Improving Diet and Exercise in Acute Lymphoblastic Leukemia (IDEAL Weight in ALL)
Phase: NA
Conditions: B Precursor Type Acute Leukemia
Sponsor: Children's Hospital Los Angeles

11 
Trial Protocol 
NCT#02708108
Initial Protocol Date: 
April 4, 2016 
Amendment #1: May 31, 2016 
Amendment #2: June 29, 2017 
Amendment #3: October 18, 2017 
Amendment #4: May 3, 2018 
Improving Diet and Exercise in Acute Lymphoblastic Leukemia (IDEAL Weight in ALL Trial): 
Environment and Microenvironment #3 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR 
USED FOR ANY OTHER PURPOSE. 
PRINICIPAL INVESTIGATOR: 
Etan Orgel, M.D., M.S. 
Division of Hematology, Oncology, 
& Blood and Marrow Transplantation 
Children’s Hospital Los Angeles 
4650 Sunset Blvd, MS#54 
Los Angeles, California 90027 

12 
TABLE OF CONTENTS 
 PAGE 
STUDY COMMITTEE ............................................................................................................... 13 
ABSTRACT .............................................................................................................................. 14 
EXPERIMENTAL DESIGN SCHEMA .......................................................................................... 14 
1.0 
GOALS AND OBJECTIVES .............................................................................................. 14 
2.0 
BACKGROUND AND SIGNIFICANCE .............................................................................. 16 
3.0 
PRELIMINARY DATA .................................................................................................... 18 
4.0 
SCREENING AND ENROLLMENT ................................................................................... 21 
5.0 
PATIENT CRITERIA FOR ELIGIBILITY.............................................................................. 23 
6.0 
STUDY PLAN ................................................................................................................ 25 
7.0 
MODIFICATIONS OF INTERVENTION FOR TOXICITY ..................................................... 28 
8.0 
SUPPORTIVE CARE GUIDELINES ................................................................................... 28 
9.0 
 REQUIRED OBSERVATIONS ......................................................................................... 28 
12.0 CRITERIA FOR REMOVAL FROM THERAPY AND OFF-STUDY CRITERIA .......................... 33 
13.0 STATISTICAL CONSIDERATIONS AND EVALUATION CRITERIA ....................................... 34 
14.0 ADVERSE EVENT REPORTING REQUIREMENTS ............................................................ 36 
15.0 RECORDS AND REPORTING ......................................................................................... 37 
16.0 DATA AND SAFETY MONITORING PLAN ...................................................................... 38 
17.0 LITERATURE CITED ....................................................................................................... 38 

 
13 
 
STUDY COMMITTEE
Etan Orgel, M.D, M.S.  (PI) 
Division of Hematology-Oncology/BMT 
Children’s Hospital Los Angeles 
4650 Sunset Boulevard, Mailstop # 54 
Los Angeles, California 90027-6016 
Phone: 323-361-2121/562-933-8600 
Fax: 323-361-7128 
Email: eorgel@chla.usc.edu 
 
Steven Mittelman, M.D, Ph.D. (Co-I) 
Division of Endocrinology 
David Geffen School of Medicine, UCLA 
10833 Le Conte Ave, MDCC 22-331 
Los Angeles, CA  90095 
Phone:  310-825-6496 
Email: smittelman@mednet.ucla.edu 
 
David Freyer, D.O, M.S. (Co-I)   
Division of Hematology-Oncology/BMT 
Children’s Hospital Los Angeles 
4650 Sunset Boulevard, Mailstop # 54 
Los Angeles, California 90027-6016 
Phone: 323-361-8953 
Fax: 323-361-7128 
Email:  dfreyer@chla.usc.edu 
 
Katie Villabroza (Study Coordinator) 
Division of Hematology-Oncology/BMT  
Children’s Hospital Los Angeles 
Division of Hematology-Oncology/BMT 
4650 Sunset Boulevard, Mailstop # 54 
Los Angeles, California 90027-6016 
Phone: 323-361-6132 
Email: kvillabroza@chla.usc.edu 
 
Celia Framson, MPH, RD  (Dietary Guidance) 
Department of Clinical Nutrition Services 
Children’s Hospital Los Angeles 
4650 Sunset Blvd  
Los Angeles, CA 90027 
Phone: 323-361-8555 
Email: cframson@chla.usc.edu 
 
 
 
 
 
Rubi Vazquez PT, DPT  (Exercise Guidance) 
Department of Rehabilitation Services 
Children’s Hospital Los Angeles 
4650 Sunset Blvd., Mailstop 56 
Los Angeles, CA 90027 
Phone: 323-361-2118 
Fax: 323-361-8032   
Email: ruvazquez@chla.usc.edu 
 
Christina M. Dieli-Conwright, PhD, CSCS (Exercise 
Physiology) 
University of Southern California 
1540 E. Alcazar St., CHP 155 
Los Angeles, CA 90033 
Phone: 323-442-2905 
Fax: 323-442-1515 
Email: cdieli@usc.edu  
 
Matthew Oberley, M.D, Ph.D. (Flow 
Cytometry/MRD) 
Director of Hematopathology 
Children’s Hospital Los Angeles 
4650 Sunset Boulevard 
Los Angeles, California 90027-6016 
Phone: 323-361-8940 
Fax:  
323-361-8005 
Email: moberley@chla.usc.edu 
 
Richard Sposto, PhD (Study Statistician) 
Division of Hematology-Oncology/BMT 
Children’s Hospital Los Angeles 
4650 Sunset Boulevard, Mailstop # 54 
Los Angeles, California 90027-6016 
Phone: 323-361-8582 
Fax:  
323-361-7128 
Email: rsposto@chla.usc.edu 
 
 
 
 
 

 
14 
 
ABSTRACT 
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy with almost 2,000 
children diagnosed per year in the United States alone. While 5-year event-free survival rates have 
topped over 90% in the past decade, overweight and obese pediatric ALL patients have a 50% greater 
risk of relapse than normal weight children. With about 1 in 6 US children being overweight or obese, it 
is urgently necessary to combat the negative role of obesity on ALL treatment in the clinical setting. 
 
In our previous study, we have observed that: 1) nearly half ALL patients are overweight or obese at 
diagnosis, 2) all patients, regardless of starting weight, gain significant fat mass over the first month of 
therapy (on average 20-30%), and 3) obesity at the time of diagnosis is associated with a higher 
likelihood of poor response to chemotherapy as evidenced by persistent leukemia (minimal residual 
disease) after induction therapy. Together, these data show that body fat is a significant risk factor for 
ALL treatment failure, and that its negative effects are evident within the first month of treatment.  
Recent laboratory and clinical data illustrates the ability of diet restriction and physical activity to 
improve chemotherapy efficacy, reduce treatment-related toxicities and better overall quality of life.  
 
However, to our knowledge, no clinical trial has demonstrated the efficacy of such a comprehensive, 
integrative medicine approach to improve chemotherapy efficacy and quality of life in ALL patients 
during intensive therapy, let alone any pediatric cancer population.  Given the importance of successful 
induction therapy in predicting long term survival and the negative role of obesity on treatment success, 
we are proposing a complete personalized dietary and exercise intervention for pediatric ALL patients 
that aims to reduce fat gained during induction therapy, thereby improving their treatment response 
and also quality of life. 
 
EXPERIMENTAL DESIGN SCHEMA 
 
1.0  
GOALS AND OBJECTIVES 
 
1.1 
Hypothesis: 

 
15 
 
In pre-adolescents, adolescents, and young adults (AYA) diagnosed with NCI/Rome High-Risk B-
precursor acute lymphoblastic leukemia (HR-ALL), reducing gains in adiposity (i.e. fat mass) will 
improve leukemia sensitivity to induction chemotherapy, reduce post-induction minimal residual 
disease (MRD), reduce fatigue and obesity-associated toxicities, and improve quality of life. 
 
1.2 
Primary aim:   
 
In AYA patients newly diagnosed with HR-ALL, to quantify the impact of a personalized dietary 
and activity intervention to mitigate chemotherapy-induced body fat gain throughout the critical 
first month of treatment ("induction").  
 
1.3 
Secondary aims:   
 
In AYA subjects newly diagnosed with HR-ALL: 
 
1. To compare the rate of leukemia “positive” minimal residual disease (MRD) in the bone 
marrow at end of induction (≥0.01% mononuclear cells) in those who received the 
intervention as compared to a historical controls. 
 
2. To assess adherence to, and feasibility of, implementing a personalized and comprehensive 
dietary and exercise intervention during the first month of intensive chemotherapy  
 
1.4. 
Exploratory aims: 
 
In AYA subjects newly diagnosed with HR-ALL: 
 
1. To evaluate persistence or extinguishing of this effect over months of continued dose-
intensive pre-Maintenance phases of chemotherapy  
2. To characterize the direct impact as compared to baseline of the intervention on self- and 
family- reported quality of life (QOL) outcomes including fatigue, mood, social interaction, 
and cognitive impairment reported via the PedsQL questionnaire and Child and Adolescent 
Scale of Participation (CASP) following the induction phase and serially during dose-intensive 
phases of chemotherapy. 
3. To quantify the effect of adiposity on the activity of leukemogenic JAK2/STAT3, 
PIK3K/AKT/mTOR, MAPK/ERK , and other signaling pathways in leukemia cells as determined 
by kinase phosphorylation. 
4. To quantify the effect of adiposity and of the intervention on the metabolic activity of 
leukemia blasts and of adipocytes as assessed by IGF-1, other obesity-associated cytokine 
signaling pathways, adiponectin, leptin, free fatty acid synthesis and metabolism, and levels 
oxidative stress. 

