Cardiovascular Reserve Evaluation in Survivors of Transplantation (CREST)
Conditions: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Hematopoietic and Lymphoid Cell Neoplasm, Hodgkin Lymphoma, Myelodysplastic Syndrome, Non-Hodgkin Lymphoma, Plasma Cell Myeloma
Sponsor: City of Hope Medical Center

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CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF OUTCOMES RESEARCH  
TITLE: Cardiovascular Reserve Evaluation in Survivors of Transplantation (CREST) 
 
CITY OF HOPE PROTOCOL NUMBER: 
IRB # 19424  
Protocol Date: 12/11/2024 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
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PRINCIPAL INVESTIGATOR: 
Saro Armenian, DO, MPH  
 
COLLABORATING INVESTIGATORS: 
Stephen Forman, MD 
Faizi Jamal, MD 
Kyuwan Lee, PhD 
Rusha Bhandari, MD 
June-Wha Rhee, MD 
Sonal Khemani, MD 
Brittany Echevarria                          Hannah Komai, NP 
 
    Molly Thornock, RN 
Itaua Leston Araujo, MD                 Andri Lemarquis, MD, PhD 
    Natalie Smith 
Jayvi Villamin                                  Louiselle David                  
    Avigail Dolleton 
Vanessa Mendoza                          Biraj Bista, MD  
 
    Deniz Urgun, MD 
Carol Canete                                   Keimya Sadeghi 
 
    Lee Jones, PhD 
 
PARTICIPATING CLINICIANS: 
Vaibhav Agrawal, MD 
Monzr Al Malki, MD 
Ibrahim Aldoss, MD 
Haris Ali, MD 
Joseph Alvarnas, MD 
Idoroenyi Amanam, MD 
Ahmed Aribi, MD 
Shukaib Arslan, MD 
Andrew Artz, MD  
John Baird MD 
Brian Ball, MD 
Pamela Becker, MD, PhD 
Amanda Blackmon DO 
Azra Borogavac, MD 
Elizabeth Budde, MD 
Ji-Lian Cai, MD 
Thai Cao, MD 
Peter Curtin, MD 
Alexey Danilov, MD, PhD 
Amrita Desai, MD 
Len Farol, MD 
James Godfrey, MD 
Scott Goldsmith, MD 
Alex Herrera, MD 
Myo Htut, MD 
Murali Janakiram, MD 
Avyakta Kallam, MD 
Swetha Kambhampati, MD 
Nicole Karras, MD 
Niloufer Khan, MD 
Paul Koller, MD 
Amrita Krishnan, MD 
Larry Kwak, MD 
Peter Lee, MD 
Joshua Mansour, MD 
Guido Marcucci, MD 
Matthew Mei, MD 
Ryotaro Nakamura, MD 
Nitya Nathwani, MD 
Liana Nikolaenko, MD 
Salman Otoukeshi, MD 
Anna Pawlowska, MD 
Tycel Phillips, MD 
Leslie Popplewell, MD 
Hoda Pourhassan, MD 
Vinod Pullarkat, MD 
Michael Rosenzweig, MD 
Firoozeh Sahebi, MD 
Amandeep Salhotra, MD 
Yazeed Samara, MD 
Karamjeet Sandhu, MD 
Geoffrey Shouse, DO 
Tanya Siddiqi, MD 
Eileen Smith, MD 
Ricardo Spielberger, MD 
Anthony Stein, MD 
Forrest Stewart, MD 
Leo Wang, MD, PhD 
Jasmine Zain, MD 
 
 
 
 
STUDY STATISTICIAN: 
Lennie Wong, PhD 
Sitong Chen 
Xinyi Du 
 
 
NON PHYSICIAN CONSENTER: 
Liezl Atencio, CCRP, CRC 
Meagan Echevarria, CRC 
Claudia Herrera, CRA 
Lanie Lindenfeld, CCRP 
 
 
Caitlyn Estrada, CRA                     Derek Lance, CRA   
Stephanie Rodarte, CRA               Emma Grigorian, CRA                            
                       
 
 

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ABSTRACT 
There are currently 200,000 hematopoietic cell transplantation (HCT) survivors in the U.S. today, 
a number that will exceed 500,000 by 2030. Despite improvements in overall survival, long-term 
HCT survivors remain at high risk for chronic health complications such as cardiovascular disease 
(CVD). Cardiovascular complications, such as myocardial infarction and cardiomyopathy/heart 
failure, are not only more common in HCT survivors, but they occur earlier than in the general 
population; in essence, HCT is associated with accelerated cardiovascular aging. However, as 
highlighted by the recent NIH HCT Late Effects Consensus Conference, the biological 
mechanisms underlying this problem remain unknown. Our overall hypothesis is that multiple 
sequential organ system and metabolic impairments sustained prior to, during, or after HCT 
accelerates depletion of cardiovascular physiologic reserves (cardiovascular reserve capacity), 
predisposing to early onset CVD. To test this hypothesis, we will measure cardiovascular reserve 
capacity in a group of HCT survivors over time. Peak oxygen consumption (VO2peak), as derived 
from cardiopulmonary exercise testing, is the gold standard measure of cardiovascular reserve 
capacity, because it represents the integrative efficiency with which multiple organ systems 
deliver and use oxygen for ATP resynthesis. Using a longitudinal study design, we will evaluate 
VO2peak at baseline (prior to HCT), 6 months, one year and two years post-HCT, allowing us to 
determine its trajectory over time. We will also determine the impact VO2peak on self-reported 
physical functioning, and identify populations at high risk for accelerated VO2peak decline after 
HCT. Importantly, we will use novel diagnostic strategies to define the organic-specific 
determinants of VO2peak and its impairment after HCT. By the end of our study, we will have: 1) 
established initial VO2peak in patients undergoing HCT and characterized its post-HCT trajectory 
over time, identifying patients at highest risk for decline after HCT; 2) informed the screening for 
subclinical CVD, using strategies that are readily applicable in the clinical setting; and 3) identified 
mechanisms by which organ-specific impairments, alone and in combination, contribute to 
abnormalities in VO2peak after HCT. This study builds on our previous successful research and will 
address important knowledge gaps about cardiovascular complications in HCT survivors. 
Information obtained from this study will support development of evidence-based interventions to 
decrease the risk of CVD after HCT. The growing population of long-term HCT survivors makes 
development of prevention strategies imperative, to ensure that these survivors live long and 
healthy lives well after completion of HCT. 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
SECTION ................................................................................................................................. PAGE 
LIST OF ABBREVIATIONS ............................................................................................................................ 4 
1.0 
PURPOSE OF STUDY ........................................................................................................................ 6 
2.0 
SPECIFIC AIMS .................................................................................................................................. 6 
2.1 
AIM 1: ........................................................................................................................................................... 6 
2.2 
AIM 2: ........................................................................................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ................................................................................................... 7 
3.1 
BURDEN OF CVD IN HCT SURVIVORS ............................................................................................................ 7 
3.2 
COMPLEX MECHANISMS OF ACCELERATED CARDIOVASCULAR AGING ........................................................ 7 
3.2.1 Multiple organ systems contribute to cardiovascular reserve capacity maintenance ................................. 8 
3.2.2 Comorbidities indirectly contribute to depletion of cardiovascular reserves. .............................................. 8 
3.3 
CARDIOPULMONARY EXERCISE TESTING (CPET) TO MEASURE CARDIOVASCULAR RESERVE CAPACITY .. 9 
4.0 
ELIGIBILITY ........................................................................................................................................ 9 
4.1 
INCLUSION CRITERIA .................................................................................................................................... 9 
4.2 
EXCLUSION CRITERIA ................................................................................................................................. 10 
5.0 
SUBJECT RECRUITMENT ............................................................................................................... 10 
5.1 
SUBJECT IDENTIFICATION AND RECRUITMENT ........................................................................................... 10 
5.2 
INFORMED CONSENT PROCESS .................................................................................................................. 10 
6.0 
METHODS .......................................................................................................................................... 11 
6.1 
ECHOCARDIOGRAPHIC EVALUATION ......................................................................................................... 14 
6.2 
SYMPTOM-LIMITED CARDIOPULMONARY EXERCISE TEST (CPET) ............................................................ 14 
6.3 
PULMONARY FUNCTION EVALUATION ......................................................................................................... 15 
6.4 
MUSCULOSKELETAL ULTRASOUND (US) EVALUATION ............................................................................. 15 
6.5  
BIOELECTRICAL IMPEDANCE ANALYSIS (BIA) ............................................................................................ 16 
6.6 
BIOLOGICAL SAMPLE COLLECTION AND PROCESSING ............................................................................... 16 
6.6.1 Peripheral blood collection ......................................................................................................................... 16 
6.6.2 Blood sample handling and processing ...................................................................................................... 17 
6.7  
FUNCTIONAL TESTING  ..................................................................................................................................... 17 
6.7.1  
30 Second Sit to Stand Test (30STS) ................................................................................................... 17 
6.7.2 2-Minute Step in Place Test (2MSPT) ......................................................................................................... 17 
6.7.3  
Timed Up and Go ............................................................................................................................... 18 
6.8  
STUDY QUESTIONNAIRE PACKET ......................................................................................................................... 18 
6.8.1 SF-36 .......................................................................................................................................................... 18 
6.8.2 FACIT-fatigue scale..................................................................................................................................... 18 
6.8.3 Godin Leisure-Time Exercise Questionnaire ............................................................................................... 18 

