REBOUND: REsiliency in Older Adults UNDergoing BOne Marrow Transplant - A Pilot Study of Resiliency Measures in Older Patients Undergoing Allogeneic Blood and Marrow Transplant
Conditions: Leukemia, Lymphoma, Blood Cancer, Myelodysplastic Syndrome, Acute Myelogenous Leukemia, Non-Hodgkins Lymphoma
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Title:  REBOUND: REsiliency in older adults UNDergoing BOne marrow transplant - A pilot 
study of resiliency measures in older patients undergoing allogeneic blood and marrow 
transplant 
 
 
Protocol Number:   
 
J1849 
 
IRB Application#: IRB00165139 
 
 
Principal Investigator: 
       Philip Imus, MD 
 
  Office:  410-955-8839 
 
  Pager:  410-283-1369 
 
  Email: pimus1@jhmi.edu 
 
 
 
Co-Investigators: 
  Rick Jones, MD 
 
  Jeremy Walston, MD 
 
  Karen Bandeen-Roche, PhD 
 
  Ravi Varadhan, PhD 
 
  Qian Li Xue, MS, PhD 
 
  Ora White 
 
  Jackie Langdon 
 
  Meredith Dobrosielski 
 
  Amy DeZern, MD, MHS 
 
  Ephraim Fuchs, MD 
 
  F. Javier Bolaños-Meade, MD 
 
  Leo Luznik, MD 
 
  Richard Ambinder, MD, PhD 
 
  Mark Levis, MD 
 
  Douglas Gladstone, MD 
 
  Gabriel Ghiaur MD, PhD (Lab correlates) 
 
  Frederick Sieber, MD (Lab correlates) 
 
  Susumu Mori, PhD (MRI correlatives) 
   
Haris Sair, MD (MRI interpretation) 
 
  Sean Leng, MD, PhD (Lab correlates) 
 
 
Statisticians:  
 
Ravi Varadhan, PhD (Biostatistics), PhD (Environmental Eng) 
 
 
550 N. Broadway, Suite 1111-E 
 
 
Baltimore, MD 21205 
 
 
ravi.varadhan@jhu.edu 
 
 
 
 
Hua-Ling Tsai, Sc.M. 
 
Study Coordinator: 
            
Patrick Lowery 
 
Head Research Nurse:  
Laura Ackley 
 
 
 
 

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Schema 
 
Prior to D-6  
 
 
 
Pre-BMT Assessments 
Study Assessments 
↓ 
Day -6 to -1 
 
 
Non-myeloablative stem cell conditioning 
(fludarabine, cyclophosphamide, total body irradiation) 
↓ 
Day 0 
 
 
Allogeneic T-cell replete stem cell infusion 
↓ 
Day +3-60 
 
 
 
GVHD prophylaxis 
(cyclophosphamide Day 3,4 
MMF Day 5-35 
Calcineurin Inhibitor Day 5-60) 
Collection of research data 
Study Assessments on Day 30 
↓ 
Day 60 
 
 
 
Disease Assessment, GVHD, chimerism 
↓ 
Day 180  
 
 
Disease Assessment 
Study Assessments 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 Primary Objective ..........................................................................................................6 
1.2 Secondary Objectives.....................................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 Study Diseases ...............................................................................................................6 
2.2 Rationale 6 
2.3 Relevance of Resilience in bone marrow transplantation ..............................................8 
3. 
PATIENT SELECTION ......................................................................................................9 
3.1 Eligibility Criteria ..........................................................................................................9 
3.2 Exclusion Criteria ..........................................................................................................9 
3.3 Inclusion of Women and Minorities ..............................................................................9 
4. 
REGISTRATION PROCEDURES .....................................................................................9 
4.1 Recruitment ....................................................................................................................9 
4.2 Screening 10 
4.3 Obtaining Consent .......................................................................................................10 
5. 
TREATMENT ...................................................................................................................10 
6. 
Study Procedures ...............................................................................................................10 
6.1 Assessment of Physical Function.................................................................................10 
6.2 Health History ..............................................................................................................11 
6.3 Cognitive function .......................................................................................................12 
6.4      Psychosocial measures: ...........................................................................................12 
6.5 Physiological Indicators ...............................................................................................13 
6.6 Definition of Endpoints................................................................................................16 
6.7 Duration of Follow Up .................................................................................................17 
7. 
Correlative methods ...........................................................................................................17 
7.1 Ex vivo responses in PBMCs .......................................................................................17 
7.2 Performance of Assessments .......................................................................................17 
8. 
Data Management ..............................................................................................................18 
9. 
STUDY CALENDAR .......................................................................................................20 
10. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................21 
10.1 
Study Oversight .........................................................................................21 
10.2 
Protocol Amendments ................................................................................21 
11. 
STATISTICAL CONSIDERATIONS...............................................................................21 
11.1 
Sample Size/Accrual Rate ..........................................................................24 

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11.2 
Subject Disposition ....................................................................................24 
12. 
APPENDIX A PERFORMANCE STATUS CRITERIA ..................................................25 
REFERENCES ..............................................................................................................................26 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objective 
1.1.1 To pilot test candidate indicators of physical resiliency to include static and dynamic, as 
well as global and stressor-specific, measures. 
 
1.2 
Secondary Objectives 
1.2.1 For each indicator, to gather data on feasibility, reliability, and biological mechanism, 
and for the collection of indicators, to explore construct validity.  
 
2. BACKGROUND 
 
2.1 
Study Diseases 
 
Allogeneic blood and marrow transplantation (alloBMT) is the only potentially curative therapy 
for many forms of leukemia, lymphoma, and other hematologic malignancies.  As with many 
forms of cancer, many of the most common indications for alloBMT (including but not limited to 
acute myelogenous leukemia [AML], myelodysplastic syndrome [MDS], non-Hodgkins 
lymphoma [NHL]) disproportionally affect older people. Although treatments have improved for 
older adults undergoing therapies for these diseases, the outcomes are variable and there is little 
biological knowledge to help identify specific factors that would predict why some people do 
well with treatment and others develop functional and cognitive decline and other adverse health 
outcomes. 
 
