Home or Away From Home: Comparing Clinical Outcomes Relevant to the Care of Pediatric Acute Myeloid Leukemia During Periods of Neutropenia
Conditions: Acute Myeloid Leukemia, Neutropenia, Bacteremia
Sponsor: Children's Hospital of Philadelphia

 
Observational Template: February 16, 2011 
Title: 
Home or away from home: comparing clinical outcomes 
relevant to the care of pediatric acute myeloid leukemia or  
myelodysplastic syndrome during periods of neutropenia 
 
Short Title: 
Aim 1: Managing neutropenia in pediatric AML/MDS 
 
NCT Number: 
NCT02774850 
 
Protocol Date: 
April 2, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
ii
Title: 
Home or away from home: comparing clinical outcomes 
relevant to the care of pediatric acute myeloid leukemia or  
myelodysplastic syndrome during periods of neutropenia 
Short Title: 
Aim 1: Managing neutropenia in pediatric AML/MDS 
Sponsor: 
Patient-Centered Outcomes Research Institute (PCORI) 
eIRB Number: 
15-012074 
Protocol Date: 
April 2, 2019 
 
Amendment 1 Date: August 28, 2015                     Amendment 19 Date: December 19, 2016 
Amendment 2 Date: August 28, 2015                     Amendment 20 Date: April 12, 2016 
Amendment 3 Date: September 23, 2015                Amendment 21 Date: May 25, 2017 
Amendment 4 Date: October 2, 2015                      Amendment 22 Date:Withdrawn June 2, 2017 
Amendment 5 Date: October 26, 2015                    Amendment 23 Date: June 9, 2017 
Amendment 6 Date: February 15, 2016                  Amendment 24 Date: June 29, 2017 
Amendment 7 Date: March 28, 2016                      Amendment 25 Date: August 1, 2017 
Amendment 8 Date: April 26, 2016                        Amendment 26 Date: August 30, 2017  
Amendment 9 Date: May 27, 2016                         Amendment 27 Date: December 7, 2017  
Amendment 10 Date: June 7, 2016                         Amendment 28 Date: December 27, 2017 
Amendment 11 Date: June 21, 2016                       Amendment 29 Date: February 9, 2018 
Amendment 12 Date: July 8, 2016                          Amendment 30 Date: April 18, 2018 
Amendment 13 Date: July 16, 2016                        Amendment 31 Date: May 21, 2018 
Amendment 14 Date: August 9, 2016                     Amendment 32 Date: June 15, 2018 
Amendment 15 Date: August 23, 2016                   Amendment 33 Date: October 19, 2018 
Amendment 16 Date: September 15, 2016             Amendment 34 Date: January 4, 2019 
Amendment 17 Date: October 12, 2016                 Amendment 35 Date: February 28, 2019 
Amendment 18 Date: November 28, 2016             Amendment 36 Date:  
 
Richard Aplenc, MD, PhD 
The Children’s Hospital of Philadelphia 
3501 Civic Center Blvd 
Philadelphia, PA, 19104 
Phone 267-426-7252 
email: aplenc@chop.edu 

 
  
 
 
 
 
