A Prospective Cohort Study to Define Infectious Burden, the Seroprevalence of Vaccine Preventable Pathogens and Immune Recovery in the First Year Following Completion of Therapy in Patients With Acute Lymphoblastic Leukemia (ALL)
Conditions: Acute Lymphoblastic Leukemia, Pediatric
Sponsor: Children's Hospital of Philadelphia

 
  
 
 
i 
Title: 
A prospective cohort study to define infectious burden, the 
seroprevalence of vaccine preventable pathogens and immune 
recovery in the first year following completion of therapy in 
patients with acute lymphoblastic leukemia (ALL) 
Short Title 
 Vaccine Immune Recovery After Leukemia   
Sponsor: 
Merck & Co.  
eIRB Number 
NCT# 
IRB 21-019426 
NCT05622682 
Protocol Date: 
Amendment #1 Date: 
Amendment #2 Date: 
Amendment #3 Date: 
Amendment #4 Date: 
Amendment #5 Date: 
Amendment #6 Date: 
Amendment #7 Date: 
Amendment #8 Date: 
Amendment #9 Date: 
January 14, 2022 
August 31, 2022 
November 1, 2022 
March 3, 2023 
May 2, 2023 
September 21, 2023 
October 27, 2023 
January 30, 2024 
April 16, 2024 
February 11, 2025 
 
 
Brian T. Fisher, DO, MSCE, MPH (Principal Investigator) 
Children’s Hospital of Philadelphia- 
The Roberts Center for Pediatric Research 
2716 South Street 
Philadelphia, PA 19146 
Phone 267-426-0196 
email: fisherbria@email.chop.edu 
 
 
 
 
Leena Chehab, MD, MS (Lead Investigator) 
Children’s Hospital of Philadelphia 
Hub for Clinical Collaboration, 3rd floor 
3500 Civic Center Blvd 
Philadelphia, PA 19104 
Phone 215-301-6239 
email: chehabl@chop.edu  

 
  
 
 
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Table of Contents 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract .................................................................................................................................. v 
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 .................................................................................................................... 3 
2 
STUDY OBJECTIVES .............................................................................................................................. 3 
2.1 
PRIMARY OBJECTIVE (OR AIM) ............................................................................................................ 3 
2.2 
SECONDARY OBJECTIVE (OR AIM) ....................................................................................................... 3 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 3 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 3 
3.2 
TOTAL NUMBER OF STUDY SITES/TOTAL NUMBER OF SUBJECTS PROJECTED ...................................... 4 
3.2.1 
Duration of Study Participation ...................................................................................................... 4 
3.2.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 4 
3.3 
STUDY POPULATION ............................................................................................................................. 5 
3.3.1 
Inclusion Criteria for ALL Cohort .................................................................................................. 5 
3.3.2 
Exclusion Criteria for ALL Cohort ................................................................................................. 5 
3.3.3 
Inclusion/Exclusion Criteria for Matched Healthy Controls Cohort .............................................. 5 
4 
STUDY PROCEDURES ............................................................................................................................ 6 
4.1 
SCREENING ........................................................................................................................................... 6 
4.2 
VISIT SCHEDULE ................................................................................................................................... 6 
4.2.1 
Visit ................................................................................................................................................. 6 
4.3 
OBSERVATIONAL PERIOD ..................................................................................................................... 6 
4.4 
SUBJECT COMPLETION/WITHDRAWAL ................................................................................................. 6 
5 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 7 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS .................................................. 7 
5.1.1 
Medical Record Review ................................................................................................................... 7 
5.1.2 
Laboratory Evaluations................................................................................................................... 8 
5.1.3 
Social Determinants of Health Survey .......................................................................................... 10 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 11 
6.1 
PRIMARY ENDPOINT ........................................................................................................................... 11 
6.2 
SECONDARY ENDPOINT ...................................................................................................................... 11 
6.3 
STATISTICAL METHODS...................................................................................................................... 11 
6.3.1 
Baseline Data ................................................................................................................................ 11 
6.3.2 
Analysis of Aim 1 ........................................................................................................................... 11 
6.3.3 
Analysis of Aim 2 ........................................................................................................................... 12 
6.3.4 
Control of Bias and Confounding ................................................................................................. 12 
6.4 
SAMPLE SIZE AND POWER .................................................................................................................. 13 
7 
STUDY ADMINISTRATION ................................................................................................................. 15 
7.1 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 15 
7.2 
CONFIDENTIALITY .............................................................................................................................. 16 
7.3 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 16 
7.3.1 
Risk Assessment ............................................................................................................................. 16 
7.3.2 
Potential Benefits of Study Participation ...................................................................................... 16 
7.3.3 
Risk-Benefit Assessment ................................................................................................................ 16 
 

 
 
 
 
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7.4 
RECRUITMENT STRATEGY .................................................................................................................. 17 
7.5 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 17 
8 
PUBLICATION ........................................................................................................................................ 18 
9 
REFERENCES ......................................................................................................................................... 19 
10 
APPENDICES ........................................................................................................................................ 211 
 

 
  
 
 
iv
ABBREVIATIONS AND DEFINITIONS OF TERMS 
ALL 
CCSS 
CHOP 
 
Acute lymphoblastic leukemia 
Childhood Cancer Survivor Study 
Children’s Hospital of Philadelphia 
COG 
CRB 
CT 
DFCI 
HCT 
HMH 
IgG 
 
Children’s Oncology Group 
Central Review Board 
Computed Tomography 
Dana-Farber Cancer Institute 
Allogeneic Hematopoietic Cell Transplantation 
Household Material Hardship   
Immunoglobulin G 
IRB 
IPD 
MRI 
 
Institutional Review Board 
Invasive Pneumococcal Disease 
Magnetic Resonance Imaging 
NCCN 
PMBCs 
 
National Comprehensive Cancer Network 
Peripheral blood mononuclear cells 
REDCapTM 
Tfh 
 
Research Electronic Data Capture 
T follicular helper cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
 
 
v
ABSTRACT 
Context: 
 
Advancements in therapy have led to significant improvement in outcomes for children 
diagnosed with acute lymphoblastic leukemia (ALL), with overall survival rates now 
exceeding 90%. Although this therapy is lifesaving, it is well known to impact vaccine- and 
infection-acquired immunity. The morbidity and mortality associated with infection is 
significant but education, early diagnosis and prevention through vaccination has the 
potential to improve outcomes. Assessing infection risk and longitudinal recovery of 
immune function post-ALL therapy are necessary to establish evidenced based therapeutic 
approaches.  
 
