Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting Risk of Complications and Mortality Following Allogeneic HCT (BMT CTN #1202)
Conditions: Allogeneic Hematopoietic Stem Cell Transplantation
Sponsor: Medical College of Wisconsin

Page 1 of 39 
 
 

BMT CLINICAL TRIALS NETWORK 
 
Biomarkers – Protocol #1202 
 
 
Version 3.0 dated March 17, 2015 
 
 
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Core Study Participants: 
Baylor College of Medicine 
Blood and Marrow Transplant Program at 
Northside Hospital 
Case Western (Consortia) 
- 
Cleveland Clinic 
- 
University Hospitals of Cleveland 
Oregon Health & Science UniversityCity of 
Hope 
COG (Consortia) 
- 
Nemours/Alfred I. duPont Hospital for 
Children 
- 
Nemours Childrens Clinic 
- 
New York Medical College 
Dana Farber (Consortia) 
- 
Brigham & Women’s Hospital 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
H. Lee Moffitt Cancer Center  
Johns Hopkins University 
Memorial Sloan-Kettering Cancer Center 
Ohio State (Consortia) 
- 
Ohio State Medical Center 
- 
Roswell Park Cancer Institute 
- 
University of North Carolina at Chapel 
Hill 
- 
Virginia Commonwealth University/ 
Medical College of Virginia 
Pediatric Blood and Marrow Transplant 
Consortium (PBMTC) 
- 
All Children’s Hospital 
- 
Ann & Robert H. Lurie Children’s 
Hospital of Chicago 
- 
Children’s Healthcare of Atlanta 
- 
Children’s Hospital at Oakland 
- 
Children’s Medical Center of Dallas 
- 
Children’s National Medical Center 
- 
Cook Children’s Hospital 
- 
Hackensack 
- 
Phoenix Children's Hospital 
- 
Texas Transplant 
- 
University of Alabama at Birmingham 
- 
University of California, San Francisco 
- 
University of Utah, Primary 
Children’s Medical Center 
Stanford Hospitals and Clinics 
University of California,  
San Diego (Consortia) 
- 
Rady Children’s Hospital 
University of Florida (Consortia) 
- 
Emory University 
- 
University of Florida/Shands 
University of Michigan (Consortia) 
- 
Mayo Clinic, Rochester 
- 
Mount Sinai 
University of Minnesota 
University of Nebraska (Consortia) 
- 
University of Kansas 
- 
University of Nebraska Medical 
Center 
University of Pennsylvania 
University of Texas/MD Anderson 
Washington University 
Affiliate/Cooperative Study Participants: 

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Biomarkers – Protocol #1202 
 
 
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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL #1202 
 
Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting Risk of 
Complications and Mortality Following Allogeneic HCT 
 
 
Study Chairpersons: 
John Levine, M.D. and John Hansen, M.D. 
 
Objective: 
The goal of this protocol is to establish a cohort of biologic samples 
collected prospectively from patients treated in BMT CTN centers that 
will be a shared biospecimen resource for conducting future allogeneic 
hematopoietic stem cell transplantation (HCT) correlative studies. 
 
Accrual Objective: 
A minimum of 1,500 patients will be enrolled.  
 
Accrual Period: 
The estimated accrual period is 4 years. 
 
Eligibility Criteria: 
All U.S. Allogeneic Transplant Donors and Recipients weighing 10 or 
more kg may participate in the collection of samples.  
 
Treatment Plan: 
Conditioning regimens, GVHD prophylaxis, and other supportive care 
will follow institutional guidelines.  
 
Study Duration: 
Patients will be followed for 24 months post-HCT; long-term follow-up 
data will be collected through usual procedures of the Center for 
International Blood and Marrow Transplant Research (CIBMTR). 
 

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TABLE OF CONTENTS 
 
1. 
BACKGROUND ............................................................................................................ 1-1 
2. 
ELIGIBILITY ................................................................................................................ 2-1 
2.1. 
Inclusion Criteria Hematopoietic Stem Cell Recipients ............................................. 2-1 
2.2. 
Inclusion Criteria Hematopoietic Cell Donors ............................................................ 2-2 
2.3. 
Conditioning Regimens ................................................................................................. 2-2 
2.4. 
GVHD Prophylaxis ........................................................................................................ 2-2 
3. 
BIOMARKER CORRELATIVE OUTCOMES AND DATA COLLECTION ....... 3-1 
3.1. 
Acute GVHD................................................................................................................... 3-1 
3.2. 
Chronic GVHD............................................................................................................... 3-1 
3.3. 
Infection .......................................................................................................................... 3-2 
3.4. 
Relapse/Progression ....................................................................................................... 3-2 
3.5. 
Acute Liver Injury/SOS/Kidney Injury ....................................................................... 3-3 
3.6. 
Lung Injury .................................................................................................................... 3-3 
3.7. 
Transplant-related Mortality (TRM) ........................................................................... 3-4 
3.8. 
Graft Failure................................................................................................................... 3-4 
3.9. 
Real-Time GVHD Data Analysis .................................................................................. 3-5 
4. 
ENROLLMENT, DATA COLLECTION AND SAMPLE COLLECTION/ 
PROCESSING................................................................................................................ 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.2. 
Study Monitoring ........................................................................................................... 4-1 
4.2.1. 
Follow-up Schedule .................................................................................................... 4-1 
4.2.2. 
Data Collection and Patient Assessments ................................................................... 4-2 
4.2.3. 
Adverse Event Reporting ............................................................................................ 4-4 
4.3. 
Collection of Research Blood Samples ......................................................................... 4-4 
4.3.1. 
Collection of Donor Samples ...................................................................................... 4-4 
4.3.2. 
Collection of Recipient Samples ................................................................................. 4-4 
4.3.3. 
Collection of Patient Serum Samples for Proteomic Studies ...................................... 4-5 
4.3.4. 
Collection of Patient Peripheral Blood RNA for Gene Expression Studies ............... 4-5 
4.3.5. 
Sample Collection in the Event of Relapse/Progression/Graft Failure ....................... 4-6 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Genetic/DNA Sample Sets and Future Studies ........................................................... 5-1 
5.2. 
Proteomic Studies........................................................................................................... 5-2 
5.3. 
Transcriptional Gene or Protein Expression Studies (240 patient subset) ............... 5-2 
5.4. 
African American Cohort ............................................................................................. 5-2 
5.5. 
Pediatric Cohort ............................................................................................................. 5-2 
 
LIST OF APPENDICES 
APPENDIX A – HUMAN SUBJECTS 
APPENDIX B – INFORMED CONSENT AND ASSENT FORMS 
APPENDIX C – REFERENCES 

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CHAPTER 1 
 
 
1. 
BACKGROUND 
 
While hematopoietic stem cell transplantation (HCT) offers the only cure for many patients with 
malignant and non-malignant hematologic diseases, this treatment is associated with significant 
risks, leading to high rates of morbidity and mortality.  There is a critical need for more effective 
prevention and treatment strategies for HCT-associated complications.  The most serious of the 
latter include graft-versus-host disease (GVHD), cancer recurrence, organ toxicity and 
opportunistic infection.  Although some clinical variables (e.g., recipient age, donor-recipient 
human leukocyte antigen [HLA] mismatch) predict higher risk of some events (e.g., GVHD, 
infection), no diagnostic tests exist that reliably predict occurrence, severity or response to 
therapy of any of these complications.  Recent compelling results from single center studies 
suggest that biomarkers can be identified that stratify patients into discrete risk groups for some 
outcomes and for overall mortality.  However, these relatively small studies generally lack the 
statistical power or validation necessary to allow their results to be incorporated into practice.  
One key factor in the success of biomarker studies is the quality of clinical outcomes data that is 
linked to the specimens being analyzed.  An adequate resource for these studies requires 
longitudinal sample collection integrated with longitudinal collection of comprehensive, 
standardized, high quality clinical data regarding complications, from onset to resolution, and 
regarding other clinical variables affecting risk of post-HCT outcomes.  
 