 
iii
TABLE OF CONTENTS 
Table of Contents .................................................................................................................. iii 
Abbreviations and Definitions of Terms.............................................................................. v 
Abstract ................................................................................................................................. vi 
Figure 1: Study Diagram ..................................................................................................... vii 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
1.1 
INTRODUCTION ..................................................................................................................................... 1 
1.2 
RELEVANT LITERATURE AND DATA ..................................................................................................... 1 
1.3 
COMPLIANCE STATEMENT .................................................................................................................... 2 
2 
STUDY OBJECTIVES .............................................................................................................................. 3 
2.1 
OBJECTIVES .......................................................................................................................................... 3 
2.1.1 
Compare the incidence of bacteremia among children with AML monitored in the outpatient 
setting during neutropenia (“early discharge”) relative to those who remain hospitalized (“inpatient”). . 3 
2.1.2 
Compare the length of time to initiation of the subsequent chemotherapy course between children 
with AML monitored in the outpatient setting during neutropenia to similar children who remain 
hospitalized. ................................................................................................................................................. 3 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 3 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 3 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................... 3 
3.3 
TOTAL NUMBER OF STUDY SITES/TOTAL NUMBER OF SUBJECTS PROJECTED ...................................... 3 
3.3.1 
Duration of Study Participation ...................................................................................................... 3 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 4 
3.4 
STUDY POPULATION ............................................................................................................................. 4 
3.4.1 
Aim 1 Inclusion Criteria .................................................................................................................. 4 
3.4.2 
Aim 1 Exclusion Criteria ................................................................................................................. 4 
There are no exclusion criteria for this protocol. All patients that meet the inclusion criteria in 3.4.1 will 
contribute data.  ........................................................................................................................................... 4 
4 
STUDY PROCEDURES ............................................................................................................................ 5 
4.1 
AIM 1 ................................................................................................................................................... 5 
4.1.1 
Retrospective Patient Identification: ............................................................................................... 5 
4.1.2 
Prospective patient identification: .................................................................................................. 5 
4.1.3 
Data Abstraction ............................................................................................................................. 5 
4.2 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................. 5 
5 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 5 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .................................................. 5 
5.1.1 
Medical Record Review ................................................................................................................... 5 
6 
STATISTICAL CONSIDERATIONS ...................................................................................................... 7 
6.1 
PRIMARY ENDPOINT ............................................................................................................................. 7 
6.2 
CONTROL OF BIAS AND CONFOUNDING ................................................................................................ 7 
6.3 
STATISTICAL METHODS........................................................................................................................ 8 
6.3.1 
Analysis of Primary Outcomes of Interest ....................................................................................... 8 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................... 9 
7 
SAFETY MANAGEMENT ....................................................................................................................... 9 
7.1 
CLINICAL ADVERSE EVENTS ................................................................................................................ 9 
7.2 
ADVERSE EVENT REPORTING ............................................................................................................... 9 

 
  
 
 
 
 
 
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8 
STUDY ADMINISTRATION ................................................................................................................... 9 
8.1 
DATA COLLECTION AND MANAGEMENT .............................................................................................. 9 
8.1.1 
Data sources.................................................................................................................................. 10 
8.2 
CONFIDENTIALITY .............................................................................................................................. 10 
8.3 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 10 
8.3.1 
Data and Safety Monitoring Plan ................................................................................................. 10 
8.3.2 
Risk Assessment ............................................................................................................................. 10 
8.3.3 
Potential Benefits of Study Participation ...................................................................................... 11 
8.3.4 
Risk-Benefit Assessment ................................................................................................................ 11 
8.4 
RECRUITMENT STRATEGY .................................................................................................................. 11 
8.5 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 11 
8.5.1 
Waiver of Consent ......................................................................................................................... 11 
8.5.2 
Waiver of Assent ............................................................................................................................ 12 
8.5.3 
Waiver of HIPAA Authorization .................................................................................................... 12 
8.6 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 12 
9 
PUBLICATION ........................................................................................................................................ 12 
10 
REFERENCES ......................................................................................................................................... 12 
 
 

 
  
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATIONS 
 
 
AML 
ANC 
CHOP 
 
Acute Myeloid Leukemia 
Absolute Neutrophil Count 
The Children’s Hospital of Philadelphia 
CI 
COG 
ICU 
MDS                     
PCORI 
 
Confidence Intervals 
Children’s Oncology Group 
Intensive Care Unit 
Myelodysplastic syndrome 
Patient-Centered Outcome Research Institute 
REDCap™ 
SD 
 
 
 
Research Electronic Data Capture 
Standard Deviation  
 
 
 
 
DEFINITIONS 
 
 
 
Bacteremia 
Positive blood culture for a bacterial pathogen unless the bacterium is 
an organism considered a common commensal organism by the 
National Healthcare Safety Network 
Early Discharge 
Discharge to outpatient management during neutropenia within 3 days 
 
 
 
after chemotherapy completion in a given course 
Neutropenia   
Absolute Neutrophil Count <200/L 

 
  
 
 
 
 
 
vi
ABSTRACT 
Context: (Background)  
Treatment for pediatric acute myeloid leukemia (AML) or myelodysplastic syndrome 
(MDS) involves intensive chemotherapy regimens that result in periods of profound 
neutropenia leaving patients susceptible to severe infectious complications. Infectious 
complications are the leading cause of treatment related mortality among AML and MDS 
patients, but there are little clinical data to inform whether management of neutropenia post 
AML chemotherapy should occur in an outpatient or inpatient setting.  
Objectives:  
The primary objective of this study is to compare the clinical effectiveness of outpatient 
versus inpatient management of neutropenia in children with AML or MDS receiving 
standard intensive AML frontline chemotherapy. 
Study Design:  
This is a bidirectional observational cohort study.  
Setting/Participants: 
Participants will be less than 19 years of age at their initial AML or MDS diagnosis 
receiving or having received frontline AML chemotherapy from seventeen participating 
pediatric hospitals across the United States (US). We anticipate that approximately 540 
subjects will be evaluable for chart abstraction over the study period in order to study 
clinical outcomes including the occurrence of bacteremia and time to the start of the next 
course in the chemotherapy regimen, in relation to neutropenia management strategy.   
Study Interventions and Measures:  
There is no study intervention.  Main outcomes include occurrences of bacteremia after 
completion of an AML chemotherapy course, and time from completion of one course to the 
next planned course of chemotherapy.