Objectives: 
 
There are three main objectives to be accomplished by Aim 1 and Aim 2. Aim 1 will be to 
determine the overall infection incidence rate within the first year following completion of 
therapy for ALL, compared with the incidence of infection in matched healthy controls 
during the same time period. Aim 2 will describe seroprevalence for pneumococcus, 
varicella, and measles at approximately 3, 6, and 12 months following completion of therapy 
in patients with ALL and describe B and T lymphocyte subset recovery, specifically CD4+ 
T follicular helper cells (Tfh), using peripheral blood mononuclear cells (PMBCs) at about 
3, 6, and 12 months following completion of ALL therapy 
 
Study Design:  
 
This study will assemble a prospective, multicenter observational cohort of approximately 
115 patients that are completing ALL chemotherapy at one of several pediatric 
hematology/oncology centers in the US (Children’s Hospital of Philadelphia (CHOP), Lurie 
Children’s Hospital of Chicago, Seattle Children’s Hospital, Helen DeVos Children’s 
Hospital, Children’s Hospital at Vanderbilt, Christus Children’s Hospital (Baylor College of 
Medicine), and Children’s Hospital Los Angeles). Consented subjects will have a baseline 
enrollment visit followed by monthly check-ins via phone and/or chart review to determine 
if the enrolled patient had any documented viral or bacterial infections or symptoms (Aim 1) 
and 2) in-person visits at roughly 3, 6, and 12 months post-completion of ALL therapy to 
obtain blood samples to perform immune function studies (Aim 2).  
 
For comparison of infection rates in patients post-ALL therapy to those of healthy control 
patients, once the follow-up period for the enrolled ALL cohort patients has ended, a cohort 
of matched healthy control patients will be assembled. Controls will be selected at a ratio of 
3:1, with the full healthy control cohort including up to 330 total patients. The healthy 
control patients will be followed for the same one-year period as their matched ALL cohort 
patients. Control patients will be selected from patients who received care at CHOP 
beginning in 2022 and matched to ALL cohort patients based on age and sex.  
 
Setting/Participants: 
 

 
  
 
 
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This is a multicenter study at several pediatric hematology/oncology centers in the US 
(CHOP, Lurie Children’s Hospital of Chicago, Seattle Children’s Hospital, Helen DeVos 
Children’s Hospital, Children’s Hospital at Vanderbilt, Christus Children’s Hospital (Baylor 
College of Medicine), and Children’s Hospital Los Angeles). The study cohort will consist 
of up to 110 evaluable patients prospectively enrolled over the course of this study. Eligible 
patients include: Children, adolescents, and young adults diagnosed with B or T ALL at age 
12 months or older; have completed up-front ALL therapy within the past three months or 
will complete ALL therapy in the upcoming three months, and are three years of age or 
older at time of enrollment. Patients who have a diagnosis of infant ALL, evidence of 
disease relapse, have a history of primary immunodeficiency (except related to Down 
Syndrome), received a stem cell transplant or cellular immunotherapy, or prior malignancy 
or condition requiring chemotherapy other than for current ALL diagnosis will be excluded.  
All matched healthy control patients will be selected from the Children’s Hospital of 
Philadelphia’s Pediatric Research Consortium patient population regardless of where their 
matched ALL cohort patient was enrolled in the study.  
Study Measures:  
 
Aim 1 will capture any infection documented at any inpatient or outpatient encounter 
documented by the managing medical team in the first year after completing ALL 
chemotherapy. An incident infection rate will be calculated for the cohort and compared 
with that of age- and sex-matched healthy controls during the same time period. The 
secondary aim will assess the seroprevalence for pneumococcus, varicella and measles 
among study subjects at approximately 3, 6, and 12 months after completion of therapy. This 
aim will also describe B and T lymphocyte subset recovery at these same timepoints. The 
outcomes for Aim 1 and Aim 2 will be described by certain demographic characteristics and 
underlying diagnoses, as well as ALL treatment protocol. Additionally, laboratory reports 
will be prospectively collected. These data will serve to define the infection rate in the first 
year after completing ALL chemotherapy and inform immune recovery overall and to 
specific vaccine preventable illnesses (i.e. varicella, measles, and pneumococcus). 

 
 
 
 
 
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FIGURE 1: STUDY DIAGRAM 
  
FIGURE 2: STUDY DIAGRAM 
 

 
  
 
  
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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
 
The treatment modalities of childhood cancer often have a significant impact on the immune 
system on survivors of childhood cancer. Although there is a robust body of literature that 
describes immunological outcomes, testing recommendations, and revaccination guidelines 
after allogeneic hematopoietic cell transplantation (HCT), immunological assessments are 
not routinely included in surveillance guidelines for survivors of childhood cancer that have 
not received HCT. As a result, survivorship care providers might not fully consider the 
impaired recovery of a child’s immune system after cancer treatment if the child has not 
undergone HCT. Currently, survivors of childhood cancer who received standard therapy 
and missed scheduled vaccinations during their cancer therapy restart their vaccination 
schedule anywhere between 6 to 12 months after completion of treatment. For patients that 
completed a vaccine series, the Children’s Oncology Group (COG) Hematopoietic Cell 
Transplant/ Immune/Dermatology Late Effects Taskforce recommends that providers and 
survivors consider either the use of boosters for previously administered vaccines, or the 
measurement of titers on which to base the administration of boosters. Despite these 
recommendations there are limited data on timing of immune reconstitution after ALL 
chemotherapy and effectiveness of the response to vaccines if administered. It is also 
acknowledged that there is a paucity of data on the frequency and outcome of infections 
among survivors in the first year after completion of therapy.  Determining the frequency of 
infection in the first year post chemotherapy and documenting the recovery of immune 
function overall and to specific vaccine preventable pathogens will provide foundational 
data to guide current clinical decision-making and inform future clinical trials. 
 
