Clinical Transplant-Related Long-term Outcomes of Alternative Donor Allogeneic Transplantation (BMT CTN 1702)
Phase: NA
Conditions: Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, Non-hodgkin Lymphoma, Hodgkin Lymphoma, Acquired Aplastic Anemia, Sickle Cell Disease
Sponsor: Center for International Blood and Marrow Transplant Research



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PROTOCOL SYNOPSIS - BMT CTN PROTOCOL 1702 
 
Clinical Transplant-Related Long-term Outcomes of Alternative Donor Allogeneic Transplantation (CTRL-
ALT-D) 
 
 
 
Study Chairpersons:  
Stefan Ciurea, M.D. and Stephanie Lee, M.D., M.P.H. 
 
Study Design: 
This is a multicenter, interventional and observational study to understand factors 
affecting the likelihood of transplantation in patients without a human leukocyte antigen 
(HLA) matched family donor and to compare outcomes associated with pursuing an HLA-
identical unrelated versus other alternative donor graft sources. Alternative donors are 
defined as any donor other than an HLA-matched or 1 antigen-mismatched related donor. 
Patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), 
myelodysplastic syndromes (MDS), Non-Hodgkin lymphoma (NHL), Hodgkin 
lymphoma (HL), acquired aplastic anemia (AA) or sickle cell disease (SCD) are eligible. 
The primary comparison for the interventional study will be between two arms based on 
biologic assignment, analyzed on an intention-to-treat basis: Arm 1: Patients who are 
Very Likely to find a matched unrelated donor (MUD), defined as having a >90% chance 
of finding an 8/8 HLA-matched unrelated donor, for whom a fully matched unrelated 
donor will be pursued; and Arm 2: Patients who are Very Unlikely to find a MUD, defined 
as having a <10% chance of finding an 8/8 HLA-matched unrelated donor, for whom a 
haploidentical, cord blood, or mismatched unrelated donor transplant will be pursued. 
Patients with a Less Likely chance of finding a MUD, i.e., those not falling into the other 
two groups (a 26% chance), will be enrolled onto the observational component of the 
study and analyzed for all relevant endpoints but will not be included in the primary 
comparison. 
 
Primary Objective: 
The primary objective is to estimate and compare overall survival between the two arms: 
patients who are Very Likely to find a MUD versus those who are Very Unlikely to find 
a MUD. 
 
Secondary Objectives: Secondary objectives include all patients, regardless of donor search prognosis: 
 
1. To estimate and compare the cumulative incidence of receiving a transplant according 
to donor search prognosis 
2. To describe barriers to achieving transplantation with different alternative donor 
search strategies 
Post-transplant Objectives:  
3. To compare survival, relapse, disease-free survival, treatment-related mortality, and 
acute and chronic graft-versus-host-disease (GVHD) in patients transplanted for 
malignant diseases, according to the alternative donor used 
4. To describe survival and acute and chronic GVHD in patients with acquired aplastic 
anemia and sickle cell disease after transplantation, according to the alternative donor 
used 

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5. In patients with AML or ALL in first complete remission and early stage MDS 
(refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia 
with multilineage dysplasia, 5q- syndrome or <5% bone marrow blasts) who are 
treated with a limited subset of conditioning and GVHD prophylaxis regimens and 
transplanted with either matched unrelated donors or haploidentical related donors 
(approximately 286 patients meeting eligibility criteria), to compare quality of life 
(QOL) and describe the incidence of primary graft failure, chronic GVHD, time until 
off systemic immunosuppression, acute grade III-IV and chronic GVHD requiring 
immunosuppression-free, relapse-free survival (GRFS), moderate-severe chronic 
GVHD relapse-free survival (CRFS), current CRFS, number of hospital days, 
infections, immune reconstitution and late effects after transplantation, according to 
the alternative donor used (QOL Substudy). All clinical data will be captured on 
Center for International Blood and Marrow Transplant Research (CIBMTR) 
comprehensive report forms (CRFs) while QOL data will be collected centrally. 
 
Accrual Objective: 
The study will enroll 1022 patients in the MUD Very Likely plus MUD Very Unlikely 
search prognosis groups and approximately 710 patients in the Less Likely to find a MUD 
group. 
 
Accrual Period:  
The estimated accrual period is 3 years. 
 
Study Duration: 
Total study duration from first enrollment through last follow-up will be approximately 
5 years.  Adults included in the QOL substudy will be asked to consent to a final QOL 
assessment done at 5 years after transplantation. This 5 year QOL assessment will be 
separately funded and conducted through CIBMTR, referencing Protocol 1702 as the 
source of consent. 
 
Eligibility Criteria: 
Patients of all ages with AML, ALL, MDS, NHL, HL, AA or SCD are eligible. Patients 
must be considered suitable allogeneic hematopoietic cell transplantation (HCT) 
candidates based on available medical history, physical examination, and laboratory tests.  
Specific testing for organ function is not required for eligibility but, if available, these 
tests should be used to judge transplant suitability. Centers must confirm their intention 
both to follow the recommended search algorithm and to perform the transplant within the 
next 6 months if a suitable donor is identified. Patients who consent are considered 
evaluable once the center determines no suitable HLA-matched or 1 antigen mismatched 
related donor is available (center will also confirm that the patient is still considered a 
transplant candidate). Patients may be enrolled on other studies. 
 
Interim Analysis:  
No interim analysis or stopping guidelines for efficacy or futility are planned for this 
study.  We will review the study design assumptions, particularly the ratio of patients 
who are Very Likely to find a MUD vs. patients who are Very Unlikely to find a MUD 
and percentage proceeding to transplant, on a periodic basis, and may adjust the sample 
size if needed to maintain power in the event that our assumptions are incorrect.   
 
Stopping Guidelines:     Monitoring of a key safety endpoint of post-transplant mortality will be conducted 
monthly to ensure that the donor selection recommendations for the Very Unlikely to 
find a MUD group are not leading to significantly lower than expected post transplant 
outcomes.  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 

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described in the BMT CTN's Manual of Procedures.  The stopping guideline serves as 
trigger for consultation with the DSMB for additional review. 
 
Correlative Studies:       QOL Substudy involving patients with AML or ALL in first complete remission and 
early stage MDS who are treated with a limited subset of conditioning and GVHD 
prophylaxis regimens and transplanted with either matched unrelated donors or 
haploidentical related donors, to compare quality of life (QOL) and describe the 
incidence of primary graft failure, chronic GVHD, time until off systemic 
immunosuppression, acute grade III-IV and chronic GVHD requiring 
immunosuppression-free, relapse-free survival (GRFS), moderate-severe chronic GVHD 
relapse-free survival (CRFS), current CRFS, number of hospital days, infections, 
immune reconstitution and late effects after transplantation, according to the alternative 
donor used. If funding for research samples is received, immune reconstitution and other 
testing will be performed for the Substudy population. 

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STUDY SCHEMA 
 
 
  

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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE .................................................................................................... 1-1 
1.1. 
Barriers to Identifying Matched Unrelated Donors .............................................................................. 1-1 
1.2. 
Alternative Donor Graft Sources Provide Outcomes Comparable to Matched Unrelated Donors .. 1-2 
1.3. 
Quality of Life and Late Effects .............................................................................................................. 1-7 
1.4. 
Key Research Questions ........................................................................................................................... 1-8 
1.5. 
Study Design Rationale............................................................................................................................. 1-8 
1.6. 
Potential Concerns About the Study Design ........................................................................................ 1-11 
1.6.1. 
Concerns About Minority Imbalance ................................................................................................... 1-11 
1.6.2. 
Concerns About the Comparator Group .............................................................................................. 1-11 
1.6.3. 
Choice of Interventional Design .......................................................................................................... 1-12 
2. 
STUDY DESIGN ....................................................................................................................................... 2-1 
2.1. 
Study Overview ......................................................................................................................................... 2-1 
2.2. 
Study Objectives........................................................................................................................................ 2-3 
2.2.1. 
Primary Objective .................................................................................................................................. 2-3 
2.2.2. 
Secondary Objectives ............................................................................................................................. 2-3 
2.2.3. 
Post-Transplant Objectives: ................................................................................................................... 2-3 
2.3. 
Patient Eligibility ...................................................................................................................................... 2-3 
2.3.1. 
Intention-to-treat Cohort .................................................................................................................... 2-4 
2.3.2. 
QOL Substudy ...................................................................................................................................... 2-4 
2.4. 
Donor Selection Guidelines ...................................................................................................................... 2-5 
2.5. 
Study Treatments ...................................................................................................................................... 2-0 
2.6. 
Quality of Life ........................................................................................................................................... 2-0 
2.6.1. 
PROMIS Global ..................................................................................................................................... 2-0 
2.6.2. 
PROMIS Domains ................................................................................................................................. 2-0 
2.6.3. 
Lee Chronic GVHD Symptom Scale ..................................................................................................... 2-1 
2.6.4. 
Occupational Functioning ...................................................................................................................... 2-1 
2.6.5. 
Sociodemographic Data ......................................................................................................................... 2-1 
2.7. 
Participant Risks ....................................................................................................................................... 2-4 
3. 
ENDPOINTS ............................................................................................................................................. 3-1 
3.1. 
Primary Endpoint ..................................................................................................................................... 3-1 
3.2. 
Secondary and Post-transplant Endpoints ............................................................................................. 3-1 
3.2.1. 
Transplantation Rate .............................................................................................................................. 3-1 
3.2.2. 
Barriers to Transplantation ..................................................................................................................... 3-1 
3.2.3. 
Relapse ................................................................................................................................................... 3-1 
3.2.4. 
Disease-free Survival ............................................................................................................................. 3-1 
3.2.5. 
Treatment-related Mortality ................................................................................................................... 3-1 
3.2.6. 
Acute GVHD .......................................................................................................................................... 3-1 
3.2.7. 
Chronic GVHD ...................................................................................................................................... 3-1 
3.3. 
Endpoints for the QOL Substudy ............................................................................................................ 3-2 
3.3.1. 
Chronic GVHD ...................................................................................................................................... 3-2 
3.3.2. 
Time Until Off Immunosuppression for Patients Diagnosed with Chronic GVHD .............................. 3-2 
3.3.3. 
GVHD, relapse-free survival (GRFS) .................................................................................................... 3-2 
3.3.4. 
Moderate-severe Chronic GVHD, Relapse-free Survival (CRFS) and Current CRFS ......................... 3-2 

