Sleep Disruption in Hematopoietic Cell Transplantation Recipients Prevalence Severity and Clinical Management

Biol Blood Marrow Transplant xxx (2014) 1e20
1 64
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Sleep Disruption in Hematopoietic Cell 65
3 Transplantation Recipients: Prevalence, ASBMT 66
4 American Society for Blood
67
5 Severity, and Clinical Management and Marrow Transplantation
68
6 69
7 Q 14 Heather S.L. Jim 1, *, Bryan Evans 1, Jiyeon M. Jeong 2, 70
8 Brian D. Gonzalez 1, Laura Johnston 2, Ashley M. Nelson 3, 71
9 72
Shelli Kesler 2, Kristin M. Phillips 2, Anna Barata 1, 4,
10 73
11 Joseph Pidala 1, Oxana Palesh 2 74
12 Q 12 1
Moffitt Cancer Center, Tampa, Florida 75
2
13 Stanford School of Medicine, Stanford Cancer Institute, Stanford, California 76
3
14 University of South Florida, Tampa, Florida 77
4
Psychiatry and Legal Medicine PhD Program, Universitat Autònoma de Barcelona, Barcelona, Spain
15 78
16 79
17 80
18 Article history: a b s t r a c t 81
Received 27 December 2013 Sleep disruption is common among hematopoietic cell transplantation (HCT) recipients, with over 50% of
19 Accepted 9 April 2014
82
patients experiencing sleep disruption pretransplantation, up to 82% experiencing moderate to severe sleep
20 83
disruption during hospitalization for transplant, and up to 43% in the post-transplantation period. These rates
21 Key Words: of sleep disruption are substantially higher than the general population. Although sleep disruption can be 84
22 Sleep disruption distressing to patients and contribute to diminished quality of life, it is rarely discussed during clinical visits. 85
23 Hematopoietic cell transplant The goal of the current review is to draw attention to sleep disruption as a clinical problem in HCT to facilitate 86
Management of sleep
24 patient education, intervention, and research. The review opens with a discussion of sleep disruption mea- 87
disruption
25 surement and clinical diagnosis of sleep disorders. An overview of the prevalence, severity, and chronicity of 88
26 sleep disruption and disorders in patients receiving HCT follows. Current evidence regarding sociodemo- 89
27 graphic and clinical predictors of sleep disruption and disorders is summarized. The review concludes with 90
28 suggestions for behavioral and pharmacologic management of sleep disruption and disorders as well as di- 91
29 Q 2
rections for future research.
92
Ó 2014 American Society for Blood and Marrow Transplantation.
30 93
31 94
32 95
33 INTRODUCTION discussed sleep with their patients during at least half of 96
34 The number of both autologous and allogeneic hemato- clinical visits [5]. 97
35 poietic cell transplants (HCTs) has increased dramatically in The goal of the current review is to draw attention to 98
36 recent years, with more than 50,000 performed worldwide sleep disruption as a clinical problem in HCT and to provide 99
37 each year [1]. This increase in HCT is due to a greater number clinicians and researchers with an overview of current evi- 100
38 of indications for its use as well as advances in therapy, dence to facilitate diagnosis, patient education, intervention, 101
39 including more frequent use of peripheral blood stem cells, and research. The review begins with a brief discussion of the 102
40 reduced-intensity conditioning regimens, greater use of cells assessment and clinical diagnosis of sleep disruption and 103
41 from unrelated and alternative donors, improvements in common sleep disorders (ie, insomnia, obstructive sleep 104
42 supportive care, and advances in histocompatibility typing. apnea [OSA], and restless legs syndrome [RLS]). We then 105
43 Survival has generally improved as well [1], resulting in a synthesize and critically review evidence regarding the 106
44 growing number of patients living with the short- and long- prevalence, severity, and chronicity of sleep disruption and 107
45 term side effects of HCT. disorders in patients before HCT, during the acute trans- 108
46 Sleep disruption is frequently overlooked as a side effect plantation phase, and early, middle, and long-term survi- 109
47 of HCT. Sleep disruption includes difficulty falling asleep, vorship. This review focuses on HCT studies published in the 110
48 staying asleep, awakening earlier than intended, and/or past decade to ensure greater relevance to current transplant 111
49 nonrestorative sleep [2]. It can occur without a clinical practices. Sociodemographic and clinical risk factors are 112
50 diagnosis of a sleep disorder, although a clinical diagnosis described, with an emphasis on those relevant to HCT. We 113
51 may be warranted if sleep disruption is chronic and impairs conclude with recommendations for management of sleep 114
52 daily functioning. Sleep disruption is common after HCT, disruption and disorders in the transplant setting as well as 115
53 distressing to patients [3], and associated with greater fa- directions for future research. 116
54 tigue and reduced quality of life [3,4]. Nevertheless, sleep 117
55 disruption is seldom the focus of patienteprovider commu- ASSESSMENT OF SLEEP DISRUPTION 118
56 nication. A survey of 180 HCT physicians found that only 17% Objective and self-report measures of sleep disruption 119
57 have been developed to facilitate differential diagnosis and 120
58 to monitor sleep over time. The gold standard for objective 121
59 measurement is polysomnography, which measures multi- 122
60 Financial disclosure: See Acknowledgments on page 18. ple biologic processes of sleep, including electrical activity in 123
* Correspondence and reprint requests: Heather S. L. Jim, PhD, Depart-
61 the brain and heart, limb movement, and eye movements. In 124
ment of Health Outcomes and Behavior, Moffitt Cancer Center, MRC-PSY,
62 12902 Magnolia Drive, Tampa, FL 33612. addition to collecting essential data for diagnosing sleep 125
63 E-mail address: heather.jim@moffitt.org (H.S.L. Jim). disorders, polysomnography allows the additional advantage 126
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
REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce

2 H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20
127 of monitoring the progression of sleep stages (eg, rapid eye difficulty that occurs at least 3 nights a week for at least 192
128 movement sleep or dreaming) and brain arousal during 3 months; (4) sleep difficulty that occurs despite adequate 193
129 sleep, which can elucidate the occurrence of sleep in- opportunity to sleep; and (5) symptoms that cannot be 194
130 terruptions. It is typically conducted in a sleep lab or hospital, explained by another mental or medical disorder [2]. 195
131 although home-based polysomnography is increasingly used Regarding OSA, a sleep history and physical exam 196
132 because of its lower cost. including symptoms and risk factors (eg, snoring, gasping/ 197
133 An alternative to polysomnography is actigraphic moni- choking at night, daytime sleepiness, obesity, type 2 dia- 198
134 toring in which a small, nonintrusive piezoelectric monitor betes, congestive heart failure, treatment-refractory hyper- 199
135 similar to a wristwatch is worn on the nondominant wrist to tension) are indicated [17]. Patients deemed to be at high risk 200
136 detect and record motion. Specialized software is used to should then be evaluated using polysomnography or home- 201
137 determine sleep versus waking using algorithms validated based monitoring for definitive diagnosis [17]. Criteria for 202
138 against polysomnography. Actigraphy data, in combination diagnosis are (1) evidence by polysomnography of at least 5 203
139 with patients’ self-reports of bedtime and rising time, have apneas or hypopneas per hour of sleep (ie, snoring, snorting/ 204
140 been found to be a reliable and valid measure of circadian gasping, breathing pauses); (2) daytime sleepiness, fatigue, 205
141 sleep patterns [6]. Parameters assessed include time in bed or unrefreshing sleep despite sufficient opportunity for 206
142 asleep, time until sleep onset, number and length of night- sleep; (3) symptoms are not better explained by another 207
143 time awakenings, number and length of daytime naps, and mental or sleep disorder or medical condition; or (4) evi- 208
144 circadian variation in sleep and activity. Periodic limb dence by polysomnography of 15 or more obstructive apneas 209
145 movement can also be assessed. Actigraphs are relatively and/or hypopneas per hour of sleep regardless of accompa- 210
146 inexpensive and can be worn at home or in the hospital for nying symptoms [2]. 211
147 several days or weeks, enabling the naturalistic study of Regarding RLS, diagnosis is based primarily on self-report, 212
148 sleep disruption over time. Actigraphy is typically used for although polysomnography and actigraphy can be used [18]. 213
149 research rather than diagnostic purposes. Diagnostic criteria for RLS are (1) an urge to move the legs 214
150 Despite the widespread availability of polysomnography accompanied by or in response to uncomfortable and un- 215
151 and actigraphy, to our knowledge only 1 study in HCT pa- pleasant sensations in the legs; (2) the urge begins or 216
152 tients has been published using these measures to assess worsens during periods of rest or inactivity, is partially or 217
153 sleep [7]. Thus, objective sleep patterns of HCT patients are totally relieved by movement, and is worse or occurs only in 218
154 largely unknown. the evening or at night; (3) symptoms occur at least 3 times a 219
155 Regarding self-report measures of sleep, several have week for 3 months; (4) symptoms are accompanied by sig- 220
156 been validated in cancer patients [8,9]. The most common nificant distress and/or impairment in functioning; and (5) 221
157 are the Insomnia Severity Index [10] and the Pittsburgh Sleep symptoms are not attributable to another mental or medical 222
158 Quality Index [11]. These measures typically ask patients to disorder [2]. 223
159 estimate how long it takes them to fall asleep, how many 224
160 hours they sleep each night, their use of sleep medications, SLEEP DISRUPTION AND DISORDERS BEFORE 225
161 and their perceptions of sleep quality. Additional measures TRANSPLANT 226
162 used include the Epworth Sleepiness Scale [12] to evaluate Research on sleep disorders before HCT is limited to case 227
163 daytime sleepiness and the International Restless Legs Syn- studies of lymphomas presenting as OSA (eg, [19]). In addi- 228
164 drome Study Group rating scale to evaluate RLS symptom- tion, a study of polysomnography in 12 multiple myeloma 229
165 atology [13]. patients receiving high-dose chemotherapy [7] reported 230
166 In addition to self-report measures, sleep diaries can play greater respiratory events and lower-than-normal levels of 231
167 an important role in research and clinical diagnosis. Patients arterial oxygen saturation, on average. Periodic limb move- 232
168 are typically asked to fill out the diary on a daily basis for ments in the sample were high and increased during the 233
169 several days or weeks. Requested information includes course of chemotherapy. No studies have reported on the 234
170 bedtime and rising times as well as duration of sleep, sleep incidence or prevalence of pretransplant sleep disorders. 235
171 quality, difficulty initiating and maintaining sleep, daytime Numerous precipitating factors can contribute to sleep 236
172 napping, medications taken, and other details [14,15]. Diaries disruption in patients before transplant, however. Patients 237
173 can be particularly useful in both the research and clinical typically undergo several rounds of standard-dose chemo- 238
174 settings for obtaining detailed information regarding pat- therapy that is associated with short- and long-term sleep 239
175 terns of disruption, contributing factors, and targets of disruption [20]. Side effects of chemotherapy, such as pe- 240
176 intervention. ripheral neuropathy, may also contribute to sleep disrup- 241
177 tion [20]. Among cancer patients treated with standard- 242
178 CLINICAL DIAGNOSIS OF SLEEP DISORDERS dose chemotherapy, the prevalence of RLS was 18% (ie, 243
179 Guidelines for clinical evaluation of sleep disorders double that of the general population), with longer 244
180 depend on the disorder under consideration. Regarding chemotherapy associated with greater risk of RLS [21]. In 245
181 insomnia, diagnosis is based on a detailed sleep, medical, addition, many patients have elevated levels of anxiety and 246
182 substance, and psychiatric history in addition to a physical depressive symptomatology [22]; anxiety can contribute to 247
183 and mental status examination. Sleep diaries are often used sleep disruption, whereas both insomnia and hypersomnia 248
184 as well. The goal is to establish the type and evolution of are symptoms of depression and share some common eti- 249
185 insomnia, perpetuating factors, extent of daytime dysfunc- ology [2]. 250
186 tion, and identification of comorbid medical, substance, and/ Regarding the prevalence of sleep disruption outside the 251
187 or psychiatric conditions [16]. context of a diagnosable sleep disorder, 16 studies have 252
188 Diagnostic criteria for insomnia include (1) difficulty examined sleep before transplantation (Table 1). Of these, 9 253
189 initiating sleep, maintaining sleep, and/or early morning studies did not provide estimates of prevalence of sleep 254
190 awakening with the inability to return to sleep; (2) signifi- disruption or comparisons with individuals not receiving 255
191 cant distress and/or impairment in functioning; (3) sleep HCT [7,23-30]. The remaining 7 studies are heterogeneous in 256