The Resource proposed in this application will address the important problem that no multicenter 
biospecimen collections exist that contain appropriate types and/or numbers of specimens, 
together with detailed, rigorously reviewed clinical data collected from adequate numbers of 
patients, for biomarker studies.  We propose to address this clear unmet need through a multi-
center initiative to uniformly collect and store high quality biological specimens and high quality 
clinical data from a large, prospective cohort of patients and their donors.  This Resource will be 
made available to the biomedical community and is expected to facilitate studies that will 
establish the utility of specific biomarkers for risk assessment, diagnosis and monitoring to allow 
more rational treatment strategies.  These studies are also likely to provide mechanistic insights 
and to identify new therapeutic targets leading to development of more targeted and effective 
therapies. 
 
The goal of this protocol is to establish a cohort of biologic samples collected prospectively from 
patients treated in BMT CTN centers that will be a shared biospecimen resource for conducting 
future allogeneic HCT correlative studies.  This resource is designed to allow genomic, 
proteomic and transcriptional data to be integrated with high quality clinical phenotype and 
outcomes data to identify risk factors for development and severity of acute GVHD, chronic 
GVHD, organ toxicity, relapse, mortality, infection and other clinically significant complications 
occurring after allogeneic HCT.  
 
To achieve this goal, patients and donors will be recruited and consent obtained at the time that 
they enroll on BMT CTN protocols where enrollment occurs at or before transplantation or prior 
to start of conditioning for patients enrolled on non-BMT CTN studies or treated as standard of 

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care.  Samples will be collected: (1) from patients and donors pre-transplant; and, (2) from 
patients post-transplant on a calendar schedule through the first 3 months post-HCT.  For 
patients co-enrolled on BMT CTN studies, clinical data will be collected in the context of the 
primary transplant protocols.  For patients not enrolled on BMT CTN protocols, clinical data on 
early post-transplant events will be collected using the same data collection forms and systems 
that are used on BMT CTN trials.  Additional clinical data for both BMT CTN and non-BMT 
CTN patients will be available from data submitted to the Center for International Blood and 
Marrow Transplant Research (CIBMTR) using the CIBMTR Comprehensive Report Forms.  
This protocol also leverages ongoing pre-transplant donor-recipient sample collection performed 
by the CIBMTR and National Marrow Donor Program (NMDP).  Success in establishing this 
shared resource will inspire future investigator initiated research proposals and will allow 
investigators to take advantage of National Institutes of Health (NIH) funding initiatives. 
 

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CHAPTER 2 
 
 
2. 
ELIGIBILITY 
 
2.1.Inclusion Criteria Hematopoietic Stem Cell Recipients 
 
1. Recipients of first allogeneic hematopoietic cell transplants that are transplanted in U.S. 
centers that participate in the NMDP/CIBMTR’s “Protocol for a Research Sample 
Repository for Allogeneic Hematopoietic Stem Cell Transplantation and Marrow Toxic 
Injuries” and receive a cord blood graft or receive a bone marrow or peripheral blood 
graft from a related donor or from an unrelated donor in an NMDP-affiliated Donor 
Center or Registry participating in that same protocol.  
 
This transplant and donor center restriction is to allow linkage with pretransplant donor 
specimens collected under the NMDP/CIBMTR protocol.  Current data indicate that 
>90% of donors approached under this protocol agree to provide samples. 
 
2. Patients with any malignant or non-malignant hematologic disorder will be eligible for 
enrollment on this protocol. Upon reaching accrual of 1500 patients, only non-Caucasian 
adults and pediatric participants will be eligible for enrollment. A subset of 240 
sequential patients with acute leukemia in first or second remission will also provide 
research samples for gene expression studies. A minimum of 200 African American 
participants will be enrolled on this protocol.  
 
3. Children may participate in this study but must weigh at least 10 kilograms given the 
volume (100 mL) and number of blood draws during this study (see Section 4.3.3 for 
blood volume adjustments for patients weighing between 10 and 20 kg).  Subjects must 
weigh at least 30 kg to provide research samples for gene expression studies (additional 
40 mL). A minimum of 200 pediatric participants, defined as <18.0 years at the time of 
enrollment, will be enrolled on this protocol. 
 
4. All participants or parent/legal guardian must sign an informed consent for this study. 
Because studies using this resource will require linking with clinical data collected by 
CIBMTR, all participants or parent/legal guardian must also consent to participate in 
“Protocol for a Research Database for Hematopoietic Cell Transplantation and Marrow 
Toxic Injuries”.  
 
NMDP/CIBMTR research sample repository and CIBMTR research database protocols 
and consent forms referenced above are found at: 
http://www.cibmtr.org/DataManagement/ProtocolConsent/Pages/index.aspx 
 

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2.2.Inclusion Criteria Hematopoietic Cell Donors 
 
The data and samples obtained from patients on this protocol are linked to donor data and 
samples obtained from a separate NMDP/CIBMTR protocol, “Protocol for a Research Sample 
Repository for Allogeneic Hematopoietic Stem Cell Transplantation and Marrow Toxic 
Injuries.”  No donor specimens will be collected under this protocol.  Samples from donors will 
be obtained under the protocol specified above using the standard NMDP mechanism for the 
collection of donor samples. 
 
2.3.Conditioning Regimens 
 
This protocol allows institutional choice in conditioning regimen.  
 
2.4.GVHD Prophylaxis 
 
This protocol allows institutional choice in GVHD prophylaxis. 
 

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CHAPTER 3 
 
 
3. 
BIOMARKER CORRELATIVE OUTCOMES AND DATA COLLECTION 
 
The study is designed to capture the outcomes listed below as main outcomes of interest for 
future correlative studies.  Data collection will focus on fields necessary for rigorous scientific 
study of these endpoints.  For the first 100 days post-HCT, highly detailed data is collected.  
After Day 100, summary data is collected, primarily using CIBMTR forms, through 2 years post-
HCT.  Additional guidance for the data collection and definitions for the outcomes is found in 
the BMT CTN 1202 Biomarker Data Management Handbook.  
 
3.1.Acute GVHD 
 
The date of onset, severity, target organ involvement, treatment, and evolution over time, 
including response to treatment of acute GVHD is the main outcome of interest for future testing 
of the collected samples.  
 
For each assessment period all medications given for GVHD prevention and/or treatment are 
collected.  
 
Through Day 100 when the diagnosis of GVHD is uncertain, or when GVHD is present, but 
there is more than one simultaneous possible cause of GVHD symptoms (e.g. C. difficile 
infection in the setting of proven GI GVHD), all etiologies, proven and possible, as part of 
recording diagnostic certainty in the database (definite, probable, uncertain) for future analyses 
will be collected. 
 
Weekly GVHD staging and treatment will be collected from Day 0 to Day 100 will be collected 
using the BMT CTN AdvantageEDC data reporting system.  After Day 100, acute GVHD 
assessments are reported on CIBMTR forms 2100 and 2200 at Days 100, 180, 1 year and 2 years 
using FormsNet. 
 
3.2.Chronic GVHD 
 
The date of onset, severity, target organ involvement, and evolution of chronic GVHD through 
the first 2 years post-HCT Chronic GVHD assessments at Day 100, 180, 1 year and 2 years are 
submitted using both AdvantageEDC and FormsNet.  The BMT CTN Chronic GVHD Provider 
Survey (see BMT CTN 1202 Biomarker Data Management Handbook) is submitted via 
AdvantageEDC.  Additional information regarding chronic GVHD will be collected on the 
CIBMTR forms 2100 and 2200 and submitted using FormsNet.   
 

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3.3.Infection 
 
Only Grade 3 severe infections occurring through Day 100 will be collected.  These include: 
 
Grade 3 Bacterial Infections: 
a. Bacteremia with deep organ involvement 
b. Severe sepsis with bacteremia 
c. Fasciitis requiring debridement 
d. Pneumonia requiring intubation 
e. Brain abscess or meningitis without bacteremia 
f. Clostridium difficile toxin positive stool with toxic dilatation or renal insufficiency 
with/without diarrhea. 
 