 
16 
 
 
2.0  
BACKGROUND AND SIGNIFICANCE 
 
2.1 
INTRODUCTION 
Obesity is a major cause of morbidity and mortality in the U.S. and worldwide. We and others have shown 
that obesity increases the risk of cancers such as leukemia, and can impair leukemia treatment and patient 
survival (1-3).  In adults treated for breast and colorectal cancer, altering nutritional intake and increasing 
physical activity during treatment improves efficacy (4,5) while limiting treatment symptoms like fat gain 
and fatigue (6).  In this proposed study, we will explore how a dieting and exercise intervention throughout 
the first month of treatment may counteract the adverse impact of body fat on leukemia therapy efficacy, 
toxicity, and quality of life. 
 
2.2 
FAT MASS AND ALL 
Obesity increases the incidence of many cancer types, and obese cancer patients have a higher risk of 
mortality from their disease (3). In 2007, a landmark study in the Children’s Oncology Group (COG) led by 
Dr. Butturini from the Children’s Hospital Los Angeles (CHLA) demonstrated in two large cohorts (4,314 
and 1,160 patients) that obesity at the time of diagnosis increases risk of relapse in children with National 
Cancer Institute/Rome High-Risk B-precursor ALL (HR-ALL) by 50% (1), a finding independently confirmed 
in a different population of children (7) in obese adults (8), and by meta-analysis (2).  In a recent study, 
36% of children with ALL were overweight or obese at diagnosis (9), while in another cohort 23% of 
children with HR-ALL continued to be obese throughout therapy (10).  In our earlier cohort of adolescent 
and young adults with HR-ALL treated at CHLA, we found an even higher prevalence of high body fat 
whereas 48% were overweight or obese at diagnosis. Our data also showed that all individuals – both 
those lean and those obese- gain a significant amount of adipose tissue during the first month of 
treatment alone (“induction”).  On average, patients gained ~20-30% of fat above their starting body fat 
percentage.  The use of glucocorticoids such as dexamethasone and prednisone during induction therapy 
likely contribute to this fat gain, as they stimulate adipogenesis and appetite.  Predisposition to inactivity 
due to intensive leukemia treatment combined with steroid-induced dietary derangements are therefore 
likely moderating factors of this marked gain in body fat.  As response to leukemia treatment in the first 
month of therapy is a key determinant of overall prognosis and risk for relapse, and as obesity and body 
fat are risks factors for relapse, an intervention aimed at reducing the gain in body fat has potential to 
improve leukemia therapy efficacy starting from the initial time of diagnosis.  
 
 
 
2.3 
DIETING, ACTIVITY AND CANCER 
The concept of introducing caloric restriction in animal cancer models has been explored throughout the 
last century (11). Recent experiments have focused on the theory of “differential stress resistance,” a diet 
restrictive metabolic state that increases normal tissue, but not cancer cell, tolerance to chemotherapy 
(12). During carcinogenesis, cancer cells acquire mutations to various metabolic oncogenes, such as Akt 
and Ras, which allow uncontrolled proliferation.  During dietary restriction and the subsequent lack of 
nutrients and growth factors, normal cells down-regulate their metabolic activity while cancer cells 

 
17 
 
maintain their elevated metabolic state, a condition that promotes greater chemotherapy specificity 
toward cancer cells. This was demonstrated in a transgenic mice with human neuroblastoma fasted for 
48 hours prior to etoposide treatment. The fasted mice not only survived longer than non-fasted mice but 
also suffered less drug-induced toxicity (13).  
 
While such a severe starvation diet is not feasible in the clinical setting, altering dietary composition 
and/or reducing caloric intake is sufficient to see similar results. In a murine prostate cancer model, mice 
fed with either a low-fat or no-carbohydrate diet had significantly reduced tumor growth compared to 
mice on a “Western” diet (14). Similarly, a low carbohydrate, high protein, isocaloric diet limited 
squamous cell carcinoma and breast cancer growth in mice (14).Even restricting total caloric intake during 
treatment by 30% regardless of dietary makeup reduced breast tumor aggressiveness and tumoral fat 
content (15). Our own preliminary research (described below) has demonstrated a similar effect of caloric 
and fat restriction on reducing weight and improving survival of obese mice with ALL. 
 
Physical activity during therapy has also been shown efficacious to augment cancer sensitivity. Mice that 
were allowed to run on a wheel had slower breast tumor growth and improved immune function 
compared to non-exercised mice (16). Furthermore, the amount of running inversely correlated with the 
size of the tumor. Similarly, serum from men who exercise for one hour prevented prostate cancer growth 
in vitro compared to cells in serum from non-exercising men (17).  Despite this history and the breadth of 
research into diet and exercise interventions as adjuvants to chemotherapy, the translation of these 
laboratory findings into the clinical setting has remained a barrier. 
 
Diet and exercise have concrete benefits in addition to potentially augmenting chemotherapy efficacy. 
Multiple clinical trials conducted in the last ten years have demonstrated the ability of diet and/or exercise 
to prevent chemotherapy-associated fat gain, reduce fatigue and improve emotional well-being in adults 
with solid tissue and hematological cancers (5, 18, 19). Furthermore, the American Cancer Society has 
recommended that proper nutrition and physical activity play a role in all phases of cancer treatment (20).  
 
 
2.4 
DIET AND ACTIVITY INTERVENTIONS FOR OBESITY 
With 16.9% of 2-19 year olds being obese (21) and at risk for serious co-morbidities (22), there is a 
necessity for effective obesity-targeted pediatric interventions.  While many interventions have long 
existed for obese adults, their efficacy in obese children has only begun to be explored recently. Obese 
children without cancer randomized to an intervention prescribing 90 minutes of moderate exercise three 
times per week, a hypocaloric diet, and weekly meetings with a dietician had a lower BMI, body fat 
percentage and LDL cholesterol level than children receiving only individual diet or exercise (23). Similarly, 
a 16 week low-carbohydrate plus aerobic and strength training intervention proved more effective in 
reducing BMI, body fat and fasting glucose compared to diet or exercise alone (24).  
 
2.5 
QUALITY OF LIFE DURING ALL THERAPY 
As the treatment for ALL has become more successful, the assessment and improvement of patient QOL 
are becoming the focus for new studies and treatment modalities. To date, multiple assessment tools 

 
18 
 
have been developed to assess QOL in the pediatric cancer population. One such tool, the Pediatric Quality 
of Life Inventory (PedsQL), in conjunction with the PedsQL 3.0 Fatigue Module, has been shown to be 
particularly effective in assessing physical, emotional and social functioning, fatigue, pain, nausea, anxiety 
and cognitive problems among others (25).  
 
Using this assessment tool, it has been shown that children actively undergoing chemotherapy have a 
lower QOL than healthy children (26) or even those 1 year removed from chemotherapy (27). Additionally, 
researchers have measured the changes in patient QOL over the course of ALL therapy. In patients with 
SR-ALL or HR-ALL, nausea, procedural and treatment anxiety and worry were worse during induction 
compared to maintenance therapy (28). Another similar study demonstrated a lower health-related QOL 
in patients in induction therapy compared to all other phases of treatment (29).  
 
Little research has been performed to analyze the effect of physical activity on QOL in ALL patients 
undergoing chemotherapy.  One randomized trial demonstrated improved QOL in pediatric cancer 
patients, including those with ALL, who participated in physical activity sessions during hospitalization 
(30). In adolescent survivors of ALL, leisure-time physical activity was also associated with improved QOL 
(31). Greater research is needed to better understand the ability of physical activity, and dietary 
intervention, to improve patient QOL during and after chemotherapy. 
 
2.6 
STUDY SIGNIFICANCE 
To our best knowledge, no clinical study has reported the effect of a combined diet and activity program 
as an adjuvant to chemotherapy in overweight and obese pediatric patients with any cancer diagnosis.  
However, with the combined expertise of our integrative medicine team of dieticians, physical therapists, 
oncologists and endocrinologists, we are confident that a comprehensive obesity-targeted intervention 
will reduce fat gain and lean muscle loss to improve treatment efficacy and QOL during therapy.  The 
intervention will have the added benefit of promoting healthier lifestyle choices throughout the rest of 
treatment and into adulthood. 
 
3.0 
PRELIMINARY DATA  
 

 
19 
 
Obesity is a common problem in our patients with ALL.  
In our cohort of adolescents with HR-ALL at CHLA, 48% 
were overweight or obese at diagnosis. Further, from the 
time of diagnosis to the end of the induction phase, 
subjects had an ~25% increase in body fat over these first 
28 days of chemotherapy alone (from 23.3±9.1% at time 
of diagnosis to 33.7±9.8% at end of induction, p<0.001, 
Fig. 1). Even more striking, this gain in body fat pecentage 
was present in the entire cohort regardless of starting 
body composition (Fig 1.). Body fat then increased even 
further, to a mean of 37.1±7.9% by the end of Delayed 
Intensification, following approximately seven months of 
intensive chemotherapy (p<0.001, not shown).   Overall, 
this increase in body fat represents a gain of 5.2±4.9 kg of 
adipose tissue over the entire study period.  Given our 
findings that adipose tissue can directly impair chemotherapy efficacy on ALL (32,33), this gain in body fat 
during such the  critical chemotherapy dose-intensive treatmentr period is very concerning. 
 
