid eye movement; RIC, reduced-intensity conditioning; SF-36, medical outcomes study short forme36; SIP, sickness impact profile; TBI, total body irradiation; VP16, etoposide; WHOQOL100, World Health Organization Quality of Life Questionnaire 100.
Q 11
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1235
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terms of their sample composition, sample size, measure of
sleep, and clinical cut-off [3,4,31-35]. Thus, it is not surprising that there is substantial heterogeneity among study
findings. Studies using single-item measures of sleep
disruption suggest that approximately 8% of autologous patients report moderate to severe sleep disruption [31],
whereas more than 50% of allogeneic patients report sleep
disruption of any severity [3]. In contrast, the 2 studies using
validated measures (ie, Pittsburgh Sleep Quality Index and
Epworth Sleepiness Scale) found that 32% of patients reported clinically significant sleep disruption before autologous or allogeneic transplant [4] and 43% of multiple
myeloma patients reported clinically significant daytime
sleepiness before autologous transplantation [35]. A direct
comparison of sleep disruption between patients receiving
allogeneic versus autologous HCT using a single-item measure suggested that sleep was significantly better among
allogeneic patients, although sample sizes were small and
findings were confounded by group differences in diagnosis
and remission status [33]. Comparisons between HCT patient
and population norms are mixed, with 1 large study
reporting that patients reported significantly worse sleep
before autologous transplant or treatment with melphalan or
prednisone [32], whereas 2 smaller studies found no differences, perhaps due to low statistical power [33,34]. In summary, although findings are mixed, available data suggest
that sleep disruption before transplant is common but relatively mild on average.
SLEEP DISRUPTION AND DISORDERS DURING THE ACUTE
TRANSPLANT PERIOD
The first 100 days post-transplant are typically characterized by multiple acute side effects of the conditioning
regimen, including mucositis, enteritis, nausea and emesis,
episodes of delirium, and, in the case of allogeneic transplant,
acute graft-versus-host disease (GVHD) and immunosuppressive therapies. These side effects and their treatment
may disrupt sleep [36]. Moreover, these side effects
frequently occur in the context of hospitalization, which can
have an additive effect on disrupted sleep [4]. Consequently,
sleep disruption tends to be most pronounced in the first
100 days post-transplant. The most extensive research on
sleep disruption in HCT patients has also been conducted
during this period [3,4,24-26,30-32,37-39], although it is
characterized by several limitations, including small samples, which are heterogeneous in terms of diagnosis and
transplant type as well as low statistical power. In addition,
data are lacking regarding the prevalence and onset of sleep
disorders during this time, with the exception of 1 study
reporting a prevalence rate of clinically significant insomnia
of 26% [37]. Available data suggest that sleep disruption was
the most distressing symptom among allogeneic HCT recipients at day 0 and was significantly correlated with bowel
changes and fatigue [3]. Sleep disruption significantly
increased during the first 100 days, with greatest disruption
seen during the conditioning regimen and WBC count nadir
[31]. Mean changes of 27 points on the European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire Core 30 sleep disruption item were observed
from pretransplant baseline to its peak approximately
2 weeks after HCT [25], corresponding to a large increase and
effect size of 1.1 standard deviations (SDs) [25]. These data
are consistent with a quantitative review of all published
studies using the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire Core 30 to
11
assess quality of life in HCT patients, which found large increases in sleep disruption during hospitalization [26].
Difficulty maintaining sleep was the most common
problem in hospitalized HCT patients (82%), followed by
nonrestorative sleep (61%), problems falling asleep (52%),
difficulties falling back to sleep once awake (48%), and early
morning awakening (21%) [4]. Patients largely attributed
these problems to the hospital environment, such as noise
from medical equipment and nursing staff, and to emotional
agitation and stress [4,37]. A small study found that allogeneic transplant patients reported better sleep before transplant but worse sleep during hospitalization [4]. At the time
of hospital discharge, the average severity of sleep disruption
among allogeneic and autologous patients was still moderately elevated relative to baseline symptomatology (ie, .51
SD) [26]. Nevertheless, it appeared that increases in sleep
disruption were generally transient; by day 100, sleep
disruption returned to levels comparable with pre-HCT
[4,25,31], although these levels were substantially elevated
even before the transplant. Patients receiving allogeneic HCT
demonstrate similar levels of sleep disruption near day 100
to patients receiving autologous transplant [4].