Grade 3 Fungal Infections: 
a. Fungemia, including candidemia 
b. Proven or probable invasive fungal infections (e.g. Aspergillus, Mucor, Fusarium, 
Scedosporium) 
c. Disseminated fungal infections 
d. Pneumocystis jiroveci pneumonia 
 
Grade 3 Viral Infections: 
a. Severe VZV infection with either associated coagulopathy or organ involvement 
b. CMV end organ involvement 
c. EBV Post-transplant lymphoproliferative disorder (PTLD) 
d. Adenovirus with end organ involvement (except adenoviral conjunctivitis or upper 
respiratory tract disease) 
e. All lower respiratory tract viruses 
f. Viral encephalitis or meningitis  
 
The infections will be reported on an event driven basis using the BMT CTN AdvantageEDC 
data reporting system. 
 
3.4.Relapse/Progression 
 
Recurrence or progression of the disease for which HCT was performed through 2 years post-
HCT   
 
Research sample collection is discontinued in patients who relapse within the first 100 days post-
HCT therefore relapses that occur within 100 days post-HCT will be reported through the BMT 
CTN AdvantageEDC system.  Relapse/Progression occurring after Day 100 will be reported 
using CIBMTR post-HCT disease specific forms at Days 100, 180, 1 year, and 2 years. 
 

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3.5.Acute Liver Injury/SOS/Kidney Injury 
 
The diagnosis of veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) is defined 
using the Baltimore criteria:1 
 
Total bilirubin ≥ 2 mg/dL and either a liver biopsy showing VOD or SOS OR at least 2 of the 
following 3: 
• Ascites 
• Weight gain ≥5% above baseline weight  
• Hepatomegaly, or presence of a liver biopsy showing VOD or SOS  
 
The diagnosis of thrombotic microangiopathy (TMA) is defined using BMT CTN consensus 
criteria2 which requires the presence of: 
• 
RBC fragmentation and ≥2 schistocytes per high-power field on peripheral smear  
• 
Concurrent increased serum LDH above institutional baseline  
• 
Concurrent renal and/or neurologic dysfunction without other explanations  
• 
Negative direct and indirect Coombs test results  
 
Renal dysfunction is considered as either a doubling of serum creatinine from baseline (where 
baseline is the serum creatinine before hydration and conditioning) or 50% decrease in creatinine 
clearance from baseline. 
 
VOD/SOS and TMA will be collected on CIBMTR Form 2100 on Day 100 using FormsNet. 
 
3.6.Lung Injury 
 
The occurrence of lung injury as defined below will be collected through 2 years post-transplant. 
 
The diagnosis of Idiopathic Pneumonia Syndrome (IPS) is defined by NIH Consensus Criteria3 
and requires all three of the following criteria:  
• Multilobar infiltrates on chest radiograph (CXR) or computed tomography (CT) that are 
not due to fluid overload. 
• Presence of clinical symptoms (hypoxia, requirement for supplemental oxygen, dyspnea, 
cough, or rales). 
• Absence of lower respiratory tract infection (by broncho-alveolar lavage [BAL] or 
surgical lung biopsy).  
 
Bronchiolitis Obliterans Syndrome (BOS) is defined using NIH Consensus Criteria4 and requires 
all the following criteria to be met:  
• Forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio < 0.7 and 
FEV1  < 75% of predicted. 
• Evidence of air trapping or small airway thickening or bronchiectasis on chest CT, OR 
residual volume > 120%, OR pathologic confirmation of constrictive bronchiolitis. 
• Absence of infection in the respiratory tract, documented with investigations directed by 
clinical symptoms, such as radiologic studies (radiographs or computed tomographic 

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scans) or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, 
sputum culture, or bronchoalveolar lavage). 
 
COP was previously termed bronchiolitis obliterans with organizing pneumonia (BOOP).  No 
consensus criteria for COP have been established following HCT, but recommendations have 
been published and will be used for this study.5  The diagnosis of COP can be made on the basis 
of: 
• Lung biopsy showing organizing pneumonia OR both of the following: 
• Radiographic evidence of patchy or diffuse, “fluffy” consolidations, ground glass 
opacities, and/or nodules on chest radiograph or CT scan 
• Absence of infection in the respiratory tract, documented with investigations directed by 
clinical symptoms, such as radiologic studies (radiographs or computed tomographic 
scans) or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, 
sputum culture, or bronchoalveolar lavage) 
 
Pulmonary function tests are NOT required to make the diagnosis of COP, but commonly reveal 
a forced vital capacity < 80% predicted (a restrictive defect). 
 
Lung injury data will be collected using CIBMTR forms 2100 and 2200 at Days 100, 180, 1 year 
and 2 years using FormsNet.  
 
3.7.Transplant-related Mortality (TRM) 
 
TRM is defined as death from causes other than relapse/progression of the disease for which the 
transplant was performed.  
 
Transplant-related mortality/Death is reported using CIBMTR Forms 2900 and post-HCT 
disease specific forms using FormsNet at whichever time point (Day 100, 180, 1 year, or 2 years) 
occurs first after death up to 2 years post-HCT.  The date and primary and contributing causes of 
death will be captured.  
 
3.8.Graft Failure 
 
Graft failure is not an endpoint on this study, but requires definition because research sample 
collection is discontinued in subject who experience graft failure.  
 

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Graft failure is defined as failure to ever engraft neutrophils (persistent ANC < 500/mm3) or 
irreversible decline (without additional cell infusions) to ANC < 500/mm3 following an initial 
engraftment.  Graft failure should not be declared prior to Day 28 for marrow or peripheral blood 
transplants or prior to Day 42 for cord blood transplants.  An exception to this rule is if the 
treating center determines graft failure occurred earlier than these timepoints AND additional 
cells were infused (ie, subsequent HCT).  Late graft failure (neutropenia following initial 
engraftment) should only be declared if the ANC is consistently below 500/mm3 and the 
neutropenia is persistent. 
 
3.9.Real-Time GVHD Data Analysis 
 
Near real-time (8-10 weeks post diagnosis) data reviews of GVHD onset data will identify and 
resolve inconsistencies in interpretation of GVHD signs and symptoms between centers, thereby 
improving the quality of GVHD staging and facilitating the correlation of GVHD serum 
biomarkers at GVHD onset with outcomes, such as maximum severity, response to treatment and 
non-relapse mortality.  These reviews will act as a surrogate to a single continuity grader used to 
resolve inconsistencies among attending physicians.  The value of “near real-time analyses” will 
be assessed by recording all cases where the staging by the adjudication panel differed from the 
participating center.  The number of cases where adjudication differs from the participating 
center will be compared to the same rate on other BMT CTN studies where this type of review is 
typically done after accrual is complete.

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4-1 
CHAPTER 4 
 
 
4. 
ENROLLMENT, 
DATA 
COLLECTION 
AND 
SAMPLE 
COLLECTION/ 
PROCESSING 
 
4.1.Enrollment Procedures 
 
Patients will be registered using the BMT CTN AdvantageEDC system.  Prior to initiation of 
conditioning regimen, an authorized user at the transplant center enters the patient demographics, 
consent date, and proposed start date for conditioning into Segment A in AdvantageEDC. 
 
The planned transplant date will dictate when pre-transplant samples should be collected.  The 
actual transplant date will be captured in the transplant form and dictate when post-transplant 
samples and clinical data will be collected.   
 
A visit schedule based on transplant date is displayed for printing and is referred to as ‘Segment 
A Follow-up.’ 
 
4.2.Study Monitoring 
 
4.2.1. Follow-up Schedule 
 
The follow-up schedule for calendar-driven study visits is outlined in Table 4.2.1.   A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the BMT CTN 1202 Biomarker Data Management Handbook.   
 
Forms that are not entered into AdvantageEDC within the specified time will be considered 
delinquent.  A missing form will continue to be requested either until the form is entered into the 
AdvantageEDC and integrated into the Data and Coordinating Center’s (DCC) master database 
or until an exception is granted and entered into the Missing Form Exception File, as detailed in 
the BMT CTN AdvantageEDCSM User’s Guide. 
 