1.2 
Relevant Literature and Data 
 
Advancements in therapy have led to significant improvement in outcomes for children 
diagnosed with ALL, with overall survival rates now exceeding 90%. Although this therapy 
is lifesaving, its use is well known to impact vaccine- and infection-acquired immunity.1, 2 
As a result, infection remains a significant cause of morbidity and mortality during therapy.3, 
4 Published literature has documented that children with ALL have a 10-fold higher risk of 
invasive pneumococcal disease (IPD) during treatment for their cancer, with the highest risk 
occurring during maintenance chemotherapy.5, 6 Importantly, this risk likely persists beyond 
the period of therapy receipt. The Childhood Cancer Survivor Study (CCSS) reported that 
survivors of all cancer were 1.6 to 2.7 times more likely to be hospitalized for infection >5 
years following the completion of therapy compared with age-matched and sex-matched 
individuals in the general population.7 While these data are compelling there is a paucity of 
data documenting the frequency of infections or type of infections that occur in the first year 
following completion of therapy in children and adolescents with ALL.4, 8 As such, 
clinicians do not have the necessary information to discuss infection risk with parents and 
their patients in this post-therapy period. 
 
Additionally, there are limited data regarding the retention of seroprevalence for vaccine 
preventable infections during this post chemotherapy period.9 Significant interest exists in 
revaccinating children and adolescents after completion of therapy for ALL, however, the 

 
  
 
  
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necessity of such an intervention has not been clearly defined.10 Studies completed to date 
document that some children have low antibody titers to vaccine antigens immediately 
following treatment with therapy.1, 11, 12 However, these studies did not consider the 
possibility that patients further removed from their therapy will have more robust immune 
function recovery inclusive of vaccine antigen specific immune response.  It is necessary to 
assess longitudinal recovery of immune function post-ALL therapy to better inform the need 
for revaccination among these children.  
 
The proposed multicenter study will serve to define infection rates in the post-ALL therapy 
period in children, adolescents, and young adults and define the seroprevalence for vaccine 
specific antigens as well as presence of lymphocyte subsets at discrete time-points after 
therapy completion.  These data will be immediately informative to clinicians aiming to 
manage expectations of parents for infection risk in their child post ALL therapy. 
Additionally, this prospective cohort represents an ideal opportunity to compare 
management decisions for children regarding timing of vaccination following completion of 
ALL therapy. Currently, The National Comprehensive Cancer Network (NCCN) 
recommend that survivors of childhood cancer who received standard (non- HCT) therapy 
and missed scheduled vaccinations during their cancer therapy should be given all 
vaccinations that were missed, beginning at 6 to 12 months after completion of treatment. 
Based upon lower-level evidence, the NCCN recommends that survivors of childhood 
cancer who were fully vaccinated before diagnosis, and who were treated with 
chemotherapy or radiotherapy (non- HCT), or both, engage with their provider in a shared 
decision making to determine approaches to revaccination that might be considered for the 
individual survivor11.  
 
One such approach might be to administer booster doses for all routine vaccinations without 
checking pre-vaccination titers. A different approach would be to measure antibody titers to 
determine levels of seroprotection first and then recommending booster doses if inadequate 
levels of seroprotection are found. Finally, in the absence of data for necessity to administer 
booster dosing, some centers may elect not to measure antibody titers or provider booster 
dosing. Not surprisingly, these options have led to variability in practice, even when centers 
have developed institution-specific guidelines.13 A survey of Canadian pediatric oncology 
centers found wide variation in the performance of post-treatment titers and reimmunization 
practices for survivors of ALL who have not had HCT.14 Data from this descriptive study 
will serve to inform future comparative trials designed to optimize vaccination protocols in 
the period after completion of ALL therapy.    
 
At the end of 2024, the Children’s Oncology Group reported data from a randomized 
controlled trial revealing improved effectiveness of ALL chemotherapy regimens inclusive 
of the novel biological agent blinatumomab. The improved outcomes of patients receiving 
ALL chemotherapy inclusive of blinatumomab has led to immediate transition to this 
regimen as standard of care for most patients with ALL. While blinatumomab may have 
improved effectiveness for cure of cancer it may alter immune reconstitution trajectories in 
the survivorship period.15 Because most of this study cohort was enrolled prior to the 
institution of blinatumomab as standard of care, it is uniquely positioned to now enroll ALL 
survivors that have or will have received blinatumomab as part of their chemotherapy 

 
  
 
  
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regimen. Including blinatumomab recipients will provide exploratory data on potential 
differences in immune reconstitution between patients receiving this new standard of care 
relative to prior standard of care ALL chemotherapy regimens.   
 
1.3 
Compliance Statement 
 
This study will be conducted in full accordance all applicable local Policies and Procedures 
and all applicable Federal and state laws and regulations including 45 CFR 46 and the 
HIPAA Privacy Rule. All episodes of noncompliance will be documented. The investigators 
will perform the study in accordance with this protocol, will obtain consent and assent, 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 
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 
2.1 
Primary Objective (or Aim) 
 
Aim 1: To determine the overall infection incidence rate within the first year following 
completion of therapy for acute lymphoblastic leukemia and compare that rate with the rate 
of infections occurring in age- and sex-matched healthy control patients during the same 
time period. 
 
• Sub-aim: To examine infection incidence in patients who received the monoclonal 
antibody blinatumomab as part of their ALL treatment protocol versus that of 
patients who did not receive blinatumomab.  
 
2.2 
Secondary Objective (or Aim) 
 
Aim 2a: To describe total IgG levels and specific seroprevalence for pneumococcus, 
varicella, and measles at approximately 3, 6, and 12 months following completion of therapy 
in patients with ALL 
 
Aim 2b: To describe B and T lymphocyte subset recovery, specifically CD4+ Tfh, using 
PMBCs at approximately 3, 6 and 12 months following completion of ALL  
 
• Sub-aim: To examine the immune function markers as outlined above in patients 
who received the monoclonal antibody blinatumomab as part of their ALL treatment 
regimen versus patients who did not receive blinatumomab.  
 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
 
This is a prospective, multicenter observational study that will assemble a cohort of 
approximately 115 patients that recently completed or are about to complete ALL therapy at 

 
  
 
  
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one of several pediatric hematology/oncology centers in the US (CHOP, Lurie Children’s 
Hospital of Chicago, Seattle Children’s Hospital, DeVos Children’s Hospital, Children’s 
Hospital at Vanderbilt, Christus Children’s Hospital (Baylor College of Medicine), and 
Children’s Hospital Los Angeles), including a sub-cohort of 20-25 patients who received 
blinatumomab as part of their chemotherapy regimen. The same 115 individuals will 
contribute to both Aim 1 and Aim 2 (Figure 1 and Figure 2). Only patients receiving care at 
a participating site will be eligible for enrollment in this cohort.  
 