Obesity impacts ALL survival within the first month of treatment. Treatment for childhood ALL generally 
lasts for 2-3 years. The first month of treatment (induction) is intense including prolonged high doses of 
steroids, and weekly chemotherapy, and frequent 
physician visits. Response to induction therapy 
through clearance of leukemia from the bone marrow 
as measured by flow cytometry and reported as 
“minimal residual disease” (MRD) is generally 
accepted as one of the best predictors of long-term 
survival (34).  Given the association observed 
between obesity at diagnosis and EFS (1), we 
examined whether weight status at diagnosis would 
increase the risk of residual leukemia at the end of 
induction as measured by MRD.  To do this, we 
retrospectively evaluated the records of 198 children 
treated at CHLA for B-precursor ALL. We observed 
that MRD positivity (as defined per COG by MRD with 
multicolor flow cytometry ≥0.01%) was increased in 
children who were overweight or obese (Fig 2 above). 
The strongest association was in obese patients, who had a statistically and clinically significant higher risk 
of persistent MRD (Odds ratio 2.5, 95% CI 1.2 – 5.1, p = 0.014, adjusted for NCI risk group and validated 
leukemia risk factors) but with increased risk present in the overweight too (OR 1.37, p=0.046 for the 
three weight-group analysis).  Evaluation of BMI percentile as a continuous variable further confirmed 
increased prevalence beginning in the overweight range (Fig. 2).  Thus, the effect of overweight and 
obesity to worsen EFS is present during Induction. 
Fig 2. BMI percentile and MRD positivity 
(≥0·01%).   

 
20 
 
 
The effects of obesity are reversible. As 
weight is not static during ALL therapy (10), 
we recently evaluated the effect of duration 
of exposure to extreme weight on survival 
(Fig. 3, 35).  In a restrospective COG study 
led by Orgel et. al., in 2,008 children with 
HR-ALL, we determined that while children 
who were obese for greater than 50% of the 
early intensive chemotherapy phase had a 
poorer event free survival (HR of event = 
1.43 [1.04-1.96] compared to those of 
“normal” weight), obese children whose 
weight normalized out of the obese range 
for more than 50% of the time of early intensive therapy had an improved outcome similar to those never 
obese (HR = 0.99 [0.62-1.58]). These data suggest the effect of obesity might be reversible.  
 
To address this important question, we designed 
experiments to determine whether or not 
dietary intervention that was initiated when 
leukemia is diagnosed could improve outcome. 
Diet-induced obese (DIO) mice and matched 
controls were transplanted with ALL cells and 
chemotherapy with vincristine (VCR) was 
initiated 7 days after transplant, as previously 
described (32). At this point, half of the obese 
mice were switched to a low (10%) fat diet. Thus, 
this experiment simulated the clinical condition 
in which a dietary intervention could be initiated 
at the time of diagnosis, namely at the same time 
that 
chemotherapy 
would 
be 
started. 
Remarkably, obese mice switched to a low fat 
diet had a substantially improved survival compared to the non-switched animals (p<0.001), and even 
survived longer than controls that had been raised on the low fat diet (p<0.01, Fig 4). Thus, switching mice 
from high fat to low fat diet when treatment is started substantially improves leukemia survival.  
 
Obesity increases toxicity.  As part of the same COG desribed above (Orgel et. al)., we also evaluated 
obesity as an ongoing risk for toxicity. In doing so, we found a striking effect of obesity on toxicity within 
each phase of pediatric ALL chemotherapy for children with HR-ALL: in 2,008 children (representing 
13,946 cycles of chemotherapy), obesity was associated with increases in hepatic (OR = 1.32 [1.15-1.51], 
p<0.001) and pancreatic (OR = 1.53 [1.22-1.92], p<0.001) toxicity within each cycle of chemotherapy as 
compared to lean or underweight children. Toxicity affecting the liver and pancreas are specifically 
Fig 3. EFS per BMI during HR-ALL Therapy  
Fig 4. Diet affects ALL survival. Dieted mice 
were switched to 10% fat diet on day 7, when 
vincristine (VCR) treatment was initiated. 

 
21 
 
notable in ALL regimens as they limit our ability to deliver optimal dosing of chemotherapy. Of note, and 
germane to the secondary objectives of this proposal, obese children also suffered from reduced strength 
during therapy (OR = 1.33 [1.08-1.64], p<0.001) as compared to those lean/underweight. Healthy 
reduction in body fat therefore has significant potential to not only improve survival, but to reduce key 
toxicities during ALL therapy. 
 
Physical activity can be targeted in ALL. In a recent pilot study on preferences for physical activities and 
engagement in children and adolescents with ALL, we assessed 37 patients ages 10-18 (68% male; 65% 
Latino) using the Activity Preferences and Participation Scale (APPS), a newly developed measure designed 
to identify activity preferences, activity frequency, and social engagement in activity. The tool was 
administered on an iPad, and included perceptions of activity levels, self-reported changes in activity 
levels since diagnosis, and perceived barriers to engaging in physical activity and the importance of 
physical activity. Of the participants, 14 were in the induction/consolidation phase of treatment, 12 in 
Maintenance, and 11 off- treatment.  Forty percent of individuals in the sample were overweight or obese. 
At all phases of treatment, participants strongly preferred and participated in sedentary activities. There 
was a high correlation between activity preference and activity participation in moderate-vigorous 
activities. Of particular relevance to the present study is that more than half of the participants in the 
induction/consolidation phase stated that fatigue, poor balance or weakness, and energy levels were 
barriers to participation in physical activity, while approximately 1/3rd reported that feeling sick or 
nauseated was a barrier. Most participants reported being less physically active since they were diagnosed 
with ALL, with the greatest declines reported in the induction/onsolidation (100%). All participants 
reported that they would like to be more physically active.  As would be anticipated, induction 
chemotherapy fosters a non-active lifestyle; an integrative medicine intervention educating subjects and 
families how to safely exercise is both urgently needed and desired by families. 
 
4.0 
SCREENING AND ENROLLMENT 
 
4.1 
SUBJECT IDENTIFICATION  
Physicians who wish to enroll patients should first contact the local site’s research coordinator to 
determine if the study is currently open to accrual.  Patients with newly diagnosed HR-ALL greater than 
or equal to 10 years of age are to be identified for eligibility screening by the oncology care team and/or 
study investigators. Screening logs with a coded identifier are to be maintained by each site; for eligible 
subjects not enrolled, the reason should be recorded. 
 
4.2 
IRB APPROVAL 
Local IRB approval at each site must be confirmed by the research coordinator prior to enrolling a patient. 
 
4.3 
SCREENING PROCEDURES 
Studies or procedures performed solely for clinical indications (and not done for purposes of determining 
study eligibility) may be used to screen for initial study eligibility and thereafter may be used for baseline 
values even if the studies were done before informed consent was obtained. 

 
22 
 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial must only be 
done after obtaining written informed consent. 
 
4.4 
INFORMED CONSENT/ASSENT  
Potential subjects and/or their parent(s) or guardian(s) (as applicable) will have the following carefully 
explained as described in the IRB-approved consent/assent documents: (1) the investigational nature of 
the research, (2) the objectives of the research, (3) the procedures involved in the research, and (4) any 
and all risks and discomforts due to participation. Clarification questions will then be elicited from the 
potential subject and/or their parent(s) or guardian(s). Only afterwards will an informed consent and 
assent document be signed as per institutional guidelines, with a copy to be given to the patient and the 
original placed in the research record. 
Study participants are to be consented by the study investigators during their routine comprehensive 
study consent conference and/or by study investigators. As is the departmental standard practice 
regarding opening and accruing patients to clinical trials, care teams are to be fully briefed about the study 
details prior to study opening and will have the opportunity to ask clarifying questions.  In addition, care 
teams will be kept apprised of any developments in study operation over the course of the study.  Study 
investigators will also be available at all times to clarify any questions prior to the consent conferences. 
 
4.5 
CONTACT REQUIREMENTS 
After eligibility requirements are met as per below, the principal investigator should be notified via email 
of subject eligibility and enrollment status.  
 
4.6 
ELIGIBILITY CHECKLISTS 
The “Eligibility Checklist” must be completed, signed, and dated by the clinical research coordinator (or 
study investigator) prior to official study enrollment. This form must then be maintained in the study 
record. 
 
4.7 
STUDY ENROLLMENT 
Once all applicable eligibility requirements are met, the patient will be enrolled in the study by the 
research coordinator.  
 
Timing of Enrollment:  Patients will ideally be enrolled prior to starting systemic chemotherapy (not 
including steroid pre-treatment/steroid prophase) but must be enrolled within 24 hours of starting 
systemic chemotherapy. Enrollment after 24 hours of starting systemic chemotherapy will be allowed at 
the discretion of the PI (or delegate) though the end of “chemotherapy day” 4. 
 
4.8 
PATIENT REGISTRATION 
After subjects have been enrolled on the study, the coordinating center (CHLA) will assign a unique study 
identifier to be emailed to each site.  Thereafter, they will be identified only by this unique identifier. All 
medical information will be protected as per the section below on “Records and Reporting.” 

 
23 
 
 
5.0 
PATIENT CRITERIA FOR ELIGIBILITY 
 
The eligibility criteria listed below are to be interpreted literally.  All clinical and laboratory data required 
for determining eligibility of a patient enrolled on this trial must be available in the patient’s medical and 
research record which will serve as the source document for verification at the time of audit. 
 