 
  
 
 
 
 
 
vii
FIGURE 1: STUDY DIAGRAM 
 
 

 
  
 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE  
1.1 Introduction 
Acute myeloid leukemia (AML) is the second most common pediatric hematologic 
malignancy with approximately 600 new cases per year among patients under 20 years of 
age.  Although AML accounts for only about 20% of leukemias in children, it is responsible 
for more than half of pediatric leukemia deaths (1).  
All pediatric patients with newly diagnosed AML receive multiple consecutive courses of 
intensive myelosuppressive chemotherapy aimed to attain complete remission (induction) 
and to prevent relapse (intensification) (2). Each regimen is followed by a period of 
prolonged severe neutropenia during which patients are at high risk for infection and 
hemorrhage.  Previous reports have found that 57-80% of febrile neutropenia episodes 
among pediatric AML patients are compromised by at least one microbiologically 
documented infection (3, 4) with bacteremia constituting the most prevalent infection (5). 
These infectious complications remain a major cause of therapy-associated morbidity and 
mortality in children with AML (6, 7). 
Recently published pediatric neutropenia guidelines make no specific recommendations 
regarding discharge from hospital after chemotherapy for AML because “there are no 
validated schemas for defining those patients at high-risk of developing complications of 
fever and neutropenia” (8). As a result, clinicians are left to decide whether to keep a child 
in the hospital until the neutropenia resolves (on average 35 days) or discharge a child to 
outpatient management within a few days of chemotherapy completion with instructions to 
return if symptoms of infection develop. Physicians that elect to observe patients with 
neutropenia in the hospital do so under the assumption that hospital observation will reduce 
the risk of serious infection and thereby reduce delays in starting the next course of 
chemotherapy.  There is documented variation in practice across Children’s Oncology 
Group (COG) institutions on inpatient versus outpatient management of neutropenia with 
approximately 60% of COG institutions reporting a policy to always keep patients 
hospitalized during severely neutropenic periods and the remaining 40% of hospitals 
reporting a policy of home management some or all of the time (9, 10).  This variation in 
practice highlights the need for additional data on clinician-centered outcomes to 
appropriately guide the management of neutropenia in pediatric AML patients.   
Myelodysplastic syndromes (MDSs) are a rare heterogenous group of hemopoietic clonal 
disorders characterized by ineffective hemopoiesis and frequent evolution to leukemia. 
Children with clinical and morphological features of MDS but with the cytogenetic features 
typical of AML are often treated with same intensive frontline chemotherapy used to treat 
AML (23). Thus, questions regarding clinician-centered and patient-centered outcomes in 
relation to outpatient versus inpatient management of neutropenia would apply equally to 
such patients. 
1.2 Relevant Literature and Data  
The limited literature on the clinical consequences of outpatient versus inpatient 
management of neutropenia in AML is focused on the experience of adult patients. Adult 

 
  
 
  
 
 