2.2 
Rationale 
 
Conceptualization of Resiliency to Physical Stressors: Resilience is defined as the dynamic 
ability to maintain or recover appropriate function in response to a stressor. Although much 
recent attention has been given to this area of investigation, minimal progress has been made in 
part because of the lack of a viable framework from which to study resiliency to physical 
stressors. In order to meet the goals of this study, we have built on our long-standing 
investigations into complex dynamical systems in older adults. Within this framework, we define 
resilience as the capacity of an organism to absorb significant shocks (stressors) and respond so 
as to still retain the same function and structure. Said intuitively, resilience is the capacity to 
change in order to maintain the same identity, i.e. “to bend rather than break”. In the language of 
dynamical systems, resiliency is the capacity to retain the same control parameters. The greater 
the residual impacts of a stressor, in terms of long-lasting physiological changes, the less resilient 
the biological system with regards to that particular stressor. Thus, resilience is a dynamical 
property not only of the biological system but also depends upon the type and intensity of the 
stressor:  An individual may be resilient to chemotherapy but vulnerable to infections. We 
hypothesize that resilience can be identified through identification of pre-existing determinants 
as well as phenotypic, physiologic, and molecular signatures of resiliency related to outcomes 
after a physical stressor.  The figure displays the conceptual framework from which we have 
developed our approach. Here, pre-existing determinants provide a baseline for organismal 
resiliency, and physical stressors influence phenotypic, physiological, and molecular processes 
within these domains which in sum drive resilient or non-resilient outcomes. Our prior work in 

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measurement within these domains, especially dynamic physiological measures related to stress 
response systems, has greatly informed sub-domains (figure 1) hypothesized to drive resiliency 
and provide an organizational framework for the measures proposed in this study.   
 
Prior Work as Rationale for Approach and Measures: Our research team has performed a series 
of stimulation tests of stress response systems and evaluated dynamical responses in human 
subjects.  We have long focused on developing study designs and modeling approaches for 
characterizing the physiology underlying the loss of global robustness and resilience in 
connection with our work on the geriatric syndrome of frailty[1-3]. Our group conceptualized 
frailty 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”[1]. We have characterized and refined numerous “static” physiological measures in 
conjunction with frailty:  nonlinear multisystem dysregulation[4]; allostatic load[5]; resting 
metabolic rate[6]; insulin resistance and inflammation[7]; coagulation and inflammation[3]; 
Figure 1: Conceptual framework of resilience 

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hormonal deficiencies[8]; white blood cells[9]. Moreover we were the first to propose the 
classical dynamical systems approach to the study of stimulation tests to characterize the loss of 
global resilience associated with frailty[10].  This framework was deployed in a series of 
hallmark studies of physiological stimulation tests in participants aged 83-92 years in the 
Women’s Health and Aging Studies.  These included: oral glucose tolerance test to evaluate 
glucose metabolism[11, 12], ACTH stimulation test for HPA axis, magnetic resonance 
spectroscopy for studying muscle energetics, and characterizing immune response to influenza 
vaccination. In addition, we have also utilized a variety of autonomous (unstimulated) dynamical 
response data to examine the physiology of impaired global resilience: diurnal cycle of 
cortisol[13], control of autonomic nervous system and complexity of heart rate variability[13, 
14], and inflammatory signaling[15].  
 
This body of knowledge supports our hypothesis that stress response systems lie at the center of 
physiology that either promotes resilience when functioning optimally, or prevents rapid 
recovery after stressors when damaged or senescent. These systems can be measured through 
obtaining levels of inflammatory molecules, hormones, autonomic nervous system tone, energy 
metabolism, cellular composition and function, as well as higher level organ function.  
Resilience may be defined as an ability to restore optimal function of these systems after 
encountering a stress.  Finally, because age is so crucial to declines in resiliency, we propose to 
explore important features related to molecular aging in these studies. 
 
2.3 
Relevance of Resilience in bone marrow transplantation 
 
Older patients who undergo allogeneic BMT to cure their hematologic malignancy are already a 
select group: they have largely recovered from the toxicities of induction chemotherapy; their 
disease has been put into remission; and their organs function well after decades of use.  The use 
of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), a refinement of 
the Charleston Comorbidity Index, allows an estimate of non-relapse mortality, and incorporates 
15 variables that span the major organ systems.  The HCT-CI was developed on a cohort of 
patients aged 0-70, with few patients older than 60; a score of 0 means no major organ 
dysfunction, and higher scores indicate more preexisting organ damage.  It has been validated in 
patients older than age 50[16], and in 372 patients aged 60-75 treated between 1998 and 2008 
across 19 institutions[17]; in both cases, HCT-CI scores of 0 predicted better overall survival.  In 
the latter study, non-relapse mortality was 8% at 3 years with an HCT-CI score of 0, but 25% 
with a score of 3 or more. 
 
