A Multi-Center, Phase III, Randomized Trial of RIC and Transplantation of (dUCB) Versus HLA-Haplo Related Bone Marrow for Patients With Hematologic Malignancies.(BMT CTN #1101)
Phase: PHASE3
Conditions: Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Burkitt's Lymphoma, Follicular Lymphoma, Hodgkin Lymphoma, Mantle Cell Lymphoma, Non-Hodgkin Lymphoma
Sponsor: Medical College of Wisconsin

 
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity(RIC) 
Conditioning and Transplantation of Double Unrelated Umbilical Cord 
Blood (dUCB) versus HLA-Haploidentical Related Bone Marrow (Haplo) for 
Patients with Hematologic Malignancies  
 
(Posted on clinincaltrials.gov as NCT01597778) 
EudraCT 2013-004536-28 
 
BMT CTN PROTOCOL 1101 
VERSION 8.0 
 
Study Chairpersons 
Ephraim Fuchs, M.D.1; Paul O’Donnell, M.D., Ph.D.2; Claudio Brunstein, M.D.3 
 
Protocol Team 
Omar Aljitawi, M.D.4  
Joseph Antin, M.D.5 
Karen Ballen, M.D.6  
Kate Bickett7 
Achintya Jaitly7 
Luciano Costa, M.D.8  
Corey Cutler, M.D., M.P.H.5 
Peter Dawson, Ph.D.7 
Steven Devine, M.D.9 
Nahed El Kasser, M.D., Ph.D.15 
Mary Eapen, M.D.10 
Mary Horowitz, M.D., M.S.10 
Javier Bolaños Meade, M.D.1  
Adam Mendizabal, Ph.D. 7  
Chatchada Karanes, M.D.11 
Brent Logan, Ph.D.10 
Rachel Salit, M.D.14 
Elizabeth Shima Rich, M.D., Ph.D.12 
John Wingard, M.D.13 
Jamie Garrison, M.S.7 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
_________________________________________ 
 
___________________________________________ 
Approval Signature (Protocol Chair/Officer) 
 
 
Approval Signature (Protocol Chair/Officer) 
1 Johns Hopkins University 
2 Massachusetts General Hospital Cancer Center 
3 University of Minnesota 
4 University of Rochester Medical Center 
5 Dana Farber Cancer Institute  
6 University of Virginia 
7 The Emmes Corporation 
8 University of Alabama at Birmingham 
9 Ohio State University  
10 CIBMTR, Medical College of Wisconsin 
11 City of Hope National Medical Center  
12 Astellas Pharma Global Development  
 13 University of Florida College of Medicine 
14  Fred Hutchinson Cancer Research Center 
 15 National Heart, Lung and Blood Institute 

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Core Study Participants: 
Affiliate Study Participants: 
Blood & Marrow Transplant Program at 
Northside Hospital 
Case Western Reserve University Consortium 
   - University Hospitals of Cleveland/Case   
        Western 
   - Cleveland Clinic 
   - West Virginia University 
City of Hope National Medical Center 
Dana Farber Cancer Institute 
   - Brigham & Women’s Hospital 
   - Massachusetts General Hospital 
Duke University Medical Center 
Fred Hutchinson Cancer Research Center 
Johns Hopkins University 
Ohio State Consortium 
   - Ohio State/Arthur G. James Cancer    
        Hospital 
   - Roswell Park 
   - University of North Carolina 
   - Virginia Commonwealth University, MCV    
        Hospital 
Stanford Hospital and Clinics 
University of Florida Consortium 
   - University of Florida College of Medicine 
   - Emory University 
University of Michigan Consortium 
   - University of Michigan Medical Center 
   - Mayo Clinic, Rochester 
   - Mount Sinai  
University of Minnesota  
University of Nebraska Consortium 
   - University of Kansas 
University of Pennsylvania 
University of Texas, MD Anderson Cancer 
Center 
 
Florida Hospital Cancer Institute 
Jewish Hospital 
Karmanos Cancer Center 
Penn State College of Medicine 
Spectrum Health/West Michigan  
Stony Brook Medical Center  
University of Alabama at Birmingham 
University of California, Los Angeles 
University of Oklahoma 
University of Rochester Medical Center 
University of Virginia 
Weill Cornell Medical College 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS – BMT CTN 1101 
 
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning and 
Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) versus HLA-
Haploidentical Related Bone Marrow (haplo-BM) for Patients with Hematologic 
Malignancies  
 
 
Principal Investigators: 
Ephraim Fuchs, M.D., Paul O’Donnell, M.D., Ph.D., Claudio 
Brunstein, M.D.  
 
Study Design:  
This study is a multi-center, Phase III, randomized trial of reduced 
intensity conditioning followed by transplantation of two unrelated 
cord blood units with calcineurin inhibitor and mycophenolate 
mofetil (MMF) for GVHD prophylaxis versus HLA-haploidentical 
related bone marrow with posttransplant cyclophosphamide, 
calcineurin inhibitor, and MMF for GVHD prophylaxis in patients 
with: 
1) Acute lymphoblastic leukemia/lymphoma, acute myelogenous 
leukemia, dendritic cell leukemias, natural killer cell 
malignancies or Burkitt’s lymphoma in remission.  
2) Lymphoma, including marginal zone lymphoma, follicular 
lymphoma, or chemotherapy-sensitive large-cell, Hodgkin or 
mantle 
cell 
lymphoma, 
enteropathy-associated 
T 
cell 
lymphoma, or hepatosplenic gammadelta T cell lymphoma.  
 
Primary Objective:  
The primary objective is to compare progression-free-survival at 2 
years post-randomization between patients who receive unrelated 
double cord blood unit transplantation versus HLA-haploidentical 
related bone marrow transplantation. 
 
Secondary Objectives: 
Patients enrolled in this study will also be followed for the 
following endpoints: neutrophil recovery, graft failure, platelet 
recovery, donor cell engraftment, acute graft-versus-host-disease 
(GVHD) and chronic GVHD, overall survival, treatment-related 
mortality, infections, hospital admission and length of stay, health 
related quality of life, relapse/progression, and cost effectiveness 
(see companion 1101 study document for ancillary cost 
effectiveness protocol).   
 
Accrual Objective: 
 
The target sample size is 410 patients.  
 
Accrual Period: 
The target accrual period is 4 years.   
 
Eligibility Criteria: 
Patients > 18 and ≤ 70 years of age with a diagnosis of a 
hematologic malignancy with two partially HLA-matched UCB 

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units, each with a minimum of 1.5 x 107/kg pre-cryopreserved total 
nucleated cell dose (for non-red blood cell depleted units, the 
minimum cryopreserved total nucleated cell dose of each unit must 
be at least 2.0 x 107/kg), and a partially HLA-mismatched related 
donor.   
 
Adequate organ function defined as: 1) left ventricular ejection 
fraction ≥ 40%; 2) DLCO, FEV1, FVC > 50% predicted; 3) total 
bilirubin ≤ 2.5 mg/dL except for patients with Gilbert’s syndrome 
or hemolysis, and ALT, AST, and alkaline phosphatase all < 5 x 
upper limit of normal (ULN); 4) serum creatinine within normal 
range, or if serum creatinine outside normal range, must have 
measured or estimated creatinine clearance > 40 mL/min/1.73m2; 
5) Karnofsky performance score ≥ 70; and 6) if applicable, > 6 
months since a previous autologous transplant. 
 
Treatment Description: 
Eligible patients will be randomized to dUCB or haplo-BM 
transplantation: 
The preparative regimen for haplo-BM transplantation will consist 
of: 
 
- Fludarabine 30 mg/m2 IV Days –6, –5, –4, –3, –2 
- Cyclophosphamide (Cy) 14.5 mg/kg IV Days –6, –5 
- Total body irradiation (TBI) 200cGy Day –1 
- Day 0 will be the day of infusion of non-T-cell depleted bone 
marrow 
The GVHD prophylaxis regimen for haplo-BM transplantation will 
consist of: 
- Cy 50 mg/kg IV Days 3, 4 
- Tacrolimus (IV or po) beginning Day 5 with dose adjusted to 
maintain a trough level of 5-15 ng/mL.  Cyclosporine (trough 
level of 200-400 ng/mL) may be substituted for tacrolimus if 
the patient is intolerant of tacrolimus or per institutional 
practice. 
- Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum 
dose 1 g po TID beginning Day 5 until Day 35 
Supportive care for haplo-BM transplantation includes: 
- Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 5 until 
ANC >1500/mm3 for 3 consecutive measurements on at least 
two different days 
The preparative regimen for dUCB transplantation will consist of: 
- Fludarabine 40 mg/m2 IV Days –6, –5, –4, –3, –2 
- Cyclophosphamide 50 mg/kg IV Day –6 
- Total Body Irradiation (TBI)  
- 200 cGy Day –1 for patients who have received cytotoxic 

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chemotherapy within the last 3 months or an autologous 
transplant within 24 months of enrollment  
- 300 cGY Day -1 for patients who have not received 
cytotoxic chemotherapy within 3 months of enrollment or an 
autologous transplant within 24 months of enrollment 
- Day 0 will be the day of the double UCB transplant 
The GVHD prophylaxis regimen for dUCB transplantation will 
consist of: 
- Cyclosporine beginning Day –3 with dose adjusted to 
maintain a trough level of 200-400 ng/mL.  Tacrolimus 
(trough level of 5-15 ng/mL) may be substituted for 
cyclosporine if the patient is intolerant of cyclosporine or per 
institutional practice. 
- Mycophenolate mofetil (MMF) 15 mg/kg po TID, maximum 
dose 1 g po TID beginning Day-3 until Day 35. 
Supportive care for dUCB transplantation includes: 
- Filgrastim (G-CSF) 5 mcg/kg/day beginning Day 1 until 
ANC >1500/mm3 for 3 consecutive measurements on at least 
two different days 
 
Study Duration: 
Patients will be followed for three  years after transplantation.  

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TREATMENT SCHEMA 
 
 
 
Patient ≥ 18 and ≤70 yrs. 
Acute leukemia or lymphoma 
Available both 
1) 4-6/6 HLA-matched 
UCB units 
2) 4-6/8 HLA matched 
related donor 
Adequate organ function 
Performance score ≥70 
Double UCB 
Haplo-BM 
Randomization 
Stratified by Transplant Center 

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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ............................................................................ 1 
1.1. 
Background ....................................................................................................................... 1 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.1.1. Hypotheses and Specific Objectives ................................................................................ 2-1 
2.1.1.1. 
Hypotheses ................................................................................................................ 2-1 
2.1.1.2. 
Study Objectives ....................................................................................................... 2-1 
2.2. 
Eligibility Criteria for Enrollment and Randomization............................................. 2-1 
2.2.1. Patient Inclusion Criteria ................................................................................................. 2-1 
2.2.2. Patient Exclusion Criteria ................................................................................................ 2-3 
2.3. 
Additional Patient Eligibility Criteria for Conditioning ............................................ 2-3 
2.3.1. Patients with Adequate Physical Function as Measured by............................................. 2-3 
2.3.2. Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm 2-4 
2.3.3. Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord 
Blood Arm ....................................................................................................................... 2-4 
2.3.4. Additional Patient Exclusion Criteria .............................................................................. 2-4 
2.4. 
Donor Selection for Haploidentical-BM ...................................................................... 2-5 
2.4.1. Donor Inclusion Criteria .................................................................................................. 2-5 
2.4.2. Donor Prioritization Schema............................................................................................ 2-5 
2.5. 
Graft Selection for Double Umbilical Cord Units ....................................................... 2-5 
2.6. 
Treatment Plans ............................................................................................................. 2-6 
2.6.1. Treatment Plan for Patients Randomized to Haplo-BM .................................................. 2-6 
2.6.1.1. 
Fludarabine ............................................................................................................... 2-7 
2.6.1.2. 
Pre-transplantation cyclophosphamide ..................................................................... 2-7 
2.6.1.3. 
Total body irradiation (TBI) ..................................................................................... 2-7 
2.6.1.4. 
Transplantation of haplo-BM ................................................................................... 2-7 
2.6.1.5. 
Post-transplantation cyclophosphamide ................................................................... 2-8 
2.6.1.6. 
Immunosuppressive therapy ..................................................................................... 2-8 
2.6.1.7. 
Tacrolimus ................................................................................................................ 2-8 
2.6.1.8. 
Mycophenolate mofetil (MMF) ................................................................................ 2-8 
2.6.1.9. 
Growth factor support ............................................................................................... 2-9 
2.6.2. Treatment Plan Selection for Patients Randomized to dUCB ......................................... 2-9 
2.6.2.1. 
Fludarabine ............................................................................................................. 2-10 
2.6.2.2. 
Cyclophosphamide ................................................................................................. 2-10 
2.6.2.3. 
Total body irradiation (TBI) ................................................................................... 2-10 
2.6.2.4. 
Cyclosporine A ....................................................................................................... 2-11 
2.6.2.5. 
Mycophenolate mofetil (MMF) .............................................................................. 2-11 
2.6.2.6. 
UCB infusion .......................................................................................................... 2-11 
2.6.2.7. 
Growth factor support ............................................................................................. 2-12 
2.7. 
Additional Supportive Care ........................................................................................ 2-13 
2.7.1. Post Transplant Maintenance Therapy ........................................................................... 2-13 
2.7.2. Infection Prophylaxis ..................................................................................................... 2-13 

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2.7.3. Transfusion Support ....................................................................................................... 2-13 
2.7.4. Indwelling Central Venous Catheter .............................................................................. 2-13 
2.7.5. Pre-infusion Medication and Hydration Regimen ......................................................... 2-13 
2.7.6. Anti-Ovulatory Treatment ............................................................................................. 2-13 
2.7.7. Management of Slow Engraftment and Graft Failure.................................................... 2-13 
2.8. 
Risks and Toxicities ..................................................................................................... 2-14 
2.9. 
Health-Related Quality of Life Assessments ............................................................. 2-15 
2.9.1. Instruments ..................................................................................................................... 2-15 
2.9.2. Administration ............................................................................................................... 2-16 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoint .......................................................................................................... 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. Neutrophil Recovery ........................................................................................................ 3-1 
3.2.2. Primary Graft Failure ....................................................................................................... 3-1 
3.2.3. Secondary Graft Failure ................................................................................................... 3-1 
3.2.4. Platelet Recovery ............................................................................................................. 3-1 
3.2.5. Donor Cell Engraftment ................................................................................................... 3-1 
3.2.6. Acute GVHD ................................................................................................................... 3-2 
3.2.7. Chronic GVHD ................................................................................................................ 3-2 
3.2.8. Overall Survival ............................................................................................................... 3-2 
3.2.9. Treatment-Related Mortality (TRM) ............................................................................... 3-2 
3.2.10. Infections.......................................................................................................................... 3-2 
3.2.11. Hospital Admission and Length of Stay .......................................................................... 3-2 
3.2.12. Health-Related Quality of Life (HQL) ............................................................................ 3-2 
3.2.13. Relapse, Residual Disease and Disease Progression ....................................................... 3-3 
3.2.14. Cost-effectiveness Analysis ............................................................................................. 3-5 
4. 
PATIENT ENROLLMENT AND EVALUATION .................................................... 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.1.1. Screening and Eligibility Procedures ............................................................................... 4-1 
4.2. 
Study Monitoring and Data Submission ...................................................................... 4-1 
4.2.1. Follow-up Schedule ......................................................................................................... 4-1 
4.2.2. Criteria for Forms Submission ......................................................................................... 4-2 
4.2.2.1. 
Electronic Case Report Forms (eCRFs) ................................................................... 4-2 
4.2.2.2. 
Access to Data .......................................................................................................... 4-3 
4.2.2.3. 
Record Retention ...................................................................................................... 4-3 
4.2.3. Study Monitoring ............................................................................................................. 4-3 
4.2.4. Adverse Events ................................................................................................................ 4-4 
4.2.4.1. 
Adverse Event Reporting .......................................................................................... 4-4 
4.2.4.2. 
Adverse Event Monitoring ....................................................................................... 4-5 
4.2.4.3. 
Adverse Event Definitions ........................................................................................ 4-8 
4.2.5. Patient Assessments ......................................................................................................... 4-9 
4.2.5.1. 
Pre-transplant evaluations ......................................................................................... 4-9 
4.2.5.2. 
Post-transplant evaluations ..................................................................................... 4-11 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 

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5.1. 
Study Design and Objectives......................................................................................... 5-1 
5.1.1. Accrual ............................................................................................................................. 5-1 
5.1.2. Randomization ................................................................................................................. 5-1 
5.1.3. Primary Endpoint ............................................................................................................. 5-1 
5.1.4. Primary Hypothesis .......................................................................................................... 5-1 
5.2. 
Sample Size and Power Considerations ....................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.3.1. Interim Analysis for Efficacy and Futility ....................................................................... 5-2 
5.3.2. Guidelines for Safety Monitoring .................................................................................... 5-5 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-6 
5.5. 
Analysis Plan .................................................................................................................. 5-6 
5.5.1. Analysis of the Primary Endpoint .................................................................................... 5-6 
5.5.2. Analysis of Secondary Endpoints .................................................................................... 5-7 
5.5.2.1. 
Secondary analysis of PFS........................................................................................ 5-7 
5.5.2.2. 
Overall survival ........................................................................................................ 5-7 
5.5.2.3. 
Treatment-related mortality ...................................................................................... 5-7 
5.5.2.4. 
Relapse/progression .................................................................................................. 5-8 
5.5.2.5. 
Hematologic recovery ............................................................................................... 5-8 
5.5.2.6. 
Donor cell engraftment ............................................................................................. 5-8 
5.5.2.7. 
Acute GVHD of grades II-IV and III-IV .................................................................. 5-8 
5.5.2.8. 
Chronic GVHD ......................................................................................................... 5-8 
5.5.2.9. 
Incidence of primary graft failure ............................................................................. 5-8 
5.5.2.10. 
Incidence of secondary graft failure ......................................................................... 5-9 
5.5.2.11. 
Incidence of toxicities grade ≥ 3 per CTCAE version 4.0 ........................................ 5-9 
5.5.2.12. 
Incidence of infections .............................................................................................. 5-9 
5.5.2.13. 
Hospital admission and length of stay ...................................................................... 5-9 
5.5.2.14. 
Health-Related Quality of life .................................................................................. 5-9 
5.6. 
Subgroup Analysis ......................................................................................................... 5-9 
6. 
ETHICS AND REGULATORY ................................................................................... 6-1 
6.1. 
Good Clinical Practice Guidelines ................................................................................ 6-1 
6.1.1. Patient Consent ................................................................................................................ 6-1 
6.1.2. Patient Withdrawal........................................................................................................... 6-1 
6.1.2.1. 
Patient withdrawal from intervention ....................................................................... 6-1 
6.1.2.2. 
Patient withdrawal from data collection ................................................................... 6-1 
6.1.2.3. 
Patient Removal From Study .................................................................................... 6-1 
6.1.3. Confidentiality ................................................................................................................. 6-2 
6.1.4. Participation of Women and Minorities ........................................................................... 6-2 
6.2. 
Protocol Amendments ................................................................................................... 6-2 
6.3. 
Protocol Deviations ........................................................................................................ 6-3 
6.4. 
Premature Termination of the Trial ............................................................................ 6-3 
6.5. 
Publication Policy........................................................................................................... 6-3 
 
 

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LIST OF APPENDICES 
 
APPENDIX A 
ABBREVIATIONS 
APPENDIX B 
INFORMED CONSENTS AND DONOR ASSENT 
APPENDIX C 
LABORATORY PROCEDURES 
APPENDIX D 
APPROVED CYTOTOXIC CHEMOTHERAPY REGIMENS 
APPENDIX E 
REFERENCES 
 
 
 

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1-1 
CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. Background 
 
Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older 
and less clinically fit patients to receive potentially curative treatment with allogeneic BMT for 
high risk or advanced hematological malignancies.1, 2, 3, 4
, 5  Patients lacking an HLA-matched 
sibling may receive a graft from a suitably HLA-matched unrelated donor.  However, up to a 
third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated 
donor (i.e., no more than a mismatch at a single locus).  Even when a suitably matched unrelated 
donor is identified, data from the National Marrow Donor Program (NMDP) indicate that a 
median of four months is required to complete searches that result in transplantation; thus, some 
number of patients succumb to their disease while awaiting identification and evaluation of a 
suitably matched adult unrelated donor.6  
 
Single or dual center studies have shown that partially HLA-mismatched related bone marrow 
(haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor 
cells for RIC BMT, thus extending this treatment modality to patients who lack other donors.7, 8, 
9, 10, 11, 12  In order to study the reproducibility, and thus, the wider applicability of these two 
alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network 
(BMT CTN) conducted two parallel multicenter prospective phase II clinical trials.  These two 
studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB 
(BMT 
CTN 
0604) 
transplantation 
after 
RIC.  
Eligibility criteria for the two 
trials were the same and 
included patients up to 70 
years with: poor-risk acute 
leukemia or Burkitt lymphoma 
in 
remission, 
Hodgkin 
lymphoma, 
mantle 
cell 
lymphoma, or aggressive non-
Hodgkin 
lymphoma 
in 
sensitive relapse, or multiply 
relapsed marginal zone or 
follicular lymphoma.  The 
target accrual of 50 patients 
per trial was achieved in just 
20 months (16 months faster 
than expected).  The primary 
objective was to determine overall survival (OS) 180 days after BMT, with examination of: 
neutrophil and platelet recovery, graft failure, acute GVHD, chronic GVHD, incidence of 
 
Figure 1.  Schemas for non-myeloablative conditioning and transplantation 
of either double unrelated umbilical cord blood (A) or HLA-haploidentical 
related donor bone marrow (B). 

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infection, treatment-related mortality (TRM), time to relapse/progression, and current 
progression-free survival (PFS). 
 
Figure 1 shows the schemata for reduced intensity conditioning (RIC) and transplantation of 
either dUCB or haplo-BM grafts.  Recipients of dUCB grafts were conditioned with fludarabine 
(Flu) 40 mg/m2/day intravenously (IV) from Days -6 to -2 (total dose of 200 mg/m2), 
cyclophosphamide (Cy) 50mg/kg IV on Day -6, and 2 Gy total body irradiation (TBI) in a single 
fraction on Day -1 (Figure 1A).  Graft-versus-host disease (GVHD) prophylaxis included 
mycophenolate mofetil (MMF) and cyclosporine A (CsA), with tacrolimus as an acceptable 
substitution for CsA.  Filgrastim 5 mcg/kg/day was initiated on Day 1 and continued until the 
absolute 
neutrophil 
count 
(ANC) was ≥2,000/µL for 3 
consecutive days. 
 
Recipients of haplo-BM were 
conditioned 
with 
Flu 
30 
mg/m2/day IV daily from Days 
-6 to -2 (total dose of 150 
mg/m2), Cy 14.5 mg/kg IV on 
Day -6 and -5, and 2 Gy TBI in 
a single fraction on Day -1 
(Figure 
1B). 
 
GVHD 
prophylaxis consisted of Cy 50 
mg/kg IV on Days 3 and 4 
followed 
by 
MMF 
and 
tacrolimus beginning on Day 5, 
with CsA as an acceptable 
substitution 
for 
tacrolimus.  
Filgrastim 5 mcg/kg/day was 
initiated on post-transplantation 
Day 5 and continued until the 
ANC was ≥ 1000/µL for three 
consecutive days. 
 
Patient 
and 
graft 
characteristics  
 
Characteristics of the patients enrolled in the two trials are summarized in Table 1 (BMT CTN 
0603 and 0604).  Fifty-four patients were registered on the dUCB trial but 4 of these patients 
were not treated according to protocol and excluded from the analysis; one withdrew consent, 
and three had disease relapsed/progression.  Accrual occurred between January 2009 and March 
2010.  Among recipients of dUCB transplantation the median combined nucleated cell dose at 
the time of cryopreservation was 5.0 x 107/kg and at infusion, 4.2 X 107/kg.  Donor-recipient 
HLA disparity was assigned based on the more highly mismatched of the two dUCB units; 
33 donor-recipient pairs were categorized as 4/6 matches, 14 pairs as 5/6, and 3 pairs as 
6/6 HLA-matched.  Matching criteria used intermediate resolution typing at HLA-A and B with 

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high resolution typing at HLA-DRB1.  Cord blood units for 35 donor-recipient pairs (70%) were 
mismatched to each other at two HLA loci.  
 