SLEEP DISRUPTION AND DISORDERS AFTER THE ACUTE
TRANSPLANT PERIOD
New precipitating factors of sleep disruption may occur
after the acute transplant period. Patients who experienced
resolved sleep disruption or never experienced sleep
disruption during transplantation may develop late-onset
sleep problems due to corticosteroid treatment for chronic
GVHD, inflammation due to GVHD or infection, fear of disease progression, pain, or additional treatments for relapsed
disease. For example, evidence suggests that long-term
corticosteroid use is a risk factor for OSA, perhaps because
of weight gain [40]. Insomnia is also a common side effects of
taking corticosteroids, particularly if the medication is taken
closer to bedtime. Muscle cramps and neuropathy have been
found to be common among patients with GVHD and to
disrupt sleep [41]; neuropathy is also a risk factor for RLS
[42]. These factors and others can also perpetuate existing
sleep problems and contribute to the development of
persistent (lasting more than 3 months) or recurrent sleep
problems. Additional perpetuating factors of insomnia
include cognitive distortions and maladaptive behaviors that
begin in reaction to a stressor and persist after the stressor is
resolved [43]. Examples of cognitive distortions that can
make sleep disruption worse are as follows: “I’m going to feel
terrible tomorrow if I don’t sleep well” or “I’m never going to
get to sleep.” Maladaptive behaviors can include spending
prolonged time in bed, going to bed excessively early,
sleeping late, and staying in bed while no longer asleep.
Although these behaviors may initially be helpful, particularly for people experiencing acute illness, eventually they
can contribute to irregular sleep patterns that result in
insomnia long after the patient has recovered from the acute
stressor or illness [43].
Only 1 study has examined the prevalence of sleep disorders after transplant. Among 61 allogeneic HCT recipients
transplanted 1 to 10 years previously, 23% met criteria for a
diagnosis of insomnia and 3% for hypersomnia; no other
sleep disorders were observed [44]. In addition, no studies
have examined precipitating versus perpetuating factors of
sleep disruption after the acute transplant period. Nevertheless, 23 studies have reported on sleep disruption outside
the context of a diagnosed sleep disorder 90 days or more
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12
Table 2
Online Resources for Sleep Disorders and Disruption
Relevant Disorder(s)
Resource
Internet Address
Description
Evidence Base
Cost
Cognitive-behavioral
interventions
Insomnia
SHUTi
www.shuti.me
Cancer patients
Adults
$129.00 For 16 weeks
of access
Insomnia
RESTORE
www.restorecbt.com
Interactive online program that includes videos
from insomnia experts, interactive quizzes, and
vignettes dealing with real-life sleep issues
Progress is tracked
Provides recommendations tailored to individuals’
sleep difficulties
Treatment consists of 5 modules with instructive
videos and downloadable MP3 files
Adults
Insomnia
Sleepio
www.sleepio.com
Cost unspecified. Made
available through patients
health care provider.
Also works with health
insurance providers.
Three payment plan options:
$9.99 per week, $79.99
for 12-week access, and
$119.99 for 24-week access.
All sleep disorders
National Sleep
Foundation
www.sleepfoundation.org
All sleep disorders
Sleep Education
www.sleepeducation.com
All sleep disorders
Your Sleep
http://yoursleep.aasmnet.org
OSA
American Sleep
Apnea Association
http://sleepapnea.org/
RLS
Willis-Ekbom Disease
Foundation
http://www.rls.org/
Insomnia
National Cancer
Institute
www.cancer.gov
General sleep health
American Cancer
Society
www.cancer.org
Insomnia
Cancer Support
Community
www.cancersupportcommunity.org
Education about
insomnia and
treatment
Cancer-specific
education about
insomnia and
treatment
Interactive online treatment is delivered by a
virtual therapist and consists of 6 personally
tailored interactive stages
Progress is tracked and each stage is adjusted
accordingly
Comprehensive information about sleep, support
groups, video and audio library, and sleep
professional location assistance
Comprehensive information about sleep
difficulties, video archive, and sleep professional
location assistance
Comprehensive information about sleep,
self-administered sleep assessments, downloadable
sleep diary, online forum, and sleep professional
location assistance
Self-administered screening for OSA, information
about OSA, and information on support groups
for people with OSA
Self-administered screening for RLS, information
about RLS, and information on support groups
for people with RLS
Information specific to cancer related sleep
difficulties, symptom management tips, and
modules
To find sleep information type "sleep" into the
"search" box located on the upper righthand
corner on the home page
Information specific to cancer-related sleep
difficulties and treatment and symptom
management tips, and modules
Available in Spanish.