Transplant outcomes at Johns Hopkins Hospital are superior to this historical data in older 
patients[18], with 1 year non-relapse mortality of 12% in 271 patients older than age 50.  These 
outcomes are likely related to the use of non-myeloablative conditioning and post-transplant 
cyclophosphamide for GVHD prophylaxis.  Furthermore, while HCT-CI scores greater than 5 
seem to predict increased non-relapse mortality, lower scores do not appear to raise this risk 
appreciably.  Data specific to patients older than 65 are sparse.  In none of these studies have 
geriatric assessment measures in domains such as cognition and function been evaluated.  Given 
the low incidence of non-relapse mortality in our older patients, we have a unique opportunity to 
study the factors that influence not only mortality but function after hematopoietic stem cell 
transplantation.  We aim to be able to counsel patients more specifically about likely outcomes 

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after transplant.  
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Undergoing allogeneic bone marrow transplant at Johns Hopkins Hospital, the indication 
for which is a hematologic malignancy 
3.1.2 Age ≥60 years 
3.1.3 Ability to walk without human assistance 
3.1.4 Enrollment in concomitant clinical research is permitted but not required 
3.1.5 English-speaking 
3.1.6 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Unwillingness or inability to return at 6 months after transplantation for repeated evaluation 
3.2.2 Non-English-speaking 
 
3.3 
Inclusion of Women and Minorities 
 
Men and women of all races and ethnicities will be recruited without prejudice, and consistent 
with the population in our catchment. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Recruitment 
Potential participants will be identified during initial consultation for bone marrow 
transplantation.  They will be given a copy of a consent form at this visit, and be asked by their 
attending physician if they are interested in learning more about the study or it will be sent to 
them.  Research staff will contact the patient by phone to address any questions. 
In addition, potential participants may contact the study team directly. This contact may be in the 
form of telephone, email, etc. Initial discussions regarding study participation may take place by 
phone, email, etc., and individuals may be provided with the IRB approved consent form and 
other IRB reviewed and approved materials (e.g., Patient Handout), as applicable.  
In all cases, as much time as is needed to consider study participation will be allowed to possible 
participants; resulting in multiple phone calls, visits, emails, or other communication, as 
necessary. For individuals who choose to take part, informed consent will happen as per the 
consent process.  

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4.2 
Screening 
 Ensure eligibility: PHI will be retained to justify screen failures, and will be stored 
under the same secure conditions as all study-related data for the length of the trial. 
 Collect registration data [age, diagnosis] 
 
4.3 
Obtaining Consent 
Those members of the research team (principal investigator, co-investigator, research nurses) 
who consent patients have been trained in informed consent procedures, are familiar with the 
protocol, and are listed as a consenter in the application document. Patients are given adequate 
time and privacy to consider the research study. Before the patient signs the consent, the 
consenter must be satisfied that the participant understands the information provided, has had an 
opportunity to discuss the information and ask questions, and is aware that he/she may withdraw 
from the study at any time. Non-English speaking participants will be unable to participate. 
5. TREATMENT 
 
Bone marrow transplantation will be conducted according to our institution’s standard of care, or 
else according to research protocol (if applicable).  Decisions regarding clinical care before, 
during, and after bone marrow transplantation will be the sole responsibility of the subject’s 
attending physician. 
 
6. STUDY PROCEDURES 
 
Study visits that include the performance of assessments in sections 6.1 and 6.2 will occur prior 
to the start of conditioning chemotherapy and at 1 month and 6 months post-BMT.  All dates are 
+/- 7 days.  The initial study visit will take place during standard of care pre-transplant 
evaluations, which typically span 3-4 days.  The post-BMT visits will take place before or after 
regularly-scheduled BMT follow up. The clinical coordinator will organize the research study 
measures listed below around necessary clinical studies.   
 
In addition, baseline clinical factors will be collected from the electronic medical record.  These 
data include characteristics of the recipient, donor, disease, disease status and treatment received, 
HCT-CI and DRI risk assessments, all of which are collected as routine clinical care. We will 
also utilize many clinical measurements that are taken as part of the pre-transplantation work up 
and incorporate them into the research database. These measures include all laboratory values, 
spirometry, echocardiogram, and CT scans.  
 
6.1 
Assessment of Physical Function 
 
Both performance-based (e.g. SPPB) and self-reported measures (e.g. mobility, ADL, IADL) 
will be collected. 
 
 
Short Physical Performance Battery (SPPB)[19]: a performance-based assessment comprising 
3 tasks: 1) repeated chair stands; 2) standing balance; and 3) a 4-meter usual paced walk in 
those with and without a walk aid (meters/second [m/s]).  

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 
Instrumental Activities of Daily Living/Activities of Daily Living (IADL/ADL)[20, 21]: used 
by other studies of the aging population to measure disability in the context of restrictions in 
ability to carry out daily tasks such as bathing and taking medications.  The IADL/ADL 
involves a series of questions about ability to perform activities of daily living such as 
bathing, dressing, and walking.   
 
 
Accelerometry (Toosizadeh et al., 2017a; Toosizadeh, Joseph, et al., 2016a; Toosizadeh, 
Mohler, & Najafi, 2015a; Toosizadeh, Mohler, Wendel, & Najafi, 2015b; Toosizadeh, Najafi, 
et al., 2016b; Toosizadeh, Wendel, Hsu, Zamrini, & Mohler, 2017b): A newly developed 
validated measure of upper extremity function that can be easily utilized in all stressor 
populations that involves moving the arm with a wand like device that records the number 
of movements that an individual makes over a timed period.  Accelerometry will be 
assessed using the Actigraph Link accelerometer, a water-resistant, wrist-worn device that 
can be worn 24 hours a day (except during swimming), measuring physical activity and 
sedentary behaviors continuously. Participants will be fitted with the device during pre-
transplant evaluations and wear it for 7 consecutive days at three points during the study, 
once during pre-BMT evaluations, once at day +30 post-BMT, and again at day +180 post-
BMT. 
 
 
Overnight catecholamines: Subjects will be given a plastic collection jug and urine collection 
device that fits into the toilet seat to ease collection for female participants. They will be 
given instructions for at-home overnight urine collection. They will be asked to store the 
collection jug with urine in refrigerator until submitted. Sample will be delivered to the 
laboratory for processing, freezing, and future measurement of catecholamines by ICTR core 
chemistry laboratory. 
 