Fifty-five patients were registered on the haplo-BM trial, but five were not treated according to 
the protocol and excluded from the analysis; one withdrew consent, two were found to have 
disease relapsed/progression, and two were not eligible for the protocol.  Accrual occurred 
between December 2008 and May 2010.  Seventeen donors were siblings of the recipient, 15 
were parents and 18 were children.  More than three quarters of the HLA-haploidentical related 
donors were mismatched for four or more HLA loci using high-resolution typing (HLA-A, -B, -
C, -DRB1, and –DQB1) in both the graft-versus-host and host-versus-graft directions (not 
shown).  
 
Hematopoietic Recovery and Chimerism 
 
After dUCB transplantation, the cumulative incidence of neutrophil recovery >500/µL at Day 56 
was 94% (95%CI, 87-100%) with a 
median time to recovery of 15 days 
(range, 
4-47). 
 
The 
cumulative 
incidence 
of 
platelet 
recovery, 
≥ 
20,000/µL at Day 100 was 82% 
(95%CI, 71-93%) with a median time to 
recovery of 38 days (range, 3-87).  The 
corresponding probability for platelets ≥ 
50,000/µL was 59% (95%CI, 44-73%) 
with a median time to recovery of 43 
days (range, 29-323).  There were five 
cases of primary graft failure and one 
secondary graft failure.  Three graft 
failure patients died at Days 23, 28, and 
193 (after second dUCB transplant).  
Two 
patients 
had 
autologous 
reconstitution and died of relapse at 
Day 99 and 117.  The patient with 
secondary graft failure was determined 
to have lost chimerism at Day 183, had 
leukemia relapse at Day 330, and died 
at Day 347.  Median donor chimerism in marrow or peripheral blood was 92% (range, 0-100%) 
on Day 28 and 100% (range, 25-100%) on Day 56 after transplantation (not shown).  In BMT 
CTN 0604, we only enrolled patients who had received immune suppressive chemotherapy 
within 3 months of enrollment.  Earlier pilot data suggested that for patients who had not 
received chemotherapy within 4 months of a planned dUCB transplant with a regimen of similar 
intensity as described in BMT CTN 0604, graft failure rates were as high as 35% (University of 
Minnesota, unpublished data).  
 
 
Figure 2.  Acute (A,C) or chronic (B,D) graft-
versus-host disease after RIC and transplantation of 
dUCB (A,B) or Haplo-marrow (C,D) 

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Recent data from the Fred Hutchinson Cancer Research Center (FHCRC) demonstrated that 300 
cGy, instead of 200 cGy, is able to overcome this engraftment barrier with no obvious adverse 
effect on other outcomes.13,14 
 
After haplo-BM the cumulative incidence of neutrophil recovery >500/µL at Day 56 was 96% 
(95%CI, 90-100%) with a median time to recovery of 16 days (range, 12-83).  The cumulative 
incidence of platelet recovery ≥ 20,000/µL at Day 100 was 98% (95%CI, 93-100%) with a 
median time to recovery of 24 days (range, 1-92).  The corresponding probability for platelets  
≥ 50,000/µL was 76% (95%CI, 64-88%) with a median time to recovery of 26 days (range, 1-
126).  There was one case of primary graft failure.  This patient did not receive a second 
transplant and died on Day 67.  Median donor chimerism in marrow or peripheral blood was 
100% (range 72-100%) on Day 28 and 100% (range 0-100%) on Day 56 after transplantation 
(not shown). 
 
Graft-versus-host disease 
 
After dUCB transplantation, the cumulative incidences of grade II-IV and III-IV acute GVHD at 
Day +100 were 40% (95% CI, 26-54%) and 21% (95% CI, 6-37%), respectively (Figure 2A).  
The cumulative incidence of chronic GVHD at 1 year was 25% (95% CI, 12-39%; Figure 2B).   
 
After haplo-BM transplantation, the cumulative incidence of grade II-IV acute GVHD at Day 
+100 were 32% (95% CI, 19-45%; Figure 2C).  There were no reported cases of grade III-IV 
acute GVHD.  The cumulative incidence of chronic GVHD at 1 year was 13% (95% CI, 3-23%; 
Figure 2D). 
 
Treatment-Related-Mortality, Relapse, and Survival 
 
After dUCB transplantation, the median follow-up of surviving patients was 365 days (range, 56-
411 days).  The 1-year cumulative incidence of TRM was 24% (95% CI, 11-36%) and of 
relapse/progression was 31% (95% CI, 17-44%; Figure 3A).  Twenty-one patients (42%) have 
died: 10 from relapse, 4 from acute or chronic GVHD, 3 from graft failure, 1 from infection, and 
3 from other causes.  Six-month survival, which was the primary endpoint, was 74% (95% CI, 
59-84%).  The 1-year probability of progression-free survival was 46% (95% CI, 31-60%) and 
overall survival 54% (95% CI, 38-67%; Figure 4B). 
 
After haplo-BM, the median follow-up of surviving patients was 357 days (range 103-441).  The 
1-year cumulative incidence of TRM was 7% (95% CI, 0-15%) and of relapse/progression was 
45% (95% CI, 30-61%; Figure 4C).  Sixteen patients have died: 13 from relapse, 2 from 
infection, and 1 from graft failure.  Six-month survival, which was the primary endpoint, was 
84% (95%CI, 70-92%).  The 1-year probability of progression-free survival was 48% (95% CI, 
32-62%) and overall survival 62% (95% CI, 44-76%; Figure 4D). 
 

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These early results of the RIC 
followed by haploidentical related 
(0603) or double UCB (0604) 
transplantation 
in 
multicenter 
Phase 
II 
trials 
are 
quite 
encouraging.  Importantly, in this 
cooperative group setting (17 
different centers entered patients 
on the haploidentical trial and 16 
on the UCB trial), both of these 
alternative 
donor 
approaches 
produced early results similar to 
that 
reported 
with 
unrelated 
donor, and even HLA-matched 
sibling, BMT1.  These data 
demonstrate not only the efficacy 
of both of these approaches, but 
also that both can be safely 
exported from the single center 
setting.  Both haplo-BM and 
dUCB grafts can be obtained 
rapidly for >90% of patients 
lacking an HLA-matched donor.  
The BMT CTN dUCB results (0604) are quite similar to those reported for a single institution 
trial in a similar group of patients.9  The BMT CTN haplo-BM results (0603) may even be a 
little better than those initially reported by Johns Hopkins and Fred Hutchinson,12 probably 
because of inclusion of somewhat better-risk patients in the BMT CTN trial.  When comparing 
0603 and 0604, engraftment, especially of platelets, appeared slower with UCB.  There also 
appeared to be a higher rate of TRM in the BMT CTN UCB trial (0604).  Recently, we updated 
the results of the phase II trials.  The 3-year probabilities of progression-free survival after haplo-
identical related (0603) and double UCB (0604) were 35% (95% CI 21%-48%) and 36% (95% 
CI 23%-49%).15  Consistent with our earlier observation, the pattern of treatment failure varied 
by donor source.  For recipients of haploidentical related transplantation, relapse was the 
predominant cause of treatment failure and for recipients of double UCB transplantation, TRM 
was the predominant cause of treatment failure.  Recent data also suggest that delayed immune 
recovery leading to increased serious infections may be an issue with UCB transplantation in 
older adults; because of thymic dysfunction, immune reconstitution after BMT in older patients 
appears to primarily arise from memory lymphocytes whose numbers are very low in UCB 
units.16, 17, 18  However, the numbers of patients in the two BMT CTN trials are relatively small, 
assignment was not randomized, and longer follow-ups are needed.  Moreover, some concern has 
been raised about the durability of remissions, especially in myeloid malignancies, after  RIC 
haploidentical BMT.  Thus, carefully controlled clinical trials are required to determine the best 
graft source for adult patients requiring alternative donor BMT.  
 
Accordingly, this protocol describes a Phase III, randomized, open label, multicenter, 
prospective, comparative trial of double UCB versus related haplo-BMT transplantation after 
 
Figure 3.  Relapse, NRM (A,C), overall survival, and event-
free survival (B,D) after RIC and transplantation of dUCB (A,B) 
or Haplo-marrow (C,D). 

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RIC in patients with hematologic malignancies.  Confirming the safety and efficacy of UCB 
and/or haploidentical related BMT would allow access to BMT for essentially all patients in 
need.  Moreover, a successful MUD search takes a median of 3-4 months,19 a time-frame that is 
too long for many patients with aggressive diseases.  UCB, and haploidentical related donors, 
can usually be identified as quickly as HLA-matched sibling donors, again allowing many 
patients whose disease currently will not remain quiescent long enough for a MUD search, the 
option of BMT. 
 
The central hypothesis of this trial is that progression-free survival (PFS) at two years after RIC 
haplo-BM transplantation is similar to the PFS after RIC dUCB transplantation.  Accordingly, 
the primary endpoint of the trial will be two year PFS, with secondary endpoints of TRM, 
progression/relapse, overall survival, hematopoietic recovery, acute and chronic GVHD, 
infections, hospital admissions, and health-related quality of life (HQL). 
 
Extended Family Members as Haploidentical Donors 
   
Preliminary data (Fuchs E, et al., 
unpublished) 
in 
which 
10 
patients 
 
with 
high-risk 
hematologic 
malignancies 
received 
HLA-haploidentical 
transplants from extended family 
donors 
(aunt, 
uncle, 
niece, 
nephew, 
cousin, 
grandchild) 
showed no negative impact on 
transplant outcomes compared to 
results using first degree family 
donors.  Use of extended family 
members as potential donors 
when a suitable first degree 
relative is unavailable or unsuitable is supported by another Johns Hopkins study which used the 
1101 haploidentical transplantation protocol for recipients of grafts from 20 heavily HLA-
mismatched unrelated donors (Kasamon Y, et al. presented at ASH 2015 and submitted for 
publication) where genetic heterogeneity would be expected to be much greater between donor 
and recipient than in transplants using family donors.  In this study, there was a median of 2 
HLA mismatches and included three 7/10 matches, one 6/10 match and one 5/10 match.  Full 
CD3 chimerism was 93% at day 60 and there was no grade 3 acute GVHD. The cumulative 
incidences of grade 2 acute GVHD and any chronic GVHD were 19% and 7%, respectively.  
Data from both extended family donors and HLA-mismatched unrelated donors showed high 
rates of engraftment and acceptably low incidences of acute or chronic GVHD and non-relapse 
mortality.  
 
Figure 4.  Data from HLA-mismatched unrelated donors showing low 
incidences of acute or chronic GVHD (A), and non-relapse mortality (B).  

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CHAPTER 2 
 
 
2. 
STUDY DESIGN 
 
2.1. Study Overview 
 
This is a Phase III randomized, open label, multicenter trial to compare PFS at 2 years post-
randomization between patients who receive RIC followed by a dUCB transplant versus a related 
haplo-BM transplant for hematologic malignancy.   
 
2.1.1. Hypotheses and Specific Objectives 
 
2.1.1.1. Hypotheses 
 
Primary Hypothesis: Two year PFS is similar after related haplo-BM donor transplantation or 
after dUCB transplantation. 
 
Secondary Hypotheses:  TRM is significantly lower but relapse is significantly higher after 
haplo-BM versus dUCB transplantation. 
 
2.1.1.2. Study Objectives 
 
The primary objective is to compare PFS at 2 years post-randomization between patients who 
receive a dUCB transplant with patients who receive a related haplo-BM transplant.  Secondary 
objectives include comparing neutrophil recovery, primary and secondary graft failure, platelet 
recovery, donor cell engraftment, acute GVHD, chronic GVHD, overall survival, TRM, 
relapse/progression, hospital admission and length of stay, health-related quality of life, and cost-
effectiveness.  
 
2.2. Eligibility Criteria for Enrollment and Randomization 
 
2.2.1. Patient Inclusion Criteria 
 
Patients will be enrolled regardless of gender.  Patients fulfilling the following criteria are 
eligible for enrollment:  
1. Age: Subjects ≥ 18 and ≤ 70 years old 
2. Patients must have available both:  
a. One or more potential related mismatched donors (biologic parent (s) or siblings (full 
or half), children or other extended family members). At least low resolution DNA 
based typing at HLA-A, -B and –DRB1 is required pre-randomization for potential 
haplo-identical donors other than biological parents and children.   

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b. At least two potential umbilical cord blood units identified.  
i. 
Each unit must have a minimum of 1.5 x 107/kg pre-cryopreserved total 
nucleated cell dose.  For non-red blood cell depleted units, the minimum pre-
cryopreserved total nucleated cell dose of each unit must be at least 
2.0 x 107/kg.  
ii. 
Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, 
HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high 
resolution using DNA based typing). Confirmatory typing is not required for 
randomization.  
3. Acute Leukemias (includes T lymphoblastic lymphoma): 
a. Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) (see 
remission definition in Chapter 3) that is NOT considered favorable-risk as defined 
by the presence of at least one of the following:  
i. 
Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other MLL 
rearrangements,  
ii. 
White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 
100,000/mcL (T-ALL) at diagnosis, 
iii. 
Recipient age older than 30 years at diagnosis, 
iv. 
Time to CR greater than 4 weeks 
b. Acute Myelogeneous Leukemia (AML) in first complete remission (CR1) (see 
remission definition in Chapter 3) that is NOT considered as favorable-risk.  
i. 
Favorable risk is defined as having one of the followingt(8,21) without CKIT 
mutation 
ii. 
inv(16) without CKIT mutation or t(16;16) 
iii. 
FLT3 ITD and TKD mutations without concurrent mutations in NPM1 or core 
binding factors (inv(16) and t(8:21)).  
iv. 
Normal karyotype with double mutated CEBPA 
v. 
APL in first molecular remission at end of consolidation 
Please consult with the protocol chairs for patients meeting one of the above criteria   
but with additional features that may be considered high risk. 
c. Acute Leukemias in 2nd or subsequent CR (see remission definition in Chapter 3). 
d. Biphenotypic/Undifferentiated/Prolymphocytic/Dendritic Cell Leukemias and Natural 
Killer Cell Malignancies in first or subsequent CR, adult T-cell leukemia/lymphoma 
in first or subsequent CR 
4. Burkitt’s lymphoma: second or subsequent CR. 

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5. High risk lymphomas in first CR, including, enteropathy-associated T cell lymphoma, or 
hepatosplenic gammadelta T cell lymphoma.  
6. Chemotherapy-sensitive (at least stable disease; see response criteria in Chapter 3) 
lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are 
INELIGIBLE for an autologous transplant. Patients with CLL are not eligible regardless 
of disease status. 
7. Performance status: Karnofsky score ≥ 70%. 
 
2.2.2. Patient Exclusion Criteria 
 
Patients fulfilling the following criteria are ineligible for registration onto this study:  
1. Patients with suitably matched related or unrelated donor, as defined per institutional 
practice. 
An unrelated donor search is not required for a patient to be eligible for this protocol, or a 
search and donor mobilization may be abandoned, if the clinical situation dictates an 
urgent transplant.  Clinical urgency is defined as 6-8 weeks from referral to transplant or 
a low-likelihood of finding a matched, unrelated donor. 
2. Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if 
disease recurrence occurred < 6 months from their autologous hematopoietic stem cell 
transplant. 
3. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with 
evidence of progression of clinical symptoms or radiologic findings).  
4. Prior allogeneic hematopoietic stem cell transplant. 
5. Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis. 
6. Planned use of prophylactic donor lymphocyte infusion (DLI) therapy. 
7. Anti-donor HLA antibodies.  Positive anti-donor HLA antibody is defined as a positive 
crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric 
testing) or the presence of anti-donor HLA antibody to the high expression loci HLA-A,  
-B, -C, or –DRB1 with mean fluorescence intensity >1000 by solid phase immunoassay.   
8. Fertile men or women unwilling to use 2 effective forms of birth control or abstinence.  
 
2.3. Additional Patient Eligibility Criteria for Conditioning 
 
2.3.1. Patients with Adequate Physical Function as Measured by 
a. Cardiac: Left ventricular ejection fraction at rest must be ≥ 40%, or shortening 
fraction > 25%. 
b. Hepatic:  
i. 
Bilirubin ≤ 2.5 mg/dL, except for patients with Gilbert’s syndrome or 
hemolysis;  
ii. 
ALT, AST, and Alkaline Phosphatase < 5 x ULN. 

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c. Renal: Serum creatinine within normal range, or if serum creatinine outside normal 
range, then renal function (measured or estimated creatinine clearance or GFR) > 40 
mL/min/1.73m2. 
d. Pulmonary: DLCO (corrected for hemoglobin), FEV1, and FVC > 50% predicted. 
 
2.3.2. Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm 
Patients must be HLA typed at high resolution using DNA based typing at the following HLA-
loci: HLA-A, -B, -C and DRB1 and have available: 
A related haploidentical BM donor with 2, 3, or 4 HLA-mismatches.  A unidirectional 
mismatch in either the graft versus host or host versus graft direction is considered a 
mismatch.  The donor and recipient must be HLA identical for at least one antigen 
(using high resolution DNA based typing) at the following genetic loci: HLA-A, 
HLA-B, HLA-C, and HLA-DRB1.  Fulfillment of this criterion shall be considered 
sufficient evidence that the donor and recipient share one HLA haplotype, and typing 
of additional family members is not required.  See Section 2.4 for donor selection 
criteria.   
 
2.3.3. Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord
 Blood Arm 
1. Patients must have available two UCB units fulfilling the following criteria: 
a. Each unit must have a minimum of 1.5 x 107/kg pre-cryopreserved total nucleated cell 
dose.  For non-red blood cell depleted units, the minimum pre-cryopreserved total 
nucleated cell dose of each unit must be at least 2.0 x 107/kg.  
b. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B 
(at low resolution using DNA based typing), and HLA-DRB1 (at high resolution 
using DNA based typing).  
c. See Section 2.5 for graft selection criteria.   
2. Patients must have received at least one cycle of the cytotoxic chemotherapy regimens 
(or regimen of similar intensity) listed in Appendix D within 3 months of enrollment 
(measured from the start date of chemotherapy) OR have had an autologous transplant 
within 24 months of enrollment OR receive 300 cGy as part of the preparative regimen.  
 
2.3.4. Additional Patient Exclusion Criteria 
 
Patients fulfilling the following criteria are ineligible to proceed to transplant:  
1. Pregnancy or breast-feeding. 
2. Evidence of HIV infection or known HIV positive serology. 
 

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2.4. Donor Selection for Haploidentical-BM 
 
2.4.1. Donor Inclusion Criteria 
1. Donors must be HLA-haploidentical relatives of the patient.  Eligible donors include 
biological parents, siblings (full or half), children or extended family members.  
2. For donors < 18 years, the maximum recipient weight (idealbody weight in kg) should 
not exceed 1.25 times the donor weight (actual body weight in kg). 
 
2.4.2. Donor Prioritization Schema 
 
In the event that two or more eligible donors are identified, the following order of priority is 
suggested but NOT mandated: 
1. For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative donor 
2. Red blood cell compatibility 
a. RBC cross-match compatible 
b. Minor ABO incompatibility 
c. Major ABO incompatibility 
 
2.5. Graft Selection for Double Umbilical Cord Units 
1. Unit selection is based on pre-cryopreserved total nucleated cell dose & HLA-A, -B, and 
-DRB1.  See Section 2.2.1 for HLA typing criteria. 
2. After attaining the minimum total nucleated cell dose threshold of 1.5 x 107/kg (or 2.0 x 
107/kg for units that were not red cell-depleted), it is recommended HLA-match take 
priority for unit selection.  However, within the best available HLA match grade (e.g. 
5/6), units with the largest total nucleated cell dose per kg recipient body weight should 
be chosen.  
3. It is recommended two mismatches at a single HLA-locus be avoided if possible.   
4. Matching the two units is recommended but NOT mandated.  The recommendation is that 
units be HLA matched at a minimum of 4/6 to each other but not necessarily at the same 
HLA-loci as with the recipient.  
 
For additional guidance on graft or donor selection, please contact the study chairs or protocol 
officer via the EMMES protocol coordinator.   
 

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2.6.Treatment Plans 
 
Dose Adjustment Formulas 
 
Estimated creatinine clearance determined by the Cockcroft Formula: 
 
 
 
CCr = (140 – age) x ideal body weight (IBW) (kg)   x   0.85 (for female) 
 
 
                       PCr x 72 
 
Ideal Body Weight (IBW) Formulas: 
 
Males IBW = 50 kg + 2.3 kg/2.5 cm over 1.52  meters 
 
Females IBW = 45.5 kg + 2.3 kg/2.5 cm over 1.52   meters 
 
Adjusted Ideal Body Weight Formula: 
 
 
AIBW = IBW + [(0.25) x (ABW - IBW)] 
 
2.6.1. Treatment Plan for Patients Randomized to Haplo-BM 
 
All patients randomized to the haplo-BM arm will receive preparative therapy as shown in Table 
2.6.1. 
 
TABLE 2.6.1 - HAPLO PREPARATIVE REGIMEN  
 
Day –6, -5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide 14.5 mg/kg IV over 1-2 hours* 
Day –4→ -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day –1 
TBI 200 cGy 
Day   0 
Non-T-cell depleted bone marrow 
Days 3, 4 
Cyclophopshamide 50 mg/kg IV 
Mesna 40 mg/kg IV* 
Day   5 
Begin tacrolimus (or cyclosporine), mycophenolate 
mofetil, and G-CSF 
*Uroprophylaxis may be altered per institutional preference (see below) 
 

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2.6.1.1. Fludarabine 
 
Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous infusion on 
Days –6 through –2 for a total dose of 150 mg/m2.  Fludarabine will be dosed according to the 
recipient’s actual body weight.  For patients who have an estimated or measured creatinine 
clearance < 70 mL/min/1.73 m2, or either prior CNS disease, prior brain radiation, or prior 
intrathecal chemotherapy, the fludarabine dose should be reduced by 20%.  Fludarabine dosing is 
based on the last creatinine clearance prior to the start of conditioning.  The fludarabine dose 
should be the same on Days -6 to -2, even if the patient’s creatinine changes.   
 
Fludarabine must be administered before cyclophosphamide on Days -6 and -5. 
 
2.6.1.2. Pre-transplantation cyclophosphamide  
 
Hydration prior to cyclophosphamide may be given according to institutional standards.  A 
recommended approach is as follows: Patients are instructed to increase fluids overnight before 
cyclophosphamide administration.  Hydration with normal saline at 3 mL/kg/hr IV will be started 
2 hours prior to cyclophosphamide, then the rate will be reduced to 2 mL/kg/hr for 1 hour pre-
cyclophosphamide and continued at 2 mL/kg/hr for 8 hours post-cyclophosphamide. 
 
Mesna may be administered per institutional standards.  Mesna dose will be based on the 
cyclophosphamide dose being given.  A suggested approach is as follows: divided doses IV 30 
min pre- and at 3, 6, and 8 hours post-Cy.  The total daily dose of mesna must be ≥ 80% of the 
total daily dose of Cy.   
 
Cyclophosphamide 14.5 mg/kg/day will be administered as a 1-2 hour intravenous infusion on 
Days –6 and –5.  Cyclophosphamide will be dosed according to the recipient’s ideal body weight 
(IBW), unless the patient weighs more than 125% of IBW, in which case the drug will be dosed 
according to the adjusted IBW (AIBW; see above for formulas). If the recipient’s actual body 
weight (ABW) is less than the ideal body weight (IBW) and in the best interest of the recipient, 
the cyclophosphamide dosing can be based on the ABW. Uroprotection can be administered 
according to institutional guidelines.  Mesna is recommended to accompany pre-transplantation 
Cy, but is not required. 
 
2.6.1.3. Total body irradiation (TBI) 
 
200 cGy TBI will be administered in a single fraction on Day –1.  Radiation sources and dose 
rates will be defined by the institution.  TBI may be delivered from either linear accelerator or 
Cobalt sources.  Graft may be infused on the same day as TBI administration as long as there is 
4-6 hours between administration of TBI and infusion of bone marrow. 
 
2.6.1.4. Transplantation of haplo-BM 
 
On Day 0, patients will receive unprocessed marrow unless there is a major ABO 
incompatibility, in which case red blood cells will be depleted from the donor marrow using 
institutional practices.  Institutional practices will determine if there will be processing for minor 

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ABO incompatibilities.  Donor bone marrow will be harvested with a target yield of 4 x 108 
nucleated cells/kg recipient IBW, and a recommended minimum yield of 2.5 x 108 nucleated 
cells/kg of recipient IBW.  We recommend taking no more than 10 mL per aspirate.  In addition 
to calculating the total nucleated cell dose /kg, a sample of the product to be infused will be sent 
for flow cytometry to determine the content of CD34+cells.  The use of cryopreserved marrow is 
not permitted.   
 
