Maintaining Fitness: Exercise in Patients With Hematologic Malignancy
Phase: NA
Conditions: Hematopoietic and Lymphoid Cell Neoplasm
Sponsor: Ohio State University Comprehensive Cancer Center

 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title:  Maintaining Fitness: Exercise in Patients with Hematologic Malignancy 
 
Principal Investigator:  Ashley Rosko, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version Date: Jul 2019 
 

 
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Table of Contents 
 
1.0 
HYPOTHESIS AND OBJECTIVES...……………………………………...……...4 
 
1.1 
Hypotheses…………………………………………………………………….4 
1.2 
Primary objective……………………………………………………………...4 
 
1.3 
Secondary objective(s)………………………………………………………...4 
 
1.4 
Primary Endpoint………………………………………………………….…..4 
2.0 
BACKGROUND AND SIGNIFICANCE……………………………………..…....4 
 
2.1 
Background of Medical Need..………………………………………………..4 
 
2.2 
Short Physical Performance Battery (SPPB) and Otago Exercise Programme  
(OEP)………………………………………………………………………….5 
2.3 
Molecular   biomarkers   are   associated   with   aging,   frailty,   and  physical 
inactivity…………………………………………………………………….....5 
 
2.4 
Falls…………………………………………………………………………....6 
 
2.5 
Frailty……………………………………………………………………….…6 
 
2.6 
Goals……………………………………………………………………….….7 
3.0 
METHODS……………………………………………………………………….…..7 
 
3.1 
Patient Selection…………………………………………………….…….…...7  
 
3.2 
Patient Selection Inclusion Criteria………………………………….…….......7 
3.3 
Patient Selection Exclusion Criteria……………………………………..…....8 
 
3.4 
Informed Consent……………………………………………………………..8 
 
3.5 
Inclusion of Women and Minorities…………………………………….…….8 
 
3.6 
Study Procedures………………………………………………………….......8 
4.0 
STUDY DESIGN……………………………………………………………….…....8 
 
4.1 
Overview……………………………………………………………….......…8 
 
4.2 
Study Schema……………………………………………………………........9 
 
4.3 
Self-Efficacy in Physical Activity…………………………………………….9 
4.4 
Information-Motivation-Behavioral Model and Self-Efficacy Schema….….11 
4.5 
Study Measures ……………………………………………...………………11 
 
 
4.5.1 Short Physical Performance Battery (SPPB)……………...……........11 
 
 
4.5.2 Geriatric Assessment (GA) Tools………………………………....…11 
 
 
4.5.3 PROMIS……………………………………………………….…......12 
 
 
4.5.4 Falls……………………………………………………………..........12 
 
 
4.5.5 Exercise Intervention: Otago Exercise Programme (OEP)…..…..…..13 
 
 
4.5.6 Otago Exercise Programme (OEP) Evaluation……………………....13 
 
 
4.5.7    Blessed Orientation-Memory Concentration Test (BOMC)…………13 
 
 
4.6 
Potential Risks………………………...…………...………….…..…14 
5.0 
DATA COLLECTION AND MANAGEMENT………………………...…..…....15 
 
5.1 
Registration Process………………………………………………….……....15 
 
5.2 
Electronic Data Capture……………………………………….…...….….….15 
 
 
5.2.1 iPAD Survey Administration……………………………….………..15 
 
 
5.2.2 Survey Software and Data Management…………………………......15 
 
5.3 
Baseline Demographics………………………………......………….…........16 
 
5.4 
Clinical Data to Be Obtained……...………………………………………....16 
 
5.5 
Adverse Events………………………………………….……………....…...16 
 
5.6 
Duration of Followup……………………………………..……………........17 
 
5.7 
Criteria for Removal from Study…………………………………..…….......17 
 
5.8 
Travel Reimbursement…………………………………………………….....17 

 
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6.0 
STATISTICAL CONSIDERATIONS…………………………………………….17
 
6.1 
Primary Endpoint………………………………………………………..…...17 
 
6.2 
Secondary Endpoint……………………………………………………...…..17 
 
6.3 
Correlative Analysis…………………………………………………….........18 
7.0 
CORRELATIVE/SPECIAL STUDIES……………………………………….......18 
7.1 
Overview……………………………………………………………………..18 
7.2 
p16 Aging Biomarker………………………………………………....…..…18 
7.3 
Correlative Analysis Procedures………………………………………….….19 
7.4 
Feasibility Preliminary Data……………………………………...……….....19 
7.5 
Obtaining samples…........................................................................................19 
7.6 
Sample processing………………………………...………………………....19 
7.7 
RNA recovery and basic analysis of mRNA and miRNA…………….…......20 
7.8 
p16 mRNA Isolation and Analysis……………………………………......…20 
7.9 
Bone marrow analysis …………………………………………………..…....21 
8.0 
STUDY CALENDAR………………………………...……………………….…....22 
9.0 
REFERENCES……………………………………………………………..….........21 
10.0 
APPENDECES (attached)……..………………………………………….…..........26 
 
10.1  Appendix A: Non-enrollment Survey……………………………………..…26 
 
10.2  Appendix B: Physical Therapy Progress Tracker………….…………...……27 
10.3  Appendix C: Motivation Evaluation…………………………………...…….28 
10.4 
Appendix D: Self-efficacy Assessment……………………………………...32 
10.5 
Appendix E: Barriers to at Home Exercise………………………………......33 
10.6 
Appendix F: Short Physical Performance Battery………………………..….34 
 
10.7  Appendix G: Cancer and Aging Research Group Geriatric Assessment….....36 
10.8  Appendix H: PROMIS Health Related Quality of Life Global Health Scale..51 
 
10.9  Appendix I: Fall Risk Screening Questionnaire……………………….…….52 
10.10  Appendix J: Walking, Exercise and Fall Diary ………………………..…....53 
10.11   Appendix K: Otago Exercise Programme Evaluation ……………...……….54 
10.12  Appendix L: Blessed Orientation-Memory-Concentration Test….……...…..55 
 
10.13 Appendix M: Enrollment Handbook  …………………………………..…...56 
 
10.14 Appendix N: Physical Therapy Tracker………………...………………...…57 
 
10.16 Appendix O: Participant Payment Receipt………………….…………...…..58 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1.0 HYPOTHESIS AND OBJECTIVES 
 
1.1 Hypothesis 
We hypothesize that it is feasible to recruit patients and implement the Otago Exercise 
Programme (OEP) safely in patients with hematologic malignancies. 
We hypothesize that exercise will improve health related quality of life and decrease 
functional decline associated with hematologic malignancy. 
 
1.2 Primary Objective  
To assess the feasibility of implementing a structured exercise program by evaluating 
recruitment and retention, exercise program adherence, sustainability, adverse events, and 
implementation challenges. 
 
1.3 Secondary Objective(s) 
To calculate preliminary effect sizes of the impact of an exercise program in patients with 
hematologic malignancy undergoing therapy, as measured by: 
• Cancer and Aging Research Group (CARG) Geriatric Assessment Tool 
parameters  
• Change in Short Physical Performance Battery (SPPB)  
• Number and severity of falls 
• Hospital readmission rates (if applicable) 
• Length of inpatient stays (if applicable) 
• Patient Reported Outcome Measurement Information System (PROMIS) for 
Health related quality of life (HRQL) 
• Correlative analysis of peripheral blood biomarkers of aging and inflammation 
(p16, inflammatory biomarkers, immunosenescence, miRNA) 
 
1.4 Primary Endpoint  
The primary end point is feasibility. Feasibility is defined as 80% eligible of participants 
completing the Otago Exercise Programme (OEP). 
 