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Table 1
Observational Studies of Sleep in HCT Recipients
Study Sample Demographics Time Frame Sleep Measures Statistical Analyses Main Relevant Findings
Anderson et al. Auto-HCT (N ¼ 100) Age: Longitudinal; 5 MDASI-BMT (a single- Repeated measures The percentage of patients
(2007) [31] Included both disease-free and Mean ¼ 53.6 (9.7) assessments: pre-HCT, 3rd- item measure of sleep ANOVA reporting disturbed sleep at
relapsed patients Range ¼ 24-75 4th day of conditioning, day disruption) moderate or severe levels at
NHL (34%), MM (66%) Gender: 0, nadir, day 30 each time point were as
M ¼ 60% follows: 8% at baseline, 34%
F ¼ 40% at conditioning, 39% at
Race: nadir, 14% at day 30.
Caucasian ¼ 81% 8% reported sleep
African American ¼ 12% disruption at baseline, 34%
Hispanic ¼ 5% at conditioning, 26% at

Other ¼ 2% transplant, 39% at nadir,
and 14% at day 30.
Sleep disruption was one of
most severe symptoms at
H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20
nadir, returned to pre-HCT
levels by day 30 post-HCT
Sleep disruption was
significantly worse for NHL
than MM patients (P ¼ .024)
Andrykowski et al. HCT survivors (N ¼ 662) and Mean age: 50.1 (14.2) Cross-sectional; mean of MOS-Sleep MANOVA (univariate HCT survivor group
(2005) [48] age- and sex-matched healthy Gender: 7 yr (84 mo) post-HCT analyses) reported more sleep
control subjects (N ¼ 158) M ¼ 30% (inclusion criteria: >12 mo problems than healthy
Allo (41%), auto (59%), Race: post-HCT) control group (effect size ¼
missing (1%) White ¼ 95% .39, P < .001).
AML (29%), CML (19%), ALL (7%),
Breast cancer (23%), lymphoma
(20%), other (1%)
Bevans et al. Allo-HCT (N ¼ 76) Mean age: 40.2 (13.5) Longitudinal; baseline Symptom Distress Scale Univariate descriptive At baseline, approximately
(2008) [3] RIC (54%), myeloablative (46%) Gender: (before transplant analyses 55% of patients reported
Included patients in remission M ¼ 67% conditioning), day 0, day insomnia, 86% had
and with progressive disease F ¼ 33% 30, day 100 insomnia at day 0, nearly
Acute leukemia (17%), chronic Race: 70% had insomnia at day 30,
leukemia (38%), lymphoma or White ¼ 46% and at day 100 insomnia
MM (29%), MDS (12%), Hispanic ¼ 30% levels went down to
nonhematologic malignancy Asian ¼ 9% baseline levels.
(4%) Black ¼ 7% Insomnia was the most
Other ¼ 8% distressing symptom at day
0 (reported by 32% of
participants).
Bieri et al. (2008) Allo-HCT (N ¼ 124) Age: Cross-sectional; median of EORTC QLQ-C30 Descriptive statistics, Significantly higher sleep
[49,50] AML (n ¼ 40), ALL (n ¼ 20), CML Median ¼ 34 7.3 yr post-HCT t-test disruption among HCT
(n ¼ 31), CLL (n ¼ 1), MDS Range ¼ 14-65 patients compared with
(n ¼ 8), lymphoma (n ¼ 14), Gender: Norwegian population
MM (n ¼ 1), MPS (n ¼ 3), AA M ¼ 79 norms. Unclear where
(n ¼ 6) F ¼ 45 normative data came from.
Difference of .33 SD.
Univariate analysis
indicated that employment
status was associated with
sleep disruption.
(continued on next page)
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Table 1
4
(continued )
Bishop et al. HCT (N ¼ 177), partners (N ¼ Mean age: 50 (10) Cross-sectional; mean of MOS-Sleep Mixed Effect Patients showed
(2007) [50] 177), control subjects (N ¼ 133) Gender: 7 yr (84 mo) post-HCT Linear Models significantly higher rates of
Allogeneic ¼ 78 (44%), F ¼ 50% (inclusion criteria: >12 mo sleep problems than control
Autologous ¼ 99 (56%) Race: post-HCT) subjects (ES ¼ .39).
AML or ALL (39%), CML (22%), White ¼ 94% Partners showed
breast cancer (18%), lymphoma significantly higher rates of
(21%) sleep problems than control
subjects (ES ¼ .22).
Boland et al. Auto-HCT (n ¼ 29), allo-HCT Age: Cross-sectional: mean EORTC QLQ C-30 Spearman’s correlations Sleep disruption
(2013) [60] (n ¼ 3), tandem HCT (n ¼ 10) Median: 60 5.5 yr post-diagnosis significantly correlated
MM (100%) Range: 41-71 (range, 2-12) with serum IL-6 levels (P ¼
MEL (n ¼ 29), maintenance Gender: .02)
lenalidomide (n ¼ 3), M ¼ 17
maintenance interferon-a F ¼ 15
(n ¼ 1)
Boonstra et al. Hospitalized HCT (N ¼ 69) Gender: Cross-sectional; day 14 ISI Descriptives and No insomnia ¼ 26%,
(2011) [37] Allo (n ¼ 46), auto (n ¼ 23) Male ¼ 41 post-HCT (reflective of chi-square tests subthreshold insomnia ¼
Disease sites not reported Female ¼ 26 2-week period) 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%), anxiety-
others (35%), and noise
(24%) most common
reasons for sleep
disruption.
Cohen et al. Diverse HCT (N ¼ 164) Mean age: 45 Longitudinal; 8 MDASI Longitudinal linear mixed Sleep disruption was 1 of
(2012) [28] Allo (62%), auto (38%) Range ¼ 19-74 assessments: pre-HCT to models, correlations the 5 worst reported
Disease sites not reported Gender: day 100 post-HCT symptoms; associated with
HD (n ¼ 24), NHL (n ¼ 21), AML M ¼ 56% myeloablative regimens
(n ¼ 11) F ¼ 44% and worse functional
38 Chemotherapy, 20 Race: status.
radiochemotherapy Black ¼ 15%
Latino ¼ 23%
White ¼ 62%
Danaher et al. HCT (N ¼ 20 at baseline; N ¼ 17 Mean age: 48.65 (23-64) Longitudinal; pre-HCT and EORTC QLQ-C30 t-tests Sleep disruption
(2006) [24] post-HCT) Gender: 5 and 8 d post-HCT significantly worse post-
Auto ¼ 10 (59%), allo ¼ 7 (41%) M ¼ 45% HCT.
Lymphoma (23%), CML (6%), F ¼ 55%
AML (18%), ALL (6%), MM (29%), Race:
myelofibrosis (12%), plasma cell White ¼ 35%, Black ¼ 40%,
leukemia (6%) Latino ¼ 15%, Asian ¼ 5%,
Other ¼ 5%
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De Souza et al. Allo-HCT (N ¼ 26) Age: Cross-sectional; mean of WHOQOL-100: single- Wilcoxon rank sum, No differences in sleep
(2002) [77] All in complete remission Range ¼ 19-61 1248 d post-HCT item assessment: “Do Kruskal-Wallis tests between patients receiving
BM (n ¼ 13), PBSC (n ¼ 13) Gender: you have difficulties BM versus PBSC.
CML (n ¼ 21), AML (n ¼ 3), MDS M ¼ 14 with sleeping?”
(n ¼ 1), ALL (n ¼ 1) F ¼ 12
Diez-Campelo et al. RIC allo-HCT (n ¼ 47), auto-HCT Age range, 16-70 Longitudinal; 6 FACT sleep disruption Descriptives 14.3% of allo-RIC and 26.3%
(2004) [39] (n ¼ 70) assessments: item: “I am sleeping of auto patients had
AML (n ¼ 15), ALL (n ¼ 3), CML days þ7, þ14, þ21, þ90, well” problems sleeping at 1 yr
(n ¼ 5), MDS (n ¼ 7), NHL (n ¼ þ270, þ360 post-HCT post-transplant (P ¼ .29).
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)
Enderlin et al. Age: Cross-sectional; pre-HCT (1 Polysomnography Descriptives Patients had a short sleep
(2013) [7] MM only Mean ¼ 61 assessment before, 1 time, excessive time spent
All participants on the Total Range ¼ 48-72 assessment after chemo awake after sleep onset,
Therapy 3 protocol Gender: cycle) poor sleep efficiency, more
M ¼ 10 time in non-REM sleep, low
F¼2 arterial oxygen saturation,
Race: elevated periodic limb
White ¼ 10 movements as measured by
African American ¼ 2 polysomnography.
Faulhaber et al. Allo-HCT (N ¼ 61) Mean age: 36.5 (12.3) Cross-sectional; 1-10 yr DSM-IV-TR criteria for Multivariate analysis The prevalence of sleep
(2010) [44] CML (37.7%), severe AA (21.3%), Gender: post-HCT sleep disorders disorders was 26.2%.
AML (14.7), ALL (8.1%), NHL M ¼ 54.1% Multivariate analysis
(6.5%), HD (4.9%), Other (6.5%) F ¼ 45.9% indicated that busulfan-
BU/CY (65.6%), RIC (18%), Cy cyclophosphamide was an
(9.8%), TBI/CY (6.6%) independent risk factor for
sleep disorders (included
sex and age).
Frick et al. HCT (N ¼ 282) Age: Cross-sectional; pre-HCT EORTC QLQ-C30 Pearson’s correlation Compared patients with
(2006) [23] Allo (35%), auto (62%) Median ¼ 48.5 coefficient sample of German
AML/MDS (11.7%), ALL (5%), SD ¼ 11.9 populationd36.6 patients
CML (16%), HD (4.3%), NHL Gender: versus 16.4 population (no
(29.9%), MM (29.5%), Other F ¼ 39% SDs or SEs given).
(3.6%); (97% hematologic Sleep disruption was
malignancies) positively correlated with
problematic social support
(.183)
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Table 1
6
(continued )
Frodin et al. Auto-HCT (N ¼ 111) Based on 96 patients: Longitudinal; baseline, EORTC QLQ-C30 The results are presented Worst sleep disruption at 2
(2011) [25] MM (n ¼ 56), lymphoma (n ¼ Age: week 1, week 2, week 3, using descriptive statistics, weeks post-HCT.
32), testicular cancer (n ¼ 3), Mean ¼ 54 (12) week 4, month 2, month 3, means adjusted for gender Sleep returned to baseline
AML (n ¼ 2), multiple sclerosis Gender: month 6, year 1, year 1.5, and age levels by 2 mo post-HCT,
(n ¼ 1) M ¼ 62 year 2, year 2.5, and year 3 and remained relatively
Conditioning: MEL (n ¼ 56), F ¼ 34 stable thereafter through
BEAM (n ¼ 33), CEC (n ¼ 3), BU/ the 3-year follow up.
MEL (n ¼ 2), ZAM (Aavados, Increase of 1.1 SD from pre-
ARA-C, melphalan) (n ¼ 2) HCT baseline to 2 wk follow