5.1 
INCLUSION CRITERIA 
 
Subjects: 
• 
Are greater than or equal to 10 years of age and less than or equal to 21 years of age at time of 
diagnosis  
• 
Have a new diagnosis of untreated NCI/Rome High Risk B-precursor ALL (HR-ALL) 
• 
(with the exception of steroid pre-treatment/steroid prophase or the administration of 
intrathecal chemotherapy) 
• 
Are beginning treatment on- or as per- a CCG-COG1 protocol with a 4-drug Induction including 
vincristine, daunorubicin (or doxorubicin), asparaginase, and at least 14 days of glucocorticoid 
steroids 
 
5.2 
EXCLUSION CRITERIA 
 
Subjects cannot: 
• 
Have a diagnosis of Down syndrome (Trisomy 21) or any genetic disease associated with abnormal 
body composition 
• 
Be underweight or “at risk for underweight” with moderate weight loss, defined as a starting Body 
Mass Index (BMI) <10th percentile for age and sex (for those >20 years of age, defined as an 
absolute BMI < 18.5)2 
• 
Have pre-existing abnormal intestinal function (e.g. protein-wasting enteropathy, fat 
malabsorption)   
• 
Be unable to comply with both the recommended diet and activity interventions (as determined 
by study or treatment team) 
• 
Have a history of prior chemotherapy or radiation for other cancers 
• 
Be unable to complete the necessary radiology examinations with fully interpretable data (e.g. 
hip replacement and metal prostheses preclude evaluation by DXA) 
• 
Be pregnant (to be confirmed by urine or serum pregnancy test as per institutional routine care 
for chemotherapy and radiology exams) 
 
 
1 COG = Children’s Oncology Group.  CCG = Children’s Cancer Group 
2 Per the latest definition of Center for Disease Control and Prevention, underweight is defined 
for those <20 years of age as a BMI <5th percentile for age and sex and an absolute BMI <18·5 in 
adults >20 years of age. “At-risk for underweight” is a study-specific definition outlined above.  

 
24 
 
5.3 
CONCOMITANT THERAPY  
Patients may be receiving concurrent therapies including investigational agents for the treatment of their 
underlying malignancy.   
 
5.4 
CO-ENROLLMENT ON RESEARCH STUDIES 
As per the Children’s Oncology Group (COG) standard practice, this study is a behavioral intervention and 
does not include an investigational agent and is therefore not excluded from co-enrollment on COG trials.  
Moreover, the study behavioral intervention occurs during a treatment period (induction) where no COG 
or other research intervention is planned through the duration of this protocol.  Of note, the relevant COG 
trial AALL1131 specifically outlines multiple concomitant therapies that are excluded but does not include 
behavioral interventions such as this one.  For patient specimens, collection of samples for research will 
be coordinated closely with the clinical leukemia team; should a conflict arise for patient samples, priority 
will be first accorded to clinical care.  Second priority will then be afforded to COG studies required for co-
enrollment on COG therapeutic trials. Following both these uses, remaining sample will be obtained for 
this research study. 
 
 
 

 
25 
 
6.0 
STUDY PLAN  
 
6.1 
SUMMARY OF STUDY PLAN  
Pre-adolescent and AYA patients with newly diagnosed HR-ALL will have dietary and activity preferences 
assessed by a registered dietician (RD) and physical therapist (PT) at the start of induction.   
 
Subjects will receive an individualized comprehensive dietary and physical activity plan.  The RD and PT 
will devise a personalized dietary and activity intervention aimed at creating a minimum 10% caloric deficit 
each day (10% nutritional + exercise) throughout the four weeks of induction therapy.  Adherence to the 
intervention will be assessed by the RD and PT at regular weekly intervals at routine clinic visits for 
chemotherapy and with home phone-calls between clinic visits.  Home and hospital activity will also be 
recorded using a wearable electronic movement monitoring device (Fitbit ®) for all participants.  A list of 
representative “menu” of possible activity interventions from which subjects may choose is provided as a 
separate Appendix.   The primary efficacy of the intervention will be assessed in comparison to a recent 
historical control via determining the change in body fat percentage (and lean muscle) during induction 
as quantified by dual-energy x-ray absorptiometry (DXA).  A key secondary aim will be the effectiveness 
of the intervention to reduce chemoresistance as evidenced by decreased prevalence of leukemia minimal 
residual disease (MRD) at the end of induction. MRD using multicolor flow cytometry is routinely assessed 
as a predictor of outcome in all patients with HR-ALL.  Exploratory analyses will also examine biomarkers 
of the proposed mechanism including adiposity and intervention-related changes in leukemogenic 
signaling pathways, oxidative stress, and cellular metabolism.  Parent- and subject-reported QOL 
assessments will consist of the PedsQL and Child and Adolescent Scale of Participation (CASP) surveys (see 
separate Appendix) and will be conducted pre- and post-induction and at two delayed time-points (mid-
point of intensive chemotherapy [3 months from diagnosis] and at end of intensive chemotherapy phase 
[10 months from diagnosis] to assess the psychosocial benefits of the intervention. 
 
6.2 
TREATMENT PLAN  
6.2.1 
DIETARY INTERVENTION  
The dietary intervention will be performed by an RD and is designed to achieve an at minimum ≥10% daily 
caloric deficit to prevent fat gain along with a moderate  fat (20-25%), high protein (20-25%), and low 
glycemic index/high fiber carbohydrate (45-55%) nutritional plan to prevent loss of lean muscle mass loss 
and to maintain micronutrient intake.  The subject’s basal metabolic rate (BMR) will be calculated using 
the Schofield equation as per the World Health Organization recommendations (World Health 
Organization, Energy and Protein Requirements, Technical Report Series 724, 1985) with an activity factor 
of 1.3 (“for a well-nourished child at bedrest with mild to moderate stress”) applied to better estimate 
the subject’s resting energy expenditure (REE) from which to calculate the initial 10% caloric deficit goal.   
At the initial counseling session, the dietician and family will determine which dietary technique is most 
likely to lead to dietary adherence.  Dietary management tools will incorporate the My Plate (USDA) and 
the Traffic Light Diet tools to help educate families regarding portion size and eating habits.  The RD will 
use a menu of common foods that meet the intake goals above as well as help families choose 
“exchanges” on the menu to personalize the menu options to maximize adherence.  During the initial 

 
26 
 
hospitalization, the RD will visit with the subject to assess caloric and nutrient intake using a 3-day food 
intake log, counsel subjects and their families on nutrition and eating habits, and instruct how to monitor 
food intake using a simplified log.  If available, and if the family so desires, the option will be available for 
families to use their personal cell phone or digital camera to take pictures of meals (before consumption 
and after consumption) to email to the RD to help guide the dietary intervention.  
 
During subsequent weekly outpatient chemotherapy clinic visits (or if the subject remains hospitalized), 
the RD will follow-up with families on their perceived adherence and obtain intermittent dietary intake 
via 24 hour diet histories.  Between clinic visits, the RD will also contact the family to provide 
reinforcement/motivation, answer questions, and obtain interval dietary history if necessary.  Specific 
dietary recommendations for foods/drinks, meals, and snacks will be adjusted weekly in discussion with 
families to meet the daily caloric deficit and goal diet as described.  The caloric goals may also be adjusted 
±5% depending on insufficient/excessive weight or body composition changes.  At the end of the acute 
intervention, the RD will discuss with the subject and family their dietary status and sustainable healthy 
eating behaviors.  
 
6.2.2 
PHYSICAL ACTIVITY INTERVENTION 
The physical activity intervention will be performed by a PT who regularly works with children on therapy 
for ALL as well as generally with pediatric oncology populations.  The PT will meet the subject and family 
surrounding the time of initial diagnosis.   The PT will assess at baseline the subject’s usual activity level, 
choices/preferences, and available activities at home once discharged.  A key component of this baseline 
assessment, and of beginning the exercise program during the initial hospitalization, will be education 
provided to subjects and their families to allay concerns over potential muscle weakness and/or fatigue 
and demonstrate with positive reinforcement how to exercise safely during leukemia therapy.  During the 
assessment, the subject’s “rate of perceived exertion” (RPE) will be assessed to gain insight into the 
subjects thresholds for exercise intensity. 
 
A target of 200 minutes/week will be set for a combination of “moderate” cardiovascular exercise and 
resistance training (36) with progressive goals based on adherence and capacity. As per latest guidelines 
from the American Heart Association, this weekly target may be accomplished with a minimum of 
30minutes/day or divided into 15-minute sessions over the course of the day with the goal of daily 
exercise. To quantify the prescribed “moderate” exercise, metabolic equivalents (METs) were assigned to 
a variety of exercise modes from which the subject may choose, which best suit their preference and 
home capabilities (Appendix I).   While the goal exercise prescription in METs is uniform for the 
intervention, the PT will work with the family and subject to outline an individual path to meet that goal 
based on the subject’s physical capabilities, preference, and home availability.  METs will be converted to 
“points” and the subject will be able to choose from suggested exercise modes with the appropriate 
number of minutes to meet daily and weekly “point” goals.  Subjects will be asked if there are any 
additional activities/exercises they would like to include. If so, these will be added and the “points” (METs) 
calculated for them.  Participants and their parents will be asked to record the selected mode and number 
of minutes performed on a study log (or calendar) and weekly total scores will be tabulated (METs-

 
27 
 
minutes). For patients who do not complete (or do not bring) the study log, adherence will be assessed 
by the PT at the time of visit via subject self-report of days meeting activity goals.  The following scale will 
be used: 0% (<1day/week), 25% (1-2days/week), 50% (3-4days/week), 75% (5-6days/week), 100% 
(7days/week).  Reported activity must meet 100% of that recommended for each qualifying day.   
The exercise program will be progressive by nature such that the Daily Goal is increased each week 
depending on adherence, ability, and clinical condition.   
 