 
2
patients discharged early to outpatient supportive care consistently had shorter cumulative 
lengths of stay than inpatients (11-18). Additionally, early discharge of adult AML patients 
receiving chemotherapy has been associated with fewer and shorter febrile episodes (15, 
19), a better response to first line antibiotics, and shorter duration of intravenous antibiotic 
administration (13, 15, 18, 19). While these adult studies provide some reassurance that 
outpatient management may be safe and feasible they are limited as most included data from 
only a single institution, had very small sample sizes, or lacked an appropriate inpatient 
reference population. Furthermore, it is not appropriate to extrapolate these adult findings to 
pediatric patients as the risk profile for children may be much different.  
The published literature with respect to outpatient management of neutropenia in pediatric 
AML is limited to a single study of only 13 patients from one hospital, which found similar 
rates of relapse and mortality for outpatient versus inpatient management of neutropenia 
(20).  In our own preliminary analyses based on administrative resource utilization data from 
43 free-standing children’s hospitals in the US, we found that patients who were discharged 
early to outpatient management following AML induction and intensification chemotherapy 
courses incurred fewer cumulative days of hospitalization, but were frequently readmitted 
and had higher rates of antibiotic, vasopressor, and supplemental oxygen utilization than 
patients who remained inpatient during the entirety of their neutropenia. In the absence of 
clinical data and laboratory confirmation, it is unclear whether these observed increases in 
resource utilization are an accurate proxy for a greater incidence of infection or more severe 
infection in the early discharge patients. 
In order to appropriately inform the decision for outpatient versus inpatient management of 
neutropenia associated with pediatric AML chemotherapy, a comprehensive study that 
collects pertinent clinical outcomes is necessary. Given that infectious complications are the 
leading cause of treatment related mortality among AML patients (22) and among MDS 
patients (24, 25), identifying such a neutropenia management strategy that leads to the best 
clinical outcomes will have a substantial impact on care of these patients.  
Bacteremia, a cause of transient cardiac decline, occurs frequently during AML treatment 
and contributes to the development of cardiac dysfunction.(26) COG guidelines for re-
challenging patients to anthracycline chemotherapy distinguish infection-associated LV 
systolic dysfunction (LVSD) from LVSD not associated with infection, allowing patients 
who experience resolution of infection-associated LVSD to receive additional anthracycline 
therapy. However, there are no data comparing the longitudinal trajectories of EF/SF or the 
impacts on subsequent cardiomyopathy and treatment outcomes for these distinct 
presentations of cardiotoxicity. 
1.3 Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46. All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol and will report 
unanticipated problems involving risks to subjects or others in accordance with The 
Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal 

 
  
 
  
 
 
 
3
requirements. Collection, recording, and reporting of data will be accurate and will ensure 
the privacy, health, and welfare of research subjects during and after the study. 
 
2 
STUDY OBJECTIVES 
The purpose of this study is to compare the effectiveness of outpatient versus inpatient 
management of AML neutropenia or MDS in individuals receiving standard AML frontline 
chemotherapy. We plan to accomplish this through the following Objectives: 
 
2.1 Primary Objectives 
2.1.1 Compare the incidence of bacteremia among children with AML or MDS 
receiving standard intensive AML frontline chemotherapy monitored in the 
outpatient setting during neutropenia (“early discharge”) relative to those 
who remain hospitalized (“inpatient”). 
2.1.2 Compare the length of time to initiation of the subsequent chemotherapy 
course between children with AML or MDS receiving standard intensive 
AML frontline chemotherapy monitored in the outpatient setting during 
neutropenia to similar children who remain hospitalized.  
2.2 Secondary Objectives 
2.2.1 Identify subpopulations based on distinct longitudinal patterns of LV ejection 
fraction (EF) and fractional shortening (SF) decrease and recovery and 
evaluate the impact of bacteremia on the longitudinal patterns of LVEF and 
LVSF. Compare relapse risk (RR) and OS in subgroups.  
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This observational cohort study will evaluate clinical outcomes of inpatient versus outpatient 
management of neutropenia following chemotherapy in children with AML or MDS by 
abstracting data from medical records. 
3.2 Study Duration, Enrollment and Number of Sites 
The study plans to include patients treated for AML or MDS anytime from January 1, 2012 
or after.    
3.3 Total Number of Study Sites/Total Number of Subjects Projected 
3.3.1 Duration of Study Participation 
No direct patient contact is necessary for this study; only medical record abstraction. The 
chart abstraction window for each participant will include the time period from the start of 
the first course of chemotherapy until the date of last patient contact or death.  

 
  
 
  
 
 