2.0 BACKGROUND AND SIGNIFICANCE 
 
2.1 Background of Medical Need   
Patients with hematologic malignancy are particularly vulnerable to functional decline due to 
anemia, resulting in an increased risk of functional dependence, falls, chemotherapy induced-
toxicity and mortality.1 Historically, patients were advised to abstain from physical activity 
due to chemotherapy-induced immune suppression and fatigue resulting in further physical 
deconditioning. In recent years, the perspective on physical activity has changed significantly 
in cancer patients, and many reports document the benefit of exercise in the cancer patient 
population.2-4 Physical fitness is highly predictive of survival,5 yet gauging physical fitness 
remains a challenge for oncologists and we lack interventions to help this population 
maintain and/or regain their fitness successfully. Many factors are not modifiable in patients 
with blood cancer, such as age of diagnosis, genetics of disease, comorbidities, or response to 
therapy; however exercise is an intervention that can be implemented with a broad range of 
therapeutic effects. Oncologists require objective assessment of fitness and introducing the 
physiologic aging biomarker, p16, is potentially practice chap1nging for clinicians to 
objectively gauge fitness for treatment and/or transplant. This proposal is the first to compare 

 
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a biomarker of aging (p16) with baseline physical performance metrics and the first to 
explore if exercise can improve p16 transcript expression.   
 
Given the serious toll on health status associated with chemotherapy and transplant, the main 
purpose of this proposal is to conduct a feasibility study to examine predictive measures 
(SPPB and p16 expression) and preventative measures (OEP) to improve outcomes in 
patients with hematologic malignancies.  Engaging patients in physical activity during 
therapy is a significant departure from the standard, as patients were previously deemed too 
ill or too chemotherapy toxic for physical activity intervention.  However, with novel 
therapies and advances in supportive care, our proposed approach to preventing functional 
decline during transplant is overdue. However, a feasibility study in a single institution is 
necessary in order to address practical issues in patient recruitment and retention, OEP 
implementation, and barriers to optimal study delivery and patient safety in this patient 
population. Here, p16 will be evaluated in the context of a clinical phenotype of fitness, 
which has not been previously explored. The work accomplished here will inform future 
multi-study centers to test the effectiveness of the OEP in improving fitness and treatment 
outcomes (e.g., fall reduction, shorter length of stay during transplant, improvement in 
quality of life) among hematologic malignancy patients.  
 
2.2 Short Physical Performance Battery (SPPB) and Otago Exercise Programme (OEP)  
Prolongation of life is central to cancer care, but the preservation of independent living with 
functional health is equally important. People who lose functional independence have high 
rates of morbidity, disability and mortality.6 Functional decline is amplified in patients with 
cancer and is a predictor of early death.7,8 Simple performance tests are powerful predictors 
of functional decline and can be used for high risk populations. Patients with hematologic 
malignancy are particularly vulnerable to functional decline due to the protracted process of 
bone marrow transplant. The SPPB is an objective, validated tool used to capture at risk 
patients and has been shown to be prognostic in predicting decline in function, re-
hospitalization, and mortality.9 Each 1-unit increase in the SPPB score predicts a 12% 
reduction in mortality.5 Functional decline is not an inevitable part of illness or aging, and 
exercise programs are proven to prevent functional decline, especially in older adults.6 Older 
adults who are long-term cancer survivors especially benefit from exercise to reduce 
functional decline and improve quality of life.10 The  OEP has been found to be an effective 
exercise regimen to improve functional balance, muscle strength, and prevent fall-related 
injury and mortality.11 It has been included successfully in various fall prevention programs, 
reducing the risk of falls by 30-60%, and was sustainable in 70% of participants after one 
year.11  
 
2.3 Molecular biomarkers are associated with aging, frailty, and physical inactivity 
Advances in biomarkers of aging can improve upon subjective measures and better quantify 
physiologic age. Recently, investigators have refined the ability to quantify biologic age by 
use of a molecular marker, p16. p16 is a tumor suppressor protein that inhibits cell cycle 
progression, promotes cellular senescence, and has been associated with frailty phenotypes, 
physical inactivity, and age related comorbidities.12  p16, originating from the INK4/ARF 
locus on chromosome 9p21, belongs to a family of cyclin-dependent kinase (CDK) cell cycle 
inhibitors and prevents cell cycle progression by blocking CDK4/6 dependent 
phosphorylation of the retinoblastoma tumor suppressor (Rb).13 Prolonged expression of p16 

 
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promotes irreversible cell cycle arrest or cellular senescence. p16 tumor suppressor levels 
increase exponentially with chronologic aging across most mammalian species including 
humans.14,15 Beyond age, p16-induced senescence can be triggered by variety of internal 
stressors including DNA damage, replication errors, telomere erosion, and reactive oxygen 
species.16 External stressors can also trigger p16 expression such as physical inactivity, 
chemotherapy, and tobacco exposure. Additionally, single nucleotide polymorphisms located 
near the INK4/ARF locus are linked with age-related diseases including cardiovascular 
disease, diabetes and decreased physical function.17-19 Therefore, it is believed that p16 levels 
reflect a physiologic age or fitness. Recently Liu and colleagues demonstrated a means of 
quantifying this molecular marker of age in peripheral blood T-cells,20 providing a feasible 
and relatively non-invasive strategy to monitor p16 expression over time in a clinical setting 
to predict treatment tolerance and guide clinical decision making. In this research proposal, 
we focus on the most validated biomarker (p16) however, we are also exploring 
immunosenescence of aging (T-cell subpopulations, CD28 expression), markers of energy, 
and epigenetic markers (DNA methylation, miRs). Additional biomarkers of aging and an 
immunosenescence panel will be collected and explored. 
 
2.4 Falls 
Functional decline in the cancer population is multifaceted and complex and is often 
associated with falls, increased length of stay, and hospital re-admissions.21 Older adults with 
hematologic malignancy are especially prone to mobility impairments,22 and falls are a 
morbid consequence of functional decline. Falls increase risk of death, among older adults 
and are the leading cause of fatal and non-fatal injuries.23 Falls lead to serious complications 
resulting in some form of injury nearly a third of the time, with serious injury or death 
reported at rates of 3-8%.24,25 Risk analyses of patients undergoing bone marrow transplant 
indicate falls or near-miss episodes in 50-60% of patients analyzed.26,27 The consequences of 
a fall in cancer patients results in injury 42% of the time.25 Thus, malignant hematology 
patients have much higher rates of adverse consequences compared to the general cancer 
population.  
 