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3.3.5. 
Primary Graft Failure ............................................................................................................................. 3-2 
3.3.6. 
QOL ....................................................................................................................................................... 3-2 
3.3.7. 
Hospital Days ......................................................................................................................................... 3-3 
3.3.8. 
Infections ................................................................................................................................................ 3-3 
3.3.9. 
Immune Reconstitution .......................................................................................................................... 3-3 
3.3.10. 
Late Effects ............................................................................................................................................ 3-3 
4. 
PATIENT ENROLLMENT AND EVALUATION ............................................................................... 4-1 
4.1. 
Enrollment Procedures ............................................................................................................................. 4-1 
4.1.1. 
Screening and Eligibility Procedures ..................................................................................................... 4-1 
4.1.2. 
Evaluations at Enrollment ...................................................................................................................... 4-1 
4.1.3. 
Evaluations at Evaluability .................................................................................................................... 4-1 
4.1.4. 
Donor Search and Identification ............................................................................................................ 4-2 
4.2. 
Methodology and Documentation of Study Events ............................................................................... 4-2 
4.2.1. 
Approaching Patients, Eligibility, Screening, and Obtaining Consent .................................................. 4-3 
4.3. 
Study Monitoring ...................................................................................................................................... 4-3 
4.3.1. 
Transplant Data ...................................................................................................................................... 4-3 
4.3.2. 
Collection of QOL Data ......................................................................................................................... 4-3 
4.3.3. 
Locating Missing Patients ...................................................................................................................... 4-4 
4.3.4. 
Adverse Event Reporting ....................................................................................................................... 4-4 
4.4. 
Research Samples Pre-transplant and Post-transplant ......................................................................... 4-4 
5. 
STATISTICAL CONSIDERATIONS .................................................................................................... 5-1 
5.1. 
Study Overview ......................................................................................................................................... 5-1 
5.1.1. 
Accrual ................................................................................................................................................... 5-1 
5.2. 
Sample Size and Power Calculations ...................................................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines ............................................................................................. 5-2 
5.3.1. 
Guidelines for Safety Monitoring .......................................................................................................... 5-3 
5.4. 
Analysis Populations ................................................................................................................................. 5-5 
5.5. 
Demographic and Baseline Characteristics ............................................................................................ 5-6 
5.6. 
General Analysis Considerations............................................................................................................. 5-6 
5.6.1. 
Analysis of the Primary Endpoints ........................................................................................................ 5-6 
5.6.2. 
Analysis of Secondary Endpoints for Primary Analysis Population ..................................................... 5-7 
5.6.3. 
Analysis of Secondary Endpoints for Less Likely to find a MUD Population ...................................... 5-7 
5.6.4. 
Analysis of Secondary Endpoints for Transplant Population ................................................................ 5-7 
5.6.5. 
Analysis of Secondary Endpoints for QOL Substudy participants ........................................................ 5-8 
6. 
APPENDICES ........................................................................................................................................... 6-1 
6.1. 
APPENDIX A.  LIST OF ABBREVIATIONS ....................................................................................... 6-1 
6.2. 
APPENDIX B.  HUMAN SUBJECTS .................................................................................................... 6-2 
6.3. 
APPENDIX C. LIKELIHOOD OF A MATCHED UNRELATED DONOR TRANSPLANT BY 
DONOR SEARCH PROGNOSIS ....................................................................................................... 6-3 
6.4. 
APPENDIX D. CURRENT 1 YEAR AND 100 DAY SURVIVAL FOR VARIOUS PATIENT AND 
DONOR GROUPS BASED ON 2012-2015 CIBMTR DATA .......................................................... 6-5 
6.5. 
APPENDIX E. DERIVATION OF A SQUENTIAL TEST STATISTIC FOR CENSORED 
EXPOENTIAL DATA ......................................................................................................................... 6-1 
6.6. 
APPENDIX F.  REFERENCES............................................................................................................... 6-3 
 

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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. Barriers to Identifying Matched Unrelated Donors 
 
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment and is 
standard of care for patients with high-risk or advanced hematologic malignancies and other 
hematologic diseases. The use of allogeneic HCT has expanded rapidly over the past decades 
owing to substantial advances in transplant procedures and supportive care.1,2 However, providing 
a suitable donor for all potential HCT patients in an optimal period of time remains an unmet need. 
Even though a fully HLA-matched related donor (MRD) is considered the first graft choice for 
transplantation, approximately two-thirds of patients who need a transplant do not have a MRD 
available; most patients must rely on alternative donor choices.3 Historically, an HLA-matched 
adult unrelated donor has been accepted as the next best option. The success of unrelated donor 
HCT was primarily influenced by the degree of HLA matching between the donor and the 
recipient. High resolution matching at 8 alleles at HLA-A, -B, -C, and -DRB1 (8/8 match) is 
considered standard for unrelated donor transplantation,4,5 and transplant outcomes after unrelated 
donor grafts approximate those of matched related donor grafts.6-9 Hence, most transplant centers 
usually proceed with an unrelated donor search for all patients in need of a transplant if no matched 
related donor is available. However, identification of an unrelated donor may be challenging due 
to low donor availability for non-Caucasian populations or mixed race individuals.10 In addition, 
the unrelated donor search and procurement of stem cell product usually takes longer (on average 
3-4 months) than that of a matched related donor (approximately 1 month). As a result, patients 
may develop progressive disease11 or become medically unfit while waiting for an unrelated donor 
transplant, which might have a negative impact on overall survival. With recent improvements in 
haploidentical donor transplant outcomes using post-transplant cyclophosphamide for graft-
versus-host disease (GVHD) prophylaxis, an increasing number of patients without an HLA-
matched donor are receiving grafts from HLA-mismatched relatives. Some data suggest outcomes 
of haploidentical sibling donor HCTs are similar to those of HLA-identical HCTs, though numbers 
of evaluable patients remain small and follow-up relatively short.12,13 Centers also continue to use 
cord blood and mismatched unrelated donors. It is currently unclear which is the best alternative 
donor source and if it is better to proceed with an alternative donor as soon as possible or wait and 
complete an unrelated donor search, even if it takes a longer period of time to perform 
transplantation. 
 
Work by Dehn and colleagues has defined a “donor search prognosis” based on HLA allele 
frequencies and race/ethnicity. This score predicts the likelihood of successfully identifying a 
10/10 matched unrelated donor.14 Patients who are Very Likely to find a MUD have a >90% 
likelihood of finding a matched unrelated donor, while those who are Very Unlikely to find a MUD 
have a <10% chance. Patients who are Less Likely to find a MUD have a 26% chance of finding 
a matched unrelated donor. Worse search prognosis is associated with racial and ethnic minority 
status but not with other patient and disease biology characteristics that might influence the success 
of HCT. Thus, the use of donor search prognosis in this trial as a tool for biologic assignment to 

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matched unrelated donors vs. mismatched donors provides a mechanism to minimize bias from 
disease characteristics. 
 
A recent survey (July 2018) of donor choice practices by different BMT CTN core and affiliate 
transplant centers revealed that the majority of centers (78%) will initially start a formal unrelated 
donor search in the absence of a matched related donor, while only 16% may proceed to a 
haploidentical donor transplant without a formal unrelated donor search. If a patient lacks a 
matched related or unrelated donor, 69% of the centers would likely choose a haploidentical donor, 
16% a mismatched unrelated donor and 15% a cord blood donor. Eighty nine percent said they 
would be comfortable proceeding to transplant with a haploidentical related donor or cord blood 
without a formal unrelated donor search if a predictive algorithm could identify patients with a 
<10% chance of finding a matched unrelated donor. 
  
1.2. Alternative Donor Graft Sources Provide Outcomes Comparable to Matched 
Unrelated Donors 
 
While most centers would choose a readily available matched unrelated donor over other 
alternative donors for a patient lacking an HLA-identical sibling donor, in reality the reported 
outcomes for all alternative donor transplants appear similar (Section 6.4. Appendix D). Survival 
for transplanted patients is anticipated to be superior to outcomes without transplantation. 
  
Mismatched Unrelated Donor Transplantation 
 
Despite the availability of more than 32 million worldwide potential donors for HCT accessible 
through the National Marrow Donor Program registry, the probability of finding a suitable HLA-
matched donor for HCT varies considerably, from 75% in Caucasians to 16-35% among other 
races.10 One of the alternative options in such cases is the use of an HLA- mismatched unrelated 
donor; however, previous studies found an increased risk of graft-versus-host disease (GVHD) and 
treatment-related mortality with reduced overall survival and progression-free survival compared 
to HLA-matched donor transplantation.4,8,15 
The standard pharmacological GVHD prophylaxis regimen for HLA-matched unrelated donor or 
-matched related donor transplantation includes a calcineurin inhibitor (commonly tacrolimus or 
cyclosporine) and methotrexate.8,16 This is often intensified with in vivo T-cell depletion, generally 
with antithymocyte globulin (ATG) or alemtuzumab in mismatched unrelated donor HCT.17,18 
With this intensive regimen, the incidence of grade II–IV acute GVHD (20–35%), grade III–IV 
aGVHD (4–20%) and cGVHD (22–67%) in mismatched unrelated donor HCT approaches 
comparable levels to those seen after matched unrelated donor HCT.17,18 However, in vivo T-cell 
depletion delays T-cell immune reconstitution19 and poses heightened risk of bacterial and viral 
infections, including herpes simplex virus, cytomegalovirus (CMV), Epstein–Barr virus, and 
infection-related deaths,20 as well as fatal post-transplant lymphoproliferative disorder (PTLD).21 
An alternative approach to prevention of GVHD in mismatched unrelated donor HCT is the use of 
post-transplant cyclophosphamide (PTCy), administered in a similar fashion as in haploidentical 
transplantation on days +3 and +4, along with tacrolimus and mycophenolate mofetil (MMF). A 
recent retrospective comparison for patients with mismatched unrelated donor HCT treated with 
either PTCy or conventional GVHD showed a lower incidence of grade II-IV aGVHD in the first 

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month post-transplant period with PTCy and similar incidence of cGVHD, 2-year non-relapse 
mortality, relapse, progression-free survival,  and overall survival.22 
 
Cord Blood Transplantation 
 
Since the first umbilical cord blood transplant (UCBT) performed in 1988,23 the field of UCBT 
has evolved significantly. Due to reduced stringency of the HLA-match requirement and faster 
availability of banked cryopreserved umbilical cord blood units, cord blood has served as an 
alternative source of hematopoietic stem cells, and contributed to increased access to HCT for 
patients who lack of an HLA-matched related or unrelated donor, primarily in younger patients. 
So far, over 750,000 cord blood units have been stored for transplantation worldwide,24 and 
approximately 3,000 UCBTs have been performed each year for both hematologic malignancies 
and non-malignant diseases.25  
 
In pediatric patients with acute leukemia, Eapen et al. demonstrated a leukemia-free survival at 3 
years of 60% after HLA-matched UCBT, 36% after 1 HLA-mismatched UCBT with low cell dose 
(<3 X107 TNCs/kg), 45% after 1 HLA-mismatched UCBT with high cell dose, and 33% after 2 
HLA-mismatched UCBT.26 The encouraging results have also been demonstrated in pediatric 
patients with benign diseases such as thalassemia, sickle cell anemia27 and Fanconi anemia23. 
 
Although there have been no randomized prospective studies comparing outcomes of UCBT and 
other donor sources, results from several retrospective and prospective studies have demonstrated 
that UCBT is associated with lower rates of GVHD and can provide long-term survival rates 
comparable to HLA-matched unrelated donor transplants.28-32 A recent meta-analysis included 9 
studies of pediatric and adult patients with acute lymphoblastic leukemia (ALL) or acute myeloid 
leukemia (AML) and showed a similar relapse rate, overall survival and progression-free survival 
of unrelated single-unit UCBT and unrelated donor bone marrow transplantation. However, time 
to neutrophil and platelet recovery was shorter after unrelated donor transplantation compared to 
UCBT.32 The median age of UCBT patients included in this meta-analysis was 27.5 years. 
 