up.
Sleep disruption did not
differ between myeloma
and lymphoma patients.
Gallardo et al. Allogeneic BMT (N ¼ 820; N ¼ Peripheral blood group Retrospective; EORTC QLQ-C30, Chi-square, t tests There were no significant
(2009) [61] 150 QOL assessed) (N ¼ 410): follow up for alive patients: Spanish Version differences in sleep
Peripheral blood group (N ¼ Age: median 43.8 mo for difficulties reported
410): AML (25.9%), ALL (24.1%), Median ¼ 35 patients receiving between patients who
CML (30.7%), MM (2.7%), NHL Range ¼ 15-59 peripheral blood, median received bone marrow (n ¼
(7.3%), HD (0.5%), MDS (7.8%), Gender: 46.6 mo for patients 73, M ¼ 15.9, SD ¼ 26.7)
Other (1%) M ¼ 58.9% receiving bone marrow. versus peripheral blood
Bone marrow group (N ¼ 410): F ¼ 41.1% (n ¼ 77, M ¼ 18.2, SD ¼
AML (25.9%), ALL (24.1%), CML Bone marrow group 26.2).
(30.7%), MM (2.7%), NHL (7.3%), (N ¼ 410):
HD (0.5%), MDS (7.8%), Other Age:
(1%) Median ¼ 35
Peripheral blood group: Range ¼ 15-59
conditioning regimen with Gender:
TBI ¼ 198 (48.3%) M ¼ 62.3%
Bone marrow group: F ¼ 37.7%
conditioning regimen with
TBI ¼ 200 (48.8%)
Gruber et al. HCT (N ¼ 163) Age at BMT: Cross-sectional; within SF-36, EORTC QLQ-C30, Mann-Whitney analysis, Unemployed, divorced, and
(2003) [29] Allo (85%), auto (12%), syngenic Median ¼ 34 (9.2) 16 yr post-HCT; (inclusion SIP, Herschbach Stress correlations distressed patients
(3%) Gender: criteria: 2 yr post-HCT, in Cancer Patients reported significantly
Included both disease-free and M ¼ 62.6% transplanted b/w 1979- greater sleep problems.
relapsed patients F ¼ 37.4% 1996)
CLL/CML (n ¼ 69), ALL/AML (n ¼
58), Other (n ¼ 36)
Grulke et al. Quantitative review of 33 Age Range (14-70) Longitudinal; pre-HCT, EORTC QLQ-C30 Categorized data by time of Sleep problems increase
(2011) [26] papers reporting EORTC scores Gender: during hospitalization, at assessment, unweighted during inpatient stay then
in HCT and covering 2800 M ¼ 50.1% discharge, up to 6 mo, arithmetic means. return to baseline levels
patients 7-12 mo, 1-3 yr, >3 yr after discharge (change of
Range of participants (15-415), 25 points).
total N ¼ 2804 Sleep problems described
Allo ¼ 52.6% by authors as “persistent”
Auto ¼ 48.4% and at a “high level.”
Acute leukemia (28%), CML
(15.3%), other hematologic
diseases (42.1%), solid tumors
(14.8%)
776
775
774
773
772
771
770
769
768
767
766
765
764
763
762
761
760
759
758
757
756
755
754
753
752
751
750
749
748
747
746
745
744
743
742
741
740
739
738
737
736
735
734
733
732
731
730
729
728
727
726
725
724
723
722
721
720
719
718
717
716
715
714
713
712
841
840
839
838
837
836
835
834
833
832
831
830
829
828
827
826
825
824
823
822
821
820
819
818
817
816
815
814
813
812
811
810
809
808
807
806
805
804
803
802
801
800
799
798
797
796
795
794
793
792
791
790
789
788
787
786
785
784
783
782
781
780
779
778
777
Gulbrandsen et al. Auto-HCT (N ¼ 274) Not reported Longitudinal; pre-HCT, 1 EORTC QOLQ-C30 Linear regression model Reference population of
(2004) [32] MEL/prednisone only (n ¼ 203), mo, 6 mo, 12 mo, 24 mo, with forward stepwise population-based study of
MM only and 36 mo post-HCT selection 3000 Norwegians aged 18-
93 yr
Statistically significant
difference between newly
diagnosed multiple
myeloma patients and
population norms, small in
magnitude with worse
scores in patients.
Hacker et al. HCT (pre-HCT N ¼ 16, 6 wk Mean age: 46.56 Longitudinal; 4 EORTC QLQ-C30 One-way repeated Sleep differences were
(2003) [30] post-discharge N ¼ 8) (11.31) assessments: measures ANOVA with found between T1 (M ¼
Allo (n ¼ 11), auto (n ¼ 5) Gender: pre-HCT, hospital paired samples t-tests 41.67) and T2 (M ¼ 73.33)
Lymphoma (n ¼ 4), CML (n ¼ 3), M ¼ 50% discharge, 2 weeks and Bonferroni corrections (baseline to immediately
AML (n ¼ 3), ALL (n ¼ 1), MM F ¼ 50% post-discharge, 6 weeks before discharge) and
(n ¼ 3), myelofibrosis (n ¼ 3) Race: post-discharge between T2 and T3 (M ¼
White ¼ 10
33.33) (immediately before
Black ¼ 2 discharge to 2 wk post-
Latino ¼ 2 hospitalization). T4 M ¼
Native American ¼ 1 33.33
Asian ¼ 1
Harder et al. HCT (N ¼ 40) Age at HCT: Cross-sectional; 22-82 mo EORTC QLQ-C30 Descriptives Sleep disruption M ¼ 18.3
(2002) [78] Allo HCT (87.5%); allo MRD ¼ Mean ¼ 37.2 post-HCT (SD ¼ 22.6)
26, allo MUD ¼ 9, auto ¼ 5 Range ¼ 15-55 Sleep disturbances were
ALL (n ¼ 8), AML (n ¼ 10), CML Gender: one of the most commonly
(n ¼ 6), NHL (n ¼ 6), MDS (n ¼ M ¼ 24 reported complaints.
4), MM (n ¼ 4), AA (n ¼ 2) F ¼ 16
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)
Hayden et al. Sibling allo-HCT (N ¼ 51) Based on 51 patients Cross-sectional; median of EORTC QLQ-C30 Descriptives No difference in sleep
(2004) [53] (original sample of 75 HCT alive in 2003: 98 mo post-HCT disruption between HCT
patients) Age at BMT: patients and reference
CY/TBI (32%); BU/CY (68%) Median ¼ 35 population.
Range ¼ 14-55 Reference population not
Gender: described.
M ¼ 31
F ¼ 20
Hendriks & HCT (N ¼ 52 at T1; N ¼ 33 at T2) Age: Longitudinal; mean of 2.5 EORTC QLQ-C30 Mann-Whitney U test, No differences in sleep
Schouten Auto (81%), allo (19%) at T1 Mean ¼ 41 yr and 4.5 yr post-HCT correlations disruption over time.
(2002) [45] Relapse free Gender: Patients reported more
Lymphoma (40%), breast cancer M ¼ 42% sleep disruption than
(29%), acute leukemia (29%) F ¼ 58% general Norwegian
population.
Physicians tended to
underestimate sleep
problems.
7
906
905
904
903
902
901
900
899
898
897
896
895
894
893
892
891
890
889
888
887
886
885
884
883
882
881
880
879
878
877
876
875
874
873
872
871
870
869
868
867
866
865
864
863
862
861
860
859
858
857
856
855
854
853
852
851
850
849
848
847
846
845
844
843
842
971
970
969
968
967
966
965
964
963
962
961
960
959
958
957
956
955
954
953
952
951
950
949
948
947
946
945
944
943
942
941
940
939
938
937
936
935
934
933
932
931
930
929
928
927
926
925
924
923
922
921
920
919
918
917
916
915
914
913
912
911
910
909
908
907
Table 1
8
(continued )
Hjermstad et al. HCT (N ¼ 130), chemotherapy Age at baseline: Longitudinal; pre-HCT and EORTC QLQ-C30 Wilcoxontest or No statistically significant
(2004) [33] patients (N ¼ 118) Median ¼ 35 3-5 yr post-HCT 1-way ANOVA as changes in sleep disruption
Allo (n ¼ 61), auto (n ¼ 69) Range ¼ 17-55 appropriate. Confidence from baseline to 3-5 yr in
HCT group: HD (n ¼ 15), high- Gender: intervals for graphic allo or auto groups, but CT
grade NHL (n ¼ 43), low-grade M ¼ 56% illustrations group reported improved
NHL (n ¼ 11), CML (n ¼ 31), F ¼ 44% sleep quality over time.
AML (n ¼ 19), ALL (n ¼ 11) Allo patients reported
better sleep, auto worse
sleep than general