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6.8.4 Study-specific questionnaire ...................................................................................................................... 18 
6.8.5 Activities of Daily Living (ADL) .................................................................................................................... 18 
6.9  
KARNOFSKY PERFORMANCE RATING SCALE (KPS) .................................................................................................. 18 
7.0 
HUMAN SUBJECTS ISSUES ........................................................................................................... 18 
7.1 
POTENTIAL BENEFITS ....................................................................................................................................... 19 
7.2 
POTENTIAL RISKS ...................................................................................................................................... 19 
7.3 
ALTERNATIVES ........................................................................................................................................... 20 
7.4 
CONFIDENTIALITY ....................................................................................................................................... 20 
7.5 
FINANCIAL COMPENSATION AND OBLIGATION ........................................................................................... 20 
7.6 
INCLUSION OF WOMEN AND MINORITIES ................................................................................................... 20 
8.0 
STATISTICAL CONSIDERATIONS AND POWER CALCULATIONS ............................................ 21 
8.1 
STATISTICAL ANALYSES ............................................................................................................................. 21 
9.0  
DATA SAFETY AND MONITORING ................................................................................................. 27 
9.1 
DEFINITION OF RISK LEVEL ........................................................................................................................ 27 
9.2 
MONITORING AND PERSONNEL RESPONSIBLE FOR MONITORING ............................................................ 27 
9.3 
UNANTICIPATED PROBLEMS (UP) INVOLVING RISKS TO SUBJECTS OR OTHERS .................................... 27 
9.4 
DEVIATIONS ................................................................................................................................................ 28 
9.5 
REPORTING DEVIATIONS ........................................................................................................................... 28 
9.6 
SINGLE SUBJECT EXCEPTION (SSE) AMENDMENT REQUEST .................................................................. 28 
 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Meaning 
2MSPT 
2-Minute Step in Place Test 
30STS 
30-second sit to stand test 
ACLS 
Advanced Cardiovascular Life Support 
ACC 
American College of Cardiology 
ADL 
Activities of Daily Living 
AHA 
American Heart Association 
AR(1) 
Autoregressive one 
ASE 
American Society of Echocardiography 
BIA 
Bioelectrical Impedance Analysis 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CAPA 
Corrective and Preventative Action 
CBC 
Complete Blood Count 
COH 
City of Hope 
CPET 
Cardiopulmonary exercise testing 
CVD 
Cardiovascular disease 
CS 
Compound Symmetry 
CSA 
Cross-Sectional Area 
CRA 
Clinical Research Assistant 
DL/VA 
DLCO/Volume 
DLCO 
Carbon monoxide diffusing capacity of the lungs 
ECG 
Electrocardiogram 
EF 
Ejection fraction 
ESP 
End-Systolic Pressure 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicular stimulating hormone 
FVC 
Forced vital capacity 
GEE 
Generalized Estimating Equation 
GLM 
Generalized Linear Models 
GvHD 
Graft vs. Host Disease 
HRQOL 
Health-Related Quality Of Life 
HCT 
Hematopoietic cell transplantation 
IRB 
Institutional Review Board 
KPS 
Karnofsky performance scale 
LH 
Luteinizing hormone 
LV 
Left ventricular 
MOS 
Medical outcomes study 
MRI 
Magnetic Resonance Imaging 
O2 
Oxygen 
OR 
Odds Ratio 

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PMM 
Pattern Mixture Models 
SAE 
Serious adverse event 
SV 
Stroke Volume 
T4 
Free thyroxin 
TUG 
Timed Up and Go 
TBI 
Total body irradiation 
TLC 
Total lung capacity 
TSH 
Thyroid stimulating hormone 
UP 
Unanticipated problem 
US 
Ultrasound 
VA 
Ventricular-Arterial 
VO2peak 
Peak oxygen consumption 
VTI 
Velocity Time Integral 
 
 
 

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1.0 
PURPOSE OF STUDY  
Advances in hematopoietic cell transplantation (HCT) have led to a 10% improvement in 
survival each decade since the 1980’s.1 As a result, there are currently 200,000 HCT 
survivors in the U.S today, a number that will exceed 500,000 by 2030.2 Despite these 
improvements in survival, long-term HCT survivors remain at high risk of chronic health 
complications such as cardiovascular disease (CVD).3 Indeed, cardiovascular 
complications, including cardiomyopathy/heart failure and myocardial infarction, are not 
only more common (2-fold to 4-fold higher risk),4 but also occur significantly earlier in HCT 
survivors than in the general population;4 in essence, HCT is associated with accelerated 
cardiovascular aging. However, the pathophysiology and mechanisms underlying this 
phenomenon remain unknown. To improve the lives of HCT survivors, it is of critical 
importance to address these knowledge gaps. This will catalyze future strategies to more 
effectively monitor and treat HCT patients, and ultimately decrease the burden of CVD in 
this population. 
The cardiovascular system has an inherent reserve capacity maintained by integrative 
cross-organ function among the pulmonary, cardiac, hematologic/vascular, and 
musculoskeletal systems. Collectively, these systems possess tremendous ability to 
withstand and adapt to physiologic perturbations.5 However, reserve capacity is finite, and 
continued organ injuries can lead to cardiovascular aging.5 Our overall hypothesis is that 
repeated direct and indirect perturbations to these organ systems prior to, during, and 
shortly after HCT accelerate depletion of cardiovascular reserve capacity, resulting in 
premature onset of CVD in HCT survivors. 
Peak oxygen consumption (VO2peak), as derived from cardiopulmonary exercise testing, is 
the gold standard measure of cardiovascular reserve capacity, because it represents the 
integrative efficiency with which multiple organ systems (pulmonary, cardiac, 
hematologic/vascular, musculoskeletal) deliver and use oxygen for ATP resynthesis.6,7 
VO2peak is inversely and independently correlated with cardiovascular and all-cause 
mortality in a broad range of adult populations.6-9 Accordingly, it is used as a reliable 
endpoint to measure treatment efficacy for interventions designed to reduce CVD risk.6,8 
However, there is virtually no information on initial VO2peak in patients undergoing HCT, its 
post-HCT trajectory over time, or whether its decline has a measurable impact on health-
related quality of life (HRQOL) and CVD risk after HCT. Importantly, very little is known 
regarding organ-specific contributions to depletion of VO2peak after HCT.  
 
2.0 
SPECIFIC AIMS 
2.1 
AIM 1: Evaluate cardiovascular reserve capacity, as measured by VO2peak, in HCT 
survivors. We will measure initial VO2peak in patients prior to HCT and its post-HCT 
trajectory over time; compare VO2peak in HCT survivors at baseline (pre-HCT), 6m, 1Y, and 
2Y post-HCT to established age- and sex-normative data; and define the association 
between VO2peak and self-reported health-related quality of life (HRQOL) at baseline/over 
time. 

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2.2 
AIM 2: Define the determinants of VO2peak impairment in HCT survivors. We will use 
advanced imaging and functional measures to examine the organ-specific contributions 
to VO2peak at baseline, 6m, 1Y, and 2Y post-HCT. 
 
3.0 
BACKGROUND AND RATIONALE 
 3.1 
BURDEN OF CVD IN HCT SURVIVORS 
Cardiovascular disease (CVD) and cardiovascular aging are important problems in long-term 
hematopoietic cell transplantation (HCT) survivors. Despite improvements in long-term outcomes, 
HCT survivors continue to have substantially higher mortality rates compared with the general 
population.10-12 In particular, the risk of cardiovascular-related mortality is more than twice that of 
the general population,11-13 and the magnitude of risk increases with time from HCT.13 However, 
examining CVD-associated mortality alone underestimates the true burden of CVD morbidities 
after HCT. HCT survivors have a 4-fold higher risk of developing CVD compared to the general 
population,14 adding to the already high burden of chronic health-related conditions in these 
survivors.15 Among HCT survivors, median age at first cardiovascular event such as myocardial 
infarction is 53 years (range 35–66 years),16 much lower than would be expected in the general 
population (67 years).17 The markedly increased risk of CVD, coupled with the development of 
complications earlier than would be expected in the general population, suggests the presence of 
an accelerated cardiovascular aging phenotype in HCT survivors. 
3.2 
COMPLEX MECHANISMS OF ACCELERATED CARDIOVASCULAR AGING 
Complex mechanisms contribute to accelerated cardiovascular aging. Biologic aging involves 
multiple complex changes in structure and function that lead to decreased reserve capacity across 
virtually all organ systems, with increased vulnerability to age-related diseases.5 Similarly, we can 
envision CVD as being induced by sequential and concurrent pathologic perturbations to the 
organ systems that maintain cardiovascular reserve: pulmonary, cardiac, hematologic/vascular, 
and musculoskeletal. Injury to one or more of these systems is initially offset by a compensatory 
response in others (e.g. activation of the renin-angiotensin system to enhance stroke volume (SV) 
during cardiac dysfunction, or increase in hemoglobin during chronic hypoxemia), a process 
termed coordinated adaptation. However, continued direct or indirect injuries to these 
systems over time results in a decline in cardiovascular reserve capacity (Figures 1-2),  
which in turn drives accelerated cardiovascular aging.5,18 
The following preliminary studies provide the scientific premise for studying impaired 