To find sleep information type "sleep" into the
“search” box located on the center on the home
page
Information specific to cancer-related sleep
difficulties, tips for managing insomnia,
hyperinsomnia, and nightmares
To find sleep information type “sleep” into the
“search” box located on the upper righthand
corner on the home page
Adults
N/A
Free
N/A
Free
N/A
Free
N/A
Free
N/A
Free
N/A
Free
N/A
Free
N/A
Free
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Type of Intervention
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Free
Free
N/A
http://clinicaltrials.gov/
National Institutes
of Health
All sleep disorders
Search engine for nationwide cancer clinical trials
To find sleep-related clinical trials type “sleep”
into the “keywords/phrases” box towards the
middle of the page
Search engine for nationwide clinical trials
To find sleep-related clinical trials with cancer
patients type “sleep AND cancer” into the
“search for studies” box at the top of the page
http://www.cancer.gov/clinicaltrials/
search
National Cancer
Institute
All sleep disorders
Clinical trials
search engines
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13
after HCT. Notably, 20 assessed sleep using a single item as
part of a larger quality of life scale, whereas only 3 included
validated measures of sleep. Seventeen studies were crosssectional; many included mixed samples of autologous and
allogeneic recipients who ranged widely in terms of time
from transplant. Thus, definitive conclusions are difficult to
draw. However, available data suggest that after peaking
during the acute transplant period, the prevalence and
severity of sleep disruption remains relatively constant over
time. Most studies found no significant change in sleep
disruption between 1 and 10 years post-transplant [44-47].
HCT survivors tend to report worse sleep disruption
compared with population norms and noncancer comparison groups (ie, .33 to .39 SD) [45,47-50], but the evidence is
mixed [34,51-53]. A cross-sectional study of allogeneic recipients 1 to 10 years post-transplant found that 23% met
criteria for clinical diagnosis of insomnia [44], a rate similar
to that of the general population (ie, 22%) [54]. Furthermore,
sleep disruption in patients treated with HCT also does not
differ from that in patients treated with standard-dose
chemotherapy at 8 to 9 years post-treatment [55].
Although most evidence suggests no significant change in
sleep disruption after the first 100 days post-transplant, estimates of the prevalence of sleep disruption in HCT patients
vary widely. At 1 year post-HCT, 14% of patients receiving
allogeneic transplant with reduced-intensity conditioning
and 26% of patients receiving autologous transplantation
reported sleep disruption [39]. A mean of 2 years after
transplant (range, 1 to 3 years), 20% of patients reported
sleep disruption [56]. In contrast, 2 to 5 years after transplant, 49% of patients reported none or slight, 43% reported
moderate, and 8% reported severe sleep disruption [46]. Five
or more years after transplant, 44%, 42%, and 14% of patients
reported none or slight, moderate, and severe sleep disruption, respectively [46]. A mean of 10 years after transplant,
14% reported moderate or severe sleep disruption [52]. An
average of 13 years after transplant (range, 10 to 18), 81% of
patients reported they were not bothered or only mildly
bothered by sleep disruption, whereas 19% reported they
were moderately or severely bothered [57]. In summary, the
overall prevalence of any sleep problems after the acute
transplant period (ie, after 100 days) ranges from 14% to 51%,
with the prevalence of moderate problems ranging from 14%
to 43% and severe problems ranging from 8% to 14%. Variability in prevalence rates likely stems from sample bias due
to small sample sizes in this literature.
SOCIODEMOGRAPHIC AND CLINICAL PREDICTORS OF
SLEEP DISRUPTION AND DISORDERS
A clinically relevant question is how to identify HCT patients at risk for sleep disruption and disorders. Risk factors
for insomnia among cancer patients include female gender,
anxiety, surgical treatment, and maladaptive beliefs about
sleep [58]. Among HCT patients, 1 small study observed that
conditioning with busulfan and cyclophosphamide was a
risk factor for insomnia [44]. Risk factors for OSA in the
general population include obesity, type 2 diabetes,
congestive heart failure, kidney disease, and treatmentrefractory hypertension [17].