2.6.1.5. Post-transplantation cyclophosphamide 
 
Hydration and uroprotection may be given according to institutional standards.  See Section 
2.6.1.2 for a recommended strategy. 
 
Cyclophosphamide 50mg/kg will be given as an IV infusion over 1-2 hours (depending on 
volume) on Days 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 
4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide).  Cyclophosphamide 
will be dosed according to the recipient’s ideal body weight (IBW), unless the patient weighs 
more than 125% of IBW, in which case the drug will be dosed according to the adjusted IBW 
(AIBW; see Section 2.6). If the recipient’s actual body weight (ABW) is less than the ideal body 
weight (IBW) and in the best interest of the recipient, the cyclophosphamide dosing can be based 
on the ABW. 
 
2.6.1.6. Immunosuppressive therapy 
 
Corticosteroids may not be used as an anti-emetic agent and should not be administered 
until 24 hours after the completion of post-transplantation cyclophosphamide, unless used 
for adrenal support or during a medical emergency (e.g. treatment of anaphylaxis). 
 
2.6.1.7. Tacrolimus 
 
Tacrolimus will be given at a dose of 1 mg IV qd or 1 mg PO bid, and then will be changed to a 
PO dosing schedule once a therapeutic level is achieved or as per institutional standards.  
Tacrolimus prophylaxis will begin on Day 5 post-transplant.  Serum levels of tacrolimus will be 
measured around Day 7 and then should be checked weekly thereafter and the dose adjusted 
accordingly to maintain a trough level of 5-15 ng/mL.  Tacrolimus will be discontinued after the 
last dose around Day 180, or may be continued if active GVHD is present.   
 
Cyclosporine ( trough level of 200-400 ng/mL) may be substituted for tacrolimus if the patient is 
intolerant of tacrolimus or per institutional practice (see Section 2.6.2.4).   
 
2.6.1.8. Mycophenolate mofetil (MMF) 
 
MMF will be given at a dose of 15 mg/kg PO or IV TID (based upon actual body weight) with 
the maximum total daily dose not to exceed 3 grams (1 g PO TID).  MMF prophylaxis will begin 
on Day 5 post-transplant and will be discontinued after the last dose on Day 35, or may be 
continued if active GVHD is present.  
 

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2.6.1.9. Growth factor support 
 
G-CSF will be given beginning on Day 5 at a dose of 5 mcg/kg/day (rounding to the nearest vial 
dose is allowed), until absolute neutrophil count (ANC) is ≥ 1,500/mm3 for three consecutive 
measurements on two different days.  G-CSF may be restarted to maintain ANC > 1,000/mm3.  
G-CSF may be given by IV or subcutaneously.  
 
2.6.2. Treatment Plan Selection for Patients Randomized to dUCB 
 
All patients who are randomized to the double umbilical cord blood transplant arm and who have 
received cytotoxic chemotherapy within 3 months of enrollment or an auto HSCT within 24 
months of enrollment (see Appendix D) will receive preparative therapy as shown in Table 2.6.2. 
 
TABLE 2.6.2a - dUCB PREPARATIVE REGIMEN FOR PATIENTS WHO HAVE 
RECEIVED CYTOTOXIC CHEMOTHERAPY WITHIN 3 MONTHS OF 
ENROLLMENT OR AUTO HSCT WITHIN 24 MONTHS OF ENROLLMENT 
 
Day –6 
Fludarabine 40 mg/m2 IV over 30-60 minutes, 
then Cyclophosphamide 50 mg/kg IV over 2 hours 
Day –5→ -2 
Fludarabine 40 mg/m2 IV over 30-60 minutes 
Day –3 
Begin cyclosporine (or tacrolimus) and MMF 
Day –1 
TBI 200 cGY 
Day 0 
UCB Transplant 
Day 1 
Begin G-CSF 
 
All patients who are randomized to the double umbilical cord blood transplant arm and who have 
NOT received cytotoxic chemotherapy within 3 months of enrollment or an auto HSCT within 
24 months of enrollment (see appendix D) will receive preparative therapy as shown in Table 
2.6.2b. 
 
TABLE 2.6.2b - dUCB PREPARATIVE REGIMEN FOR PATIENTS WHO HAVE NOT 
RECEIVED CYTOTOXIC CHEMOTHERAPY1 WITHIN 3 MONTHS OF 
ENROLLMENT OR AUTO HSCT WITHIN 24 MONTHS OF ENROLLMENT 
 
Day –6 
Fludarabine 40 mg/m2 IV over 30-60 minutes, 
then Cyclophosphamide 50 mg/kg IV over 2 hours 
Day –5→ -2 
Fludarabine 40 mg/m2 IV over 30-60 minutes 
Day –3 
Begin cyclosporine (or tacrolimus) and MMF 
Day –1 
TBI 300 cGY 
Day 0 
UCB Transplant 
Day 1 
Begin G-CSF 
1See Appendix D for list of approved cytotoxic chemotherapy regimens 

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2.6.2.1. Fludarabine 
 
Fludarabine 40 mg/m2/day will be administered over 30-60 minutes intravenous infusion on 
Days -6 through -2 for a total dose of 200 mg/m2.  Fludarabine will be dosed according to the 
recipient’s actual body weight.  For patients who have a estimated or measured creatinine 
clearance < 70 mL/min/1.73 m2, or prior CNS disease, or prior brain radiation, or prior 
intrathecal chemotherapy, the fludarabine dose should be reduced by 20%.  Fludarabine dosing is 
based on the last creatinine clearance prior to the start of conditioning.  The fludarabine dose 
should be the same on Days -6 to -2, even if the patient’s creatinine changes.   
 
Fludarabine must be administered before cyclophosphamide on Day -6. 
 
2.6.2.2. Cyclophosphamide  
 
Hydration prior to cyclophosphamide may be given according to institutional standards.  A 
recommended approach is as follows: Patients are instructed to increase fluids overnight before 
Cy administration.  Hydration with normal saline at 3 mL/kg/hr IV will be started 2 hours prior 
to Cy, then the rate will be reduced to 2 mL/kg/hr for 1 hour pre-cyclophosphamide and 
continued at 2 mL/kg/hr for 8 hours post-cyclophosphamide. 
 
Mesna may be administered per institutional standards.  Mesna dose will be based on the 
cyclophosphamide dose being given.  A suggested approach is as follows: divided doses IV 30 
min pre- and at 3, 6, and 8 hours post-cyclophosphamide.  The total daily dose of mesna must be 
≥ 80% of the total daily dose of cyclophosphamide.   
 
Cyclophosphamide 50mg/kg x 1 day to be administered on Day -6.  Cyclophosphamide will be 
dosed according to the recipient’s ideal body weight (IBW), unless the patient weighs more than 
125% of IBW, in which case the drug will be dosed according to the adjusted IBW (AIBW; see 
Section 2.6). If the recipient’s actual body weight (ABW) is less than the ideal body weight 
(IBW) and in the best interest of the recipient, the cyclophosphamide dosing can be based on the 
ABW. 
 
2.6.2.3. Total body irradiation (TBI) 
 
200 cGy TBI will be administered in a single fraction on Day –1 for patients who have received 
cytotoxic chemotherapy within 3 months of enrollment or an auto HSCT within 24 months of 
enrollment.  300 cGY TBI will be administered in a single fraction on Day –1 for patients who 
have NOT received cytotoxic chemotherapy within 3 months of enrollment or an auto HSCT 
within 24 months of enrollment.  Radiation sources and dose rates will also be defined by the 
institution.  TBI may be delivered from either linear accelerator or Cobalt sources.  Graft may be 
infused on the same day as TBI administration as long as there is 4-6 hours between 
administration of TBI and infusion of the umbilical cord blood units. 
 
 

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2.6.2.4. Cyclosporine A  
 
Cyclosporine will be administered IV beginning on Day –3 and doses will be adjusted to 
maintain a trough level of 200-400 ng/mL by HPLC or 250-500 ng/mL by TDX method (or 100-
250 ng/mL by Tandem MS or equivalent level for other CSA testing methods) or within 
therapeutic level per institutional standard testing.  Dose adjustments will be made on the basis 
of toxicity or low cyclosporine levels (trough level of < 200 ng/mL).  Once the patient can 
tolerate oral medications and has a normal gastro-intestinal transit time, cyclosporine will be 
converted to an oral form at 2-3x the current IV dose.  Cyclosporine dosing will be monitored 
and altered as clinically appropriate.  Patients will receive cyclosporine until Day +100.  In the 
absence of GVHD, the dose will be tapered 10% per week beginning on Day 101, to be 
discontinued approximately Day 180-200. 
 
Tacrolimus (trough level of 5-15 ng/mL) may be substituted for cyclosporine if the patient is 
intolerant of cyclosporine or per institutional practice (see Section 2.6.1.7).   
 
2.6.2.5. Mycophenolate mofetil (MMF) 
 
MMF will be given at a dose of 15 mg/kg PO or IV TID (based upon actual body weight) with 
the maximum total daily dose not to exceed 3 grams (1 g PO TID) beginning on the morning of  
Day -3.  MMF prophylaxis will be discontinued after the last dose on Day 35, or may be 
continued if active GVHD is present.  
 
2.6.2.6. UCB infusion 
 
Following the administration of the preparative therapy, all subjects randomized to the UCB arm 
will undergo UCB transplantation.  Under NO circumstances should the cord blood units be 
irradiated.  No in-line leukocyte filter should be used and no medications or fluids should be 
given piggyback through the catheter lumen that is being used for the cord blood unit infusion.  
The graft MUST be infused through a central line.  Vital signs should be monitored before 
beginning the infusion and periodically during administration.  The two units for dUCB 
transplantation are infused one after the other with an interval between unit infusion no longer 
than 6h.  It is recommended a minimum interval of 30 min between the infusion of the two units 
in order to observe and manage any acute infusional toxicity related to the infusion of the first 
unit.  The order of infusion of the units will follow institutional practice.  Infusion should be 
initiated as soon as possible after thaw. 
 
The cord blood should be thawed, diluted with or without wash per validated institutional or 
supplying cord blood bank procedures with the exception that bedside thawing and direct 
infusion is not allowed.  Bedside thaws are not allowed because of the inability to rescue the 
product if there is loss of integrity of the UCB bag on thaw at the bedside and because of the 
instability of the cells in 10% DMSO post-thaw.  Contingency plans for UCB units which cannot 
be infused due for example loss of integrity of the bag with contamination or poor viability, will 
follow institutional policies.   
 

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All transplant centers/cellular therapy laboratories must be familiar with thawing of cord blood 
units.  They must have validated procedures and maintain competency in the thaw process.  The 
cord blood unit must be thawed in a qualified laboratory by trained personnel.  Generally the 
cryopreserved unit is removed from the protective cassette, placed in a zippered plastic bag (e.g. 
ZiplockTM or equivalent) and thawed rapidly in a 37◦C waterbath.  The zippered plastic bag 
allows for recovery of cells if the cryopreservation bag cracks or leaks during the thawing 
process, a rare but possible event.  Once the contents of the bag reach a slushy consistency, the 
cells can be diluted in dextran/albumin, a hypertonic solution that buffers against the intracellular 
hypertonicity created by DMSO.  Cell suspensions can subsequently be washed to remove 
DMSO, free hemoglobin and other cellular debris allowing for resuspension in a volume 
appropriate for the size of the patient to be transplanted.   
 
Based on the NMDP Cord Blood Advisory Board Group the following recommendations are 
relevant, particularly for larger volume units (e.g. RBC replete or “whole blood” untis) which 
have been, on rare occasion, associated with transient cardiomyopathy (Takotsubo syndrome).  
These recommendations are not intended to supersede manufacturer’s instructions or preclude 
the use or development of validated thawing and infusion procedures. 
1. If a product is washed, after unit is spun and supernatant is removed, resuspend in a 
minimum of 50 mL of reconstitution solution. 
2. Filter the product with standard 170 - 260 micron blood filter. 
3. Thaw units independently, with preference toward thawing the second unit after the first 
unit was infused successfully.  
4. Infuse unit independently.  Should a reaction occur, appropriately manage the reaction 
before the second unit is thawed for infusion. 
5.  Time from initiation of thaw to completion of infusion should be minimized.  Preferably 
this should be less than 2 hours, but data show stem cell integrity is maintained for longer 
periods. 
6. Infusion rate should not exceed 250 mL/h or 5 mL/min.  The order of infusion of the 
units will follow institutional practice.   
 
Benadryl, epinephrine, and hydrocortisone should be available for emergency use if necessary.  
Oxygen with nasal prongs for standby use should be present in the room. 
 
2.6.2.7. Growth factor support 
 
G-CSF will be given beginning on Day 1 at a dose of 5 mcg/kg/day (rounding to the nearest vial 
dose is allowed), until absolute neutrophil count (ANC) is ≥ 1,500/mm3 for three consecutive 
measurements on two different days.  G-CSF may be restarted to maintain ANC > 1,000/mm3.  
G-CSF may be given by IV or subcutaneously. 
 
 
 
 

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2.7. Additional Supportive Care 
 
2.7.1. Post Transplant Maintenance Therapy  
 
Plans for the use of post transplant maintenance therapy must be disclosed prior to 
randomization, and must be used irrespective of the outcome of the randomization.  
 
2.7.2. Infection Prophylaxis  
 
Patients will receive infection prophylaxis and nutritional support according to institutional 
guidelines.  Infection prophylaxis should include, but is not limited to, agents or strategies (e.g., 
PCR screening and preemptive therapy) to reduce the risk of bacterial, herpes simplex, CMV, 
HHV-6, EBV, Pneumocystis jiroveci, and fungal infections.   
 
2.7.3. Transfusion Support 
 
Transfusion thresholds for blood product support will be according to standard institutional 
guidelines.  All blood products will be irradiated. 
 
2.7.4. Indwelling Central Venous Catheter 
 
Placement of a double or triple lumen central venous catheter will be required for the 
transplantation procedure and administration of IV medications and transfusion of blood 
products.  This catheter may be removed and replaced as clinically indicated.  However, the graft 
MUST be infused through a central line. 
 
2.7.5. Pre-infusion Medication and Hydration Regimen 
 
The pre-medication and hydration regimen prior to blood products transfusion and 
transplantation will be given following institutional guidelines. 
 
2.7.6. Anti-Ovulatory Treatment 
 
Females of childbearing potential should be started on an anti-ovulatory agent prior to the 
initiation of the preparative regimen per institutional practice. 
 
2.7.7. Management of Slow Engraftment and Graft Failure 
 
Slow engraftment or graft failure shall be managed according to institutional practices, and may 
include the administration of colony stimulating factors and prophylactic antibiotics. 

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2.8.Risks and Toxicities 
 
Cyclophosphamide: 
 
Cyclophosphamide side effects include: nausea/vomiting, cardiomyopathy, skin rash, mucositis, 
stomatitis, sterility, diarrhea, hemorrhagic cystitis, fluid weight gain/edema, alopecia, and 
hemolytic/anemia. 
 
Fludarabine: 
a. Neurotoxicity: Agitation or confusion, blurred vision, loss of hearing, peripheral 
neuropathy or weakness have been reported.  Severe neurologic effects, including 
blindness, coma, and death are seen in 36% of patients treated with doses approximately 
four times greater than recommended; severe CNS toxicity is rarely seen with doses in 
the recommended range for nontransplant therapy of hematologic malignancies.  Effect 
of chronic use on the CNS is unknown, although patients have received recommended 
doses for up to 15 courses.  The dose used in this study is approximately 1.5 times the 
usual one-course dose given in non-transplant settings.  Doses and schedules such as 
those used in this study have been used in adult and pediatric patients and increased 
neurotoxicity has not been observed.  
b. Anemia: Life-threatening and sometimes fatal autoimmune hemolytic anemia has been 
reported after one or more cycles of therapy in patients with or without a previous history 
of autoimmune hemolytic anemia or a positive Coombs’ test and who may or may not be 
in remission; no mechanisms for development of this complication have been identified.  
Corticosteroids may or may not be effective in controlling these episodes.  The majority 
of patients re-challenged developed a recurrence of the hemolytic process.  
c. Cardiovascular: Deep venous thrombosis, phlebitis, transient ischemic attack, and 
aneurysm (1%) are reported.    
d. Fever: 60% of patients develop fever. 
e. Skin Rash: 15% of patients develop a skin rash, which may be pruritic.  
f. Digestive: Gastrointestinal side effects include: nausea/vomiting (36%), diarrhea (15%), 
stomatitis (9%), anorexia (7%), GI bleeding and esophagitis (3%), mucositis (2%), liver 
failure, abnormal liver function test, constipation, dysphagia (1%), and mouth sores.  
g. Some other effects are: Chills (11%), peripheral edema (8%), myalgia (4%), osteoporosis 
(2%), pancytopenia, arthralgia (1%), dysuria (4%), urinary tract infection and hematuria 
(2%); renal failure, abnormal renal function test, and proteinuria (1%); and, very rarely, 
hemorrhagic cystitis and pulmonary toxicity.  
 
Total Body Irradiation: 
 
TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, usually 
self-limited), generalized mild erythema, hyperpigmentation, fever, mucositis, and alopecia. 
 

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Late effects include: possible growth retardation, vertebral deformities, cataracts, probable 
increased risk of secondary malignant neoplasms, sterility, nephropathy, interstitial pneumonitis 
and veno-occlusive disease.  
 
Mycophenolate Mofetil: 
 
Side effects include: pancytopenia, nausea, vomiting, diarrhea, hypertension, headache, 
dizziness, insomnia, hyperglycemia, electrolyte imbalances, rash, and leg cramps/bone pain. 
 
Tacrolimus and Cyclosporine-A: 
 
Side 
effects 
include: 
reversible 
renal 
insufficiency, 
hypertension, 
hyperglycemia, 
hypomagnesemia, hypokalemia, and neurologic toxicity.   
 
2.9. Health-Related Quality of Life Assessments 
 
2.9.1. Instruments 
 
FACT-BMT: The Functional Assessment of Cancer Therapy – Bone Marrow Transplant 
subscale version 4.0 instrument is a 37 item scale comprised of a general core questionnaire, the 
FACT-G, that evaluates the health-related quality of life (HQL) of patients receiving treatment 
for cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related 
questions specific to bone marrow transplant.  The FACT-G consists of four subscales developed 
and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Well-
being, and Functional Well-being.  Each subscale is positively scored, with higher scores 
indicating better functioning.  The FACT-BMT Trial Outcome Index, comprised of the physical 
well being scale, the functional well being scale and the BMT specific items, will be used as the 
outcome measure in summarizing the FACT-BMT data.  The FACT-BMT takes 6 minutes to 
complete, and is being used to collect HQL data in BMT CTN 0201, 0801 and 0901. 
 
MOS SF-36: The Medical Outcomes Study Short Form 36 is a 36 item general assessment of 
health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, 
General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health 
Index.  Each domain is positively scored, indicating that higher scores are associated with 
positive outcome.  This scale has been widely applied in a variety of outcome studies and is 
being used in this protocol as a generic measure of quality of life.  To facilitate comparison of 
the results with published norms, the Physical Component Summary (PCS) and Mental 
Component Summary (MCS) will be used as the outcome measures in summarizing the SF-36 
data.  These summary scores are derived by multiplying the z-score for each scale by its 
respective physical or mental factor score coefficient and summing the products.  Resulting 
scores are then transformed into T-scores (mean=50; standard deviation=10).  The SF-36 takes 6 
minutes to complete, and is being used to collect HQL data in BMT CTN protocols 0801 and 
0901. 
 
Global HQL: Four standard questions will assess patient self-assessed Karnofsky performance 
status, overall health and overall quality of life, (excellent, very good, good, fair, poor) and a 

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rating scale for overall quality of life (where 0 equals death and 100 equals perfect quality of 
life).  In addition, the presence and severity of chronic GVHD will be assessed (mild, moderate, 
severe).  These questions take 1 minute to complete and are being collected for BMT CTN 
protocols 0201, 0801, and 0901. 
 
Occupational Functioning: Occupational functioning will be measured using 6 items that assess 
current job status, type of work (will be captured using Hollingshead categories), number of 
hours of paid and unpaid work, school, importance of work and change in work goals.  The same 
scale has been used in NHLBI-sponsored HCT studies and BMT CTN protocol 0201 and 0901. 
 
EQ-5D: The EQ-5D will collect data that may be used to calculate patient-reported utilities for 
cost-utility analyses.  The EQ-5D contains a five item survey with three response levels per item 
measuring mobility, self-care, usual activities, pain/discomfort and anxiety/depression.  The EQ-
5D takes approximately 1 minute to complete (Agency for Healthcare Research and Quality, 
2005). 
 
2.9.2. Administration 
 
The self report questionnaires will be completed prior to transplantation and subsequently at 12 
months, and 24 months from randomization or until death.  Only patients able to read and speak 
in English or Spanish are eligible to participate in the HQL component of this trial.  Surveys are 
completed by participants using self-completed instruments as a first choice.  If this method of 
data collection is not possible, then surveys and response options may be read verbatim to 
participants, either in person or over the phone, to collect data.  The method of survey 
completion, the date, and the language will be recorded in the database.  Surveys may not be 
completed by surrogates. 
 
TABLE: 2.9 REQUIRED PATIENT-REPORTED OUTCOMES DATA COLLECTION 
Instrument 
N 
items 
Pre-
transplant 12 mos 
24 mos 
Socio-demographics 
8 
X 
 
 
Global quality of life 
4 
X 
X 
X 
FACT-BMT 
37 
X 
X 
X 
MOS SF-36 
36 
X 
X 
X 
Occupational functioning 
6 
X 
X 
X 
EQ-5D 
5 
X 
X 
X 
Alternative contacts 
2 
X 
X 
X 
TOTAL N ITEMS 
 
98 
92 
92 
ANTICIPATED TIME 
 
30 min 
30 min 
30 min 
 

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CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. Primary Endpoint 
 
The primary endpoint is PFS at 2-years from the date of randomization.  PFS is defined as the 
time interval from date of randomization and time to relapse/progression, to death or to last 
follow-up. 
 
3.2. Secondary Endpoints 
 
3.2.1. Neutrophil Recovery  
 
Neutrophil recovery is defined as achieving an ANC ≥ 500/mm3 for three consecutive 
measurements on three different days.  The first of the three days will be designated the day of 
neutrophil recovery.  The only competing event for neutrophil recovery is death without 
neutrophil recovery.   
 
3.2.2. Primary Graft Failure 
 
Primary graft failure is defined as < 5% donor chimerism on all measurements up to and 
including Day 56.   
 
3.2.3. Secondary Graft Failure 
 
Secondary graft failure is defined as initial whole blood or marrow donor chimerism ≥ 5% 
declining to < 5% on subsequent measurements.   
 
3.2.4. Platelet Recovery  
 
Platelet recovery is defined by two different metrics as the first day of a sustained platelet count 
> 20,000/mm3 or > 50,000/mm3 with no platelet transfusions in the preceding seven days.  The 
first day of the sustained platelet count will be designated the day of platelet engraftment. 
 
3.2.5. Donor Cell Engraftment  
 
Donor cell engraftment is defined as donor chimerism ≥ 5% on Day ≥ 56 after transplantation.  
Chimerism may be evaluated in whole blood or blood cell fractions, including CD3 and CD33 or 
CD15 fractions).  The actual measurement dates may be within +/- 7 days of the above 
recommended time points. 
 

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3.2.6. Acute GVHD 
 
The cumulative incidences of grade II – IV and III – IV acute GVHD will be determined.  Acute 
GVHD will be graded according to the BMT CTN MOP.  The time to onset of acute grades II-IV 
GVHD and grades III-IV GVHD will be recorded, as well as the maximum grade achieved.   
 
3.2.7. Chronic GVHD 
 
The cumulative incidence of cGVHD will be determined.  Data will be collected directly from 
providers and chart review according to the recommendations of the NIH Consensus Conference.  
Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement.  
Liver function and pulmonary function results will  also be recorded.  These data will allow 
calculation of the NIH global severity scores of mild, moderate, and severe chronic GVHD, 
which has been associated with transplant related mortality and overall survival.20   
 
3.2.8. Overall Survival 
 
Overall survival is defined as the time interval between date of randomization and death from 
any cause or for surviving patients, to last follow-up.  The time interval between date of 
transplant and death from any cause or for surviving patients, to last follow-up will also be 
analyzed.   
 