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cardiovascular reserve and accelerated cardiovascular aging in HCT survivors 
3.2.1 Multiple organ systems contribute to cardiovascular reserve capacity maintenance 
Pulmonary: Nearly half of all patients undergoing allogeneic HCT will develop acute pulmonary 
toxicity, and pulmonary complications account for up to 40% of transplant-related deaths within 
the first year after HCT.19,20 Pulmonary complications can be due to injuries sustained during HCT 
(conditioning chemotherapy, total body irradiation [TBI], infection) or non-infectious complications 
that develop after HCT (e.g. bronchiolitis obliterans, idiopathic pneumonia syndrome).20 In a 
recently completed study, we showed a high prevalence (35%) of diffusion capacity defects in 
HCT survivors, corresponding to a greater than five-fold risk compared to age-matched non-
cancer controls (OR: 5.2, p<0.01).21 
Cardiac: It is well-established that cancer treatments involving the heart can lead to physiologic 
alterations in the heart and its blood vessels.4 Anthracycline cardiotoxicity is related to myocardial 
injury through generation of damaging free radicals and intracardiac metabolic derangements.22 
For HCT survivors treated with anthracyclines prior to HCT, additional exposures such as high-
dose cyclophosphamide during conditioning may further compromise cardiomyocyte architecture 
and function.4 We have shown that cumulative anthracycline dose ≥250 mg/m2 is associated with 
a ten-fold risk of heart failure in HCT survivors (odds ratio [OR]=9.9, p<0.01),23 a dose threshold 
that is markedly lower than conventionally recognized cutoffs (350–450 mg/m2) in non-HCT 
cancer populations.24 Radiation can cause direct myocardial injury, or result in endothelial cell 
proliferation and atherosclerosis.25 Among allogeneic HCT patients, graft versus host disease 
(GvHD) can lead to additional microvessel disease, due to endothelial infiltration of alloreactive 
cytotoxic T lymphocytes,26 suggesting an immunological mechanism for accelerated arterial 
disease.26 
Musculoskeletal: Chronic corticosteroid exposure, TBI, prolonged inactivity, or poor nutritional 
status can lead to abnormal body composition that manifests as an increase in total percent fat 
mass and a reduction in muscle mass (sarcopenia).27 We have shown that pre-HCT sarcopenia 
is associated with increased risk of CVD-related and non-relapse mortality in HCT survivors.28 
Moreover, patients who survive HCT often do not adhere to national exercise recommendations, 
and have significant declines in physical activity levels from pre-to-post HCT.29 Patients with 
GvHD are more likely to demonstrate physical inactivity due to the disproportionate muscle 
atrophy seen in lower extremity and back extensor muscles. In HCT survivors, physical inactivity 
combined with reduction in muscle mass can compromise the efficiency of capillary transport and 
utilization of oxygen (O2), contributing to additional impairments in cardiovascular reserve.29 
Hematologic: Persistent post-HCT abnormalities such as myelodysplastic syndrome, 
myelofibrosis, or bone marrow failure,20 while rare, may further contribute to decline in 
cardiovascular reserve over time. 
3.2.2 Comorbidities indirectly contribute to depletion of cardiovascular reserves. 
Traditional cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia are 
important modifiers of CVD risk in the general population.17 We have shown that nearly one-third 
of HCT survivors (32%) have multiple (≥2) cardiovascular risk factors, compared to only 21% in 
the general population,30 and that each risk factor confers an incremental risk of CVD over time 
(10-year incidence of CVD: 4% [no risk factor], 7% [one], 11% [at least two]; p<0.01). CVD 

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incidence is highest (15%) among HCT survivors with multiple risk factors who had also been 
exposed to cardiotoxic therapies. Other health conditions such as thyroid dysfunction, chronic 
kidney disease, and gonadal dysfunction are established CVD risk factors in the general 
population,17 and are highly prevalent in HCT survivors.3 There is a paucity of information 
regarding the contribution of these conditions to long-term CVD risk in HCT patients, a knowledge 
gap we will address in the current study. 
Taken together, these findings support our overall hypothesis is that repeated direct and indirect 
perturbations to these organ systems prior to, during, and shortly after HCT accelerate depletion 
of cardiovascular reserve capacity, resulting in premature onset of CVD in HCT survivors. 
3.3 
CARDIOPULMONARY EXERCISE TESTING (CPET) TO MEASURE CARDIOVASCULAR RESERVE 
CAPACITY 
VO2peak is an optimal measurement of cardiovascular reserve capacity. In clinical practice, 
cardiovascular function is almost exclusively determined via resting assessment of cardiac left 
ventricular ejection fraction (EF). However, resting EF provides only a snapshot of the heart’s 
performance under optimal circumstances, and is a poor prognosticator of future cardiovascular 
events or mortality in patients undergoing HCT.18,31 Importantly, EF does not provide information 
on the functional integrity of other organ systems involved in maintaining cardiovascular 
reserve.32-34 A better measure of cardiovascular reserve is VO2peak, a measurement of 
cardiopulmonary function that represents maximal O2 uptake capacity. Indeed, VO2peak derived 
from cardiopulmonary exercise testing (CPET) is the gold standard measure of cardiovascular 
reserve because it represents the integrative efficiency with which multiple organ systems 
(pulmonary, cardiac, hematologic/vascular, and musculoskeletal) deliver and use O2 for ATP 
synthesis. 
VO2peak is reduced in cancer patients. VO2peak was evaluated in colorectal cancer (CRC) 
patients without CVD and matched controls.35 In CRC patients, mean VO2peak was 23% below that 
of controls, despite the presence of comparable resting EF (EF: 59% [CRC] vs. 62% [controls]).35 
Interestingly, even chemotherapy-naïve patients with CRC had significantly lower VO2peak when 
compared to controls (23.4 ml/kg/min vs. 28.0 ml/kg/min, p<0.01),35 underscoring the message 
that reduced VO2peak may be a hallmark of both the cancer and the treatments used for curative 
intent. In breast cancer patients, anthracycline chemotherapy, chest radiation, and anti-Her2 
therapy contribute to an increased risk of CVD, compared to women without cancer.36-38 In fact, 
CVD is now the leading cause of mortality in older women (>50 years) with early stage disease.37 
In a study of 248 breast cancer patients with normal resting cardiac function (EF ≥50%), VO2peak 
was on average 27% less than that of age-matched sedentary women without a history of cancer.9 
Remarkably, the study found that patients with breast cancer reached a predicted VO2peak for a 
particular age group (e.g. 40 years) approximately 20 to 30 years earlier than healthy women 
without a history of breast cancer.9 
4.0 
ELIGIBILITY 
4.1 
INCLUSION CRITERIA  
The subject must meet all criteria below to qualify for a screening visit: 
• 
Age at HCT ≥ 18 years 

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• 
Diagnosis of Acute Leukemia (myeloid, lymphoid), Lymphoma (non-Hodgkin, 
Hodgkin), Multiple Myeloma or Myelodysplastic Syndromes.  
• 
Planning to undergo first autologous or allogeneic transplant. 
• 
Able to read, understand and write in English or Spanish. 
• 
Able to understand and sign the study specific Informed Consent Form (ICF) 
• 
Physically able and willing to complete all study procedures. 
4.2 
EXCLUSION CRITERIA 
The following are absolute contraindications to cardiopulmonary exercise testing: 
• 
Unstable bone lesions per electronic medical record review and/or notification from 
patient’s primary physician 
• 
Unstable angina or history of acute myocardial Infarction (< 5 days of any planned 
study procedures) 
• 
Recurrent syncope 
• 
Acute myocarditis or pericarditis 
• 
Symptomatic severe aortic stenosis 
• 
Uncontrolled arrhythmia causing symptoms 
• 
Pulmonary embolus < 3 month of study procedures 
• 
Thrombosis of lower extremities 
• 
Moderate or Severe Persistent asthma (National Asthma Education & Prevention) 
• 
Room air desaturation at rest ≤ 85% 
• 
Non-cardiopulmonary disorders that may affect exercise performance or be 
aggravated by exercise (i.e. infection, renal failure, thyrotoxicosis) 
• 
Anemia (Hgb <8 g/dL) on the day of the cardiopulmonary exercise test 
5.0 
SUBJECT RECRUITMENT 
5.1 
SUBJECT IDENTIFICATION AND RECRUITMENT 
Eligible patients will be identified and recruited at COH from existing databases, referrals and 
EMR reports, using the inclusion criteria outlined in Section 4.1. Study staff will pre-screen each 
individual by reviewing the medical charts and will exclude anyone with conditions or reasons that 
may prohibit study entry. To ensure that participants enrolled on the current study reflect the 
demographics of all eligible patients, we will recruit patients stratified by key variables (age at 
recruitment, sex, diagnosis, HCT type [auto/allo]). After preliminary determination of eligibility, the 
patient’s primary physician will be contacted for permission to approach the patient. 
5.2 
INFORMED CONSENT PROCESS 
After identifying a patient, informed consent will be obtained in person or via mail, electronic mail, 
or other electronic applications (i.e. DocuSign™,) to obtain electronic signatures from each patient 
per standard practice. At the time of consent, the study will be reviewed with the subject either by 
a study investigator or clinician or by a specially trained clinical research staff member who will 
answer any questions that the subject may have prior to signing consent. Informed consent will 
be obtained from each subject who agrees to participate. The investigational nature and 
objectives of the study, the procedures involved, and their possible risks and discomforts will be 
carefully explained while obtaining informed consent. Subjects that agree to participate will be 

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given a signed copy of the consent form and experimental subjects’ bill of rights to keep. The 
Principal Investigator will be available to speak to the subject in the event that the subject asks a 
question that the consenter is unable to answer or if the subject requests to speak with the 
Principal Investigator. 
6.0 
METHODS 
The screening process will begin after the subject signs the informed consent and bill of rights. 
The research team will review the physical examinations conducted by the participants primary 
hematologist prior to each CPET to access physical ability. The study participants will be asked 
a few questions focusing on signs and symptoms outlined in Section 4.2.  
Participants who do not pass the screening procedure will be deemed as “screen fail” and will not 
be enrolled to the study.  
Participants that do pass the screening procedure will be enrolled to the study and will complete 
the following study procedures: 
1) Echocardiographic evaluation (Section 6.1) 
2) Symptom-limited cardiopulmonary exercise test w/ 12-lead 
electrocardiography (Section 6.2) 
3) Pulmonary function evaluation (Section 6.3) 
4) Musculoskeletal ultrasound (Section 6.4) 
5) Bioelectrical impedance analysis (BIA) (Section 6.5) 
6) Blood draw for CBC and study evaluations (Section 6.6) 
7) Functional Testing (Section 6.7) 
8) Study questionnaire packet to assess/obtain information on (Section 6.8)   
a. Quality of life (SF-36) 
b. Fatigue (FACIT-fatigue scale) 
c. Exercise (Godin Leisure-Time Exercise Questionnaire)  
d. Demographics, family history, comorbidities, and lifestyle behavior 
e. Activities of Daily Living (ADL) 
9) Karnofsky Performance Scale (KFS) (Section 6.9) 
All study measurements and assessments do not need be in sequential order nor be completed 
on the same day. All pre-HCT testing should be performed ≤ 60 days from the start of conditioning 
therapy. In the case that a participant completes study procedures and their transplant is 
subsequently delayed, the participant will be asked to repeat the study procedures if the first set 
of procedures are outside the 60-day window. If repeating study procedures is not feasible based 
on physician discretion, then we will utilize the most recent set of study procedures for analysis. 
For subsequent 6M, 1Y and 2Y post-transplant time points study participants will be allowed ±6 
weeks from the expected date to complete the time point. In addition, if the participant is physically 
unable or unwilling to complete all study procedures at the subsequent time points, we will ask 

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them to complete as many study measurements and assessments listed above as possible. For 
the post-HCT timepoint, the subjects may be asked to repeat any of the study procedures within 
that timepoint if the physician determines it is necessary for safety and screening purposes. If the 
participant tests positive for COVID-19 or has a medical condition that has to be resolved during 
the ±6 week window, an extension of 4 weeks will be added to the end of the procedure window 
to allow time for the participant to fully recover and to be compliant with all City of Hope policy 
and procedures for testing. 
 