3.2 
Total Number of Study Sites/Total Number of Subjects Projected 
3.2.1 Duration of Study Participation 
Patients will be followed from the date of enrollment until the first of the following events: 
approximately one year from completion of therapy, loss to follow-up or death.   
 
Data abstraction from the medical record will be used to determine their end of therapy date. 
Their medical record will also be examined to collect specified relevant data related to 
reported infectious history as well as vaccination history. The in-person enrollment visit will 
require approximately one-hour of direct contact with the patient and caregiver to obtain 
consent (and when necessary, assent) and to complete the enrollment encounter. Once 
enrolled, followed by in-person visits at approximately 3, 6, and 12 months. At these visits 
an interim infectious history will be obtained and patients will have blood drawn for 
research assays as detailed below.  These visits and the associated blood draw will be 
aligned with regularly scheduled oncology visits. The blood specimen will be drawn by the 
oncology nursing team and/or phlebotomy and whenever possible will be obtained at the 
same time as a clinical blood draw. Between in-person visits, study staff will contact 
caregivers for enrolled patients via phone call, text message, or email (as preferred by 
caregiver) to capture interim infection events. If text message or email is used to contact 
caregiver, but additional information is needed, a phone call will be made when necessary. 
 
At the end of participants’ study follow-up periods, age- and sex-matched healthy control 
patients will be identified from the CHOP Pediatric Research Consortium (PeRC) for 
comparison. Three controls will be randomly selected from a list of otherwise healthy 
individuals with similar age and sex and matched to each ALL patient enrolled. Infection 
events will be captured for these controls during the same time period the study participant 
was followed to compare the rate of infection events in the post-ALL therapy cohort with 
that of matched healthy controls.  
 
3.2.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at seven investigative sites in the United States. Other sites may 
be added in the future. It is expected that approximately 115 subjects will be enrolled over 
the course of this study to produce 110 evaluable subjects. Evaluable patients will be defined 
as patients that are enrolled and at least one blood specimen collected.  
 
For each of the 110 enrolled evaluable subjects in the ALL cohort, at the end of the follow-
up period, three age- and sex-matched healthy control patients will be selected for 
comparison, to assemble a cohort of 330 total healthy control patients. The full cohort, 

 
  
 
  
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including both ALL patients and 3:1 matched controls, is anticipated to include 440 
evaluable patients.  
 
3.3 
Study Population 
3.3.1 Inclusion Criteria for ALL Cohort 
1. Children, adolescents, and young adults ages 3 years to 31 years diagnosed with B or T 
ALL at age 12 months or older 
 
2. Completed ALL chemotherapy within the past three months or will complete ALL 
chemotherapy in the upcoming three months (+/- 4 weeks) 
 
• Blinatumomab sub-cohort (n = 20-25): received ALL chemotherapy including the 
monoclonal antibody blinatumomab 
 
3. Three years of age or older at time of enrollment.  
 
3.3.2 Exclusion Criteria for ALL Cohort 
1) Diagnosis of infant ALL 
 
2) Evidence of disease relapse 
 
3) History of primary immunodeficiency (except related to Down Syndrome) 
 
4) History of a stem cell transplant or cellular immunotherapy 
 
5) History of prior malignancy or condition requiring chemotherapy other than for current 
ALL diagnosis. 
 
Subjects that do not meet all the enrollment criteria may not be enrolled. Any violations of 
these criteria must be reported in accordance with IRB Policies and Procedures.  
3.3.3 Inclusion/Exclusion Criteria for Matched Healthy Controls Cohort 
Matched healthy control patients will be selected based on age- and sex-matching to ALL 
cohort patients. All healthy patients who received care at the Children’s Hospital of 
Philadelphia beginning in 2022 during the follow-up period that the ALL cohort patients are 
followed for the study will be eligible for inclusion in the matched cohort.  
Patients with a history of any oncologic diagnosis or other condition that could predispose 
them to a higher risk of infection (e.g., primary immunodeficiency except related to Down 
syndrome, receipt of chemotherapy or immunomodulating drugs for treatment of any 
condition, etc.) will be excluded from the healthy controls cohort to ensure a comparator 
group that mirrors the typical population of healthy children as closely as possible.  
 
 

 
  
 
  
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4 
STUDY PROCEDURES 
4.1 
Screening 
 
A registry of patients diagnosed with ALL that are expected to complete therapy on or after 
December 1, 2021 will be complied to identify potentially eligible patients. Subjects will be 
screened for eligibility in accordance with inclusion and exclusion criteria outlined in 
section 3.3. The following will be performed during screening: 
• Medical record review to identify potentially eligible patients 
• Completion of a screening log for all screened patients to ensure study eligibility 
• Approach eligible patients for informed consent and, if appropriate, child assent  
4.2 
Visit schedule 
4.2.1 Visit 
Once enrolled, subjects will have a baseline visit, followed by in-person visits at 
approximately 3, 6, and 12 months. Prior to or at the time of the baseline visit, vaccination 
records will be obtained. At the baseline and follow-up visits an interim infectious history 
will be obtained. Patients will have blood drawn for research assays as detailed below at 3-, 
6-, and 12-month visits.   
 
4.3 
Observational Period 
 
Patients will be followed up to approximately one year from enrollment. Patients will also 
have specified relevant data collected from prior to the day of enrollment. During the 
observational period, the following will be performed: 
• Data abstraction from the Medical Record  
4.4 
Subject Completion/Withdrawal 
 
Subjects may withdraw from the study at any time without prejudice to their care.  