3.2.9. Treatment-Related Mortality (TRM) 
 
The cumulative incidence of TRM will be estimated at Days 100, 180, and at 1 and 2 years after 
transplantation.  An event for this endpoint is death without evidence of disease progression or 
recurrence.   
 
3.2.10. Infections 
 
All Grade 2 and 3 infections will be reported according to the BMT CTN MOP.  Grade 1 CMV 
infections through Day 56 will also be reported.   
 
3.2.11. Hospital Admission and Length of Stay 
 
The total number of hospital admissions within the first six months after transplantation, 
indication for admission, and length of stay per hospital admission will be captured.  
 
3.2.12. Health-Related Quality of Life (HQL) 
 
The instruments will be scored according to the recommendations of the developers.  See Section 
2.9.1 for detailed descriptions of the instruments.  The FACT-BMT instrument will be 
summarized by the Trial Outcome Index, comprised of the physical, functional and BMT-
specific items.  The MOS SF-36 will be summarized by the Physical Component Summary 
(PCS) and Mental Component Summary (MCS).  The EQ-5D utility score will be calculated. 
 

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HQL will be described and compared between the two treatment arms over time.  The self report 
questionnaires will be completed prior to transplantation and subsequently at 12 and 24 months 
from randomization or until death.  Only patients able to read and speak in English or Spanish 
are eligible to participate in the HQL component of this trial. 
 
3.2.13. Relapse, Residual Disease and Disease Progression 
 
Relapse of Malignancy – Testing for recurrent malignancy in the blood, marrow or other sites 
will be used to assess relapse after transplantation.  For the purpose of this study, relapse is 
defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-
transplant features, or radiologic evidence (including the recurrence of fluoro-deoxyglucose 
[FDG]-avid lesions on PET scan) of progressive lymphoma.  When in doubt, the diagnosis of 
recurrent or progressive lymphoma should be documented by tissue biopsy.   
 
Minimal Residual Disease – Minimal residual disease is defined by the sole evidence of 
malignant cells by flow cytometry, or fluorescent in situ hybridization (FISH), or Southern blot, 
or Western blot, or polymerase chain reaction (PCR), or other techniques, in absence of 
morphological or cytogenetic evidence of disease in blood or marrow.  Since the frequency of 
testing for minimal residual disease is highly variable among centers, and the sensitivity is highly 
variable among laboratory techniques, evidence of minimal residual disease alone will not be 
sufficient to meet the definition of relapse in the context of this trial.  However, minimal residual 
disease that progresses (see above) will be considered as relapse and the date of relapse will be 
the date of detection of minimal residual disease that prompted an intervention by the treating 
physician.  Data on tapering immunosuppression, administering chemotherapy or biological 
agents to in response to detection of minimal residual disease will be captured in the case report 
forms. 
 
Acute Leukemia – Relapse will be diagnosed when there is: 
1. The reappearance of leukemia blast cells in the peripheral blood; or, 
2. > 5% blasts in the marrow, not attributable to another cause (e.g., bone marrow 
regeneration); or, 
3. The appearance of new dysplastic changes within the bone marrow; or, 
4. The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid; or, 
5. The reappearance of cytogenetic abnormalities present prior to transplantation. 
 
 

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Lymphoma – Relapse will be diagnosed when there is: 
1. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
2. At least a 50% increase from nadir in the sum of the product diameters (SPD) of any 
previously involved nodes, or in a single involved node, or the size of other lesions (e.g., 
splenic or hepatic nodules).  To be considered progressive disease, a lymph node with a 
diameter of the short axis of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 
x 1.5 cm or more than 1.5 cm in the long axis.  
 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (<.1.5 cm in its long axis by CT). 
 
 
Institution of any therapy to treat persistent, progressive or relapsed disease, 
including withdrawal of immunosuppressive therapy or DLI, will be considered 
evidence of relapse/progression regardless of whether the criteria described above 
are met. 
 
TABLE 3.2 RESPONSE CRITERIA FOR LYMPHOMA 
From Cheson, B.D. et al.  Revised response criteria for malignant lymphoma.  J Clin 
Oncol 5:579-586, 2007. 
 

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Response Criteria for Acute Leukemia 
 
Remission is defined as < 5% blasts with no morphological characteristics of acute leukemia 
(e.g., Auer Rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing 
ANC >1000/µl, including patients in CRp. 
 
Response Criteria for Lymphoma 
 
Response criteria for lymphoma are described in Table 3.2. 
 
3.2.14. Cost-effectiveness Analysis 
 
The primary endpoint for the CEA is the cost per QALY from the societal perspective with two 
time horizons: (1) within trial, and (2) lifetime using economic modeling. 
 
The secondary endpoints for the CEA include costs from a narrower third party payer 
perspective and a separate analysis of the value of informal caregiving.  

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CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCSM).  The following procedures should be followed: 
 
1. An authorized user at the transplant center enters the patient demographics and HLA 
typing results of the recipient, haplo donor, and both CBUs into Segment 0 in 
AdvantageEDC.  HLA match scores will be calculated to confirm eligibility prior to 
randomization.  Further review by the DCC will be triggered if the institutional match 
score disagrees with the calculated match score.  The DCC review must be completed 
prior to proceeding to Segment A.  The eligibility screening includes a question 
confirming that the patient (or legal guardian) signed the informed consent.  
 
2. Upon successful completion of the Segment 0 HLA forms, an authorized user at the 
transplant center will enter the remainder of the eligibility criteria required prior to 
randomization on the Segment A enrollment form.  In addition, the transplant center must 
commit to using or not using post transplant maintenance therapy, irrespective of the 
treatment assignment.  
 
3. If the patient is eligible, the patient will be randomized to the dUCB or Haploidentical 
transplant arm and the treatment assignment will be displayed along with the generated 
patient number.  Patients should be registered as close as possible to the initiation of the 
conditioning regimen. 
 
4. A visit schedule based on treatment start date is displayed for printing and is referred to 
as ‘Segment A Follow-up.’ 
 
4.2. Study Monitoring and Data Submission 
 
4.2.1. Follow-up Schedule 
 
The follow-up schedule for scheduled 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 Data Management Handbook and User’s Guide. 
 

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TABLE 4.2.1:  FOLLOW-UP SCHEDULE 
 
Study Visit 
Target Day Post-Transplant 
1 week 
 7 ± 3 days 
2 week 
14 ± 3 days 
3 week 
21 ± 3 days 
4 week 
28 ± 3 days 
5 week 
35 ± 3 days 
6 week 
42 ± 3 days 
7 week 
49 ± 3 days 
8 week 
56 ± 3 days 
9 week 
63 ± 3 days 
10 week 
70 ± 3 days 
11 week 
77 ± 3 days 
12 week 
84 ± 3 days 
13 week 
91 ± 3 days 
6 month 
180 ± 45 days 
12 month 
365 ± 45 days 
24 month 
730 ± 60 days 
36 month 
            1095 ± 60 days 
 
4.2.2. Criteria for Forms Submission  
 
4.2.2.1. Electronic Case Report Forms (eCRFs) 
 
All data for patients are recorded in the electronic Case Report Forms (eCRF) exclusively 
designed for the study.  The Principal Investigator at each of the participating center’s is 
responsible for complete, accurate and timely reporting of data.   
 
Criteria for timeliness of submission for all study forms are detailed in the Data Management 
Handbook and User’s Guide.  Forms that are not entered into AdvantageEDC (the electronic data 
entry system) within the specified time will be considered delinquent and addressed with the 
delinquent center.  When data are unavailable because a measure has not been taken, a test not 
performed or data are unknown, a form or field exception is requested by the center.  A form will 
continue to show as “missing” either until the form is entered into the AdvantageEDC system 
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 Data 
Management Handbook. 
 
Corrections in the eCRF are to be conducted only by authorized personnel and may require 
authorization prior to implantation of corrections. However, all earlier entires are retrievable 
despite corrections. All corrections are recorded automatically concerning date, time point and 
person. Plausibility and completeness of the eCRF are verified by personnel at the Data 
Coordinaring Center.   

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At all times, the Principal Investigators at the participating centers have full  responsibility for 
ensuring accuracy and authenticity of all clinical and laboratory data entered on the eCRFs.  
 
Reporting Patient Deaths:  Recipient death information must be entered into AdvantageEDC 
within 24 hours of knowledge of the patient’s death.  If the cause of death is unknown at that 
time, it need not be recorded at that time.  However, once the cause of death is determined, the 
form must be updated in AdvantageEDC. 
 
CIBMTR Data Reporting:  Centers participating in BMT CTN trials must register pre- and 
post-transplant outcomes on all consecutive hematopoietic stem cell transplants done at their 
institution during their time of participation to the Center for International Blood and Marrow 
Transplant Research (CIBMTR).  Registration is done using procedures and forms of the Stem 
Cell Transplant Outcomes Database (SCTOD).  (Note: Federal legislation requires submission of 
these forms for all US allotransplant recipients.)  Enrollment of BMT CTN #1101 must be 
indicated on the SCTOD pre-transplant registration form.  Additionally, CIBMTR pre- and post- 
transplant Comprehensive Report Forms must also be submitted for all patients enrolled on this 
trial.  CIBMTR forms will be submitted directly to the CIBMTR at the times specified on the 
Form Submission Schedule. 
 
GVHD Monitoring:  GVHD should be monitored in accordance with BMT CTN guidelines as 
specified in the Manual of Procedures.  Patients should be assessed weekly until Day 90 post-
transplant for GVHD.  After Day 90 patients will be assessed at each follow-up visit (Day 180, 
365, and 730) for the presence of GVHD.   
 
4.2.2.2. Access to Data 
 
Participating sites and their Principal Investigators must agree to allow trial-related on-site 
monitoring, including audits and regulatory inspections by BMT CTN DCC personnel such that 
the DCC has direct access to source data/documents as required.   
 
4.2.2.3. Record Retention 
 
Responsibilities of the Sponsor:  As required by law, all study documents must be stored by the 
sponsor for at least 10 years after the clinical trial was finished or stopped. 
 
Responsibilities of the Principal Investigator: The Investigator agrees to keep records, 
including the identity of all participating patients, all original signed informed consent forms, 
copies of all CRFs, source documents, detailed records of treatment disposition and other trial-
related documents. The trial-related records should be retained by the Investigator for at least 10 
years or as specified by contract, whichever is longer.   
 
4.2.3. Study Monitoring 
 
Monitoring and audits will be performed during the clinical study to ensure that the study meets 
the quality criteria.   
 
 

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The investigator agrees that the monitor will visit the study center in appropriate intervals. 
During these visits, the monitor will check the quality of the data recording and ensure that the 
study center adheres to the timeframe as set in the study protocol. The investigators agree to 
provide any relevant information and documentation whenever requested by the monitor. This 
includes access to all original study documents and source data including access to electronic 
source documents if necessary. Source data are checked and compared with entries in the data 
base. The participant has given consent to this procedure by signing the patient information and 
written informed consent form. 
 
The monitor has the responsibility to treat all information confidentially and to safeguard the 
integrity and personal privacy of the study participants. 
 
Following a monitoring visit, the Monitor will provide a report to the sponsor and the site, which 
will summarize the documents reviewed and a statement of findings, deviations, deficiencies, 
conclusions, actions taken and actions required. The Principal Investigator at each site will be 
responsible for ensuring that monitoring findings are addressed (this may be delegated to an 
appropriate member of staff). 
 
Details of monitoring activities will be included in the Site Monitoring Plan. 
 
4.2.4. Adverse Events 
 
4.2.4.1.Adverse Event Reporting 
 
Adverse event reporting will be conducted according to the BMT CTN’s manual of operating 
proceedures (MOP). 
Unexpected AE Reporting:  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.   
 
The principal investigator is responsible for submitting follow-up reports to the DCC for all 
Grade 3-5 Unexpected AEs regarding the patient’s subsequent course until the Unexpected AE 
has resolved or until the patient’s condition stabilizes (in the case of persistent impairment), or 
the patient dies. 
 
Expected AE Reporting:  Expected AEs will be reported using NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form 
Submission Schedule.  All fatal (Grade 5) expected adverse events will be reported in an 
expedited manner to the DCC.  Most protocol-specific life-threatening or disabling (Grade 4) and 
other non-fatal expected adverse events will be reported on study forms submitted on a defined 
forms submission schedule.  Grade 4 adverse events not collected on study forms should be 
reported in an expedited manner. 
 
 

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4.2.4.2.Adverse Event Monitoring 
 
Unexpected Adverse Events:  Unexpected adverse events will be reported via a web-based 
adverse event (AE) system.  The Adverse Event Coordinator will review daily all submitted 
unexpected adverse events and forward the information to the Medical Monitor for review. 
 
All unexpected adverse events will be reviewed by the Medical Monitor within 2 business days 
of receiving the summary of the adverse event from the transplant center.  If the Medical 
Monitor requires additional information to make his/her assessment, transplant centers will have 
4 business days to respond to the request for additional information. 
 
The Medical Monitor has medical expertise relevant to the study protocol and may request the 
participant's treatment assignment when reviewing the adverse event.  A designated person at the 
DCC is responsible for notifying the Project Officer (National Heart Lung and Blood Insttiute 
[NHLBI]) immediately of all Grade 3-5 unexpected adverse events and of any concerns 
regarding the frequency or type of adverse event(s) on a study or study treatment arm.  The 
NHLBI Project Officer (or designee) is responsible for reviewing the adverse event materials to 
determine if the materials are complete.  If there are any concerns regarding the type or 
frequency of the event, the NHLBI Project Officer will request that the Data Saftey Monitoring 
Board (DSMB) Executive Secretary notify the DSMB Chair.  The DSMB Chair will review the 
adverse event materials, determine if the information is complete, determine if additional DSMB 
review is required and make recommendations to the NHLBI concerning continuation of the 
study.  Full documentation of the procedures will be available at the DCC. 
 
The Medical Monitor will review cumulative unexpected grades 3-5 SAEs on a quarterly basis 
(data will be reported in a blinded fashion).  The Medical Monitor may seek additional guidance 
from one of the DCC Principal Investigators, based on the expertise required, for their 
assessments as long as the DCC Principal Investigator’s institution is not participating in the 
protocol under consideration, and the DCC Principal Investigator is not considered to be 
otherwise in conflict by the NHLBI or by the Steering Committee.  If there any concerns 
regarding safety, the NHLBI Program Directors will be notified immediately.  The Medical 
Monitor will provide a written summary of the safety concern. 
 
The DCC will prepare semi-annual summary reports of all unexpected adverse events for the 
NHLBI Project Officer and DSMB Chair.  Semi-annual reports will be made available on a 
secure website and the NHLBI Project Officer and DSMB Chair will be notified by e-mail when 
the materials are posted.  
 
Expected Adverse Events:  The DCC will prepare semi-annual summary reports of all Grade 5 
expected adverse events for the NHLBI Project Officer and the DSMB Chair.  Semi-annual 
reports will be made available on a secure website and the NHLBI Project Officer and DSMB 
Chair will be notified by e-mail when the materials are posted.  Grade 3-5 expected adverse 
events defined in the interim analysis plan will be reported as defined in the protocol.  Any 
concern regarding the type or frequency of a Grade 3-5 expected adverse event will be reported 
to the NHLBI Project Officer who will determine if referral to the DSMB is warranted.  If 
required, data materials will be provided by the DCC.  The DSMB Executive Secretary will 

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arrange for review by the DSMB Chair.  The Chair will determine if additional DSMB review is 
required and make recommendations to the NHLBI concerning continuation of the study.  The 
DCC will ensure that any additional reporting requirements defined by the NHLBI Project 
Officer, DSMB Chair and other oversight groups are identified and implemented. The DCC in 
collaboration with the NHLBI Project Officer will determine the exact content of these summary 
reports and the reporting schedule. 
 
The Protocol Coordinator and Medical Monitor will review the adverse events monitored for 
stopping guidelines at least monthly.  
 
Additionally, the Protocol Coordinator and Medical Monitor will review events reported on the 
protocol-specific toxicity form, the GVHD forms and the infection forms on a regular basis (at 
least semi-annually) to assess whether there are safety concerns that should be referred to the 
DSMB.  The Medical Monitor may seek additional guidance from one of the physicians at the 
DCC in these assessments as long as this physician’s institution is not participating in the 
protocol under consideration.   
 
TABLE 4.2.4.1 REPORTING UNEXPECTED ADVERSE EVENTS ON A BMT CTN  
PHASE II OR III STUDY 
 
SEVERITY 
GRADE 
ATTRIBUTION 
TRANSPLANT CENTER  
REPORTING REQUIREMENTS 
5 - Fatal 
4 - Life-threatening 
     or Disabling 
 
All attributions 
 
Submit unexpected adverse event form to the DCC within 
24 hours of the event.  For Grade 5, also submit study 
death form to the DCC. 
Submit a summary of the adverse event to the DCC within 
4 working days.  For Grade 5, the summary should 
include potential contributing causes of death. 
Information reported for the adverse event must include: 
Name of adverse event, date of first onset, peak severity, 
relationship to study drug/device/treatment, resolution 
date, actions taken with respect to administration of study 
drug/device/treatment, and other treatment for the adverse 
event. 
3 – Severe 
 
 
All attributions 
 
 
 
 
Definite 
Probable 
Possible 
 
 
 
Submit unexpected adverse event form to the DCC within 
3 working days of the adverse event.   
Submit a summary of the adverse event to DCC within 4 
working days 
Information reported for the adverse event must include: 
Name of adverse event, date of first onset, peak severity, 
relationship to study drug/device/treatment, resolution 
date, actions taken with respect to administration of study 
drug/device/treatment, and other treatment for the adverse 

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Unlikely 
Unrelated 
event.  
Multiple recurrences of the same adverse event should be 
reported separately. 
Information reported for the adverse event must include: 
name of adverse event, date of first onset, peak severity, 
and relationship to the study drug/device/treatment.  
Multiple recurrences of the same adverse event should be 
reported together.  
Note: Any adverse event prompting a change in the 
administration of study drug/device/treatment must 
include resolution date, actions taken with respect to 
administration of study drug/device/treatment, and other 
treatment for the adverse event. 
 
TABLE 4.2.4.2 REPORTING EXPECTED ADVERSE EVENTS ON BMT CTN  
PHASE II OR III STUDIES 
 
SEVERITY 
GRADE 
ATTRIBUTION 
TRANSPLANT CENTER  
REPORTING REQUIREMENT 
5 – Fatal  
 
All attributions 
Submit study death form to the DCC within 24 hours of 
death. 
Submit death summaries and/or autopsy reports of the 
expected adverse event to DCC quarterly or as requested. 
The summaries should include potential contributing 
causes of death. 
4 – Life-threatening 
      or disabling 
All attributions 
Submit study form(s) capturing data on the expected 
adverse event to the DCC at the form’s scheduled due 
date.  If the event is not captured on a study from, report 
using the AE system in an expedited manner. 
Note: Selected Grade 3-5 events will be tracked and 
regularly monitored by the DCC and DSMB as specified 
in protocol-specific monitoring plans.  
3 – Severe 
 
All attributions 
Submit study form(s) capturing data on the expected 
adverse event to the DCC at the form’s scheduled due 
date.  
 
 

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4.2.4.3. Adverse Event Definitions 
 
Adverse Event - Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or procedure 
(attribution of definite, probable, possible, unlikely, or unrelated).  
 
Life-Threatening Adverse Event - Any adverse event that places the participant, in view of the 
investigator, at immediate risk of death from the reaction. 
 
Serious Adverse Event (SAE) - Any adverse event that results in any of the following outcomes: 
death, a life threatening adverse event, in-patient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect. 
 
Unexpected Adverse Event - Any adverse event, the specificity or severity of which is NOT 
listed in the study protocol, product inserts or informed consent document. 
 
Attribution - The determination of whether an adverse event is related to a medical treatment or 
procedure.  Attribution categories: 
 
Definite 
The adverse event is clearly related to the study drug/device/procedure/ 
treatment(s).  
 
Probable 
The adverse event is likely related to the study drug/device/procedure/ 
treatment. 
For BMT CTN studies:  the adverse event is not likely to be caused by the 
subject’s underlying medical condition or other concomitant therapy, and the 
nature of the adverse event or the temporal relationship between the onset of 
the adverse event and study drug/device/treatment administration lead the 
investigator to believe that there is a reasonable chance of causal 
relationship.  
 
Possible 
The adverse event may be related to the study drug/device/procedure/ 
treatment(s). 
For BMT CTN studies: the adverse event could be attributed to the subject’s 
underlying medical condition or other concomitant therapy, but the nature of 
the adverse event or the temporal relationship between the onset of the 
adverse event and study drug/device/treatment administration lead the 
investigator to believe that there could be a causal relationship. 
 
Unlikely 
The adverse event is doubtfully related to the study drug/device/ 
procedure/treatment(s). 
 

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Unrelated 
The adverse event is clearly NOT related to the study drug/device/procedure/ 
treatment(s). 
For BMT CTN studies:  the adverse event is most plausibly explained by the 
subject’s underlying medical condition or other concomitant therapy, or the 
adverse event has no plausible biological relationship to study drug/device/ 
treatment.  
 
Common Terminology Criteria Adverse Events (CTCAE) – a descriptive terminology developed 
by the National Cancer Institute (NCI) for use in reporting adverse events.  The CTCAE includes 
a grading (severity) scale for each adverse event term.  Exhibits 6-1-1 and 6-1-2 provide 
reporting requirements for BMT-related complex/multi-component events.  A copy of the current 
CTCAE guidelines is located at http://ctep.cancer.gov/reporting/. 
 
Grade – Severity of the adverse event.  Grades were developed using the following guidelines: 
 
 
Grade 0 – No adverse event or within normal limits 
 
 
1 – Mild adverse event 
 
 
2 – Moderate adverse event 
 
 
3 – Severe adverse event 
 
 
4 – Life-threatening or disabling adverse event 
 
 
5 – Fatal adverse event 
 
4.2.5. Patient Assessments 
 
Table 4.2.2 summarizes patient clinical assessments over the course of the study. 
 
4.2.5.1. Pre-transplant evaluations 
 
The following observations must be completed ≤ 30 days prior to patient enrollment: 
1. History, physical examination, height and weight. 
2. Karnofsky performance status. 
3. CBC with differential and platelet count and blood chemistries to include: serum 
creatinine, bilirubin, alkaline phosphatase, AST, and ALT, LDH, sodium, magnesium, 
potassium, and chloride.  
4. If not already performed, HLA typing of the recipient: At least low resolution DNA 
based typing at HLA-A and -B, high resolution at  HLA-DRB1 (see Section 2.2.1) 
5. If not already performed, HLA typing (DNA-based low or high resolution acceptable) of 
at least one potential HLA-haploidentical first-degree relative (not required if potential 
haplo-donor is a biological parent or child).  
6. Leukemia patients: Bone marrow aspirates for pathology and cytogenetics and/or biopsy. 
7. Serum sample for anti-donor HLA antibodies. 
8. Lymphomas: CT scans or Whole Body PET/CT.  

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9. Declaration of post transplant maintenance therapy, if intended, and independent of the 
randomization assignment.  
 
The following observations are considered standard evaluations for transplant eligibility and 
must be determined ≤ 30 days prior to enrollment, OR ≤ 56 days prior to the initiation of 
conditioning therapy.   
1. For patients randomized to the double umbilical cord blood arm, confirmatory HLA 
typing (see Section 2.3.3), if not already performed.   
2. For patients randomized to the HLA haplo-identical bone marrow arm, high resolution 
DNA-based typing (see Section 2.3.2) of the recipient and donor, if not already 
performed. 
3. CMV antibody test, hepatitis panel (HepA Ab, HepB Sab, HepB Sag, HepB Core Ab, 
HepC Ab), herpes simplex, syphilis, HIV and HTLV1 I/II antibody, and varicella zoster 
virus. 
4. EKG. 
5. Left ventricular ejection fraction or shortening fraction. 
6. DLCO, FEV1, and FVC. 
7. Chest imaging (Chest X-Ray or Chest CT). 
8. Peripheral blood for pre-transplant chimerism, to establish a reference profile of host 
hematopoiesis. 
9. HQL questionnaires. 
10. Confidential Health Insurance Form and Caregivers Contact Information Form for the 
Cost Effectiveness Ancillary study. 
 