All subjects participating in BMT CTN 1202 must also participate in the NMDP/CIBMTR 
research database study “Protocol for a Research Database for Hematopoietic Cell 
Transplantation, Other Cellular Therapies and Marrow Toxic Injuries,” as described in Chapter 
2.  
 
 
 
 

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Table 4.2.1:  Follow-Up Schedule 
Study Visit 
Target Day 
(± 3 Days to Day 100 Post-HCT) 
(± 28 Days After Day 100 Post-HCT) 
1 week 
7 days 
2 week 
14 days 
3 week 
21 days 
4 week 
28 days 
5 week 
35 days 
6 week 
42 days 
7 week 
49 days 
8 week 
56 days 
9 week 
63 days 
10 week 
70 days 
11 week 
77 days 
12 week 
84 days 
13 week 
91 days 
14 week 
100 days 
6 month 
180 days 
1 year 
365 days 
2 year 
730 days 
 
 
4.2.2. Data Collection and Patient Assessments 
 
Patient assessments occur according to the schedule in Table 4.2.1 above.  The data collection 
associated with these assessments is listed in Table 4.2.2.  
 

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TABLE 4.2.2: BMT CTN 1202 Form Submission Schedule 
 
Form 
Baseline 
Time Post-Transplant 
0 
7 
14 21 28 35 42 49 56 63 70 77 84 91 
100 
6 
month 
1 
yr 
2 
yr 
Enrollment Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CIBMTR Recipient ID Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transplant Form 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute GVHD Weekly Assessment Form 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Acute GVHD Supplemental Form 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chronic GVHD Provider Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Laboratory Form 1 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Specimen Acquisition Form 
 
X X X 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
Death Form 
Event-driven form when Death occurs prior to Day 100 
 
 
 
Graft Failure Form 
Event-driven form when Graft Failure occurs prior to Day 100 
 
 
 
Relapse Form 
Event-driven form when Relapse/Progression occurs prior to Day 100  
 
 
 
Infection Form 
Event-driven form for all Grade 3 severe infections prior to Day 100 
 
 
 
CIBMTR 24002 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CIBMTR 2000, 2004, 2005, 2006, disease 
specific form2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CIBMTR 21003 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CIBMTR 22003 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
CIBMTR Disease-Specific Inserts4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CIBMTR 2900 
Event-driven at time of death 
Notes:  
1 Complete blood count and differentials are submitted only for the patients (n=240) who are providing PAXgene samples at Days 21, 56 and 90.  The CBC 
reported should be from the day the sample is collected and need not be on the same day as the weekly GVHD assessment 
2 Used to capture baseline, pre-transplant and transplant data, including conditioning regimen and GVHD prophylaxis 
3 Used to capture acute and chronic GVHD post Day 100, as well as lung injury, VOD/SOS, TMA 
4 Used to capture relapse/progression post Day 100 
 

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4.2.2.1.Pre-transplant evaluations 
 
No required pre-transplant evaluations are defined.   
 
4.2.2.2.Post-transplant evaluations 
 
Post-transplant evaluations will include: 
1. Physical exam to assess GVHD and other morbidity weekly until Day 100 post-
transplant, then at Days 180, 365, and 730 post-transplant.  GVHD evaluation and 
grading to be in keeping with the BMT CTN 1202 Data Management Handbook. 
2. For the Gene expression subset only: Complete blood counts, including white blood 
cell count, hemoglobin, platelet count, and differential, obtained on the same day as the 
PAXgene sample collection are submitted using AdvantageEDC, approximately Days 21, 
56 and 90. 
3. Disease status evaluation as clinically indicated. 
4. Fractionated lymphoid and myeloid chimerism is recommended around Days 28 and 90. 
5. All other evaluations should follow institutional guidelines. 
 
4.2.3. Adverse Event Reporting 
 
Reportable adverse events in this protocol are only those directly linked to the blood draw.  
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of 
knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business days 
of knowledge of the event. 
 
4.3.Collection of Research Blood Samples  
 
4.3.1. Collection of Donor Samples 
 
Collection of donor samples will be via NMDP Research Repository Program Genetic and 
Proteomic Studies. 
 
This protocol leverages an existing institutional review board (IRB)-approved protocol for pre-
transplant patient (see Section 4.3.2 below) and pre-donation donor (or cord blood unit) sample 
collection managed by the NMDP and CIBMTR.  Pre-donation blood samples for genetic and 
proteomic studies are collected on all consenting related or unrelated donors.  
 
4.3.2. Collection of Recipient Samples  
 
The schedule for recipient sample collection is shown in Table 4.3. 
 

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4-5 
Table 4.3: BMT CTN 1202 Recipient Sample Collection Schedule 
 
Biomarker 
Approach 
Sample Type 
Subjects 
Pre-HCT 
Day -1 or 0 
Days Post-HCT 
7 
± 2 
14 
± 2 
21 
 ± 2 
28 
 ± 2 
42  
± 3 
56 
 ± 3 
90 
±10 
Proteomic 
Serum 
(5 mL blood) 
All 
Patients1 
X 
X 
X 
X 
X 
X 
X 
X 
EDTA Plasma 
(5 mL blood) 
X 
X 
X 
X 
X 
X 
X 
X 
Gene 
Expression 
PAXgene 
Lysates- 
stabilized whole blood 
RNA 
(15 mL blood) 
240 
Patients2 
 
 
 
X 
 
 
X 
X 
CytoChex tube for 
Immunophenotyping 
(5  mL blood) 
240 
Patients2 
 
 
 
X 
 
 
X 
X 
Notes: 
1 Subjects weighing between 10 and 20 kg will only be required to provide a 5 mL blood sample (2.5 mL into a red-
top tube for serum and 2.5 mL into an EDTA tube for plasma) for proteomic studies. 
2This is a subset of the enrolled patients and will require additional samples to be collected at Days 21, 56 and 90 for 
gene expression studies. All proteomic samples will be collected per protocol for these patients. 
 
 
Additionally, pre-conditioning recipient samples for genetic studies are collected via the NMDP 
“Protocol for a Research Sample Repository for Allogeneic Hematopoietic Stem Cell 
Transplantation and Marrow Toxic Injuries.”  Recipients must consent to that NMDP study in 
order to participate in BMT CTN 1202. 
 
4.3.3. Collection of Patient Serum Samples for Proteomic Studies 
 
Pre- and post-transplant patient peripheral blood samples will be collected at each of the 
calendar-driven time points in Table 4.3.  The 10 mL peripheral blood samples (5 mL for 
patients weighing between 10 and 20 kg) will be split equally into Vacutainer tubes containing 
no anticoagulant (for serum) and EDTA anticoagulant (for plasma) shipped same-day to the 
BMT CTN Research Sample Repository for next-day sample processing and plasma and serum 
aliquot storage.  A combined maximum of 20 0.250 mL serum and plasma cryovial aliquots will 
be prepared and stored at -80º C. 
 
4.3.4. Collection of Patient Peripheral Blood RNA for Gene Expression Studies 
 
Post-transplant patient samples will be collected from 240 patients enrolled on the study at each 
of the three calendar-driven time points shown in Table 4.3.  A sub-set of 240 patients will be 
selected for the additional blood volume collection for WBC RNA gene expression studies.  To 
enable the most robust correlative evaluation of the HCT transcriptome, the aim is to have this 
smaller subset of patients be more homogeneous and to represent the most common 
characteristics of HCT recipients.  Enrollment will include consecutive patients with acute 
leukemia in remission pre-HCT, thereby excluding patients likely to relapse early after HCT, and 

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ensuring that adequate numbers of patients will be informative for risk assessment of transplant-
related complications.  Enrollment will continue until 240 patients are enrolled.  
 
A 15 mL peripheral blood sample will be collected in six 2.5 mL-fill PAXgene blood RNA tubes 
(provided by the BMT CTN) and shipped same day to the BMT CTN Research Sample 
Repository for sample processing and long-term storage at -80º C.  The BMT CTN Repository 
will process each PAXgene tube according to manufacturers’ protocol for long-term storage at -
80º C for a source of stabilized RNA for future studies.  
 