2.5 Frailty 
Frailty is thought to be highly prevalent among older adults and it confers high risk for 
adverse 
health 
outcomes 
including 
mortality, 
institutionalization, 
falls, 
and 
hospitalization.28,29  It is now defined as a biologic syndrome of decreased reserve and 
resistance to stressors, resulting from cumulative declines across multiple physiologic 
systems, and causing vulnerability to adverse outcomes.  Markers of frailty include age-
associated declines in lean body mass, strength, endurance, balance, walking performance, 
and low activity.30  Linda Fried, using data from the Cardiovascular Health Study, 
operationalized a frailty phenotype.  She specified that a frailty phenotype was identified by 
the presence of three or more of the following components: unintentional weight loss of ten 
or more pounds in the prior year or more than 5% of body weight in the prior year; grip 
strength in the lowest 20% at baseline, adjusted for gender and body mass index; exhaustion 
by self-report; slowness, indicated by the slowest 20% of the population, based on time to 
walk 15 feet, adjusting for gender and standing height; and being among the lowest quintile 
of physical activity based on a weighted score of kilocalories expended per week.  Patients 
with one or two criteria were considered prefrail. Mortality was six-fold higher for those who 
met frailty criteria at baseline than that for non-frail for 3-year cumulative survival.31   
 

 
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2.6 Goals 
The overarching goal of our research is to increase the years of healthy life, with full 
functional capacity, while undergoing cancer care therapy.  Serious health sequela impact 
recovery during chemotherapy including fatigue, deconditioning and distress; exercise is 
proven intervention that can positively impact these health outcomes and is underutilized.32 
Given the serious toll on health status associated with cancer treatment, the purpose of this 
proposal is to conduct a feasibility study to examine predictive and preventative exercise 
measures to improve outcomes in patients with hematologic malignancies.  Engaging patients 
in physical activity during chemotherapy is a significant departure from the standard, as 
patients were previously deemed too ill or chemotherapy too toxic for a physical activity 
intervention.  However, with novel therapies and advances in supportive care, our proposed 
approach to prevent functional decline during transplant is overdue.  The OEP fitness 
program is a means to safely improve fitness levels in a patient population that rarely utilizes 
exercise as part of the care plan. However, a feasibility study in a single institution is first 
necessary to address practical issues in patient recruitment and retention as well as OEP 
implementation, and to address any barriers to optimal study delivery and patient safety in 
this patient population. 
 
3.0 METHODS 
 
3.1 Patient Selection 
Patients will be recruited from the hematology clinics at The Ohio State University.  Patients 
who are undergoing an evaluation for treatment and, or are being treated for a hematologic 
malignancy are referred by their treating care team for participation in the study. These 
patients will receive information regarding the proposed study, and will be asked if they 
would like to undergo screening for their current level of fitness to determine eligibility for 
study participation. Those agreeing to be screened will sign the study consent and HIPAA 
forms. They will then undergo the SPPB evaluation. Patients whose total score on the SPPB 
is < 9, and who meet all other inclusion criteria, will be deemed eligible to continue in the 
study. Eligible patients who have consented to participate in this study will be assigned a 
study ID. A peripheral blood sample will also be collected from them for research purposes 
(See Section 6.0). 
 
Failed screening (i.e. >9 on SPPB) will be captured as part of feasibility. In addition, reasons 
why patients decline participation will be tracked without documenting patient identifiers 
[APPENDIX A]. For example, patient declined enrollment due to physical activity being 
judged as too difficult.   
 
3.2 Patient Selection Inclusion Criteria 
• Patients with hematologic malignancy receiving care (chemotherapy, immunotherapy, 
targeted agents, bone marrow transplant, or other) for their hematologic malignancy at 
the Ohio State University. 
• Age >60 years   
• Impairments in physical function, as defined by a score <9 on the SPPB pre-screen 
• Medical clearance from an oncologist or primary care physician stating the participant 
is able to participate in an unsupervised, moderate-intensity physical activity program 
• Ability to understand and the willingness to sign a written informed consent document 
 

 
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3.3 Patient Selection Exclusion Criteria 
• Prisoners 
• Any medical condition including, but not limited to, symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness that would 
limit compliance with study procedures. 
 
3.4 Informed Consent 
Discussions between the study coordinators and/or medical oncologists and study participants 
will occur in clinic.  The study coordinators will address all questions regarding the study and 
consent form and emphasize that the participant can withdraw from the study at any point in 
time.  If patients are interested in participating in the study and meet all eligibility criteria, 
they will sign the consent form and then be assessed for eligibility and, when applicable, 
register as detailed below.    
 
3.5 Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
3.6 Study Procedures 
A maximum of 100 patients will be recruited to the exercise protocol. Their participation will 
be supervised by a designated physical therapist (PT). Participants will meet with the PT at 
Martha Morehouse for their initial assessment and OEP instruction. The OEP will serve as a 
structured guide while providing education and motivation. Patients will undergo an initial 
assessment (short physical performance battery) measuring their strength, balance and gait as 
well as an individualized OEP based on their physical capacity and health. Patients will 
receive information on the rationale and benefit of exercise. The PT will ensure that the 
patient can perform the exercises correctly and safely, making adjustments as needed due to 
physical limitations such as pain and/or tolerance. The PT will provide home based 
instructions on exercise, assess patient safety during exercises, assess need for a walking aid, 
guide patient on appropriate footwear, fall education and exercise compliance, as examples of 
an OEP evaluation. The PT will monitor the program and provide appropriate advice on 
exercise progression based on patients’ response to exercise. [APPENDIX B]. 
 
The patient will complete a total of 3 study visits, coordinated with the patients primary 
oncologist visit. The patient will complete study visit 1 prior to their first physical therapy 
appointment. The second study visit is at the completion of the OEP and the third study visit 
is at the end of study (6 months post-visit 1 or post-physical therapy appointment 1, 
whichever occurred first).These study visits may or may not be in context of a clinical 
appointment (+/- 30 days) 
 
4.0 STUDY DESIGN 
 
4.1 Overview 
The PT will assess each patient for individualized physical therapy needs. The PT will design 
a PT program based upon the individual needs (e.g. weekly, bi-weekly etc). Patients will be 
instructed on the OEP. The OEP is a combination of physical therapist prescribed exercise 
and home based exercise recognized to improve balance and functional decline (Table 1).33 
The structured OEP focuses on strengthening, balance retraining, and walking. OEP requires 
minimal training and can be provided by any physical therapist. OEP home-based exercise 

 
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requires patient engagement and takes approximately 30 minutes, three times weekly, with 
walking twice weekly. Participants will record exercise, walking and falls in a weekly diary. 
The OEP physical therapy portion involves 8 visits over 4 months. All physical therapists 
engaged in the protocol are OEP certified. Patients will be assessed on their progress with the 
OEP at their twice monthly appointments. Following these appointments, patients who go on 
to bone marrow transplant will receive inpatient PT consults a minimum of twice weekly. 
During these visits, evaluation of strength, balance and walking will be assessed. Before 
discharge, home based exercises will be reviewed and encouraged. Documentation of 
physical therapy sessions will be noted and include the level of participation or lack thereof 
(patient in testing, unwell, declined participation). After the initial 8 physical therapy 
appointments, patients who will not have a bone marrow transplant will continue with their 
home-based exercises.  
 
4.2 Study Schema 
 
 
 
4.3 Self-Efficacy in Physical Activity 
Our intervention is a study of health behavior and is based on a model of health education 
and promotion through a structured exercise program; Otago Exercise Programme (OEP). We 
have incorporated major constructs of the self-efficacy34,35 health behavior theory to better 
understand the influences of adherence in cancer patients who participate in physical 
activity.36 This present research will evaluate the notion that self-efficacy is imperative for 
performance in sustaining physical activity.37 We aim to improve physical activity in a 
population of older adults who are at risk for functional decline and who we believe are 
motivated by their cancer diagnosis to adhere to physical activity. This model of health 
promotion is based upon the Information-Motivation-Behavioral (IMB) model38-40 where we 
have structured the design, implementation and evaluation of a physical activity program 
(OEP) based on a health behavior change (i.e. physical activity) that is intended to promote 
regular exercise and therefore improve quality of life for the participant (Information-
Motivation-Behavioral Model and Self Efficacy Schema). 
 