Even though cord blood contains a high density of hematopoietic progenitor cells (HPCs) with an 
extensive proliferative capacity and can be cryopreserved for more than 20 years33, the total 
volume of each cord blood unit infused is low, resulting in delayed hematopoietic recovery, 
delayed immune reconstitution and increased treatment-related mortality as it has been shown in 
many studies that the successful transplantation using cord blood depends primarily on number of 
HPCs in the cord blood unit.26,27,34 The optimal cell dose per recipient body weight can be achieved 
in small children while this becomes an important limitation of using cord blood cells in adult 
patients. Improvements in UCBT outcomes for adult patients are due to better HLA matching, 
supportive care, patient selection and optimal cord blood unit selection based on nucleated cell 
dose. The Japanese group reported better 5-year disease-free survival of 60–70% in selected acute 
leukemia patients receiving myeloablative single unit UCBT, presumably because lower 
recipients’ weight and less genetic variability in the Japanese population.35  
 
To overcome the low number of HPCs in a single cord blood unit, double UCBT was developed. 
In a study of 23 adults with high-risk hematological malignancies undergoing double CBT, the 
engraftment was derived from a single cord blood unit with the median time to engraftment of 23 

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days.36 This approach has been studied in several diseases, which showed promising outcomes.37,38 
However, the benefit of double as opposed to single UCBT remains unclear as demonstrated from 
a prospective randomized study comparing single versus double UCBT in children and 
adolescents, which showed a similar rate of neutrophil engraftment and survival, while a higher 
incidence of grade III-IV aGVHD and cGVHD was observed in patients receiving double UCBT.39  
 
Beside the use of double UBCT, several methods have also been pioneered to help increase 
numbers of HPCs and enhance engraftment after UCBT such as novel strategies of cord blood 
expansion40-44 or strategies to increase cord blood HPC homing45-47. So far, all of these approaches 
appear to be safe and have faster engraftment; however, survival benefits remain unclear.  
 
Haploidentical Transplantation with Post-transplant Cyclophosphamide 
 
Haploidentical HCTs have been performed ever since the beginning of transplantation. However, 
high treatment-related mortality, initially because of aGVHD seen with T-cell replete grafts, then 
due to infectious complications associated with extensive T-cell depletion, has been noted. A 
recent development is the application of PTCy with a T-cell replete donor graft, which makes 
haploidentical transplantation feasible, with lower cost, low rates of GVHD and reproducible 
results worldwide. This has allowed a significant increase in donor availability and in the number 
of haploidentical transplants performed.2  
 
Based on promising preclinical studies, O’Donnell and colleagues reported the first phase I clinical 
trial results of 13 patients who underwent haploidentical transplantation using non-myeloablative 
conditioning with fludarabine 30 mg/m2 on day -6 to -2 and 2 Gy TBI on day -1 and PTCy 50 
mg/kg on day +3.48 Additional immunosuppression included MMF (day +4 to day +35) and 
tacrolimus. Cyclophosphamide 16.5 mg/kg on day -6 and -5 was subsequently added (Flu/Cy/TBI 
regimen) after the first few treated patients experienced primary graft failure. 48,49 Subsequent 
studies refined the prevention of GVHD by administering two doses of Cy on days +3 and +4.49 
 
Since then, there has been a considerable interest in developing this approach for clinical practice. 
In 2011, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) jointly published 
results of 2 phase II studies of haploidentical and cord blood transplants. The studies were 
conducted in parallel in patients with high-risk hematological malignancies.50 BMT CTN 0603 
reported the results of haploidentical transplants with PTCy and a bone marrow graft. All patients 
were treated with reduced intensity conditioning using the Flu/Cy/TBI regimen. The patients in 
the haploidentical transplant trial had a low incidence of grade II-IV acute GVHD (32%) and, 
remarkably, there were no cases of severe (grade III-IV) aGVHD. The 1-year treatment-related 
mortality was also very low (7%), but the relapse rate was high (45%). The 1-year overall survival 
and progression-free survival were 62% and 48% in the haploidentical trial and 54% and 46% in 
the cord blood trial.  
 
The MD Anderson Cancer Center group also performed two parallel phase II trials, one exploring 
the use of PTCy-based GVHD prophylaxis for haploidentical HCT and the other for 9/10 unrelated 
donor transplants, each using the same conditioning regimen (Flu/Mel/2GyTBI).51 A total of 104 
patients were treated, 60 with a haploidentical donor and 46 with a 9/10 unrelated donor transplant. 
Most patients received a bone marrow (BM) graft and all had the same GVHD prophylaxis with 

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PTCy, tacrolimus and MMF. Engraftment with the two donor types was similar (95% and 98%). 
Cumulative incidences of grades II-IV aGVHD were 28% and 33%. Corresponding rates of grades 
III-IV acute GVHD were 3% and 13%, of cGVHD 13% and 14%, treatment-related mortality 21% 
and 31%, and relapse 19% and 25%.  One year rates of survival and progression-free survival were 
70% and 60% and 60% and 47%, respectively (Table 1).51  
 
Table 1. Outcomes of two sets of parallel Phase II trials performed by MD Anderson Cancer 
Center and BMT CTN. The first set included a trial of haploidentical donor transplants and a trial 
of 9/10 unrelated donor transplants; the second set included a trial of haploidentical transplants 
and a trial of cord blood transplants. 
 
 
MD Anderson 
BMT CTN 
 
HAPLO with 
Flu/Mel/TBI 
(N=60) 
9/10 URD with 
Flu/Mel/TBI 
(N=46) 
HAPLO with 
Flu/Cy/TBI 
(N=50) 
CBT with 
Flu/Cy/TB
I 
(N=50) 
Engraftment 
95% 
98% 
96% 
94% 
aGVHD gr II-IV 
28% 
33% 
32% 
40% 
aGVHD gr III-IV 
3% 
13% 
0% 
21% 
cGVHD 
13% 
14% 
13% 
25% 
TRM (1yr) 
21% 
31% 
7% 
24% 
RR (1yr) 
19% 
25% 
45% 
31% 
OS (1yr) 
70% 
60% 
62% 
54% 
DFS (1yr) 
60% 
47% 
48% 
46% 
 
Legend: HAPLO – haploidentical, URD – matched unrelated donor, CBT – cord blood transplant, N – number, Flu 
– fludarabine, Mel – melphalan, TBI – total body irradiation (2Gy), Cy – cyclophosphamide, aGVHD – acute graft 
versus host disease, cGVHD – chronic graft versus host disease, TRM – treatment-related mortality, RR – relapse 
rate, OS – overall survival, DFS – disease-free survival. 
 
 
Comparative Outcomes Between Haploidentical and Matched Unrelated Donor Transplants 
 
Multiple retrospective studies have shown similar outcomes between different alternative donor 
sources including haploidentical transplants and 8/8 HLA matched unrelated donor transplants.  
 
A summary of the results from the first 7 single institution studies52-57 comparing these two donor 
sources showed a median incidence of grade II-IV aGVHD of 27% (range 14%-43%) vs. 37% 
(range 22-63%) and cGVHD 24% (range 13%-38%) vs. 36% (22%-63%), respectively. In these 
studies, treatment-related mortality rates ranged from 9% at 2 years to 18% at 1 year for 
haploidentical donors vs. 8% to 34% at 2 years for unrelated donors, relapse rate ranged from 18% 
at 1 year to 40% at 2 years for haploidentical donors and from 16% at 1 year to 52% at 2 years for 
unrelated donors, while progression-free survival ranged from 41% at 3 years to 60% at 4 years 
for haploidentical and from 29% at 2 years to 52% at 2 years for unrelated donors, indicating 
considerable overlap but also showing wide confidence intervals as a result of the relatively small 
number of haploidentical transplant recipients in these studies.  
 

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In addition, several larger registry studies compared outcomes between these two donor sources 
(Table 2). Two of these studies were performed by CIBMTR, one in patients with AML12 and one 
in patients with lymphoma.13 These studies also showed similar results between the two groups. 
In the first study more than 2,000 patients were analyzed (though only 192 had a haploidentical 
donor) and the 3-year progression-free survival was similar for haploidentical and unrelated donor 
transplant patients treated with myeloablative (41% vs. 42%) and reduced intensity/non-
myeloablative conditioning (35% vs. 37%), while lower incidences of acute and chronic GVHD 
were observed in the haploidentical transplant groups.12 In the second study of 917 lymphoma 
patients, 185 had a haploidentical donor (all treated with Flu/Cy/TBI regimen), and similar results 
were observed: the 3-year progression-free survival for haploidentical transplants was 47% vs. 
49% for unrelated donor transplants performed without ATG and 38% for unrelated donor 
transplants with ATG (p=0.02), while the haploidentical transplants again had significantly lower 
incidence of severe aGVHD (8% vs. 12% vs. 17%, p<0.01) and cGVHD (13% vs. 51% vs. 33%, 
p<0.001).13 In all of these studies, the confidence intervals for the outcomes estimates were wide 
and differences as large as 10-15%, while clinically meaningful, could have been missed. There is 
need to assess these comparisons in much larger cohorts to have adequate statistical power.  
 
Table 2. Registry studies comparing haploidentical vs. 8/8 matched unrelated donor transplant 
outcomes. 
 
Diseases N 
Gr 2-4 
aGVHD 
cGVHD 
TRM 
RR 
DFS 
95% CI 
Reference 
AML 
 MAC 
 RIC 
HAPLO 
N=192 
URD N=1,982 
16% v 
33% 
19% v 
28% 
30% v 
53% 
34% v 
52% 
14% v 
20% 
9% v 
23% 
44% v 
39% 
58% v 
42% 
45% v 
50% 
46% v 
44% 
@3 
years 
N/A 
N/A 
Ciurea SO. 
Blood. 
201612 
Lymph-
oma 
HAPLO 
N=185 
URD w/ATG 
N=241 
URD w/o ATG 
N=491 
27% 
40% 
49% 
13% 
33% 
51% 
11% 
13% 
20% 
36% 
36% 
28% 
47% 
38% 
49% 
@3 
years 
40-55 
31-45 
44-54 
Kanate 
AS. Blood. 
201613 
Hodg-
kin’s 
lymph-
oma 
HAPLO N=98 
URD N=273 
33% v 
30% 
26% v 
41% 
17% v 
21% 
39% v 
32% 
43% v 
45% 
@ 2 
years 
33-54 
39-51 
Martinez. 
JCO. 
201758 
 
Legend: AML – acute myeloid leukemia, MAC – myeloablative conditioning, RIC – reduced intensity conditioning, 
HAPLO – haploidentical donor, MUD – matched unrelated donor, N – number, Gr – grade, aGVHD – acute graft-
versus-host disease, cGVHD – chronic  acute graft-versus-host disease, TRM – treatment-related mortality, RR – 
relapse rate, DFS – disease-free survival, OS – overall survival. 
 
Thus, most available data support comparability of outcomes between matched unrelated donors 
and haploidentical donors once patients make it to transplant. The figure below shows the absolute 

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difference in disease-free survival probability according to donor type. Negative numbers favor 
matched unrelated donors over haploidentical donors; none of the differences were statistically 
significant. 
 