The following tests must be completed ≤ 30 days prior to the initiation of conditioning 
therapy.   
1. Recipient blood sample for future research. 
2. Donor blood (from all Haplo-BM donors) and bone marrow (from donors ≥ 18 only) 
samples for future research.  Donor samples to be collected on Day 0. 
3. CBC with differential, and blood chemistries to include: serum creatinine, bilirubin, AST, 
and ALT.   
4. β-HCG serum pregnancy test for females of childbearing potential. 
5. Leukemia patients: bone marrow aspirate and/or biopsy for pathology.  THIS TEST 
DOES NOT NEED TO BE REPEATED IF THE PRE-ENROLLMENT BONE 
MARROW WAS OBTAINED ≤ 30 DAYS PRIOR TO INITIATION OF 
CONDITIONING. 
 

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4.2.5.2. Post-transplant evaluations 
 
The following evaluations are considered standard evaluations for transplant recipients: 
1. Physical exam to assess GVHD and other morbidity weekly until Day 90 post-transplant, 
then at Days 180, 365, and 730 post-transplant.  GVHD evaluation and grading to be in 
keeping with the BMT CTN MOP. 
2. Karnofsky performance status on Days 56, 180, 365, and 730. 
3. CBC at least three times a week from Day 0 until ANC > 500 mm3 for 3 days after nadir 
reached.  Thereafter CBC twice per week until Day 28, then weekly until Day 56, then at 
Days 180, 365, and 730 post-transplant. 
4. Creatinine, bilirubin, alkaline phosphatase, ALT, AST, LDH, sodium, magnesium, 
potassium, and chloride, twice a week until Day 28 (or four weeks) and then weekly until 
Day 56, and then at Days 180, 365, and 730. 
5. Peripheral blood on Days 28 and 56 for post-transplant chimerism assay.  Chimerism to 
be measured by standard molecular testing. FISH may only be used with haplo sex mis-
matched transplants.  T cell chimerism is recommended.  Peripheral blood for chimerism 
assay recommended on Day 180 if donor chimerism is less than 95% on Day 56.  For the 
dUCB arm, the chimerism of individual cord blood units should be reported separately. 
6. dUCB Arm: Bone marrow aspirate and biopsy with chimerism studies is required at Day 
21 if WBC < 500.  If there is zero donor chimerism on Day 21, repeat on Day 28.  At Day 
28, if the the marrow is < 5% cellular and or there is zero donor chimerism, consider 
management of graft failure per institutional guidelines.  
7. Haplo-BM Arm: if ANC is less than 500 on Day 28, a bone marrow aspirate and biopsy 
with chimerism studies is required.  If zero donor chimerism is present at this time, 
consider management of graft failure per institutional guidelines.  
8. Toxicity assessments at Days 28, 56, 180, 365, and 730.    
9. Disease status evaluation    
a. Leukemia Patients: Disease status evaluation with at minimum CBC with 
differential is required at Day 730.  Abnormal counts should be followed up with 
bone marrow biopsy or aspirate.   
b. Lymphoma Patients – CT scans or Whole Body CT/PET scan on Day 730, per 
NCCN guidelines. 
10. Weekly CMV monitoring through Day 56. 
11.  HQL questionnaires to be completed by the patient at Days 365, and 730. 
12.  Blood samples for future research on Days 28, 56, 180, and 365. 

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TABLE 4.2.2:  SUMMARY OF ASSESSMENTS 
 
Study Assessments/ 
Testing 
Baseline 
Days after Transplantation 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
180 
365 
730 
109512 
History, physical exam, height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky performance status 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
HLA Typing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC1 differential, platelet count, and blood chemistries2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
Infectious disease titers3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
EKG and LVEF or shortening fraction 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO, FEV1 and FEV  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate for pathology and cytogenetics 
and/or biopsy 
X* 
 
 
X4 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scans or Whole Body CT/PET5 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X5 
 
Chest x-ray or chest CT  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ß-HCG serum pregnancy test (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GVHD assessments6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity assessments 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
Chimerism7 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X7 
 
 
 
Anti-HLA antibody crossmatch test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for future research8 
X8 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
Haplo donor blood and bone marrow sample for future 
research9 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health-Related Quality of Life Assessments10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Confidential Health Insurance Form and Contact 
Information Form11  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comprehensive CIBMTR Forms 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Notes: 
1  CBC performed at least three times a week from Day 0 until ANC >500 mcL for three days after nadir.  CBC performed twice weekly until Day 28. CBC performed 
weekly after Day 28 until Day 56. 
2  Blood chemistries should include: serum creatinine, bilirubin, alkaline phosphatase, AST, and ALT, LDH, sodium, magnesium, potassium, and chloride.  Blood 
chemistries performed twice weekly until Day 28.  Blood chemistries performed weekly after Day 28 until Day 56. 
3  Infectious disease titers include: CMV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV 
I/II antibody, and varicella zoster. 
    *Baseline for leukemia patients only. 
4  For dUCB arm bone marrow biopsy and aspirates to pathology required at Day 21 if WBC < 500.  For both dUCB arm and Haplo-BM arm Day 28 only to be done if 
slow neutrophil recovery to evaluate for graft failure.   

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5  LYMPHOMA PATIENTS ONLY: CT scans or Whole Body CT/PET at Baseline and Day730.   
  6  GVHD assessments performed weekly until Day 90 post-transplant, and then at Day 180, 365, and 730. 
7  Chimerism to be measured by standard molecular testing of a peripheral whole blood sample.  FISH may only be used with haplo sex mis-matched transplants T cell 
chimerism is recommended.  Peripheral blood for chimerism assay recommended on Day 180 if donor chimerism is less than 95% on Day 56.  For the cord blood arm, 
chimerism of individual cord blood units should be reported separately. 
8  Baseline blood samples for future research include samples from recipient and haplo donor.  See appendix C for details. 
9  Bone marrow sample for future research from Haplo-BM donors ≥18 only.  See appendix C for details. 
10 See Section 2.9 for detailed description of HQL assessments. 
11 See companion study document for detailed description of Cost Effectiveness Ancillary study and Confidential Health Insurance and Contact Information forms. 
12 Day 1095 data to be obtained from the CIBMTR. 
  

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5-1 
CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. Study Design and Objectives 
 
The study is designed as a Phase III, randomized, multicenter prospective comparative study of 
transplantation of Double Unrelated Umbilical Cord Blood (dUCB) versus HLA-Haploidentical 
Related Bone Marrow (Haplo) using non-myeloablative conditioning for patients with 
hematologic malignancies.  The target enrollment is 410 patients, 205 for each arm. 
 
5.1.1. Accrual 
 
It is estimated that four years of accrual will be necessary to enroll the targeted sample size. 
 
5.1.2. Randomization 
 
Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks 
of random sizes.  Randomization will be stratified by center.  
 
5.1.3. Primary Endpoint 
 
The primary endpoint is the probability of PFS at 2 years post randomization.  The primary 
analysis will be performed using the intent-to-treat principle so that all randomized patients will 
be included in the analysis.  Death or progression will be considered failures for this endpoint.   
 
5.1.4. Primary Hypothesis 
 
The primary null hypothesis of the study is that there is no difference between the 2 year PFS 
probabilities for dUCB vs. haplo-BM. 
 
Ho: 
pdUCB = pHaplo 
Ha: 
pdUCB ≠ pHaplo 
 
5.2. Sample Size and Power Considerations 
 
The primary analysis will be done using a group sequential comparison of the 2 year PFS 
probabilities using the difference in Kaplan-Meier estimates21; sequential monitoring is 
described further in Section 5.3.  A pointwise comparison of PFS at 2 years is proposed for the 
primary analysis rather than a log-rank test because of the potential for crossing hazards.  Phase 
II data indicated potentially lower TRM and higher relapse rates for the haplo-BM arm, and 
differential timing between these two types of events would lead to nonproportional hazards.  
The logrank test would have poor power to detect a difference between these two groups if the 
hazards cross.  The time point of 2 years was chosen based on CIBMTR data which indicated 

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most events after UCB and haploidentical transplantation occur by 2 years.  The final patient 
enrolled will be followed up for a minimum of 3 years, so that the targeted total study duration is 
7 years (4 years accrual + 3 years follow-up on the last patient).   
 
The targeted sample size is 410 patients, 205 per treatment arm.  The baseline PFS at 2 years is 
assumed to be approximately 35-40% based on CIBMTR data on RIC transplantation using 
unrelated adult donors.  We allow for 5% censoring due to loss to follow-up by 2 years in 
addition to administrative censoring.  In addition, we anticipate up to 5% of patients will be 
randomized but do not make it to the assigned transplant, and for power calculations we assume 
that these patients will all progress or die within 6 months.  The targeted sample size of 205 
patients per group is sufficient to maintain type I error of 5% across all planned interim analyses 
(see below) while providing 80% statistical power for a two-sided test to detect a 15% increase 
in the PFS probability at 2 years.  Note that the targeted 15% increase in PFS is the effect 
attributable to the transplant type itself.  This translates to a slightly lower 14.25% increase in 
PFS in the Intention-to-Treat (ITT) populations after accounting for the 5% of patients who are 
randomized but do not make it to transplant.  We will monitor the proportion of patients who are 
randomized but do not receive a transplant, and if the proportion is higher than the anticipated 
5%, we will re-evaluate the sample size to account for the resulting decrease in treatment effect 
for the ITT populations.  Details of this power calculation are found in the section on interim 
analyses for efficacy and futility.   
 
5.3. Interim Analysis and Stopping Guidelines 
 
Interim analysis for efficacy and futility will be conducted at times coincident with regularly 
scheduled meetings of the NHLBI-appointed Data and Safety Monitoring Board (DSMB) at 
approximately one year intervals.  Policies and composition of the DSMB are described in the 
BMT CTN’s Manual of Procedures.  The stopping guidelines serve as a trigger for consultation 
with the DSMB for additional review and are not formal “stopping rules” that would mandate 
automatic closure of study enrollment.  Toxicity, adverse events, and other safety endpoints will 
be monitored regularly and reported to the DSMB at each interim analysis. 
 
5.3.1. Interim Analysis for Efficacy and Futility  
 
Analyses will be performed as described below for the primary endpoint.  At the time of each 
interim analysis (tentatively planned at approximately 3, 4, 5, and 6 years), a two-sided test using 
the difference in Kaplan-Meier estimates of the PFS at 2 years will be conducted.  These test 
statistics have independent increments as described in Gu et al.21  All patients randomized prior 
to the time of the interim analyses will be used to compute the Kaplan-Meier estimate of PFS at 
2 years.  If the test statistic exceeds the critical value for efficacy, the DSMB will discuss the 
continuation of the trial.   
 
In order to preserve the overall Type I error rate at 5%, the critical value for the test statistic will 
be inflated above 1.96, the value that would be used if no repeated testing were used.  
Equivalently, the nominal p-value at which an observed difference is declared significant will be 
reduced below 0.05.  The actual critical values and nominal p-values will be computed using 
statistical methods for group sequential testing with O’Brien Fleming type boundaries.  

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To permit necessary flexibility in scheduling interim analyses, the critical values will be 
recomputed to correspond to the actual available statistical information using the “use-function” 
approach of Lan and DeMets.  The error spending function α(t)=min(α,αt3) will be used to 
approximate the O-Brien-Fleming boundary with unequally spaced looks.22  Information is 
defined as the reciprocal of the variance of the difference in Kaplan-Meier estimates between the 
two treatments.  The final information at the end of the study reduces to the reciprocal of the 
variance of the difference in two binomial proportions, assuming no censoring prior to 2 years, 
computed as 450.55.  Then the information fraction t is the ratio of the information at an interim 
analysis to the final information at the end of the study.  
 
Interim analyses for futility will start when accrual is complete, so that these analyses do not 
impact power for secondary endpoints.  The main benefit of these interim analyses for futility is 
potentially shortening of the time until the study conclusions regarding two year survival are 
reached, since they allow for stopping prior to the completion of the two year follow-up for the 
last patient enrolled.  The stopping rule for futility will be triggered when the conditional power 
to reject the null hypothesis at the observed effect size is less than 10%. 
 
Phase II data on dUCB and haplo transplants as well as longer-term CIBMTR data on unrelated 
adult donor transplants with RIC indicate PFS probabilities at 6 months, 1 year, and 2 years of 
65%, 47%, and 35%.  We also assume that 5% of patients will be randomized but not make it to 
the assigned transplant, and that all of these patients will progress or die by 6 months, so that the 
anticipated PFS curves in the ITT population are 62%, 45%, and 33%.  We also target a 
difference in 2 year PFS due to transplant type of 15%, which translates to a 14.25% difference 
in PFS at 2 years in the ITT population.   
 
Table 5.3.1a shows the information accumulated, the critical values for efficacy and futility, and 
the nominal significance levels for tests conducted at interim analyses at 3, 4, 5, and 6 years from 
the start of the study.  The information calculations assume uniform accrual of patients over 4 
years with 2 years of follow-up on the final patient enrolled.  The information fraction at each 
interim analysis comes from the reciprocal of the variance of the Kaplan-Meier estimate, which 
is approximated using a piecewise constant hazard function assuming PFS probabilities as 
described above.  Interim analyses for futility are planned to start at 4 years when accrual is 
completed. 
 
Table 5.3.1b shows the cumulative probability of stopping for efficacy or futility at each interim 
analysis from a simulation study under various scenarios, including two null hypothesis 
scenarios (PFS at two years of 35% in each treated group or 40% in each treated group) and 
under various alternative hypotheses (improvements in 2 year PFS of 10%, 15%, or 20% over 
baseline PFS of either 35% or 40%, corresponding to improvements in ITT population of 9.5%, 
14.25%, or 19%).  Simulations used 10000 Monte Carlo samples, and generated baseline 
survival curves from the piecewise constant hazard model as described previously.   
A proportional hazards model was used with hazard ratio chosen to induce the targeted increase 
in PFS in the ITT population for each scenario.  However, note that the proportional hazards 
model used in the simulation has minimum impact on the operating characteristics because all 
analyses are based on the pointwise comparison of the 2 year PFS probabilities.  In addition to 
administrative censoring induced by the accrual distribution and end of study time, the 

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simulations also accounted for additional drop out using independent exponential censoring with 
5% probability of censoring by 2 years.  The results indicate that there is > 50% power to detect 
a 15% improvement in 2 year PFS by the interim analysis at 4 years and 80% power to detect the 
same improvement by the final analysis.  When there is no difference in two year survival there 
is a 76% chance of stopping for futility by the interim analysis at 4 years. 
 
TABLE 5.3.1a CRITICAL VALUES AT EACH INTERIM ANALYSIS 
Calendar time 
since study 
start (years) 
Information 
Fraction 
Critical 
Value for 
Efficacy 
Nominal 
Type I 
Error  
Critical 
value for 
Futility 
3 
0.48 
3.0103 
0.0013 
- 
4 
0.74 
2.4534 
0.0071 
1.2057 
5 
0.94 
2.1092 
0.0175 
1.6881 
6 (Final) 
1.00 
2.0551 
0.0199 
2.0551 
 
 
TABLE 5.3.1b CUMULATIVE PROBABILITIES OF STOPPING FOR EITHER 
EFFICACY OR FUTILITY BY EACH INTERIM ANALYSIS UNDER VARIOUS NULL 
AND ALTERNATIVE SCENARIOS, FROM A SIMULATION STUDY WITH 10,000 
REPLICATES 
 
 
 
Cumulative probability of stopping and 
reaching conclusion by interim analysis at x 
years 
2 year PFS in 
treated pop 
(ITT pop) 
Diff in 
treated pop 
(ITT pop) 
Conclusion 
x=3 
4 
5 
6 (Power) 
35%,35% 
0%  
Efficacy 
0.004 
0.019 
0.044 
0.051 
(33.2%,33.2%) (0%) 
Futility 
 
0.765 
0.914 
 
40%,40% 
0%  
Efficacy 
0.003 
0.017 
0.041 
0.048 
(38%,38%) 
(0%) 
Futility 
- 
0.767 
0.911 
 
35%,45% 
10%  
Efficacy 
0.056 
0.232 
0.430 
0.479 
(33.2%,43.7%) (9.5%) 
Futility 
- 
0.300 
0.442 
 
40%,50% 
10%  
Efficacy 
0.058 
0.239 
0.431 
0.472 
(38%,47.5%) 
(9.5%) 
Futility 
- 
0.300 
0.438 
 
35%,50% 
15%  
Efficacy 
0.171 
0.534 
0.765 
0.802 
(33.2%,47.5%) (14.25%) 
Futility 
- 
0.098 
0.151 
 
40%,55% 
15%  
Efficacy 
0.188 
0.551 
0.770 
0.802 
(38%,52.2%) 
(14.25%) 
Futility 
- 
0.087 
0.142 
 
35%,55% 
20%  
Efficacy 
0.390 
0.823 
0.952 
0.967 
(33.2%,52.2%) (19%) 
Futility 
- 
0.014 
0.023 
 
40%,60% 
20%  
Efficacy 
0.432 
0.838 
0.953 
0.964 
(38%,57%) 
(19%) 
Futility 
- 
0.011 
0.021 
 
 
 

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5.3.2. Guidelines for Safety Monitoring 
 
Monitoring of TRM, a key safety endpoint will be conducted monthly, and if rates significantly 
exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised.  
Policies and composition of the DSMB are described in the BMT CTN's Manual of Procedures.  
The stopping guidelines serve as a trigger for consultation with the DSMB for additional review.  
The key safety endpoint to be monitored is the cumulative incidence of transplant-related 
mortality at Day 100.  This outcome will be monitored using a Sequential Probability Ratio Test 
(SPRT) for binary data as described below.  The SPRT conserves type I error at 5% across all of 
the monthly examinations.  No additional control of the type I error across multiple treatment 
groups will be used. 
 
The cumulative incidence of TRM at Day 100 will be monitored separately for each arm.  Each 
month, the null hypothesis that the cumulative incidence of TRM at Day 100 is ≤ 15% will be 
tested against the alternative that it is > 15%.  This null hypothesis value comes from CIBMTR 
data on RIC unrelated adult donor transplants, in which Day 100 TRM is 11% (95% confidence 
interval 6%-17%) for 7/8 HLA-matched unrelated peripheral blood stem cell transplants and 9% 
(95% confidence interval 5%-14%) for double cord blood transplants.  Day 100 TRM will be 
monitored using a SPRT for binary outcomes.  The SPRT can be represented graphically.  At 
each interim analysis, the total number of patients enrolled is plotted against the total number of 
patients who have experienced transplant-related mortality.  The continuation region of the 
SPRT is defined by two decision boundaries.  Only the upper boundary will be used for 
monitoring the study to protect against high incidences of TRM.  If the graph falls above the 
upper boundary, the SPRT rejects the null hypothesis, and concludes that the TRM incidence is 
higher than predicted by the observed number of patients enrolled on study.  Otherwise, the 
SPRT continues until enrollment reaches the target goal.  The SPRT for TRM was developed 
from the following SPRT: 
A SPRT contrasting 15% versus 25% 100-day incidence, which results in decision boundaries 
with a common slope of 0.197 and an upper intercept of 4.258, with nominal type I and II errors 
of 6% and 10%, respectively. 
 
The actual operating characteristics of this truncated test, shown in Table 5.3.2, were determined 
in a simulation study that assumed uniform accrual of 205 individuals over a four-year time 
period.   
 

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TABLE 5.3.2:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR 100 DAY TRM FROM A SIMULATION STUDY WITH 10,000 
REPLICATIONS 
True 100-Day Incidence 
15% 
20% 
25% 
Probability Reject Null  
0.052 
0.464 
0.933 
Mean Month Stopped 
49.6 
38.7 
21.7 
Mean # Endpoints in 100 Days 
29.6 
30.2 
19.9 
Mean # Patients Enrolled 
197.9 
151.3 
79.3 
 
For example, the testing procedure for a treatment which continues into Phase III testing rejects 
the null hypothesis in favor of the alternative 5% of the time when the true 100-day TRM 
incidence is 15%, and 93% of the time when the rate is 25%.  This corresponds to a type I error 
rate of α = 0.05 and a type II error rate of β = 0.07.  When the true 100-day TRM incidence is 
25%, on average, the DSMB will be consulted 22 months after opening, when 20 events have 
been observed in 79 patients.   
 
5.4. Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, risk status 
(Leukemia in CR1 vs. CR2+, Lymphoma in CR vs. PR), CMV status, HCT-comorbidity index, 
time from diagnosis to transplantation, cytogenetic at diagnosis (AML and ALL), HLA 
matching, prior autologous transplant, number of regimens prior to transplant (lymphoma only), 
cell dose/kg, and haplo donor relationship.  Between group comparisons will be performed for 
continuous variables via a Kruskal-Wallis test and for categorical variables, via the chi-square 
test.  A secondary analysis of all outcomes will adjust for age, performance status, primary 
disease, risk status, and CMV status, in addition to any other demographic and baseline 
characteristics which are statistically different between treatment arms (p<0.1).     
 
5.5. Analysis Plan 
 
5.5.1. Analysis of the Primary Endpoint 
 
The primary outcome of the trial is PFS at 2 years after randomization.  The primary null 
hypothesis of the study is that there is no difference in PFS between the treatment arms at 2 
years.  In the primary analysis, the intention-to-treat principle will be used.  The primary analysis 
will be performed using the difference in Kaplan-Meier estimates for PFS at 2 years.  A 95% 
confidence interval for the difference in PFS at 2 years will also be constructed.   
 

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5.5.2. Analysis of Secondary Endpoints 
 
5.5.2.1. Secondary analysis of PFS 
 
Several secondary analyses of PFS will be conducted.  In addition to a point-wise comparison at 
2 years, Kaplan-Meier curves will be constructed for each treatment arm.  Additional analyses to 
be performed will depend on an assessment of the original assumption of nonproportional 
hazards assumed in the study design.  A Cox proportional hazards model will be fit to PFS and 
graphical diagnostics and time-dependent covariates will be used to assess the presence of 
nonproportional hazards between treatment groups.  If there is no evidence of nonproportional 
hazards, a relative risk will be estimated from the Cox model both unadjusted and adjusted for 
other covariates.  If there appears to be nonproportional hazards, several analyses will be 
conducted.  First, confidence bands for the difference in PFS will be constructed.  Second, a 
comparison of PFS post 2 years will be conducted using the linear combination test proposed by 
Logan et al.23  This method directly compares the PFS curves starting at 2 years, and accounts 
for patients enrolled early in the study having additional follow-up past 2 years.  Finally, an 
adjusted analysis of PFS at 2 years will be conducted using the adjusted PFS probabilities 
proposed by Zhang et al.24.  The adjusted PFS probabilities are estimated using a Cox 
proportional hazards model, stratified on treatment.  Age, performance score, disease, disease 
risk, CMV status, and any other covariates which are significantly different between the 
treatments (p<0.1) will be used in any adjusted analyses.  Finally, PFS will also be described in 
each arm from the time of transplant. 
 
5.5.2.2. Overall survival 
 
Overall survival curves will be estimated using the Kaplan-Meier estimator.  Overall survival at 
2 years will be compared between treatment arms using the difference in Kaplan-Meier 
estimators.  A secondary analysis of survival will be performed by assessing proportional 
hazards and performing subsequent analysis based on the results of that assessment, using the 
same methods as those described in Section 5.5.2.1.  Overall survival will also be described in 
each arm from the time of transplant. 
 
5.5.2.3. Treatment-related mortality  
 
Incidence of TRM will be estimated using the cumulative incidence function, treating 
relapse/progression as a competing risk.  Incidence of TRM will be compared between the 
treatment arms using Gray’s test.25  In a secondary analysis, TRM will be compared between 
arms using a Cox proportional hazards model with treatment as the main effect.  Age, 
performance score, disease, disease risk, CMV status, and any other baseline characteristics 
which are significantly different between arms will be included as covariates in the Cox model to 
adjust for potential imbalances.  TRM will also be described in each arm from the time of 
transplant. 
 

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5.5.2.4. Relapse/progression 
 
Incidence of relapse/progression will be estimated using cumulative incidence function, treating 
death in remission as a competing risk.  Incidence of relapse/progression will be compared 
between the treatment arms using Gray’s test.  In a secondary analysis, relapse/progression rates 
will be compared using a Cox proportional hazards model with treatment as the main effect.  
Age, performance score, disease, disease risk, CMV status, and any other significantly 
imbalanced characteristics will be adjusted for.  Relapse/progression will also be described in 
each arm from the time of transplant. 
 
