Scholarly article on topic 'Exercise and Stress Management Training Prior to Hematopoietic Cell Transplantation: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902'

Exercise and Stress Management Training Prior to Hematopoietic Cell Transplantation: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 Academic research paper on "Health sciences"

CC BY-NC-ND
0
0
Share paper
OECD Field of science
Keywords
{"Autologous hematopoietic cell transplantation" / "Allogeneic hematopoietic cell transplantation" / Exercise / "Stress management" / "Quality of life"}

Abstract of research paper on Health sciences, author of scientific article — Paul B. Jacobsen, Jennifer Le-Rademacher, Heather Jim, Karen Syrjala, John R. Wingard, et al.

Abstract Studies show that engaging patients in exercise and/or stress management techniques during hematopoietic cell transplantation (HCT) improves quality of life. The Blood and Marrow Transplant Clinical Trials Network tested the efficacy of training patients to engage in self-directed exercise and stress management during HCT. The study randomized 711 patients at 21 centers to receive 1 of 4 training interventions before HCT: a self-directed exercise program, a self-administered stress management program, both, or neither. Participants completed self-reported assessments at enrollment and up to 180 days after HCT. Randomization was stratified by center and transplant type. There were no differences in the primary endpoints of the Physical Component Summary and Mental Component Summary scales of the Medical Outcomes Study Short Form 36 at day +100 among the groups, based on an intention-to-treat analysis. There also were no differences in overall survival, days of hospitalization through day +100 post-HCT, or in other patient-reported outcomes, including treatment-related distress, sleep quality, pain, and nausea. Patients randomized to training in stress management reported more use of those techniques, but patients randomized to training in exercise did not report more physical activity. Although other studies have reported efficacy of more intensive interventions, brief training in an easy-to-disseminate format for either self-directed exercise or stress management was not effective in our trial.

Academic research paper on topic "Exercise and Stress Management Training Prior to Hematopoietic Cell Transplantation: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902"

Accepted Manuscript

Exercise and stress management training prior to hematopoietic cell transplantation: blood and marrow transplant clinical trials network (bmt ctn) 0902

Paul B. Jacobsen , Jennifer Le-Rademacher , Heather Jim , Karen Syrjala , John R. Wingard , Brent Logan , Juan Wu , Navneet S. Majhail , William Wood , J. Douglas Rizzo , Nancy L. Geller , Carrie Kitko , Edward Faber , Muneer H. Abidi , Susan Slater , Mary M. Horowitz , Stephanie J. Lee

PII: S1083-8791(14)00325-5

DOI: 10.1016/j.bbmt.2014.05.027

Reference: YBBMT 53481

To appear in: Biology of Blood and Marrow Transplantation

Received Date: 29 April 2014 Accepted Date: 27 May 2014

Please cite this article as: Jacobsen PB, Le-Rademacher J, Jim H, Syrjala K, Wingard JR, Logan B, Wu J, Majhail NS, Wood W, Rizzo JD, Geller NL, Kitko C, Faber E, Abidi MH, Slater S, Horowitz MM, Lee SJ, Exercise and stress management training prior to hematopoietic cell transplantation: blood and marrow transplant clinical trials network (bmt ctn) 0902, Biology of Blood and Marrow Transplantation (2014), doi: 10.1016/j.bbmt.2014.05.027.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

EXERCISE AND STRESS MANAGEMENT TRAINING PRIOR TO HEMATOPOIETIC CELL TRANSPLANTATION: BLOOD AND MARROW TRANSPLANT CLINICAL TRIALS NETWORK (BMT CTN) 0902

Paul B. Jacobsen,1 Jennifer Le-Rademacher,2 Heather Jim,1 Karen Syrjala,3 John R. Wingard,4 Brent Logan,2 Juan Wu,5 Navneet S. Majhail,6 William Wood,7 J. Douglas Rizzo,8 Nancy L. Geller,9 Carrie Kitko,10 Edward Faber,11 Muneer H. Abidi,12 Susan Slater,13 Mary M. Horowitz,8 Stephanie J. Lee3

department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL; 2Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI; 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 4Division of Hematology/Oncology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL; 5The EMMES Corporation, Washington, DC; Blood and Marrow Transplant Program, 6Cleveland Clinic, Cleveland, OH; 7Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC; 8Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 9Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, MD; 10Pediatric Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI; ^Division of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE; 12Department of Medical Oncology, Wayne State University/Karmanos Cancer Institute; 13Center for Hematologic Malignancies, Knight Cancer Institute, Oregon Health and Science University.

Running head: Training in exercise and stress management before HCT

Prior presentation: American Society of Hematology Annual Meeting, December 2013, New Orleans

Correspondence: Stephanie J Lee, M.D., M.P.H., Fred Hutchinson Cancer Research Center, D5-290, PO Box 19024, Seattle, WA 98109-1024; Telephone: (206)-667-6190; Fax: (206)-667-1034; e-mail: sjlee@fhcrc.org.