An additional 5 mL peripheral blood sample will be collected in a 5 mL CytoChex tube 
(provided by the BMT CTN) and shipped same day to the 1202 protocol immunophenotyping 
laboratory.  The fixative in the CytoChex tube stabilizes the WBC cell-surface markers during 
the transport of the sample to the laboratory.  The purpose of the immunophenotyping is to 
characterize the WBC content of the stored PAXgene lysate samples to support future RNA 
expression studies.  This data will be sent back to the BMT CTN Repository and stored in a 
secure 1202 protocol sample information database.  The flow cytometry data will be provided to 
future investigators utilizing the PAXgene lysate samples for approved ancillary studies. 
 
4.3.5. Sample Collection in the Event of Relapse/Progression/Graft Failure 
 
Patients who undergo HCT for malignancy and who experience graft failure, relapse or have 
progressive disease within the first 100 days will stop sample collection and BMT CTN 1202 
forms submission via AdvantageEDC.  These patients will continue to submit required 
CIBMTR forms as part of the separate CIBMTR data collection. In order to ensure adequate 
numbers of patients for future analyses (90% of the planned sample size), if more than 150 
patients experience graft failure or relapse in the first 100 days, additional patients will be 
enrolled to replace those patients who experience graft failure or relapse within the first 100 days 
beyond the first 150.  Relapse/progression is defined as in CIBMTR HCT disease specific forms. 
Graft failure is defined in Section 3.8. 
 

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5-1 
CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
The purpose of this study is to collect samples for future studies.  Without specific research 
plans, we have modeled, for illustrative purposes, power calculations for genome-wide 
association studies (GWAS), proteomic and transcriptional studies that can potentially be 
conducted in the future assuming various settings. 
 
5.1.Genetic/DNA Sample Sets and Future Studies  
 
The DNA resource created by this proposal would not be of sufficient size for a stand-alone 
GWAS discovery study, but it could contribute significantly as an independent study population 
for candidate gene validation studies or for validating ‘hits’ from GWAS discovery studies.  The 
decreasing cost of customized arrays such as the ImmunoChip and exome sequencing of selected 
genes, increases the likelihood that a well characterized cohort like the one we propose will 
become an important addition to the growing global “genetic and phenotype database (dbGaP)” 
maintained by the National Center for Biotechnology Information.  A sample size of 1500 would 
be sufficient for candidate gene validation studies of common variants and common phenotypes.  
Suppose we want to focus on acute GVHD as the primary outcome and plan to perform separate 
analyses for recipients of related and unrelated HCT.  Assuming approximately equal 
proportions of patients with related donor and unrelated donor results in 750 patients with each 
donor type.  The patients in each donor-type group will be divided into two equal groups of 375 
for testing and validation.  Table 5.1 shows the difference in cumulative incidence of acute 
GVHD between genotypic polymorphisms that can be detected with 80% power with a sample 
size of 375.  In this scenario, the outcome is defined as the cumulative incidence (p) of 
experiencing acute GVHD at 6 months, which may range from 20% for grade 3-4 aGVHD to 
50% for grade 2-4 aGVHD.  The power calculations were based on a Chi-square test of binomial 
proportions assuming the markers have dominant effect on the outcome.  The detectable 
differences were computed for various outcome probabilities, minor allele frequencies (MAF), 
and number of SNPs being tested simultaneously using a two-sided overall type I error rate of 
0.05 with Bonferroni correction for multiple comparisons.  In general, validation sample sizes of 
375 in each donor type provide sufficient power to detect a minimum difference ranging from 
14% to 18% with 1 SNP, ranging from 18% to 23% with 10 SNPs, and from 22% to 28% with 
100 SNPs. 
 
Table 5.1: Detectable Difference with 80% Power 
 
 
Outcome 
probability (p) 
1 SNP 
10 SNPs 
100 SNPs 
10% MAF 
20% MAF 
10% MAF 
20% MAF 
10% MAF 
20% MAF 
.20 
.17 
.14 
.23 
.18 
.28 
.22 
.50 
.18 
.15 
.23 
.20 
.28 
.23 

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5.2.Proteomic Studies  
 
One of the major goals of proteomic studies is to identify biomarkers or biomarker panels which 
can reliably predict patient’s prognosis, and to confirm their accuracy of prediction.  Therefore, 
we assessed the ability of the proposed resource to support such modeling and validation studies.  
In the context of future serum biomarker studies, modeling and validation may be conducted by 
stratifying patients by conditioning regimen (MA vs. NMA) and donor type (HLA-Identical 
sibling [ID sibs] vs. matched unrelated donor [MUD] vs. mismatched unrelated donor 
[MMUD]), resulting in 6 separate subpopulations for potential modeling and validation.  Using 
CIBMTR data, we estimate that 26% of patients receive MA Sibs transplant, 19% NMA Sibs, 
22% MA MUD, 19% NMA MUD, 8% MA MMUD, and 6% NMA MMUD.  Assuming patients 
in this study follow a similar subpopulation distribution, and after splitting each subpopulation 
into testing and validation sets,  we expect to have 195 MA Sibs, 144 NMA Sibs, 165 MA MUD, 
144 NMA MUD, 59 MA MMUD, and 43 NMA MMUD available for analysis.  In the validation 
stage, researchers are interested in prediction accuracy of the biomarker levels for subsequent 
clinical outcomes, described through sensitivity and specificity.  Table 5.2 shows the widths of 
95% confidence intervals for these measures when the clinical outcome has probabilities ranging 
from 20% to 50% for each subpopulation assuming an underlying specificity of 75% and 
sensitivity of 70%.  In general, there are sufficient sample sizes in the groups receiving matched 
sibling and matched unrelated donor transplant to estimate specificity and sensitivity with 
reasonable precision.  
 
Table 5.2: Width of 95% Confidence Interval for Specificity and Sensitivity 
 
Outcome 
probability 
(p) 
Underlying 
probability 
HLA-id Sibs 
Matched Unrelated 
Mismatched Unrelated 
MA 
(n=195) 
NMA 
(n=144) 
MA 
(n=165) 
NMA 
(n=144) 
MA  
(n=59) 
NMA  
(n=43) 
20% 
Specificity (75%) 
.14 
.16 
.15 
.16 
.25 
.29 
Sensitivity (70%) 
.29 
.34 
.31 
.33 
.52 
.61 
50% 
Specificity (75%) 
.17 
.20 
.19 
.20 
.31 
.37 
Sensitivity (70%) 
.18 
.21 
.20 
.21 
.33 
.39 
 
5.3.Transcriptional Gene or Protein Expression Studies (240 patient subset) 
 
Typically gene expression microarray studies are conducted with modest sample sizes.6, 7  For 
example, consider a case control design comparing expression levels between those with acute 
GVHD and those alive without aGVHD.  The power depends on the fold change in expression 
level as well as the coefficient of variation (CV), defined as the ratio of the standard deviation of 
the expression level to its mean.  Sample sizes to detect a 2-fold change are given in the table 
below for CV values of 0.25 and 0.5 for various significance levels to account for multiple 
testing of genes. 
 

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Table 5.3: Sample Sizes Needed to Detect a 2-Fold Change in Expression Levels 
 
CV 
P<0.01 
P<0.001 
P<0.0001 
0.25 
10 
16 
20 
0.5 
26 
38 
50 
 
The sample sizes needed to support gene expression studies are typically small, we propose to 
collect 240 donor and patient samples for this resource.  We plan to obtain carefully matched 
case and control samples, particularly for less common indications, transplant types, or donor 
types.  Table 5.4 shows the expected number of samples available for several transplant types or 
donor types from these 240 samples, based on recent CIBMTR data and assuming simple 
random sampling of gene expression samples.  This size resource will provide reasonable 
numbers of samples even for less common settings.  Although oversampling of rare indications 
is an alternative way to increase our available samples for those settings, we do not consider that 
here.  This is because it is likely that even the more common transplant types display substantial 
heterogeneity which it is desirable to control, and having a larger set of samples to select from 
will help reduce heterogeneity.  Finally, note that in addition to case control studies comparing 
gene expression between those developing GVHD and those without, collection of both donor 
and recipient samples will facilitate studies comparing expression levels between the donor and 
recipient.   
 