5.5.2.5.Hematologic recovery 
 
Incidence of neutrophil and platelet engraftment from the time of transplant will be estimated 
using the cumulative incidence function with death prior to engraftment as the competing risk.  
Incidence of neutrophil engraftment at 56 days and incidence of platelet engraftment at 100 days 
will be compared between the treatment arms using a pointwise comparison of the cumulative 
incidence probabilities.    
 
5.5.2.6. Donor cell engraftment 
 
Donor chimerism at Days 28 and 56 after transplantation in each treatment arm will be described 
numerically as median and range for those evaluable as well as according to proportions with full 
(> 95%), mixed (5-95% donor cells), graft rejection (< 5%), or death prior to assessment of 
donor chimerism.  The proportions alive with ≥ 5% donor chimerism will be compared between 
the two groups using the chi-square test.   
 
5.5.2.7. Acute GVHD of grades II-IV and III-IV 
 
Cumulative incidence of acute GVHD will be estimated from the time of transplant using the 
cumulative incidence function, treating death prior to acute GVHD as the competing risk.  
Cumulative incidence of acute GVHD will be compared between treatment arms using Gray’s 
test.  
 
5.5.2.8. Chronic GVHD  
 
Cumulative incidence of chronic GVHD from the time of transplant will be estimated using the 
cumulative incidence function, treating death prior to chronic GVHD as the competing risk.  
Cumulative incidence of chronic GVHD will be compared between treatment arms using Gray’s 
test.  
 
5.5.2.9. Incidence of primary graft failure  
 
The proportions of patients alive at Day 56 but with primary graft failure will be described and 
compared between the treatment arms using the chi-square test or Fisher’s exact test as 
appropriate.   
 

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5.5.2.10. Incidence of secondary graft failure 
 
The cumulative incidence of secondary graft failure out of those who had initial engraftment will 
be described using the cumulative incidence estimator, treating death and disease 
relapse/progression prior to secondary graft failure as a competing event.   
 
5.5.2.11. Incidence of toxicities grade ≥ 3 per CTCAE version 4.0 
 
All Grade ≥ 3 toxicities will be tabulated by grade for each treatment arm, by type of toxicity as 
well as the peak grade overall.  Toxicity frequencies will be described for each time interval as 
well as cumulative over time.   
 
The cumulative incidence of Grade ≥ 3 toxicity will be compared between treatment arms at 
Days 28, 56, 180, 365, and 730.    
 
5.5.2.12. Incidence of infections 
 
The number of infections and the number of patients experiencing infections will be tabulated by 
type of infection, severity, and time period after transplant.  The cumulative incidence of severe, 
life-threatening, or fatal infections, treating death as a competing event, will be compared 
between the two treatment arms at 6, 12, and 24 months.  A secondary analysis of infections 
requiring hospitalization will be conducted in a similar way.   
 
5.5.2.13. Hospital admission and length of stay 
 
The number of hospital readmissions, the number of patients experiencing hospital readmissions, 
and the average length of stay for both hospital readmissions and the initial transplant 
hospitalization will be described.  The number of days alive and not hospitalized will be used to 
examine the total duration of hospitalization in the first 6 months accounting for mortality.  
These distributions will be compared between the two groups using Mann-Whitney tests.   
 
5.5.2.14. Health-Related Quality of life 
 
HQL at each time point will be summarized using simple descriptive statistics (mean, SD).  HQL 
among survivors at each time point will be compared between treatment arms in an initial 
analysis using two sample t-statistics.  The missing data pattern of the HQL measurements will 
be examined using graphical techniques and logistic regression models conditional on survival.  
At each time point, estimates of the difference in HQL between the treatments conditional on 
survival at that time point will be obtained using inverse probability of censoring weighting with 
independent estimating equations26 to account for missing data.     
 
5.6.Subgroup Analysis 
 
Subgroup analyses will be conducted for 2 year PFS according to disease, disease risk and age.  
Interaction tests between treatment group and subgroup will be conducted using a logistic 
regression model with treatment, subgroup, and a treatment*subgroup interaction term.  If there 

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is censoring present prior to 2 years, a logistic regression model for 2 year PFS using 
pseudovalues will be used.  A Bonferroni adjusted significance level of 0.05/3=0.0167 will be 
used for each interaction test to account for multiple testing.  If a significant interaction is 
identified, plots of Kaplan-Meier estimates of PFS by treatment will be shown separately for 
each level of the subgroup.   
 
 

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CHAPTER 6  
 
 
6. 
ETHICS AND REGULATORY 
 
6.1. Good Clinical Practice Guidelines 
 
The DCC and the clinical investigators assure that the clinical study is performed in accordance 
with the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996, 
the Declaration of Helsinki (Recommendations guiding physicians in Biomedical Research 
involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 
1989, Somerset West 1996, Edinburgh, 2000, Seoul 2008, Fortaleza 2013) and applicable 
regulatory requirements. 
 
6.1.1. Patient Consent 
 
A conference will be held with the patient, donor and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The conference will be 
conducted by the principal investigator or other designated physician.    
 
6.1.2.  Patient Withdrawal 
 
6.1.2.1. Patient withdrawal from intervention 
 
Participation in the trial is voluntary. Patients will be advised that they may voluntarily withdraw 
from the study at any time and will be instructed to notify the investigator. Patients may choose 
to withdraw for any reason(s). Patients are not obligated to reveal their reason(s) for withdrawal 
to the DCC.  
 
6.1.2.2. Patient withdrawal from data collection 
 
If a patient explicitly states they do not wish to contribute further data to the trial their decision 
must be respected and notified to the DCC in writing.  In this event details should be recorded in 
the patient’s hospital records, no further CRFs must be completed and no further data sent to the 
sponsor. 
 
6.1.2.3. Patient Removal From Study 
 
The investigator has the right to terminate the participation of any subject at any time, if s/he 
deems it in the partients’s best interest. The reason and circumstances for study discontinuation 
will be documented by the site and sent to the DCC. 
 
Reasons for study discontinuation might be: 
• Intolerable side effects of the study product. 

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• Changes in medical status of the patient such that the Investigator believes that 
patient safety will be compromised or that it would be in the best interest of the 
patient to stop  
treatment. 
• Pregnancy. 
• Withdrawal of consent. 
• Relevant non-compliance with the protocol. 
6.1.3. Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code upon enrollment in AdvantageEDC.  The code relaying the patient’s identity with 
the ID code will be kept separately at the center.   
 
6.1.4. Participation of Women and Minorities 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of leukemia 
and lymphoma in these groups.  Centers will be notified if their rates differ significantly from 
those expected and asked to develop appropriate recruitment reports. 
 
6.2. Protocol Amendments  
 
All protocol amendments containing substantive changes must be reviewed and accepted by 
members of the DSMB before distribution to Clinical Centers.  The review may take place at a 
DSMB meeting, on an arranged conference call, or by ballot.   
 
Once approved by the DSMB, participating centers (and the FDA if applicable) will be notified 
of approved protocol amendments by an e-mail announcement from the DCC.  Amendment 
documents may be included with the e-mail announcement and will be posted on the BMT CTN 
website.  The documents will include: 
1. A summary of protocol changes 
2. A revised protocol with changes highlighted 
3. A second version with the changes fully incorporated into the document 
4. A rationale for changes may be provided 
 
Other types of amendments containing non-substantive changes may be released to Centers 
before DSMB notification or deliberation.  These changes will be reviewed at the next regularly 
scheduled DSMB meeting or conference call. 
 

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The DCC PIs will determine the appropriate review process in collaboration with the NHLBI 
Project Officer. 
 
Clinical Centers are responsible for implementing all amendments according to institutional 
policy. 
 
6.3. Protocol Deviations 
 
Clinical centers should inform the DCC of any major protocol deviations.  These will be  
submitted to the DSMB on a semi-annual basis. 
 
6.4. Premature Termination of the Trial 
 
The sponsor has the right to discontinue the study due to relevant medical or administrative 
reasons. Participants who still receive medication during the time of discontinuation will undergo 
a final visit which has to be documented in the CRF. 
Possible reasons for discontinuation by the sponsor are: 
• failure in recruiting participants, 
• data quality is insufficient, 
• unforeseen circumstances at the study site that make the continuation of the study 
impossible, 
• early prove of superiority or non-inferiority of a treatment group, 
• occurrence of unjustifiable risks or toxicity, 
• new scientific knowledge that does not justify continuation of the clinical study. 
6.5. Publication Policy 
 
Manuscripts reporting the results of this trial will be prepared and submitted to a reputable peer-
reviewed medical journal in accordance with basic ethical principles, including preservation of 
the accuracy of the results and making both positive and negative results publicly available. In all 
publications the confidentiality of patients’ data will be ensured. 
 
Data analysis and authorship will be conducted according to the BMT CTN MOP.  No clinical 
trial results are released, presented or published without approval from the Publications 
Committee, the BMT CTN DCC, NHLBI and NCI. 
 
The study is registered in the clinical trials database (www.clinicaltrials.gov) which is accessible 
to the public. The ClinicalTrials.gov number NCT01597778 allocated to this trial will be quoted 
in any publications resulting from this trial. 
 

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By signing this study protocol, the investigators accept that the results of this clinical trial can be 
presented to national and international authorities. They also accept that in this context their 
name, address, qualification and grade of involvement in this trial will be published 
 

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APPENDIX A 
 
ABBREVIATIONS 
 
 
 
 
 
 
 

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APPENDIX A 
 
ABBREVIATIONS 
 
AdvantageEDCSM – Proprietary electronic data capture system 
AE – Adverse Event 
ALL – Acute Lymphoblastic Leukemia 
ALT – Alanine Aminotransferase 
AML – Acute Myeloid Leukemia 
ANC – Absolute Neutrophil Count 
AST – Aspartate Aminotransferase 
B-ALL – Acute B Lymphoblastic Leukemia 
BM – Bone Marrow 
BMT CTN – Blood and Marrow Transplant Clinical Trials Network 
RIC – Reduced Intensity Conditioning 
CBC – Complete Blood Count 
CCr – Creatinine Clearance Rate 
CD15 – Cluster of Differentiation 15 
CD3 - Cluster of Differentiation 3 
CD33 - Cluster of Differentiation 33 
CDC – Centers for Disease Control 
CEA – Cost Effectiveness Analysis 
cGVHD – Chronic Graft Versus Host Disease 
cGY - Centigray 
CHOP±R – Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone +/- Rituximab 
CI – Confidence Interval 
CIBMTR – Center for International Blood and Marrow Transplant Research 
CMV - Cytomegalovirus 
CNS – Central Nervous System 
CR - Complete Remission 
CsA – Cyclosporin A 
CT – Computed Tomography 
CTCAE – Common Terminology Criteria for Adverse Events 
CVP±R – Cyclophosphamide/Vincristine Sulfate/Prednisone +/- Rituximab 
DCC – Data and Coordinating Center 
DHAP±R – Dexamethasone/Cytarabine/Cisplatin +/- Rituximab 
DLCO – Diffusing Capacity of the Lung for Carbon Monoxide 
DLI – Donor Lymphocyte Infusion 
DMSO – Dimethyl Sulfoxide 
DNA – Deoxyribonucleic Acid 
DSMB – Data Safety Monitoring Board 
dUCB – Double Umbilical Cord Blood 
EBV – Epstein Barr Virus 
EKG - Electrocardiogram 
ESHAP±R – Etoposide, Methylprednisolone, Cytarabine, Cisplatin +/- Rituximab 
FDA – Food and Drug Administration 

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FDG - Flurodeoxyglucose 
FEV1 – Forced Expiratory Volume 1 
FHCRC – Fred Hutchinson Cancer Research Center 
FISH – Fluorescence In Situ Hybridization 
FK-506 - Tacrolimus 
FLAG – Fludarabine+High-dose Cytarabine+G-CSF 
FLT3-ITD – FLT3-Internal Tandem Duplication 
FLT3-TKD – FLT3- Tyrosine Kinase Domain 
FVC – Forced Vital Capacity 
G-CSF – Granulocyte Colony Stimulating Factor 
GFR – Glomerular Filtration Rate 
GI - Gastrointestinal 
GINA – Genetic Information Nondiscrimination Act  
GVHD – Graft versus Host Disease 
haplo-BM – Haploidentical Bone Marrow 
HCG – Human Chorionic Gonadotropin 
HCT-comorbidity – Hematopoietic Cell Transplant Comorbidity 
HepA – Hepatitis A 
HepB – Hepatitis B 
HepC – Hepatitis C 
HHV-6 – Human Herpesvirus 6 
HiDAc – High Dose Intermittent Ara-C 
HIPAA – Health Insurance Portability and Accountability Act 
HIV – Human Immunodeficiency Virus 
HLA – Human Leukocyte Antigen 
HPLC – High Performance Liquid Chromatography 
HQL – Health-related Quality of Life  
HSCT – Hematopoietic Stem Cell Transplant 
HTLV1 – Human T-Lymphotrophic Virus 1 
IBW – Ideal Body Weight 
ICE±R – Ifosfamide+Carboplatin+Etoposide+/- Rituximab 
IRBs – Institutional Review Boards 
ITT – Intension To Treat 
IUD – Intrauterine Device 
IV - Intravenous 
LDH – Lactate Dehydrogenase 
MDS – Myelodysplastic Syndrome 
MMF – Mycophenolate Mofetil 
MOP – Manual of Procedures 
MUD – Matched Unrelated Donor 
NCBI – National Center for Biotechnology Information 
NCCN – National Comprehensive Cancer Network 
NCI – National Cancer Institute 
NIH – National Institutes of Health 
NMDP – National Marrow Donor Program 
OHRP – Office for Human Research Protections 

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OS – Overall Survival 
PCR – Polymerase Chain Reaction 
PET – Positron Emission Tomography 
PFS – Progression Free Survival 
PI – Principal Investigator 
PO – Per Os (by mouth) 
PR – Partial Response  
QALY – Quality-adjusted Life Year 
RBC – Red Blood Cell 
SCTOD – Stem Cell Therapeutic Outcomes Database 
SD – Standard Deviation 
SPRT – Sequential Probability Ratio Test 
T-ALL – T-cell Acute Lymphoblastic Leukemia 
TBI – Total Body Irradiation 
TID – ter in die (three times/day) 
TRM – Treatment Related Mortality  
UCB – Umbilical Cord Blood 
ULN – Upper Limit of Normal 
WBC – White Blood Cell 

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APPENDIX B 
 
CONSENT FORMS 
 
 
 
PATIENT INFORMED CONSENT 
 
DONOR INFORMED CONSENT 
 
DONOR ASSENT 

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Informed Consent to Participate in Research 
 
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity(RIC) 
Conditioning and Transplantation of Double Unrelated Umbilical Cord Blood 
(dUCB) versus HLA-Haploidentical Related Bone Marrow for Patients with 
Hematologic Malignancies  
 
Your Name:  
________________________________ 
Study Title:  
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity(RIC) 
Conditioning and Transplantation of Double Unrelated Umbilical Cord 
Blood (dUCB) versus HLA-Haploidentical Related Bone Marrow for 
Patients with Hematologic Malignancies  
Protocol: 
 
BMT CTN #1101 
Co-Investigator:  
Ephraim Fuchs, M.D. 
Johns Hopkins University 
488 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street 
Baltimore, MD  21231 
Phone: 410- 955-8143  Email: fuchsep@jhmi.edu 
 
Co-Investigator:  
Paul O’Donnell, M.D., Ph.D. 
Massachusetts General Hospital Cancer Center, 55 Fruit St. Boston, MA 
02141Phone: 508-693-7430  Email: pvodonnell@mgh.harvard.edu  
 
Co-Investigator: 
Claudio Brunstein, M.D. 
University of Minnesota Medical Center 
420 Delaware Street SE, MMC 286, Minneapolis, MN 55455 
Phone: 612-624-5620  Email: bruns072@umn.edu 
 
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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1.  Introduction 
We invite you to join this clinical trial, also 
known as a research study. We are doing 
this research because we want to learn more 
about reduced-intensity transplants that use 
a mismatched donor. These results will help 
us understand if one kind of mismatched 
donor is better or if there is no difference at 
all. 
This study will take at least 4 years and will 
include about 400 participants. Your study 
participation will last for 3 years after your 
transplant.  
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.  
Everyone who takes part in research at 
[insert facility name] should know that: 
 Being in any research study is voluntary.  
 You may or may not benefit from being 
in the study. Knowledge we gain from 
this study may benefit others.  
 If you join the study, you can quit the 
study at any time.  
 If you decide to quit the study, it will not 
affect your care at [insert name of 
facility or institution]. 
 Please ask the study staff questions 
about anything that you do not 
understand, or if you would like to have 
more information. 
 You can ask questions now or any time 
during the study. 
 Please take the time you need to talk 
about the study with your doctor, study 
staff, and your family and friends. It is 
your decision to be in the study. If you 
decide to join, please sign and date the 
end of the Consent Form. 
You and your doctor will discuss other 
treatment choices if you do not want to 
participate in this study.
 
2.  Study Background 
The National Institutes of Health (NIH), 
through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN), are 
providing staff support and money for this 
research study. The BMT CTN will direct 
the research study. The BMT CTN and the 
NIH will make decisions about how to 
manage the study. 
A stem cell transplant is the only treatment 
at this time that may cure your disease. An 
allogeneic transplant uses blood-making 
cells from a family member or an unrelated 

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donor to remove and replace your abnormal 
blood cells. Your doctor may recommend 
that you have a transplant that uses lower 
amounts of chemotherapy and radiation. 
This type of transplant is also called a 
reduced intensity, non-myeloablative, or 
“mini” transplant. Because of your age or 
health problems and because you do not 
have a matched donor, you may have a 
higher chance of health problems from a 
standard stem cell transplant that uses high 
doses of chemotherapy and/or radiation. 
Recent studies by the BMT CTN suggest the 
results are very similar for reduced-intensity 
transplants when they use either mismatched 
cord blood or use mismatched bone marrow 
from a family member.  
There is no guarantee or promise that this 
procedure will be successful.  
 
 
 
 
 
 
3. Study Purpose  
We are inviting you to take part in this study 
because you have a cancer of the blood or 
lymph glands and a stem cell transplant is a 
treatment option.  
Tissue typing shows that you do not have a 
completely matched donor available in your 
family. You also do not have a matched 
donor outside of your family who can 
donate when you need them to. However, 
you do have two other donor choices 
available for a transplant: (1) partially 
matched units of unrelated cord blood, and 
(2) a family donor who is a partial match. 
We are doing this research to learn more 
about reduced-intensity transplants that use 
a mismatched donor. We will use either cord 
blood from an unrelated donor or bone 
marrow from a family member, and then 
compare the transplant results.  
These results will help us understand if one 
kind of mismatched donor is better or if 
there is no difference at all.   
 

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4.  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] 
Being in this study is voluntary. You can 
choose not to be in this study or leave this 
study at any time. If you choose not to take  
part or leave this study, it will not affect 
your regular medical care in any way.  
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. 
 
 
5.  Study Treatment and Tests 
We will check your health before you start 
treatment, while you receive treatment, and 
for several years after you finish your 
treatment. 
Before You Start Your Treatment 
We will ask you to take quality of life 
surveys. The surveys will ask about: 
o Any side effects of your treatment 
o Any health problems 
o How well you can do things that are 
important to you 
o How you relate to other people  
o Your feelings.  
You may skip any questions you wish. 
 
We will also ask you to provide optional 
Blood Samples for Future Research (see 
Section 18: Optional Blood Samples for 
Future Research).  
Randomization 
We will use a computer to randomly assign 
you to 1 of 2 study groups. One group will 
receive partially matched cord blood from 
an unrelated donor, and one group will 
receive bone marrow from a partially 
matched family member. You will have an 
equal chance of being placed in either group. 

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During Your Treatment 
 Conditioning Regimen Before 
Transplant (chemotherapy and 
radiation) 
You will be treated with a type of 
chemotherapy called fludarabine, which is 
given daily for 5 days. If you receive cord 
blood, you will also be given a type of 
chemotherapy called cyclophosphamide for 
1 day. If you receive bone marrow, you will 
be given cyclophosphamide for 2 days. 
After the chemotherapy is completed, you 
will receive a small dose of radiation to your 
whole body (Total Body Irradiation) in a 
single dose. The chemotherapy and radiation 
may cause side effects. Some of these side 
effects may be life-threatening (see Section 
6: Risks and Discomforts). 
If you receive cord blood, and have not had 
cytotoxic chemotherapy within the last 3 
months or an autologous transplant within 
the last 2 years, you will receive a slightly 
higher dose of radiation (300 cGy instead of 
200 cGy). This slightly higher dose of 
radiation has shown hematopoietic recovery 
is comparable to that seen with low dose 
radiation for patients who have had 
chemotherapy in the last 3 months or an 
autologous transplant in the last 2 years.  
 Reinfusion of Stem Cells (Transplant) 
On your transplant day, if you receive cord 
blood, it will be given to you through your 
catheter like a blood transfusion. If you 
receive bone marrow, your family donor 
will have his or her marrow collected in the 
operating room. The donated marrow may 
be taken to a laboratory where red cells will 
be removed. The donor cells will be given to 
you through your catheter and will travel to 
your bone marrow where they will start to 
make healthy, new blood cells.  
If you receive cord blood you will start to 
take the immune suppressing drugs 
cyclosporine and mycophenolate mofetil 
(MMF) for 3 days before transplant. These 
drugs may help prevent a complication 
called graft versus host disease (GVHD; 
see Section 6: Risks and Discomforts).    
If you receive bone marrow, you will be 
given another dose of cyclophosphamide on 
Days 3 and 4 after your transplant. You will 
start to take the immune suppressing drugs 
tacrolimus and MMF to help prevent 
GVHD on Day 5 after your transplant. 
In both study groups (partially matched cord 
blood from an unrelated donor or bone 
marrow from a partially matched family 
member), you will continue to take MMF 
for about 5 weeks and cyclosporine or 
tacrolimus for up to 6 months.  
If you receive cord blood, you will be given 
filgrastim (G-CSF) through your catheter 
or by injection under your skin beginning on 
day 1 after your transplant. If you receive 
bone marrow, you will be given filgrastim 
(G-CSF) beginning on Day 5 after your 
transplant.  Filgrastim speeds up the 
recovery of white blood cells. In both study 
groups, you will receive filgrastim daily 
until your white blood cells have recovered.  

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The immune suppressing drugs and filgrastim 
may cause side effects. These side effects 
may be life-threatening (see Section 6: Risks 
and Discomforts).  
If needed, you will receive blood transfusions 
to maintain normal blood cell levels and 
antibiotics to treat or prevent infection. You 
may also receive extra nutrients and pain 
drugs during or after your transplant. They 
will be given to you through your catheter.    
 Health Evaluations 
We will test (evaluate) your health during 
the study. These tests and how often they are 
scheduled are standard care for patients 
receiving an allogeneic transplant. They 
would be done even if you were not part of 
this study. You will be watched closely for 
any signs and symptoms of GVHD. 
 
Health evaluations after treatment:  
1) Physical exam to assess toxicities, and 
infections weekly until Day 56 and then 
at Days 180, 365, and 730. 
2) Physical exam to assess GVHD weekly 
until Day 90 and then at Days 180, 365, 
and 730. 
3) Routine blood tests (cell counts and liver 
and kidney function) weekly until Day 
56 and then at Days 180, 365, and 730. 
4) Blood or bone marrow tests to find the 
amount of donor cells in your body on 
Days 28 and 56. This is also called 
chimerism. 
5) Restaging tests to see how much cancer 
you have after treatment on Day 730. 
6) A quality of life survey (see Before You 
Start Your Treatment) at Days 365 and 
730.  
7) Optional blood samples for future 
research (see Section 19: Blood 
Samples for Future Research). 
 
Long-term follow-up  
Data regarding your clinical situation after 2 
years may be obtained from the CIBMTR, 
which captures information on all US 
transplants. 
 
 
 
6.  Risks and Discomforts 
You will have side effects while on the 
study. Side effects can range from mild to 
very serious.  
The risks and discomforts in participating in 
this study will be similar to what you may 
have with blood or marrow cell transplant if 
you do not participate in this trial. Other 
complications from transplants, such as 
graft-versus-host disease (GVHD) and 
infections happen equally in patients who 
have either type of regimen.  
Your health care team will give you 
medicines to help lower side effects such as 
feeling sick to your stomach (nausea). In 
some cases, side effects can be long lasting 
or may never go away.  