 
4
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
Chart abstraction will be conducted at the following seventeen US investigative sites: Ann 
Arbor (C.S. Mott Children’s Hospital), Atlanta (Children’s Healthcare of Atlanta), Chicago 
(Ann & Robert H Lurie Children’s Hospital of Chicago), Dallas (Children’s Medical Center 
of Dallas – University of Texas Southwestern Medical Center), Detroit (Children’s Hospital 
of Michigan), Houston (Texas Children’s Hospital), Jackson (Children’s of Mississippi), 
Little Rock (Arkansas Children’s Hospital), New Orleans (Ochsner Medical Center for 
Children), Palo Alto (Lucile Packard Children’s Hospital Stanford), Philadelphia 
(Children’s Hospital of Philadelphia), Salt Lake City (Primary Children’s Medical Center), 
San Diego (Rady Children’s Hospital), Seattle (Seattle Children’s Hospital), Denver 
(Children’s Hospital of Colorado), Nemours/A.I. duPont Hospital for Children, and 
DFCI/Boston Children’s Hospital (Boston, MA). These sites were chosen based on 
geographic location, their substantial AML/MDS patient volume, and the variation in 
primary strategy of neutropenia management (inpatient versus outpatient).  
We expect to identify a total of approximately 600 newly diagnosed AML patients across 
the seventeen participating institutions over the study period of which approximately 540 are 
expected to meet early discharge eligibility criteria.  
3.4 Study Population 
The study population will include all AML and MDS patients who received or will receive 
chemotherapy starting January 1, 2012 at any of the seventeen participating pediatric 
institutions across the US. Patients discharged within 3 days after completion of that 
chemotherapy course will be categorized as ‘early discharge’ to outpatient management 
during neutropenia. Patients meeting eligibility criteria for ‘early discharge’ but remaining 
in the hospital more than 3 days after completion of that chemotherapy course will be 
categorized as inpatient management. Patients will be considered early discharge-eligible if 
there is no evidence of fever, infection or intensive care unit (ICU) level care within ± 3 
days of the last dose of chemotherapy.  
3.4.1Aim 1 Inclusion Criteria 
1) Males or females less than 19 years of age at initial AML/MDS diagnosis.   
2) Receipt or planned receipt of standard intensive AML frontline chemotherapy any time 
from January 1, 2012 or after. 
3.4.2Aim 1 Exclusion Criteria  
 Patients being treated for relapsed AML  
 Patients with Acute Promyelocytic Leukemia (APML) 
 Patients undergoing stem cell transplant (SCT) 
 Patients receiving reduced intensity frontline chemotherapy 
 

 
  
 
  
 
 
 
5
4 
STUDY PROCEDURES 
4.1 Aim 1 
The only study procedure for this cohort is chart abstraction; thus, there will be no study 
visits or other patient contact encounters required from the participant.  
4.1.1 Retrospective Patient Identification:  
Local study investigators (pediatric oncologists and study coordinators) at each of the 
seventeen participating pediatric institutions will review their hospital AML or MDS 
registry to identify patients from January 1, 2012 through the date of IRB approval that meet 
enrollment criteria.  
4.1.2 Prospective patient identification: 
The prospective data abstraction timeline begins the date of IRB approval and lasts through 
the duration of the study. Study investigators at each institution will communicate on a 
weekly basis with their inpatient leukemia service to identify AML or MDS patients 
potentially eligible for study enrollment. Once identified, study personnel will review each 
patient for study eligibility criteria. 
4.1.3 Data Abstraction 
For all enrolled patients, chart abstraction will be performed by CHOP personnel or local 
site staff using standardized data abstraction processes. Trained CHOP study personnel will 
first abstract data for CHOP patients identified between January 1, 2012 and date of IRB 
approval.  They will then travel to the other 16 sites to assist and educate local study 
personnel on the chart abstraction procedures for patients identified at those institutions. 
Alternatively, CHOP personnel can perform medical record abstraction remotely for sites 
who grant CHOP remote EMR access. All data will be abstracted directly into REDCap™ 
via standardized electronic case report forms developed by CHOP study personnel. Details 
on data to be abstracted from the medical record are included in sections 5.1.1 and 6.1 
below.  
4.2 Subject Completion/Withdrawal 
This is an analysis of data that are documented in the course of providing clinical care to 
subjects. As there are no additional interventions necessary for the execution of this study 
and we do not foresee any adverse effects stemming from the research, a waiver of consent 
will be submitted to address the issue of subject withdrawal.  
 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
The following variables will be abstracted from the medical chart:  

 
  
 
  
 
 
 
6
Variable 
 
Date of birth 
Sex 
Patient race/ethnicity 
Date of AML/MDS diagnosis 
Age at AML/MDS diagnosis 
Vital status 
Date of death or date of last known follow-up 
Location of death (in hospital or at home) 
AML subtype 
AML risk classification and cytogenetics 
Hospital admission start/stop dates 
Chemotherapy course  
Chemotherapy regimen and start/stop dates 
Course start/stop dates 
Clinical trial enrollment and specific protocol 
Documentation of deviation from planned chemotherapy course 
Presence/type of central line 
MRD post courses and dates of MRD obtained 
Post course remission status 
Daily max. fever; how was temperature taken 
Infections during chemotherapy courses 
ICU care during chemotherapy courses 
ANC measurements post chemotherapy 
Dates of ANC measurements 
Dates and results of microbiological cultures/PCRs onset during post chemotherapy course 
follow-up 
Mucositis by course 
Systematic antimicrobial prophylaxis at each course 
Height, weight, and body surface area at start of chemotherapy course 
Nutritional status/supplemental support requirements on day of chemotherapy completion 
Ability to practice oral hygiene 
Insurance status at course start (private, self-pay, public, other) 
English spoken? 
Home address 
Availability of working telephone 
Automobile/taxi voucher requirements 
Date of relapse 
Site of relapse 
Date of transplant 
Type of transplant 
Echocardiographic evaluations (e.g., dates, resulting measurements, measurement mode)  
Blood pressure and heart rate at echocardiographic evaluations 
Dexrazoxane administration 
Malignant blast percentage 