Norwegian population at
baseline and 3-5 yr post-
HCT.
Kiss et al. Allo-HCT (N ¼ 28) Age: Cross-sectional; mean of Single item from a Descriptives 21 of 26 patients were
(2002) [57] Included both disease-free and Mean ¼ 32.6 13.2 yr post-HCT symptom checklist mildly bothered by sleep
relapsed patients Range ¼ 18.2-49.2 developed at the disruption, whereas 5 of 26
CML only Gender: hospital were moderately or
CY/TBI/ARA-C (n ¼ 27), BU/CY M ¼ 16 severely bothered.
(n ¼ 1) F ¼ 12
Kopp et al. HCT (N ¼ 34) and age- and sex- Mean age: 44.7 (9.4) Cross-sectional; patients EORTC-QLQ C30 Mann-Whitney U-tests No significant differences in
(2005) [51] matched noncancer control Gender: were at least 5 yr post-HCT sleep between HCT patients
subjects (N ¼ 68) M ¼ 50% and healthy control
Allo-HCT (61.8%), auto-HCT F ¼ 50% subjects; patients had
(38.2%) worse sleep by .06 SD.
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%)
Messerer et al. Allo-HCT (N ¼ 121) and Allogeneic BMT: Cross-sectional; HCT EORTC QLQ-C30 Chi-square, stratified No difference in sleep
(2008) [55] chemotherapy (N ¼ 221) Age at diagnosis: patients were a median of Mantel-Haenszel, non disruption between allo
Disease free Median ¼ 38 8 yr post-HCT; chemo parametrics HCT patients and
AML Only Gender: patients were a median of chemotherapy patients (.06
F ¼ 52% 9 yr post-chemo SD).
Mosher et al. HCT (N ¼ 406) Mean age: 49.25 (12.82) Cross-sectional; mean of FACT-BMT Percentage 80% of patients reported
(2011) [56] Auto (60.3%), allo (29.1%) Gender: 21 mo post-HCT sleeping well.
Relapse free M ¼ 51.5%
NHL (22.4%), HD (6.2%), AML/ F ¼ 47.8%
CML (11.6%), ALL/CLL (3.4%), Race:
MDS/MPS (8.4%), MM/ White ¼ 83.7%, African
amyloidosis (33.7%), Other American ¼ 5.7%,
(1.5%) Hispanic ¼ 3.9%, West
Indian ¼ 1.5%,
Other ¼ 4.4%
1036
1035
1034
1033
1032
1031
1030
1029
1028
1027
1026
1025
1024
1023
1022
1021
1020
1019
1018
1017
1016
1015
1014
1013
1012
1011
1010
1009
1008
1007
1006
1005
1004
1003
1002
1001
1000
999
998
997
996
995
994
993
992
991
990
989
988
987
986
985
984
983
982
981
980
979
978
977
976
975
974
973
972
1101
1100
1099
1098
1097
1096
1095
1094
1093
1092
1091
1090
1089
1088
1087
1086
1085
1084
1083
1082
1081
1080
1079
1078
1077
1076
1075
1074
1073
1072
1071
1070
1069
1068
1067
1066
1065
1064
1063
1062
1061
1060
1059
1058
1057
1056
1055
1054
1053
1052
1051
1050
1049
1048
1047
1046
1045
1044
1043
1042
1041
1040
1039
1038
1037
Pallua et al. Allo-HCT (N ¼ 100) Age: Cross-sectional; mean of EORTC QLQ-C30 Effect Sizes ¼ Cohen’s d, t-tests, No significant association
(2010) [47] AML (41%), CML (22%), ALL Mean ¼ 46.3 (14.7) 95.4 mo post-HCT 1-way ANOVA between sleep disruption
(12%), lymphoma (6%), MDS Range ¼ 16-76 and time since transplant.
(6%), MM (4%), AA (4%), MPD Gender: Sleep disruption was
(2%), PNH (2%), CLL (1%) M ¼ 55% greater in patients with
F ¼ 45% 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).
Rischer et al. HCT (N ¼ 50 at pre-HCT, N ¼ 32 Mean age: 53.3 (12.6) Longitudinal; 3 PSQI, sleep diary Chi-square, McNemar Prevalence of sleep
(2009) [4] at day 100 post-HCT) Gender: assessments: pre-HCT, tests, repeated measures disruption 32% before HCT,
Allo (78%), auto (22%) M ¼ 74% during hospital stay, and ANOVA Spearman’s 77% during hospitalization,
F ¼ 26%
AML (36%), MM (22%), NHL day 100 post-HCT correlation coefficients 28% at day 100.
(14%), MDS (10%), During hospitalization:
osteomyelofribrosis (10%), difficulties maintaining
Others (8%) 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
Sherman et al. Pre-BMT (N ¼ 61) Age: Cross-sectional; mean of Epworth Sleepiness Descriptives, percentages, Pilot study
(2003) [35] MM (85.3%), MGUS (8.2%), Mean ¼ 57 (12.3) 7.4 mo post-diagnosis; all Scale and Spearman correlations 43.33% exceeded the
amyloid (6.6%) Gender: were assessed before BMT clinical cut-off of daytime
M ¼ 63.9% sleepiness.
F ¼ 36.1% Older age associated with
Race: more daytime sleepiness.
White ¼ 91.8% Lower hemoglobin levels
Other ¼ 8.2% associated with more
daytime sleepiness.
9
1166
1165
1164
1163
1162
1161
1160
1159
1158
1157
1156
1155
1154
1153
1152
1151
1150
1149
1148
1147
1146
1145
1144
1143
1142
1141
1140
1139
1138
1137
1136
1135
1134
1133
1132
1131
1130
1129
1128
1127
1126
1125
1124
1123
1122
1121
1120
1119
1118
1117
1116
1115
1114
1113
1112
1111
1110
1109
1108
1107
1106
1105
1104
1103
1102
1231
1230
1229
1228
1227
1226
1225
1224
1223
1222
1221
1220
1219
1218
1217
1216
1215
1214
1213
1212
1211
1210
1209
1208
1207
1206
1205
1204
1203
1202
1201
1200
1199
1198
1197
1196
1195
1194
1193
1192
1191
1190
1189
1188
1187
1186
1185
1184
1183
1182
1181
1180
1179
1178
1177
1176
1175
1174
1173
1172
1171
1170
1169
1168
1167
Table 1
10
(continued )
Syrjala et al. HCT survivors (N ¼ 137) and BMT survivors: Cross-sectional; 10 yr post- Checklist of symptoms Paired t-tests, McNemar, 14% of survivors reported
(2005) [52] age- and sex-matched control Mean Age: 34.6 (9.0) HCT developed for the study Wilcoxon signed ranks tests moderate or severe sleep
subjects from the NHANES Gender: Alphas set at .01. problems compared with
study (N ¼ 4020) M ¼ 48% 9% of control subjects;
Allo (88%), auto (12%) Race: results were not
CML (chronic phase) (45%), CML White ¼ 95% statistically significant.
(accelerated or blast crisis) (7%), non-white,
acute leukemia in remission non-Hispanic ¼ 3%
(14%), acute leukemia in relapse Hispanic ¼ 2%