 
 
To date, only limited data on differences in immunologic reconstitution between different 
alternative donor sources exists. The MD Anderson group compared immunologic reconstitution 
between haploidentical transplants performed with PTCy and HLA matched related and unrelated 
donor transplants performed with conventional GVHD prophylaxis for patients with AML/MDS. 
They reported similar recovery of CD3+ cells, CD3+CD4+, CD3+CD8+, CD3-CD56+ (NK cells) 
and CD19+ (B-cells) between these 3 groups starting at 3 months post-transplant. However, at day 
+30 matched related donor transplants had significantly higher CD3+ cells, CD3+CD4+, 
CD3+CD8+ T-cells compared with the other two donor sources.59 Although in depth evaluation 
of immune reconstitution is beyond the scope of this trial, the study will examine rates of clinically 
significant infections and may provide an opportunity for sample collection for further, separately 
funded assessment of immune markers, depending on identification of additional resources beyond 
BMT CTN. 
 
 
1.3. Quality of Life and Late Effects 
 
Quality of life (QOL) refers to every dimension of life except for its length and includes physical 
abilities, symptoms, social well-being, psycho-emotional status, and spiritual/existential qualities.  
It reflects how well people feel, what they can accomplish, how satisfied they are with their lives, 
and whether their lives have meaning and purpose. HCT survivors generally report high global 
QOL following HCT, but many specific symptoms60-65 and limitations on their daily activities.66 
 
The purpose of the QOL component of this trial is to explore the long-term QOL implications of 
using an 8/8 HLA-matched unrelated donor vs. a haploidentical donor. While the trial is powered 
with survival as the primary endpoint, QOL will be an especially important secondary endpoint if 
survival is not statistically different.  It is also possible that immunologic recovery, peri-transplant 
experiences and complications, speed of physical recovery, and expectations may influence 

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ultimate QOL. Since patients are already consented to BMT CTN 1702, the incremental effort of 
collecting QOL data on a subset of informative patients is worth the potential information gained. 
 
It is very important that data collection is centralized, patients’ response burden is minimized and 
QOL assessments are fully integrated into the trial to maximize the chance of complete data 
collection. With this goal in mind, the number of survey items will be minimized and focused on 
answering the research questions. 
 
Late effects occurring more than 1 year after HCT may be related to the disease, treatment before 
transplant, or the transplant itself. The most common late effects are chronic GVHD and 
complications related to its treatment, bone density loss, hypothyroidism, diabetes, cardiovascular 
complications and subsequent neoplasms.67 These late effects will be captured via the CIBMTR 
CRFs. No additional data collection forms are required. 
 
1.4. Key Research Questions 
 
Donor availability for patients who do not have an HLA-identical related donor remains a major 
factor in determining the success of transplantation. Overall, this study aims to assess donor 
availability and outcomes of patients receiving alternative donor transplants. More specifically, 
the primary objectives of this study are: 1) To understand how donor search prognosis affects the 
likelihood and timing of undergoing transplantation; and 2) To understand survival differences 
between MUD Very Likely and MUD Very Unlikely prognosis search groups, where MUD Very 
Likely search prognosis patients are anticipated to undergo matched unrelated donor HCT after 
some delay to identify a donor and MUD Very Unlikely search prognosis patients will instead 
pursue a mismatched donor source with less delay.  
  
1.5. Study Design Rationale 
 
Current transplant statistics show that haploidentical donor transplant numbers are increasing in 
the US and internationally, while unrelated donor and cord blood numbers are stable or declining. 
Physicians and patients wish to know which alternative donor source is preferable in which clinical 
situations. Because disease progression is a major reason that transplants are not performed, both 
the speed of getting to transplant and the outcome of transplantation are important determinants of 
which donor source is preferable.11 
 

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Although the best study design would be a randomized controlled trial among patients who do not 
have a suitable HLA-identical sibling 
donor, the number of patients required 
is too large and preliminary assessment 
suggested that this type of study is not 
feasible. Thus, the protocol team opted 
for 
an 
intention-to-treat 
biologic 
assignment design, where biologic 
assignment 
is 
made 
to 
matched 
unrelated donors vs. all other alternative 
donors (haploidentical family members, 
cord blood, mismatched adult unrelated 
donors) based on the donor search 
prognosis 
score.14 
The 
score 
is 
calculated using the patient’s HLA 
typing and race. Recent unpublished 
data suggest that patients who are Very 
Likely to find a MUD (about 44% of 
patients) have a >90% chance of finding a matched unrelated donor. Patients who are Very 
Unlikely to find a MUD (about 15% of patients) have <10% chance of finding a matched unrelated 
donor (J Dehn, BeTheMatch, personal communication to provide the current distribution of search 
prognoses). These two patient groups, those who are Very Likely to find a MUD and those who 
are Very Unlikely to find a MUD, will be analyzed for the primary endpoint since the biologic 
assignment is not associated with disease type, disease stage and most other patient factors known 
to be associated with transplant outcome. Patients who are Less Likely to find a MUD (about 41% 
of patients) have a 26% chance of finding a matched unrelated donor. Patients who are Less Likely 
to find a MUD will be enrolled and their outcome tracked but they will not be included in the 
primary analysis because there is no consensus on whether and for how long to search for a 
matched unrelated donor. Donor search prognosis is correlated with race/ethnicity but not with 
disease or disease stage. Thus, donor search prognosis will be used to assign patients to a group 
that is very likely to find a matched unrelated donor and a group that is very unlikely to find a 
matched unrelated donor, while minimizing biases due to disease status. It is acknowledged that 
the groups will be unbalanced for race (13% racial/ethnic minorities in the Very Likely to find a 
MUD group and 37% in the Very Unlikely to find a MUD group based on 229 searches conducted 
in a 2 week period in 2018; personal communication J Dehn) and comparisons will be stratified 
on this variable. 
 
Because of the inherent biases in alternative donor selection, we plan to collect key data that will 
allow us to understand and adjust as much as possible for these biases. First, we will have centers 
keep screening logs so that we understand why potentially eligible patients were not enrolled, for 
example, disease considerations, logistics, patient refusal etc. We want to enroll patients once they 
are considered “serious” transplant candidates but before too many have been lost to factors that 
could be associated with a preferred donor source. For example, if it takes too long to identify or 
arrange for a certain type of donor, then we want to understand how this impacts relapse and 
toxicity due to need for additional chemotherapy etc. We will track survival for all patients enrolled 
on the study, irrespective of whether or not they are transplanted and which donor source is used. 

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This will fill a large unmet need for information about the patient evaluation and donor search 
process and the reasons that otherwise seemingly eligible patients do not receive a transplant. 
There are few data about these barriers (especially collected prospectively in a systematic manner 
across multiple centers), which may include, as noted above, disease progression and non-HCT-
related complications but may also include patient reluctance, financial barriers, lack of social 
support and others.  
 
The rationale for limiting the in-depth outcome analyses requiring complete clinical and patient-
reported data collection to a smaller, more homogeneous subset (QOL Substudy) is to use 
resources wisely to focus QOL questions on a group of patients who will provide interpretable 
data. Patients with rare diseases, advanced disease status or unusual conditioning regimens or 
GVHD prophylaxis approaches may increase the background noise and/or lead to subtle 
confounding effects on the main outcomes comparisons. The power for this analysis is limited but 
it will provide important information for planning future studies that aim to improve QOL. Little 
additional work is required other than collecting patient-reported outcomes and assigning patients 
eligible for the QOL Substudy to the CIBMTR CRF track.  
 
Given the large number of patients to be followed and understanding that data quality and burden 
of data collection are often inversely related, we opted to be parsimonious about endpoints. Thus, 
we will focus on overall survival. Secondary endpoints include relapse, disease-free survival, 
treatment-related mortality, aGVHD and cGVHD, all endpoints that can be derived from data 
routinely collect on the CIBMTR Transplant Essential Data (TED) forms, which are mandated for 
all US allogeneic HCT recipients. Detailed cGVHD data, number of hospital days, primary graft 
failure, infection/immune reconstitution and late effects data are limited to a smaller homogenous 
population of patients with AML or ALL in first complete remission or early stage MDS 
(refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with 
multilineage dysplasia, 5q- syndrome or <5% bone marrow blasts), with data collected on the 
CIBMTR CRFs. For example, GRFS (acute grade III-IV aGVHD and cGVHD requiring 
immunosuppression-free, relapse-free survival) and CRFS (moderate-severe cGVHD-free, 
relapse-free survival) can only be derived from the CRF forms and not TED forms, so these 
endpoints are not reported for the entire cohort but will only be reported for the QOL Substudy. 
Both GRFS and CRFS will be reported to allow comparisons with other BMT CTN studies. 
Because patient-reported outcomes data require specialized infrastructure and attention, QOL data 
will also be reported only for the QOL Substudy patients. We limited the QOL assessments to pre-
transplant and 1 and 2 years after transplant in order to focus on times where we anticipate more 
complete collection will result in more meaningful data. Participants also consent to a 5 year QOL 
assessment when they sign the study consent form but this data collection will be performed 
separately by CIBMTR, referencing BMT CTN 1702 as the source of consent. 
 
This protocol also outlines research blood sampling but no funding currently exists for collection. 
Patients in the QOL Substudy will be asked to consent for potential future research samples, and 
it will be made clear that this sampling is contingent on securing additional funding. If additional 
funding is obtained, patients will be notified and research sampling will commence. Appropriate 
sample volume adjustments for patient age and weight will be included. If no additional funding 
is secured, no research blood samples will be taken as part of this protocol. Donor blood samples 

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are not included in the protocol now because of the complicated donor consent issues. If additional 
funding is obtained to support donor research sampling, this protocol will be modified. 
 
1.6. Potential Concerns About the Study Design 
 
 
1.6.1. Concerns About Minority Imbalance 
 
Will a higher proportion of racial/ethnic minorities in the Very Unlikely to find a MUD group be 
problematic in interpretation of study results or an ethical concern for the study? 
 
Racial and ethnic minorities comprise a greater proportion of the group that is Very Unlikely to 
find a MUD (37% of 292, n=108) than the Very Likely to find a MUD group (13% of 730, n=95) 
but because of the different sizes of the groups, the absolute number of racial/ethnic minorities is 
comparable in the  Very Likely and Very Unlikely groups. All analyses will adjust for 
racial/ethnic minority status to try to address other, non-HLA factors that might be confounders.  
 
Racial/ethnic minorities in the Very Unlikely to find a MUD group have the lowest chance of 
finding a matched unrelated donor, so prompt use of another alternative donor is expected to 
benefit them most by allowing them to proceed to transplant. Further analysis of the Wadsworth 
et al study showed none of the 104 minority patients in the Very Unlikely to find a MUD group 
had a matched unrelated donor transplant, and in fact, only 21% were transplanted using a 
mismatched unrelated donor or cord blood (haploidentical transplants could not be tracked). 
Racial and ethnic minorities in the Very Likely to find a MUD group achieved a 40% transplant 
rate, closer to the 49% transplant rate achieved in the Caucasians in the Very Likely to find a 
MUD group, suggesting that failure to promptly identify a donor is contributing to the barrier to 
transplantation experienced by the Very Unlikely to find a MUD group. Thus, while racial/ethnic 
minorities comprise a higher proportion of the Very Unlikely to find a MUD group, they are still 
less than 40% of that group. Use of the donor search prognosis score and rapid use of an 
alternative donor is anticipated to benefit everyone in the Very Unlikely to find a MUD group. 
 