Theories, or ideas that explain behavior, on motivation or behavioral change factors that 
affect individual physical activity are an active area of investigation.41 With this background, 
we have integrated determinants of the individual cancer patient (cancer type, stage, 
treatment) with a structured environment to promote physical activity. We aim to study the 
importance of motivation, physical ability, and opportunity as mediators of physical activity. 

 
10 
 
Motivation will be analyzed via a questionnaire based upon the theory of reasoned action and 
behavior,42 where we examine the relationship of belief, attitudes, intentions and behavior at 
baseline.43 We will therefore examine by validated tools the attitudes toward physical 
activity, subjective norms, and perceived behavioral norm [Appendix C]. Our IMB model 
focuses on self-efficacy, imperative for home based exercise, in which the participant must 
develop skills and confidence in one’s own ability. Self-efficacy is based upon the social 
cognitive theory in which the action of physical activity is more likely when the participant is 
confident in their ability resulting in sustained behavior. We will assess self-efficacy using a  
baseline 15-item instrument (Garcia & King, 1991) where items are rated on a 0%-100% 
scale  (e.g., I could walk when tired, I could walk when my schedule is hectic) (0% = Cannot 
do it at all, 100% = Certain that I can do it) (Cronbach’s α pre = .95) [Appendix D].  These 
theories have helped guide our infrastructure in developing a structured exercise program to 
induce behavior change (i.e. physical activity). Therefore, we will include a self-efficacy 
validated scale that will be incorporated at baseline and also during monthly physical therapy 
assessments with the physical therapist (Table 2). The Clinical Research Coordinator (CRC) 
will gather exercise logs and administer the self-efficacy validated tools; we will explore 
barriers to exercise using both open-ended and direct questions [Appendix E]. The CRC will 
discuss any discordance in reported physical activity and barriers of physical activity (i.e. are 
you having any problems with exercising at home?). These open ended questions will be 
captured and recorded.  
 
We have identified that patients with hematologic malignancy are vulnerable to functional 
decline due to anemia, resulting in an increased risk of functional dependence, falls, 
chemotherapy induced-toxicity and mortality1. The benefit of physical activity in patients is 
well established however behavioral and environmental factors are barriers to activity and 
structured interventions to improve upon physical activity are lacking.2-4 We have applied 
this model by identifying the factors that influence motivation using Geriatric Assessment 
(GA) tools, where we examine many aspects of health that influence disease outcomes and 
health behaviors such as: social support, baseline physical activity, cognition, anxiety, 
depression, fatigue. The social assessment is influenced by the health, behavior and 
environment that is also being collected (i.e. distance to OSU cancer center, cancer type, 
stage of disease, chemotherapy treatment). Educational factors contribute to baseline health 
behavior and these factors will also be captured. Finally the OEP program is a validated 
educational strategy to promote healthy functional activity. The second portion of our theory 
analysis is based upon feasibility that we can implement and evaluate the process of a 
structured exercise program within the cancer center program. We aim to also evaluate the 
impact of the exercise program via patient reported outcomes. In conclusion, as a secondary 
analysis, we aim to calculate preliminary effect sizes based upon change of Geriatric 
Assessment score parameters, change in Short Physical Performance Battery (SPPB) scores, 
number and severity of falls, hospital readmission rates, length of inpatient stays and change 
in Patient Reported Outcome Measurement Information System (PROMIS) for Health related 
quality of life (HRQL) scores. This planning model of a structured exercise program is 
schematically represented below.  
 
 
 
 
 

 
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4.4 Information-Motivation-Behavioral Model and Self Efficacy Schema 
 
  
 
 
4.5 Study Measures 
 
4.5.1 Short Physical Performance Battery (SPPB)   
At the time of screening patients will undergo a SPPB [APPENDIX F]; patients with a SPPB 
score of <9 will be allowed to enroll in the study. Patients will complete an SPPB at the 
completion of the OEP and at 6 months (3 times total). This test will be administered by the 
Clinical Research Coordinator and scores will be captured. The SPPB is a validated tool 
composed of a simple battery of objective physical performance tests that involve gait speed, 
balance and ability to rise from a chair. The SPPB was designed to evaluate balance, gait, 
strength, and endurance initially in a cohort of 5000 community-dwelling seniors. The tool 
can be administered in approximately 10 minutes. The SPPB can predict mortality and 
nursing home admissions among older adults.  Interestingly, the measure can also detect a 
gradient of risk for mortality and nursing home admission among older adults with no current 
disability.9 It also has been shown to predict mortality in cancer survivors.5 The tool assesses 
balance through use of the side-by-side stand, semi-tandem stand, and tandem stand; strength 
is assessed with the chair stand test and repeated chair stands; and gait speed is evaluated 
through use of an 8-foot walk test.  Scores are assigned for each of the tests and an aggregate 
score is assigned ranging from 0-12, with higher scores indicating greater physical function.  
SPPB scores are classified into 4 categories: very low physical function (0-3); low physical 
function (4-6); moderate physical function (7-9) and high physical function (10-12). An alpha 
internal consistency of 0.76 has been reported.9 The SPPB will be performed twice while the 
patient is on study, once as a pre-screen enrollment and a second SPPB at completion of the 
structured exercise program. 
 
4.5.2 Geriatric Assessment Tools (GA) 
At the time of screening patients will undergo a GA [APPENDIX G]. The GA will be 
repeated at the completed of the OEP and at 6 months (3 times total). This test is self-
administered survey with the aid of a CRC; scores for the GA will be captured. 
 
Geriatric assessments are performed in a traditional geriatric population to identify current 
health problems and guide interventions to reduce adverse outcomes and optimize the 
functional status of elderly patients.  In an oncology setting, it may be useful to identify 
occult geriatric syndromes and provide interventions that can improve the ability of patients 

 
12 
 
to undergo treatment for their cancer. The typical domains of a comprehensive geriatric 
assessment (GA) include evaluations of functional status, comorbid medical conditions, 
cognitive status, psychological state, falls, social support, nutritional status, and a review of 
the medication list.   
 
A geriatric assessment is utilized to capture information about a patient's medical history as 
well as functional, cognitive, and psychosocial status, which can then be used by treating 
physicians to identify the most vulnerable patients (for example, those at high risk for 
chemotherapy toxicity). However, these assessments have not been routinely used in 
oncology practice because of the time and resources required for their administration. A 
geriatric assessment tool (that can be completed primarily by patients) was developed for 
incorporation into oncology clinical trials and routine care settings.44,45  As an example, 
among older adults with newly diagnosed AML, overall survival was found to be 
significantly shorter for patients who screened positive for objectively measured impairment 
in mobility and cognition providing conclusive evidence that a comprehensive assessment 
tool can at least improve risk stratification for patients undergoing intensive therapy.46  
Furthermore, geriatric assessments can predict survival and toxicities in older adults with 
multiple myeloma.47 Barriers to incorporate geriatric assessments into routine clinical care 
include lack of infrastructure to support these assessments and how to utilize the data to make 
treatment decisions. 
A clinical research coordinator will be trained to administer the Cancer and Aging Research 
Group’s geriatric assessment (CARG GA) and healthcare provider assessments. Training for 
the geriatric assessment is available through the CALGB geriatric assessment instrument 
training website: 
 
https://www.allianceforclinicaltrialsinoncology.org/training/auth/1%3A1%3A0%3A0%3A0/ 
 
A copy of the GA results may be made available to the patient’s primary oncologist. Medical 
records may also be reviewed to determine if any actions were performed by the primary 
oncologist, as a result of the GA information (e.g.: a patient was identified to have nutritional 
concerns and on a subsequent visit a nutritionist was consulted). 
 