Word count: 3050 Abstract word count: 207 Tables: 4 Figures: 1 References: 56

Keywords: autologous hematopoietic cell transplantation; allogeneic hematopoietic cell transplantation; exercise; stress management; quality of life

Abstract:

Studies show that engaging patients in exercise and/or stress management techniques during hematopoietic cell transplantation (HCT) improves quality of life. The Blood and Marrow Transplant Clinical Trials Network tested the efficacy of training patients to engage in self-directed exercise and stress management during their HCTs. The study randomized 711 patients at 21 centers to receive one of four training interventions before HCT: a self-directed exercise program, a self-administered stress management program, both or neither. Participants completed self-reported assessments at enrollment and up to 180 days after transplant. Randomization was stratified by center and transplant type. There were no differences in the primary endpoints of the physical (PCS) and mental (MCS) component scales of the SF36 at day 100 among the groups based on an intention-to-treat analysis. There were no differences observed in overall survival, hospital days through day 100 post-HCT, or in other patient-reported outcomes, including treatment-related distress, sleep quality, pain, and nausea. Patient randomized to training in stress management reported more use of those techniques; patients randomized to training in exercise did not report more physical activity. Although other studies have reported efficacy of more intensive interventions, brief training in an easy-to-disseminate format for either self-directed exercise or stress management was not effective in our trial.

Introduction

The adverse effects of hematopoietic cell transplantation (HCT) on short and long-term quality of life (QOL) are well documented.1 Patients experience numerous adverse symptoms such as nausea, fatigue, and sleep disturbance that are accompanied by declines in physical and mental well-being. Although most longitudinal studies find the majority of patients return to baseline functioning, it may take years to reach this goal.2-7 Currently, there are no national guidelines about use of exercise or stress management techniques during HCT. Transplant centers generally do not have the resources to provide intensive or ongoing supervision for exercise or stress management techniques to their patients.

Previous single institution studies, including some randomized controlled trials, showed that engagement in exercise8-25 and stress management26-31 during or after HCT improved many outcomes in HCT patients. The tested interventions varied from active, guided sessions to home-based interventions. Outcomes included self-reported measures such as QOL, mood, fatigue, and distress as well as objective measures of functional status, strength, stamina, hospital days and survival. In these studies, stress management interventions primarily improve mental health outcomes and nausea, while relaxation and imagery are associated with less pain after HCT.30 The impact of exercise interventions was more variable; most studies and metaanalyses reported physical health benefits,20,32 while some studies also reported mental health benefits.24,33 In randomized controlled trials in patients with solid tumors, stress management training has been shown to improve both mental and physical health.27 Combining stress management and exercise training is feasible and well-tolerated by oncology patients,31,34,35 and a recent randomized controlled trial found that the combination was more effective than usual care in improving anxiety and depression over the course of outpatient chemotherapy.28

The current study was designed to test whether a brief training session to encourage use of a self-administered stress management program and/or self-directed exercise program

would improve both physical and mental well-being of autologous and allogeneic patients following HCT compared to usual care.

Methods: Participants

Patients (n=711) at 21 US centers were enrolled between January 2011-June 2012 through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0902). Inclusion criteria were: age 18 years or older, ability to speak and read English, ability to exercise at low to moderate intensity (as judged by self-reported ability to walk up one flight of stairs), no requirement for supplemental oxygen, and planned autologous or allogeneic HCT within 6 weeks. Exclusion criteria were: orthopedic, neurologic or other problems which prevented safe ambulation or protocol adherence, participation in another clinical trial with QOL or functional status as a primary endpoint, planned anti-cancer therapies other than tyrosine kinase inhibitors or rituximab within 100 days after HCT, planned donor lymphocyte infusion within 100 days after HCT, and planned tandem transplant.

Study Design

The study was designed as a phase III, randomized, controlled, multicenter trial. After enrollment and baseline patient self-reported information was collected, patients were randomized using a factorial design to one of four groups: exercise training, stress management training, the combination of exercise and stress management training, or usual care. The intervention was given prior to HCT as a 20-minute introduction to the self-directed program. Trained site personnel served as the interventionists who reviewed a pamphlet summarizing the main points of the self-directed program and gave the patients a DVD reinforcing the program. Patients received a diary in which they could track their participation in exercise and/or stress management. In addition, the interventionists reviewed the goals for use of the program, proper

technique, identification of barriers to engagement in exercise or stress management and plans to overcome them. The exercise component also included calculation of target heart rate and provision of a pedometer. The stress management component also included provision of a relaxation CD. For all intervention groups, the interventionists re-contacted patients at 30 and 60 days after HCT to review the training goals, discuss barriers, and provide encouragement. To ensure fidelity of the delivered intervention, the first two patient interactions of each interventionist were audiotaped and reviewed centrally. Ten percent of subsequent interactions were observed by another study person at the center to ensure critical material was delivered consistently. All three intervention groups and the usual care group received a 45 minute DVD of general information about HCT which included very brief and nonspecific comments about keeping active and minimizing stress during transplantation.36

The exercise goal was walking 3-5 times a week for at least 20-30 minutes at 50-75% of estimated heart rate reserve, consistent with guidelines for exercise in cancer patients developed by the American College of Sports Medicine.37 The stress management goal targeted paced abdominal breathing,38 progressive muscle relaxation with guided imagery,39 and coping self-statements40 to decrease and manage stress.41

The full protocol is available on the BMT CTN website (www.bmtctn.net). The research protocol was approved by a protocol review committee appointed by the National Heart, Lung and Blood Institute (NHLBI), and by local institutional review boards or ethics committees. All participants provided written informed consent. An NHLBI-appointed Data and Safety Monitoring Committee provided oversight. This study is registered with ClinicalTrials.gov, number NCT01278927. All patient materials used in this trial are available through the Be The Match organization at www.bethematch.org. Readers interested in additional details of the interventions, including training scripts, should contact BMT CTN.