 
  
 
  
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5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Variables to be abstracted into the REDCapTM database from the medical charts of ALL 
cohort patients enrolled at each site will include the following: 
• Date of study days 
• Weight 
• Height 
• Demographics (sex, race, ethnicity) 
• Underlying conditions (e.g., type of leukemia) 
• Co-morbid conditions 
• Laboratory values (e.g. Creatinine, AST, ALT, Bilirubin, coagulation profile, WBC, 
platelets) 
• Level of illness (e.g. need for ICU admission, intubation, vasopressors) 
• Immune suppression therapies most recently associated with the qualifying condition  
• Vital status at last date of follow-up 
• Vaccination records 
• Social determinants of health-related data (e.g. block group number (zip code plus 4) 
of residence, insurance type) (Optional – to be collected only for ALL cohort 
patients/families who consent to having these data collected and for healthy control 
patients)  
Results from the following reports will be collected when available 
• Pathology reports 
• All radiology reports 
• Microbiology results 
• Non-culture mycology testing (e.g., Histoplasma urine antigen) 
• Interventional radiology reports 
• Surgical and procedural reports (e.g. bronchoscopy, eye and sinus exams) 

 
  
 
  
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Variables to be collected for matched healthy control cohort patients selected from CHOP’s 
PeRC include: 
• Date of study days (assigned to mirror the follow-up period of the matched ALL 
cohort patients) 
• Demographics (sex, race, ethnicity, age) 
• Underlying conditions 
• Co-morbid conditions 
• Laboratory values (e.g. Creatinine, AST, ALT, Bilirubin, coagulation profile, WBC, 
platelets) 
• Details of any infection-related healthcare encounters occurring during the assigned 
study period (e.g. date of infection(s), lab results related to infection, physical 
examination findings, medications) 
• Level of illness (e.g. need for ICU admission, intubation, vasopressors) 
• Vaccination records 
• Social determinants of health-related data (e.g. block group number (zip code plus 4) 
of residence, insurance type) 
Results from the following reports will be collected when available and related to infections 
occurring in the study follow-up period: 
• Pathology reports 
• All radiology reports 
• Microbiology results 
• Non-culture mycology testing (e.g., Histoplasma urine antigen) 
• Interventional radiology reports 
5.1.2 Laboratory Evaluations 
5.1.2.1 Baseline Blood Specimen Collection 
Patients enrolled in the ALL cohort will have blood collected at approximately 3, 6, and 12 
months once inclusion criteria are met. 
 
A maximum of 25 ml of whole blood will be collected into separate tubes and processed for 
eventual testing as detailed below. Any subject that is less than 5 kg is not eligible for the 
study. Therefore, no more than 5 ml/kg of blood will be obtained from any subject during a 

 
  
 
  
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12-week period. Processed specimens will be stored at -80°C at each site.  Approximately 
every 3 to 6 months, specimens will be batch shipped from participating sites to the central 
laboratory where antibody testing will be performed. Relevant CHOP specimens will be 
tested for immune function evaluation. Results will not be available to clinicians in real 
time. Subjects will have the option to consent to storage of excess blood samples for future 
non-genetic and genetic studies. These sample remnants will be held at a central laboratory. 
 
5.1.2.1.2 Blood Specimen Testing Pneumococcal, Varicella zoster virus (VZV), and 
Measles virus immunoglobulin G (IgG) and Total IgG for ALL cohort participants 
 
Blood samples collected at each visit will be processed for serum extraction.  Serum will be 
stored locally and batched shipped to the central laboratory for performance of the following 
antibody specific assays: Pneumococcal 23 serotype specific IgG (1, 2, 3, 4, 5, 6B, 7F, 8, 
9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F). These 23 
Pneumococcal serotypes were included because, as a group, they account for approximately 
90% of invasive pneumococcal infections. Additionally, varicella zoster virus (VZV) and 
measles virus IgG assays will be performed. Testing for these assays will be performed by 
Mayo Clinic BioPharma Diagnostics. Participant results will be compared to standard age 
specific reference ranges of healthy children.  
 
Serum from these samples will also be used to obtain a total IgG level to aid in interpretation 
of pneumococcal, varicella, and measles IgG results. This testing will be performed at the 
CHOP Translational Core Laboratory.   
 
5.1.2.1.3 Laboratory Analysis for Peripheral Blood Mononuclear Cells and CD4+ T-
Follicular Helper Cells for ALL cohort participants 
 
For a subset of enrolled ALL cohort patients (estimated to be 40, including up to 10 patients 
who received blinatumomab as part of their chemotherapy regimen), blood samples will be 
processed for cellular immunophenotyping. Blood samples will be collected into sodium 
heparin tubes at approximately 3, 6 and 12 months following the completion of therapy, 
processed for peripheral blood mononuclear cells, and cryopreserved. Deep cellular 
immunophenotyping of the recovering immune system will be performed using high 
dimensional flow cytometry and T cell receptor (TCR) sequencing in the laboratory of Dr. 
Laura Vella at the Children’s Hospital of Philadelphia: 
(1) High Dimensional Flow cytometry: The frequency and phenotype of B and T 
lymphocytes, with a specific interest in Tfh, will be measured across the three time 
points and compared to healthy reference controls. The high-dimensional (30-
marker) panel has been optimized for use on the Cytek Aurora spectral cytometer 
and will allow for deep phenotyping beyond Tfh and B cell subsets, resulting in >200 
features of returning mononuclear cells.  
(2) Sorting and TCR sequencing of Tfh and non-naïve CD4 T cells: The clonal diversity 
will be measured by isolating desired cell populations with a BD Aria II cell sorter 
and extracting nucleic acid for Adaptive Biotechnology (TCR) sequencing. Clonality 
scores will be tracked over time and compared to the TCR sequence diversity of 
healthy subjects.  

 
  
 
  
10 
 
These cellular assays will serve as exploratory measures of immune recovery and vaccine 
readiness after ALL therapy. 
 
5.1.3 Social Determinants of Health Survey 
Participants in this study will be offered the opportunity at the time of enrollment to 
participate in a brief, one-time Household Survey (Appendix A) intended to capture self-
reported data related to social determinants of health and household material hardship 
(HMH) (e.g., food and/or housing insecurity, lack of access to reliable transportation, etc.).16 
The survey will be hosted within the study REDCap™ database, and the participant (age 18 
or older) or parent/guardian will be provided a secure link to access the survey after 
consenting to participate. Limited English proficiency participants and families will also be 
eligible to complete the survey but will do so in person via an interpreter if they consent to 
survey participation. 
 
The Household Survey to be used in this study is based on an abbreviated version of the 
Household Material Hardship surveys developed by the Dana-Farber Cancer Institute 
(DFCI) and utilized in clinical trials DFCI 16-001 (NCT03020030), COG AALL1731 
(NCT03914625) and COG ANBL1531 (NCT03126916), with demonstrated feasibility of 
data collection and minimal site or family burden. The Household Survey,17 developed by 
the Bona Lab at the DFCI, includes single-item evaluations of self-reported race, ethnicity 
and health literacy utilizing a validated 1-item screen,18 educational attainment, HMH, and 
household income.  
 