All subjects will be provided a wearable electronic activity monitor (Fitbit®) to assist in recording home 
activity levels in minutes of activity; the Fitbit® has the important secondary benefit of providing visual 
reinforcement for the subject of their progress toward their Daily Goal as set by the study team.   
 
6.2.3 
MOTIVATIONAL INTERVIEWING (PROMOTION OF ADHERENCE TO INTERVENTION) 
To facilitate adherence to the dietary and behavioral changes above, motivational interviewing (MI) 
techniques will be employed by the study team. MI is a patient-centered method for enhancing intrinsic 
motivation to change health behavior by exploring and resolving ambivalence through the use of 
empathetic, nonjudgmental, and supportive communication techniques (37). Numerous studies have 
illustrated the efficacy of MI as a promising strategy to encourage positive health behavior change (38), 
including promoting health behavior change and weight loss in nutrition and exercise interventions in 
children and adults (37, 39). Specifically, MI has been used to promote diet and exercise in breast cancer 
patients with some success (41). 
 
6.2.4 
INTEGRATION OF INTERVENTION INTO ALL THERAPY 
While induction chemotherapy for pediatric ALL is a highly morbid and overwhelming time, the study 
team has significant experience working both with this specific population as well as other populations 
with high morbidity.  While lifestyle changes in general are difficult to achieve, short-term changes are 
generally more successful and patients and families in general are more receptive to short-term 
achievable goals.   
 
In this context, the 28 day intervention proposed here is purposefully designed to naturally integrate into 
the four week induction phase beginning with the start of systemic chemotherapy.  This phase routinely 
includes an initial hospitalization followed by weekly clinic visits with the treating provider for delivery of 
chemotherapy and evaluation of toxicity.  The study intervention and assessments are therefore 
formulated around this routine clinical schedule.  
 
Subjects will be enrolled surrounding the time of initial diagnosis within 24 hours of starting systemic 
chemotherapy.  Children are routinely hospitalized for a minimum of four days from the start of systemic 
chemotherapy.  During this time, they will have their baseline DXA scan (within 96 hours from start of 
systemic chemotherapy), the initial PT and RD assessments, and start with the supervised activity 
intervention and diet intervention.  Bedside nursing will be available to provide reinforcement during that 
time.  Following anticipated discharge, the subjects will be assessed at each weekly clinic visit to have 
their diet and activity interventions monitored and adjusted as needed and also to receive 

 
28 
 
education/motivation from the psychosocial team.  At the final clinic visit at the end of induction, subjects 
will receive the post-intervention assessments along with additional motivation/education.  Subjects will 
then continue on chemotherapy per routine care with ~8-9 additional months of intensive chemotherapy; 
subjects will receive PT, RD, and QOL assessments midway at the start of “interim maintenance” and again 
at the final time-point at the start of the low-intensity maintenance phase. These follow-up visits will help 
gauge whether the effect of the intervention and education extinguished or persisted during the 
intervening post-intervention months. 
 
6.3 
SUBJECT REMUNERATION 
While no payment is provided to subjects for participation, a Fitbit© will be provided to participants, as 
part of the study assessments as indicated in the schema and described further below. At the conclusion 
of the study’s follow-up portion, the subjects (or parent/guardian if the subject is <13 years of age) will be 
permitted to keep the Fitbit should they wish to do so. 
 
7.0 
MODIFICATIONS OF INTERVENTION FOR TOXICITY 
 
7.1 
MODIFICATION OF ACTIVITY INTERVENTION 
Instances may arise throughout the course of induction therapy in which subjects may not be able to 
adhere to the prescribed activity intervention due to complications from leukemia treatment. Initially, 
attempts will be made by the PT to lower the intensity of the intervention until complications subside. If 
treatment-toxicity is persistent or severe (i.e. subject in the PICU), the activity intervention will be 
suspended until the subject is deemed to be able to resume the intervention by the PT in consultation 
with the subject’s treatment team. 
 
7.2 
MODIFICATION OF DIETARY INTERVENTION 
Similarly, a subject may not be able to adhere to the nutrition intervention for reasons such as, 
nausea/emesis or the treatment team determining the subject cannot receive liquids or food by mouth 
(NPO). In such instances, the study team will continue to track all data at specified time-points and the 
registered dietician will re-assess nutritional caloric goals. Moreover, for subjects at lower BMI 
percentiles, despite the anticipated body fat gain, should the BMI percentile decrease to <5th percentile, 
the subject will come off-therapy as per Section 12.1. 
 
8.0 
SUPPORTIVE CARE GUIDELINES  
 
All supportive care should be provided as per standard of care and institutional guidelines.  No specific 
precautions are required for patients on study. 
 
9.0 
 REQUIRED OBSERVATIONS  
 
Please see “experimental schema” in study preamble for overview of treatment and required 
observations.   
 

 
29 
 
9.1 
REQUIRED OBSERVATIONS 
“At Diagnosis” blood samples should be collected before or in closest proximity as possible to starting 
systemic chemotherapy (steroid pre-treatment, steroid prophase, or intrathecal therapy may have 
already been given), but all samples must be collected before the start of the activity/nutrition 
intervention and prior to the end of chemotherapy day 4 
 
The DXA scan should be done in closest proximity to diagnosis as is feasible, but must be done within 96 
hours from the beginning of systemic chemotherapy and ideally before the start of the activity/nutrition 
intervention.  The timing of the DXA scan in relation to chemotherapy and the intervention will be 
recorded. 
 
STUDY MEASURE 
Diagnosis 
(Day 1) 
Day 
8 
Day 
15 
Day 
22 
End  
Induction 
(Day 29) 
Start 
IM#1 
Start 
Maint 
Patient History 
Clinical History1* 
X 
X 
X 
X 
X 
X 
X 
Anthropo-
metrics 
Height/Weight* 
X 
X 
X 
X 
X 
X 
X 
Tricep skin folds 
X 
X 
X 
X 
X 
X 
X 
Waist to hip ratio 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Assessments 
RD Assessment- 
3 day food log 
X 
 
 
 
X 
 
 
RD Assessment- 
24 hr recall 
X 
X 
X 
X 
X 
X 
X 
PT 
Assessment- 
Complete BOT2 
X 
 
 
 
X 
 
 
PT 
Assessment- 
BOT2 –Brief 
 
X 
X 
X 
 
X 
X 
Fitbit Tracker 
Continuous from time of study entry until study end 
Laboratory Tests 
(blood)2 
Liver 
function 
tests3* 
(AST/ALT/Bili) 
X 
X 
X 
X 
X 
 
 
Lipid Panel 
X 
 
 
 
X 
X 
X 
Mittelman Labs 
X 
 
 
 
X 
X 
X 
Peripheral 
blood 
leukemia blasts4 
X 
 
 
 
 
 
 
Pregnancy Test* 
X 
 
 
 
X 
 
 
Pathology Tests 
Bone 
Marrow 
Aspirate5* 
X 
 
 
 
X 
 
 
Biopsy 
Marrow 
Biopsy5 
X* 
 
 
 
X 
 
 

 
30 
 
Radiology 
Tests 
DXA Scan 
X 
 
 
 
X6 
 
 
Survey 
Instruments7 
PedsQL - Core 
X 
 
 
 
X 
X 
X 
PedsQL - Fatigue 
X 
 
 
 
X 
X 
X 
CASP 
X 
 
 
 
X 
X 
X 
*Indicates test per Standard of Care (SOC).  1 Clinical History includes any time NPO, any use of 
nasogastrointestinal (NG) or nasojejunal (NJ) nutrition, any parenteral nutrition, any surgeries, any ICU 
admissions, Grade 3 or 4 hepatic or pancreatic toxicity, presence of osteonecrosis or fracture.  2Research 
laboratories to include IGF-1 and obesity-related interleukins/signaling factors, leptin, adiponectin. 
Peripheral blood will not be collected in patients who are Jehovah Witness or with a medical 
contraindication. 3 Will record if collected routinely per SOC.  Each visit ±3 days.  End of induction includes 
any time prior to start of Consolidation phase. If Grade 3 hepatic toxicity during induction, will record values 
with date of resolution through start of IM#1 (<grade 2).  4To be collected in those with a circulating absolute 
blast count ≥500/uL.  5Extra aspirate for research will be collected as per below only if sufficient specimen 
is available; only specimens from bone marrow biopsies processed in saline will be collected for study.6 End 
of induction scan to be done between days 29 and 36 of therapy in as close proximity to day 29 as possible 
and prior to any subsequent systemic chemotherapy. 7Available in Spanish and English; if subject does not 
speak either, will be administered in an assisted manner using in-person or phone-based medical 
interpreters.  
 
 
 
9.2 
RADIOLOGY 
For those subjects who are female and of reproductive age, in addition to a pregnancy test at study entry 
as per routine care prior to chemotherapy, pregnancy will be assessed as per institutional guidelines at 
each site prior to any radiological tests. The results of these tests will be confidential. 
 