 
  
 
  
 
 
 
7
Bone marrow malignant blast percent 
Empiric/definitive anti-infective use 
Preferred language 
Treatment and positive blood cultures at outside hospital (y/n) 
Down Syndrome diagnosis 
CNS status at the end of each course 
Outpatient encounters (e.g., clinic/day hospital, ED) 
 
Some information will be retained for all screened patients to document the reasons for 
ineligibility. Specifically, we will be retaining information on age, leukemia diagnosis, 
treatment course, and whether the patient received reduced intensity chemotherapy. 
 
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary outcomes will include the following two endpoints (ascertained from patient 
medical records):  
1.) Occurrence of post-chemotherapy bacteremia 
Identification of bacteremia will begin three days after completion of a 
chemotherapy course and will continue until recovery of neutrophil count (ANC > 
200 L), or until the start of the next course (for a very small number of patients who 
begin the next course of chemotherapy prior to count recovery). Bacteremia will be 
defined as a single positive blood culture for a bacterial pathogen (including Viridans 
group Streptococci). If the bacterium is an organism considered as a common 
commensal organism by the National Healthcare Safety Network, two separate 
positive blood cultures will be required for classification as bacteremia. 
 
2.) Time to the initiation of the next chemotherapy course  
Time to next course of chemotherapy will be measured as the number of days from 
the three days after the completion chemotherapy in a given course until the first day 
of the next course. 
 
6.2 Control of Bias and Confounding 
This is an observational cohort study, so subjects are not assigned by a process of 
randomization and are therefore subject to bias. However, analyses of our data will control 
for potential confounding by various patient- and hospital- level factors.  Additionally, there 
is a possibility of exposure misclassification given that patients who are discharged more 
than 3 days after chemotherapy completion but well before neutropenia recovery will still be 
included in the inpatient management group.  To account for this imperfect specificity, 
sensitivity analyses will be performed utilizing a less strict threshold for discharge 
classification (e.g., 5- or 10 days post-chemotherapy).  

 
  
 
  
 
 
 
8
6.3 Statistical Methods 
6.3.1 Analysis of Primary Outcomes of Interest 
Propensity score analyses will be used to adjust for potential confounding by baseline 
covariates.  First, bivariate analyses will be performed to evaluate relationships between 
each baseline covariate and neutropenia management strategy as well as each outcome of 
interest. Next, propensity scores will be derived from the predicted probabilities estimated 
from logistic regression models of the use of outpatient versus inpatient management during 
neutropenia conditional on all baseline factors determined to be true confounders (i.e., those 
associated with both exposure and outcome) and those determined to be potential 
confounders (i.e., those associated only with the outcome interests).  Patients will then be 
stratified into five groups using quintiles of the estimated propensity score. The distributions 
of exposure within the quintiles will be examined for sufficient sample sizes and balance. 
Within each stratum, the patients managed as outpatient and those managed as inpatient will 
ideally have similar values of the propensity score and likewise the distribution of measured 
baseline covariates will be comparable between them. 
Log-binomial regression will be used to estimate risk ratios with 95% confidence intervals 
(CI) comparing the incidence of bacteremia following outpatient versus inpatient 
neutropenia management strategy. Control for confounding will be accomplished through 
adjustment for propensity score by quintiles as well as any remaining unbalanced patient- or 
hospital-level confounders.  
Generalized linear regression models will be utilized to compare time (in days) from three 
days after completion of one chemotherapy course to initiation of the next course of 
chemotherapy by neutropenia management strategy (outpatient versus inpatient). Before 
model fitting, the normality of the outcome will be assessed. If the normality assumption 
holds, then traditional linear models (normal distribution with an identity link) will be 
utilized. If the distribution of time to next course is significantly skewed, then models 
assuming a gamma or log-normal distribution as appropriate will be used.  Again, control 
for confounding will be accomplished through adjustment for propensity score by quintiles 
as well as any remaining unbalanced confounders.  
Although there will be limited power to quantify heterogeneity of effects across strata of 
covariates, hypothesis-generating subanalyses will be performed to evaluate the potential for 
effect measure modification (on both absolute and relative scales) by age, race, and 
insurance status (as a proxy for socioeconomic status) via stratification to inform future 
studies.   
6.3.1 Analysis of Secondary Outcome of Interest 
One secondary outcome of interest is LV function quantified as EF and SF over the courses 
of therapy and post-treatment follow-up. LVEF and LVSF trajectories will be determined by 
group-based latent trajectory modeling, a type of structural equation modeling which 
identifies distinct clusters of individuals based on development, progression, and resolution 
patterns pertaining to the repeated measures of a given variable. The following factors will 
be explored as predictors identified trajectory phenotypes: age, gender, race, ethnicity, 
weight group, presenting white blood cell count, and baseline EF/SF. Univariate and 