(8%), lymphoma in remission
(10%), lymphoma in relapse
(7%), MDS (7%), Other (4%)
Watson et al. HCT (N ¼ 171) and For all groups: Cross-sectional; at least 1 yr EORTC QLQ-C30 Wilcoxon 2 sample test, t-test, 45% of patients reported
(2004) [59] chemotherapy (n ¼ 310) Age: post-HCT generalized linear models sleep disruption.
Allo (n ¼ 97), auto (n ¼ 74) Median ¼ 39 Sleep disruption more
CY (n ¼ 147), BU (n ¼ 26), Range ¼ 15-58 severe in older patients
mesna (n ¼ 27), MEL (n ¼ 18), Gender: than younger patients. No
TBI (n ¼ 135) M ¼ 45% difference in sleep
F ¼ 55% disruption between allo,
auto, or chemotherapy
groups. No differences in
sleep disruption between
males and females.
Wettergren et al. Auto-HCT (N ¼ 22), compared Age: Longitudinal; pre-HCT and EORTC QLQ-C30 McNemar test, paired t-test No significant changes in
(2008) [34] with Swedish population Median ¼ 50 1 yr post-HCT sleep disruption (ES ¼ .03),
norms Range ¼ 31-66 no differences compared
HD (n ¼ 1), NHL (n ¼ 3), AML Gender: with Swedish population
(n ¼ 6), MM (n ¼ 12) M ¼ 13 norms
F¼9
Worel et al. Allo or syngeneic HCT (N ¼ 155) Age: Cross-sectional; at least 2 yr EORTC QLQ-C30 Descriptives Divided patients 2-5 yr
(2002) [46] Disease free Median ¼ 34 post-HCT post-HCT and more than 5
ALL/AML (n ¼ 9/43), CML (n ¼ Range ¼ 17-57 yr post-HCT. Of all patients,
56), MM (n ¼ 5), MDS (n ¼ 7), Gender: 45% had none or slight sleep
NHL (n ¼ 15), AA (n ¼ 19), M ¼ 86 disruption, 43% had
testicular cancer (n ¼ 1) F ¼ 69 moderate sleep disruption,
TBI/CY, CY, CY/ATG, BU/CY and 12% had severe sleep
disruption. Percentages
were comparable for
patients 2-5 yr post-HCT
and more than 5 yr post-
HCT.
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, Q 11
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 dis-
ease; 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; VP-
16, etoposide; WHOQOL100, World Health Organization Quality of Life Questionnaire 100.
1296
1295
1294
1293
1292
1291
1290
1289
1288
1287
1286
1285
1284
1283
1282
1281
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1279
1278
1277
1276
1275
1274
1273
1272
1271
1270
1269
1268
1267
1266
1265
1264
1263
1262
1261
1260
1259
1258
1257
1256
1255
1254
1253
1252
1251
1250
1249
1248
1247
1246
1245
1244
1243
1242
1241
1240
1239
1238
1237
1236
1235
1234
1233
1232
H.S.L. Jim et al. / Biol Blood Marrow Transplant xxx (2014) 1e20 11
1297 terms of their sample composition, sample size, measure of assess quality of life in HCT patients, which found large in- 1362
1298 sleep, and clinical cut-off [3,4,31-35]. Thus, it is not surpris- creases in sleep disruption during hospitalization [26]. 1363
1299 ing that there is substantial heterogeneity among study Difficulty maintaining sleep was the most common 1364
1300 findings. Studies using single-item measures of sleep problem in hospitalized HCT patients (82%), followed by 1365
1301 disruption suggest that approximately 8% of autologous pa- nonrestorative sleep (61%), problems falling asleep (52%), 1366
1302 tients report moderate to severe sleep disruption [31], difficulties falling back to sleep once awake (48%), and early 1367
1303 whereas more than 50% of allogeneic patients report sleep morning awakening (21%) [4]. Patients largely attributed 1368
1304 disruption of any severity [3]. In contrast, the 2 studies using these problems to the hospital environment, such as noise 1369
1305 validated measures (ie, Pittsburgh Sleep Quality Index and from medical equipment and nursing staff, and to emotional 1370
1306 Epworth Sleepiness Scale) found that 32% of patients re- agitation and stress [4,37]. A small study found that alloge- 1371
1307 ported clinically significant sleep disruption before autolo- neic transplant patients reported better sleep before trans- 1372
1308 gous or allogeneic transplant [4] and 43% of multiple plant but worse sleep during hospitalization [4]. At the time 1373
1309 myeloma patients reported clinically significant daytime of hospital discharge, the average severity of sleep disruption 1374
1310 sleepiness before autologous transplantation [35]. A direct among allogeneic and autologous patients was still moder- 1375
1311 comparison of sleep disruption between patients receiving ately elevated relative to baseline symptomatology (ie, .51 1376
1312 allogeneic versus autologous HCT using a single-item mea- SD) [26]. Nevertheless, it appeared that increases in sleep 1377
1313 sure suggested that sleep was significantly better among disruption were generally transient; by day 100, sleep 1378
1314 allogeneic patients, although sample sizes were small and disruption returned to levels comparable with pre-HCT 1379
1315 findings were confounded by group differences in diagnosis [4,25,31], although these levels were substantially elevated 1380
1316 and remission status [33]. Comparisons between HCT patient even before the transplant. Patients receiving allogeneic HCT 1381
1317 and population norms are mixed, with 1 large study demonstrate similar levels of sleep disruption near day 100 1382
1318 reporting that patients reported significantly worse sleep to patients receiving autologous transplant [4]. 1383
1319 before autologous transplant or treatment with melphalan or 1384
1320 prednisone [32], whereas 2 smaller studies found no differ- SLEEP DISRUPTION AND DISORDERS AFTER THE ACUTE 1385
1321 ences, perhaps due to low statistical power [33,34]. In sum- TRANSPLANT PERIOD 1386
1322 mary, although findings are mixed, available data suggest New precipitating factors of sleep disruption may occur 1387
1323 that sleep disruption before transplant is common but rela- after the acute transplant period. Patients who experienced 1388
1324 tively mild on average. resolved sleep disruption or never experienced sleep 1389
1325 disruption during transplantation may develop late-onset 1390
1326 SLEEP DISRUPTION AND DISORDERS DURING THE ACUTE sleep problems due to corticosteroid treatment for chronic 1391
1327 TRANSPLANT PERIOD GVHD, inflammation due to GVHD or infection, fear of dis- 1392
1328 The first 100 days post-transplant are typically charac- ease progression, pain, or additional treatments for relapsed 1393
1329 terized by multiple acute side effects of the conditioning disease. For example, evidence suggests that long-term 1394
1330 regimen, including mucositis, enteritis, nausea and emesis, corticosteroid use is a risk factor for OSA, perhaps because 1395
1331 episodes of delirium, and, in the case of allogeneic transplant, of weight gain [40]. Insomnia is also a common side effects of 1396
1332 acute graft-versus-host disease (GVHD) and immunosup- taking corticosteroids, particularly if the medication is taken 1397
1333 pressive therapies. These side effects and their treatment closer to bedtime. Muscle cramps and neuropathy have been 1398
1334 may disrupt sleep [36]. Moreover, these side effects found to be common among patients with GVHD and to 1399
1335 frequently occur in the context of hospitalization, which can disrupt sleep [41]; neuropathy is also a risk factor for RLS 1400
1336 have an additive effect on disrupted sleep [4]. Consequently, [42]. These factors and others can also perpetuate existing 1401
1337 sleep disruption tends to be most pronounced in the first sleep problems and contribute to the development of 1402
1338 100 days post-transplant. The most extensive research on persistent (lasting more than 3 months) or recurrent sleep 1403
1339 sleep disruption in HCT patients has also been conducted problems. Additional perpetuating factors of insomnia 1404
1340 during this period [3,4,24-26,30-32,37-39], although it is include cognitive distortions and maladaptive behaviors that 1405
1341 characterized by several limitations, including small sam- begin in reaction to a stressor and persist after the stressor is 1406
1342 ples, which are heterogeneous in terms of diagnosis and resolved [43]. Examples of cognitive distortions that can 1407
1343 transplant type as well as low statistical power. In addition, make sleep disruption worse are as follows: “I’m going to feel 1408
1344 data are lacking regarding the prevalence and onset of sleep terrible tomorrow if I don’t sleep well” or “I’m never going to 1409
1345 disorders during this time, with the exception of 1 study get to sleep.” Maladaptive behaviors can include spending 1410
1346 reporting a prevalence rate of clinically significant insomnia prolonged time in bed, going to bed excessively early, 1411
1347 of 26% [37]. Available data suggest that sleep disruption was sleeping late, and staying in bed while no longer asleep. 1412
1348 the most distressing symptom among allogeneic HCT re- Although these behaviors may initially be helpful, particu- 1413
1349 cipients at day 0 and was significantly correlated with bowel larly for people experiencing acute illness, eventually they 1414
1350 changes and fatigue [3]. Sleep disruption significantly can contribute to irregular sleep patterns that result in 1415
1351 increased during the first 100 days, with greatest disruption insomnia long after the patient has recovered from the acute 1416
1352 seen during the conditioning regimen and WBC count nadir stressor or illness [43]. 1417
1353 [31]. Mean changes of 27 points on the European Organiza- Only 1 study has examined the prevalence of sleep dis- 1418
1354 tion for Research and Treatment of Cancer Quality of Life orders after transplant. Among 61 allogeneic HCT recipients 1419
1355 Questionnaire Core 30 sleep disruption item were observed transplanted 1 to 10 years previously, 23% met criteria for a 1420
1356 from pretransplant baseline to its peak approximately diagnosis of insomnia and 3% for hypersomnia; no other 1421
1357 2 weeks after HCT [25], corresponding to a large increase and sleep disorders were observed [44]. In addition, no studies 1422
1358 effect size of 1.1 standard deviations (SDs) [25]. These data have examined precipitating versus perpetuating factors of 1423
1359 are consistent with a quantitative review of all published sleep disruption after the acute transplant period. Never- 1424
1360 studies using the European Organization for Research and theless, 23 studies have reported on sleep disruption outside 1425
1361 Treatment of Cancer Quality of Life Questionnaire Core 30 to the context of a diagnosed sleep disorder 90 days or more 1426