9.3  
BONE MARROW ASPIRATE & BIOPSY 
As per the preceding CHLA ALL Obesity Environment & Microenvironment Study #2, subjects on study 
may require extra bone marrow aspirate and biopsy for study purposes. The bone marrow aspirates will 
be collected during the same anesthesia and procedure being done for clinical care purposes and will be 
collected after the clinical specimen is obtained.  If there is insufficient specimen available, there will be 
no additional aspirates (needle punctures) performed for study purposes only and no bone marrow 
leukemia cells will be expected from that time-point for study.  If a routine bone marrow biopsy at 
diagnosis was performed with sufficient extra specimen, a piece will be collected for study purposes.  
Subjects undergoing bone marrow aspiration at end of induction for clinical purposes will also require a 
single additional research-only bone marrow biopsy to be performed at the same time.  For sites that do 
not (or cannot) collect bone marrow biopsies in saline, marrow biopsies will not be collected for this study.  

 
31 
 
Similarly, bone marrow biopsies not collected in saline (for any reason) will not be obtained for this study 
as it precludes analysis of the marrow fat.   
 
9.4 
EXTRA SAMPLE 
Any extra blood or bone marrow specimens collected at time of diagnosis or later while on this study, 
which is not needed for clinical purposes by the laboratory or pathology department may be used for 
further research purposes. Blood may be used for measurements of other related tests including but not 
limited to amino acids, cytokines, adipose tissue hormones, and/or collection of viable leukemia cells. 
Extra bone marrow aspirate/biopsy material may be used for examination, culture and studies to 
investigate cells type and functions. All testing will be done in the context of further investigating the 
relationships between bone marrow microenvironment, nutrition, osteoblasts, adipocytes and leukemia. 
 
9.5 
LABORATORY INFORMATION 
Serum levels of standard lipid panel and all other tests performed per standard of care will be performed 
by the hospital clinical laboratories.  Blasts, marrow adipocytes, and serum collected at CHLA for the 
assessment of obesity-associated laboratories will be stored at The Saban Research Institute until being 
batch shipped to Dr. Mittelman’s laboratory where they will be assayed in a batched manner.   
 
Samples collected from patients enrolled at other sites will be stored at that site and shipped directly to 
the Dr. Mittelman’s Laboratory (i.e. these will not be received at CHLA).  
Serum is to be aliquoted in 1ml cryovials and FROZEN at -80C.  Serum is to be labeled with (1) Study ID, 
(2) Date, and (3) Study visit.   
 
Coded samples will be shipped to the laboratory of Dr Mittelman:    
Steven Mittelman, M.D., Ph.D. 
David Geffen School of Medicine, UCLA 
10833 Le Conte Ave, MDCC 22-331 
Los Angeles, CA  90095 
 
In brief, subjects will have central catheters accessed (if applicable) by heme/onc nursing per routine 
clinical care. Phlebotomy if necessary will be performed by heme/onc clinical nursing or hospital-based 
clinical laboratory. Blood draws will be coordinated with routine collection where-ever possible.  It is 
recommended that study bags be provided to nursing prior to study visits that will contain all necessary 
specimen tubes and instruction regarding volumes to be drawn. Labels and/or instructions will be included 
regarding specimen distribution and specimen processing. At CHLA, for reference (and if study bags 
unavailable), please see Appendix I which contains all relevant details.   
 
10.0 
RADIOLOGY SAFETY INFORMATION 
Radiological studies will expose subjects to small amounts of radiation. Subjects will have quantification 
of body fat content by DXA. This type of scan is necessary as it provides complementary information and 
is the “gold standard” method to quantify body fat.   

 
32 
 
Each DXA examination exposes the subjects to less radiation than a single standard chest x-ray (DXA = 
~1/6 a standard chest x-ray).   DXA confers a radiation total effective dose equivalent (TEDE) of ~0.5 mREM 
of radiation per scan. This is a total study exposure of ~1 mREM for subjects (2 DXA scans). The critical 
organ exposed is the gonads; DXA contributes a total study exposure of 0.24 mREM to gonads in subjects. 
The total radiation exposure from the DXA scans is minimal and well beneath the 100 mREM upper limit 
considered to be “minimal risk” by the radiation safety committee. 
 
In common terminology, everyone receives a small amount of unavoidable radiation each year named 
“background radiation.” Some of this radiation comes from space and some from naturally-occurring 
radioactive forms of water and minerals. Participation on this research study gives the subject the 
equivalent of about 1 extra day of this natural radiation and is less than that of a single standard chest 
x-ray.  
 
11.0 
MISCELLANEOUS PATIENTS RISKS 
 
11.1 
BLOOD COLLECTION 
Subjects with central venous catheters will have extra blood collected for the study when there catheters 
are being accessed and blood drawn for clinical purposes.  As per above, patients with religious (Jehovah 
Witness) or medical contraindications will not have blood collected.  The collection of extra blood for 
study will prolong the procedure for less than 2 minutes and will not cause any significant discomfort.  
Subjects without central venous catheters will require venipuncture at each visit (using a needle to draw 
blood from a vein).  This may cause mild pain or a bruise at the site where the blood is to be collected.  
Occasionally, a person may feel faint during the time of blood collection.  The risk for infection is very rare 
since only sterile one-time equipment will be used.  If possible, sample collection will be coordinated with 
venipuncture for clinical purposes.  
 
11.2 
BONE MARROW ASPIRATE & BIOPSY 
All research procedures will be coordinated with clinical bone marrow aspirates and biopsies.  If there is 
insufficient specimen available from the bone marrow aspirate, there will be no additional aspirates 
performed for study purposes only.  As such, there is minimal additional risk to this procedure.  The 
research-only biopsy at the end of induction will be coordinated with the routine bone marrow aspirate; 
the biopsy will be obtained per standard practice using the same skin puncture with minimal prolongation 
of anesthesia (typically less than 3 minutes) with minimal additional post-operative discomfort due to the 
addition of the biopsy to the aspirate.  Post-operative care routinely includes assessments of discomfort 
and the clinical care teams will assist in managing this as needed. 
 
11.3 
POTENTIAL RISKS OF INTERVENTION  
We do not anticipate any risks directly due to the dietary intervention. Subjects may be at risk for syncope, 
falling and injury during the activity intervention. The PT will design an activity intervention for each 
subject that will aim to reduce the risk of fall and injury in patients that experience or develop minor 
difficulties balancing. In-hospital activity interventions will be properly supervised by a PT with vast 
experience handling pediatric cancer patients undergoing therapy. The potential risks of home-based 

 
33 
 
activities and methods for reducing risks will be discussed with patients and their families. Changes in 
weight and body composition are being carefully monitored by both a RD and PT throughout the 
intervention. Subjects that are unable to adhere to the dietary and/or activity intervention may be at risk 
for psychological distress (i.e. depression, anxiety, etc.). The treatment team will work to proactively 
address these risks in each patient through positive discussion and adjustment of the intervention if 
necessary.  Additionally, each patient may be at risk for psychological distress following the introspective 
nature of the QOL assessment. Psychological distress from any facet of the intervention will be monitored 
by the treatment team and referred to the psychosocial team if necessary. 
 
 
 
11.4 
OTHER RISKS 
As described above, there is a risk of radiation exposure from DXA scans to pregnant subjects. This risk 
will be minimized through routine procedures for women of child-bearing age undergoing chemotherapy 
including a pregnancy test at start of chemotherapy, tests per hospital policy prior to radiology exams, 
and guidance for adequate birth control or abstinence provided per routine by the primary treatment 
team. Confidentiality will be maintained to the standards set by Good Clinical Practice including no 
identification by name in any published research. Despite best efforts, there remains a risk for “breach of 
confidentiality” of the collected information. 
 
12.0 
CRITERIA FOR REMOVAL FROM THERAPY AND OFF-STUDY CRITERIA 
 
12.1 
OFF-THERAPY CRITERIA  
1. Continuation of the intervention is determined by physician judgment to not be in the best 
interest of the patient 
2. Subject refuses study interventions (but desires to continue with study observations) 
3. Subject’s BMI decreases to <5th percentile for age- and sex- (or <18.5 for those >20 years) 
 
Subjects who are off study therapy will continue to be followed with collection of laboratory, radiographic, 
survey, and assessment data unless they meet the criteria for off study (see below).    
 
For off-therapy patients, by family request and/or in response to questions during the assessments, 
routine clinical guidance for healthy diet and exercise will be provided by the PT and RD.  
 
12.2 
OFF-STUDY CRITERIA 
1. Death  
2. Relapse of Leukemia 
3. Change in treatment plan during induction (i.e. during the study intervention) that no longer 
meets initial eligibility requirements  
4. Lost to follow-up  
5. Subject withdrawal of consent 
6. Study closure 

 
34 
 
 
Study Closure:  The study will remain open for follow-up only for a period of 5 years from the last day of 
follow-up for the final subject.  During this time, there will be no study-specific visits or tests, but study 
personnel may contact patients in clinic or via telephone to obtain information relevant to patient health 
and diet and activity habits, and/or other relevant information that may become apparent throughout the 
course of the study, including but not limited to interventions performed by other care providers, survival, 
or relapse. For this purpose, study records and coding information will be maintained in a confidential 
database as below until study closure.   
 