Table 5.3.1: Expected Demographic Characteristics of Patient/Donor Pairs  
for 240 Gene Expression Samples 
 
 
Related 
Donor 
Unrelated donor 
PB or BM 
UCB 
Matched 
Mismatched 
 
Myeloablative conditioning 
60 
46 
17 
16 
RIC/NST conditioning 
45 
37 
11 
9 
 
 
5.4.African American Cohort 
 
Table 5.4 shows the minimum detectable difference in gene frequency among African American 
recipients compared to Caucasian recipients with at least 80% power for a sample size of 200 
African Americans and 1200 Caucasians.  The detectable difference was calculated for various 
gene frequencies among Caucasians and for various numbers of genes being tested 
simultaneously using a two-sided overall type I error rate of 0.05.  Bonferroni correction was 
used to correct for multiple comparisons in scenarios where two or more genes are being tested 
simultaneously.  When only one gene is considered, the proposed sample size provides sufficient 
power to detect a minimum difference of 8% - 11% in gene frequency in African American 
recipients compared to Caucasian recipients.  When the frequencies of 50 genes are compared 
simultaneously, this study is powered to detect a minimum change of 13% - 16%. 
 

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5-4 
Table 5.4 Detectable difference in gene frequency among African American recipients 
compared to Caucasian recipients with 80% power 
 
Number of 
genes 
Gene frequency in Caucasian population 
10% 
20% 
30% 
40% 
50% 
1 
08% 
10% 
11% 
11% 
11% 
5 
10% 
12% 
13% 
13% 
13% 
10 
11% 
13% 
14% 
14% 
14% 
50 
13% 
15% 
16% 
16% 
16% 
 
5.5.Pediatric Cohort 
 
One of the hypotheses to address is whether the concentration of GVHD biomarkers is lower in 
children than in adults at the time of GVHD onset.  The power to detect a two-fold difference in 
biomarker concentration with a coefficient of variation (CV) of 2 was calculated for various rates 
of grade II- IV GVHD (Table 2) using a two-sided overall type I error of 0.05.   Bonferroni 
correction was used to correct for multiple comparisons in scenarios where two or more 
biomarkers are being compared simultaneously.  Assuming Grade II – IV GVHD occurs in 45% 
of children and 50% of adults, there is more than 90% power to detect a two-fold difference in 
biomarker concentration between children compared to adults when up to 50 biomarkers are 
compared simultaneously.  When Grade II – IV GVHD occurs in 35% of children and 40% of 
adults, there is more than 90% power to detect a difference of this size when up to 10 biomarkers 
are compared simultaneously and there is 83% power when 50 biomarkers are compared 
simultaneously. 
 
Table 5.5 Power to detect a two-fold difference in biomarker concentration between 
children and adults with CV=2 
Number of biomarkers 
tested 
GVHD probability in Children vs. Adults 
(n1 = number of children, n2 = number of adults) 
45% vs. 50% 
(n1=90, n2=650) 
40% vs. 45% 
(n1=80, n2=585) 
35% vs. 40% 
(n1=70, n2=520) 
1 
.99 
.99 
.98 
5 
.98 
.97 
.95 
10 
.97 
.96 
.92 
50 
.93 
.89 
.83 

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Version 3.0 dated March 17, 2015 
 
 
A-1 
APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. Patient Consent 
A conference will be held with the patient and family to discuss this study.  The Principal 
Investigator or another designated physician will conduct the conference.  The consent document 
should be reviewed with the patient and family. 
 
Informed consent from the patient will be obtained using a form approved by the Institutional 
Review Board of the institution enrolling the patient.   
 
 
2. Confidentiality 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code linking the patient’s identity with the ID code will be kept separately at 
the center. 
 
 

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B-1 
 
APPENDIX B 
 
INFORMED CONSENT and ASSENT FORMS 
 

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B-2 
Informed Consent to Participate in Research 
 
 
Prospective Multi-Center Cohort for the Evaluation of Biomarkers 
Predicting Risk of Complications and Mortality Following  
Allogeneic Hematopoietic Cell Transplant (HCT) 
 
Your Name:  
________________________________ 
Study Title:  
Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting 
Risk of Complications and Mortality Following Allogeneic Hematopoietic Cell 
Transplant (HCT) 
Protocol: 
            BMT CTN #1202 
Principal 
Investigator:   
 
 
Principal 
Co-Investigator:  
 
 
Transplant Center 
Investigator:  
________________________ 
(Insert contact information for PI at your site) 
Sponsor:   
The National Institutes of Health (NIH) is sponsoring this study by 
providing financial support through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN).  
 
 
 
 

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B-3 
1. Introduction 
We invite you to join this clinical trial, also 
known as a research study. We are doing 
this study because we want to learn more 
about what makes related and unrelated 
(allogeneic) bone marrow, blood stem cell 
and umbilical cord blood transplants work 
well.  
This study will include at least 1,500 
participants enrolled over a 4 year period. 
Your study participation will last for 2 years 
after your transplant.  
Being in this study is voluntary. You may 
choose whether or not to take part in this 
study. If you choose not to take part or leave 
this study, it will not affect your regular 
medical care in any way. 
This Consent Form will tell you about the 
purpose of the study, the possible risks and 
benefits, other options available to you, and 
your rights as a participant in the study.  
2. Study Purpose  
We invite you to join this research study 
because you are already receiving a 
transplant. For this study, we are collecting 
health information and extra blood samples 
from transplant patients, like you. If you 
agree to join the study, we will ask for: 1) 
information about your health after your 
transplant (such as graft-versus-host disease 
(GVHD)) and 2) samples of your blood 
before and after your transplant that we will 
use in future research studies.  
We will use your health information and 
blood samples in future studies, but we don’t 
know what the studies will be about right 
now. For example, we may use your health 
information and blood samples to learn more 
about graft-versus-host disease (GVHD) or 
cancers that come back (relapse). Your 
health information and blood samples may 
also be used for studies that aren’t about 
transplant. 
 
3. Right to Ask Questions and/or Withdraw 
You have the right to ask questions about 
the study at any time. If you have questions 
about the study or you want to leave the 
study, please contact:  
[insert contact info for site PI] 
If you decide not to continue being in the 
study, you may choose not to allow future 
blood samples or data collection. You can 
also decide to have any blood samples you 
already provided destroyed; however, 
samples and information that have already 
been shared with other researchers cannot be 
taken back or destroyed. 

BMT CLINICAL TRIALS NETWORK 
 
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B-4 
Your study doctor and study staff will be 
available to answer any questions that you 
may have about taking part in or leaving this 
study.  
You do not waive any legal rights by signing 
this form. 
Your study doctor may decide to remove 
you from being in the study without your 
permission if your study doctor feels it is in 
your best interest.  
We will tell you about new information that 
may affect your health, welfare, or 
willingness to stay in this study 
4. Your Health Information and Blood Samples 
If you agree to provide your health 
information and blood samples for future 
research, here is what will happen: 
a.) Your health information (this will not 
include personal information such as 
your name) will be collected during the 
2 years you are participating and given 
to the BMT CTN. This information will 
be tied to your blood samples and will be 
made available to researchers for future 
studies.  
b.) We will collect blood samples before 
and after transplant. 
▪ Before your transplant: We will 
collect about 1 tablespoon of blood 1 
time.  
▪ After your transplant: We will 
collect about 2 tablespoons of blood 
7 times over 90 days.  Each blood 
draw will be about 1-2 weeks apart.  
▪ The blood will be drawn either from 
a central line or from a vein in your 
arm.  
c.) The blood samples will be sent to the 
BMT CTN Repository for processing 
and storage. A repository is a place that 
protects, stores and sends out samples 
for approved research studies. All 
research samples will be coded. A small 
sample of your blood may be sent to a 
laboratory partnering with BMT CTN 
Repository to count and describe the 
different white blood cell types in the 
sample. This information will be sent 
back to the Repository and stored with 
the other sample-related information. 
d.) Materials stored in the Repository will 
be used mainly by doctors and 
researchers in the BMT CTN network. 
In the future, the unused blood samples 
and health information will be made 
available outside of this network (see 
section ‘e’ below).  
e.) Researchers can apply to study the 
health information and blood samples in 
the Repository. The BMT CTN Steering 
Committee and/or the BMT CTN 
Executive Committee must approve each 
request before they will share samples or 
information with researchers. This is to 
make sure that the investigators 
requesting the samples are qualified, and 
that the research is of high quality. 