Some of the risk factors that lead to sleep disruption and
disorders may be more prevalent after HCT (eg, diabetes,
hypertension). Risk factors for RLS in the general population
include female gender, pregnancy, low blood ferritin, high
alcohol intake, poor renal function, high blood glucose levels,
and obesity [42]. Although HCT patients are more likely to
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have high (rather than low) blood ferritin, they may experience high blood glucose levels and weight gain because of
treatment with corticosteroids. In addition, several autoimmune diseases are risk factors for RLS (eg, rheumatoid
arthritis, multiple sclerosis, Crohn’s disease), suggesting that
high levels of inflammation may play a role [42]. These
findings have relevance for GVHD as a potential risk factor for
RLS, although data are lacking. Thus, in general, risk factors
for clinical sleep disorders include female gender, obesity,
comorbidities such as diabetes and poor renal function,
anxiety, and maladaptive beliefs about sleep.
Regarding sleep disruption outside the context of a
diagnosed sleep disorder, evidence suggests that women are
more likely to endorse sleep problems than men [44]. Evidence also suggests that sleep disruption is more severe in
older patients [44,59]. Systemic inflammation has been
associated with worse sleep, although the sample was small
and primarily consisted of autologous HCT recipients [60].
Regarding transplant type, allogeneic recipients tend to
report better sleep than autologous recipients before transplant and 3 years later [33] but worse sleep during the acute
transplant period [4,28,37]. Among allogeneic recipients,
significant associations between GVHD and sleep disruption
have not been found [47]; however, literature examining this
relationship is sparse. Other clinical variables, such as bone
marrow versus peripheral blood stem cell transplantation,
have not shown significant differences in the prevalence of
sleep problems [61]. Nevertheless, comparisons by GVHD
and type of hematopoietic stem cell collection are likely
underpowered because of small sample sizes. Regarding
psychosocial risk factors, research is scarce, but available
studies suggest that divorced HCT recipients have higher
rates of sleep problems than unmarried patients [29] and
unemployed recipients report worse sleep than recipients
who are working at the time of assessment [29,49]. In
addition, distress, depression, and anxiety are associated
with worse sleep [29]. Thus, available evidence suggests that
risk factors for sleep disruption outside the context of a
diagnosed sleep disorder are older age, female gender,
divorce, unemployment, distress, and autologous transplant.
Additional research is needed to confirm these findings in
larger samples.
TREATMENT OF SLEEP DISRUPTION AND DISORDERS
Treatments for sleep disorders are varied and depend on
the underlying cause. Regarding insomnia, the National
Institutes of Health Consensus and the American Academy
of Sleep Medicine recommend cognitive behavioral therapy
for insomnia (CBT-I) as the standard treatment [18].
Extensive research has shown that CBT-I can be as effective
as some pharmacologic agents in the treatment of insomnia
in the general population [62]. There have been no studies
to date on the effectiveness of CBT-I specifically in patients
undergoing HCT. Nevertheless, numerous well-designed
studies in cancer patients have shown that CBT-I can
indeed be effective in improving objectively (eg, actigraphy)
and subjectively measured (eg, self-reported insomnia
severity and sleep diaries) sleep disruption during and after
treatment [63].
Therapeutic effects of CBT-I have been found to last for up
to 12 months in cancer survivors [63]. The American Academy of Sleep Medicine recommends that when pharmacotherapy is used for insomnia, short- or intermediate-acting
benzodiazepine receptor agonists or ramelteon (Rozerem), a
melatonin receptor agonist, be prescribed [16]. Examples of
medications in various drug classes, along with indications,
contraindications, and long-term efficacy from randomized
placebo-controlled trials in patients with primary insomnia,
are listed in Table 3. The choice of medications within a class Q 3
of drugs should depend on patients’ symptomatology (eg,
delayed sleep onset versus difficulty maintaining sleep),
patients’ preferences regarding use of a controlled substance,
and contraindications of the medication. It should be noted
that no studies have examined pharmacotherapy for
insomnia specifically in the context of HCT.
The first-line treatment for OSA is positive airway pressure, which pneumatically splits the upper airway through a
device worn on the nose and/or mouth during sleep [17].
Additional therapies for OSA include surgery, oral appliances,
implanted upper airway stimulation devices, and behavioral
strategies to lose weight, exercise, adjust sleep position, and
avoid alcohol and sedatives at bedtime [17]. No studies have
examined treatments for OSA among patients treated with
HCT.