 

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Study Calendar: 
 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
 
 
Screening* 
 
Pre-HCT 
6 mo 
Post-HCT 
1 yr 
Post-HCT 
2 yr 
Post-HCT 
Sign Consent 
X 
- 
- 
- 
- 
Screening Questions 
X 
X 
X 
X 
X 
Pulse Oximeter Reading 
 
X 
X 
X 
X 
Blood Test 
 
X 
X 
X 
X 
Echocardiogram 
 
X 
X 
X 
X 
Musculoskeletal Ultrasound  
 
X 
X 
X 
X 
Bioelectrical Impedance 
Analysis (BIA) 
 
X 
X 
X 
X 
Pulmonary Function Test 
 
X 
X 
X 
X 
Electrocardiogram  
 
X 
X 
X 
X 
Vitals and Physical 
Examination** 
 
X 
X 
X 
X 
Cardiopulmonary Exercise 
Test (CPET)**** 
 
X*** 
X 
X 
X 
Functional Testing 
 
X 
X 
X 
X 
Questionnaires-Overall 
health, fatigue and physical 
activity  
 
X 
X 
X 
X 
*Screening procedures may be completed on the same day as Visit 1 Pre-HCT.  
** Physical examination will be completed by the patient’s primary oncologist. 
*** If PI requested, Hemoglobin Test will be done prior to beginning the CPET.  
**** If PI requested, any study procedure may be repeated within a timepoint for safety and screening 
purposes. 
 

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6.1 
ECHOCARDIOGRAPHIC EVALUATION 
We will assess cardiac function and mechanics using comprehensive 2D echocardiography 
with Doppler imaging. Cardiac structure and function will be quantified at rest and peak stress as 
recommended by the American Society of Echocardiography (ASE).39,40 For consistency and 
reproducibility, we will acquire and perform all measurements using an established research 
protocol. We successfully used this research protocol to evaluate cardiac function in cancer 
survivors (R01CA196854, R21CA178344 [S. Armenian]) and demonstrated excellent inter-
observer correlation (range 0.94–0.97).41 We will record heart rate, quantify LV volumes in systole 
and diastole in the apical 4- and 2-chamber views in triplicate using the biplane method of discs 
to calculate EF, as recommended by the ASE.42 At rest and peak stress, we will estimate SV 
using the equation: SV = (LV outflow tract diameter/2)2 × LV outflow tract velocity time integral 
(VTI). We will also derive effective arterial elastance (Ea), end-systolic elastance (Ees), and Ea/Ees. 
Ea, which is a measure of systemic arterial stiffness, will be estimated as end-systolic pressure 
(ESP)/SV, and ESP will be estimated as 0.90 x systolic pressure, obtained by blood pressure 
(BP) cuff at the time of the echo. Ees is a measure of LV contractility, and will be derived using a 
modified single-beat algorithm using BP, SV, pre-ejection and total systolic ejection timing 
intervals.43 VA coupling provides insight into chamber efficiency and is also predictive of cardiac 
dysfunction and will be indexed by the ratio Ea/Ees. Quantifying these parameters while 
concomitantly measuring VO2peak permits dissection of each component of the Fick Equation 
(VO2peak = AVO2D X Cardiac Output; Cardiac Output = Heart rate x SV). We will also obtain 
detailed measures of LV diastolic function, including pulsed Doppler measurement of mitral valve 
inflow, peak velocities of early filling (E-wave) and filling during atrial systole (A-wave), mitral 
annular myocardial e’ and a’ velocities, mitral E/A and E/e’ ratios, and mitral deceleration time. 
We will evaluate peak systolic strain using commercially available analysis software (EchoPAC 
vBT08; GE Healthcare, USA). Measurements will include peak longitudinal (global and all LV 
segments), as well as regional and global circumferential strain.44 These will be used in secondary 
analyses to determine their relationships with VO2peak. 
6.2 
SYMPTOM-LIMITED CARDIOPULMONARY EXERCISE TEST (CPET) 
Evaluate peak O2 consumption (VO2peak) using an electronically braked cycle ergometer with 
breath-by-breath expired gas analysis. If PI requested, prior to beginning the test for the pre-HCT 
visit, a member of the study team will check the patients’ hemoglobin using the Germaine™ Hb 
Hemoglobin (Hb) Test System analyzer and blood will be collected via a finger stick. After 
recording resting metabolic data, participants will begin a 1-minute period of unloaded exercise, 
followed by a continuous incremental ramp increase of 5-30 W/min until volitional exhaustion or 
until a symptom limitation is achieved.6 VO2peak will be defined as the highest VO2 value for a given 
30-second interval within the last 60 seconds of exercise.45 During exercise, we will monitor O2 
saturation continuously, while blood pressure will be measured using an automated 
sphygmomanometer.6 Acceptable test criteria for this assessment will include any of the following: 
1) a plateau in O2 consumption concurrent with increased power output, 2) an RER >1.1, 3) 85% 
predicted maximal HR is achieved, or 4) peak exercise ventilation approaches or exceeds 
maximal ventilatory capacity.6,46 Tests in which these parameters are not achieved will be 
excluded. VO2peak will be defined as the highest VO2 value for a given 30-second interval within 
the last 60 seconds of exercise.45,46 Gas exchange, HR, and ECG monitoring will continue for 5 
minutes of recovery (2 minutes active recovery followed by 3 minutes passive recovery) to permit 
derivation of exercise recovery patterns that have recently been shown to be highly prognostic in 
patients with established CVD.47 This protocol has been demonstrated to be appropriate for 

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measuring VO2peak in studies of early- and advanced-stage cancer patients,8,48 and has been 
successfully implemented in our recent feasibility trial in HCT survivors.49 Participants will be 
monitored continuously with an electrocardiogram (ECG) during exercise and recovery.  
All COH personnel who administer the test are trained to read exercise ECGs and are trained in 
Advanced Cardiovascular Life Support.If we observe any ECG abnormalities either prior to, 
during, or after the exercise test, suggestive of ischemia or malignant arrhythmia, all procedures 
will be stopped. At this point, a staff cardiologist will review the ECG to determine the appropriate 
course of action. The participant will not be allowed to leave the facility until such an examination 
has been performed. We will define severe adverse events (SAEs) as the occurrence of: (1) 
sustained ventricular tachycardia, (2) myocardial ischemia, (3) syncope, (4) provision of cardiac 
life support medications, (5) direct admission to emergency room/equivalent, or (6) death. Of note, 
the reported incidence of SAEs during CPET ranges from 0.001% to 0.01%.6 Criteria for ischemic 
changes in ECG will include 0.1 mV deviation of the ST segment horizontal to/away from the 
baseline isoelectric line at 0.08 seconds after the J-point in the absence of significant resting ST-
T abnormalities. 
CPET-derived measures to be obtained: We will apply an integrative approach that includes 
(1) assessment of the overall quality of the test, subject effort, and reasons for stopping, (2) 
tabulation and graphical depiction of the key data to determine whether obtained data is normal 
or abnormal, with comparison to appropriate reference values,46 (3) use CPET measures to 
determine causes of exercise limitation and patterns of exercise response; this will be done by 
plotting the cardiopulmonary response of each patient using outcomes per established 
guidelines.46 The plots will include but are not limited to: 1) VO2 (x-axis) versus: VT, fR, HR, VCO2; 
VE/VO2; PETO2 and PETCO2; 2) WR (x-axis) versus VO2; 3) VE (x-axis) versus WR, VO2, VCO2. We 
will use information obtained from arterial blood gas analysis (e.g. pH, arterial oxygen pressure 
(PaO2) and oxygen saturation (SaO2), alveolar-arterial difference for O2 pressure (P[A-a]O2), ratio 
of physiologic dead space to tidal volume (VD/VT) to examine efficiency of pulmonary gas 
exchange, as well as for potential underlying acid-base imbalance.46  
6.3 
PULMONARY FUNCTION EVALUATION 
Pulmonary function testing (PFT) will be per American Thoracic Society recommendations.50,51 
Measurements will include spirometry; lung volumes; diffusion capacity; total lung capacity (TLC); 
forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1/FVC ratio; 
diffusing capacity of the lungs corrected for hemoglobin content (DLCOcorr), and DLCO/volume 
of air (DL/VA). We will calculate percent of predicted normal values using reference values for 
adults ≥18y.50,51 For each patient we will integrate PFT data with measurements of minute 
ventilation and ventilator efficiency to determine breathing reserve and whether subjects encroach 
on a pulmonary mechanical limit to exercise. 
6.4 
MUSCULOSKELETAL ULTRASOUND (US) EVALUATION  
Quantification of lower extremity skeletal muscle cross-sectional area (CSA) and volume will be 
assessed by musculoskeletal ultrasound. The decision to use musculoskeletal ultrasound was 
founded on concerns regarding the prohibitive costs of magnetic resonance imaging (MRI) for 
population-based screening, and to remove the radiation exposure from a dual energy x-ray 
absorptiometry. The skeletal muscle cross-sectional area will be evaluated using an ultrasound 
machine and probe (GE LOGIQ E, USA). The device will be calibrated prior to each use to ensure 
accuracy. Additionally, we will  use  standard of care CT scans obtained as part of pre-HCT 