Data collected via this survey is intended to be exploratory and will be used to inform 
further study of possible disparities in infection rates and immune reconstitution. 

 
  
 
  
11 
6 
STATISTICAL CONSIDERATIONS 
6.1 
Primary Endpoint 
 
The primary endpoint for Aim 1 of this study is to determine the incident infection rate in a 
cohort of subjects in the first year following completion of ALL therapy. Infections will 
include both clinical and/or microbiologically confirmed infections. All unique infections 
for a given subject will be captured and included in the final infection rate per person time 
estimate. Infections will also be reported in subsets of infections such as microbiologically 
confirmed (i.e., bacteremia, urinary tract infection or pneumonia with a positive sputum 
culture) or clinically defined infections. Additionally, a specific subset of infections to be 
described are sinopulmonary infections. This will include a medical encounter for otitis 
media, sinusitis, or pneumonia for which an antibiotic was prescribed. Infection events for 
matched healthy control patients will also be captured and used for comparison to the 
incident infection rate determined for the ALL participants.  
 
The primary endpoint for Aim 2a is the proportion of patients with measles, varicella and 
pneumococcus antibodies at each study timepoint.  Of note, pneumococcal serology results 
will include 23 serotypes: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 
18C, 19A, 19F, 20, 22F, 23F, and 33F. Patients with detectable antibody to 50% or more of 
these serotypes will be considered to have seroprevalence for pneumococcus. This aim will 
also describe the total IgG levels at each time point at the individual and cohort level. 
Understanding the total IgG level will inform interpretation of vaccine-specific serology 
measures.   
 
6.2 
Secondary Endpoint 
 
The secondary endpoint for Aim 2b will be the frequency and phenotype of circulating B 
and T lymphocytes, which will be measured at roughly 3, 6, and 12 months for each subject. 
We specifically have an interest in the recovery of Tfh as they provide required help to B 
cells in the follicles of lymphoid tissues.19 
 
6.3 
Statistical Methods 
 
6.3.1 Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive 
summaries. Categorical variables will be summarized by frequencies while continuous 
variables will be summarized by using mean, standard deviation, median, twenty-fifth and 
seventy-fifth percentiles, minimum and maximum.  
 
6.3.2 Analysis of Aim 1 
Aim 1 (total number of unique infections identified within the first year after completing 
chemotherapy) will be reported as a rate per 1000 follow-up days.  This rate will be reported 
for the entire cohort, by study site, and by demographics (e.g., age, race, gender). This 
outcome will also be reported within subsets of infection type (i.e., microbiologically 
documented infections and bacterial sinopulmonary infections) also reported as a rate per 

 
  
 
  
12 
1000 follow-up days for the entire cohort, by study site and by specific demographic 
variables. All infection rates will be reported as a post estimate with 95% confidence 
intervals. Patients will be censored at time of lost to follow-up or death.  
 
Infection rates for enrolled patients will also be compared to those of controls matched on 
age and sex selected from the CHOP Pediatric Research Consortium (PeRC). Three healthy 
controls will be selected for each participant for a case to control ratio of 1:3. Control patient 
infection data will be obtained for the same follow-up time period as that of the matched 
case patient in order to match risk for infection from seasonal pathogens (e.g., if a case 
patient completed ALL therapy and enrolled in the study in January 2023, infection data for 
the matched controls would be collected from January 2023 through December 2023, the 
same follow-up period as that of the case patient). All control patients will be randomly 
selected, and control data will be collected when follow-up is complete for participants in 
the ALL cohort.  
 
Infection rates will also be generated for patients who received blinatumomab as part of 
their chemotherapy regimen and those who did not receive blinatumomab.  
 
6.3.3 Analysis of Aim 2  
The total IgG levels and specific seroprevalence proportions for each of the three pathogens 
(measles, pneumococcus, and varicella) of interest will be determined for the entire cohort 
and by demographics (e.g. age, race, gender) at each study follow-up time point (i.e. about 
3, 6 and 12 months). Additionally, seroprevalence at each time point will be described for 
subjects that had and had not completed their primary vaccine series before starting ALL 
chemotherapy, as well as for those who received blinatumomab as part of their 
chemotherapy regimen and those who did not.   
 
T and B lymphocyte subsets will be measured for a subset of the 110 enrolled subjects.  
These measurements will be reported for each subject at approximately 3, 6, and 12 months. 
The trajectory of these measurements will be displayed graphically across the three 
timepoints of interest to assess relative recovery of lymphocyte quantities after completion 
of ALL chemotherapy. 
 
6.3.4 Control of Bias and Confounding 
For Aim 1, patients will be contacted once monthly for symptom reporting. Capture of the 
primary outcome will be dependent on completion of study visits, phone calls and complete 
data collection from the medical record. Accordingly, study procedural protocols will be 
implemented to ensure systematic approach for each enrolled subject. We will also develop 
a database that will inform a systematic approach to medical record review. This is a 
descriptive study and thus is not vulnerable to confounding.  
 
To control for possible confounding in the comparison of infection incidence rates of ALL 
patients to those of healthy control patients, all healthy control patients will be matched to 
ALL cohort patients based on both age and sex, and controls will be assigned the same one-
year “follow-up” period as those of their matched ALL cohort patients, to account for seasonal 
variation in infection rates as described above. Demographic data and vaccination histories 

 
  
 
  
13 
will be collected as outlined above for both ALL cohort patients and healthy controls to 
monitor for balance with respect to these important factors. Healthy control patients will be 
included only if they do not have pre-existing medical conditions that might put them at 
increased risk for infection to ensure assembly of a healthy cohort that most closely mirrors 
the general population of healthy children. Further, to reduce the risk of selection bias in the 
healthy control cohort, a waiver of consent and HIPAA authorization will be requested for 
these patients. 
 
6.4 
Sample Size and Power 
 
This study aims to enroll 110 ALL cohort subjects across several centers for Aims 1 and 2. 
The complexity of specimen processing for Aim 2b will limit performance of these assays to 
approximately 40 of the overall 110 subjects.  
 