The first-line treatment for RLS includes the dopamine
agonists pramipexole and ropinirole [18]. Additional medication options include levodopa with dopa decarboxylase
inhibitor, opioids, gabapentin, enacarbil, and cabergoline.
Although no treatment studies for RLS have been conducted
specifically among HCT recipients, pregabalin shows promise for treating RLS secondary to neuropathy and/or neuropathic pain [64]. Also, some data suggest that some
antidepressants may contribute to increased risk of RLS,
including citalopram, paroxetine, amitriptyline, mirtazapine, and tramadol, although evidence is mixed [18]. Thus,
avoidance or discontinuation of use of these medications
should be considered in patients with RLS.
To our knowledge, only 1 behavioral intervention study
has been conducted in HCT recipients with the primary aim
of improving sleep disruption outside the context of a diagnosed sleep disorder [65]. In addition, 5 behavioral intervention studies have examined sleep disruption as a
secondary outcome [66-70]. All 6 studies were randomized
trials of psychoeducation, stress management, aerobic exercise, and resistance training alone or in combination during
the inpatient period; 1 study also followed patients for
6 months post-HCT [66]. Samples consisted of patients
receiving allogeneic HCT [67,69], autologous HCT [70], tandem autologous HCT [65], and either allogeneic or autologous HCT [66,67]. All reported null results for sleep
disruption compared with usual care. Sample sizes ranged
from 42 to 700. Thus, available data suggest that sleep
disruption does not improve with exercise or stress management during the inpatient period. Additional studies
focusing on long-term transplant survivors are needed.
DISCUSSION
Sleep disruption is a common problem among HCT recipients. In addition to being distressing in its own right,
sleep disruption may affect other clinically important outcomes. For example, previous research in patients undergoing standard-dose chemotherapy suggests that sleep
disruption occurs first in a cascade of symptoms, contributing to increases in fatigue and in turn depression [71]. In
addition, preliminary research suggests that sleep disruption
may negatively impact immune response and reconstitution
[72], although this has not been demonstrated in the context
of HCT. Taken together, these studies argue for early intervention to manage sleep disruption and disorders in HCT
recipients.
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1837
1838
1839
1840
1841
1842
1843
1844
1845
1846
1847
1848
1849
1850
1851
1852
1853
1854
1855
1856
1857
1858
1859
1860
1861
1862
1863
1864
1865
1866
1867
1868
1869
1870
1871
1872
1873
1874
1875
1876
1877
1878
1879
1880
1881
Table 3
Medications Recommended for Treatment of Insomnia by the American Academy of Sleep Medicine [16]
FDA-Approved
for Sleep Onset
[79]
FDA-Approved for
Sleep Maintenance
[79]
Controlled
Substance
Generic
Available
Relevant Contraindications
Include [79]
RCT-Demonstrated
Efficacy for Insomnia
up to
Relevant Drug Interactions
Short/intermediate
acting benzodiazepine
receptor agonists
Eszopiclone
(Lunesta)
Yes
Yes
Yes
Yes
6 mo
CNS depressants, rifampicin,
ketoconazole
Temazepam
(Restoril)
Yes
Yes
Yes
Yes
8 wk
CNS depressants, hypnotics,
diphenhydramine
Triazolam
(Halcion)
Yes
No
Yes
Yes
Impaired motor/cognitive
performance with higher
dosage in elderly
Oversedation, confusion,
ataxia with higher dosage
in elderly
Compromised respiratory
function, renal or hepatic
impairment, pulmonary
insufficiency
5 wk
Zaleplon
(Sonata)
Yes
No
Yes
Yes
Conditions affecting
metabolism or hemodynamic
responses or compromised
respiratory function
4 wk
Zolpidem
(Ambien)
Yes
No
Yes
Yes
8 mo
Zolpidem
(Ambien CR)
Yes
Yes
Yes
Yes
Zolpidem
(Intermezzo)
No
Yes
Yes
No
Compromised respiratory
function, conditions affecting
metabolism or hemodynamic
responses, renal or hepatic
impairment, risk of impaired
motor/cognitive performance
in elderly
Compromised respiratory
function, conditions affecting
metabolism or hemodynamic
responses, renal or hepatic
impairment, risk of impaired