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Risks Related to Medications or Total Body 
Irradiation Used in Conditioning Regimens  
All chemotherapy and radiation treatments 
used as conditioning regimens in this study 
are commonly used in allogeneic 
hematopoietic cell transplantation.  
 
TABLE 1 – Risks and Side Effects 
 
Likely 
What it means: This type of side effect is expected to occur in more than 
20% of patients. This means that 21 or more patients out of 100 might get 
this side effect. 
Less Likely 
What it means: This type of side effect is expected to occur in 20% of 
patients or fewer. This means that 20 patients or fewer out of 100 might get 
this side effect. 
Rare, but 
Serious 
What it means: This type of side effect does not occur very often – in fewer 
than 2% of patients – but is serious when it occurs. This means that 1 or 2 
patients (or fewer) out of 100 might get this side effect. 

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Cyclophosphamide (Cytoxan®) 
Likely  
Less Likely 
Rare, but Serious 
 Decreased white blood cell 
count with increased risk of 
infection 
 Temporary hair loss 
 Nausea 
 Vomiting 
 Loss of appetite 
 Sores in mouth or on lips 
 Diarrhea 
 Stopping of menstrual periods 
in women 
 Decreased sperm production 
in men 
 Decreased platelet count 
(mild) with increased risk of 
bleeding 
 Blood in urine 
 Anemia 
 Temporary tiredness 
 Damage to the fetus if 
you become pregnant 
while taking drug 
 
 Scarring of lung 
tissue, with cough and 
shortness of breath 
 Severe heart muscle 
injury and death at 
very high doses 
 New (secondary) 
cancers 
 
 
Fludarabine (Fludara®) 
Likely  
Less Likely 
Rare, but Serious 
 Decreased white blood cell 
count with risk of infection 
 Decreased platelet count 
with increased risk of 
bleeding 
 Anemia 
 Tiredness 
 Nausea 
 Vomiting 
 Diarrhea 
 Numbness and 
tingling in hands 
and/or feet related to 
irritation of nerves 
of the hand and/or 
feet 
 Changes in vision 
 Pneumonia 
 Agitation or 
nervousness 
 Confusion 
 Cough 
 Difficulty breathing 
 Weakness 
 Severe brain injury 
and death 
 

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Filgrastim  (G-CSF; Neupogen) 
Likely  
Less Likely 
Rare, but Serious 
 Ache or pain inside the bones 
 Increased levels of liver 
enzymes and uric acid in the 
blood 
 Low number of platelets in the 
blood 
 Headache 
 Tiredness 
 Local irritation (skin) 
at the injection site 
 Nausea 
 
 Allergic reaction 
 Low fever 
 Enlargement or 
rupture of the 
spleen 
 Worsening of pre-
existing skin rashes 
 
Mycophenolate mofetil (MMF; CellCept) 
Likely  
Less Likely 
Rare, but Serious 
 Miscarriage 
 Birth defects 
 Diarrhea 
 Damage to unborn baby 
 Limited effectiveness of birth 
control 
 Stomach pain 
 Upset stomach 
 Vomiting 
 Headache 
 Tremors 
 Low white blood cell count 
with increased risk of 
infection 
 Increased blood cholesterols 
 Swelling of the hands, feet, 
ankles, or lower legs 
 Anemia 
 Rash 
 Difficulty falling 
asleep or staying 
asleep 
 Dizziness 
 Uncontrollable 
hand shakes 
 Difficulty breathing 
 Unusual bruising 
 Fast heartbeat 
 Excessive tiredness 
 Weakness 
 Blood in stool 
 Bloody vomit 
 Change in vision 
 Secondary cancers, 
such as 
lymphoproliferative 
disease or lymphoma  
 Progressive Multifocal 
Leukoencephalopathy 
 

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Total Body Irradiation 
Likely 
Less Likely 
Rare, but Serious 
 Fatigue 
 Hair loss 
 Infertility 
 Loss of 
appetite 
 Mouth sores 
 Nausea 
 Vomiting 
 Cataracts 
 Inflammation of the parotid glands 
 Skin pigmentation (reversible) 
 Stunted Growth  
 Low white blood cell count with increased 
risk of infection 
 Low platelet count with increased risk of 
bleeding 
 Anemia 
 Diarrhea 
 Lung fibrosis 
 Second 
cancers 
 
Tacrolimus (Prograf; FK-506)/Cyclosporine 
Likely 
Less Likely 
Rare, but Serious 
 Kidney problems 
 Loss of magnesium, calcium, 
potassium 
 High blood pressure 
 Tremors 
 Increases in cholesterol and 
triglyceride 
 
 Nausea 
 Vomiting 
 Liver problems 
 Changes in how 
clearly one can 
think 
 Insomnia 
 Unwanted hair 
growth 
 Confusion 
 Seizures 
 Changes in vision 
 Dizziness 
 Red blood cell 
destruction 
 
It is very important that you do not eat grapefruit or drink grapefruit juice while taking 
Tacrolimus.  Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs used in this study.  Common soft drinks that have bergamottin are Fresca, 
Squirt, and Sunny Delight.  
 

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Risks and Toxicities Related to Transplant 
The following problems may occur as a 
result of cord blood or marrow transplant. 
These risks may occur whether a transplant 
was done as part of the study or not:  
1. Slow recovery of blood counts. The red 
blood cells, white blood cells, and platelets 
can be slow to recover after blood or 
marrow transplant. Until your blood counts 
recover, you will need blood and platelet 
transfusions, and will be at risk for bleeding 
and infections. To speed the recovery of the 
white cells as much as possible you will 
receive Filgrastim.   
2. Graft failure. The cord blood or bone 
marrow stem cells (the “graft”) may fail to 
grow inside your body. Past experience 
suggests that there can be up to a 10-15% 
chance of graft failure. If graft failure occurs, 
this may result in low blood counts for a long 
period of time. If your counts do not recover, 
you may need to receive a second transplant. 
Graft failure can be fatal. 
3. Graft-Versus-Host Disease (GVHD). 
GVHD results from the bone marrow or cord 
blood cells in the graft recognizing your body 
as foreign and attacking it. In most cases, 
GVHD can be successfully treated. 
Sometimes GVHD is severe or difficult to 
treat and may lead to death. You will be 
watched closely for this complication and 
given drugs to prevent and/or treat it.  
Acute GVHD may produce skin rash, nausea, 
vomiting, diarrhea, abdominal pain, 
abnormalities of liver function, and an 
increased risk of infection. Chronic GVHD 
may produce skin rashes, hair loss, thickened 
dry skin, dry eyes, dry mouth, liver disease, 
weight loss, diarrhea, and an increased risk of 
infection. To confirm the diagnosis of acute 
or chronic GVHD, you may be asked to have 
a biopsy (a small sample of your tissue to 
look at under the microscope) of your skin, 
gut, or, rarely, your liver.  
4. Other complications. Other complications 
may include: 
a. Damage to the vital organs in your 
body. The transplant could cause 
problems in any body organ such as the 
heart, lungs, liver, gut, kidneys and 
bladder, or brain. The kidneys and the 
liver are most likely to be damaged. Some 
patients will experience serious lung 
problems from infections or the 
chemotherapy and radiation.  
b. Serious infections. Full and complete 
recovery of your immune system may 
take many months. During this time, there 
is an increased risk of infections. You will 
be prescribed certain drugs to reduce the 
chance of those infections. However, 
these treatments do not always work. If 
you have an infection, you may have to 
stay in the hospital longer or be re-
hospitalized after transplant. Although 
most infections can be successfully 
treated, some infections may result in 
death.  
c. Relapse of disease or a new blood 
cancer. Your leukemia or lymphoma may 
come back even if the transplant is 
initially successful. In rare cases, a new 
blood cancer may develop from the donor 
cells. Cyclophosphamide can cause 
damage to blood cells, which may result 
in a blood cancer such as 
myelodysplastic syndrome (MDS) or 
acute myeloid leukemia (AML). The 
blood cancer usually develops 2-10 

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years after treatment, or 6 years on 
average.  
The risk of developing a new blood 
cancer after allogeneic blood or marrow 
transplant is probably less than 2%. 
However, if you receive bone marrow, 
your donor’s marrow is exposed to the 
chemotherapy drug, cyclophosphamide, 
after the transplant. There is a risk that a 
blood cancer may develop in your 
donor’s blood cells. This risk is 
unknown, but it may be as high as 5%. If 
cancer develops in your donor’s blood 
cells, you may require additional 
treatment with chemotherapy or another 
blood or marrow transplant. 
d. Risk to the unborn. The treatments in 
this study have not been proven to be safe 
at any stage of pregnancy. Therefore, if 
you are pregnant or nursing, you are not 
eligible for this study. Women who can 
become pregnant must refrain from all 
acts of vaginal sex (abstinence) or use two 
forms of effective birth control while 
receiving chemotherapy, TBI, and drugs 
to prevent GVHD. Effective birth control 
is defined as the following: 
1. Consistent use of birth control pills 
2. Injectable birth control methods 
(Depo-Provera, Norplant) 
3. Tubal sterilization or male partner 
who has undergone a vasectomy 
4. Placement of an IUD (intrauterine 
device) 
5. Use of a diaphragm with 
contraceptive jelly and/or condoms 
with contraceptive foam every time 
you have sex. 
 
Reproductive Risks  
The drugs used in this research study may 
damage your reproductive organs, affect 
your ability to have children or possibly 
cause birth defects if you take them while 
you are pregnant. It is important that a 
woman is not pregnant or breast-feeding and 
does not become pregnant during the course 
of the study. 
If you are a woman and can become 
pregnant, you will need to take a pregnancy 
test before you start the study. You should 
discuss ways to prevent pregnancy while 
you are in the study. Women who have gone 
through puberty may find that their 
menstrual cycle becomes irregular or stops 
permanently. This does not mean that you 
cannot become pregnant. You must still use 
two effective methods of birth control or 
abstinence during your transplant and 
continue until you are finished with your 
GVHD prevention treatment. 
If you are a man, your body may not be able 
to produce sperm (become sterile). You 
should talk with your doctor about banking 
your sperm before having a transplant. 
Please check with your doctor to understand 
more about these risks. 
Unforeseen Risks  
New risks might appear at any time during 
the study. These risks might be different 
from what is listed in this Consent Form. 
We will promptly tell you about new 
information that may affect your decision to 
take part in the study. We may learn new 
things about reduced-intensity transplants that 
might make you want to stop being in the 
study. We will let you know if this happens 
and you can decide if you want to continue in 
the study.  

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Additional Information about MMF 
 MMF could be damaging to an unborn 
baby if you are pregnant or become 
pregnant while receiving the drug.  
 MMF can make birth control pills less 
effective and increase your chances of 
becoming pregnant while you are taking 
it. 
 If you could become pregnant, you must 
use 2 effective forms of birth control or 
abstinence for 4 weeks before starting 
MMF, during treatment, and for 6 weeks 
after stopping MMF. 
 In this study, you will be assigned to 
receive MMF for about 5 weeks, so you 
should not become pregnant during that 
time. If you think you might be pregnant 
or could be become pregnant during the 
upcoming 5 weeks, you should not join 
the study. 
Other Treatments or Drugs  
Some drugs react with each other. It is 
important to tell the study doctor or staff 
about any other drugs or treatments you are 
taking. This includes over-the-counter drugs, 
vitamins and herbal treatments.  
It is also important that you tell the study 
staff about changes to any of your drugs 
during the study. 
For more information about risks and side 
effects, ask your study doctor. 
 
 
7.  Alternative Treatments
Participation in this study is optional. If you 
choose not to take part, you may still receive 
an allogeneic transplant to treat your 
disease. The treatment and evaluations you 
would receive could be very similar to what 
would receive if you join this study.  
Your study doctor will talk with you about 
your options. If you decide not to participate 
in this study, your medical care will not be 
affected in any way. 
Your other choices may include: 
 Treatment with other drugs, radiation, or 
a combination of drugs and radiation 
without a transplant  
 An allogeneic blood or marrow 
transplant that is not part of the study, or 
another type of transplant 
 Participation in another clinical trial, if 
available (check with your doctor) 
 No treatment for your blood cancer at 
this time 
 Comfort care 
Every treatment option has benefits and 
risks. Talk with your doctor about your 
treatment choices before you decide if you 
will take part in this study. 
 
 
 

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8.  Possible Benefits
Taking part in this study may or may not 
make your health better. The information 
from this study will help doctors learn more 
about reduced-intensity transplant as a 
treatment for people with a blood cancer and 
who have a mismatched donor. This 
information could help people with a blood 
cancer who may need a transplant in the 
future. 
 
 
9.  New Information Available During the Study 
During this study, the study doctors may learn 
new information about the study drug or the 
risks and benefits of the study. If this happens, 
they will tell you about the new information. 
The new information may mean that you can 
no longer take part in the study, or that you 
may not want to continue in the study.  
If this happens, the study doctor will stop 
your participation and will offer you all 
available care to meet your needs and 
medical conditions. 
 
 
 
10.  Privacy, Confidentiality and Use of Information 
Your confidentiality is one of our main 
concerns. 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. (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. 

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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.  
Information about your transplant from your 
original medical records may be seen or sent 
to national and international transplant 
registries, including: 
 
 /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 
A description of this clinical trial will be 
available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will 
not include information that can identify 
you. At most, the Web site will include a 
summary of the results. You can search this 
Web site at any time.   
For questions about access to your medical 
records, please contact /name/ at /number. 
 
 
11.  Ending Your Participation 
The study doctor or the study sponsor may 
stop the study at any time, and we may ask 
you to leave the study. If we ask you to 
leave the study, the reasons will be 
discussed with you. Possible reasons to end 
your participation in this study include: 
 You do not meet the study 
requirements.  
 You need a medical treatment not 
allowed in this study. 
 The study doctor decides that it 
would be harmful to you to stay in 
the study. 
 You are having serious side effects. 
 You become pregnant. 

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 You cannot keep appointments or 
take study drugs as directed. 
 The study is stopped for any reason. 
You could have serious health risks if 
you stop treatment during the 
conditioning process before you receive 
your transplant. If you stop taking the 
immune suppressing drugs (see Section 
6: Risks and Discomforts) too soon 
after transplant, your body could reject 
the donor stem cells or you could 
develop serious complications and 
possibly die.  
We ask that you talk with the research 
doctor and your regular doctor before 
you leave the study. Your doctors will 
tell you how to stop safely and talk with 
you about other treatment choices.  
 If you decide to leave this study after 
the start of treatment, or your doctor 
asks you to leave the study for 
medical reasons, you will need to 
come back to the doctor’s office for 
tests for your safety. Even if you 
leave the study, the information 
collected from your participation will 
be included in the study results, unless 
you specifically ask that it not be 
included. 
 
 
 
 
12.  Physical Injury as a Result of Participation 
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.
 
 
 

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13.  Compensation or Payment
You will not be paid for taking part in this 
study. You will not be compensated or 
reimbursed for any extra costs (for example, 
travel and meals) from taking part in this 
study.
 
14.  Costs and Reimbursements 
Most of the visits for this study are standard 
medical care for your allogeneic transplant 
and will be billed to your insurance company. 
You and/or your health plan/insurance 
company will need to pay for the costs of 
standard treatment in this study.  
Some health plans will not pay these costs 
for people taking part in studies. Check with 
your health plan or insurance company to 
find out if they will pay.  
You or your insurance will not be charged for 
tests that are only done for research on this 
study. 
 
For questions about your costs, financial 
responsibilities, and/or medical insurance 
coverage for your transplant and this study, 
please contact /Center/ Financial Counselor 
at /Number/. 
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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15.  For More Information 
If you need more information about this 
study, or if you have problems while taking 
part in this study, you can contact the study 
doctor or his/her staff. They can be reached at 
the telephone numbers listed here:   
[Insert name and contact detail] 
 
 
16.  Contact Someone about Your Rights 
If you wish to speak to someone not directly 
involved in the study, or if you have any 
complaints about the project, or any questions 
about your rights as a research participant, 
then you may contact:  
[Insert appropriate contact details] 
The ethical aspects of this research study have 
been reviewed and approved by [name of 
IRB]. 
 
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).  
 
 
17. Cost-effectiveness Research 
Study purpose: The study doctors want to 
learn more about the costs of the two types of 
transplant that are being tested in the larger 
transplant study: 1) partially matched units of 
unrelated cord blood and 2) family donors 
who are a partial match. This research will 
help doctors know which type of transplant is 
more cost effective.  
Lead study doctor: Scott Ramsey of the 
Fred Hutchinson Cancer Research Center in 
Seattle is the lead study doctor for the cost-
effectiveness research. Dr. Ramsey is a 
medical doctor and well-known health 
economist.  
Your health insurance and out-of-pocket 
medical costs: If you agree to join this study, 
we will ask for the following information 
about your health insurance: 
1) Type 

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2) Provider 
3) Policy number 
4) Group number 
5) Policy holder’s name and date of birth 
We will also want to know about your out-of-
pocket transplant costs (costs not covered by 
your insurance). The out-of-pocket costs you 
and your family have to cover are important 
in understanding the overall cost of 
transplant, so we want to collect information 
this information as well. For example, we 
want to know how much you spend on: 
1) Medical costs (for example, co-pays, 
prescriptions) 
2) Travel and lodging  
3) Cost of time away from work for both 
you and your caregivers (family and 
friends).  
Your health insurance and out-of-pocket 
information is called the ‘study data’ in this 
consent form. 
How we will use your health insurance 
information: After you have finished the 
transplant study, we will use your insurance 
information to learn about the 
reimbursements your health insurer made and 
calculate the cost of your transplant. Illness 
and transplant-related costs happen before the 
transplant and go on for many years after, so 
we want to collect reimbursement 
information for the 12 months before your 
transplant, and for the 2 years following.   
Privacy, confidentiality and use of 
information: Only the study doctors at the 
Fred Hutchinson Cancer Research Center 
will have access to your health insurance and 
out-of-pocket cost information (study data). 
To maintain your confidentiality, we will not 
link your name to the study data. Also, all of 
the study doctors signed a confidentiality 
agreement and promised to keep electronic 
data protected under passwords and physical 
data (paper or other media such as CDs) in 
secure facilities (for example, on-campus 
locked offices and locked filing cabinets).   
Collecting the study data: We will collect 
your health insurance and out-of-pocket 
information using an online questionnaire 
and diary. You will get a user ID number and 
password to log on to the system. The system 
was designed to be very user friendly, but we 
will help you with the online questionnaire 
and diary over the phone if needed. We will 
also send email reminders. The option to 
complete a mail-out survey will also be 
available. 
As stated above, we will collect 
reimbursement information starting 12 
months before your transplant until 2 years 
after.    
We will collect out-of-pocket costs 1 month 
after your transplant, and again 4 and 7 
months after your transplant date. We think 
each online entry will take between 5 and 25 
minutes, but this depends on how much 
information there is to enter.  
Help from your caregiver(s): We ask that 
you give us the name(s) and contact 
information of your main caregiver(s). This 

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may be your spouse, partner, parent, adult 
child or sibling, and friends. You may not 
feel like using the online diary when you’re 
recovering from your transplant, so we ask 
that your caregiver(s) help enter this 
information    
We also want to know the time your 
caregiver(s) spend caring for you after your 
transplant and the time they spend away from 
work or school.   
Be sure to talk to your caregiver(s) about this 
study and get their permission before giving 
us their name and contact information. If you 
give us the name of your caregiver(s), we 
will explain the study to them and what they 
would need to do. They will also get their 
own consent form to participate in this study.   
Risks to participating: The risks to 
participating in the cost-effectiveness study 
are small. We will make every effort to keep 
your health insurance and out-of-pocket cost 
information private. We will only use this 
data to get reimbursement information. A 
possible risk is the loss of confidentiality 
about your medical information, but the 
chance of this happening is very small.  
Payment and costs: You will not get paid 
for participating in this study. You will not 
be charged for taking part in this study.   
If you provide out-of-pocket costs, we will 
give you a summary of these costs at the end 
of the study. This may be helpful information 
for tax reporting.   
Right to ask questions and/or withdraw: 
You do not have to be part of the cost-
effectiveness research study. Your 
involvement is totally voluntary and 
deciding not to be part of this study will not 
affect the medical care or services you are 
receiving. You can also leave the study at 
any time.  
For more information:  Jordan Steelquist, 
Fred Hutchinson Cancer Research Center, 
Seattle (206)-267-7438 or 
email:jsteelqu@fredhutch.org. 
 
18.  Blood Samples for Research (Optional) 
This section of the informed consent form is 
about future research studies that will use 
blood samples from people who are taking 
part in the main study. You may choose to 
give blood samples for these future research 
studies if you want to. You can still be a part 
of the main study even if you say 'no' to give 
blood samples for future research studies. 
There are no major risks associated with 
drawing blood. Having your blood drawn 
can be uncomfortable and can sometimes 
cause a bruise. In rare cases, a blood draw 

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can cause fainting. Only trained people will 
draw your blood. 
 
If you agree to provide blood samples, here 
is what will happen: 
a.) We will collect five extra blood samples 
at the same time you have routine blood 
tests done. The amount of blood 
collected from you is about 4 
tablespoons (50mL) each time. If you 
weigh less than 50 kg, the amount of 
blood collected will be based on your 
weight (1 mL per kg).  
b.) We will collect samples at five different 
dates in the study: Prior to transplant, 
Day 28, Day 56, Day 180, and Day 365. 
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 given a bar 
code that cannot be linked to your name 
or other identifying information by 
future researchers testing your samples. 
d.) Samples stored in the Repository will be 
used mainly by clinicians and 
researchers in the BMT CTN network. 
In the future, the unused research 
samples and clinical information will be 
made available outside of this network.  
e.) Researchers can apply to study the 
materials stored 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. 
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 hundreds of 
thousands 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). 
The NCBI will never have any 
information that would identify you, 
or link you to your information or 
research samples.  
Some general things you should know about 
letting us store your blood samples for 
research are: 
 We will only store samples from people 
who give us permission. 
 Research is meant to gain knowledge that 
my help people in the future. You will not 

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get any direct benefit from taking part. 
Additionally, you or your doctor will not 
be given results and they will not be 
added to your medical record. 
 A possible risk is the loss of 
confidentiality about your medical 
information. We will use safety measures 
with both your samples and clinical 
information to make sure that your 
personal information will be kept private. 
The chance that this information will be 
given to someone else is extremely small.  
 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. 
You can change your mind at any time 
about allowing us to use your samples and 
health information for research.  
We ask that you contact [Principal 
Investigator] in writing and let him/her 
know you do not want us to use your 
research samples or health information for 
research. His/her mailing address is on the 
first page of this form. However, samples 
and information that have already been 
shared with other researchers cannot be 
taken back or destroyed.  
 