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treatment response assessment to retrospectively measure body muscle quantity and quality 
using a validated software (Data Analysis Facilitation Suite (DAFS).52 
6.5  
BIOELECTRICAL IMPEDANCE ANALYSIS (BIA) 
Body composition (total lean body mass and percent body fat) will be measured using bioelectrical 
impedance analysis (BIA). Participants stand on the bioelectrical impedance scale with bare feet 
in contact with the electrode foot pads and hands holding the hand electrode. Body weight will be 
measured by the device followed by body composition. The device will be calibrated prior to each 
analysis to ensure accuracy. Participants will be asked to remove any wearable metal prior to 
each assessment. Participants with an implantable defibrillator or pacemaker will not undergo the 
BIA procedure. 
6.6 
BIOLOGICAL SAMPLE COLLECTION AND PROCESSING 
6.6.1 Peripheral blood collection 
Peripheral blood collection, processing, and reporting 
Approximately 15 mL of peripheral blood will be procured at baseline and during the subsequent 
6M, 1Y and 2Y post-transplant time points. Within a timepoint, an additional draw of approximately 
15 mL of peripheral blood will be requested if the physician determines it is necessary for safety 
and screening purposes prior to the CPET. For each study-related lab draw, the following tests 
will be run in real time: complete blood count (CBC), lipid panel, hemoglobin A1-C, thyroid 
stimulating hormone (TSH), free thyroxin (T4), luteinizing hormone (LH), follicular stimulating 
hormone (FSH) and testosterone. We recognize that emerging blood biomarkers of aging (e.g. 
clonal hematopoiesis, DNA methylation)53-56 may provide additional insight into the trajectory of 
cardiovascular aging in these patients. As such, approximately 5 mL of blood will be drawn during 
each study-related blood collection into a 6-mL lavender-top tube for future correlative and 
exploratory analyses. Further details below: 
To better understand serum markers correlating with cardiotoxicity and/or depletion of CVRD in 
HCT survivors, we plan to conduct multiomics analysis (e.g. proteomics, metabolomics) of the 
longitudinally collected plasma samples in this study. De-identified plasma samples of the 
participants eligible for the analysis will be shipped to the Sapient laboratory (10421 Wateridge 
Circle, Suite 100, San Diego, CA 92121) for metabolomic profiling and the Pfizer/Azenta Life 
Sciences laboratory (2910 Fortune Circle West, Suite E, Indianapolis, IN, 46241, USA) for 
proteomics profiling. The results will be returned to City of Hope and will be analyzed and 
interpreted to identify novel sensitive serum markers for cardiotoxicity. Leftover samples will be 
destroyed or returned to City of Hope. 
To better understand delayed T-cell immune reconstitution and/or lack of T-cell production 
correlating with depletion of CVRD and accelerated cardiovascular aging in HCT survivors, we 
plan to measure T Cell Receptor Excision Circles (TRECs) pre and post-HCT. TRECs are 
byproducts of the rearrangement of the DNA at the T cell receptor locus, as a result of combining 
TCR chains (Alpha & beta). In addition to using the TREC multi-step technique in measuring TCR 
combination, a highly sensitive digital PCR (dPCR) will be used to detect low concentrations of 
DNA target within a single analysis. Lastly, a newly designed tool combining these 2 metions 
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fluorophores using the Integrated DNA Technologies (IDT) OligoAnalyzer™ 3.1 program and the 
Bio-Rad QX600 ddPCR recommendations will be used as well.   
 
If sufficient biological material for anything mentioned above is not obtained for any reason, a 
leftover sample will be requested and obtained from linked study, IRB#00029 Long-term follow-
up following Hematopoietic cell transplanation and cellular therapy, if available.  
 
 
6.6.2 Blood sample handling, processing and storage 
Immediately after blood collection, the 6-mL lavender-top tube should be inverted 8-10 times to 
gently mix the blood in EDTA. Study staff will transport the blood within approximately 24 hours 
of collection at room temperature to the Outcomes Research laboratory for processing and 
storage. Plasma and buffy coat samples will be prepared by spinning the tube in a balanced 
centrifuge at 1200 x g for 10-15 min. Plasma is aliquoted into up to 5 study-labeled cryovials with 
approximately 0.5 mL in each aliquot and the buffy coat will be collected in 1 study-labeled 
cryovial. If there is not enough plasma to store 0.5 mL in each aliquot, 3 aliquots will contain 
approximately 0.5 mL and the remaining 2 aliquots will contain approximately 0.25mL. Aliquots 
will be labeled with study IRB number, study specific participant ID, date of blood draw, “Plasma 
EDTA” or “Buffy Coat EDTA”, and aliquot number (1-5) using permanent marker or preprinted 
freezer-ready labels. Samples will be stored in a -80 freezer located in Furth Lab immediately 
after processing. 
6.7  
FUNCTIONAL TESTING   
6.7.1  30 Second Sit to Stand Test (30STS) 
The 30-second sit to stand test is a test that has been used to indicate functional status of patients 
with cancer, cardiovascular diseases as well as chronic obstructive pulmonary disease patients. 
It is highly correlated with VO2peak obtained via CPET. This test will be performed with a stable 
chair that is prevented from sliding backwards. Participants will be instructed to sit in the middle 
of the chair, with their hands on the opposite shoulders, crossed at the wrists. Participants will be 
instructed to keep their feet flat on the floor and to keep their back straight, with arms against the 
chest. On “ready, go” the participants will be asked to rise to a full standing position and then sit 
back down, repeating this standing-sitting action for as many times as possible in 30 seconds. 
The number of repetitions of full sit-to-stand motions completed in 30 seconds will be recorded.  
6.7.2 2-Minute Step in Place Test (2MSPT)  
The 2-minute step in place test is a test that measures aerobic endurance. The participants will 
be asked to stand up straight next to the wall while a mark is placed on the wall at the level 
corresponding to midway between the patella (kneecap) and iliac crest (top of the hip bone). 
The participants then march in place for two minutes, lifting the knees to the height of the mark 
on the wall. The number of steps in which the participants reach the marked level on the wall in 
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6.7.3  Timed Up and Go (TUG) 
Timed Up and Go is a performance test of physical mobility. The test measures how many 
seconds it takes an individual to stand up from a standard armchair (approximate seat height of 
46 cm), walk a distance of 10 ft, turn, walk back to the chair, and sit down again. The time it takes 
for participants to perform this test will be recorded.  
6.8  
STUDY QUESTIONNAIRE PACKET  
The questionnaires will be self-administered or administered by the study staff. 
6.8.1 SF-36 is a patient-reported outcome measure that quantifies health status and 
measures health-related quality of life.  
6.8.2 FACIT-fatigue scale is a 13-item instrument designed to assess fatigue/ tiredness and 
its impact on daily activities and functioning.  
6.8.3 Godin Leisure-Time Exercise Questionnaire will assess physical activity level by 
asking “During a typical 7-Day period, how many times on average do you do the 
following kinds of exercise for more than 15 minutes during your free time?”  
6.8.4 Study-specific questionnaire will obtain data on demographics, family history, current 
medications, 
lifestyle 
behaviors 
(exercise 
[Godin 
Leisure-Time 
Exercise 
Questionnaire]57, alcohol and tobacco use), and history of other cardiovascular risk 
factors and other comorbidities (hypertension, diabetes, dyslipidemia, chronic renal 
disease, thyroid disorder, hypogonadism. 
6.8.5 Activities of Daily Living (ADL) is a subscale of the Medical Outcomes Study (MOS) 
Physical Health. The MOS Physical Health Scale measures a broad range of physical 
functioning, with questions ranging from “Can you bathe and dress yourself?” to “Can 
you perform vigorous activities, such as running or lifting heavy objects?” Items are 
rated on a 3-point Likert scale measuring independence in performing the activity. 
6.9  
KARNOFSKY PERFORMANCE RATING SCALE (KPS)  
KPS is a general measure of patient independence in carrying out normal activities and self-care 
needs (score: 0-100) and is a global indicator of functional status. 
7.0 
DATA COLLECTION 
 