motor/cognitive performance
in elderly
Compromised respiratory
function, risk of impaired
motor/cognitive performance
in elderly
Ketoconazole, itraconazole,
nefazodone, HIV protease
inhibitors, medications that
impair the oxidative
metabolism mediated by CYP3A4
Promethazine; rifampin; CYP3A4
inducers; CYP3A4 inhibitors;
cimetidine; additive CNS
depression with other
psychotropic medications,
anticonvulsants, antihistamines,
narcotic analgesics, anesthetics,
ethanol, and other CNS depressants
CNS depressants; other sedativehypnotics; imipramine;
chlorpromazine; alcohol;
sertraline; CYP3A4 inhibitors;
rifampin; fluoxetine; ketoconazole
Melatonin receptor
agonist
Ramelteon
(Rozerem)
Yes
No
No
Yes
Intermediate/long acting
benzodiazepine
receptor agonist
Clonazepam
(Klonopin)
No
No
Yes
Yes
CNS depressants; other sedativehypnotics; imipramine;
chlorpromazine; alcohol;
sertraline; CYP3A4 inhibitors;
rifampin; fluoxetine; ketoconazole
4 wk
CNS depressants; imipramine;
chlorpromazine; rifampin;
ketoconazole
Hepatic impairment, may affect
reproductive hormones
6 mo
Renal or hepatic impairment,
respiratory diseases, elderly
patients, glaucoma
None
CYP inducers, CYP1A2 inhibitors,
CYP3A4 inhibitors, CYP2C9
inhibitors; donepezil; doxepin;
zolpidem; CNS depressants; alcohol
CYP450 inducers; propantheline;
CYP3A inhibitors; alcohol;
narcotics; barbiturates; hypnotics;
antianxiety agents; phenothiazines;
thioxanthene; butyrophenone
antipsychotics; MAOIs; TCAs;
anticonvulsant drugs; CNS
depressants; valproic acid
(continued on next page)
15
6 mo
H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20
Agent(s)
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Drug Class
1882
1883
1884
1885
1886
1887
1888
1889
1890
1891
1892
1893
1894
1895
1896
1897
1898
1899
1900
1901
1902
1903
1904
1905
1906
1907
1908
1909
1910
1911
1912
1913
1914
1915
1916
1917
1918
1919
1920
1921
1922
1923
1924
1925
1926
1927
1928
1929
1930
1931
1932
1933
1934
1935
1936
1937
1938
1939
1940
1941
1942
1943
1944
1945
1946
1947
1948
1949
1950
1951
1952
1953
1954
1955
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
Drug Class
Agent(s)
FDA-Approved
for Sleep Onset
[79]
FDA-Approved for
Sleep Maintenance
[79]
Controlled
Substance
Generic
Available
Relevant Contraindications
Include [79]
RCT-Demonstrated
Efficacy for Insomnia
up to
Relevant Drug Interactions
Estazolam (ProSom,
Eurodin)
Yes
No
Yes
Yes
Renal or hepatic impairment,
compromised respiratory
function, depression
1 wk
Flurazepam
(Dalmane)
Yes
Yes
Yes
Yes
3 wk
Lorazepam
(Ativan)
No
No
Yes
Yes
Amitriptyline
No
No
No
Yes
Depression, hepatic or renal
impairment, pulmonary
insufficiency
Compromised respiratory
function, impaired renal or
hepatic function, elderly
Liver dysfunction
CNS-acting drugs; anticonvulsants;
antihistamines; alcohol; barbiturates;
MAOIs; narcotics; phenothiazines;
psychotropic medications; CNS
depressants; smoking; CYP3A
inhibitors; CYP3A inducers
CNS depressants; alcohol
Doxepin (Silenor)
3-6 mg
No
Yes
No
Yes
Compromised respiratory
function
12 wk
Mirtazapine
(Remeron)
No
No
No
Yes
Neutropenia and hyponatremia
reported, renal or hepatic
impairment, conditions affecting
metabolism or hemodynamic
responses, elderly, may cause
orthostatic hypotension
None
Trazodone
(Oleptro)
No
No
No
Yes
Hypotension and syncope
reported, elderly, renal or hepatic
impairment, hyponatremia may
occur
1 wk
None
None
CNS depressants; clozapine;
valproate; probenecid; theophylline;
aminophylline
Guanethidine; CNS depressants;
CYP2D6 inhibitors; TCAs; SSRIs;
“caution with thyroid drugs”;
disulfiram; ethchlorvynol;
anticholinergics; sympathomimetics;
neuroleptics; cimetidine
Alcohol; CNS depressants; sedating
antihistamines; CYP2C19 inhibitors;
CYP2D6 inhibitors; CYP1A2 inhibitors;
CYP2C9 inhibitors; cimetidine;
tolazamide; sertraline
MAOIs; serotonergic drugs; drugs
affecting hepatic metabolism; CYP
enzyme inducers; drugs metabolized
by or inducers of cytochrome P450;
antihypertensives known to cause
hyponatremia; phenytoin;
carbamazepine; hepatic metabolism
inducers; cimetidine; ketoconazole;
cimetidine; alcohol; diazepam;
CYP3A4 inhibitors; HIV protease