Data Collection Instruments

Participants completed self-reported assessments at enrollment and 30, 60, 100 and 180 days after transplant. Instruments included: (1) Medical Outcomes Study SF36 (SF36), version 2.0, a 36-item, generic multidimensional QOL measure with two summary domains, a physical component summary (PCS) scale and mental component summary (MCS) scale, and eight subscales including a 2-item Bodily Pain subscale. The age- and sex-adjusted norm for the PCS and MCS scales is 50 with a standard deviation of 10 points. Higher scores indicate better QOL; (2) Cancer and Treatment Distress (CTX-D),7,42 a 27-item measure of distress with subscales of Uncertainty, Health Burden, Family Strain, Identity, and Managing the Medical System as well as distress interference with function; (3) Pittsburgh Sleep Quality Index (PSQI),43-45 a 7-item measure of sleep patterns and difficulties such as sleep quality, sleep latency, sleep efficiency and use of sleeping medications; and (4) Nausea, measured by 2 items formatted similar to the SF36 Bodily Pain subscale. For instruments 2-4, higher scores indicate greater symptom burden. Other secondary outcomes included hospital days within the first 100 days after graft infusion and survival.

Measures of adherence were collected to see if patients were engaging in the self-administered programs. The Leisure Score Index (LSI of the Godin Leisure-Time Exercise Questionnaire46) was used to measure physical activity.47 Participation in stress management activities in the past week was measured by a 5-item Stress Reduction Checklist.27 We also collected participants' impressions of the perceived program effectiveness, program importance, and skill of the interventionist on 7-point Likert scales.

Statistical Analyses

The co-primary endpoints were the SF-36 PCS and MCS at day 100. The study was designed to have 85% power to detect a clinically meaningful difference of 0.5 standard

deviation (STD) units in the exercise or stress management groups on each of the two endpoints, maintaining an overall type I error rate of 0.05. The sample size was inflated to adjust for a 5% failure to undergo HCT, 10% death before day 100, and 15% missing day 100 self-reported data from surviving participants, resulting in a target accrual of 700 patients. Randomization was stratified by center and transplant type (autologous, myeloablative allogeneic, non-myeloablative allogeneic). Primary analysis was on an intention-to-treat (ITT) basis that includes all randomized patients classified according to their assigned treatment. The Exercise groups (exercise only arm and the exercise/stress management arm) were compared to the No Exercise groups (usual care arm and the stress management arm). The Stress Management analysis was conducted analogously. Patients who died within 100 days of transplant were assigned PCS and MCS scores of zero (lower than the lowest observed score), and those alive at the last follow-up with missing PCS and MCS were assigned scores of five (lower than the lowest observed score but higher than the score assigned to patients who died within the first 100 days). Day 100 PCS and MCS were compared without adjustment for baseline scores or other clinical characteristics using the Mann-Whitney test, a non-parametric test which only tests the ranks of the scores rather than the actual scores. Each test was conducted at the 0.025 significance level to adjust for the co-primary endpoints for each factor.

Secondary analyses examining main effects for PCS and MCS in survivors were conducted using multiple linear regression adjusting for baseline assessments and other covariates associated with the outcome. Number of days alive and out of the hospital through day 100 post-HCT and survival within 12 months were compared using the Kruskal-Wallis and log-rank tests. Three sensitivity analyses for handling missing assessments were conducted for the day 100 outcomes conditional on being alive: all available data, multiple imputation to impute missing day 100 values and an inverse probability weighted generalized estimating equations model to account for missing data.48 Available data for PCS, MCS, pain, sleep quality, nausea, and cancer and treatment distress at day 100 were evaluated using linear regression

models adjusting for baseline scores. Because of multiple testing, p values <0.01 were considered significant.

Exploratory subgroup analyses were conducted to see if there was a differential treatment effect on day 100 PCS and MCS scores according to autologous versus myeloablative allogeneic versus non-myeloablative allogeneic HCT (since this was a stratification factor) or in groups with high versus low baseline PCS or MCS or high versus low engagement in exercise and stress management, dichotomized at the median. These analyses adjust for baseline PCS and MCS scores. Statistical analyses were performed using SAS/STAT software, version 9.3 (SAS Institute, Inc., Cary, NC).

Results:

Participant characteristics

The study included 711 participants, evenly distributed between allogeneic and autologous transplant recipients. Participants were enrolled a median (interquartile range) of 7 (3-13) days before HCT. The groups were well-balanced for baseline characteristics. (Table 1) At enrollment, only 2.6% met the American College of Sports Medicine guidelines of 150 minutes of moderate intensity activity per week as measured by the LSI. Approximately 60% of participants had a Karnofsky performance status of 90% or greater. Sixty seven percent used at least one of the stress management techniques: 53% used self-talk to help coping, 41% used self-guided relaxation, 34% used deep breathing, 12% listened to relaxation audiotapes, and 4% watched videos/DVDs about managing stress.

Five (0.7%) patients did not have a transplant, 21 (2.9%) did not have a training session and two (<0.1%) received the incorrect training. These patients were analyzed with their assigned groups for the ITT analysis. Additional attrition was due to death and failure to return surveys (Figure). Survival and missing data rates were similar across study arms. The primary cause of death within the first six months in all treatment arms was relapse.

Primary endpoint: Day 100 PCS and MCS

There were no differences in the primary endpoints of PCS and MCS at day 100 between the Exercise and No Exercise groups or between the Stress Management and No Stress Management groups (all p-values > 0.14, Table 2).

Secondary endpoints - Day 100 and Day 180

Results of analyses conditional on being alive and using only available data or accounting for missing data by multiple imputation or by inverse probability of censoring weighted generalized estimating equations48 led to the same conclusion as the primary analyses for PCS and MCS. There were no differences in day 100 cancer and treatment distress, sleep quality, pain, and nausea (Table 3) or the SF36 subscales (data not shown). There was no interaction between the two interventions. No differences were observed in overall survival at 1 year (p=0.15) or number of days alive and out of the hospital through day 100 post-HCT (p=0.42). After adjusting for baseline scores, there was no association between assigned group and day 180 patient-reported outcomes, including PCS, MCS, cancer and treatment distress, sleep quality, pain, and nausea (data not shown).