 
13.0 
STATISTICAL CONSIDERATIONS AND EVALUATION CRITERIA 
 
13.1 
SAMPLE SIZE AND STUDY DURATION 
Based on available data over a recent 3-year period (2012-2014), we predict at least 43-45 subjects ≥10 
years of age with HR-ALL patients will be eligible for enrollment during the three year study.  We anticipate 
>85% of subjects to be enrolled & evaluable for the primary and secondary aim surrounding the Day 29 
time-point, for an effective sample size of at least 36 subjects.  As of AMD03, additional site(s) were added 
to gain experience with the study intervention at outside institutions; there is no change to the target 
study accrual goal of 36 evaluable subjects. 
 
As subjects historically gain body fat during induction irrespective of starting body composition (i.e. both 
those lean and those overweight/obese gain body fat), we will enroll a goal of 18 overweight/obese and 
18 lean subjects on the study to evaluate for an overall effect of the intervention, as well as a differential 
effect in those “lean” by BMI percentile.  We will continuously monitor accrual by weight category with a 
minimum final target accrual of 14 overweight/obese and 22 lean subjects (40/60) which, as below, 
preserves our ability to detect an effect on body fat and on the key secondary aim of MRD.  For assessment 
of the delayed endpoints, we expect that 80% of the initial cohort will additionally be evaluable for 
secondary the aims at the final pre-start of maintenance time-point (due to treatment-related 
morbidity/mortality/lost-to-follow-up).  
 
13.2 
PRIMARY ENDPOINT EVALUATION 
The primary endpoint for efficacy is a reduction in gain of body fat percent (per DXA) from diagnosis to 
the end of induction. From data on 36 patients from the historical cohort at CHLA with DXA scans pre and 
post induction, there was a significant average fat gain during induction therapy of 5.5±3.3 percent (mean 
± s.d.), p<0.001.  Based on a two-sample (36 historical, 36 present study) two-sided t-test with 5% Type I 
error, there will be at least 90% power to detect a 2.5 percentage point reduction in change in body fat as 
a result of intervention (e.g. from gain of 5.5 to a gain of 3.0%).  Hence, this study has sufficient power to 
detect subtle, achievable effects on body fat during induction, and will with certainty detect stabilization 
of or a decrease in body fat during induction.   
 
13.3 
SECONDARY ENDPOINTS Evaluation 

 
35 
 
To compare the rate of leukemia “positive” minimal residual disease (MRD) in the bone marrow at end of 
induction (≥0.01% mononuclear cells) in those who received the intervention as compared to historical 
controls. 
 
The key secondary endpoint for efficacy is whether or not the bone marrow is “positive” for MRD at the 
end of induction (using the COG definition of ≥0.01% mononuclear cells).  From the retrospective study at 
CHLA of B-precursor ALL/obesity and end-induction MRD, 69 patients in the cohort had HR-ALL over the 
age of 10 at diagnosis.  Of these, 53% of those overweight or obese (n=30) were MRD positive at the end 
of induction as compared to only 26% of those lean at diagnosis (n=39).  Using this cohort as the historical 
comparison group, for the overweight/obese subset only, this study will have approximately 80% power 
to detect a reduction in the MRD positive rate to approximately that of the historical lean group (i.e from 
53% to 24%) based on a two-sample, one-sided test of proportions with a Type I error of 0.10 (as a 
commonly used “go/no go” threshold to continue to Phase III trials).  For the overall cohort, again in 
comparison to the historical cohort (MRD+ 38%, n=26/69) using a similar two-sample, one-sided test of 
proportions, the study will have the ability at ~80% power to detect a decrease in MRD by 20%.  The study 
will therefore provide data on the potential reduction in the MRD positive rate that can be expected in 
preparation for the subsequent randomized Phase III trial for efficacy.  These analyses will be adjusted for 
risk group, age, and other factors as appropriate and also compared to external published rates for MRD 
positivity.    
 
To assess adherence to, and feasibility of, implementing a personalized and comprehensive dietary and 
exercise intervention during the first month of intensive chemotherapy  
 
This endpoint will be reported as the proportion of study subjects who adhere to proposed dietary and 
activity interventions.  A threshold of 80% of RD and PT visits (combined, RD only, PT only) completed will 
determine feasibility of incorporating the intervention itself into induction therapy.  Adherence to each 
component of the intervention will be further assessed using a threshold of 75% MET-minutes 
prescribed/completed and 75% of dietary adherence prescribed/actual intake (overall, and to each 
macronutrient group).  Further exploratory analysis will examine which sets of activities and dietary 
recommendations afforded the greatest level of adherence and any trends toward adherence by age, sex, 
race, and/or ethnicity.   
 
13.4 EXPLORATORY ENDPOINTS EVALUATION 
 
To evaluate persistence or extinguishing of this effect during continued dose-intensive phases of 
chemotherapy 
 
Reported continued adherence to activity and dietary recommendations will be evaluated by the RD and 
PT as per last prescribed or recommended from the intervention versus actual minutes/dietary intake at 
the delayed time-points of start of Interim Maintenance (~+3 months) and start of Maintenance (~+10 
months).  Activity and dietary intake patterns will also be compared to baseline at-diagnosis levels. Similar 
exploratory analysis will examine the effect of age, sex, race, and/or ethnicity. 

 
36 
 
 
To characterize the direct impact as compared to baseline of the intervention on self- and family- reported 
quality of life (QOL) outcomes including fatigue, mood, social interaction, and cognitive impairment 
reported via the PedsQL questionnaire and Child and Adolescent Scale of Participation (CASP) following 
the induction phase and serially during dose-intensive phases of chemotherapy 
 
The PEDSQL questionnaire returns a QOL score between 0-100 for each patient at each time-point.  The 
CASP is scored as a percentage and then normalized to a 100 point score.   Differences during therapy will 
be compared using a two-sided, paired t-test during induction (the intervention) and using repeated 
measures analysis for all four time-points.   
 
To quantify the effect of adiposity at diagnosis on the activity of leukemogenic JAK2/STAT3, 
PIK3K/AKT/mTOR, MAPK/ERK, and other signaling pathways in leukemia cells as determined by kinase 
phosphorylation 
 
Differences in levels of expression of the pathways will be analyzed according to body fat percentage 
(adiposity) using a two-sided, two-sample t-test for the different pathways as well visually for overall 
trends in related pathways. 
 
To quantify the effect of adiposity and of the intervention on the metabolic activity of leukemia blasts and 
of adipocytes as assessed by IGF-1, other obesity-associated cytokine signaling pathways, adiponectin, 
leptin, free fatty acid synthesis and metabolism, and levels oxidative stress. 
 
Exploratory analyses using similar t-tests will be performed to explore the effects of adiposity at diagnosis 
on adipokines, obesity-associated cytokines, oxidative stress, and measures of cellular metabolism. The 
effect of the intervention on oxidative stress and free fatty acid synthesis will be analyzed using paired t-
tests for pre/post intervention and compared to samples from the historical cohort. 
 
14.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
Adverse event (AE) data collection and reporting are required as part of every clinical trial to ensure the 
safety of patients enrolled in the studies as well as those who will enroll in future studies using similar 
agents. Adverse events are reported in a prescribed manner at scheduled times during the trial. 
 
Induction chemotherapy has many associated toxicities due to the intensity of regimen, and these will be 
monitored per routine care by the treatment team and/or by the appropriate research team if the subject 
is enrolled on a concurrent therapeutic research study.  
 
We will not record non-targeted toxicities (those described in clinical history Section 9.1) due to the 
underlying leukemia or treatment regimen. 
 

 
37 
 
As this trial consists of behavioral interventions (diet and exercise) that are within the scope of standard 
of care for patients, we will ONLY collect AE’s that occur during or immediately following the exercise 
activities.    If this should occur, the AE will be reported to the local IRB and the coordinating IRB (CHLA). 
 
For an AE that occurs as above, we will record and report using the National Cancer Institute Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE) available for download at http://ctep.cancer.gov. 
 
All reporting of adverse events must include: 
• 
severity (grade) of the event 
• 
duration of the event 
• 
attribution to the study (i.e. how the event is related to the study).  
• 
whether hospitalization was necessary (or prolonged) for subjects 
 
Categories of attribution in order of increasing likelihood are:  
• 
Unrelated 
• 
Unlikely 
• 
Possible 
• 
Probable 
• 
Definite 
 
All adverse events will be labeled “unexpected” for this behavioral study intervention.  
 
14.1 
EXPEDITED REPORTING OF ADVERSE EVENTS 
As a behavioral intervention that does not pose more than minimal risk to the subject, expedited reporting 
will only be required in the case: 
 
Toxicities that occur during this protocol-specified activity (as described above) and cause or prolong 
hospitalization will be reported in an expedited manner to the IRB within 5 business days. 
 
Toxicities that are ≥ Grade 4 and occur during the protocol-specified activity (as described above) will be 
reported in an expedited manner to the IRB within 5 business days. 
 
15.0 
RECORDS AND REPORTING 
 
Research records will be maintained through paper study-specific case reporting forms (CRF).  Research 
records for this study will be maintained in locked cabinets in the Clinical Trials Office (CTO) or institutional 
research offices accessible only to the investigators and study team.  The master list linking subjects to 
their unique identifier will be kept in the regulatory binder locked in the CTO office and in a password-
protected database.  Regulatory binder and CRFs will be maintained primarily by the research coordinator 
with assistance from the PIs/investigators as needed. 
 