 
  
 
  
 
 
 
9
multivariable mixed effects regression models will be fitted to quantify the association 
between bacteremia and longitudinal EF and SF measurements. 
6.4 Sample Size and Power 
Assuming 100% capture of eligible patients (waivers of consent obtained from all 
participating sites), we expect to identify a total of 600 newly diagnosed AML/MDS patients 
across the seventeen participating centers. Assuming 90% of identified patients will be early 
discharge eligible, the anticipated study population will be 540 patients. Based on the rates 
for the individual participating sites, approximately 27% of the study population will be 
managed as outpatients (n= 146) and the remaining will be managed as inpatients (n=394) 
during neutropenia. Assuming a baseline risk of bacteremia of 60%, the proposed size of the 
two study arms would provide greater than 80% power to detect a 13% difference in 
bacteremia rates among patients managed as outpatients versus those that remain 
hospitalized, with a significance level of 0.05. A 13% difference in bacteremia rates would 
also be a clinically significant difference.  For time to next chemotherapy course, we used a 
two sample t-test in the power calculation to be conservative (i.e., statistical analysis using a 
generalized linear model with correct distribution will result in creased power over a t-test). 
Assuming each patient contributes one treatment course and an average time to next 
chemotherapy course of 29 days and a standard deviation (SD) of 10 (based on preliminary 
data), our study will have 85.0% power to detect a difference of 3 days between the two 
groups, with a significance level of 0.05.  
 
7 
SAFETY MANAGEMENT 
7.1 Clinical Adverse Events 
As this is a medical record review, there is no possibility of a clinical adverse event (AEs).  
7.2 Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) these will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review. 
 
8 
STUDY ADMINISTRATION 
8.1 Data Collection and Management 
Medical record data will be abstracted directly into electronic case report forms via 
REDCap™, a secure, web-based application designed exclusively to support data capture 
for research studies. We will utilize REDCap™, automated export processes to seamlessly 

 
  
 
  
 
 
 
10
download the chart abstraction data to statistical packages for review and analysis. All 
statistical output and generated data files, tables and figures will be stored in password 
protected files on a secure server, which is automatically backed up each night. A unique 
study identification number will be assigned to participants so that no study file contains 
identifiable information.  Each site will maintain their own master list linking each patient’s 
unique study identification number to their medical record number. These site master lists 
will be stored in password-protected files that are only accessible by approved local study 
personnel.  Identifiers will be destroyed after publication. Access to identifiable information 
by investigators, programmers, analyst, and statisticians will be kept to the minimum 
necessary mandated by HIPAA regulations. Coded, limited data sets will be shared with 
participating sites upon approved request, as specified in Section 8.2. Only aggregate level 
data will be shared with the study sponsor PCORI. 
8.1.1 Data sources  
Patients’ electronic medical records will be queried for demographic information, clinical 
information, and hospital admission/discharge dates.  The complete list of variables is 
detailed in Section 5.1.1.  
8.2 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy.  The Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study.  No identifiable data will be used for future study without first obtaining IRB 
approval. The investigator will obtain a data use agreement between provider (the PI) and 
any recipient researchers (including others at CHOP) before sharing a limited dataset (dates 
and zip codes).  Safeguards to protect confidentiality were described in Section 8.1 and are 
also detailed in Section 8.3.2. 
8.3 Regulatory and Ethical Considerations 
8.3.1 Data and Safety Monitoring Plan 
Given the types of data and the observational study design, specifically the absence of an 
imposed intervention, there will be no Data and Safety Monitoring Board associated with 
this study. However, if any risks are identified, the Principal Investigator will notify the IRB 
promptly. 
8.3.2 Risk Assessment 
This is a minimal risk study.  There are no new patient interventions or treatments associated 
with the work outlined in this proposal. As such, there are no expected additional health 
risks that a patient would incur as a result of participation in this study. The medical care of 
subjects will not be affected in any way by their participation in this study.  
An unlikely but possible risk is the loss of confidentiality.  We will institute strict 
procedures to maintain confidentiality. Each site will maintain their own master list linking 
each patient’s unique study identification number to their medical record number. These site 
master lists will be stored in password-protected files that are only accessible by approved 