4.5.3 PROMIS: Patient-Reported Outcome Measurement Information System Global Health 
Scale Short Form v1.1 HRQL measures provide invaluable information to the clinician 
regarding the patient experience of treatment or intervention. Large population based studies 
have demonstrated that patients with hematologic malignancy report some of the poorest 
HRQL.48 However, exercise is reported to improve HRQL in cancer patients undergoing 
active treatment.49 The PROMIS Global Health Scale has been rigorously tested for 
reliability and validity and can be applied to all populations.50 It consists of 10 questions and 
will be self-administered to patients monthly. [APPENDIX H] 
 
4.5.4 Falls 
Falls in patients receiving chemotherapy are associated with a 3-fold greater risk of 
mortality.51  Fall and fall severity will be captured as self-report of calendar recorded falls, 
where patients denote on the calendar day when they had a fall associated with commentary 
on the event (e.g. fall with abrasion). Calendar recorded events is a valid method of self-
reporting fall events and is shown to be more accurate than short term recall in patients with 
falls.52 Falls will be captured twice monthly. Research coordinators may contact the patient 

 
13 
 
by phone if a fall has occurred to identify the severity of the fall and/or injuries [APPENDIX 
I]. 
Inpatient admission falls will be captured per institution guidelines, as all falls are required to 
be reported to the Quality and Patient Safety Department. Specific information regarding 
patients enrolled in both as an Exercise Participant and Survey Participant will be gathered. 
Hospital Injury Level and the National Database of Nursing Quality Indicators (NDNQI) 
injury level will be captured.  
 
4.5.5 Exercise Intervention: Otago Exercise Programme (OEP) 
Exercise interventions are an established method of improving physiologic and functional 
performance in older adults. The structured OEP focuses on strengthening, balance retraining, 
and walking. OEP requires minimal training and can be provided by any physical therapist. 
OEP requires patient engagement and takes approximately 30 minutes three times weekly, 
with walking twice weekly. All physical therapist engaged in the protocol are OEP certified. 
The OEP is 8 physical therapy visits over 4 months. Participants will record daily of walking, 
exercise and falls in an exercise journal [APPENDIX J]. 
 
Patients may require more than 2 sessions monthly of physical therapy according to the 
physical therapist prescribed recommendations. In this event, exercise logs and fall diaries 
will be collected at their 1st and 3rd visit monthly. Patients will be reimbursed for their travel 
at these two visit times only (see Section 5.8). 
 
Table 1. Otago Exercise Programme (OEP) 
 
 Strengthening 
Balance Retraining 
Walking 
Assessment 
30 Second Chair Stand 
Test 
Four-Stage balance Test 
Timed Up and Go 
Activity 
Five leg muscle 
strengthening exercises 
Four levels of difficulty 
Twelve balance 
retraining exercises 
Four levels of difficulty 
Advice about walking 
Intensity 
Moderate Challenge 
 
8-10 repetitions before 
fatigue 
Moderate Challenge 
Each exercise at a level 
the patient can safely 
perform  
Usual pace with usual 
walking aid 
Progressions 
Increases from one to 
two sets 
Increase amount of 
ankle weight after 2 
sets of 10 
Supported exercise and 
unsupported exercise 
Walk indoors 
Advance to walking 
outdoors when 
strength and balance 
have improved 
Length of 
Exercise 
Sessions 
Approximately 30 minutes total for exercises; 
Exercises can be divided up over the day 
30 minutes; can be 
split into three 10 
minute walks 
throughout the day 
Home Based 
Frequency 
3 times a week 
At least 3 times a week 
Twice a week 
Duration 
Physical therapy (8 visits, twice monthly, until transplant or 4 months) 
Transplant physical therapy consult (twice weekly physical therapy consult 
during transplant admission). Home based exercise throughout their 6 
month enrollment. 

 
14 
 
4.5.6 OEP Evaluation 
At the completion of the OEP, patients will be asked to indicate their likes and dislikes about 
the program, any logistical challenges, how worthwhile the program was to them personally, 
and ways in which the implementation of the program could be improved.  Records will be 
kept of any patient adverse events during the course of the OEP [APPENDIX K]. 
 
4.5.7 Blessed Orientation-Memory-Concentration Test (BOMC) 
The BOMC [APPENDIX L] is a widely used screening test for dementia and evaluation of 
orientation, registration, and attention. The test allows providers and caregivers to screen for 
suspected dementia in older patients. It was originally validated on older patients living in 
both skilled nursing facilities and community-dwelling. The BMOC is a weighted 6-item 
instrument and takes less than 10 minutes to complete. Scores range from 0-28, and scores 
greater than 10 are consistent with dementia.  
 
Table 2. Study Measures 
 
Study Visit 1: 
Baseline 
 
Study Visit 2: 
Completion of OEP*  
Study Visit 3: 
6 months*  
CARG GA 
X 
X 
X 
SPPB 
X 
X 
X 
PROMISa 
X 
X  
X 
Fallsb 
X 
X 
X 
OEP Evaluation 
 
X 
 
Physical Therapy 
Adherencec 
 
X 
X 
Biomarkerd 
X 
X 
X 
Motivation  
X 
 
 
Self-Efficacy 
X 
X 
X 
Barriers 
X 
X 
X 
Blessede 
X* 
X* 
X* 
*(+/- )30 days;  administered monthly;  biomarkers (+/-) 14 days  
a. PROMIS measures are captured monthly from the time of OEP enrollment (maximum 6 
surveys) 
b. Falls are captured twice monthly from the time of OEP enrollment via self-report calendar; 
inpatient falls are captured during hospitalization and are not a self-report. 
c. Physical therapy adherence will be captured by the number of visits (inpatient and 
outpatient) and if patient is achieving the standard based upon the physical therapist 
assessment (1-achieving the standard, 2-progressing toward the standard, 3-limited progress 
or not meeting the standard) 
d. Blood work will be collected during the study visit with the patients’ outpatient 
hematologist. Attempts will be made to collect blood work during the routine draw, however 
this is not mandated.  Biomarker collection (+/-) 14 days within study visit. 
e. If not administered prior to patient’s enrollment, the Blessed test will be administered one 
time at a point after the patient’s enrollment in the study. 
 
4.6 Potential Risks 
We anticipate that this study will entail minimal physical and psychological risks for study 
participants.  Informed consent will be obtained from all participants prior to study 

 
15 
 
enrollment.  There is a small risk to participants of sustaining an injury while participating in 
the exercise intervention. Prior to participating in the intervention, all participants must have 
documentation from their primary oncologist or primary care physician stating that they are 
capable of participating in a moderate-intensity exercise intervention. There is a small risk of 
psychological distress associated with completion of the questionnaires. If this occurs, study 
staff will speak to the participant about the difficulties that the questionnaires have caused 
and will offer a referral to a mental health professional if necessary.  
 