 
Frailty Assessment: We will measure frailty using the Frailty Phenotype instrument, 
developed by Fried, Walston and colleagues (2001) in the Cardiovascular Health Study, and 
validated by Bandeen-Roche and colleagues (2006) in the Women’s Health and Aging 
Studies. The frailty assessment measures participants’ walking speed and grip strength, and 
includes questions about exhaustion, physical activity, weight loss.  The 4-meter walk is 
measured at comfortable pace in a normal hallway on a marked course and recorded using 
stopwatch (2 trials); this will be completed as part of the SPPB (described above). Grip 
strength is recorded using a handheld dynamometer (3 trials). Standardized self-reported 
questionnaires will be used to capture exhaustion, physical activity, and weight loss.  The 
algorithm from the Hopkins Frailty Assessment Calculator 
(http://hopkinsfrailtyassessment.org/) will be used to determine a participant’s frailty status. 
 
 
Pittsburgh Fatigability Scale for Older Adults (PFS) (Glynn et al., 2015): a validated self-
report tool that normalizes activities in terms of intensity and duration.  
 
 
Fatigability in response to physical demand: a novel measure of perceived fatigability in 
response to physical demand will be assessed immediately after a slow-paced 5-minute 
treadmill walk (1.5 mph; 0.67 m/s; 0% grade) using the Borg Rating of Perceived Exertion 
(RPE) scale (42;43).   
 
6.2 
Health History 
Self-Report of Health - two item questionnaire on the participant’s self-report of their 
general health, and their current health compared to health one year ago 

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 
Medical History and Diseases/Conditions - Questionnaire of past medical history of diseases 
and health conditions. 
 
Health Behaviors Questionnaire - documents current and past health behaviors of each 
participant, which permits the assessment of overall health 
 
Hospitalizations, Surgeries, and Falls - Questionnaire with two items on hospitalizations; 9 
items (with sub-questions) on surgeries; and 3 items (with sub-questions) on falls. 
 
Pain Assessment - Overall bodily pain measurements will be taken using 2 questions on pain 
intensity/frequency and pain-related function/interference 
 
Anxiety Questionnaire: 8 questions to assess feelings of anxiety; this questionnaire assesses 
both the presence and severity of anxiety-related feelings. 
 
 
Trauma Questionnaire: 6 questions to assess any past experiences of several kinds of traumas. 
This includes assessment of trauma experienced by the participant and by a close loved one. 
 
6.3 
Cognitive function 
 
 
The Modified Mini-Mental State Examination (3MS): the best validated measure of global 
cognitive function (range 0-100; higher scores represent better function) is frequently used in 
studies of cognition.  It captures a broad array of cognitive domains and is easily 
administered in clinical settings.  
 
 
Montreal Cognitive Assessment (MoCA): an alternative to 3MS and measures global 
cognitive function across the cognitive impairment continuum and is more sensitive to mild 
cognitive impairment (106). A brief, iPad-based protocol using sensitive component 
measures from the NIH Toolbox (46;47) will be collected to assess levels of executive 
inhibitory function (Flanker task; 3 min.), episodic memory (picture sequence test; 7 min.), 
and processing speed (Pattern Comparison; 3 min.). 
 
 
Flanker Inhibitory Control and Attention Test: Measures attention and inhibitory control. 
Participant focuses on a given stimulus while inhibiting attention to stimuli flanking it. 
 
 
Digit Symbol Substitution Test (DSST) - The DSST requires that the participant fill in a 
series of symbols correctly coded within 90 seconds.  In this test the higher the score the 
better the person’s performance. 
 
 
6.4      Psychosocial measures: 
 
 
Coping Self-Efficacy Scale: 11-point Likert scale measures perceived ability to cope 
effectively with life challenges, has 3 domains (problem-focused coping, stop unpleasant 
emotions & thoughts, get support) 

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 
Purpose in Life: Subscale of Ryff Psychological Well-being Scales: 7-item Likert type scale 
(from strongly disagree to strongly agree) Measures sense of direction and perception of 
purpose for the future 
 
 
Meaning in Life Questionnaire (MLQ): Presence of Meaning Subscale (adaptation): 3 items 
on Likert-type scale measuring perception of meaning and satisfaction with life 
 
 
Ten Item Personality Inventory (10 items): 7-point Likert-type scale of disagree to agree 
with various aspects of personality (e.g. extraverted, enthusiastic), measuring: 
extraversion, agreeableness, Neuroticism, Openness, Conscientiousness 
 
 
Life Orientation Test-Revised (3-items): 5 point Likert scale, assessing optimism 
 
 
Loneliness Scale- 3 item: Based on evaluation and factor analysis of Revised UCLA 
Loneliness Scale; can be administered via telephone, survey or interview 
 
 
U.S. comparison of socio-economic status: uses a 10-rung ladder to assess a participant’s 
perception of their status in society, strongly linked to health statusf 
 
 
Financial Strain: 2-item measure evaluating difficulty and anxiety about money 
 
 
Social Cohesion: 3-item adapted for use in NHATS to accommodate multiple residential 
settings, rating statements about the community by rate of agreement (e.g. People in your 
community know each other well. Agree a lot, a little, do not agree) 
 
 
Social Isolation/Engagement: 7-item measure evaluating social isolation, participation and 
engagement in the last week and year including visiting friends/ family, attending religious 
services and participation in clubs 
 
 
Religion/Spirituality: 5-Item measure for use in epidemiological studies regarding 
spirituality. 
 
 
Patient Health Questionnaire (PHQ-8): Measures depressive symptoms in the last 2 weeks, can 
influence IL-6 levels and self-efficacy indices. Has been successfully used in older adults with 
chronic disease. 
 