BMT CLINICAL TRIALS NETWORK 
 
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f.) DNA from your stored blood samples 
might be used in genome-wide 
association (GWA) studies for a future 
project either done or supported by the 
National Institutes of Health (NIH). 
Genome-wide association studies are a 
way for scientists to find genes that have 
a role in human disease or treatment. 
Each study can look at millions of 
genetic changes at the same time. 
If your coded samples are used in 
such a study, the researcher is 
required to add your test results and 
sample information into a shared, 
public research database. This public 
database is called the NIH Genotype 
and Phenotype Database and it is 
managed by the National Center for 
Biotechnology Information (NCBI). 
It is very unlikely that the NCBI 
could identify you, or link you to 
your information or research 
samples.  
 
Your blood will be used only for research 
and will not be sold. The research done with 
your blood may help to develop new 
products in the future. You will not get paid 
for any samples or for any products that may 
be developed from current or future 
research. 
 
5. Risks and Discomforts 
The risk of injury while being in this study 
is considered small. 
 
If your blood samples are collected from 
your arm (instead of your central line), you 
may bleed a little bit and/or develop a small 
bruise. Infection from blood draws is rare, 
but may happen. If you are uncomfortable at 
the sight of blood you may feel light-headed 
or faint.  
 
A possible risk is the loss of confidentiality 
about your medical information. We will use 
safety measures with both your samples and 
health information to make sure that your 
personal information will be kept private. 
It’s very unlikely that your personal 
information will be given to someone else 
(see the Privacy, Confidentiality and Use of 
Information section below).   
 
6. Possible Benefits
Taking part in this study will not make your 
health better. You will not get any direct 
benefit from taking part in this study. The 
information from this study will help doctors 
and researchers learn more about how well 
unrelated transplant works as treatment for 
people with a blood disease. 
This information could help people with a 
blood disease who may need a transplant in 
the future.

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B-6 
7. Privacy, Confidentiality and Use of Information 
Your confidentiality is our main concern. 
We will do our best to make sure that the 
personal information in your medical record 
is kept private. However, we cannot 
guarantee total privacy. All your medical 
and demographic (such as race and 
ethnicity, gender and household income) 
information will be kept private and 
confidential. [insert name of Transplant 
Center] and the organizations listed below 
will not disclose your participation by any 
means of communication to any person or 
organization, except by your written request, 
or permission, or unless required by federal, 
state or local laws, or regulatory agencies.  
Individuals authorized by the organizations 
below will have access to your research and 
medical information. They may use this 
information for inspections or audits to 
study the outcomes of your treatment. In 
agreeing to participate, you consent to such 
inspections and to the copying of parts of 
your records, if required by these 
organizations. 
We may give out your personal information 
if required by law. If information from this 
study is published or presented at scientific 
meetings, your name and other personal 
information will not be used.  Some of your 
health information will be taken from 
another research database you signed up for 
called the “Research Database for 
Hematopoietic Cell Transplantation and 
Marrow Toxicities.” 
Information about your transplant from your 
original medical records may be seen by or 
sent to the following organizations: 
▪ /Institution/ 
▪ The National Institutes of Health (NIH) 
▪ The National Heart, Lung, and Blood 
Institute (NHLBI)  
▪ The National Cancer Institute (NCI) 
▪ Office of Human Research Protection 
(OHRP) 
▪ The Food and Drug Administration (FDA)  
▪ Institutional Review Boards (IRBs) 
responsible for this study 
▪ Data and Safety Monitoring Board 
(DSMB), not part of /Institution/ 
▪ Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), including 
the Center for International Blood and 
Marrow Transplant Research (CIBMTR), 
the National Marrow Donor Program 
(NMDP) and the EMMES Corporation 
who are coordinating the studies of the 
BMT CTN 
▪ Study investigators and future researchers 

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B-7 
Information that does not include personally 
identifiable information about this study has 
been or will be submitted, at the appropriate 
and required time, to the government-
operated clinical trial registry data bank, 
which contains registration, results, and 
other information about registered studies.  
This data bank can be accessed by you and 
the general public at:  
www.ClinicalTrials.gov. Federal law 
requires study information for certain 
studies to be submitted to the data bank. 
 
8. Physical Injury as a Result of Participation 
The risk of injury is considered small. 
However, it is important to tell your study 
doctor, __________________ 
[investigator's name(s)] or study staff if you 
feel that you have been injured from taking 
part in this study. You can tell the doctor in 
person or call him/her at 
__________________ [telephone number]. 
You will get all available medical treatment 
if you are injured from taking part in this 
study. You and/or your health plan will be 
charged for this treatment. The study will 
not pay for medical treatment.  
In case you are injured in this study, you do 
not lose any of your legal rights to receive 
payment by signing this Consent Form. 
 
9. Payment
You will not be paid for taking part in this study. 
10. Costs and Reimbursements 
It will not cost you anything to participate in 
this study. You or your insurance will not be 
charged for tests that are only done for this 
study. 
 
For more information on clinical trials and 
insurance coverage, you can visit the 
National Cancer Institute’s Web site at 
http://cancer.gov/clinicaltrials/understanding
/insurance-coverage. You can print a copy 
of the “Clinical Trials and Insurance 
Coverage” information from this Web site. 
Another way to get the information is to call 
1-800-4-CANCER (1-800-422-6237) and 
ask them to send you a free copy.
 
 

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11. Questions about Your Rights 
For questions about your rights while taking 
part in this study, call the __________[name 
of center] Institutional Review Board (a 
group of people who review the research to 
protect your rights) at __________________ 
(telephone number).  
 
 
12. HIPAA 
Health Insurance Portability and 
Accountability Act 1 (HIPAA1) 
Authorization to use and disclose 
research purpose 
A. Purpose:   
As a research participant, I authorize the 
Principal Investigators and the researcher’s 
staff to use and disclose my individual 
health information for the purpose of 
conducting the research study:  
Prospective Multi-Center Cohort for the 
Evaluation of Biomarkers Predicting Risk of 
Complications and Mortality Following 
Allogeneic Hematopoietic Cell Transplant 
(HCT) 
B. Individual Health Information to be 
Used or Disclosed:  
My individual health information that may 
be used or disclosed to do this research 
includes:  
▪ Demographic information (for example: 
date of birth, sex, weight).  
 