Intervention Credibility and Adherence

Participants receiving exercise training thought it would improve their QOL and would want the training to be available to other patients (p<0.0001), whereas this was not the case with the stress management training. Training in exercise or stress management had no effect on self-reported exercise activity at day 30, day 60, and day 100 except physical activity was higher at day 180 (p = 0.04) in patients assigned to Exercise training after adjusting for baseline

exercise activity. Assignment to Exercise training had no effect on self-reported stress management activity after adjusting for baseline stress management activity, but assignment to Stress Management training was strongly associated with an increase in stress management activity at all time points (p<0.0003).

Exploratory Analyses

We analyzed predictors of better QOL at day 100 using multiple regression and multiple imputation for missing values. Higher PCS at day 100 was associated with higher PCS at enrollment, being employed, and having an autologous transplant rather than a myeloablative allogeneic HCT or reduced intensity/non-myeloablative allogeneic HCT. There was no difference between the two types of allogeneic conditioning intensities. Higher MCS at day 100 was associated with higher MCS at enrollment and higher income (Table 4).

To support future research directions in the HCT population, we explored whether specified subgroups may have benefited more than others from the training interventions. No benefits were seen in subgroups of autologous vs. allogeneic groups, lower vs. higher baseline PCS or MCS scores, or lower vs. higher baseline engagement in exercise or stress management (data not shown).

Discussion

Despite the fact that meta-analyses of RCTs of exercise and stress management training suggest benefits for HCT recipients,32,33 our large, multicenter, randomized controlled trial (RCT) did not show any measurable benefit to a brief training session to encourage patients to use self-directed exercise or stress management during their HCT. There are a number of possible explanations for our findings. First, our brief training sessions may have lacked sufficient intensity to promote adoption of exercise, as we did not see differences at day 30, 60, and 100. Perhaps the peri-transplant time, in the midst of intensive medical preparation for HCT

and the subsequent acute toxicities of HCT, was too intrinsically stressful and physically limiting to allow patients to benefit from a low intensity, self-administered exercise program. Similarly, although patients who received stress management training reported great use of stress management techniques, these strategies may have been inadequate to ameliorate the negative physical and emotional effects of transplant. A second possibility is that the self-report measures used in this study were not sufficiently sensitive to detect intervention effects. One randomized study in HCT patients reported differences in some objective measures of strength and endurance, but not in self-reported symptoms or QOL, suggesting that the detected functional differences were not clinically meaningful49 or that these measures are not reflective of physical functioning.50 The SF-36 PCS and MCS are global subscales that may not capture improved strength or endurance. However, the CTXD was developed specifically to measure distress related to HCT, and it has shown sensitivity to change over the course of treatment.7,42 Measuring the primary outcome at day 100 may have been too early, if physical functioning is dominated by transplant toxicity at that time, regardless of whether patients were engaging in exercise or stress management.

A third possibility is that broad application of the intervention obscured effects that would have been observed in some vulnerable or more adherent subgroups. Two trials in HCT suggested benefits were greatest in the less fit group.14,51 However, we failed to find potential beneficiaries in exploratory analyses including those undergoing different types of transplants or those with more impaired PCS and MCS scores.

It is unlikely that our negative results are due to sufficient participation in exercise and stress management under usual care, or that patients randomized to usual care benefitted from the training being delivered to other patients. Although it is common for transplant providers to encourage patients to stay as active as possible and minimize stress during HCT, exercise engagement was low in all groups including the usual care group. There was no increase in use of stress management techniques in patients who did not receive the stress management

training. Some limitations should be noted. We purposefully did not test an intensive guided exercise or stress management program because many transplant programs do not have the resources to provide this degree of supervision.52 Studies that provided more intensive training generally showed more differences,24 although a Cochrane review suggested that a self-directed component was important to maintain behavior change beyond the intervention period.53 We also did not collect process information or patient-reported insights to understand why the training interventions were not successful.

The results of this study suggest several directions for future research on improving QOL through stress management and exercise training for HCT patients. First, interventions may be more effective if introduced a sufficient time before transplant to allow patients to incorporate these practices into their routines, or after transplant when patients have recovered from short-term treatment side effects, as suggested by our finding showing that intervention assignment had no effects on exercise activity until day 180. Second, it is also possible that targeting patients with a demonstrated need for increased exercise (i.e., sedentary individuals) or stress management (i.e., distressed individuals) would be more effective.51,54 Third, the intervention may be more effective if more intensive or personalized. Internet-based strategies represent one means of increasing the frequency of contact with participants and tailoring to specific patient needs without the necessity of adding local professional resources.55,56 Other approaches such as exercise in shorter, more intensive sessions, supervised group exercise, use of ancillary motivating devices (e.g., FitBit, Nike, Jawbone etc) or other forms of exercise (e.g., reclining bicycles) might be more effective in the HCT population. These methods require more intensive training and follow-up but may be necessary to achieve change. Given the unexpected results of the present study, the importance of conducting rigorous evaluations to determine the efficacy of other potential interventions is clear.

In conclusion, our study does not support a benefit to including a single brief instruction in exercise or stress management for all HCT recipients to reduce distress or improve physical

or mental functioning during transplant and recovery. While this brief intervention does not require further testing in our estimation, other methods that might improve physical and mental health outcomes, while remaining feasible in cost and patient energy required, would merit testing.