 
Adverse Childhood Events (ACE) Scale: 10-item measure of Yes/No style questions 
assessing childhood abuse and household dysfunction’s relationship to leading causes of 
mortality in adults.  
 
 
Perceived Stress Scale: 5-point Likert scale measures the cognitive appraisal and 
perceptions of stress in life over the last month, used successfully in older adults 
 
6.5 
     Physiological Indicators 
 
Physiologic, cellular, and molecular markers suspected to be involved in the re-establishment 
of homeostasis will be collected.  Many physiological measures are captured in routine 
clinical and laboratory assessments. Others were chosen in part because of a previously 
identified relationship with frailty.   
 

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Blood tests will be performed according to the table below.  Twenty (20) mL of bone marrow 
aspirate will be collected during standard of care bone marrow biopsies pretransplant and at 
day 180 for research as well.  These tests will be performed twice: during pre-BMT 
evaluations, and at 6 months after BMT.  The research portion of the blood tests will account 
for 160 mL of blood during evaluations, and 90mL of blood at the day 180 visit.  If a patient 
has required a red blood cell transfusion in the past week, he or she will not be eligible for 
the research blood draw portion of the study.   
 
In addition to the phlebotomy required, an MRI will be performed in a subset of 10 subjects 
in order to characterize cerebral white matter disease and alterations that may contribute to 
adverse cognitive outcomes after BMT.  MRI will be assessed at baseline and six months in a 
subset of 10 subjects.  In brief, sixty-five transverse slices will be acquired with no slice gap 
and 2.2 mm nominal isotropic resolution. Diffusion weighting will be applied along 96 
directions with a b-value of 1,000-3,000 s/mm2. Five minimally weighted images will be 
acquired. MRI data analysis to derive anatomical states and functional connectivity features 
will be performed using state of the art methods including a segmentation tool. 
 
The MRI will be reviewed by a qualified neuroradiologist in order to screen for clinically 
relevant findings.  These will be reported according to JHH policy. The principle investigator 
in consultation with the neuroradiologist will talk to the subject if there is an incidental 
finding. The subject does not have the option to decline information about an incidental 
finding. 
 
 Salivary cortisol: Subjects will be asked to collect saliva at home at 4 time points 
(7am, 11am, 4pm, and 11pm) during a single 24 hour period before BMT for a 
measure of cortisol. 
 
ACTH Stimulation Test: After the baseline blood draw is taken, 1mcg (low dose) 
Cosyntropin (synthetic ACTH) will be given intravenously over 1-2 minutes by research 
nursing staff. Serum samples will be collected at 0 (pre ACTH), 30, and 60 minutes, and 
cortisol and DHEA levels will be measured in the samples. The test assesses reactivity of 
HPA axis. 
 
Oral Glucose Tolerance Test (OGTT):  Participants will be asked to fast overnight and will be 
given the 75 gram glucose oral load after arrival in the ICTR in the form of an orange 
flavored sweet beverage (Metter et al, Diabetes Care, 2008). Blood draws will occur at 0 
(prior to the administration of the glucoal drink as described above), and then again at 30, 60, 
and 120 minutes after glucose administration (Kalyani, et al, J Gerontol, 2012). Rationale: 
Older adults with abnormal glucose status may represent a vulnerable subset at high risk for 
adverse outcomes. Dysregulation in response to glucose challenge may signal a physiologic 
vulnerability associated with a lack of resiliency.   
 
Holter monitor:  A myPatch Holter recorder, a small, lightweight digital device that records 
and stores electrocardiogram on a continuous basis, will be placed on the subject at the 
beginning of the visit and removed at the end of the visit as described below.  This will allow 
us to capture heart rate variability data.  The Holter recorder fits into an adhesive backed 

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patch, like a very large Band-Aid, that will be attached to the middle of the subject chest, just 
below the collarbone.  
After the recorder is removed, at the end of the clinic visit, the datafile from the recorder will 
be downloaded to a PC.  The file will be identifiable only by a unique deidentified ID.  The 
file will be sent to the Washington University School of Medicine in Saint Louis Heart Rate 
Variability Laboratory where it will be loaded only special Holter scanning software in order 
to derive measures of heart rate variability and counts of abnormal beats (if any).  If any 
suspected abnormality is seen on the Holter analysis, the PI will be notified of any 
abnormalities that could impact health, and the subject would be notified and informed to 
contact their physician.  
Bone Marrow Aspirate:  Bone marrow aspirate will be studied for clonal hematopoiesis in 
hematopoietic cells.  Bone marrow stromal cells will be studied for structure and function as 
well.   
 
 
 
 
 

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Table 1: Proposed physiologic studies – Table 1 lists tests we are planning. Most involve a single 
routine phlebotomy with exceptions listed under "Research": 
 
Part of Routine Clinical Care 
Research 
 
Vital signs 
 
ECOG/Karnofsky PS (71,72) 
 
HCT-CI[22] 
 
Complete blood counts and 
metabolic panels that assess renal 
and hepatic function 
 
free T4 and TSH, vitamin D3, 
cholesterol, fibrinogen, D-dimer 
 
Hormones: IGF-1, free and total 
testosterone (men), DHEA-S and 
bioavailable estradiol (women), total 
ghrelin, 24 hour salivary cortisol, 
overnight urinary catecholamine 
 
ACTH stimulation test (250 μg 
cosyntropin) 
 
OGTT[23] 
 
Inflammatory markers 
o IFN-γ, IL-10, IL-12p70, IL-
1β, IL-2, IL-4, IL-5, and 
TNF-α 
 
Immune cell phenotype 
characterization: 
o CD3, CD4, CD8, CD28, 
CD45RA, CCR7, CD56, and 
CD57, TNFα R1 
 
Immune cell functional assays  
 
Factor VIII, and tissue plasminogen 
activator  
 
Holter monitor 
 
Brain MRI  
 
 
 