1.6.2. Concerns About the Comparator Group 
 
The study tests the hypothesis that rapid access to a transplant improves survival compared to 
delayed progress to transplant after a more extensive donor search to try to identify a matched 
unrelated donor. What is the comparator group to measure this outcome? Is the primary 
outcome appropriate given the inherent ethnic/racial imbalance? 
 
Appendix C shows the outcomes of transplantation from matched unrelated donors vs. other 
alternative donors. Multiple other studies (Section 1.2) suggest that once patients undergo 
transplantation, outcomes are fairly similar between the different graft sources. However, the 
greatest barrier to getting to transplant in the Very Unlikely to find a MUD group is identifying a 
donor. Under current practice, half as many patients in the Very Unlikely to find a MUD group 
get to transplant with a mismatched unrelated donor or cord blood, whether racial/ethnic 
minorities or Caucasians, and almost no one has a matched unrelated donor transplant. We do 
not know what happens to those patients who do not undergo transplantation but presumably 

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their survival is much worse since transplantation was recommended for them, and we will track 
the outcomes for non-transplanted patients in this study.  
 
1.6.3. Choice of Interventional Design 
 
What will be the impact of the study on the field given the expected rapid changes in transplant 
and disease management? How will evolving practice such as shifts in preference in donor 
selection be addressed?  
 
If the field shifts to rapid alternative donor transplant for patients in the Very Unlikely to find a 
MUD group that means centers have evaluated the observational data themselves and concluded 
that this is the best algorithm for their patients. However, our study question is not about how to 
improve the outcomes in the Very Unlikely to find a MUD group, although this is anticipated to 
be a derivative of the study. Our study question is how does a matched unrelated donor 
transplant compare to use of another alternative donor, specifically haploidentical donors. The 
donor search prognosis score serves as a biologic assignment tool to define groups for this 
primary comparison. 
 
Would the same study with prospective data collection but omitting the algorithm be sufficient to 
identify current practice including barriers to transplantation and result in identifying 
hypotheses for future testing? 
 
The study team considered an observational study but this design would only address the barriers 
to transplantation, not the outcomes comparison of matched unrelated donors to other alternative 
donor sources. 

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CHAPTER 2 
 
 
2. 
STUDY DESIGN  
 
2.1. Study Overview 
 
The study hypotheses are: (1) disease and clinical status are the major determinants of deferred 
transplants rather than inability to identify a donor; and (2) if donor search prognosis is used to 
guide the donor selection strategy, Very Unlikely and Very Likely to find a MUD patients will 
have less than a 10% difference in survival, adjusting for baseline clinical variables, despite having 
different donor sources.  
 
To test these hypotheses we need to enroll patients before a formal alternative donor search is 
launched. Patients may be enrolled as early as when initial HLA-typing is sent or at the time of 
initial evaluation for transplantation, preferably but not necessarily before results of the recipient 
HLA typing are back. Patients are not considered evaluable until they are declared to have no 
suitable HLA-matched or 1-antigen mismatched family member donor and the center confirms 
they are still transplant candidates based on available information. Enrollment is facilitated by 
allowing patients with any planned conditioning or GVHD prophylaxis regimen to participate and 
relying on standard CIBMTR forms for almost all outcomes data.  
 
Data about the alternative donor search is collected on a Donor Search Tracking form. Data 
collection about the search focuses on barriers to transplantation and choices about donor type. 
The intention is that centers use the donor search prognosis to guide their search strategies. If a 
patient is Very Likely to find a MUD, a MUD is prioritized with the expectation that >90% will 
identify a fully matched unrelated donor. If a patient is in the Very Unlikely to find a MUD group, 
the center will move rapidly to the alternative donor of choice - a haploidentical family member, 
cord blood or mismatched unrelated donor because fewer than 10% will be able to find a fully 
matched unrelated donor. The eligibility criteria will ensure that at the time of enrollment the intent 
is to tailor the donor search according to the donor search prognosis. It is expected that >90% of 
patients transplanted in the Very Likely to find a MUD group will have a matched unrelated donor 
and the 70%, 15% and 15% of patients transplanted in the Very Unlikely to find a MUD group 
will have a haploidentical, mismatched unrelated donor or cord blood transplant, respectively.  
 
Patients who do not undergo transplant will be followed long-term for survival only for at least 2 
years after they are declared evaluable, through telephone contact with the patient/family, medical 
records review or search of administrative databases such as the social security death index.  
 
All enrolled and evaluable Very Likely and Very Unlikely to find a MUD patients will be 
considered in the intention-to-treat primary analysis of survival. A Donor Search Tracking form 
will be designed to capture details of the alternative donor search and selection. This form also 
captures information about the patient’s health and clinical status that are relevant to the timing of 
transplant. Data from the regular TED and CRF CIBMTR forms are sufficient for secondary 
endpoints such as occurrence of acute and chronic GVHD, relapse, disease-free survival, and 
treatment-related mortality. The CRFs but not the TED forms will capture primary graft failure, 

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NIH graded moderate-severe cGVHD, date of discontinuation of steroid and non-steroid 
immunosuppression, infections, number of hospital days in the first 100 days post-transplant, basic 
immune reconstitution data and late effects.  
 
 

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2.2. Study Objectives 
 
2.2.1. Primary Objective 
 
The primary objective is: 
  
1. Compare overall survival between Very Likely to find a matched unrelated donor search 
prognosis patients and Very Unlikely to find a matched unrelated donor search prognosis 
patients who are evaluable 
2.2.2. Secondary Objectives 
 
Secondary objectives include all patients regardless of donor search prognosis: 
1. To estimate and compare the cumulative incidence of receiving a transplant according to 
donor search prognosis  
2. To describe barriers to achieving transplantation with different donor search strategies 
 
2.2.3. Post-Transplant Objectives: 
 
Post-transplant objectives include all patients who are transplanted regardless of donor search 
prognosis: 
3. To compare overall survival, relapse, disease-free survival, treatment-related mortality, 
and acute and chronic GVHD in patients transplanted for malignant diseases, according to 
the donor search prognosis and the alternative donor used. 
4. To describe survival and acute and chronic GVHD in patients with acquired aplastic 
anemia and sickle cell disease after transplantation, according to the donor search prognosis 
and the alternative donor used 
5. In patients with AML or ALL in first complete remission or early stage MDS (refractory 
anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage 
dysplasia, 5q- syndrome or <5% bone marrow blasts) treated with a limited subset of 
conditioning and GVHD prophylaxis regimens and transplanted with either matched 
unrelated donors or haploidentical related donors (QOL Substudy), to compare QOL and 
describe primary graft failure, cGVHD, time until off systemic immunosuppression, 
aGVHD grade III-IV and cGVHD requiring immunosuppression-free, relapse-free 
survival (GRFS), moderate-severe cGVHD relapse-free survival (CRFS), current CRFS 
(still on systemic treatment for cGVHD), hospital days in the first 100 post-transplant days, 
infections, immune reconstitution and late effects after transplantation, according to the 
donor search prognosis and alternative donor used.  
 
2.3. Patient Eligibility 
 
Patients must meet specified eligibility criteria for entry into the intention-to-treat cohort and the 
QOL Substudy.   

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2.3.1. Intention-to-treat Cohort 
 
Patient Inclusion Criteria 
 
Patients fulfilling the inclusion criteria will be eligible for enrollment in this study. Of those who 
consent, only patients who lack a suitable HLA-identical or 1 allele or antigen mismatched related 
donors are evaluable. Patients with an HLA-identical sibling or 1 allele or antigen mismatched 
family member donor are evaluable as long as the center deems the family member donor as 
unsuitable for other reasons. Patients may co-enroll with other interventional or observational 
studies. 
1. Patients of all ages with AML, ALL, MDS, NHL, HL, AA, or SCD are eligible.  
2. Any planned conditioning regimen and GVHD prophylaxis approach is eligible. 
3. Patients must be considered suitable allogeneic transplant candidates at the time of 
enrollment based on medical history, physical examination, and available laboratory tests.  
Specific testing for organ function is not required for eligibility but, if available, these tests 
should be used by the treating physician to judge transplant suitability. 
4. Patient and physician must intend to proceed with allogeneic HCT within the next 6 months 
if a suitable donor is identified. 
5. Center plans to follow the algorithm for alternative donor identification: (a) for subjects 
who are Very Likely to find a MUD, attempt to identify a matched unrelated donor; (b) for 
a subjects who are Very Unlikely to find a MUD, proceed expeditiously to a haploidentical, 
cord blood or mismatched unrelated donor. 
6. Signed informed consent, and assent if applicable. Consent may be signed prior to 
completion of family typing but patients will only be considered evaluable upon 
confirmation that there is no suitable HLA-identical or 1 allele or antigen mismatched 
related donor available. 
 
Patient Exclusion Criteria 
 
Patients with the following will be ineligible for enrollment onto this study: 
1. Prior allogeneic HCT (prior autologous transplant is allowed)  
2. Previous formal unrelated donor search 
 
2.3.2. QOL Substudy 
 
Patient Inclusion Criteria (QOL Substudy) 
 
Patients fulfilling the following criteria will be eligible for inclusion in the Substudy: 
 
1. 8/8 HLA-matched unrelated donor or haploidentical family member donor 

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2. AML or ALL in first complete remission and early stage MDS (as defined according to 
CIBMTR criteria) at the time of transplantation. Early stage MDS is refractory anemia, 
refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage 
dysplasia, 5q- syndrome or <5% bone marrow blasts 
3. Conditioning regimen from the list below: 
a) Cyclophosphamide and total body irradiation +/- fludarabine 
b) Cyclophosphamide and busulfan +/- total body irradiation 
c) Fludarabine and melphalan +/- total body irradiation 
d) Fludarabine and busulfan  
e) Fludarabine and myeloablative dose total body irradiation 
4. GVHD prophylaxis from the list below: 
a) Calcineurin-inhibitor and methotrexate or mycophenolate mofetil +/- antithymocyte 
globulin 
b) Calcineurin-inhibitor and sirolimus 
c) Post-transplant cyclophosphamide +/- others 
 
Patient Exclusion Criteria (QOL Substudy) 
 
Patients with the following are ineligible for inclusion in the QOL component of the QOL 
Substudy. They are eligible for all other QOL Substudy components. 
1. For the QOL component, have not celebrated 8th birthday at the time of enrollment 
2. For the QOL component, psychosocial conditions that would prevent study compliance  
3. For the QOL component, inability to read English or Spanish  
 
 
2.4. Donor Selection Guidelines 
 
Once a participant is enrolled and (a) the HLA typing and race/ethnicity data are transmitted to 
NMDP and (b) the patient is deemed evaluable, NMDP will provide treating centers with a report 
detailing: the donor search prognosis, aggregate results of a preliminary search, and a qualitative 
estimate of the likelihood of finding a fully matched unrelated donor (see below for examples). 
However, specific donors will be selected by centers, according to their current methods. Guidance 
is provided in the BMT CTN 1702 Study Procedure and Guidance Manual. Testing for donor-
specific antibodies (DSA) is highly recommended for all HLA-mismatched transplants. The Study 
Procedure and Guidance Manual contains guidance on interpretation of DSA and outlines methods 
of depleting DSA prior to transplantation. 
 