Funding

This work was supported by the National Heart, Lung, and Blood Institute and the National Cancer Institute (U10HL069294).

Authorship

All authors designed the study, collected and analyzed data, and wrote the paper. JL and BL performed the statistical analysis and edited the paper. All authors critically revised the manuscript for important intellectual content and approved the manuscript to be published.

Conflict-of-interest disclosure

The authors declare no competing financial interests related to this study.

References

1. Pidala J, Anasetti C, Jim H. Quality of life after allogeneic hematopoietic cell transplantation. Blood. 2009;114(1):7-19.

2. Andrykowski MA, Greiner CB, Altmaier EM, et al. Quality of life following bone marrow transplantation: findings from a multicentre study. Br J Cancer. 1995;71(6):1322-1329.

3. Bush NE, Donaldson GW, Haberman MH, Dacanay R, Sullivan KM. Conditional and unconditional estimation of multidimensional quality of life after hematopoietic stem cell transplantation: a longitudinal follow-up of 415 patients. Biol Blood Marrow Transplant. 2000;6(5A):576-591.

4. Gruber U, Fegg M, Buchmann M, Kolb HJ, Hiddemann W. The long-term psychosocial effects of haematopoetic stem cell transplantation. Eur J Cancer Care (Engl). 2003;12(3):249-256.

5. Lee SJ, Fairclough D, Parsons SK, et al. Recovery after stem-cell transplantation for hematologic diseases. J Clin Oncol. 2001;19(1):242-252.

6. Syrjala KL, Chapko MK, Vitaliano PP, Cummings C, Sullivan KM. Recovery after allogeneic marrow transplantation: prospective study of predictors of long-term physical and psychosocial functioning. Bone Marrow Transplant. 1993;11(4):319-327.

7. Syrjala KL, Langer SL, Abrams JR, et al. Recovery and long-term function after hematopoietic cell transplantation for leukemia or lymphoma. Jama. 2004;291(19):2335-2343.

8. Carlson LE, Smith D, Russell J, Fibich C, Whittaker T. Individualized exercise program for the treatment of severe fatigue in patients after allogeneic hematopoietic stem-cell transplant: a pilot study. Bone Marrow Transplant. 2006;37(10):945-954.

9. Coleman EA, Coon S, Hall-Barrow J, Richards K, Gaylor D, Stewart B. Feasibility of exercise during treatment for multiple myeloma. Cancer Nurs. 2003;26(5):410-419.

10. Coleman EA, Coon SK, Kennedy RL, et al. Effects of exercise in combination with epoetin alfa during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for multiple myeloma. Oncol Nurs Forum. 2008;35(3):E53-61.

11. Courneya KS. Exercise interventions during cancer treatment: biopsychosocial outcomes. Exerc Sport Sci Rev. 2001;29(2):60-64.

12. Cunningham BA, Morris G, Cheney CL, Buergel N, Aker SN, Lenssen P. Effects of resistive exercise on skeletal muscle in marrow transplant recipients receiving total parenteral nutrition. JPEN J Parenter Enteral Nutr. 1986;10(6):558-563.

13. Decker WA, Turner-McGlade J, Fehir KM. Psychosocial aspects and the physiological effects of a cardiopulmonary exercise program in patients undergoing bone marrow transplantation (BMT) for acute leukemia (AL). Transplant Proc. 1989;21(1 Pt 3):3068-3069.

14. DeFor TE, Burns LJ, Gold EM, Weisdorf DJ. A randomized trial of the effect of a walking regimen on the functional status of 100 adult allogeneic donor hematopoietic cell transplant patients. Biol Blood Marrow Transplant. 2007;13(8):948-955.

15. Dimeo F, Bertz H, Finke J, Fetscher S, Mertelsmann R, Keul J. An aerobic exercise program for patients with haematological malignancies after bone marrow transplantation. Bone Marrow Transplant. 1996;18(6):1157-1160.

16. Dimeo F, Fetscher S, Lange W, Mertelsmann R, Keul J. Effects of aerobic exercise on the physical performance and incidence of treatment-related complications after high-dose chemotherapy. Blood. 1997;90(9):3390-3394.

17. Dimeo F, Schwartz S, Fietz T, Wanjura T, Boning D, Thiel E. Effects of endurance training on the physical performance of patients with hematological malignancies during chemotherapy. Support Care Cancer. 2003;11(10):623-628.

18. Dimeo FC, Stieglitz RD, Novelli-Fischer U, Fetscher S, Keul J. Effects of physical activity on the fatigue and psychologic status of cancer patients during chemotherapy. Cancer. 1999;85(10):2273-2277.

19. Hayes S, Davies PS, Parker T, Bashford J, Newman B. Quality of life changes following peripheral blood stem cell transplantation and participation in a mixed-type, moderate-intensity, exercise program. Bone Marrow Transplant. 2004;33(5):553-558.

20. Jarden M, Baadsgaard MT, Hovgaard DJ, Boesen E, Adamsen L. A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT. Bone Marrow Transplant. 2009;43(9):725-737.

21. Kim SD, Kim HS. A series of bed exercises to improve lymphocyte count in allogeneic bone marrow transplantation patients. Eur J Cancer Care (Engl). 2006;15(5):453-457.

22. Mello M, Tanaka C, Dulley FL. Effects of an exercise program on muscle performance in patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant. 2003;32(7):723-728.