For Aim 1, a cohort of 330 matched healthy control patients will be assembled for the purpose 
of comparison of infection incidence rates in healthy patients versus those who recently 
completed ALL therapy. Based on preliminary data collected on this study’s cohort of ALL 
patients, the infection incidence rate in the first year after completion of chemotherapy is 
estimated to be 1.88 events per person-year. For this power calculation, we assume the rate of 
infection for the entire ALL cohort will mirror the currently estimated rate of 1.88 events per 
person-year, assume a two-sided type I error of 0.05, and range the values of overdispersion 
parameter from 1 to 3.  
 
With 50 ALL patients and 150 matched healthy participants (1:3 match) and one year of 
follow up on each participant, the detectable effect size with at least 80% power is summarized 
in Table 1. For example, under the assumption of no overdispersion (overdispersion 
parameter=1), we will have 80.1% power to detect an IRR of 1.45, i.e., incidence rate of 1.88 
for cancer cohort vs. 1.30 for healthy cohort. Under the conservative assumption of a larger 
overdispersion parameter of 3, we will have 80% power to detect an  
IRR of 1.90, i.e., 
incidence rate of 
1.88 for cancer 
cohort vs. 0.99 
for 
healthy 
cohort. Although  
we do not have an 
accurate estimate 
of the event rate 
in 
the 
healthy 
cohort, an IRR in 
the range of 1.45 
to 1.90 represents 
a clinically meaningful effect size for which we will have sufficient power to detect.  
 
Table 1. Power calculation Across Multiple Estimates of Baseline 
infection Event Rate, Detectable Incidence Rate Ratios, and 
Overdispersion Parameters 
 
Infection event rate 
in the healthy cohort IRR 
Overdispersion 
parameter 
Power 
1.30 
1.45 
1 
80.1% 
1.19 
1.58 
1.5 
81.0% 
1.11 
1.69 
2 
80.1% 
1.04 
1.81 
2.5 
81.2% 
0.99 
1.90 
3 
80.0% 

 
  
 
  
14 
The descriptive and comparative results from Aim 1 will provide important point estimates 
for infection in the first year post ALL chemotherapy that clinicians can use to manage family 
expectations for this recovery period. 
 
Outcomes for Aim 2 are descriptive and thus power calculations are not provided. The point 
estimates for seroprevalence will inform if children retain protection against specific 
pathogens from vaccination administered prior to their diagnosis of and treatment for ALL. 
Point estimates for seroprevalence will be described for the entire cohort and by subsets of 
patient characteristics (e.g., chemotherapy inclusive of blinatumomab). The trajectory of 
recovery of B and T cell subsets will also be described for the sub-cohort of patients enrolled 
at CHOP. Differences in trajectories by patient specific characteristic (e.g., chemotherapy 
inclusive of blinatumomab) will also be explored. These granular descriptive immune function 
data will inform the need for revaccination in this patient population and if necessary, will 
provide guidance for the optimal design of revaccination studies.   
 
 
 
 

 
  
 
  
15 
7 
STUDY ADMINISTRATION 
7.1 
Data Collection and Management 
 
Data elements for this study will be obtained from outpatient and inpatient medical records 
managed at the local sites where subjects will be enrolled. Data will also be collected 
regarding specimen collection and the results of specimen processing. Data will be captured 
in a REDCapTM database. The data will be gathered and entered by trained data abstractors 
at the participating sites. Categories of data captured from the health records include, but are 
not limited to: demographics, baseline characteristics, comorbidities, laboratory results, 
clinical outcomes, medications received, and imaging, microbiology and pathology results 
as outlined in section 5.1.1. 
 
The REDCapTM Database will be hosted by CHOP. REDCapTM is a software toolset and 
workflow methodology that supports the electronic collection and management of research 
and clinical trial data and relies on a thorough study-specific data dictionary defined in an 
iterative self-documenting. REDCapTM’s Data access group function allows for confidential 
data entry and storage from multiple sites. At the time of enrollment and data entry initiation 
a unique study identifier will be assigned to each subject. Each enrolling site will maintain 
its own master list that will capture the local medical record number and the unique study 
identifier for enrolled subjects. Only study personnel approved at that site will have access 
to the site master list. The master list will be maintained in case there are any data fidelity 
issues in REDCapTM that would require re-abstraction of data. Access of members of the 
research team to any patient identifiers will be limited to the minimum necessary to carry 
out the proposed research. In addition, research material will be accessible only to members 
of the investigative team that have completed all required trainings in the Protection of 
Human Subjects. Individual site abstractors will only have access to their own site’s data, 
not the data of the entire study from all centers. Study personnel at CHOP will have access 
to the entirety of the REDCapTM database for the purposes of database management, data 
cleaning, and data analyses. 
 
The REDCapTM database has numerous pre-programmed edit checks to ensure complete, 
consistent and accurate data. These include logical checks, out-of-range checks, missing and 
completeness checks. After automated checks, the CHOP coordinator will manually verify 
data consistency and completeness. Discrepancies identified in data review will be queried 
for clarification. Once entry, review, and resolution of queries have been completed, the 
database will be closed.  
 
In accordance with CHOP policy A-3-9, all study data, including PHI and the master list, 
and study-related documents will be maintained for a minimum of 6 years after completion 
of the study. 
 
Data for matched healthy control patients will be obtained via automated pull from the EHR, 
supplemented by chart abstraction as needed to capture the same infection event data as is 
collected for the ALL cohort. REDCapTM will also be used to store data for controls.  
 

 
  
 
  
16 
7.2 
Confidentiality 
 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and the Investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. Safeguards are described under Data Collection and Management. At the time of 
consent for this study, patients and their parents and/or legal guardians will be asked to also 
consent to the storage of any remaining research or clinical specimens collected for the 
purposes of completing the aims described in this study. Consent for future use of remaining 
specimen will be obtained for both non-genetic and genetic testing. Any specimen remaining 
after completion of this research project for patients that did not consent to future use will be 
destroyed. Remaining specimens of patients consenting to future use will be stored at a 
central laboratory. No personal information, such as names, contact information, or social 
security numbers, will be stored in the primary study database. Each clinical site will 
maintain a local patient master list linking the patients’ unique study identification to their 
medical record number. This master list will be stored on a protected local institution 
location, for example, on a secure local server under password protection, and only 
accessible by local site personnel. Any future research on the remaining specimens or on the 
data collected will first require IRB approval. 
 