 
5.0 DATA COLLECTION AND MANAGEMENT 
 
5.1 Registration Process 
• Potential patient identified 
• Patient signs informed consent and HIPAA form 
• Eligibility Screening  
• Worksheet documentation note by the primary oncologist giving the patient medical 
clearance to participate in physical therapy 
• Provide patient with Enrollment Handbook [APPENDIX M] 
• Register the patient on the study (Oncore) 
• Assign a patient study number 
• Pend blood work orders 
• Documentation of Consent in EPIC 
• Schedule twice monthly physical therapy sessions for next 4 months 
 
5.2 Electronic Data Capture 
 
5.2.1 iPAD Survey Administration: Many of the assessments are self-administered (CARG 
GA, PROMIS, Motivation, Self-efficacy and OEP evaluation) and, when possible, will be 
administered electronically. Some portions of the survey questionnaires are administered by a 
research coordinator (portions of the Barriers survey and CARG GA). Electronic 
administration will be done via an iPad. The questionnaires will be given within the context 
of routine clinical care. Patients will be provided with an iPad to complete the self-
administered surveys. The clinical research coordinator administers the functional and 
cognitive assessments. The feasibility of an iPad to electronically capture functional 
assessments requires additional information to determine practicality in an oncology setting. 
Patients unable to use an iPad or prefer not to use an iPad will have a paper survey options. 
Data on paper survey preference will be captured. Patients who choose to participate but then 
discontinue enrollment due to iPad use will be tabulated. In addition, the iPad questionnaire is 
a timed session and will be compared to published data for each questionnaire/battery to 
determine efficiency. Furthermore, data capture is complete; questionnaires were designed so 
one could not advance to the next question without a response including the option “I choose 
not to answer” for select sensitive questions. 
 
5.2.2 Survey Software and Data Management: All data obtained via the iPad survey 
platform is supported by Qualtrics, a secure password protected online service. OSU 
Purchasing has contracted with Qualtrics to provide a single contract and OSU-managed 
single sign on to the cloud service for provisioning surveys for research at the university. 

 
16 
 
Qualtrics is the preferred survey tool at OSU and the only tool on contract.  Information 
regarding Data Safety is linked here: 
 
http://fisher.osu.edu/offices/technology/services/support-services/qualtrics 
 
Patients will be enrolled into the Qualtrics survey platform system with a unique identifier 
code given to them during the registration process in OnCore. The unique identifier code 
linked to patient identification will be kept in REDCap. All protected health information will 
be kept in REDCap. REDCap is an electronic data collection (EDC) tool supported by the 
CCTS. It is a secure, web-based application designed exclusively to support data capture for 
research studies. Clinical data, and patient diaries will be captured in REDCap. 
 
5.3 Baseline Demographic Questionnaire 
Information will be collected on patient demographic information collected via a standard 
questionnaire administered at baseline and from IHIS 
 
5.4 Clinical data to be obtained 
Clinical follow-up for patients with hematologic malignancy will be performed according to 
the standard institutional guidelines.  Clinical data regarding specifics of hematologic 
malignancy will be obtained from IHIS including but not limited to, diagnosis, date of 
diagnosis, stage, cytogenetics, prognostic information, treatment history, medications, 
physical exam parameters, hospitalizations, hospitalization length of stay, rehabilitation 
needs, bone marrow transplant length of stay, readmissions, transplant outcomes, 
hematologic and chemistry parameters e.g. CR, LDH, β2-microglobulin.   
 
Patients will be required to complete a follow up geriatric tool assessment at completion of 
the OEP, this may or may not be in context of a clinical appointment (+/- 30 days). 
 
The following data will be collected from participants at baseline (Study Visit 1), post-OEP 
(Study Visit 2) and 6 month visits (Study Visit 3), and/or on a monthly basis 
• Clinical Information  
• CARG GA 
• SPPB  
• PROMIS HRQL 
• Self- Efficacy Questionnaire 
• Barriers 
• Adverse events  
• Motivation (study visit 1 only) 
• OEP Evaluation (study visit 2 only) 
• Physical Therapy Tracker [APPENDIX N] (every other physical 
therapy appointment) 
• Physical Therapy Progress Tracking (study visit 2 and 3 only) 
 
The following data will be collected from participants twice monthly at OEP appointments 
• Walking, Exercise and Fall Diary 
 
 
 

 
17 
 
5.5 Adverse Events 
Individuals will be asked about exercise-related adverse events at the time of study visit.  Any 
exercise-related injuries will be reported to Dr. Rosko (Principal Investigator). Any reported 
events will be evaluated for the likelihood that they occurred as a result of exercise. An 
adverse event is considered serious if it results in any of the following outcomes: 1.) death; 
2.) a life-threatening event; 3.) inpatient hospitalization or prolongation of an existing 
hospitalization >24 hours; 4.) persistent or significant incapacitation or substantial disruption 
to the participants ability to conduct normal life functions; 5.) congenital anomaly/birth 
defect;  6.) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization but may be considered serious when, based upon medical 
judgement, the event may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. Serious adverse events 
related to exercise experienced by patients in this protocol will be reported to the OSU CCC 
Clinical Trials Office and the Cancer Institutional Review Board (IRB). Information reported 
will include the number of patients affected, number of patients treated, summary of all 
adverse events reported to date using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 grading, a specific list of adverse events 
requiring expedited reporting to include all serious adverse events [SAEs], and, on an annual 
basis or as it arises, significant literature reporting developments that may affect the safety of 
participants or the ethics of the study. Data safety and monitoring activities for each study 
will continue until all patients have completed their intervention and all patients are beyond 
the time point at which study-related adverse events would likely be encountered.   
 
5.6 Duration of follow-up 
Patients will be followed for approximately 6 months at The Ohio State University Wexner 
Medical Center. 
 
5.7 Criteria for removal from study 
Patients will be removed from the study by patient preference or MD request otherwise will 
remain on study for 6 months. 
 
5.8 Travel Re-imbursement 
Patients who elect to become vendors [APPENDIX O] of The Ohio State University will be 
paid $25 (a maximum of twice monthly) for each physical therapy visit at a total of $200, if 
they complete all 8 visits. Payment will be given in cash at the time of the physical therapy 
visit. If patients are scheduled for additional physical therapy sessions, as prescribed by their 
physical therapist in accordance with routine care, patients will be reimbursed at only one 
physical therapy appointment, per week, every other week of the month. 
 
6.0 STATISTICAL CONSIDERATIONS 
 
6.1 Primary Endpoint 
The primary endpoint is feasibility, defined by 80% of eligible participants completing the 
Otago Exercise Programme (OEP). Program completion is the primary indicator of this 
feasibility pilot project. 80% completion was chosen based upon the Otago Exercise 
Programme controlled trials, where the effectiveness of home based exercise to reduce falls 
in injuries in elderly adults in the community had a 90% completion rate of the trial.53 When 
the Otago Exercise Programme was delivered in different centers 87% of participants 

 
18 
 
completed the trial54 . When the Otago Exercise Programme was introduced into the primary 
care practice, older adults (>80) approximately 47% participation occurred and 79% 
completed one year assessments 55.  Therefore, 80% completion was chosen as the feasibility 
endpoint to achieve the desired effects of improving strength and balance via OEP. 
 