23. Wilson RW, Jacobsen PB, Fields KK. Pilot study of a home-based aerobic exercise program for sedentary cancer survivors treated with hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35(7):721-727.

24. Wiskemann J, Dreger P, Schwerdtfeger R, et al. Effects of a partly self-administered exercise program before, during, and after allogeneic stem cell transplantation. Blood. 2011;117(9):2604-2613.

25. Oechsle K, Aslan Z, Suesse Y, Jensen W, Bokemeyer C, de Wit M. Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial. Support Care Cancer. 2014;22(1):63-69.

26. Gaston-Johansson F, Fall-Dickson JM, Nanda J, et al. The effectiveness of the comprehensive coping strategy program on clinical outcomes in breast cancer autologous bone marrow transplantation. Cancer Nurs. 2000;23(4):277-285.

27. Jacobsen PB, Meade CD, Stein KD, Chirikos TN, Small BJ, Ruckdeschel JC. Efficacy and costs of two forms of stress management training for cancer patients undergoing chemotherapy. J Clin Oncol. 2002;20(12):2851-2862.

28. Jacobsen PB, Phillips KM, Jim HS, et al. Effects of self-directed stress management training and home-based exercise on quality of life in cancer patients receiving chemotherapy: a randomized controlled trial. Psychooncology. 2013;22(6):1229-1235.

29. Syrjala KL, Cummings C, Donaldson GW. Hypnosis or cognitive behavioral training for the reduction of pain and nausea during cancer treatment: a controlled clinical trial. Pain. 1992;48(2):137-146.

30. Syrjala KL, Donaldson GW, Davis MW, Kippes ME, Carr JE. Relaxation and imagery and cognitive-behavioral training reduce pain during cancer treatment: a controlled clinical trial. Pain. 1995;63(2):189-198.

31. Wilson RW, Taliaferro LA, Jacobsen PB. Pilot study of a self-administered stress management and exercise intervention during chemotherapy for cancer. Support Care Cancer. 2006;14(9):928-935.

32. van Haren IE, Timmerman H, Potting CM, Blijlevens NM, Staal JB, Nijhuis-van der Sanden MW. Physical exercise for patients undergoing hematopoietic stem cell transplantation: systematic review and meta-analyses of randomized controlled trials. Phys Ther. 2013;93(4):514-528.

33. Persoon S, Kersten MJ, van der Weiden K, et al. Effects of exercise in patients treated with stem cell transplantation for a hematologic malignancy: a systematic review and meta-analysis. Cancer Treat Rev. 2013;39(6):682-690.

34. Moonsammy SH, Guglietti CL, Mina DS, et al. A pilot study of an exercise & cognitive behavioral therapy intervention for epithelial ovarian cancer patients. J Ovarian Res. 2013;6(1):21.

35. Rabin C, Pinto B, Dunsiger S, Nash J, Trask P. Exercise and relaxation intervention for breast cancer survivors: feasibility, acceptability and effects. Psychooncology. 2009;18(3):258-266.

36. Office of Patient Advocacy NMDP. Words of Experience. Stories of Hope. A Guide to Marrow and Cord Blood Transplant for Patients and Caregivers. [DVD]; 2008.

37. Courneya KS, Mackey JR, Quinney HA. Neoplasms. In: Myers J, Herbert W, Humphrey R, eds. American College of Sports Medicine's resources for clinical exercise physiology: musculoskeletal, neuromuscular, neoplastic, immunologic and hematologic conditions. New York: Lippincott; 2002.

38. Turk DC, Meichenbaum D, Genest M. Pain and behavioral medicine: A cognitive-behavioral perspective. New York: Guilford Press; 1983.

39. Burish TG, Snyder SL, Jenkins RA. Preparing patients for cancer chemotherapy: effect of coping preparation and relaxation interventions. J Consult Clin Psychol. 1991;59(4):518-525.

40. Meichenbaum D. Stress inoculation training. New York: Pergamon Press; 1985.

41. Penedo FJ, Molton I, Dahn JR, et al. A randomized clinical trial of group-based cognitive-behavioral stress management in localized prostate cancer: development of stress management skills improves quality of life and benefit finding. Ann Behav Med. 2006;31(3):261-270.

42. Syrjala KL, Abrams J. Scoring Manual for the Cancer and Treatment Distress (CTXD) scale; 2005.

43. Broeckel JA, Jacobsen PB, Horton J, Balducci L, Lyman GH. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol. 1998;16(5):1689-1696.

44. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193-213.

45. Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res. 1998;45(1 Spec No):5-13.

46. Godin G, Jobin J, Bouillon J. Assessment of leisure time exercise behavior by self-report: a concurrent validity study. Can J Public Health. 1986;77(5):359-362.

47. Jacobs DR, Jr., Ainsworth BE, Hartman TJ, Leon AS. A simultaneous evaluation of 10 commonly used physical activity questionnaires. MedSci Sports Exerc. 1993;25(1):81-91.

48. Kurland BF, Heagerty PJ. Directly parameterized regression conditioning on being alive: analysis of longitudinal data truncated by deaths. Biostatistics. 2005;6(2):241-258.

49. Knols RH, de Bruin ED, Uebelhart D, et al. Effects of an outpatient physical exercise program on hematopoietic stem-cell transplantation recipients: a randomized clinical trial. Bone Marrow Transplant. 2011;46(9): 1245-1255.

50. Knols RH, de Bruin ED, Uebelhart D, Aaronson NK. The relationship between ambulatory step activity, self-reported physical functioning and standardised timed walking in patients with haematological malignancies. Disabil Rehabil. 2010;32(22):1819-1826.