7.3 
Regulatory and Ethical Considerations 
7.3.1 Risk Assessment 
One potential risk involved in this study is loss of confidentiality. However, several 
safeguards will be in place to prevent disclosure of patient identifiable information as 
described above in Data Collection and Management. A secondary potential risk involved in 
this study is adverse events due to the collection of blood obtained from study subjects. 
Please see section 5.1.4.1 for maximum restrictions on blood draws. Further, every attempt 
will be made to time study blood draws with clinically dictated blood draws to reduce the 
number of venipuncture events that would otherwise not be clinically necessary. 
 
7.3.2 Potential Benefits of Study Participation 
The subjects involved in the study will not directly benefit from the proposed research. 
Results from the study can be applied in the future to all patients with ALL. Establishing the 
risk of infection and the clinical utility of vaccine titers and immune function studies will 
provide the necessary guidance to clinicians for more definitive therapeutic decisions in the 
future. These data will serve to inform future comparative trials designed to determine the 
utility of vaccination in the period after completion of ALL chemotherapy.  
 
7.3.3 Risk-Benefit Assessment 
This is a minimal risk study using data that will be collected prospectively from medical 
charts. The only potential risk would be loss of confidentiality. However, strict measures 
will be implemented to maintain confidentiality as detailed in this protocol. With the 
appropriate confidentiality measures in place, the risk to the subjects should be negligible. 
For the risk involved in obtaining blood collection, study teams will not obtain blood on a 
specific day if the clinical team determines that it will be detrimental to the study subject.  

 
  
 
  
17 
In view of the minimal risks to subjects participating in this study, and the considerable 
clinical and public health benefits which may ensue from it, the risk/benefit ratio is 
favorable. 
 
7.4 
Recruitment Strategy 
 
Each study site will begin prospective identification of patients for enrollment in the ALL 
cohort once IRB approval is granted at their site. Recruitment will continue for the duration 
of this study. Methods for identification of eligible subjects will be dictated by the clinical 
infrastructure of each enrolling site. The primary screening point for each center will be a 
registry of patients with ALL that will complete therapy on or after December 1, 2021. Then 
that patient will be further assessed for eligibility criteria prior to approaching for 
enrollment.  Parents and/or legal guardians and patients of assenting age who are eligible 
will be approached by site study staff either in person or by phone to inform them of the 
study. 
 
Healthy control patients will be identified and selected from the CHOP Pediatric Research 
Consortium (PeRC) via medical record review. A list of eligible healthy controls for 
potential selection will be obtained via a data pull from CHOP’s electronic health record 
(the Clinical Data Warehouse and/or Clarity) of patients meeting the outlined inclusion 
criteria for controls. 
 
7.5 
Informed Consent/Assent and HIPAA Authorization 
 
It is our expectation that all enrolled sites will use the CHOP IRB as the IRB of record. 
CHOP will first attempt to set up agreements with each participating center to have CHOP 
serve as the Single IRB for the study. A letter from each local IRB stating that they will rely 
on CHOP as the IRB of record will be submitted to CHOP prior to the start of any study 
activities at each site. In the scenario in which a site’s local IRB refuses to recognize CHOP 
as the Single IRB, that site will submit the study protocol and informed consents to their 
local IRB for review. Sites that refuse to recognize CHOP as the IRB of record must provide 
documentation of local IRB approval before enrolling.  The signed informed consent form 
will be utilized and maintained at the local site in a secure location. 
 
CHOP will submit a template informed consent document to the IRB with space for sites to 
customize the form to include local contact information and to meet any requirements set 
forth by their IRB. Once approved, this template will be distributed to all participating sites 
for modification as necessary. The site will submit the modified form back to the CHOP 
IRB for approval. Each site which requires translated versions of the informed consent 
document will have their site-specific forms translated and will submit those translations to 
the CHOP IRB for approval. 
 
The eConsent process will be utilized to obtain and document informed consent whenever 
possible. Any eConsent forms will be submitted to the IRB for approval prior to use. When 
eConsent is not possible, a physical copy of the informed consent document will be signed 
and filed securely. 

 
  
 
  
18 
 
If the patient is under 18 years of age at the time of consent, the patient’s parent(s) or legal 
guardian(s) will be asked to sign the informed consent form. Subjects that turn 18 years old 
during the study follow-up period will be re-approached for their consent prior to continued 
data collection. Among these subjects, age-appropriate assent will also be obtained from 
patients at least 7 years old in addition to parent/guardian consent. 
 
Study staff will seek consent directly from any patients that are at least 18 years of age at the 
time of consent. Communication with a patient’s care team will be used to provide a 
conservative assessment on whether adult patients are capable of consenting. If an adult is 
not capable of consenting, a review of the medical records or communication with the 
patient's care team will identify the Legally Authorized Representative on file for consent. 
 
Upon approach, site study staff will explain the study in a thorough manner. Study staff will 
describe risk and benefit, purpose, all procedures and how to contact site study staff. Ample 
opportunity will be made for the study representative and the subject and their 
parent(s)/legal guardian(s) to share information and ask questions.  
 
In the case of subjects or parent(s)/legal guardian(s) with limited English proficiency, the 
short form consent process, including use of hospital interpreter services, will be followed, 
and consent will be documented on paper. 
 
This research will also utilize the PHI of decedents. In accordance with 45 CFR 
164.512(i)(1)(iii), the use or disclosure being sought is solely for research on the protected 
health information of decedents, the protected health information being sought is necessary 
for the research, and, at the request of the covered entity (CHOP), documentation of the 
death of the individuals about whom information is being sought can be provided. Since 
decedents are no longer human subjects, their data/samples included in this research will not 
be included in the enrollment numbers for this study and research activities using these 
samples/data will not be reported as part of the continuing review. 
 
For patients included in the matched healthy controls cohort, a waiver of consent/HIPAA 
authorization will be requested, as these patients will be identified and have existing data 
collected after the ALL cohort patients to which they are matched have completed their 
study follow-up period.  
 
8 
PUBLICATION 
 
At the conclusion of this effort, we plan to submit an abstract for presentation at a national 
meeting. Subsequently, we anticipate that this body of work will result in one or more 
publications in a peer reviewed journal. No individually identifiable PHI will be published.   
 
 
 
 
 

 
  
 
  
19 
9 
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21 
10 APPENDICES 
 
Appendix A. Household Survey

 
  
 
  
22 

 
  
 
  
23