Additional data, such as therapeutic exposures and related variables, will be collected through 
medical record abstraction and gathered by completing a Therapeutic Summary form. 
Information will be recorded up to the completed 2-year time point or the date of the first relapse 
post-HCT. 
Data may also be obtained from linked studies. Only data variables approved for collection 
under these linked studies will be obtained. Study linkages are specified under the "Research 
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8.0 
HUMAN SUBJECTS ISSUES 
8.1 
POTENTIAL BENEFITS 
Subjects will not receive any additional benefit from participating in the current protocol. The 
knowledge gained from the current study may be used to develop more comprehensive screening 
strategies in at-risk populations, as well as assist in the development of novel endpoints to be 
used in intervention studies to improve cardiovascular reserve capacity. 
8.2 
POTENTIAL RISKS 
The eligibility criteria and screening procedures for the current study have been established to 
exclude individuals for whom graded exercise testing, echocardiography, pulmonary function 
testing, and blood collection, and are not appropriate. Next, the primary physician at City of Hope 
will be contacted to obtain approval to approach their patients and to potentially identify patients 
who may not be eligible for any other reasons. Finally, in-person assessments will be performed 
by the study staff to screen/verify participants for cardiovascular or ECG contraindications on a 
symptom-limited graded exercise test. This multi-gated comprehensive approach should 
systematically identify and screen out any individual for whom this study is contraindicated. 
For the subsequent visits (6M, 1Y, 2Y), study participants will be re-screened to look for any 
conditions or reasons that may prohibit them from undergoing study diagnostics. 
Anticipated (expected) side-effects associated with symptom-limited CPET include (5-10% of 
individuals)6,58 fatigue, muscle soreness, joint pain, lower back pain, and leg cramps. 
Unanticipated but possible side-effects that are rare (0.001%-0.01%),6,59 but serious include: 
angina, arrhythmias, myocardial ischemia, sudden cardiac death, and cerebrovascular accident. 
As detailed above, all study participants will be closely monitored by experienced personnel who 
have received training in ACLS, or Pediatric Advanced Life Support (PALS). Both of these 
American Heart Association certifications are designed to give you the knowledge, skills, and 
confidence needed to successfully provide life-saving interventions in emergency situations. If 
any ECG abnormalities are observed either prior to, during, or after the exercise test, all 
procedures will be immediately stopped. At this point, the staff cardiologist will be asked to review 
the ECG to determine the appropriate course of action. The participant will not be allowed to leave 
the facility until such an examination has been performed by a cardiologist. 
Additional protection against risk: Strategies to protect against risk are discussed above 
(Potential Risks), as part of a preemptive strategy to address participant safety. Of note, we 
previously evaluated the feasibility of CPET, along with resting measures cardiovascular and 
pulmonary health in twenty (10 allogeneic, 10 autologous) HCT survivors at COH (P30 CA33572, 
[Project PI: S. Armenian]). Participation rate was 87%, median time from HCT: 9.8 years (range 
2-20 years), median age at assessment: 57 years (range 38-75 years), and median Karnofsky 
Performance: 90 (range 70–100). All participants successfully completed the study tests including 
CPET, echocardiogram with strain, PFT, neuromuscular and functional assessment (, 30 second 
sit to stand test, 2 minute step in place test, timed up and go), and patient-reported outcomes 
(activities of daily living subscale, fatigue, sleep, quality of life). Importantly, there were no adverse 
events reported during CPET testing, and all studies were considered adequate for interpretation 
(reached 80% of maximal heart rate and respiratory exchange ratio >1.1 in all participants). We 
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HCT; 86% of participants successfully completed both baseline (pre-HCT) and 6-month measures 
outlined in the current study, including arterial blood gas testing.60 No unanticipated adverse 
events were reported in our most recent feasibility study. 
In order to protect participants from any potential risks associated with the current study, the 
following assurances will be adhered to: (1) participation is voluntary and consent to participate 
can be withdrawn at any point within the study without penalty, (2) prospective participants who 
do not wish to volunteer for the current study will not lose their access to medical services at COH, 
(3) all participants will be informed of foreseeable benefits and risks, (4) all data collected from 
participants or via medical chart review will be stored in a secure computer network folder and/or 
locked file cabinet(s), (5) participants will be informed that they have the right to refuse to continue 
their participation without penalty if they experience significant emotional discomfort, or for any 
other personal reason. If significant distress is evident during the course of the study, participants 
will be encouraged to seek appropriate treatment, and a list of referrals will be provided as 
needed. 
8.3 
ALTERNATIVES 
The subject may choose not to participate in the study.  
8.4 
CONFIDENTIALITY 
All data collection will remain confidential. All database records require a password in order to 
access data. Only personnel directly involved with the study will have access to the database. 
Any paper records will be kept in a secure locked cabinet in an access-controlled building. All 
study electronic files will be kept in access-controlled files on the COH server. Subject data in 
published study results will not include personal identifiers. 
8.5 
FINANCIAL COMPENSATION AND OBLIGATION 
There is no charge for participation in this study; all procedures will be covered through grant 
funding. All study participants will receive a $200 gift card at each time point, which will be 
provided following completion of study testing procedures. In the event that a participant is asked 
to repeat study procedures for a specific time point, they will receive an additional $200 as 
compensation for their time and effort. In addition, if a participant lives more than 30 miles from 
the Duarte campus they will also receive a $25 gas card to compensate for the distance traveled. 
The participant may opt out of receiving the financial compensation; however, this option will not 
be offered to the participant unless he or she requests not to receive any compensation. If the 
participant is unable or unwilling to complete all study procedures for a time point, but completes 
at least one of the study procedures listed in Section 6.0, the participant will still receive the study 
compensation. 
8.6 
INCLUSION OF WOMEN AND MINORITIES 
The study will be open to all individuals meeting the eligibility criteria regardless of gender or 
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9.0 
STATISTICAL CONSIDERATIONS AND POWER CALCULATIONS 
9.1 
STATISTICAL ANALYSES 
We will generate descriptive statistics for participants’ demographics (age, sex, race/ethnicity), 
lifestyle behaviors (physical activity, tobacco use), family history of CVD, and history of 
cardiovascular risk factors and other comorbidities (hypertension, diabetes, dyslipidemia, chronic 
renal disease, thyroid disorder, hypogonadism). We will obtain tobacco use history, collect a lipid 
panel and blood pressure, and calculate the American College of Cardiology/American Heart 
Association (ACC/AHA) CVD Risk Score for all participants. We will perform analyses to describe 
pre-HCT and HCT-related therapeutic exposures and complications (e.g. GvHD). We will assess 
participation bias by comparing demographic (age, gender, race/ethnicity) and treatment-related 
exposures (diagnosis, pre-HCT and HCT-related therapeutic exposures, type of HCT) among 
participants and non-participants. A two-sided Type I error=0.05 will be used in general; however, 
a Bonferroni adjustment will be used for testing multiple specific hypotheses in the Aims. 
AIM 1: Evaluate cardiovascular reserve capacity, as measured by VO2peak, in HCT survivors. 
Our working hypotheses are that: 1.1) there will be distinct trajectories of VO2peak after HCT, as 
determined by pre-HCT cardiotoxic exposures (≥250 mg/m2 anthracycline exposure), CV risk 
profile (≥intermediate risk [ACC/AHA]), HCT conditioning intensity (myeloablative), and post-HCT 
complications such as GvHD; 1.2) HCT survivors will have significantly worse VO2peak compared 
to normative data at all three time points; and 1.3) VO2peak will be strongly correlated with key 
domains of HRQOL (SF-36 PF scale), after adjusting for fatigue, demographics (age, sex), and 
clinical risk factors (HCT type, conditioning intensity, physical activity). 
Interpretation of CPET-derived measures: We will apply an integrative approach that includes 
(1) assessment of the overall quality of the test, subject effort, and reasons for stopping, (2) 
tabulation and graphical depiction of the key data to determine whether obtained data is normal 
or abnormal, with comparison to appropriate reference values,46 (3) use CPET measures to 
determine causes of exercise limitation and patterns of exercise response; this will be done by 
plotting the cardiopulmonary response of each patient using outcomes per established guidelines. 
46 The plots will include but are not limited to: 1) VO2 (x-axis) versus: VT, fR, HR, VCO2; VE/VO2; 
PETO2 and PETCO2; 2) WR (x-axis) versus VO2; 3) VE (x-axis) versus WR, VO2, VCO2. We will use 
information obtained from arterial blood gas analysis (e.g. pH, arterial oxygen pressure (PaO2) 
and oxygen saturation (SaO2), alveolar-arterial difference for O2 pressure (P[A-a]O2), ratio of 
physiologic dead space to tidal volume (VD/VT) to examine efficiency of pulmonary gas exchange, 
as well as for potential underlying acid-base imbalance.46 These data will be compiled for each 
patient and correlated with clinical data to generate a comprehensive picture of cardiopulmonary 
status. Our investigative team has utilized the proposed protocol for numerous CPETs performed 
in patients with8,48 and without cancer,61,62 and has successfully implemented it in our feasibility 
studies for patients prior to60 and after HCT.49 
Analyses: We will calculate descriptive statistics (mean, standard deviation, median, range, 
quartiles) for CPET-derived measures in all participants and by sex and HCT subtype at each 
time point: baseline, 6m, 1Y, and 2Y post-HCT. We will determine the percentage of HCT 
survivors with VO2peak impairment at each of the four time points, Symptom-limited 
cardiopulmonary exercise testing per established parameters (e.g. VO2peak required for functional 
independence).6,63 We will also examine the distribution of VO2peak by sex and HCT subtype and 
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subsequent analyses. 
Aim 1.1: Determine the initial VO2peak in patients undergoing HCT and its post-HCT 
trajectory over time. 
Our longitudinal study design will allow us to determine the impact of certain pre-HCT variables 
(cumulative lifetime anthracycline dose, ACC/AHA CVD score) as well as HCT-related risk factors 
(myeloablative conditioning, GvHD) on the trajectory of VO2peak shortly after HCT (baseline to 6m) 
as well as the long-term change after HCT (6m to 1Y, 2Y). Specifically, we will conduct a 
longitudinal analysis to examine the trajectories of VO2peak by fitting a Generalized Estimating 
Equation (GEE) model, with VO2peak as the dependent variable and three indicators of time as 
independent variables. We will also describe time trends parametrically using time since HCT, 
with a join-point at 6m to connect the baseline and post-HCT time periods. We will primarily use 
compound symmetry (CS) working covariance matrix to account for within-person correlation over 
time, but will also examine the use of the autoregressive one [AR(1)] covariance structure. We 
selected the GEE approach with the empirical sandwich estimator because it has been shown to 
provide robust parameter estimates under mis-specified correlation structure in repeated 
measurements.64 We will examine the effects of selected risk factors on longitudinal trends of 
VO2peak by including them as main effects and interactions with indicators of time (or time since 
HCT) to allow for varying effects over time, and testing their significance. Continuous 
measurements will be treated as such or dichotomized (categorized) appropriately per thresholds 
for increased risk (e.g. cumulative anthracycline dose ≥ 250 mg/m2). 
We are especially interested in understanding change in VO2peak as it pertains to pre-HCT 
(anthracycline dose), HCT-related (conditioning, GvHD) exposures, and baseline CV risk profile 
(ACC/AHA CVD risk) after adjusting for race/ethnicity (non-Hispanic white, Hispanic, African 
American, other), HCT type (autologous/allogeneic), physical activity level (Godin Questionnaire), 
and comorbidities (e.g. hypogonadism, thyroid disease, renal dysfunction). We recognize that the 
expected proportion of individuals varies in each of the four risk categories to be examined 
(myeloablative conditioning [estimated proportion, 40%]; ≥intermediate risk ACC/AHA [30%]; 
cumulative anthracycline dose ≥250 mg/m2 [20%]; acute GvHD [10%]). Therefore, we powered 
this study to enable identification of factors that affect VO2peak trajectories using a range of 
proportions (40%–10%). 
Power calculations: Aim 1.1 is powered to detect differences between two groups (cumulative 
anthracycline dose <250 mg/m2 vs. >=250 mg/m2; reduced intensity vs. myeloablative 
conditioning; no/grade I GvhD vs. grades II-IV GVHD; low vs. intermediate/high ACC/AHA CVD 
risk) at 2Y post-HCT. Assuming a Type I error=0.0125 (accounting for 4 hypothesis tests, for an 
overall Type I error=0.05); three time points post-HCT; attrition rates of 20% from pre-HCT to 6m, 
14% from 6m to 1Y, and 14% from 1Y to 2Y (a retention rate of 60% at 2Y); and a correlation 
range of 0.5 to 0.8 for within-person measurements across time,48,65 350 HCT survivors at pre-
HCT will achieve 80% power to detect an effect size of at least 0.70 at 2Y, given the sample size 
in group 1 is 10% of the total sample. An effect size of 0.7 is equivalent to an absolute mean 
difference of 3.5 ml/kg/min for VO2peak between groups, assuming a standard deviation (SD) of 
5.0 ml/kg/min.63,66 A difference in VO2peak of one metabolic equivalent (3.5 ml/min/kg) has been 
associated with a 10–15% increase in all-cause mortality in the general population,67,68 and 
represents a clinically meaningful difference. If the group 1 sample is 20% or 40% of the total 
sample size, then under the same assumptions, a pre-HCT total sample size of 185 and 153, 
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of HCT on the trajectory of VO2peak after HCT, we will compare baseline VO2peak to 6m. Assuming 
20% attrition (pre-HCT to 6m), 280 subjects with VO2peak values at both time points, there is 80% 
power to detect an effect size of 0.17 at Type I error=0.05, assuming a correlation in VO2peak 
ranging from 0.5 to 0.8. 
Aim 1.2: Compare measured VO2peak in HCT survivors at baseline (pre-HCT), six months, 
one year, and two years after HCT to established age- and sex- normative data. 
We will calculate expected VO2peak for each subject using published VO2peak age-specific 
equations for sedentary men/women 63,66 we will also calculate difference between observed and 
expected for each person. We will fit a GEE model with indicator variables of time to test whether 
the mean differences differ significantly from zero at all time points using CS and/or AR(1) working 
covariance structures to account for within-person correlation across time. If the overall test is 
significant, we will test if the mean difference at each time point differs from zero using the one-
sample t-test to examine the extent to which VO2peak worsens over time. 
Power calculations: Assuming equal numbers of men and women, the expected overall 
normative VO2peak values at baseline, 6m, 1Y, and 2Y are 29.0, 28.6, 28.4, 28.0 ml/kg/min, 
respectively, with an estimated SD=5.0 ml/kg/min.63,66 Assuming a Type I error=0.0125 
(accounting for 4 hypothesis tests at four time points, for an overall Type I error=0.05), 350 HCT 
survivors at baseline, 280 at 6m (80% retention), 240 at 1Y (68% retention), and 210 at 2Y (60% 
retention) will achieve 80% power to detect a significant minimum difference of 0.9, 1.0, 1.1, and 
1.2 ml/kg/min at the respective time points, compared to the expected normative values for 
sedentary men and women using the one-sample t-test. Longitudinal trend over time: With these 
sample sizes, assuming a correlation of 0.5 to 0.8 between two time points, we will have 80% 
power to detect a significant minimum reduction in mean VO2peak of 0.8 to 1.3 ml/kg/min between 
pre-HCT and 6m, 0.9 to 1.4 ml/kg/min between 6m and 1Y, and 0.9 to 1.5 ml/kg/min between 1Y 
and 2Y, using the two-sample paired t-test at Type I error of 0.017 (accounting for 3 tests [6m vs 
pre-HCT; 1Y vs 6m; 2Y vs 1Y], for an overall Type I error=0.05). 
Aim 1.3: Define the association between VO2peak and self-reported HRQOL at baseline and 
over time. 
We will measure patient-reported outcomes and correlate them with VO2peak at baseline and at 
6m, 1Y, and 2Y post-HCT. We will collect patient-reported HRQOL, using the SF-36 PF scale, 
specifically, to assess activity limitation.69 The PF scale is composed of 10 items encompassing 
a hierarchical range of difficulties. Each item is scored (1–3) on the basis of the limitations 
perceived by surveyed individuals, and total score is derived via summation of responses. This 
scale has good internal consistency (Cronbach α ≥ 0.81),69 and has been used as a “stand-alone” 
instrument in research describing activity limitation in HCT survivors70 and patients with CVD.71 
Fatigue will be assessed using the FACIT-fatigue scale for assessment of fatigue in cancer 
patients.72Initially, we will use multivariable linear regression to examine the association between 
VO2peak and SF-36 PF cross-sectionally at baseline, 6m, 1Y, and 2Y. We will treat VO2peak as the 
independent and PF as the dependent variable, and adjust for potential confounding variables 
such as age, sex, race/ethnicity, body mass index (BMI), physical activity level, fatigue, and 
tobacco use. We will evaluate the effect of VO2peak on PF by estimating the regression coefficient 
and testing its significance. We will also calculate the change in VO2peak and change in PF from 
baseline to 6m, 6m to 1Y, 1Y to 2Y, as well as from baseline to 2Y. A positive difference indicates 
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regression to assess the relationship between the difference in VO2peak levels, treated as 
independent variable, and the difference in PF scores, treated as dependent variable, adjusted 
for covariates. The significance of the relationships will be evaluated for each time-pair 
comparison. Finally, we will use GEE analysis to examine the relationship between VO2peak and 
PF longitudinally. We will model PF using three indicator variables of time, adjusted for covariates, 
and test the significance of VO2peak as an independent variable. 
Power calculations: With sample sizes of 350 (baseline), 280 (6m), 240 (Y1), and 210 (Y2), in 
multivariate regression, we will have 80% power to show a significant correlation (r) between 
VO2peak and PF ranging: 0.14-0.17 at baseline, 0.14-0.17 at 6m, 0.17-0.20 at Y1, 0.17-0.22 at Y2 
(Table 6), assuming a Type I error=0.0125 (accounting for 4 tests, Type I error=0.05) and that 
the covariates in the regression model have a square of the partial correlation coefficient (r2) of 
0.1-0.4 with VO2peak. 
Aim 1 Anticipated results, potential pitfalls, and alternative approaches: We anticipate that 
the trajectory of VO2peak will differ by subgroups, with a significant difference between survivors 
treated with high-dose anthracyclines or myeloablative conditioning, or having high ACC/AHA 
CVD risk scores or grades II-IV acute GvHD, when compared to HCT survivors without these 
exposures or conditions. These differences will be clinically meaningful, and will inform future 
strategies for risk-based screening. Overall, HCT survivors will have significantly lower mean 
VO2peak when compared to age- and sex-predicted normative data at each of the assessment time 
points, and there will be a strong correlation between VO2peak and self-reported PF, after 
accounting for age, sex, race/ethnicity, BMI, physical activity level, tobacco use, and fatigue. 
Attrition during the study period: Given our previous experiences with longitudinal studies in 
HCT patients,73-75 we anticipate ~20% attrition per year. This takes into consideration patient 
death, recurrence of malignancy, illness, or loss to follow-up. Note, our recent longitudinal study 
included comprehensive neurocognitive function testing (3–4 hours), brain MRI (1–2 hours), and 
HRQOL questionnaires at baseline, 6m, 1Y, and 2Y post-HCT.75 At the 2Y time point, 268 out of 
429 (63%) participants who underwent baseline (pre-HCT) testing completed all study time 
points.75 HCT recipients who completed testing at all time points did not differ from those who did 
not complete testing at one or more time points by HCT type (autologous vs. allogeneic, p=0.78), 
age at HCT (p=0.10), gender (p=0.06), race/ethnicity (p=0.42), or household income (p=0.21).75 
That said, we acknowledge that there may be differential loss to follow-up according to participant 
attributes and prognosis, which may contribute to selection or participation bias and/or survival 
bias. To minimize participation bias we will incorporate many of the strategies (e.g. reminder 
phone calls, minimizing multiple visits) that we have successfully used to maintain excellent 
participation rates in our studies to date. Attrition will be monitored in real time, allowing us to 
address obstacles in a timely manner. Differential loss to follow-up due to prognosis, death, and 
missing data, which could potentially invalidate the results, will be addressed using the methods 
of pattern mixture models (PMM)76 and multiple imputation (MI) (below). 
Selection of appropriate VO2peak normative data: We will derive expected VO2peak using age-
specific equations for sedentary men/women63,66, a strategy successfully used in patients with 
breast8,9,77 and lung59,78,79 cancer. Alternatively, we will compare our CPET-obtained results to 
those from the ongoing Framingham Heart Study Offspring Cohort in which ~3,500 individuals 
are undergoing CPET (PI: G Lewis). There is no normative data for patients with hematologic 
malignancies who have not undergone HCT, limiting our ability to directly compare cardiovascular 
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have a baseline (pre-HCT) VO2peak to which post-HCT VO2peak will be compared, allowing us to 
examine change in trajectory over time by multiple risk factors, including pre-HCT and HCT-
specific exposures. 
 