1491
1490
1489
1488
1487
1486
1485
1484
1483
1482
1481
1480
1479
1478
1477
1476
1475
1474
1473
1472
1471
1470
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1468
1467
1466
1465
1464
1463
1462
1461
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1459
1458
1457
1456
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1437
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Table 2
12
Online Resources for Sleep Disorders and Disruption
Type of Intervention Relevant Disorder(s) Resource Internet Address Description Evidence Base Cost
Cognitive-behavioral Insomnia SHUTi www.shuti.me Interactive online program that includes videos Cancer patients $129.00 For 16 weeks
interventions from insomnia experts, interactive quizzes, and Adults of access
vignettes dealing with real-life sleep issues
Progress is tracked
Provides recommendations tailored to individuals’
sleep difficulties
Insomnia RESTORE www.restorecbt.com Treatment consists of 5 modules with instructive Adults Cost unspecified. Made
videos and downloadable MP3 files available through patients
health care provider.

Also works with health
insurance providers.
Insomnia Sleepio www.sleepio.com Interactive online treatment is delivered by a Adults Three payment plan options:
virtual therapist and consists of 6 personally $9.99 per week, $79.99
tailored interactive stages for 12-week access, and
Progress is tracked and each stage is adjusted $119.99 for 24-week access.
accordingly
Education about All sleep disorders National Sleep www.sleepfoundation.org Comprehensive information about sleep, support N/A Free
insomnia and Foundation groups, video and audio library, and sleep
treatment professional location assistance
All sleep disorders Sleep Education www.sleepeducation.com Comprehensive information about sleep N/A Free
difficulties, video archive, and sleep professional
location assistance
All sleep disorders Your Sleep http://yoursleep.aasmnet.org Comprehensive information about sleep, N/A Free
self-administered sleep assessments, downloadable
sleep diary, online forum, and sleep professional
location assistance
OSA American Sleep http://sleepapnea.org/ Self-administered screening for OSA, information N/A Free
Apnea Association about OSA, and information on support groups
for people with OSA
RLS Willis-Ekbom Disease http://www.rls.org/ Self-administered screening for RLS, information N/A Free
Foundation about RLS, and information on support groups
for people with RLS
Cancer-specific Insomnia National Cancer www.cancer.gov Information specific to cancer related sleep N/A Free
education about Institute difficulties, symptom management tips, and
insomnia and modules
treatment To find sleep information type "sleep" into the
"search" box located on the upper righthand
corner on the home page
General sleep health American Cancer www.cancer.org Information specific to cancer-related sleep N/A Free
Society 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
Insomnia Cancer Support www.cancersupportcommunity.org Information specific to cancer-related sleep N/A Free
Community 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
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1557 after HCT. Notably, 20 assessed sleep using a single item as 1622
1558 part of a larger quality of life scale, whereas only 3 included 1623
1559 validated measures of sleep. Seventeen studies were cross- 1624
1560 sectional; many included mixed samples of autologous and 1625
1561 allogeneic recipients who ranged widely in terms of time 1626
1562 from transplant. Thus, definitive conclusions are difficult to 1627
1563 draw. However, available data suggest that after peaking 1628
1564 during the acute transplant period, the prevalence and 1629
Free
Free
1565 severity of sleep disruption remains relatively constant over 1630

1566 time. Most studies found no significant change in sleep 1631
1567 disruption between 1 and 10 years post-transplant [44-47]. 1632
1568 HCT survivors tend to report worse sleep disruption 1633
1569 compared with population norms and noncancer compari- 1634
1570 son groups (ie, .33 to .39 SD) [45,47-50], but the evidence is 1635
N/A
N/A
1571 mixed [34,51-53]. A cross-sectional study of allogeneic re- 1636

1572 cipients 1 to 10 years post-transplant found that 23% met 1637
1573 1638
Search engine for nationwide cancer clinical trials
criteria for clinical diagnosis of insomnia [44], a rate similar

1574 1639
To find sleep-related clinical trials type “sleep”
To find sleep-related clinical trials with cancer
to that of the general population (ie, 22%) [54]. Furthermore,

“search for studies” box at the top of the page
into the “keywords/phrases” box towards the
1575 sleep disruption in patients treated with HCT also does not 1640
Search engine for nationwide clinical trials
patients type “sleep AND cancer” into the
1576 differ from that in patients treated with standard-dose 1641

1577 chemotherapy at 8 to 9 years post-treatment [55]. 1642
1578 Although most evidence suggests no significant change in 1643
1579 sleep disruption after the first 100 days post-transplant, es- 1644
1580 timates of the prevalence of sleep disruption in HCT patients 1645
1581 vary widely. At 1 year post-HCT, 14% of patients receiving 1646
1582 1647
middle of the page
allogeneic transplant with reduced-intensity conditioning

1583 and 26% of patients receiving autologous transplantation 1648
1584 reported sleep disruption [39]. A mean of 2 years after 1649
1585 transplant (range, 1 to 3 years), 20% of patients reported 1650
1586 sleep disruption [56]. In contrast, 2 to 5 years after trans- 1651
1587 plant, 49% of patients reported none or slight, 43% reported 1652
1588 moderate, and 8% reported severe sleep disruption [46]. Five 1653
1589 or more years after transplant, 44%, 42%, and 14% of patients 1654
http://www.cancer.gov/clinicaltrials/
1590 reported none or slight, moderate, and severe sleep disrup- 1655
1591 tion, respectively [46]. A mean of 10 years after transplant, 1656
1592 14% reported moderate or severe sleep disruption [52]. An 1657
1593 average of 13 years after transplant (range, 10 to 18), 81% of 1658
http://clinicaltrials.gov/
1594 patients reported they were not bothered or only mildly 1659
1595 bothered by sleep disruption, whereas 19% reported they 1660
1596 were moderately or severely bothered [57]. In summary, the 1661
1597 overall prevalence of any sleep problems after the acute 1662
1598 1663
search
transplant period (ie, after 100 days) ranges from 14% to 51%,
1599 with the prevalence of moderate problems ranging from 14% 1664
1600 to 43% and severe problems ranging from 8% to 14%. Vari- 1665
1601 ability in prevalence rates likely stems from sample bias due 1666
National Institutes
1602 to small sample sizes in this literature. 1667

National Cancer
1603 1668
1604 SOCIODEMOGRAPHIC AND CLINICAL PREDICTORS OF 1669
of Health
Institute
1605 SLEEP DISRUPTION AND DISORDERS 1670