We will describe the proportion of screened patients who agree to participate, the proportion 
of patients who attend certain percentage of assigned PT sessions and the proportion of 
patients who complete the whole study along with respective 95% confidence intervals. 
Study implementation and challenges will be evaluated by patient exercise logs. Exercise 
levels at home will also be assessed by exercise diary log. Adverse events (AE) and their 
severity will be captured according to the CTCAE v4.0, and whether any AEs can be 
attributed to exercise.  
 
6.2 Secondary Endpoint(s) 
For the entire cohort of patients, we will describe CARG GA, number of falls, SPPB, 
PROMIS HRQL scores at all three time points when the relevant data are collected: baseline, 
after OEP completion and 6 months. Descriptive statistics of these measurements will be 
provided as well as graphs in order to help visualize the change over time. The proportion of 
patients who achieve meaningful change in these scores will be described with 95% CI. 
Difference from baseline will be tested with Wilcoxon signed rank test or McNemar’s test for 
continuous or categorical variables respectively. Take SPPB for example, with 30 patients a 
two-sided Wilcoxon signed rank test for paired observations will have at least 80% power to 
detect a medium effect size of 0.55 (i.e. 0.55 standard deviations) for the differences in scores 
before and after the OEP. Depending on patient retention rate and completeness of the 
collected data, linear mixed models with repeated measures might be fitted to quantitatively 
model the changes, but the modeling analysis will mostly be exploratory due to limited 
sample size. The correlation between these scores including their baseline values and changes 
over time and other clinical factors of interest such as age, BMI and performance status will 
also be evaluated. 
For patients undergoing transplant, we will describe the following clinical points of interest: 
inpatient falls, 90-day hospital readmission rate, and length of inpatient stays. Pre and post 
OEP changes in CARG GA, SPPB and PROMIS HRQL scores and their potential association 
with these clinical endpoints will be explored graphically.   
 
Findings will largely be exploratory and will need to be validated in larger subsequent multi-
center trial. 
    
6.3 Correlative Analysis 
Presence of deleterious genes and p16 pre-OEP and post-OEP will be correlated with clinical 
factors (age, performance status, adherence to OEP), GA profiles, SPPB scores. 
 
Serum studies evaluating mRNA will be characterized and analyzed in relation to functional 
assessment outcomes as well as clinical outcomes of interest. microRNA measures will be 
assessed in relation to cytokine measures using graphical analyses and measures of 
correlation. FDR corrections will be utilized to correct for the simultaneous comparisons of 
the multiple markers.  
 
Quantified p16 expression pre and post OEP will be described, and independently analyzed in 
relationship to functional assessment outcomes such as GA scales, SPPB Scores as well as 

 
19 
 
clinical outcomes of interest (age). In addition, p16 expression will be evaluated in relation to 
clinical outcomes, such as tolerance of OEP, adherence of OEP, length of hospitalization and 
readmissions in a descriptive manner. Generalized linear models will be used similar to those 
described above to assess the impact of p16 expression on GA scores depending on data 
completeness. Spearman rank correlation coefficients will be used in relation to continuous 
measures (e.g. age), two-sample tests (Wilcoxon rank sum tests) will be used for comparing 
p16 expression between two groups (e.g. incidence of del17), and Kruskal-Wallis tests will 
be used to compare p16 expression between more than two groups. Descriptive statistics and 
graphical analyses will be used to evaluate p16 expression within each of the groups to better 
understand potential trends of interest. 
 
 
7.0 CORRELATIVE ANALYSIS / SPECIAL STUDIES 
 
7.1 Overview 
Peripheral blood will be obtained for mRNA, miRNA, and flow cytometry analysis.  While 
specific details of the processing, extraction, and analysis are included in this protocol, these 
details may change with innovations in laboratory techniques and hence are considered 
general guidelines only. 
 
7.2 p16 Aging Biomarker: Identifying candidacy for treatment or transplant is generally 
subjective and is dependent on age, performance status, and comorbidities. The clinical need 
for objective quantitative measures of physiologic fitness remains unmet. As such, p16, a 
marker of cellular senescence, represents an attractive proxy for physiologic age and may be 
an additional tool in the clinical evaluation. Many investigations are focusing on biomarkers 
of age to weigh treatment options and gauge toxicity.56  We aim to capture physiologic fitness 
and with use of p16 expression in peripheral blood T-lymphocytes (PBTL). The molecular 
biomarker, p16INK4a (p16) is an established marker of systemic cellular senescence associated 
with physiologic aging. p16 expression increases ~16-fold over an individual’s lifetime and 
can be readily measured in PBTL.57  
 
7.3 Correlative Analysis Procedures:  Patients enrolled have peripheral blood collected for 
p16 analysis serially at three time points 1) pre-OEP 2) post-OEP and 3) 6 months. Peripheral 
blood will be obtained in EDTA coated tubes (10 ml) where CD3+ T-cells will be isolated 
using RosetteSep Reagents. RNA will be extracted using RNeasy Plus Mini Kit (Qiagen), 
and analyzed using reverse-transcription real-time quantitative PCR for p16, ARF, and 
standard housekeeping genes. p16 mRNA expression will be compared to an age-matched 
control dataset. The source of this dataset is a primary analysis study previously conducted by 
the PI, Dr. Ashely Rosko (IRB protocol number 2014C0008). The only information retrieved 
from this control dataset will be age; no protected health information will be collected. The 
full dataset has been de-identified and the study team does not have access to identifiable 
information about this population. 
 
7.4 Feasibility Preliminary Data: Recently, investigators have evaluated the impact of 
lifestyle on PBTL p16 expression in healthy volunteers.58 The authors reported that 
modifiable factors such as exercise, smoking, and body mass have an age-independent impact 
on p16 expression where physical exercise duration showed an inverse association with the 
level of p16 T-cell mRNA expression (r2=0.1922, p<0.0001). This suggests that exercise may 

 
20 
 
exert protective effects in age-dependent accumulation of senescent cells. External factors 
such as chemotherapy also impact p16 expression. In preliminary data, we identified that 
BMT also significantly increases the expression of T-cell p16 mRNA expression in patients 
with multiple myeloma pre- and post-transplant (90 day).  As such, we aim to explore if 
exercise alters p16 expression. 
 
7.5 Obtaining samples 
Peripheral blood will be obtained by clinic staff for mRNA, miRNA, and cytokine studies.  
Samples will be obtained in clinical space (currently on HTC and 5th floor James, as 
examples). 
Specifically, approximately 30ml of peripheral blood will be collected into phlebotomy tubes: 
up to 10ml in purple top EDTA tubes and 20ml in serum separator tubes.  
 
7.6 Sample processing 
Sample pick up and processing will be performed in the Leukemia Tissue Bank using the 
following general procedure for cryopreservation of serum and plasma. 
 