51. Wiskemann J, Kuehl R, Dreger P, et al. Efficacy of exercise training in SCT patients-who benefits most? Bone Marrow Transplant. 2014;49(3):443-448.

52. Somerfield MR, Rizzo JD. Can a modest exercise program really improve physical functioning and quality of life among recipients of hematopoietic SCT? Bone Marrow Transplant. 2010;45(2):217-218.

53. Foster C, Hillsdon M, Thorogood M, Kaur A, Wedatilake T. Interventions for promoting physical activity. In: Collaboration TC ed. 2012: John Wiley & Sons, Ltd.; 2012.

54. Faller H, Schuler M, Richard M, Heckl U, Weis J, Kuffner R. Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis. J Clin Oncol. 2013;31(6):782-793.

55. Ritterband LM, Bailey ET, Thorndike FP, Lord HR, Farrell-Carnahan L, Baum LD. Initial evaluation of an Internet intervention to improve the sleep of cancer survivors with insomnia. Psychooncology. 2012;21(7):695-705.

56. Yun YH, Lee KS, Kim YW, et al. Web-based tailored education program for disease-free cancer survivors with cancer-related fatigue: a randomized controlled trial. J Clin Oncol. 2012;30(12):1296-1303.

Table 1: Characteristics of the Study Population at enrollment (n=711)

Stress Exercise/

Variable Standard Exercise Mgmt Stress Mgmt P-value

Number of patients 175 180 178 178

Number of centers 19 19 20 20

Age at transplant, years 0.38

Median(range) 55 (19-76) 58 (20-76) 58 (20-75) 57 (18-75)

<=40 27 (15) 26 (14) 21 (12) 26 (15)

40-<65 111 (63) 105 (58) 123 (69) 118 (66)

>=65 37 (21) 49 (27) 34 (19) 34 (19)

Ethnicity 0.41

Hispanic or Latino 6 (3) 7 (4) 11 (6) 11 (6)

Not Hispanic or Latino 167 (95) 172 (96) 167 (94) 167 (94)

Unknown/NA 2 (1) 1 (<1) 0 0

Race 0.45

American Indian/ Alaskan 0 0 1 (<1) 0

Native

Asian 2 (1) 3 (2) 4 (2) 2 (1)

Hawaiian/Pacific Islander 1 (<1) 1 (<1) 0 1 (<1)

Black or African American 16 (9) 14 (8) 17 (10) 13 (7)

White 152 (87) 162 (90) 152 (85) 160 (90)

More than one race 3 (2) 0 1 (<1) 2 (1)

Other/unknown 1 (<1) 0 4 (2) 0

Recipient sex 0.37

Male 93 (53) 112 (62) 100 (56) 100 (56)

Female 82 (47) 68 (38) 78 (44) 78 (44)

Marital status 0.16

Married/Living with partner 122 (70) 145 (81) 137 (77) 125 (70)

Single, never married 28 (16) 12 (7) 18 (10) 26 (15)

Separated, Divorced 17 (10) 16 (9) 16 (9) 24 (13)

Widowed 6 (3) 6 (3) 4 (2) 2 (1)

Missing 2 (1) 1 (<1) 3 (2) 1 (<1)

Education 0.50

Grade school 2 (1) 0 0 0

High School 36 (21) 33 (18) 37 (21) 35 (20)

College graduate 108 (62) 114 (63) 101 (57) 100 (56)

Postgraduate 28 (16) 32 (18) 38 (21) 42 (24)

Missing 1 (<1) 1 (<1) 2 (1) 1 (<1)

Variable Standard Exercise Stress Exercise/ Mgmt Stress Mgmt P-value

Employment status 0.56

Not employed 98 (56) 99 (55) 89 (50) 97 (54)

Employed 77 (44) 80 (44) 87 (49) 81 (46)

Missing 0 1 (<1) 2 (1) 0

Income 0.31

Under $15,000 9 (5) 15 (8) 7 (4) 10 (6)

$15,000-$24,999 14 (8) 10 (6) 17 (10) 10 (6)

$25,000-$49,999 40 (23) 25 (14) 27 (15) 41 (23)

$50,000-$74,999 34 (19) 47 (26) 32 (18) 36 (20)

$75,000-$99,999 21 (12) 24 (13) 30 (17) 25 (14)

$100,000 or above 43 (25) 50 (28) 53 (30) 47 (26)

Missing 14 (8) 9 (5) 12 (7) 9 (5)

Karnofsky score,% 0.35

>=90 102 (58) 112 (62) 111 (62) 94 (53)

70-80 68 (39) 65 (36) 64 (36) 76 (43)

50-60 4 (2) 2 (1) 1 (<1) 3 (2)

Missing/Not done 1 (<1) 1 (<1) 2 (1) 5 (3)

Body Mass Index 0.16

Median (range) 28 (19-52) 27 (16-54) 28 (18-56) 29 (19-52)

Underweight (<18.5) 0 3 (2) 1 (<1) 0

Normal (18.5-24.9) 51 (29) 49 (27) 38 (21) 40 (22)

Overweight (25-29.9) 66 (38) 67 (37) 64 (36) 60 (34)

Obese (>=30) 57 (33) 60 (33) 74 (42) 74 (42)

Missing 1 (<1) 1 (<1) 1 (<1) 4 (2)

Disease/Disease status 0.83

AML/ALL 42 (24) 42 (23) 47 (26) 40 (22)

CML 2 (1) 5 (3) 5 (3) 2 (1)

MDS/MPS 13 (7) 19 (11) 16 (9) 15 (8)

MM/PCD 57 (33) 50 (28) 43 (24) 44 (25)