 
 

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Example of a VERY LIKELY to find a MUD Search Prognosis and Preliminary Search Summary report 
 
 
 
 
 

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Example of a VERY UNLIKELY to find a MUD Search Prognosis and Preliminary Search Summary report 
 
 
 
 

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Example of a LESS LIKELY to find a MUD Search Prognosis and Preliminary Search Summary report 
 
 
 

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2.5. Study Treatments  
 
Patients will be transplanted according to institutional guidelines. They may participate in other 
clinical trials as long as the cumulative data collection will not compromise adherence to data 
submission for this protocol. 
 
2.6. Quality of Life 
 
The following instruments will be used to assess QOL within one month before transplant 
(Baseline), at 1 year, 2 years and 5 years for QOL Substudy participants defined above. Only 
English- or Spanish-speaking trial participants aged 8 years and older will be included in the QOL 
studies. Patients aged 8-17 at the time of assessment will complete pediatric instruments. Proxy 
reports (e.g., parents, guardians) of child QOL will not be collected.  
 
At the Baseline time point, center or CIBMTR staff will administer QOL instruments 
electronically or on paper. At 1 year, 2 year and 5 year time points, the CIBMTR will administer 
the QOL surveys electronically or on paper upon request. The number of questions may vary based 
on method of delivery, but each time point will take approximately 14-27 minutes for adults and 
11-19 minutes for pediatric patients. The survey times vary based on method of delivery because 
computerized adaptive testing will be used for participants who complete the survey online which 
may increase the number of survey items given to provide more precise scoring with questions 
that are more closely aligned to a subject’s functioning. 
 
 
2.6.1. PROMIS Global 
 
The PROMIS Global measure contains 10 items for adults and 9 items for pediatric patients, with 
two summary scores for physical and mental functioning. The median score is 50 with a standard 
deviation of 10. Higher scores indicate better QOL.68,69 
 
2.6.2. PROMIS Domains  
 
Eight PROMIS domains for adults and seven for pediatric patients will be used to measure detailed 
functioning and symptom burden for patients. For the physical and social functioning scales, 
higher scores indicate better functioning; for fatigue, pain, anxiety, depression, and sleep scales, 
higher scores indicate a higher symptom burden.70 Scores are normalized to 50 with a standard 
deviation of 10, and scores greater than 0.5 times standard deviation (i.e., <45 or >55, compared 
to the general population) are considered clinically meaningful.  
 
The PROMIS domains for adults are: physical function, anxiety, depression, fatigue, sleep 
disturbance, ability to participate in social roles and activities, pain interference, and pain intensity. 
The PROMIS domains for pediatric patients are: physical function mobility, anxiety, depressive 
symptoms, fatigue, peer relationships, pain interference, and pain intensity. 
 

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When delivered on paper, the domains will be delivered combined in a Profile form. The PROMIS 
29 Profile for adult patients contains 7 subscales with 4 questions each, and a single item for pain 
intensity (29 total items).  
 
When delivered electronically, the domains will be delivered as Computer Adaptive Tests (CAT), 
in which the questions a person answers are tailored to that person. Each response is used to further 
refine the questions a participant receives, and thus the participant’s score, for that domain. The 
PROMIS CAT item banks for a domain typically involve 4-12 items. The first item administered 
is usually in the middle of the range of function or severity for that domain. After a participant 
responds, an estimated score is calculated. The PROMIS CAT algorithm then selects the best item 
in the item bank for refining the estimated score, and recalculates the participant’s score as they 
continue responding. The PROMIS CAT continues to administer items until a specified level of 
measurement precision is reached, or the maximum number of 12 items per measure have been 
administered. Studies have shown that the average number of items delivered in a CAT domain is 
5-8.71 
 
 
2.6.3. Lee Chronic GVHD Symptom Scale 
 
The Lee chronic GVHD symptom scale (LSS) is a 30 item measure with 7 domains referent to the 
past 7 days: skin, mouth, eye, lung, psychoemotional, vitality and nutrition.72 Responses are 
captured on a five-point Likert scale (“no symptoms, or not bothered at all”, “slightly bothered,” 
“moderately bothered,” “bothered quite a bit,” or “extremely bothered”).  Scores for each domain 
are converted to a 0-100 scale where higher scores indicate more bother. The LSS has distinguished 
between people with different severities of chronic GVHD68 and been used in randomized clinical 
trials to show difference in treatment arms.73,74 Although patients will not have chronic GVHD 
before transplant, we will still administer the instrument at baseline to capture any pre-existing 
symptoms and aid in interpreting post-transplant scores. Participants aged 12 and older will 
complete the LSS. 
 
2.6.4. Occupational Functioning 
 
Occupational functioning was measured in the NHLBI T-cell depleted trial 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.60,73 Only 
adults will complete the occupational functioning items. 
 
2.6.5. Sociodemographic Data  
 
Sociodemographic data are collected from adults in the QOL Substudy on the pre-transplant survey 
only: education, income, marital status, and religiosity. Zip code will be available from the 
TED/CRFs. Contact information including email address, cell phone numbers and alternate 
contacts will also be collected. Only adults will complete the sociodemographic questions. 
 
 
 

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Adult instruments (aged 18 and over at time of assessment) 
Instrument 
Description 
Number of items 
Estimated 
Time to 
complete 
Paper 
Electronic 
PROMIS Global 
Overall evaluation of one’s 
physical and mental health 
10 
10 
2-3 minutes 
PROMIS Physical 
function domain 
Self-reported capability rather than 
actual performance of physical 
activities. This includes the 
functioning of one’s upper 
extremities (dexterity), lower 
extremities (walking or mobility), 
and central regions (neck, back), as 
well as instrumental activities of 
daily living, such as running 
errands.  
4 
4-12 
1-2 minutes  
 
 
 
PROMIS Anxiety 
domain 
Fear (fearfulness, panic), anxious 
misery (worry, dread), 
hyperarousal (tension, nervousness, 
restlessness), and somatic 
symptoms related to arousal (racing 
heart, dizziness).     
4 
4-12 
1-2 minutes 
PROMIS 
Depression domain 
Negative mood (sadness, guilt), 
views of self (self- criticism, 
worthlessness), and social 
cognition (loneliness, interpersonal 
alienation), as well as decreased 
positive affect and engagement 
(loss of interest, meaning, and 
purpose).   
4 
4-12 
1-2 minutes 
PROMIS Fatigue 
domain 
Range of symptoms, from mild 
subjective feelings of tiredness to 
an overwhelming, debilitating, and 
sustained sense of exhaustion that 
likely decreases one’s ability to 
execute daily activities and 
function normally in family or 
social roles.     
4 
4-12 
1-2 minutes 
PROMIS Sleep 
disturbance domain 
Perceptions of sleep quality, sleep 
depth, and restoration associated 
with sleep.            
4 
4-12 
1-2 minutes 
PROMIS Ability to 
participate in social 
roles and activities 
domain 
Perceived ability to perform one’s 
usual social roles and activities.     
4 
4-12 
1-2 minutes 
PROMIS Pain 
interference domain 
Consequences of pain on relevant 
aspects of one’s life. This includes 
the extent to which pain hinders 
engagement with social, cognitive, 
emotional, physical, and 
recreational activities.        
4 
4-12 
1-2 minutes 

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Instrument 
Description 
Number of items 
Estimated 
Time to 
complete 
Paper 
Electronic 
PROMIS pain 
intensity 
How much a person hurts 
1 
1-3 
< 1 minute 
Lee Chronic 
GVHD Symptom 
Scale 
How much symptoms of skin, 
mouth, eye, lung, psychoemotional, 
vitality and nutrition bother the 
patient 
30 
30 
2-3 minutes 
Occupational 
Functioning 
Job status, type of work, amount of 
work 
6 
6 
1-2 minutes 
Sociodemographic 
At Baseline only. Education, 
income, marital status, religiosity 
5 
5 
1-2 minutes 
TOTAL 
 
         80 
80-138 
14-27 minutes 
 
Pediatric instruments (patients 8-17 at time of assessment) 
Instrument 
Description 
Number of items 
Estimated 
Time to 
complete 
Paper 
Electronic 
PROMIS Global 
Overall evaluation of one’s physical 
and mental health 
9 
9 
2-3 minutes 
PROMIS Physical 
function mobility 
domain 
Activities of physical mobility such 
as getting out of bed or a chair to 
activities such as running. 
4 
4-12 
1-2 minutes  
PROMIS Anxiety 
domain 
Fear (fearfulness, panic), anxious 
misery (worry, dread), hyperarousal 
(tension, nervousness, restlessness), 
and somatic symptoms related to 
arousal (racing heart, dizziness). 
4 
4-12 
1-2 minutes 
PROMIS 
depressive 
symptoms domain 
Negative mood (sadness, guilt), 
views of self (self- criticism, 
worthlessness), and social cognition 
(loneliness, interpersonal alienation), 
as well as decreased positive affect 
and engagement (loss of interest, 
meaning, and purpose).  
4 
4-12 
1-2 minutes 
PROMIS Fatigue 
domain 
Range of symptoms, from mild 
subjective feelings of tiredness to an 
overwhelming, debilitating, and 
sustained sense of exhaustion. 
 
4 
4-12 
1-2 minutes 
PROMIS Peer 
relationships 
domain 
Quality of relationships with friends 
and other acquaintances. 
4 
4-12 
1-2 minutes 
PROMIS Pain 
interference 
domain 
Consequences of pain on relevant 
aspects of one’s life. This includes 
the extent to which pain hinders 
engagement with social, cognitive, 
emotional, physical, and recreational 
activities. 
 
4 
4-12 
1-2 minutes 
PROMIS pain 
intensity domain 
How much a person hurts 
1 
1 
< 1 minute 

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Instrument 
Description 
Number of items 
Estimated 
Time to 
complete 
Paper 
Electronic 
Lee Chronic 
GVHD Symptom 
Scale (age 12+) 
How much symptoms of skin, mouth, 
eye, lung, psychoemotional, vitality 
and nutrition bother the patient 
30 
30 
2-3 minutes 
TOTAL 
 
64 
64-112 
11-19 minutes 
 
 
2.7. Participant Risks 
 
The majority of the physical risks are related to the transplant itself, a treatment which the 
transplant center has already deemed appropriate for the participant. Patients and their doctors 
make treatment decisions including donor source, timing of transplant, conditioning regimen 
intensity and GVHD prophylaxis. The risks of transplant will be determined by the transplant 
care plan.   
 
The intervention being applied in this study is a biologic assignment variable, i.e., the use of the 
donor search prognosis to guide the donor search strategy, is not per se being tested. Rather, it is 
being used to classify participants into two groups, those Very Likely and those Very Unlikely to 
find a MUD, for comparison. A center is not allowed to enroll a patient in the trial until they 
attest that the protocol’s donor search algorithm that uses the donor search prognosis is 
appropriate for the patient. The primary risk of participation in the study is the possibility that the 
donor search algorithm suggested by the donor search prognosis will be misleading for 
individual patients, i.e., a Very Likely to find a MUD patient may not find a matched unrelated 
donor, or conversely, a Very Unlikely to find a MUD patient may be able to identify a matched 
unrelated donor. Centers should use clinical judgment in these cases to deviate from the intended 
donor source based on the participant’s best interest. For children, the risks of this protocol 
would be the same as for adults. 
 