1 HIPAA is the Health Insurance Portability and 
Accountability Act of 1996, a federal law related to 
privacy of health information 
▪ Medical history (for example: diagnosis, 
complications with prior treatment). 
▪ Findings from physical exams. 
▪ Laboratory test results obtained at the 
time of work up and after transplant (for 
example: blood tests, biopsy results).  
C. Parties Who May Disclose My 
Individual Health Information:  
The researcher and the researcher’s staff 
may collect my individual health 
information from: 
[List hospitals, clinics or providers from 
which health care information can be 
requested]. 
D. Parties Who May Receive or Use My 
Individual Health Information:  
The individual health information disclosed 
by parties listed in item c and information 
disclosed by me during the course of the 
research may be received and used by the 
following parties: 
Principal Investigator and the researcher’s 
staff 

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Study Sponsors  
▪ National Heart, Lung, and Blood 
Institute (NHLBI) and the National 
Cancer Institute (NCI), both of the 
National Institutes of Health (NIH),  
▪ Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), data 
coordinating center 
▪ U.S. government agencies that are 
responsible for overseeing research such 
as the Food and Drug Administration 
(FDA) and the Office of Human 
Research Protections (OHRP) 
U.S. government agencies that are 
responsible for overseeing public health 
concerns such as the Centers for Disease 
Control (CDC) and federal, state and local 
health departments.  
E. Right to Refuse to Sign this 
Authorization:  
I do not have to sign this Authorization. If I 
decide not to sign the Authorization, I will 
not be allowed to participate in this study. 
My decision not to sign this authorization 
will not affect any other treatment, payment, 
or enrollment in health plans or eligibility 
for benefits.  
F. Right to Revoke:   
I can change my mind and withdraw this 
authorization at any time.  
If I withdraw this authorization, the 
researcher may only use and disclose the 
protected health information already 
collected for this research study. No further 
health information about me will be 
collected by or disclosed to the researcher 
for this study. 
G. Potential for Re-disclosure:  
My individual health information disclosed 
under this authorization may be subject to 
re-disclosure outside the research study and 
no longer protected. 
Examples include potential disclosures for 
law enforcement purposes, mandated 
reporting or abuse or neglect, judicial 
proceedings, health oversight activities and 
public health measures. 
H. Genetic Information 
Nondiscrimination Act (GINA)  
A new federal law (2009), called the Genetic 
Information Nondiscrimination Act (GINA) 
generally makes it illegal for health 
insurance companies, group health plans, 
and employers of 15 or more persons to 
discriminate against you based on your 
genetic information.  
Health insurance companies and group 
health plans may not request your genetic 
information that we get from this research. 
This means that they must not use your 
genetic information when making decisions 
regarding insurability. Be aware that this 
new federal law will not protect you against 
genetic discrimination by companies that 
sell life insurance, disability insurance, or 
long-term care insurance. 
I. 
This authorization does not have 
an expiration date. 

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13. Making Your Choice  
Please read each sentence below and think 
about your choice. After reading each 
sentence, please indicate your choice below. 
If you have any questions, please talk to 
your doctor or nurse, or call our research 
review board at ___________________.  
Statement of Consent for Research Samples 
The purpose of storing blood samples, the 
procedures involved, and the risks and 
benefits have been explained to me. I have 
asked all the questions I have at this time 
and I have been told whom to contact if I 
have more questions. I have been told that I 
will be given a signed copy of this consent 
form to keep. 
I understand that I do not have to allow the 
use of my blood for research. If I decide to 
not let you store research samples now or in 
the future, it will not affect my medical care 
in any way. 
I voluntarily agree that my blood and health 
information can be stored indefinitely by the 
BMT CTN Repository for research to learn 
about, prevent, or treat health problems.  
❑ I agree to allow my health information and 
blood samples to be stored for research. 
❑ I do not agree to allow my health 
information and blood samples to be stored 
for research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 
Certification of Counseling Healthcare Professional 
 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
donation of blood samples to the BMT CTN Repository have been explained to the above 
individual and that any questions about this information have been answered. 
 
________________________________ 
 
____________________________ 
Counseling Healthcare Professional  
 
Date 
 

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Use of an Interpreter: Complete if the subject is not fluent in English and an interpreter was 
used to obtain consent. 
 
Print name of interpreter:  ______________________  Date:  ____________________________ 
 
Signature of interpreter:  _______________________  Date:  ____________________________ 
 
An oral translation of this document was administered to the subject in  ____________________________________  
(state language) by an individual proficient in English and  ______________________________________________ 
(state language). 
  

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Pediatric Assent to Participate in Research 
 
Study Title: 
Prospective Multi-Center Cohort for the Evaluation of Biomarkers Predicting 
Risk of Complications and Mortality Following Allogeneic Hematopoietic 
Cell Transplant (HCT) 
Protocol: 
BMT CTN 1202 
 
A. Why am I here? 
We invite you to join this research study because you are already receiving a transplant. For 
this study, we will ask you for information about your health (health information) and extra 
blood samples.   
B. Why are you doing this study? 
We are collecting health information and blood samples from transplant patients, like you, to 
learn more about what makes transplants work well. We will use your health information and 
blood samples in future research studies.  
C. What will happen to me if I join the study? 
If you say you want to be in the study, we will ask you for a few things: 
▪ Information about your health after your transplant.      
▪ Some blood samples before and after your transplant.  
- Before your transplant: We will collect about 1 tablespoon of blood 1 time.  
- After your transplant: We will collect about 2 tablespoons of blood 7 times 
over 90 days.  Each blood draw will be about 1-2 weeks apart. 
We will use a small needle to collect the blood from a vein in your arm or we will collect it 
from your central line. 
You will be in the study for about 2 years after your transplant.  The study will include at 
least 1,500 people.  
 
 

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D. Will the blood draw hurt? 
If we collect your blood from a vein in your arm, it may feel like a pinch. It will hurt for a 
minute and the place where the needle went may be red and sore.  You may get a little bruise 
from the needle, but it will go away in a few days. 
E. What if I have questions? 
You can ask any questions that you have about the study.  If you forget to ask a question and 
think of it later, you can call me:  
[insert office number]. 
You can also ask your question the next time you see me. 
You can call the study office at any time to ask questions about the study. 
F. How will you use my health information and blood samples? 
We will use your health information and blood samples in future studies, but we don’t know 
what the studies will be about right now.  Doctors may use your health information and blood 
samples to learn more about how people respond to transplant.  Your health information and 
blood samples may also be used for studies that aren’t about transplant. 
G. Who will use my health information and blood samples? 
Your blood samples will be used by doctors and researchers with the BMT CTN. If your 
blood samples aren’t used, other researchers can ask for permission to use them.  The BMT 
CTN will say if your blood samples can be used by other researchers.  They do this to make 
sure your blood samples are being used correctly.  
H. How will you store my health information and blood samples? 
Your blood samples will be kept at a place called the BMT CTN Repository.  A repository is 
a place that protects, stores and sends out blood samples for research studies.  
All research samples will be tied to a number.  This number will not be linked to your name 
or other identifying information.  

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I. Will the study help me? 
This study will not help you, but it may help other people who need a transplant in the future. 
 
J. Will I be paid to be in the study? 
No, you will not be paid to be in the study. It will not cost you anything to be in the study 
either. 
 
K. Do I have to be in this study? 
If you do not want to be in the study, you need to tell us and your parent or guardian.  
Your doctor will not be angry or upset if you do not want to join. You will still need to have 
treatment for your disease.  
You can say yes now and change your mind at any time.   
Please talk this over with your parents before you decide if you want be in the study. We will 
also ask your parents to give their permission for you to join this study.  
 
Writing your name on this page means that you agree to be in the study and know what will 
happen to you.   
If you decide to quit the study, all you have to do is tell the person in charge. 
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Child 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Researcher  
 
 
 
Date 

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APPENDIX C 
 
REFERENCES 
 
 
 
1 Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone 
marrow transplantation. Transplantation. 1987;44:778-83. 
2 Ho VT, Cutler C, Carter S, et al. Blood and marrow transplant clinical trials network toxicity 
committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell 
transplantation. Biol Blood Marrow Transplant. 2005; 11:571-5. 
3 Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy HH. NHLBI workshop summary. 
Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis. 1993; 
147(6 Pt 1):1601-6. 
4 Filipovich AH, Weisdorf D, Pavletic S, et al., National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. 
Diagnosis and staging working group report. Biol Blood Marrow Transpl, 2005; 11:945-956. 
5 Yoshihara S, Yanik G, Cooke KR, Mineishi S.  Bronchiolitis obliterans syndrome (BOS), 
bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious 
pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol 
Blood Marrow Transplant. 2007; 13:749-59. 
6 Wei C, Li J, Bumgarner RE (2004) Sample size for detecting differentially expressed genes in 
microarray experiments.  BMC Genomics 5: 87. 
7 Tsai C-A, Wang S-J, Chen D-T, and Chen JJ (2005)  Sample size for gene expression 
microarray experiments.  Bioinformatics 21: 1502-1508.