inhibitors; azole antifungals;
erythromycin; nefazodone; warfarin
Serotonergic drugs; drugs which
impair serotonin metabolism;
antipsychotics; dopamine agonists;
serotonin precursors; CYP3A4
inhibitors; Carbamazepine; MAOIs;
alcohol; barbiturates; CNS
depressants; warfarin;
antihypertensives; NSAIDs; aspirin;
drugs that affect coagulation or
bleeding; diuretics; drugs that
prolong QT interval
H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20
REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce
Sedating low-dose
antidepressant
16
Table 3
(continued )
2012
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
2055
2056
2057
2058
2059
2060
2061
2062
2063
2064
2065
2066
2067
2068
2069
2070
2071
2072
2073
2074
2075
2076
2077
2078
2079
2080
2081
2082
2083
2084
2085
2086
2087
2088
2089
2090
2091
2092
2093
2094
2095
2096
2097
2098
2099
2100
2101
2102
2103
2104
2105
2106
2107
2108
2109
2110
2111
2112
2113
2114
2115
2116
2117
2118
2119
2120
2121
2122
2123
2124
2125
2126
2127
2128
2129
2130
2131
2132
2133
2134
2135
2136
2137
2138
2139
2140
2141
Other prescription
drugs
No
No
No
Yes
Liver dysfunction, elderly
None
Gabapentin
(Neurontin)
Olanzapine
(Zyprexa)
No
No
No
Yes
None
No
No
No
Yes
Liver dysfunction, hepatic
impairment
Hepatic impairment; prostatic
hypertrophy; may cause
orthostatic hypotension;
leukopenia, neutropenia, and
agranulocytosis reported; may
cause cognitive and motor
impairment
Tiagabine
(Gabitril)
No
No
No
Yes
Incapacitating weakness
reported
1 night
Quetiapine
(Seroquel)
No
No
No
Yes
May induce orthostatic
hypotension; leukopenia,
neutropenia, and agranulocytosis
reported; may impair physical/
mental abilities
None
None
Serotonergic drugs; drugs which
impair serotonin metabolism;
caution on patients on thyroid
medication; guanethidine;
cimetidine; alcohol; catecholamines;
anticholinergics; sympathomimetic
amines; local decongestants; local
anesthetics containing epinephrine;
atropine; CYP2D6 inhibitors; SSRIs;
TCAs
Maalox; naproxen sodium;
hydrocodone
Diazepam; alcohol; carbamazepine;
omeprazole; rifampin; CYP1A2
inducers; fluoxetine; fluvoxamine;
other centrally-acting drugs;
potentially hepatotoxic drugs;
antihypertensives; levodopa;
dopamine agonists; anticholinergic
drugs; parenteral benzodiazepines
Valproate; carbamazepine; phenytoin;
phenobarbital; ethanol; triazolam;
drugs that lower seizure threshold
(antidepressants, antipsychotics,
stimulants, narcotics); drugs that
induce or inhibit hepatic
metabolizing enzymes; highly
protein-bound drugs
Centrally-acting drugs; alcohol;
CYP3A4 inhibitors; CYP3A4
inducers; antihypertensives;
levodopa; dopamine agonists;
drugs known to cause electrolye
imbalance; drugs known to prolong
QTc interval (eg, antiarrhythmics,
antipsychotics, antibiotics);
anticholinergic medications
FDA indicates U.S. Food and Drug Administration; RCT, randomized controlled trial; CNS, central nervous system; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20
REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce
Trimipramine
(Surmontil)
17
2142
2143
2144
2145
2146
2147
2148
2149
2150
2151
2152
2153
2154
2155
2156
2157
2158
2159
2160
2161
2162
2163
2164
2165
2166
2167
2168
2169
2170
2171
2172
2173
2174
2175
2176
2177
2178
2179
2180
2181
2182
2183
2184
2185
2186
2187
2188
2189
2190
2191
2192
2193
2194
2195
2196
2197
2198
2199
2200
2201
2202
2203
2204
2205
2206
18
2207
2208
2209
2210
2211
2212
2213
2214
2215
2216
2217
2218
2219
2220
2221
2222
2223
2224
2225
2226
2227
2228
2229
2230
2231
2232
2233
2234
2235
2236
2237
2238
2239
2240
2241
2242
2243
2244
2245
2246
2247
2248
2249
2250
2251
2252
2253
2254
2255
2256
2257
2258
2259
2260
2261
2262
2263
2264
2265
2266
2267
2268
2269
2270
2271
H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20
Effective management of sleep disruption may be difficult in the inpatient setting due to environmental factors
that can interrupt sleep. Environmental interventions to
improve sleep among inpatients may be more effective than
patient-based interventions (eg, minimizing of nighttime
vital signs monitoring). A study conducted by Sharda et al.