1606 A clinically relevant question is how to identify HCT pa- 1671
1607 tients at risk for sleep disruption and disorders. Risk factors 1672
1608 for insomnia among cancer patients include female gender, 1673
All sleep disorders
All sleep disorders
1609 anxiety, surgical treatment, and maladaptive beliefs about 1674

1610 sleep [58]. Among HCT patients, 1 small study observed that 1675
1611 conditioning with busulfan and cyclophosphamide was a 1676
1612 risk factor for insomnia [44]. Risk factors for OSA in the 1677
1613 general population include obesity, type 2 diabetes, 1678
1614 congestive heart failure, kidney disease, and treatment- 1679
1615 refractory hypertension [17]. 1680
1616 1681
search engines
Some of the risk factors that lead to sleep disruption and

1617 disorders may be more prevalent after HCT (eg, diabetes, 1682
Clinical trials
1618 hypertension). Risk factors for RLS in the general population 1683
1619 include female gender, pregnancy, low blood ferritin, high 1684
1620 alcohol intake, poor renal function, high blood glucose levels, 1685
1621 and obesity [42]. Although HCT patients are more likely to 1686

1687 have high (rather than low) blood ferritin, they may expe- medications in various drug classes, along with indications, 1752
1688 rience high blood glucose levels and weight gain because of contraindications, and long-term efficacy from randomized 1753
1689 treatment with corticosteroids. In addition, several autoim- placebo-controlled trials in patients with primary insomnia, 1754
1690 mune diseases are risk factors for RLS (eg, rheumatoid are listed in Table 3. The choice of medications within a class Q 3 1755
1691 arthritis, multiple sclerosis, Crohn’s disease), suggesting that of drugs should depend on patients’ symptomatology (eg, 1756
1692 high levels of inflammation may play a role [42]. These delayed sleep onset versus difficulty maintaining sleep), 1757
1693 findings have relevance for GVHD as a potential risk factor for patients’ preferences regarding use of a controlled substance, 1758
1694 RLS, although data are lacking. Thus, in general, risk factors and contraindications of the medication. It should be noted 1759
1695 for clinical sleep disorders include female gender, obesity, that no studies have examined pharmacotherapy for 1760
1696 comorbidities such as diabetes and poor renal function, insomnia specifically in the context of HCT. 1761
1697 anxiety, and maladaptive beliefs about sleep. The first-line treatment for OSA is positive airway pres- 1762
1698 Regarding sleep disruption outside the context of a sure, which pneumatically splits the upper airway through a 1763
1699 diagnosed sleep disorder, evidence suggests that women are device worn on the nose and/or mouth during sleep [17]. 1764
1700 more likely to endorse sleep problems than men [44]. Evi- Additional therapies for OSA include surgery, oral appliances, 1765
1701 dence also suggests that sleep disruption is more severe in implanted upper airway stimulation devices, and behavioral 1766
1702 older patients [44,59]. Systemic inflammation has been strategies to lose weight, exercise, adjust sleep position, and 1767
1703 associated with worse sleep, although the sample was small avoid alcohol and sedatives at bedtime [17]. No studies have 1768
1704 and primarily consisted of autologous HCT recipients [60]. examined treatments for OSA among patients treated with 1769
1705 Regarding transplant type, allogeneic recipients tend to HCT. 1770
1706 report better sleep than autologous recipients before trans- The first-line treatment for RLS includes the dopamine 1771
1707 plant and 3 years later [33] but worse sleep during the acute agonists pramipexole and ropinirole [18]. Additional medi- 1772
1708 transplant period [4,28,37]. Among allogeneic recipients, cation options include levodopa with dopa decarboxylase 1773
1709 significant associations between GVHD and sleep disruption inhibitor, opioids, gabapentin, enacarbil, and cabergoline. 1774
1710 have not been found [47]; however, literature examining this Although no treatment studies for RLS have been conducted 1775
1711 relationship is sparse. Other clinical variables, such as bone specifically among HCT recipients, pregabalin shows prom- 1776
1712 marrow versus peripheral blood stem cell transplantation, ise for treating RLS secondary to neuropathy and/or neuro- 1777
1713 have not shown significant differences in the prevalence of pathic pain [64]. Also, some data suggest that some 1778
1714 sleep problems [61]. Nevertheless, comparisons by GVHD antidepressants may contribute to increased risk of RLS, 1779
1715 and type of hematopoietic stem cell collection are likely including citalopram, paroxetine, amitriptyline, mirtaza- 1780
1716 underpowered because of small sample sizes. Regarding pine, and tramadol, although evidence is mixed [18]. Thus, 1781
1717 psychosocial risk factors, research is scarce, but available avoidance or discontinuation of use of these medications 1782
1718 studies suggest that divorced HCT recipients have higher should be considered in patients with RLS. 1783
1719 rates of sleep problems than unmarried patients [29] and To our knowledge, only 1 behavioral intervention study 1784
1720 unemployed recipients report worse sleep than recipients has been conducted in HCT recipients with the primary aim 1785
1721 who are working at the time of assessment [29,49]. In of improving sleep disruption outside the context of a diag- 1786
1722 addition, distress, depression, and anxiety are associated nosed sleep disorder [65]. In addition, 5 behavioral inter- 1787
1723 with worse sleep [29]. Thus, available evidence suggests that vention studies have examined sleep disruption as a 1788
1724 risk factors for sleep disruption outside the context of a secondary outcome [66-70]. All 6 studies were randomized 1789
1725 diagnosed sleep disorder are older age, female gender, trials of psychoeducation, stress management, aerobic exer- 1790
1726 divorce, unemployment, distress, and autologous transplant. cise, and resistance training alone or in combination during 1791
1727 Additional research is needed to confirm these findings in the inpatient period; 1 study also followed patients for 1792
1728 larger samples. 6 months post-HCT [66]. Samples consisted of patients 1793
1729 receiving allogeneic HCT [67,69], autologous HCT [70], tan- 1794
1730 TREATMENT OF SLEEP DISRUPTION AND DISORDERS dem autologous HCT [65], and either allogeneic or autolo- 1795
1731 Treatments for sleep disorders are varied and depend on gous HCT [66,67]. All reported null results for sleep 1796
1732 the underlying cause. Regarding insomnia, the National disruption compared with usual care. Sample sizes ranged 1797
1733 Institutes of Health Consensus and the American Academy from 42 to 700. Thus, available data suggest that sleep 1798
1734 of Sleep Medicine recommend cognitive behavioral therapy disruption does not improve with exercise or stress man- 1799
1735 for insomnia (CBT-I) as the standard treatment [18]. agement during the inpatient period. Additional studies 1800
1736 Extensive research has shown that CBT-I can be as effective focusing on long-term transplant survivors are needed. 1801
1737 as some pharmacologic agents in the treatment of insomnia 1802
1738 in the general population [62]. There have been no studies DISCUSSION 1803
1739 to date on the effectiveness of CBT-I specifically in patients Sleep disruption is a common problem among HCT re- 1804
1740 undergoing HCT. Nevertheless, numerous well-designed cipients. In addition to being distressing in its own right, 1805
1741 studies in cancer patients have shown that CBT-I can sleep disruption may affect other clinically important out- 1806
1742 indeed be effective in improving objectively (eg, actigraphy) comes. For example, previous research in patients undergo- 1807
1743 and subjectively measured (eg, self-reported insomnia ing standard-dose chemotherapy suggests that sleep 1808
1744 severity and sleep diaries) sleep disruption during and after disruption occurs first in a cascade of symptoms, contrib- 1809
1745 treatment [63]. uting to increases in fatigue and in turn depression [71]. In 1810
1746 Therapeutic effects of CBT-I have been found to last for up addition, preliminary research suggests that sleep disruption 1811
1747 to 12 months in cancer survivors [63]. The American Acad- may negatively impact immune response and reconstitution 1812
1748 emy of Sleep Medicine recommends that when pharmaco- [72], although this has not been demonstrated in the context 1813
1749 therapy is used for insomnia, short- or intermediate-acting of HCT. Taken together, these studies argue for early inter- 1814
1750 benzodiazepine receptor agonists or ramelteon (Rozerem), a vention to manage sleep disruption and disorders in HCT 1815
1751 melatonin receptor agonist, be prescribed [16]. Examples of recipients. 1816