Interpretation of VO2peak: We acknowledge that certain study participants will not meet the criteria 
for maximum effort on which the interpretation of VO2peak depends. In these individuals, we will 
work in conjunction with the investigative team to determine indices of cardiorespiratory fitness 
that are independent of volitional effort but highly correlated with peak VO2peak, such as O2 uptake 
efficiency slope. We will also adjust for RER to account for differences in volitional effort, while 
providing standardized encouragement. Additionally, we recognize that CPET measurements 
obtained prior to HCT may not reflect the true physiologic baseline of study participants, as some 
will still be recovering from salvage therapy for relapsed/refractory disease. Nevertheless, we 
believe the measures obtained prior to and shortly after HCT may provide important information 
regarding the effect of HCT on cardiovascular reserve capacity, independent of pre-HCT 
treatment exposures. This would in turn facilitate the development of primary preventions (e.g. 
consideration of alternatives to HCT or reduction of conditioning intensity) in patients deemed to 
be at highest risk prior to HCT. Of note, the current study is powered to examine three trajectories 
of VO2peak (pre-HCT to 6m; 6m to 2y; and pre-HCT to 2y), which would allow us to examine change 
in VO2peak across different physiologic baselines over time. 
AIM 2: Define the determinants of VO2peak impairment in HCT survivors. 
As discussed previously, VO2peak represents the integrative efficiency with which O2 is delivered 
to tissues for ATP synthesis. O2 delivery and utilization are in turn determined by a series of steps 
akin to a bucket brigade, which transport O2 from the mouth to respiring mitochondria in the 
muscle. The main steps in this O2 cascade include alveolar ventilation, diffusion from alveolar gas 
into pulmonary capillary blood and loading onto hemoglobin, convective transport by the heart 
(cardiac output) and vasculature, and diffusion into skeletal muscle. We will use measures 
obtained from CPET along with advanced organ-specific imaging and functioning studies to 
deconstruct the O2 cascade in patients at baseline, 6m, 1Y, and 2Y post-HCT. Our working 
hypothesis is that cardiac systolic function, pulmonary diffusion capacity, and lean muscle mass 
will be important contributors to VO2peak, and that comprehensive interrogation of determinants of 
VO2peak will provide both quantitative and qualitative information for the development of 
interventions to improve VO2peak after HCT. 
We will use GEE and generalized linear models (GLM) to examine the relationship between 
VO2peak and measures of: a) cardiac (LV function/ contractility [systolic, diastolic, cardiac output, 
strain], ventricular-arterial (VA) coupling, arterial elastance); b) pulmonary (obstructive, restrictive 
lung disease, diffusion capacity); c) musculoskeletal (body composition [% lean muscle mass], 
muscle quality,, 30 second sit to stand test, timed up and go); and d) hematologic function, 
adjusting for potential confounding variables (e.g. age, sex) and time since HCT. 
Analyses: We will assess the influence of the variables considered in each of the physiologic 
domains (pulmonary, cardiac, hematologic/vascular, and musculoskeletal) on the variability in 
VO2peak by initially using GLM at each time point to estimate their relationship with VO2peak, 
adjusted for potential confounding variables (e.g. age, sex, physical activity, CV risk factors). For 
each physiologic domain, measures will be examined individually in GLM, adjusted for 