 
  
 
  
 
 
 
11
local study personnel. Identifiers will be destroyed after publication. Entry to the offices is 
controlled at a main entrance by identification card readers. Research materials will be 
accessible only to members of the investigative team. Access to identifiable information by 
investigators, programmers, analyst, and statisticians will be kept to the minimum necessary 
mandated by HIPAA regulations to carry out the proposed research. Any publications or 
presentations resulting from this work will not identify participants by name, but will only 
present aggregate data. Our prior research employing similar precautions has demonstrated 
that these techniques are very successful in assuring the protection of subjects.  
8.3.3 Potential Benefits of Study Participation 
The patients involved in the study might not benefit directly. Results from the study may be 
applied in the future to AML/MDS patients in making decisions about the best way to 
manage neutropenia. Improved understanding of the outcomes of outpatient versus inpatient 
management of neutropenia will be of great importance to AML/MDS patients and the 
providers who care for them.  
8.3.4 Risk-Benefit Assessment 
This is an analysis of data that are documented in the course of providing clinical care to 
subjects. There are no additional interventions necessary for the execution of this study and 
thus there is minimal risk involved with respect to the knowledge that may result from the 
research. 
8.4 Recruitment Strategy 
No advertising will be done for this study. Local study investigators (pediatric oncologists 
and study coordinators) will review their hospital’s AML registry to identify newly 
diagnosed AML and MDS patients in the retrospective period of the study. For the 
prospective component, local study investigators will identify newly diagnosed AML/MDS 
patients from weekly communications with the local inpatient leukemia service.  
8.5 Informed Consent/Assent and HIPAA Authorization 
8.5.1 Waiver of Consent 
A full waiver of consent will be requested from the Institutional Review Board. This is an 
observational study and therefore complete capture of all events is ideal to ensure accurate 
and unbiased results. It would be impracticable to obtain consent from all eligible patients as 
it would require obtaining consent from parents of critically ill children, some of whom 
would certainly refuse to participate in a research study. Some of the patients may no longer 
be followed at the given institution, or may have moved out of the area, thus up-to-date 
contact information may not be available. Each site will submit for a waiver of consent at 
their respective institutions.  
For those sites that do not enter into a cooperative agreement with the CHOP IRB, and a 
waiver of consent is not granted for prospective data collection, parents will then be given a 
thorough explanation of the study including the purpose, risks and benefits of participation, 
confidentiality, and contact information for study personnel. Families will be informed their 
medical care at that healthcare facility will not be affected if they choose not to participate in 

 
  
 
  
 
 
 
12
the proposed research.  Any site-required informed consent/assent and HIPAA 
Authorization will take place in a quiet, private space to ensure confidentiality, the family 
will be provided ample time to make an informed and thoughtful decision, and the signed 
document will be maintained at the local site in a secure location.   
8.5.2 Waiver of Assent 
A full waiver of assent will be requested to collect the electronic health record of subjects. 
This is an observational study and therefore it is necessary to include all patients to ensure 
accurate and unbiased estimates. 
8.5.3 Waiver of HIPAA Authorization 
A full waiver of HIPAA Authorization will be requested for comprehensive collection of 
pertinent clinical outcomes. It would be impracticable to obtain consent from all eligible 
patients as it would require obtaining consent from parents of critically ill children, some of 
whom would certainly refuse to participate in a research study. Study subjects may no 
longer be followed at clinic or may have moved out of the area, thus up-to-date contact 
information is not available. This is an observational study and thus complete capture of all 
events is ideal to ensure accurate and unbiased results.  
8.6 Payment to Subjects/Families 
There will be no reimbursement or gifts supplied to patients in this study.  
 
9 
PUBLICATION 
The results of this study will be prepared and submitted to peer-reviewed journals.  The 
compiled de-identified data from this study will be maintained by CHOP investigators.  
Thus all submitted manuscripts will be directed by these CHOP investigators.  Any data 
presented will be presented in summary form and there will be no potential for patient 
identification through a publication. 
   
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