6.6 
Definition of Endpoints 
 
One purpose of this pilot study is to understand the relationship between putative markers of 
resiliency and clinical outcomes after alloBMT.  The following are clinical endpoints of interest 
and their definition. 
Our aim in this phase 1 portion of our project is to characterize resilience.  Changes in any 
measure may or may not be clinically meaningful and may not contribute to our understanding of 
resilience.  We are interested in describing, via quantitative methods, homeostatic equilibrium 
for an entire organism across multiple domains.  In the face of a stressor, three responses are 
possible: a robust phenotype, wherein no perturbation is discernible; a resilient phenotype, where 
a shock is discernible but the system returns quickly to normal function; and a non-resilient 
phenotype, wherein the organism does not recover from the shock, and either reaches a new 
substandard baseline or indeed ceases functioning.  Take weight as an example during bone 
marrow transplant: some patients will maintain their weight through diet and light exercise 
throughout the transplant; others will lose weight because they are not eating but will gain it 
back, with the attendant muscle mass; and others will never regain the weight they had pre-
transplant.  The latter manifests itself as decreased muscle mass and increased frailty.   
We will collect clinically meaningful data to characterize resilience of older adults to the stressor 

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of BMT.  These will include: relapse of leukemia, days hospitalized from day 60-365, infectious 
episodes requiring specific therapy, any stays in rehab or nursing facilities, measures of patient 
activity (such as independent activities of daily living), and patient wellbeing.   
We hypothesize that many indicators of resilience will decrease in the time during and 
immediately following transplant, but that in the robust and resilient populations, they will return 
to their pre-transplant baseline at the 6-month visit.  By collecting this data, we will be able to 
look for two types of relationships.  First, which indicators of resiliency correlate with more 
clinically meaningful outcomes of resilience listed before?  Second, which pre-stressor 
characteristics are able to identify patients as being robust, resilient, or not resilient? 
 
6.7 
Duration of Follow Up 
 
Subjects will be followed through their 6-month assessment or until death, whichever comes 
first. 
 
7. CORRELATIVE METHODS 
 
Descriptions of selected correlative assays are recorded here.  Other correlative assays are 
performed either per clinical standard or per widely accepted techniques. 
 
7.1 
Ex vivo responses in PBMCs  
 
Isolated PBMCs will be stimulated with phorbolmyristate acetate (PMA) plus ionomycin, 
lipopolysaccharide (LPS) or CMV antigen peptide pools and cell proliferation. Intracellular 
cytokine production responses to stimulation will be collected as functional readouts, using 
methods developed by Dr. Leng’s group[9]. Rationale: We hypothesize that immune system 
functioning is central to stress response physiology, and hence resiliency. The test described here 
probes stress response in the immune system. We have shown that strong response to LPS 
stimulation predicts less resilient outcomes. 
 
7.2 
Performance of Assessments 
 
Details and time spent on assessments are listed in the table below. 
 
Assessment Measures 
Collection Type 
Location  
Prep + admin 
time (minutes) 
Blood and urine (biomarkers, dynamic ex 
vivo response of immune cells, physiologic 
markers) 
Blood draw 
Weinberg 
Phlebotomy 
5 
Adrenocorticotropic Hormone (ACTH) 
stimulation 
Blood draw, followed 
by ACTH injection, then 
2nd and 3rd blood draw 
IPOP 
60 
Fatigability (objective): Slow-paced 5-
minute treadmill walk, followed by Borg 
Rating of Perceived Exertion 
Performance test and 
questionnaire 
Onsite 
7 

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18 
Assessment Measures 
Collection Type 
Location  
Prep + admin 
time (minutes) 
SPPB 
Performance measure 
Onsite 
5 
MMSE / MOCA / DSST 
Questionnaire 
Onsite 
10 
Phenotypic frailty 
Standardized assessment Onsite 
10 
MRI 
Standard 
Onsite 
60 
Oral Glucose Tolerance Test (OGTT) 
Blood samples; Glucose 
load. 
Onsite 
120 
24-hour salivary cortisol profile 
Saliva samples 
Home 
15 
Accelerometry 
Actigraph Link 
Wearable technology 
Home 
10 
Psychosocial measures 
Questionnaires 
Onsite 
20 
Self-reported: Health; Mobility function 
Self-reported questions 
Onsite 
3 
Pittsburgh Fatigability Scale for Older 
Adults (self-report) 
Questionnaire 
Onsite 
5 
ADLs/IADLs 
Self-reported function 
Onsite 
10 
  
  
 
340 
 
 
 
 
8. DATA MANAGEMENT 
 
Management of Study Data – In a complex scenario in which data will be collected in multiple locations 
and extant data also will be utilized, we must implement systems and procedures to assure the highest 
standard of data quality, security, confidentiality, coherence and accessibility for analysis. To achieve 
this, we propose to create a centralized data management system on a dedicated MS SQL server, equipped 
with warehouse architecture to manage the multi-source 
origins of our data (Figure 1). Specifically, data integration 
will be accomplished into four steps: (1) we will use the 
existing Clinical Research Management System (CRMS) to 
streamline management of electronic eligibility checklists, 
eIRB approvals, consent form tracking and subject 
enrollment; clinical care-relevant data collected by CRMS 
will be transmitted to EPIC via a real time interface; (2) data 
extracted from EPIC and CRMS and data from our stressor-
specific partners captured using existing systems (e.g., 
REDCap) will be integrated into the SQL server through the Data Warehouse; (3) a web interface 
between the SQL server and end users will be built and housed on a web server to facilitate data entry and 
real-time data reporting; (4) data from different source will then be merged via the SQL server to form an 
integrated database. Our SQL database will build in features to prevent, detect and correct data entry and 
omission errors automatically. We will build assurances for data security into our system, for instance, by 
maintaining audit trails for data changes, implementing role-based authorization rules; restrictive views 
Figure 1 Integrated Data Warehouse Architecture.  