Lymphoma 50 (29) 54 (30) 60 (34) 66 (37)

CLL 7 (4) 5 (3) 4 (2) 6 (3)

Other disease 3 (2) 4 (2) 3 (2) 2 (1)

Missing 1 (<1) 1 (<1) 0 3 (2)

Prior transplant 0.79

No 156 (89) 166 (92) 162 (91) 161 (90)

Yes 19 (11) 14 (8) 16 (9) 17 (10)

Prior cytotoxic chemo 0.79

Variable Standard Exercise Stress Exercise/ Mgmt Stress Mgmt P-value

No 24 (14) 26 (14) 27 (15) 21 (12)

Yes 142 (81) 142 (79) 135 (76) 144 (81)

Missing 9 (5) 12 (7) 16 (9) 13 (7)

Patient CMV status 0.52

Positive 101 (58) 104 (58) 101 (57) 88 (49)

Negative 73 (42) 75 (42) 77 (43) 88 (49)

Missing 1 (<1) 1 (<1) 0 2 (1)

Transplant type+ 0.91

ALLO 86 (49) 89 (49) 90 (51) 86 (48)

AUTO 89 (51) 90 (50) 88 (49) 91 (51)

Missing 0 1 (<1) 0 1 (<1)

If ALLO, conditioning intensity 0.94

Myeloablative 41 (48) 40 (45) 40 (44) 37 (43)

Non myeloablative 45 (52) 49 (55) 50 (56) 49 (57)

Baseline intervention delivered 0.81

No 2 (1) 3 (2) 3 (2) 3 (2)

Yes 173 (99) 175 (97) 172 (97) 173 (97)

Missing 0 2 (1) 3 (2) 2 (1)

Baseline SF36 Physical Component 0.34

Median(range) 42.1 (13.5- 42.8 (14.4- 44.4 (16.5- 42.9 (14.0-

61.3) 64.9) 62.2) 62.5)

Baseline SF36 Mental Component 0.77

Median(range) 52.9 (7.8- 51.7 (16.7- 52.2 (11.6- 52.4 (18.9-

67.2) 74.0) 66.1) 69.8)

Table 2. Primary analyses: Intention to treat analysis of Day 100 PCS and MCS

Day 100 SF36 scores Exercise (n=358) Median (25th-75th) No Exercise (n=353) Median (25th-75th) p-value

PCS 37.5 (19.7-46.7) 39.7 (27.1-47.7) 0.14

MCS 49.4 (27.3-57.7) 50.1 (34.2-57.8) 0.33

Stress Management (n=356) Median (25th-75th) No Stress Management (n=355) Median (25th-75th)

PCS 37.8 (22.1-46.6) 39.7 (25.7-47.9) 0.21

MCS 50.7 (31.0-58.2) 49.1 (30.5-56.8) 0.30

Table 3: Secondary analyses: Available data for secondary endpoints at Day 100 adjusted for Baseline score, according to treatment arm.

Median scores Exercise Stress Management Exercise + Stress Management Usual Care P1 P2 P3 Overall p

PCS 42.2 41.8 40.6 42.5 0.62 0.18 0.13 0.39

MCS 50.8 52.4 52.1 y 50.4 0.23 0.30 0.16 0.50

Cancer and 0.96 0.88 1.04 0.94 0.54 0.31 0.51 0.37

Treatment

Distress (CTXD)

Sleep quality 4.55 3.49 4.44 4.02 0.34 0.14 0.41 0.06

(PSQI)

Pain 67.78 71.55 67.96 68.19 0.76 0.56 0.81 0.84

Nausea 2.74 2.63 2.80 2.85 0.71 0.31 0.72 0.79

P1=comparison of exercise vs. usual care; P2=comparison of stress management vs. usual care; P3=comparison of exercise and stress management vs. usual care

PCS, physical component score, age and gender adjusted mean = 50, higher score reflects better physical functioning.

MCS, mental component score, age and gender adjusted mean = 50, higher score reflects better mental functioning.

CTXD, cancer and treatment distress, higher score reflects more distress PSQI, Pittsburgh sleep quality index, higher score reflects worse sleep quality

ACCEPTED MANUSCRIPT

Table 4: Predictors of PCS and MCS at Day 100 with Multiple Imputation

PCS (n=642) MCS (n=606)

Effect Level N Estimate (95% CI) p-value Effect Level N Estimate (95% CI) p-value

Exercise No 324 0 Exercise No 304 0

Yes 318 -0.15 (-1.88, 1.57) 0.86 Yes 302 0.48 (-1.12, 2.08) 0.56

Stress Management No 327 0 Stress Management No 306 0

Yes 315 -1.44 (-2.94, 0.06) 0.06 Yes 300 0.71 (-1.12, 2.53) 0.44

Baseline PCS 0.42 (0.33, 0.51) <.0001 Baseline MCS 0.37 (0.29, 0.45) <.0001

Employed No 343 0 Income Below $50,000 201 0

Yes 299 1.73 (0.18, 3.29) 0.03 $ 50,000 or above 405 2.55 (0.59, 4.42) 0.01

Transplant type** Auto 338 0 0.0003*

MA 134 -4.48 (-6.71, -2.24) 0.0002

NMA 170 -3.43 (-5.34, -1.53) 0.0005

PCS, physical component score; MCS, mental component score; MA, myeloab ative; NMA, not myeloablative * overall p-value

** Myeloablative Allo (MA) vs. Non-myeloablative Allo (NMA), estimate 1.04 (-3.93, 1.85), p=0.46

Figure. CONSORT diagram