No sensitive psychosocial or medical data will be collected from medical records. The risks of 
the QOL Substudy are anticipated to be minimal. Completion of patient-reported outcomes is 
unlikely to cause distress, as these surveys have been administered to thousands of patients 
without complaint and they do not ask sensitive questions. Collection of research blood samples 
in the QOL Substudy is contingent on securing additional funding. If this aspect of the protocol 
is activated, additional risks to participants in the QOL Substudy include bruising and fainting. 
The small amount of blood taken is not expected to affect blood counts. 

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CHAPTER 3 
 
 
3. 
ENDPOINTS 
 
3.1. Primary Endpoint 
 
The primary endpoint for this study is survival from the time the center declares that no suitable 
matched family member is available and the patient is considered evaluable. Survival is analyzed 
as time to event with survivors censored at last follow up or 2 years, whichever is earlier. 
3.2. Secondary and Post-transplant Endpoints  
 
3.2.1. Transplantation Rate 
 
Receipt of a transplant is defined as starting conditioning, whether or not the stem cell graft is 
infused.  
3.2.2. Barriers to Transplantation 
 
Reasons for delay or cancellation of the transplant, as collected on the donor tracking form, will 
be summarized by search prognosis category and reported descriptively.  
 
3.2.3. Relapse 
 
Relapse criteria for the different malignant diseases will be according to the CIBMTR data 
dictionary. 
3.2.4. Disease-free Survival  
 
Disease-free survival is defined as the time from the date of graft infusion to the date of recurrent 
disease or death from any cause, whichever comes first in patients with malignant disease.  
Observation is censored at the date of last follow-up for patients known to be alive without 
malignancy.   
3.2.5. Treatment-related Mortality 
 
Treatment-related mortality is defined as death without prior relapse in patients with malignant 
disease. Relapse is considered a competing risk. 
 
3.2.6. Acute GVHD 
 
Grade II-IV and III-IV acute GVHD will be reported.  Acute GVHD grade will be calculated from 
the center-reported organ scores using current CIBMTR approaches. 
3.2.7. Chronic GVHD 
 

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Any chronic GVHD as reported by the center will be reported. 
 
3.3. Endpoints for the QOL Substudy 
 
All patients on the QOL Substudy will have their transplant data collected on CRFs, which will 
capture all of the planned endpoints except for QOL. 
3.3.1. Chronic GVHD 
 
Moderate and severe chronic GVHD will be defined per the NIH consensus criteria.75 
3.3.2. Time Until Off Immunosuppression for Patients Diagnosed with Chronic GVHD 
 
Defined as the time since chronic GVHD onset until all systemic immunosuppression given for 
chronic GVHD treatment is discontinued. Continuation of low dose steroids for adrenal 
insufficiency (5 mg or less of prednisone or 0.1 mg/kg prednisone for children < 18 years old) is 
not considered systemic immunosuppression. Extracorporeal photopheresis and PUVA are 
considered systemic immunosuppression. 
3.3.3. GVHD, relapse-free survival (GRFS) 
 
Events for GRFS include grade III-IV acute GVHD, chronic GVHD requiring systemic 
immunosuppression, relapse or death.  
3.3.4. Moderate-severe Chronic GVHD, Relapse-free Survival (CRFS) and Current CRFS 
 
Events for CRFS include moderate-severe chronic GVHD, relapse or death. Current CRFS will 
also be calculated, defined as the prevalence of moderate-severe chronic GVHD requiring systemic 
immunosuppression for treatment of GVHD, disease-free survival, considering chronic GVHD, as 
a potentially reversible complication if systemic immunosuppression is stopped. Although relapse 
may be treated and the patient placed back in remission, relapse will not be considered a reversible 
state. 
3.3.5. Primary Graft Failure 
 
Primary graft failure is defined among patients surviving at least 28 days after graft infusion as 
failure to achieve a post-nadir absolute neutrophil count of >500 cell/µL for 3 days or donor 
peripheral blood T-cell chimerism of at least 5%. If T-cell chimerism is not available, testing of 
unsorted blood or marrow is acceptable.  
 
3.3.6. QOL 
 
Summary and subscales of QOL instruments will be scored according to the recommendations of 
the developers. The primary QOL endpoint is the global physical health scale from the PROMIS 
Global 10. Secondary QOL endpoints are the LSS chronic GVHD summary score and the 
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and depression, and chronic GVHD subscales will be described but are not expected to differ 
substantially or to have enough power to detect differences. 
 
3.3.7. Hospital Days 
 
Number of hospital days within the first 100 days will be collected on CRFs. The CIBMTR forms 
do not distinguish ICU days from regular hospitalization days. We are not able to collect 
departmental costs due to the differing accounting systems and rules at institutions. 
3.3.8. Infections 
 
Clinically significant viral, fungal, bacterial, and parasitic-defined infections will be reported by 
pathogen, site of disease, and date of onset from the CIBMTR CRF Form 2100 at 100 day, 6 
months, 1 year and 2 years after transplant. If no clinically significant infections have occurred, 
the absence of infection will be reported.  Reporting of certain specific fungal and viral infections 
will trigger subsequent forms in order to capture more detailed information. Please refer to the 
CIBMTR forms instruction manual for more details.  
 
3.3.9. Immune Reconstitution 
 
CIMBTR CRFs will collect data about neutrophil and lymphocytes counts, immunoglobulin 
subsets and T-cell/B cell numbers, if available. If additional funding is obtained, peripheral blood 
will be collected for immune reconstitution studies for the QOL Substudy at the following time 
points: pre-transplant and up to 6 times over the first two years after transplant. Thirty milliliters 
will be drawn at each time point for research tests. Participants in the QOL Substudy will be 
consented to these research blood draws at the time of enrollment, but no sampling will be 
performed until additional funding is obtained and the protocol is modified to reflect activation of 
the research blood draws.  
 
3.3.10. Late Effects 
 
Late effects are captured on the CIBMTR CRFs, and include selected cardiac, pulmonary, renal, 
metabolic, endocrine and other late complications. 
  
 
 
 

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CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
 
1. Patients may be screened for basic eligibility criteria without informed consent based on a 
waiver for screening. A screening log will capture all patients screened and their study 
disposition, e.g., enrolled, reasons they were not approached, etc. 
2. The study is described to potentially eligible patients. The background, rationale and study 
requirements are discussed. Patients are given time to ask questions and consider whether 
they wish to participate. After the patient has given informed consent to participate on the 
study, an authorized user at the transplant center completes the BMT CTN 1702 
Registration Form.  
3. Once a patient is deemed evaluable by virtue of no suitable HLA-matched family donor 
(or 1 allele or antigen mismatched family donor if that is the center’s practice), NMDP 
Immunogenetic Operations sends the donor search prognosis and preliminary search 
information to the Center. A Donor Search Tracking form is started. 
4. Almost all of the post-transplant outcomes data for this study will be collected through the 
CIBMTR.  If a participant proceeds to transplant, centers must obtain a CIBMTR Research 
Identification (CRID) number and enter it on the BMT CTN 1702 Segment A CIBMTR 
Research ID Form (see CIBMTR Data Collection below). 
 
4.1.2. Evaluations at Enrollment 
 
Data collected when consent is signed include the following: 
 
1. Patient age, sex, patient-identified race and ethnicity 
2. Disease and disease stage 
3. Number of full siblings 
4. Number of other first degree relatives 
5. Date HLA typing sent, both low resolution and high resolution 
4.1.3. Evaluations at Evaluability 
 
A new form (BMT CTN Donor Source Tracking, see Study Procedure and Guidance Manual) will 
be started once a center determines that an alternative donor is required. The form will be updated 
at least monthly to provide information until conditioning for transplant starts, or the search for a 
donor is no longer active (survival will be captured on this form until the patient either goes to 
transplant, dies, or the study ends). The form will collect detailed data about the donor 

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identification process to understand clinical decision-making relevant to donor choice. Upon 
initiation of the Donor Source Tracking form, the NMDP will provide the donor search prognosis.  
 
Key data collected include: 
1. Initial preferred alternative donor source (priority ranking at enrollment): A rank list of 
preferred donors with “1” indicating the preferred alternative donor and descending. If a 
donor type would not be used, “0” should be entered. Options include: matched unrelated 
donor, mismatched unrelated donor, haploidentical family member donor (i.e. >2 allele 
mismatch), cord blood, or combinations of donors such as haploidentical + cord blood. For 
patients in the Very Likely to find a MUD group, this form will define the donor choice if 
a matched unrelated donor is not identified. For patients in the Very Unlikely to find a 
MUD group, it will identify the preferred donor among haploidentical, cord blood or 
mismatched unrelated donor. For the Less Likely to find a MUD group, it will capture the 
search algorithm planned by the center in the absence of protocol guidance. 
2. Target time to transplant (# of weeks to infusion) 
3. Patient weight 
4. Confirmation of patient-defined race and ethnicity 
5. Current patient diagnosis and disease stage, date of diagnosis 
6. Date of patient and full sibling typing 
7. Patient HLA typing and NMDP Recipient ID  
8. Results of any special testing and dates 
9. Date final donor selected 
10. Reasons for delay or cancellation of transplantation. 
 
See Study Procedure and Guidance Manual for the full list of collected variables. For patients who 
are never transplanted, this form will also capture survival information. 
 
4.1.4. Donor Search and Identification 
 
Once the patient is deemed evaluable, the transplant center transmits the high resolution HLA 
typing to the NMDP Immunogenetic Program who will prepare a report within 2 business days 
and send the information back to the center. Once the donor search prognosis information and 
preliminary search summary have been received and reviewed by the Center, the transplant 
coordinators at the transplant center should proceed with their institution’s standard procedure to 
identify a donor including additional family member typing and/or initiation of an unrelated donor 
and/or cord blood search. Updates on patient and search status will be requested at least monthly 
after enrollment, and include any revision to the donor priority ranking and rationale for changes. 
Details of the final donor selection and donation schedule will be captured. Guidance on the search 
is provided in the Study Procedure and Guidance Manual. 
 
4.2. Methodology and Documentation of Study Events 
 

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4.2.1. Approaching Patients, Eligibility, Screening, and Obtaining Consent 
 
Subjects may be approached for this study from the time when they are considered to be potential 
allogeneic HCT candidates through when the determination that no suitable HLA-matched or 1 
allele or antigen mismatched related donor is available. For centers who see patients for a 
transplant consult then do not see them again until a donor has been identified, consent may happen 
as soon as HLA-typing is sent. For centers that will see potential participants more frequently 
before transplant, consent may also take place once it is determined there is no suitable HLA-
matched or single mismatched related donor.  Eligible patients willing to participate in the study 
will sign an Institutional Review Board (IRB) approved consent form for this protocol. Parents or 
legal guardians will consent for minors, and minors will provide assent per local institutional 
guidelines. 
 