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19 
allowing users to access only authorized data with rigorous password protection; encryption to mask 
personally identifiable data; and transaction logs recording all access. To prevent accidental loss of data 
we manage, our production system resides on the JHU Department of Medicine (DOM) computer server 
under a secure and HIPAA compliant environment. The server is managed by DOM IT professionals. Full 
and incremental data file backup are implemented multiple times daily.  Study data will be collected on 
study-specific encrypted iPads with strong passwords, though no study data will be stored on these 
devices.   
 
 
 

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20 
 
9. STUDY CALENDAR 
 
NB: All dates are ± 3 days. 
 
 
Pre- 
Study 
Pre-
BMT 
Start of 
Conditioning 
through D56 
D30 
D180 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
 
X 
 
 
 
Physical exam 
 
X 
X 
X 
 
Measures in Table 1 (not including MRI) 
 
X 
 
 
X 
Medications 
 
X 
X 
X 
X 
Vital Signs 
 
X 
X 
X 
 
Performance status (ECOG/Karnofsky) 
X 
X 
 
X 
X 
Assessments of Physical Function (section 6.1) 
 
X 
 
X 
X 
Assessments of Cognitive Function (section 6.3) 
 
X 
X1 
X 
X 
Psychosocial measures (section 6.4) 
 
X 
 
 
X 
Physiologic measures (section 6.5) 
 
X 
 
 
X 
Flanker Test 
 
X 
X2 
X 
X 
MRI 
 
X 
 
 
X 
 
Blood tests will not be performed on Day 30 due to expected anemia. 
1–  
The flanker test will be performed once a week during days 0-60 
 

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21 
10. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
10.1 
Study Oversight 
 
Data and safety monitoring will follow SKCCC Data and Safety Monitoring Plan. Additionally, 
scheduled meetings will take place monthly and will include the protocol principal investigator, 
research nurse, data manager, and, when appropriate, the collaborators, sub-investigators, and 
biostatistician involved with the conduct of the protocol.  
 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or real 
protocol violations), data completeness, and progress of data for secondary objectives.  
 
The grant will be monitored by an National Institute on Aging (NIA) appointed board.  The 
research governing body for the UH2/UH3 project consists of the leadership of the UH2/UH3 
project and NIA staff (one voting member).The research governing body will be chaired by one 
of the UH2/UH3 PDs/PIs (Jeremy Walston).  The research governing body members will meet 
regularly to review and monitor progress, plan and design research activities, and establish 
priorities. Meetings may occur as regularly scheduled teleconferences and include at least 1 in-
person meeting each year in Bethesda, MD over the course of the UH2/UH3 project period. The 
PI(s)/PD(s) will be responsible for scheduling the teleconferences and in-person meetings, as 
well as for preparing concise minutes from teleconferences and in-person meetings.  The meeting 
minutes will be distributed to the NIA Program Office and to research team members within one 
week of the meeting. 
 
An independent Data and Safety Monitoring Board (DSMB), will be established by the NIA, 
since the research activities may involve use of novel test measures in vulnerable populations. 
The DSMB will review research progress and the safety of the study participants based on a 
safety monitoring plan and report to the NIA Program Office. The DSMB’s approval will be 
required before initiation of the UH2 phase of the project and prior to transition to the UH3 
phase.  The PD(s)/PI(s) of the UH2/UH3 will assume responsibility for reporting of the DSMB 
recommendations to their respective Institutional Review Board(s).  The NIA DSMB will 
generate reports concerning observations, deviations, and safety concerns on a yearly basis. 
 
  
10.2 
 Protocol Amendments 
 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB before implementation. 
 
11. STATISTICAL CONSIDERATIONS 
 
Primary Objectives: 1) To generate data to develop the phenotype of resiliency in the face of 
clinical stressors. 2) To identify indicators of resiliency, including dynamic stimulation tests of 

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22 
physiologic response.  
 
Note that these two objectives may consist of overlapping data.  For example, superior 
performance after transplant on the SBBP may be part of our proposed definition of resiliency 
that is carried forward to our phase 2 study; superior performance on the SBBP prior to 
transplant may predict a resilient phenotype.  The following analyses will be conducted to 
attempt to describe resilience in this population.   
 
The clinical outcome of interest in this pilot study will be the achievement of pre-transplant 
functioning.  This means that their pre-and post-transplant weight will not differ significantly 
(within 5% of pre-transplant weight), they will not be hospitalized after engraftment, and they 
will not experience grade 3-4 adverse events.  This composite clinical outcome will be assessed 
at the 6 month visit.  This endpoint is provisional, since the thrust of this project is in fact to 
characterize resilience.    
 
Objective 1:  Please refer to Section 6.5 for a definition of the phenotype of resilience.  We will 
collect clinically meaningful data to characterize resilience of older adults to the stressor of 
BMT.  These will include: survival, relapse of disease, days hospitalized from day 60-180, any 
grade 3-4 non-hematologic adverse events during the study period, any stays in rehab or nursing 
facilities, measures of patient activity (such as independent activities of daily living), and patient 
wellbeing.  [Since the study period lasts only until day 180 after transplant, only a minority of 
patients will have achieved the clinically meaningful endpoints of relapse or death.]  The 
resilient patient will be defined as not having died during transplant, having recovered from 
major organ toxicities, and having been free of adverse events since the initial period of aplasia.  
The occurrence of expected events such as graft versus host disease will not be deemed sufficient 
to categorize a subject as not resilient; rather, the experience of side effects from therapy, or a 
decrement in function from GVHD, for example, will count against a subject’s resilience. 
 