 
38 
 
Study results will be entered by each site directly into the secure REDCap database maintained by USC/SC-
CTSI.   At conclusion of the treatment portion of the study, screening logs with coded identifiers only will 
be provided from each site to enable assessment of selection bias (e.g. CONSORT diagream). The database 
will then be downloaded by the study PI for potential further secondary analysis and follow-up as 
indicated in Section 13.2 (“Study Closure”).  The database will remain under unique password-protection 
and will be remain strictly confidential.  At the conclusion of the prescribed 5-year follow-up period (final 
study closure), all identifying information will be destroyed and the database will be preserved in a 
password-protected completely de-identified format for a minimum of six years as per CCI requirements 
at which time it will be destroyed. 
 
16.0 
DATA AND SAFETY MONITORING PLAN 
 
The Principal Investigators or designees will be available to answer questions of patients on the research 
protocol. As the study intervention constitutes a standard-of-care behavioral intervention only, data and 
safety monitoring for all patients enrolled on the study will be conducted by the study committee on an 
ongoing basis while the study is open.    
 
17.0 
LITERATURE CITED 
 
1. Butturini AM, Dorey FJ, Lange BJ, et al. Obesity and outcome in pediatric acute lymphoblastic leukemia. 
J. Clin. Oncol. 2007; 25:2063-2069. 
2. Orgel E, Geninger JM, Aggarwak D, et al. Association of body mass index and survival in pediatric 
leukemia: a meta-analysis. Am J Clin Nutr, 2016; [epub ahead of print] 
3. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a 
prospectively studied cohort of U.S. adults. N. Engl. J. Med. 2003; 348:1625-1638. 
4. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: 
interim efficacy results from the Women's Intervention Nutrition Study. J Natl Cancer Inst. 2006 Dec 
20;98(24):1767-76. 
5. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and survival after colorectal cancer 
diagnosis. J Clin Oncol. 2006 Aug 1;24(22):3527-34. 
6. Demark-Wahnefried W., Case LD., Blackwell K., et al. Results of a diet/exercise feasibility trial to prevent 
adverse body composition change in breast cancer patients on adjuvant chemotherapy. Clin Breast Cancer 
2008: 8:70-9. 
7. Gelelete CB, Pereira,SH, Azevedo AM, et al. Overweight as a Prognostic Factor in Children With Acute 
Lymphoblastic Leukemia. Obesity 2011. 
8. Butturini A, Vignetti M, Gubbiotti S, et al. Obesity Independently Predicts Event Free Survival (EFS) in 
Adults with BCR-ABL-Negative Acute Lymphoblastic Leukemia (ALL). A Retrospective Analysis of Two 
GIMEMA Studies. ASH Annual Meeting Abstracts 2005; 106:1828. 
9. Esbenshade AJ, Simmons JH, Koyama T, et al. Body mass index and blood pressure changes over the 
course of treatment of pediatric acute lymphoblastic leukemia. Pediatric Blood & Cancer 2011; 56:372-
378. 

 
39 
 
10. Withycombe JS, Post-White JE, Meza JL, et al. Weight patterns in children with higher risk ALL: A report 
from the Children's Oncology Group (COG) for CCG 1961. Pediatr Blood Cancer. 2009 Dec 15;53(7):1249-
54. 
11. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. 
Trends Pharmacol Sci. 2010 Feb;31(2):89-98. 
12. Raffaghello L, Lee C, Safdie FM, et al. Starvation-dependent differential stress resistance protects 
normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci U S A. 2008;105(24):8215-
20. 
13. Mavropoulos JC, Buschemeyer WC 3rd, Tewari AK, et al. The effects of varying dietary carbohydrate 
and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res (Phila). 
2009;2(6):557-65. 
14. Ho VW, Leung K, Hsu A, et al. A low carbohydrate, high protein diet slows tumor growth and prevents 
cancer initiation. Cancer Res. 2011;71(13):4484-93. 
15. Dunlap SM, Chiao LJ, Nogueira L, et al. Dietary energy balance modulates epithelial-to-mesenchymal 
transition and tumor progression in murine claudin-low and basal-like mammary tumor models. Cancer 
Prev Res (Phila). 2012;5(7):930-42. 
16. Goh J, Tsai J, Bammler TK, et al. Exercise training in transgenic mice is associated with attenuation of 
early breast cancer growth in a dose-dependent manner. PLoS One. 2013 Nov 27;8(11):e80123. 
17. Rundqvist H, Augsten M, Strömberg A, et al. Effect of acute exercise on prostate cancer cell growth. 
PLoS One. 2013 Jul 5;8(7):e67579. 
18. Courneya KS, McKenzie DC, Mackey JR, et al. Effects of exercise dose and type during breast cancer 
chemotherapy: multicenter randomized trial. J Natl Cancer Inst. 2013 Dec 4;105(23):1821-32. 
19. Adamsen L, Quist M, Andersen C, et al. Effect of a multimodal high intensity exercise intervention in 
cancer patients undergoing chemotherapy: randomised controlled trial. BMJ. 2009 Oct 13;339:b3410. 
20. Doyle C, Kushi LH, Byers T, et al. Nutrition and physical activity during and after cancer treatment: an 
American Cancer Society guide for informed choices. CA Cancer J Clin. 2006 Nov-Dec;56(6):323-53. 
21. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood and adult obesity in the United States, 
2011-2012. JAMA. 2014 Feb 26;311(8):806-14. 
22. Pulgarón ER. Childhood obesity: a review of increased risk for physical and psychological 
comorbidities. Clin Ther. 2013 Jan;35(1):A18-32. 
23. Shalitin S, Ashkenazi-Hoffnung L, Yackobovitch-Gavan M, et al. Effects of a twelve-week randomized 
intervention of exercise and/or diet on weight loss and weight maintenance, and other metabolic 
parameters in obese preadolescent children. Horm Res. 2009;72(5):287-301. 
24. Davis JN, Tung A, Chak SS, et al. Aerobic and strength training reduces adiposity in overweight Latina 
adolescents. Med Sci Sports Exerc. 2009 Jul;41(7):1494-503. 
25. Varni JW, Burwinkle TM, Katz ER, The PedsQL in pediatric cancer: reliability and validity of the Pediatric 
Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer. 
2002 Apr 1;94(7):2090-106. 
26. Reinfjell T, Lofstad GE, Veenstra M, et al. Health-related quality of life and intellectual functioning in 
children in remission from acute lymphoblastic leukaemia. Acta Paediatr. 2007 Sep;96(9):1280-5. 

 
40 
 
27. Meeske K, Katz ER, Palmer SN, et al. Parent proxy-reported health-related quality of life and fatigue in 
pediatric patients diagnosed with brain tumors and acute lymphoblastic leukemia. Cancer. 2004 Nov 
1;101(9):2116-25. 
28. Sung L, Yanofsky R, Klaassen RJ, et al. Quality of life during active treatment for pediatric acute 
lymphoblastic leukemia. Int J Cancer. 2011 Mar 1;128(5):1213-20. 
29. Sitaresmi MN, Mostert S, Gundy CM, et al. Health-related quality of life assessment in Indonesian 
childhood acute lymphoblastic leukemia. Health Qual Life Outcomes. 2008 Nov 9;6:96. 
30. Speyer E, Herbinet A, Vuillemin A, et al. Effect of adapted physical activity sessions in the hospital on 
health-related quality of life for children with cancer: a cross-over randomized trial. Pediatr Blood Cancer. 
2010 Dec 1;55(6):1160-6. 
31. Paxton RJ, Jones LW, Rosoff PM, et al. Associations between leisure-time physical activity and health-
related quality of life among adolescent and adult survivors of childhood cancers. Psychooncology. 2010 
Sep;19(9):997-1003. 
32. Behan JW, Yun JP, Proektor MP, et al. Adipocytes impair leukemia treatment in mice. Cancer Res 2009; 
69:7867-7874. 
33. Ehsanipour EA, Sheng X, Behan JW, et al. Adipocytes Cause Leukemia Cell Resistance to L-Asparaginase 
via Release of Glutamine. Cancer Res 2013; 73:2998-3006. 
34. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood 
acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group 
study. Blood 2008; 111:5477-5485. 
35. Orgel E, Sposto R, Malvar J, et al. Impact on Survival and Toxicity by Duration of Weight Extremes 
during Treatment for Pediatric Acute Lymphoblastic Leukemia: A Report from the Children's Oncology 
Group. J Clin Oncol 2014; In Press. 
36. Donnelly JE, Blair SN, Jakicic JM, et al: American College of Sports Medicine Position Stand. Appropriate 
physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med 
Sci Sports Exerc. 2009; 41:459-71. 
37. Rollnick S, Butler CC, Kinnersley P, et al. Motivational interviewing. BMJ. 2010 Apr 27;340:c1900. 
38. Schwartz RP. Motivational interviewing (patient-centered counseling) to address childhood obesity. 
Pediatr Ann. 2010 Mar;39(3):154-8. 
39. Tripp SB, Perry JT, Romney S, et al. Providers as weight coaches: using practice guides and motivational 
interview to treat obesity in the pediatric office. J Pediatr Nurs. 2011 Oct;26(5):474-9. 
40. Lazzer S, Agosti F, De Col A, A Comparison of predictive equations for resting energy expenditure in 
severely obese Caucasian children and adolescents. J Endocrinol Invest. 2007; 30: 313-317. 
41. Djuric Z, Ellsworth JS, Weldon AL, et al. A Diet and Exercise Intervention during Chemotherapy for 
Breast Cancer. Open Obes J. 2011;3:87-97. 
42. Giuffrida A and Torgerson DJ. Should we pay the patient? Review of financial incentives to enhance 
patient compliance. BMJ 1997; 315:703-707.