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confounding factors, to identify those that are significantly associated with VO2peak, using Type I 
error=0.05. Linear and quadratic terms (and higher order as appropriate) of continuous variables 
will be considered. The identified measures will then be examined together in multiple regression 
to identify those that are independently significantly associated with VO2peak within the domain. All 
measures thus identified across domains will be considered simultaneously in step-wise multiple 
regression to determine the independently significant variables associated with VO2peak. Step-wise 
regression was selected because want to obtain an unbiased estimate of the effects of specific 
organ-function measures on VO2peak, and examine the strength of their relationship (e.g. using r2) 
with VO2peak, with an emphasis on explanatory analysis. Since the dynamics of organ-function 
measures may change with time, evaluating the relationship by time point could uncover varying 
relationships with VO2peak. We will use r2 of the measures included in the multivariate models to 
assess the percent of variance in VO2peak explained by each variable, holding other measures 
constant. 
We will also use GEE to fit a longitudinal model of VO2peak with time since HCT, using CS and/or 
AR(1) working covariance matrix, adjusted for clinically relevant variables, to identify variables in 
the four physiologic domains significantly associated with VO2peak. The univariate and multivariate 
approaches described above for cross-sectional analysis will be applied. Longitudinal (or 
repeated measures) equivalent of r2 between VO2peak and each variable of interest can be 
calculated using the formula Rk = (Zk/√N)/√(1+Zk2/N), where Zk = Wald statistic for the kth variable 
estimated from the GEE analysis and N = total number of subjects.80 The magnitude of Rk can 
inform the relative importance of the variables in the model. We will also compute the repeated 
measures equivalent of the coefficient of determination R2 (the percent of total variation explained 
by all the variables in the model).80 By computing R2 with successive inclusion of each variable in 
the model, one can see the incremental change in R2 due to that variable, thus informing the 
relative importance of that variable in explaining the total variation in VO2peak. This approach has 
been successfully used to gain insight into phenotypically heterogeneous cardiopulmonary 
conditions,81-83 optimizing their screening and management. 
Power calculations: Sample sizes of 350 (baseline/pre-HCT) and 280 (6m) will provide 80% 
power at Type I error=0.05 to detect a correlation (r) of 0.10 to 0.14 between VO2peak and a variable 
of interest when adjusted for additional covariates in the model, with r2 ranging from 0.05 to 0.5. 
A sample size of 240 at 1Y post-HCT will enable detection of an r of 0.14 to 0.17, and a sample 
size of 210 at 2Y post-HCT will enable detection of an r of 0.14 to 0.20, for the same assumptions 
made for pre-HCT. 
Missing data will be addressed by applying PMM76 and MI.84 Non-ignorable missing data from 
death or study dropout could potentially invalidate GEE results. We will define three missing-data 
patterns based on survival and study completion status: 1) deceased before 2Y (deceased/non-
completer), 2) alive at 2Y but dropped out before 2Y (alive/non-completer), and 3) alive and 
participated at 2Y (alive/completer). Pattern 1 has missing data at all time points after death, with 
possible intermittent missingness prior to death. Pattern 2 has missing data at 2Y, with possible 
intermittent missingness prior to 2Y. Pattern 3 has non-missing data at 2Y, with possible 
intermittent missingness prior to 2Y. Intermittent missing data will be multiply imputed (e.g. 20 
times) to generate monotone missing-data patterns (i.e. missing data occurring only at 
consecutive time points for which patients were alive).76 For each resulting MI data set, the data 
at preceding time points will then be used in the regression method for MI to singly impute the 
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participate. We will use the three missing-data patterns as stratification factors in the PMM 
analysis of the MI data sets using GEE to assess the effects of missing-data patterns on the 
estimated exposure factors using Rubin’s rule.84 We will include interactions between strata 
indicators and parameters of exposure factor effects in the GEE model. A significant interaction 
indicates that treatment effects vary by missing-data patterns and that they should be reported by 
pattern/strata. We will also calculate an averaged exposure effect (over missing-data patterns) to 
examine the overall effects. 
10.0  DATA SAFETY AND MONITORING 
10.1 
DEFINITION OF RISK LEVEL 
This is a Risk Level 2 study, as defined in the “City of Hope Data and Safety Monitoring Plan”, 
City of Hope Institutional Data and Safety Monitoring Plan [policy effective date: 08/23/17], 
because it involves obtaining blood samples, undergoing CPET, echocardiography, and 
pulmonary function testing, where the risk of harm is low. 
The study team has previous experience conducting similar research studies namely IRB15073 
Assessment of cardiovascular reserve capacity in hematopoietic cell transplant survivors: a pilot 
feasibility study. There were no serious adverse events during CPET, which is important, since 
CPET requires exercise to symptom limitation (volitional exhaustion).49  
10.2 
MONITORING AND PERSONNEL RESPONSIBLE FOR MONITORING 
The Principal Investigator (PI) is responsible for monitoring protocol conduct and reporting to the 
City of Hope (COH) Data and Safety Monitoring Committee (DSMC) and Institutional Review 
Board (IRB) as indicated in the sections below. 
10.3 
UNANTICIPATED PROBLEMS (UP) INVOLVING RISKS TO SUBJECTS OR OTHERS 
An unanticipated problem is any incident, experience or outcome that meets all three of the 
following criteria:  
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) 
the research procedures that are described in the protocol-related documents 
such as the IRB approved research protocol, informed consent document or 
Investigator Brochure (IB); and b) the characteristics of the subject population 
being studied; AND  
2. Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or 
outcomes may have been caused by the procedures involved in the research); 
AND  
3. Suggests that the research places participants or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized.  
Any UP that occurs during the study conduct will be reported to the DSMC and IRB in 
accordance with the City of Hope’s Institutional policy [policy effective date: 05/14/14] using the 
electronic submission system, iRIS.  

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10.4 
DEVIATIONS 
A deviation is a divergence from a specific element of a protocol and that occurred without prior 
IRB approval. Deviations from the approved protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. A Corrective and Preventative Action 
(CAPA) plan should be developed by the study staff and implemented promptly to avoid similar 
issues in the future. All deviations from the protocol must be documented in study source 
documents and promptly reported to the DSMC and IRB. 
10.5 
REPORTING DEVIATIONS 
Investigators may deviate from the protocol to eliminate immediate hazards for the protection, 
safety, and well-being of the study subjects without prior IRB approval. For any such deviation, 
the PI will notify the DSMC and IRB, within 5 calendar days of its occurrence by electronic 
submission of a Deviation Notice via iRIS. 
10.6 
 PLANNED PROTOCOL DEVIATION (PPD AMENDMENT REQUEST 
Deviations from the written protocol that are not done to eliminate an immediate hazard(s) for the 
protection, safety and well-being of study subjects but may increase risk and/or alter the protocol 
integrity require prior IRB approval. The deviation is submitted as a  Planned Protocol Deviated 
(PPD) amendment request. An IRB approved PPD does not need to be submitted as a protocol 
deviation to the DSMC. The PPD should be submitted according to the IRB guidelines and COH 
Institutional Deviation Policy [policy effective date: 11/02/11] and submitted via iRIS. 
A deviation that is not an PPD (i.e., discovered after the occurrence) must be reported to the COH 
DSMC and IRB according to the COH Institutional Deviation Policy [policy effective date: 
11/02/11] and submitted via iRIS. 
 
 

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