[73] suggests that vital sign monitoring might not be
necessary for HCT patients with low-risk profiles (ie, lack of
daytime fever and central nervous system complaints) and
may lead to improved sleep and health. In contrast, use of a
hypnotic (zolpidem) has been associated with increased
inpatient falls [74].
Regarding outpatient sleep management, several pharmacologic and behavioral management options are available.
National Comprehensive Cancer Network Survivorship
guidelines recommend screening for sleep disruption at
regular intervals, particularly when there has been a change
in clinical status or treatment [75]. Insomnia causing
decreased daytime functioning, worse quality of life, worsening of complaints, or distress to the patient should be
treated with CBT, sleep hygiene education, medication, and/
or referral to a sleep specialist [75]. In light of the strong
evidence base for CBT-I in cancer patients, we believe it
should be considered as a first choice for treatment of
chronic sleep disruption in HCT recipients. CBT-I lacks side
effects, medication interactions, and potential for abuse. In
addition, it may be more acceptable than pharmacologic
treatment for HCT recipients who would prefer to avoid
additional medication. Referral to a clinical psychologist
board certified in behavioral sleep medicine is recommended
for patients interested in CBT-I. For patients who are unwilling or unable to engage in CBT-I or for whom it is not
effective or feasible, pharmacologic treatment is a viable
alternative. Previous research has found that sleep medications commonly prescribed to cancer patients are lorazepam
(31.4%) and zolpidem (29.4%) [76], although, as noted previously, no evidence exists for their effectiveness in HCT recipients. Patients with OSA should be referred to a sleep
medicine physician, whereas patients with RLS should be
treated with medication and/or referred to a sleep medicine
physician [75]. Because of the specialized needs of HCT patients, it is advisable that patients with sleep disorders be
managed by an interdisciplinary team consisting of the
transplant physician, sleep medicine physician, and/or clinical psychologist.
Additional research is clearly needed regarding sleep
disruption in HCT recipients. Longitudinal studies should be
conducted to determine prevalence, chronicity, and natural
course of sleep disruption and disorders secondary to HCT
using well-validated objective and self-report measures of
sleep as well as clinical diagnostic criteria. The prevalence of
sleep disruption and disorders in HCT recipients should be
compared with population normative data, because they are
also common among individuals without cancer. Future
studies should also aim to identify genetic, sociodemographic, and clinical risk factors for sleep disruption and
disorders secondary to HCT. Well-designed randomized
controlled trials are needed to test the efficacy of behavioral
and pharmaceutical management of sleep problems in HCT
recipients.
In summary, sleep disruption is a common, distressing,
and under-recognized problem among HCT recipients. Clinical efforts to proactively manage sleep disruption and disorders have the potential to improve overall quality of life in
this population. Until more research is conducted with a
specific focus on HCT recipients, strategies to manage sleep
disruption and disorders should be adapted from the current
evidence base in cancer patients and the general population.
ACKNOWLEDGMENTS
Financial disclosure: Supported by National Cancer Insti- Q 1
tute grant K07 CA138499 (to H.S.L.J.), National Cancer Institute grant K07 CA132916 (to O. P.), and the Stanford Cancer Q 13
Institute Seed Award (to O. P.).
Conflict of interest statement: ---.
Q4
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2321
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2326
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