To obtain the plasma the blood collected in EDTA coated tubes will be transferred to 50 ml 
sterile tube and centrifuged at 1800 rpm for 10min at room temperature. The supernatant 
(plasma) will be collected and stored at -80°C for further studies. The cellular pellet will be 
gently re-suspended in PBS to reach 2X the original volume (for 10ml of plasma 20ml PBS) 
and then stratified in 1X of Ficoll-Paque. This will be centrifuged at room temperature for 20 
min at 2000 rpm. The white ring containing monocytes, T- and B- lymphocytes will be 
removed and washed with FBS enriched culture media. The tube will be centrifuged at 1200 
rpm at room temperature for 6 min. The cellular pellet will be resuspended in 90% FBS and 
10% DMSO and placed in cryo-tubes at -80°C and after 3 days will be placed in liquid 
nitrogen for long-term storage.  
For the serum collection the tubes will be centrifuged at 2,200-2,500 rpm for 15 min and the 
serum will be stored at -80°C.  
To obtain T cells: Whole blood collected in a purple top EDTA tube will be divided into two 
equal volume portions, approximately 5mL each.  RosetteSep Human T Cell Enrichment 
Cocktail (Stem Cell Technologies # 15061) will be added to each tube at a ratio of 50uL per 
mL of whole blood.  Tubes will be mixed by inversion and incubated for 20 minutes at room 
temperature.  Next, samples will be diluted in an equal volume of phosphate buffered saline 
containing 2% fetal bovine serum (PBS/2%FBS).  Diluted samples will be gently mixed and 
then carefully layered on top of Histopaque 1077 density medium (Sigma-Aldrich #10771) in 
a 50mL conical tube.  The amount of density medium used will equal the original blood 
aliquot volume (~5mL).  Tubes will then be centrifuged at 1200xg for 20 minutes at room 
temperature with the centrifuge brake set to ‘off’.  Following separation, enriched T-cells will 
be removed from the plasma interface using a pipette and placed into a fresh 15mL conical 
tube.  The cells will be washed by adding PBS/2%FBS to the tubes until they are filled to the 
top fill line. Tubes will then be centrifuged at 400 x g for 4 minutes at room temperature with 
maximum brake.  The resulting supernatant will be removed with a pipette and transferred to 
a 1.5 mL microcentrifuge tube.  This sample will be centrifuged at 400 x g for 4 minutes at 
room temperature with maximum brake. The resulting supernatant will be carefully and 
completely removed using a pipette.  The remaining T-cell pellet will be stored in a -80 ° 
freezer until processing.  
 

 
21 
 
7.7 RNA recovery and basic analysis of mRNA and miRNA 
Analysis of samples will start in the laboratory of Dr. Christin Burd, although this is subject 
to change. As described below, the Nucleic Acid Shared Resource (section 6.3.1) and 
occasional proprietary analysis by companies such as RayBioTech (section 6.4) may also be 
involved. For total RNA extraction from plasma/serum, 3-5ml of sample will be processed 
using the mirVana Paris kit (Ambion) following the manufacturer’s instructions. To increase 
the RNA recovery and the RNA quality from serum, 1µg of RNA carrier (#4382878, 
Ambion) will be added to the total volume to allow both a better miRNA recovery and an 
increased RNA quality from serum samples.  
 
For total RNA extraction from T-cells, cell pellets will be processed using the RNeasy Plus 
Mini Kit (Qiagen #74134) following the manufacturer’s instructions.The concentration and 
quality of all RNAs will be assessed using a NanoDrop 2000 Spectrophotometer (Thermo 
Fisher Scientific, Wilmington, DE, USA).  If the 260/280 ratio is not between 1.70 and 2.30 
the RNA sample will be subjected to an extra purification passage.   The samples will be 
submitted to the Nucleic Acid Shared Resource of The Ohio State University for further 
processing by the NanoString nCounter system for mRNA and miRNA characterization 
(NanoString, Seattle, Washington, USA). 
 
7.8 p16 mRNA Isolation and Analysis 
Under the supervision of Dr. Burd, harvested T-cell mRNA will be converted to cDNA using 
the Promega ImProm-II Reverse Transcription System (Promega #A3802) and random 
hexamer primers (Invitrogen #588875) as directed by the manufacturers.  p16 levels will be 
measured using a Taqman-based quantitative RT-PCR methods essentially as described by 
Liu et al. (20). Validated Taqman-based controls for T-cell purity (CD3G, Applied 
Biosystems #4331182 Hs00962186), sample viability (p14ARF, Applied Biosystems 
#4351370 HUMP14-ARF3) and RNA quantity (YWHAZ, Applied Biosystems #4331182 
Hs03044281) are included in this analysis. Data clean up: Data will be filtered to exclude 
relatively invariant features (IQR = 0.5) and features below the detection threshold (defined 
for each sample by a cutoff corresponding to approximately twice standard deviation of 
negative control probes plus the mean of them) in at least half of the samples. Basic analysis 
Using R/Bioconductor and the filtered dataset, linear models for microarray data analysis59 
(Smyth et al., 2005) will be employed with a contrast matrix for the comparisons. P values 
will be used to rank miRNAs and mRNA of interest, and correction for multiple comparisons 
will be done by the Benjamini-Hocheberg method60 (Benjamini et al., 1995). Raw data that is 
above background, as well as the corresponding quantile-normalized data, will be imported 
into MultiExperiment Viewer61 (Saeed et al., 2006; Pichiorri et al. 2013). 
 
7.9 Bone marrow analysis 
Some bone marrow aspirates will be obtained as standard of care and analyzed by surgical 
pathology, cytogenetics, and flow cytometry and this data may be analyzed and incorporated 
into statistical model building. 
 
 
 
 
 
 

 
22 
 
8.0 STUDY CALENDAR 
 
Table 3. Study Visit Assessments 
 
Study Visit 1:  
Baseline* (+/- 45 
days) 
Study Visit 2: 
POST-OEP 
Evaluation *(+/- 45 
days) 
 
Study Visit 3: 
6 Month Follow 
up *(+/- 45 days) 
 
Signed Informed Consent 
X 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
Registration additions 
X 
 
 
History and Physical 
X 
X 
X 
Weight and Heighta 
X 
X 
X 
Adverse Eventsb 
X 
X 
X 
KPS 
X 
X 
X 
Vitals 
X 
X 
X 
CBC with differentialc 
X 
X 
X 
Serum Chemistry and 
LFT’sd 
X 
X 
X 
Hematologic Cancer 
Specific Labse 
X 
X 
X 
β2 microglobulin, LDH, 
CRP 
X 
X 
X 
Peripheral blood for 
biomarker analysisf 
X 
X 
X 
 
a. Weight to be measured in the same fashion at each time point (with or without shoes, street 
clothes vs. gown, etc).  Height does not need to be repeated after the screening visit. 
b. Adverse events (AE) and their severity will be captured according to the CTCAE v4.0 and 
whether any AEs can be attributed to exercise (physical therapist administered or home 
based). 
c. CBCs will be performed to include at least WBC, hemoglobin, platelets, and absolute 
neutrophil count.   
d. Serum chemistry (electrolytes, BUN, creatinine) and Liver function tests to include 
transaminases and albumin 
e. Myeloma: measure clinically relevant proteins that have previously been abnormal in that 
patient to include more than one of the following: a) serum immunoglobulins by 
nephelometry, b) serum & urine protein electrophoresis and immunofixation, c) serum free 
light chains; and d) 24hr urine total protein (as necessary); NHL: LDH; AML/ALL: % 
circulating blasts 
f. Blood samples (30 mL of blood) will be cryopreserved for correlative analyses (RNA 
studies, flow cytometry etc.)  
* Survey participant data will be captured as part of routine care  
 
 
 
9.0 REFERENCES 

 
23 
 
 
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