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Table 3
Medications Recommended for Treatment of Insomnia by the American Academy of Sleep Medicine [16]
Drug Class Agent(s) FDA-Approved FDA-Approved for Controlled Generic Relevant Contraindications RCT-Demonstrated Relevant Drug Interactions
for Sleep Onset Sleep Maintenance Substance Available Include [79] Efficacy for Insomnia
[79] [79] up to
Short/intermediate Eszopiclone Yes Yes Yes Yes Impaired motor/cognitive 6 mo CNS depressants, rifampicin,
acting benzodiazepine (Lunesta) performance with higher ketoconazole
receptor agonists dosage in elderly
Temazepam Yes Yes Yes Yes Oversedation, confusion, 8 wk CNS depressants, hypnotics,
(Restoril) ataxia with higher dosage diphenhydramine
in elderly
Triazolam Yes No Yes Yes Compromised respiratory 5 wk Ketoconazole, itraconazole,
(Halcion) function, renal or hepatic nefazodone, HIV protease

impairment, pulmonary inhibitors, medications that
insufficiency impair the oxidative
metabolism mediated by CYP3A4
Zaleplon Yes No Yes Yes Conditions affecting 4 wk Promethazine; rifampin; CYP3A4
(Sonata) metabolism or hemodynamic inducers; CYP3A4 inhibitors;
responses or compromised cimetidine; additive CNS
respiratory function depression with other
psychotropic medications,
anticonvulsants, antihistamines,
narcotic analgesics, anesthetics,
ethanol, and other CNS depressants
Zolpidem Yes No Yes Yes Compromised respiratory 8 mo CNS depressants; other sedative-
(Ambien) function, conditions affecting hypnotics; imipramine;
metabolism or hemodynamic chlorpromazine; alcohol;
responses, renal or hepatic sertraline; CYP3A4 inhibitors;
impairment, risk of impaired rifampin; fluoxetine; ketoconazole
motor/cognitive performance
in elderly
Zolpidem Yes Yes Yes Yes Compromised respiratory 6 mo CNS depressants; other sedative-
(Ambien CR) function, conditions affecting hypnotics; imipramine;
metabolism or hemodynamic chlorpromazine; alcohol;
responses, renal or hepatic sertraline; CYP3A4 inhibitors;
impairment, risk of impaired rifampin; fluoxetine; ketoconazole
motor/cognitive performance
in elderly
Zolpidem No Yes Yes No Compromised respiratory 4 wk CNS depressants; imipramine;
(Intermezzo) function, risk of impaired chlorpromazine; rifampin;
motor/cognitive performance ketoconazole
in elderly
Melatonin receptor Ramelteon Yes No No Yes Hepatic impairment, may affect 6 mo CYP inducers, CYP1A2 inhibitors,
agonist (Rozerem) reproductive hormones CYP3A4 inhibitors, CYP2C9
inhibitors; donepezil; doxepin;
zolpidem; CNS depressants; alcohol
Intermediate/long acting Clonazepam No No Yes Yes Renal or hepatic impairment, None CYP450 inducers; propantheline;
benzodiazepine (Klonopin) respiratory diseases, elderly CYP3A inhibitors; alcohol;
receptor agonist patients, glaucoma narcotics; barbiturates; hypnotics;
antianxiety agents; phenothiazines;
thioxanthene; butyrophenone
antipsychotics; MAOIs; TCAs;
anticonvulsant drugs; CNS
depressants; valproic acid
15
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1914
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1912
1911
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2011
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2009
2008
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1952
1951
1950
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1947
Table 3
16
(continued )
Drug Class Agent(s) FDA-Approved FDA-Approved for Controlled Generic Relevant Contraindications RCT-Demonstrated Relevant Drug Interactions
for Sleep Onset Sleep Maintenance Substance Available Include [79] Efficacy for Insomnia
[79] [79] up to
Estazolam (ProSom, Yes No Yes Yes Renal or hepatic impairment, 1 wk CNS-acting drugs; anticonvulsants;
Eurodin) compromised respiratory antihistamines; alcohol; barbiturates;
function, depression MAOIs; narcotics; phenothiazines;
psychotropic medications; CNS
depressants; smoking; CYP3A
inhibitors; CYP3A inducers
Flurazepam Yes Yes Yes Yes Depression, hepatic or renal 3 wk CNS depressants; alcohol
(Dalmane) impairment, pulmonary
insufficiency
Lorazepam No No Yes Yes Compromised respiratory None CNS depressants; clozapine;
(Ativan) function, impaired renal or valproate; probenecid; theophylline;
hepatic function, elderly aminophylline
Sedating low-dose Amitriptyline No No No Yes Liver dysfunction None Guanethidine; CNS depressants;
antidepressant CYP2D6 inhibitors; TCAs; SSRIs;
“caution with thyroid drugs”;
disulfiram; ethchlorvynol;
anticholinergics; sympathomimetics;
neuroleptics; cimetidine
Doxepin (Silenor) No Yes No Yes Compromised respiratory 12 wk Alcohol; CNS depressants; sedating
3-6 mg function antihistamines; CYP2C19 inhibitors;
CYP2D6 inhibitors; CYP1A2 inhibitors;
CYP2C9 inhibitors; cimetidine;
tolazamide; sertraline
Mirtazapine No No No Yes Neutropenia and hyponatremia None MAOIs; serotonergic drugs; drugs
(Remeron) reported, renal or hepatic affecting hepatic metabolism; CYP
impairment, conditions affecting enzyme inducers; drugs metabolized
metabolism or hemodynamic by or inducers of cytochrome P450;
responses, elderly, may cause antihypertensives known to cause
orthostatic hypotension hyponatremia; phenytoin;
carbamazepine; hepatic metabolism
inducers; cimetidine; ketoconazole;
cimetidine; alcohol; diazepam;
CYP3A4 inhibitors; HIV protease
inhibitors; azole antifungals;
erythromycin; nefazodone; warfarin
Trazodone No No No Yes Hypotension and syncope 1 wk Serotonergic drugs; drugs which
(Oleptro) reported, elderly, renal or hepatic impair serotonin metabolism;
impairment, hyponatremia may antipsychotics; dopamine agonists;
occur 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
2076
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2020
2019
2018
2017
2016
2015
2014
2013
2012
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2128
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Trimipramine No No No Yes Liver dysfunction, elderly None Serotonergic drugs; drugs which
(Surmontil) 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
Other prescription Gabapentin No No No Yes Liver dysfunction, hepatic None Maalox; naproxen sodium;
drugs (Neurontin) impairment hydrocodone
Olanzapine No No No Yes Hepatic impairment; prostatic None Diazepam; alcohol; carbamazepine;
(Zyprexa) hypertrophy; may cause omeprazole; rifampin; CYP1A2

orthostatic hypotension; inducers; fluoxetine; fluvoxamine;
leukopenia, neutropenia, and other centrally-acting drugs;
agranulocytosis reported; may potentially hepatotoxic drugs;
cause cognitive and motor antihypertensives; levodopa;
impairment dopamine agonists; anticholinergic
drugs; parenteral benzodiazepines
Tiagabine No No No Yes Incapacitating weakness 1 night Valproate; carbamazepine; phenytoin;
(Gabitril) reported phenobarbital; ethanol; triazolam;
drugs that lower seizure threshold
(antidepressants, antipsychotics,
stimulants, narcotics); drugs that
induce or inhibit hepatic
metabolizing enzymes; highly
protein-bound drugs
Quetiapine No No No Yes May induce orthostatic None Centrally-acting drugs; alcohol;
(Seroquel) hypotension; leukopenia, CYP3A4 inhibitors; CYP3A4
neutropenia, and agranulocytosis inducers; antihypertensives;
reported; may impair physical/ levodopa; dopamine agonists;
mental abilities 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.
17
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2207 Effective management of sleep disruption may be diffi- specific focus on HCT recipients, strategies to manage sleep 2272
2208 cult in the inpatient setting due to environmental factors disruption and disorders should be adapted from the current 2273
2209 that can interrupt sleep. Environmental interventions to evidence base in cancer patients and the general population. 2274
2210 improve sleep among inpatients may be more effective than 2275
2211 patient-based interventions (eg, minimizing of nighttime 2276
2212 vital signs monitoring). A study conducted by Sharda et al. ACKNOWLEDGMENTS 2277
2213 [73] suggests that vital sign monitoring might not be Financial disclosure: Supported by National Cancer Insti- Q 1 2278
2214 necessary for HCT patients with low-risk profiles (ie, lack of tute grant K07 CA138499 (to H.S.L.J.), National Cancer Insti- 2279
2215 daytime fever and central nervous system complaints) and tute grant K07 CA132916 (to O. P.), and the Stanford Cancer Q 13 2280
2216 may lead to improved sleep and health. In contrast, use of a Institute Seed Award (to O. P.). 2281
2217 hypnotic (zolpidem) has been associated with increased Conflict of interest statement: ---. Q4 2282
2218 inpatient falls [74]. 2283
2219 Regarding outpatient sleep management, several phar- 2284
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Sleep Disruption in Hematopoietic Cell Transplantation Recipients Prevalence Severity and Clinical Management

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Sleep Disruption in Hematopoietic Cell Transplantation Recipients Prevalence Severity and Clinical Management

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Biol Blood Marrow Transplant xxx (2014) 1e20

REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce

REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce

Hispanic ¼ 5% at conditioning, 26% at

BEAM (n ¼ 37), BU/MEL (n ¼ 8),

ARA-C, melphalan) (n ¼ 2) HCT baseline to 2 wk follow

sleep than general

(14%), acute leukemia in relapse Hispanic ¼ 2%

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health care provider.

1565 severity of sleep disruption remains relatively constant over 1630

1571 mixed [34,51-53]. A cross-sectional study of allogeneic re- 1636

criteria for clinical diagnosis of insomnia [44], a rate similar

To ﬁnd sleep-related clinical trials with cancer

to that of the general population (ie, 22%) [54]. Furthermore,

patients type “sleep AND cancer” into the

1576 differ from that in patients treated with standard-dose 1641

allogeneic transplant with reduced-intensity conditioning

1602 to small sample sizes in this literature. 1667

1605 SLEEP DISRUPTION AND DISORDERS 1670

All sleep disorders

1609 anxiety, surgical treatment, and maladaptive beliefs about 1674

Some of the risk factors that lead to sleep disruption and

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REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce

(Halcion) function, renal or hepatic nefazodone, HIV protease

(Zyprexa) hypertrophy; may cause omeprazole; rifampin; CYP1A2

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REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce

REV 5.2.0 DTD YBBMT53433_proof 5 May 2014 6:32 pm ce

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