 

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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:  
A Multi-Center, Phase III, Randomized 
Trial of Reduced Intensity (RIC) 
Conditioning and Transplantation of Double 
Unrelated Umbilical Cord Blood (dUCB) 
versus HLA-Haploidentical Related Bone 
Marrow for Patients with Hematologic 
Malignancies 
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).  
 Medical history (for example: diagnosis, 
complications with prior treatment). 
 Findings from physical exams. 
                                                 
1 HIPAA is the Health Insurance Portability and 
Accountability Act of 1996, a federal law related to 
privacy of health information 
 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 
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 and 
coordinating center 
 U.S. government agencies that are 
responsible for overseeing research such 
as the Food and Drug Administration 

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(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 or 
receive any treatment related to research that 
is provided through the 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 by sending a 
written notice to the Principal Investigator to 
inform the researcher of my decision.  
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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TITLE: A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning 
and Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) versus HLA-
Haploidentical Related Bone Marrow for Patients with Hematologic Malignancies 
PROTOCOL NUMBER: BMT CTN #1101 
CO-INVESTIGATOR: 
 
Ephraim Fuchs, M.D. 
Johns Hopkins University 
488 Bunting-Blaustein Cancer Research Bldg 
1650 Orleans Street, Baltimore, MD  21231 
Phone: 410- 955-8143   
Email: fuchsep@jhmi.edu 
CO-INVESTIGATOR: 
 
Paul O’Donnell, M.D., Ph.D. 
Massachusetts General Hospital Cancer 
Center  
55 Fruit St, Boston, MA 02141 
Phone: 508-274-7430   
Email: pvodonnell@mgh.harvard.edu  
CO-INVESTIGATOR: 
 
Claudio Brunstein, M.D. 
University of Minnesota Medical Center 
420 Delaware Street SE, MMC 286 
Minneapolis, MN  55455 
Phone: 612-624-5620  
Email: bruns072@umn.edu 
 
 
I have read and understood this Consent Form. The nature and purpose of the research study has 
been explained to me. 
 I have had the chance to ask questions, and understand the answers I have been given. I 
understand that I may ask questions at any time during the study. 
 I freely agree to be a participant in the study. 
 I understand that I may not directly benefit from taking part in the study. 
 I understand that, while information gained during the study may be published, I will not be 
identified and my personal results will stay confidential. 
 I have had the chance to discuss my participation in this research study with a family member 
or friend. 
 I understand that I can leave this study at any time, and doing so will not affect my current care 
or prevent me from receiving future treatment. 
 I understand that I will be given a copy of this signed consent form.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 

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Statement of Consent for Cost Effectiveness Research 
The purpose of the cost effectiveness research, 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 participate in the cost effectiveness research. If I decide to not 
participate, it will not affect my medical care in any way. 
 I agree to be part of the cost-effectiveness research.  
 I do not agree to be part of the cost-effectiveness research.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 
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 information can be stored indefinitely by the BMT CTN 
and/or NHLBI Repositories for research to learn about, prevent, or treat health problems. I also 
understand that my DNA and clinical information may or may not be used in genome-wide 
association studies. 
 I agree to allow my blood samples to be stored for research. 
 I do not agree to allow my blood samples to be stored for research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Counseling Physician 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Counseling Physician 
 
    
 
 
Date 
 

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Donor Informed Consent to Participate in Research 
 
 
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity (RIC) Conditioning and
Transplantation of Double Unrelated Umbilical Cord Blood (dUCB) versus HLA-
Haploidentical Related Bone Marrow for Patients with Hematologic Malignancies  
 
 
Your name:_________________________________________________   
 
Study Title:  
Reduced Intensity (RIC) Conditioning and Transplantation of Double 
Unrelated Umbilical Cord Blood (dUCB) versus HLA-Haploidentical 
Related Bone Marrow for Patients with Hematologic Malignancies  
 
Protocol: 
 
BMT CTN #1101 
 
Co-Investigator:  
Ephraim Fuchs, M.D. 
Johns Hopkins University 
488 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street 
Baltimore, MD  21231 
Phone: 410- 955-8143  Email: fuchsep@jhmi.edu 
 
Co-Investigator:  
Paul O’Donnell, M.D., Ph.D. 
Massachusetts General Hospital Cancer Center55 Fruit St, Boston, MA 
012141Phone: 508-274-7430Email: pvodonnell@mgh.harvard.edu  
 
Co-Investigator: 
Claudio Brunstein, M.D. 
University of Minnesota Medical Center 
420 Delaware Street SE, MMC 286, Minneapolis, MN 55455 
Phone: 612-624-5620  Email: bruns072@umn.edu 
 
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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1.  Introduction 
This informed consent form is about future 
research studies. These studies will use 
blood and bone marrow samples from 
people who take part in the main study titled 
BMT CTN #1101. You must be 18 years of 
age or older to give bone marrow samples 
for future research. 
You may choose to give blood and marrow 
samples for these future research studies if 
you want to. Your family member can still 
be a part of the main study even if you say 
'no' to giving blood and marrow samples for 
future research. 
The main study will use either umbilical 
cord blood (cord blood) from an unrelated 
donor or bone marrow from a family 
member (you), and then compare the 
transplant results. These results will help us 
understand if one kind of mismatched donor 
is better or if there is no difference at all. 
If you agree to give blood and marrow 
samples (marrow from donors 18 and older 
only) , we will collect the blood sample at 
the same time you have routine blood tests 
done and the marrow sample at the same 
time you donate marrow. We hope to collect 
samples from 200 bone marrow donors who 
are a part of the main BMT CTN #1101 
study. 
This Consent Form will tell you about the 
purpose of the samples for future research, 
the possible risks and benefits, other options 
available to you, and your rights as a 
research participant.  
Everyone who takes part in research at 
[insert facility name] should know that: 
 Being in any research study is voluntary. 
 You will not directly benefit from being 
in the study. Knowledge we gain from 
this study may benefit others. 
 If you give blood and marrow samples 
for future research, you can change your 
mind at any time.  
 If you decide to quit the study, it will not 
affect your care or the care of your 
family member at [insert name of facility 
or institution]. 
 Please ask the study staff questions 
about anything that you do not 
understand, or if you would like to have 
more information. 
 You can ask questions now or any time 
during the study. 
 Please take the time you need to talk 
about the study with your doctor, study 
staff, and your family and friends. It is 
your decision to provide blood and 
marrow samples for future research. If 
you decide to join, please sign and date 
the end of the Consent Form. 

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The National Institutes of Health (NIH), 
through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN), are 
giving staff support and money for this 
research study. The BMT CTN will lead the 
research study and, along with the NIH, will 
make decisions about how to manage the 
study. 
We wish to collect blood and marrow 
samples from donors (marrow from donors 
age 18 and older only) to be used in future 
research. The research that may be done 
with your blood and marrow is not designed 
to help you but it may help people who have 
cancer or other diseases in the future 
 
 
2.  Study Purpose  
 
We are collecting extra blood and marrow 
samples for future research because we want 
to learn more about reduced-intensity 
transplants that use a mismatched donor.  
 
Samples may also be used in the future by 
researchers with the BMT CTN and other 
organizations 
 
 
 
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 your rights as a participant or you 
want to leave the study, please contact:  
[insert contact info] 
Giving blood and marrow samples for future 
research is voluntary. You can choose not to 
give samples, or change your mind at any 
time. If you choose not to take part or 
change your mind, it will not affect your 
donation process or the treatment of your 
family member in the main study in any 
way.  
If you change your mind, your blood and 
marrow samples will not be used for other 
research studies or tested further. 
Your study doctor and study staff will be 
available to answer any questions that you 
may have about giving samples for future 
research.
 
 

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4.  Study Treatments and Tests  
If you agree to give blood and marrow 
samples (marrow from donors age 18 and 
older only), here is what will happen: 
a.) We will collect 1 extra blood sample 
at the same time you have routine 
blood tests done. The amount of 
blood collected from you is about 4 
tablespoons (50 mL).  If you weigh 
less than 50 kg, the amount of blood 
collected will be based on your 
weight (1 mL per kg).  
b.) If you are age 18 or older, we will 
also collect up to 1 tablespoon (10 
mL) of bone marrow when you 
donate for your family member. 3-5 
mL will be saved for future research.   
c.) The blood and marrow 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 studies. All samples will be 
given a unique bar code that cannot 
be linked to you by researchers 
testing your samples. 
d.) Samples stored in the Repository 
will be used mainly by clinicians and 
researchers in the BMT CTN 
network. In the future, the unused 
research samples and clinical data 
will be made available outside of this 
network.  
e.) Researchers can apply to study the 
samples stored 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 who request the 
samples are qualified, and that the 
research is of high quality. 
f.) DNA from your stored samples 
might be used in genome-wide 
association (GWA) studies for a 
future project either done or 
supported by the 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 hundreds of 
thousands 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 to 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). 
The NCBI will never have any 
information that would identify you, 

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or link you to your information or 
research samples.   
 
 
 
5.  Risks and Discomforts 
There are no major risks to having your 
blood drawn. It can be uncomfortable to 
have your blood taken and it can sometimes 
leave a bruise. In rare cases, you might faint. 
Only trained people will take your blood.   
 
There is not a major risk to give extra 
research samples of bone marrow when the 
samples are collected at the same time you 
donate bone marrow. 
Information about the bone marrow 
donation process for this study can be found 
in a separate consent form. Your transplant 
doctor or study coordinator will give you a 
copy of the donation consent form.  
The donation consent form has more 
information about the steps to donate, and 
the risks and side effects of the donation 
process. Only trained people will collect 
your bone marrow. 
 
 
 
 
 
 
6.  Possible Benefits
You will not directly benefit from taking 
part in this study. The information from this 
study will help doctors learn more about 
reduced-intensity transplant as a treatment 
for people with a blood cancer and 
who have a mismatched donor. This 
information could help people with blood 
cancers who may need a transplant in the 
future. 
 
 
7.  Privacy, Confidentiality and Use of Information 
Your confidentiality is one of our main 
concerns. 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 

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confidential. (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.  
A description of this clinical trial will be 
available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will 
not include information that can identify 
you. At most, the Web site will include a 
summary of the results. You can search this 
Web site at any time.  
 
For questions about access to your medical 
records, please contact /name/ at /number/. 
 
 
8.  Ending Your Participation 
The study doctor or the study sponsor may 
stop the study at any time, and we may ask 
you to leave the study. We may ask you to 
leave the study if you do not follow 
directions or if you suffer from side effects 
of the blood draw or the marrow collection. 
The study sponsor may decide to end the 
study at any time. If we ask you to leave the 
study, the reasons will be discussed with 
you.  
Possible reasons to end your participation in 
this study include: 
 You do not meet the study requirements.  
 You become unable to donate bone 
marrow to your family member. 
 The study is stopped for any reason. 
 
 
 

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9.  Physical Injury as a Result of Participation 
It is important that you tell your doctor, 
__________________ [investigator's 
name(s)] or study staff if you feel that you 
have been injured because you provided 
blood and marrow samples for future 
research. 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 as a result providing blood 
and marrow samples for future research. 
You, or your health plan, or your family 
member’s health plan will be charged for 
this treatment. The study will not pay for 
medical treatment.  
In case of injury resulting from this study, 
you do not lose any of your legal rights to 
seek payment by signing this Consent Form. 
 
 
10.  Payment and Study Costs 
You will not be paid for your participation in 
the research study or for providing blood and 
marrow samples for future research. You will 
not be compensated or reimbursed for any 
extra costs (for example, travel and  meals) 
from taking part in this study. 
The visits to collect these samples are 
standard for bone marrow donors and will be 
billed to your family member’s insurance 
company.  
Your family member’s insurance will not be 
charged for tests that are only done for 
research on this study. The costs of shipping 
and storing your blood and bone marrow 
samples will be paid by the BMT CTN. 
For questions about your costs, financial 
responsibilities, and/or medical insurance 
coverage for your transplant and this study, 
please contact /Center/ Financial Counselor 
at /Number/.
 
 
 

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11.  For More Study Information 
If you need more information about providing 
blood and marrow samples for future 
research, or if you have problems while you 
are participating in this study, you can contact 
the study doctor or his/her staff. They can be 
reached at the telephone numbers listed here: 
[Insert name and contact details]. 
 
 
12.  Contact Someone About Your Rights 
If you wish to speak to someone not directly 
involved in the study, if you have any 
complaints about the project, or would like 
more information about your rights as a 
research participant, you may contact:  
[Insert appropriate contact details]. 
The ethical aspects of this research study have 
been reviewed and approved by [name of 
IRB]. 
 
For more information about your rights 
about providing blood and marrow samples 
for future research, call the 
__________[name of center] Institutional 
Review Board (a group of people who 
review the research to protect your rights) at 
__________________ (telephone number).  
 
 

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B-36 
Health Insurance Portability and 
Accountability Act (HIPAA)2 
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:  
A Multi-Center, Phase III, Randomized 
Trial of Reduced Intensity (RIC) 
Conditioning and Transplantation of Double 
Unrelated Umbilical Cord Blood (dUCB) 
versus HLA-Haploidentical Related Bone 
Marrow for Patients with Hematologic 
Malignancies 
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).  
 Medical history (for example: diagnosis, 
complications with prior treatment). 
 Findings from physical exams. 
                                                 
2 HIPAA is the Health Insurance Portability and 
Accountability Act of 1996, a federal law related to 
privacy of health information 
 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 
 
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

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 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 or 
receive any treatment related to research that 
is provided through the 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 by sending a 
written notice to the Principal Investigator to 
inform the researcher of my decision.  
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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TITLE: Reduced Intensity (RIC) Conditioning and Transplantation of Double Unrelated 
Umbilical Cord Blood (dUCB) versus HLA-Haploidentical Related Bone Marrow for 
Patients with Hematologic Malignancies  
 
PROTOCOL NUMBER: BMT CTN #1101 
CO-INVESTIGATOR: 
 
Ephraim Fuchs, M.D. 
Johns Hopkins University 
488 Bunting-Blaustein Cancer Research Bldg 
1650 Orleans Street, Baltimore, MD  21231 
Phone: 410- 955-8143   
Email: fuchsep@jhmi.edu 
CO-INVESTIGATOR: 
 
Paul O’Donnell, M.D., Ph.D. 
Massachusetts General Hospital Cancer 
Center 
55 Fruit St, Boston MA, 02151  
Phone: 508-274-7430 
Email:  pvodonnell@mgh.harvard.edu 
CO-INVESTIGATOR: 
 
Claudio Brunstein, M.D. 
University of Minnesota Medical Center 
420 Delaware Street SE, MMC 286 
Minneapolis, MN  55455 
Phone: 612-624-5620  
Email: bruns072@umn.edu 
 
 
I have read and understood this Consent Form. The nature and purpose of providing blood and 
marrow samples for future research has been explained to me. 
 
 I have had the chance to ask questions, 
and understand the answers I have been 
given. I understand that I may ask 
questions at any time during the study. 
 I freely agree to give blood and marrow 
samples (marrow samples from donors 
age 18 and older only) for future 
research. 
 I understand that I may not directly 
benefit from providing samples for 
future research. 
 I understand that, while information 
gained during research may be 
published, I will not be identified and 
my personal results will stay 
confidential.  
 I have had the chance to discuss giving 
blood and marrow samples for future 
research with a family member or friend. 
 I understand that I can change my mind 
at any time, and doing so will not affect 
my current care or prevent me from 
receiving future treatment. 
 I understand that I will be given a copy 
of this signed consent form. 
 

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Complete Appropriate Item Below, A or B 
 
A. 
Adult Donor’s Consent 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions. I hereby consent to 
give blood and marrow samples for this study. 
 
 
____________________________________ 
Signature of Adult Donor & Date Signed 
THIS CONSENT DOCUMENT HAS BEEN 
APPROVED FOR USE FROM _________ 
THROUGH __________. 
B. 
Parent's Permission for Minor Donor 
I have read the explanation about this study and 
have been given the opportunity to discuss it 
and to ask questions. I hereby give permission 
for my child to  give a blood sample for this 
study. 
 
______________________________________ 
Signature of Parent(s)/Guardian & Date 
Signed 
If other than parent, specify relationship: 
___________________________________ 
 
 
 
_____________________________________ 
Signature of Investigator & Date Signed 
 
______________________________________ 
Signature of Witness & Date Signed 
 
 

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Pediatric Assent to Provide Extra Samples for Research 
 
Study Title: 
A Multi-Center, Phase III, Randomized Trial of Reduced Intensity(RIC) 
Conditioning and Transplantation of Double Unrelated Umbilical Cord 
Blood (dUCB) versus HLA-Haploidentical Related Bone Marrow for 
Patients with Hematologic Malignancies 
Protocol: 
BMT CTN 1101 
 
A. Why am I here? 
Your bone marrow is a match for a person in your family who needs a transplant. Your bone 
marrow grows inside your bones. It helps your body make blood and keeps you healthy. A 
transplant will collect some of your marrow and give it to a person who needs it to make 
new, healthy cells. Your body will make more marrow afterwards. 
If you give us your permission, we would like to have an extra sample of your blood. We 
would collect the extra sample at the same time you have other blood tests done. We want to 
save the samples and use them for research in the future. 
 
B. Why are you collecting an extra sample of blood? 
Research with blood samples will help us learn more about transplant and other diseases. We 
will keep all of the extra samples private and store them in a place called a Repository. Your 
name will not be on the samples. Doctors and other researchers can ask to use the samples in 
the Repository as a part of their research. 
 
C. What will happen to me? 
If you say it is OK for us to collect an extra blood sample for research, we will ask you for: 
 An extra blood sample. We would collect the extra sample at the same time as you 
have other blood tests done.  
We will watch you carefully for side effects, fevers, infections or other problems. 

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D. Will it hurt? 
When you have your blood taken with a needle, it may feel like a pinch. It will hurt for a 
minute and sometimes the place where the needle went might be red and sore. You might get 
a little bruise from the needle but it goes away in a few days. 
 
E. Will the study help me? 
Giving the blood sample for research will not help you.  
 
F. What if I have questions? 
You can ask any questions that you have about giving an extra blood sample. If you forget to 
ask a question and think of it later, you can call [insert office number].   
  
G. Do I have to be in this study? 
If you do not want to give an extra blood sample, 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 can still give 
bone marrow to the person in your family who needs it. They will still get the exact same 
care.  
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 to give an extra blood 
sample for research. We will also ask your parents to give their permission for you to give an 
extra sample for research.  
 
Writing your name on this page means that you agree to give an extra blood sample and know 
what will happen to you. If you change your mind, 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 
 
LABORATORY PROCEDURES 
 
OPTIONAL RESEARCH SPECIMENS 
 
 

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APPENDIX C 
 
LABORATORY PROCEDURES 
 
OPTIONAL RESEARCH SPECIMENS 
 
Patients consenting to the optional future research will have samples collected for future, 
undefined research supporting the protocol.  All research sample aliquots will be given unique 
bar code designations that cannot be linked back to the participant’s name or other identifying 
information.  Laboratory test results, clinical information, etc., associated with the coded samples 
are provided to the Investigator only after completion of the protocol.  Samples sent to 
researchers cannot be linked with any remaining samples at the repository. 
 
Patient samples will be collected both prior to the initiation of treatment and at four post-
treatment time points as specified in the table below.  Peripheral blood and bone marrow product 
samples will also be collected from HLA-haploindentical related donors and stored to support 
future research studies.  All research samples will be collected and shipped same-day to the BMT 
CTN Repository for processing and sample aliquot storage.  Sample collection and shipping 
procedures are detailed in the BMT CTN 1101 Laboratory Sample Guide. 
 
Optional Research Samples 
Subject 
Research 
Sample Type 
Time Points 
Sample 
Quantity 
Sample 
Processing & 
Storage Site 
Stored 
Material 
Purpose 
HLA-
Haploidentical 
Related Donor 
Peripheral 
Blood 
Pre-BM 
Donation 
50 mL 
(donors 
<50kg 1 
mL/kg up to 
50kg) 
BMT CTN 
Repository 
Plasma 
Undefined 
Future 
Research 
Viable PBMC 
Stem Cell 
Product 
(BM)  
(Donors ≥18 
only) 
Product to 
be Infused 
3-5 mL 
BMT CTN 
Repository 
Viable BMMC 
Patient 
Peripheral 
Blood 
Pre-
conditioning 
50 mL    
(patients 
<50kg 1 
mL/kg up to 
50 Kg 
BMT CTN 
Repository 
Plasma 
Undefined 
Future 
Research 
Viable PBMC 
Granulocytes 
Post-
transplant      
Day 28, 56, 
180, 365 
50 mL    
(patients 
<50kg 1 
mL/kg up to 
50 kg) 
BMT CTN 
Repository 
Plasma 
Viable PBMC 

BMT CLINICAL TRIALS NETWORK 
 
RIC dUCB versus Haplo BM – Protocol # 1101 
 
 
Version 8.0 dated January 18, 2017 
 
 
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APPENDIX D 
 
APPROVED CYTOTOXIC CHEMOTHERAPY REGIMENS 
 
 

BMT CLINICAL TRIALS NETWORK 
 
RIC dUCB versus Haplo BM – Protocol # 1101 
 
 
Version 8.0 dated January 18, 2017 
 
 
D-2 
APPENDIX D 
 
APPROVED CYTOTOXIC CHEMOTHERAPY REGIMENS 
 
Patients must have received either 
a. At least one cycle of at least one of the following cytotoxic chemotherapy regimens 
(or regimen of similar intensity) within 3 months of enrollment (measured from the 
start date of chemotherapy)  
i. 
Multi-agent chemotherapy (e.g. CVP±R, CHOP±R, ICE±R, DHAP±R, 
ESHAP±R, …) 
ii. 
Chemotherapy regimens like those that are given as induction or 
consolidation of acute leukemia (7+3, HiDAc, mitoxantrone+etoposide, 
FLAG, FLIG, and others) 
iii. 
Single drug alkylator agent (cyclophosphamide ≥1.5 g/m2 or equivalent) 
iv. 
Bendamustine  
v. 
Single agent alemtuzumab or brentuximab vedotin 
Antineoplastic agents that are not considered adequate cytotoxic chemotherapy 
include:  
i. 
Single agent steroids 
ii. 
Single agent monoclonal antibody ± steroids with the exception of 
alemtuzumab 
iii. 
Single agent hypomethylating agent (e.g. azacytidine) 
iv. 
Single agent antimetabolite ± steroids (e.g. low dose methotrexate, low 
dose cytarabine) 
v. 
Single agent proteasome inhibitor ± monoclonal antibody (except for 
alemtuzumab or brentuximab vedotin) ± steroids 
vi. 
Hydroxyurea 
vii. 
Localized radiation therapy  
viii. 
Interferon 
b.  Autologous hematopoietic stem cell transplantation < 2 years prior to enrollment.   
Please consult with the protocol chairs for any drugs or regimens not listed above.

BMT CLINICAL TRIALS NETWORK 
 
RIC dUCB versus Haplo BM – Protocol # 1101 
 
 
Version 8.0 dated January 18, 2017 
 
 
E-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E 
 
REFERENCES 
 
 

BMT CLINICAL TRIALS NETWORK 
 
RIC dUCB versus Haplo BM – Protocol # 1101 
 
 
Version 8.0 dated January 18, 2017 
 
 
E-2 
APPENDIX E 
 
REFERENCES 
 
                                                 
1 Giralt S, Logan B, Rizzo D et al. Reduced-intensity conditioning for unrelated donor progenitor 
cell transplantation: long-term follow-up of the first 285 reported to the national marrow 
donor program. Biol.Blood Marrow Transplant. 2007;13:844-852. 
2 Platzbecker U, Thiede C, Fussel M et al. Reduced intensity conditioning allows for up-front 
allogeneic hematopoietic stem cell transplantation after cytoreductive induction therapy in 
newly-diagnosed high-risk acute myeloid leukemia. Leukemia 2006;20:707-714. 
3 Popat U, Heslop HE, Durett A et al. Outcome of reduced-intensity allogeneic hematopoietic 
stem cell transplantation (RISCT) using antilymphocyte antibodies in patients with high-risk 
acute myeloid leukemia (AML). Bone Marrow Transplant 2006;37:547-552. 
4 Grigg AP, Gibson J, Bardy PG et al. A Prospective Multicenter Trial of Peripheral Blood Stem 
Cell Sibling Allografts for Acute Myeloid Leukemia in First Complete Remission Using 
Fludarabine-Cyclophosphamide Reduced Intensity Conditioning. Biol.Blood Marrow 
Transplant. 2007;13:560-567. 
5 Oran B, Giralt S, Saliba R et al. Allogeneic Hematopoietic Stem Cell Transplantation for the 
Treatment of High-Risk Acute Myelogenous Leukemia and Myelodysplastic Syndrome Using 
Reduced-Intensity Conditioning with Fludarabine and Melphalan. Biol.Blood Marrow 
Transplant. 2007;13:454-462. 
6 Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell 
transplantation: Marrow or umbilical cord blood? Blood 2003;101:4233-4244. 
7 Ballen KK, Spitzer TR, Yeap BY et al. Double unrelated reduced-intensity umbilical cord 
blood transplantation in adults. Biol.Blood Marrow Transplant. 2007;13:82-89. 
8 Barker JN, Weisdorf DJ, Defor TE et al. Rapid and complete donor chimerism in adult 
recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity 
conditioning. Blood 2003;102:1915-1919. 
9 Brunstein CG, Barker JN, Weisdorf DJ et al. Umbilical cord blood transplantation after 
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10 Misawa M, Kai S, Okada M et al. Reduced-intensity conditioning followed by unrelated 
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11 Miyakoshi S, Yuji K, Kami M et al. Successful Engraftment After Reduced-Intensity 
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12 Luznik L, O'Donnell PV, Symons HJ et al. HLA-Haploidentical Bone Marrow Transplantation 
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Posttransplantation Cyclophosphamide. Biol.Blood Marrow Transplant. 2008;14:641-650. 

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13 Salit, RB, Milano F, Gutman JA, Maris MB, Chauncey T, Peterson F, Delaney C.  Umbilical 
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spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005. 
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25 Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing 
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