There are two main analyses: (i) to characterize the measures’ reliability, change over time, 
variation and covariation, and (ii) to evaluate univariate (marginal) associations of each measure 
with the resiliency phenotype. We will consider both measurement properties and strength of 
univariate associations to select candidate measures of resiliency for the larger, Phase 2 study. 
  
Beginning with (i):  Reliability and precision of single measures will be assessed through 
laboratory standard or published information; by empirical measures such as variance, intra-class 
correlation, and Kappa statistics; or longitudinally as mean change/variability ratio (in mixed 
effects models, as the ratio of random effect variability to overall variability). Rates of change in 
measured outcomes, their heterogeneity, and measures’ variability about persons’ long-term 
trends (reliabilities) will be analyzed using mixed-effects (continuous outcomes) and generalized 
estimating equation (GEE; categorical outcomes) analyses, allowing nonlinearity by polynomials 
or splines. Extent of association between connected phenotypes (e.g. magnitude of stressors and 
short- and long-term outcomes) will be considered: Distributions will be visualized using plots to 
identify proneness to outliers, skewness / need for transformation, and nonlinearity versus 
linearity of time trends. Analyses will be tailored to the scale of the outcome measure:  Binary 
outcomes (e.g. delirium occurrence) will be characterized by proportions experiencing the event 
and their extent of association with predictors via logistic and log-linear regression; continuous 

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23 
outcomes (e.g. usual pace walking speed) by mean and variance estimates and their extent of 
association with predictors via linear regression; times to events (e.g. falling) by cumulative 
incidence rates and curves (allowing recurrence / treating death as a competing risk) and their 
extent of association with predictors via Cox proportional hazards or subdistribution models. 
Recognizing the small sample size, the number of predictor variables in regression models at any 
one time will necessarily be restricted to a very few (e.g. age as a key covariate; other 
hypothesized determinants taken 1-2 at a time; stressor magnitude and interactions of this with 
single resilience measures). A key analysis will be to explore the relationship between the 
magnitude of the stressor and the extent of pre-post change. To maximize analytic precision, we 
will take the ANCOVA approach in which status before and after the stressor are considered as 
two outcomes in a single regression analysis, and an interaction between “time” (post versus pre) 
and the stressor magnitude assesses the effect of stressor magnitude on status change. 
  
Objective 2: The second primary objective is to identify short- and long-term physical resiliency 
indicators, including dynamic stimulation tests of physiologic response.  Indicators of resiliency 
have been previously described in Sections 6.1 – 6.4. We hypothesize that many indicators of 
resilience will decrease in the time during and immediately following transplant, but that in the 
robust and resilient populations, they will return to their pre-transplant baseline at the 6-month 
visit.  By collecting this data, we will be able to look for two types of relationships.  First, which 
indicators of resiliency correlate with more clinically meaningful outcomes of resilience listed 
before?  Second, which pre-stressor characteristics are able to identify patients as being robust, 
resilient, or not resilient?  
Here again, there are two types of analyses: (i) exploration of the construct validity of the various 
resiliency indicators (static and dynamic), taken as a group, for representing a shared construct of 
resiliency and (ii) univariate associations of static and dynamic indicators with outcomes. For (i), 
construct validity analyses must be simple due to small sample sizes. We will use multi-trait 
multi-method (MTMM) matrices which show reliabilities on the diagonal and correlations on the 
off-diagonal. Here the static measure domains or stimulation tests constitute "traits" and 
individual measures constitute different "methods."  MTMM analyses should provide guidance 
for simple summaries, such as averaging, for example, by suggesting sub-domains of particularly 
highly related measures for scaling. For dynamic stimulus-response indicators, we will follow 
the approach proposed in Varadhan et al. (2008), where a stimulus-response modeling paradigm 
was detailed using a dynamical systems approach for deriving summary “parameters” of system 
functioning. There are five essential elements: (1) stimulation testing to elicit response(s) from 
the physiological system of interest (e.g., ACTH stimulation of HPA axis), (2) formulation of a 
mathematical model that describes the response (typically these are differential equations), (3) 
estimation of model parameters using response data (e.g. maximum likelihood estimation for 
nonlinear models), (4) model criticism (e.g. goodness of fit, residual diagnostics), and (5) 
systems identification (determination of model parameters, e.g., amplitude or rate constants, that 
most clearly distinguish resilient versus non-resilient phenotypes).  For (ii), we will evaluate the 
ability of resiliency measures to predict outcomes, one at a time, using appropriate regression 
analyses, adjusting for age and stressor severity. Additionally, we aim to build preliminary 
composites of resiliency indicators and assess these for their effectiveness in predicting 
outcomes. 
 

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24 
11.1 
Sample Size/Accrual Rate 
 
This BMT-specific resiliency protocol is part of a larger study across JHMI looking at resiliency 
during stressors.  We plan to recruit n=35 participants in total. Conservatively using a sample 
size of n=30 for calculations: This will give us precision of (0.80s, 1.34s) to estimate population 
standard deviation of a resiliency measure to within 95% confidence, where s is the sample 
standard deviation. The design allows for the estimation of means to within ±0.36σ with 95% 
confidence. 
 
11.2 
Subject Disposition 
 
This is not a clinical trial and therefore no treatment failure or removal criteria are specified.  As 
an observational study, data will be collected before and after a planned and clinically-indicated 
bone marrow transplant.  No subjects will be removed from the study after we obtain informed 
consent unless they expressly request that their measures not be utilized for the study.   Even if 
subjects are lost to follow up or are unable to complete subsequent evaluations due to morbidity 
or mortality and do not come back for subsequent follow up visits, partial data can be utilized to 
assess feasibility and/or predictive value of the chosen measures. 

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25 
12. APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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26 
 
 
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