If patients are determined to have a suitable HLA-matched or 1 allele or antigen mismatched 
related donor (i.e. <1 mismatch; 7+/8 HLA-A, B, C, DRB1) who will serve as the donor, they are 
not considered evaluable for this study.  
 
4.3. Study Monitoring 
 
4.3.1. Transplant Data 
 
Transplant outcome data will be collected on CIBMTR forms. Whether or not a patient participates 
in BMT CTN 1702, centers must register pre- and post-transplant clinical data on all consecutive 
HCTs done at their institution through the CIBMTR, which holds the contract for the US Stem 
Cell Therapeutic Outcomes Database (SCTOD) charged with collecting data on US allogeneic 
HCTs.  Registration is done using procedures and forms of the SCTOD.  (Note: Federal legislation 
requires submission of these forms for all US alloHCT recipients.)  Enrollment on BMT CTN 1702 
must be indicated on the SCTOD pre-transplant registration form. Assignment to the TED or CRF 
track will not be affected by participation in BMT CTN 1702, unless patients are eligible for the 
QOL Substudy in which case all will be assigned to the CRF track. If they consent to QOL data 
collection, this information will be collected using CIBMTR supplemental forms. 
 
4.3.2. Collection of QOL Data 
 
At the time a patient is identified as participating in the QOL Substudy, the CIBMTR Survey 
Research Group (SRG) is notified and then adds that patient to CIBMTR’s electronic Patient 
Reported Outcomes (ePRO) system for long-term QOL tracking. 
 
Pre-transplant (baseline) QOL data will be collected by the center or CIBMTR electronically or 
on paper forms within 4 weeks of the start of conditioning. If conditioning is delayed, the QOL 
surveys should be repeated so they are within 4 weeks of conditioning. Electronically-collected 
baseline QOL surveys will be entered in the ePRO system. The center will securely email or fax 
baseline QOL instruments completed on paper to the SRG to enter into their ePRO system. Along 
with the pre-transplant QOL instruments, the center will securely email or fax a patient contact 
information form so that the SRG can reach the patient for 1, 2 and 5 year QOL time points.  
 

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The SRG will administer the 1, 2 and 5 year QOL instruments online, or on paper if requested by 
the patient. They will first confirm the patients’ status with the transplant center because reporting 
of deaths may lag. They will then contact the patient via email, phone or mail to collect the QOL 
information online or on paper.  
• 1 year +/- 2 months 
• 2 years +/- 2 months 
• 5 years +/- 3 months [funded and performed under a separate protocol] 
At the conclusion of each QOL administration, patients will be reminded of the next date of 
contact.  The SRG will notify the transplant center if a patient’s contact information has changed 
or if they find through follow-up that the patient has died. 
 
4.3.3. Locating Missing Patients 
 
If patients cannot be located through the contact information provided, or through the transplant 
center, then the SRG will request the NMDP Call Back Unit to conduct a paid search for new 
contact information using Accurint, a government website accessible to only those with 
permission.  Patients give their permission for the SRG to conduct this paid search when they sign 
the informed consent. 
 
4.3.4. Adverse Event Reporting 
 
Only adverse events related to the study consent process, collection of the optional research blood 
samples, or completing QOL surveys will be reported.  Since no other therapy is mandated in this 
study, adverse events associated with transplantation or non-transplantation will not be collected 
nor reported for this protocol.  
 
4.4. Research Samples Pre-transplant and Post-transplant  
 
If additional funding is obtained, peripheral blood samples (30 mL blood) will be collected from 
patients on the QOL Substudy pre-transplant and up to 6 times within the next 2 years after 
transplant. The study protocol will be modified prior to sample collection to specify the time points 
and additional information but participants will not have to be reconsented. 
 

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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. Study Overview 
This study is designed as a multicenter prospective study to assess outcomes of alternative donor 
search prioritizations and transplants, for patients with AML, ALL, MDS, NHL, HL, AA, or SCD 
who are considered eligible for a transplant within the next 6 months.  Patients who consent are 
considered evaluable once the center determines no suitable HLA-matched or 1 allele or antigen 
mismatched related donor is available and the center confirms the patient is still transplant eligible.   
 
The primary objective is to estimate and compare the overall survival between two arms: patients 
who are Very Likely to find a MUD, who will pursue a fully matched unrelated donor, versus 
those who are Very Unlikely to find a MUD, who will pursue a haploidentical, cord blood, or 
mismatched unrelated donor.  Patients who are Less Likely to find a MUD will be enrolled but not 
analyzed for the primary endpoint because there isn’t agreement on whether a matched unrelated 
donor should be pursued first. Additional secondary endpoints look at the cumulative incidence of 
receiving a transplant and reasons for not receiving a transplant, as well as post-transplant 
outcomes in those who receive a transplant by search prognosis arm and by type of transplant 
received.  An additional QOL substudy will examine post-transplant outcomes of a smaller, more 
homogeneous subgroup with more detailed data collection on chronic GVHD, QOL, infections, 
and immune reconstitution.   
 
5.1.1. Accrual 
 
Based on historical CIBMTR data from 2016 for the diseases included in this study, there were 
3133 HCTs from alternative donors, including 2013 from matched unrelated donors, 653 HCTs 
from haploidentical relatives, 201 from mismatched unrelated donors and 266 cord blood 
transplants at Core and non-Core BMT CTN centers. Assuming 50-70% of patients slated for 
unrelated donor transplantation actually undergo transplantation, there are potentially 4500-6000 
transplant candidates per year.  Assuming 15% of these patients participate in the trial, and 60% 
of these are in the Very Likely or Very Unlikely to find a MUD groups, we would be able to accrue 
between 400-540 patients per year who are eligible for the primary analysis.  Based on these 
assumptions and accounting for variable time to open protocols at participating centers, it is 
estimated that approximately 3 years of accrual are necessary to enroll the targeted sample size for 
the primary analysis.    
 
5.2. Sample Size and Power Calculations 
 
Sample size requirements for this study are based on enrolling sufficient patients to have adequate 
power for the primary analysis, which is to compare the overall survival between patients who are  
Very Likely to find a MUD vs. those who are Very Unlikely to find a MUD, starting at the time 
of evaluability for the study when a center confirms that there is no suitable matched or 1 allele or 
antigen mismatched related donor.  We assumed baseline survival probabilities for patients who 
are in the Very Likely to find a MUD group would be approximately 30% at 2 years, since 

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approximately half are expected to make it to transplant, and most patients who do not make it to 
transplant are not expected to survive past 2 years.  Calculations use a log-rank test with a two-
sided significance level of 5% for the primary comparison of the Very Likely vs. Very Unlikely to 
find a MUD groups.  We account for approximately 5% exponential rate of loss to follow-up per 
year, and we assume 3 years of accrual, total study time of 4.5 years (or 18 months after last 
evaluable patient enrolled when the primary analysis is conducted), and we censor all patients at 
2 years since few events are expected to occur after 2 years.  We assume that the sample size ratio 
between MUD Very Likely and MUD Very Unlikely donor search prognosis is 2.5 to 1, based on 
preliminary data.  The targeted total sample size of n=1022 (n=730 MUD Very Likely; n=292 
MUD Very Unlikely donor search prognosis) patients would provide >85% power to detect a 
Hazard Ratio (HR) of 0.76, corresponding approximately to a 10% improvement in overall 
survival at two years for either group. Although preliminary data suggest a <5% survival difference 
between matched URD and haploidentical transplants (Steve Devine, personal communication), 
we assume that patients having haploidentical donor transplant are able to proceed to transplant 
earlier and thus have higher transplantation rates and better overall survival in an intention-to-treat 
analysis. We are using a two-sided test of the primary endpoint because we do not want to miss 
the possibility that matched URD recipients have better survival. 
 
The targeted sample size for the Very Likely to find a MUD and Very Unlikely to find a MUD 
patients is based on the ratio of patients who are Very Likely to find a MUD to patients who are 
Very Unlikely to find a MUD . This number will be monitored throughout the study and the sample 
size may be increased or decreased depending on the ratio of Very Likely to Very Unlikely to find 
a MUD patients; potential increases in sample size are shown in the table below.   
 
  
Sample size ratio (MUD Very Likely DSP vs. MUD Very Unlikely DSP) 
  
2.5 to 1 
1.5 to 1 
1 to 1 
2 yr OS 
(Very 
Likely 
DSP) 
80% 
power 
85% 
power 
90% 
power 
80% 
power 
85% 
power 
90% 
power 
80% 
power 
85% 
power 
90% 
power 
30% 
889 
1022 
1190 
745 
850 
995 
702 
802 
938 
40% 
1001 
1148 
1344 
835 
955 
1115 
786 
898 
1052 
DSP = donor search prognosis 
 
 
 
 
While the targeted sample size for the power calculation is based on the primary comparison 
between patients who are Very Likely and patients who are Very Unlikely to find a MUD, we will 
also concurrently enroll patients who are Less Likely to find a MUD for analysis of secondary 
research questions (expected to be approximately 40% of all eligible patients, or n=710).   
 
5.3. Interim Analysis and Stopping Guidelines 
 
No interim analysis or stopping guidelines for efficacy or futility are planned for this study.  We 
will review the study design assumptions, particularly the ratio of patients who are Very Likely to 
find a MUD vs. patients who are Very Unlikely to find a MUD and percentage proceeding to 
transplant, on a periodic basis, and may adjust the sample size if needed to maintain power in the 
event that our assumptions are incorrect.  In order to ensure safety of patients who are Very 

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Unlikely to find a MUD who are biologically assigned to prioritize an alternative donor for 
transplant to improve likelihood of transplant, we will monitor a key safety endpoint of overall 
mortality within 100 days post transplant in the Very Unlikely to find a MUD group.  Details of 
this safety monitoring are below. 
 
 
5.3.1. Guidelines for Safety Monitoring 
 
Monitoring of a key safety endpoint of post transplant mortality will be conducted monthly to 
ensure that the donor selection recommendations for the Very Unlikely to find a MUD group are 
not leading to significantly lower than expected post transplant outcomes.  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 guideline serves as trigger for consultation with the DSMB for additional review. 
 
The key safety endpoint for this study is mortality post transplant.  The rate of mortality will be 
monitored up to 100 days post-transplant, and only Very Unlikely to find a MUD patients who are 
transplanted will be included in this monitoring rule, which is designed to minimize the likelihood 
risk that patients are exposed to a risk of early mortality that is higher than would be expected with 
match unrelated donor transplantation.  Monitoring will be applied to two separate cohorts, defined 
by malignant vs. non-malignant disease.  Monitoring will be performed monthly beginning when 
at least 3 patients are evaluable for the monitoring rule (died or been followed for at least 100 days 
post transplant), until enrollment is closed.  At least three deaths must be observed, along with 
crossing of a stopping boundary as described below, in order to trigger referral to the DSMB for 
further review. The expected probability of 100 day mortality is <=15% for malignant disease and 
<=10% for nonmalignant disease, based on CIBMTR data for HLA-identical unrelated donor 
transplantation. Each month, the null hypothesis that the 100-day mortality rate is less than or 
equal to a specified probability (10% for nonmalignant disease, 15% for malignant disease) is 
tested.  An extension of the sequential probability ratio test (SPRT) for censored exponential data 
will be used for monitoring, as described in greater detail below and in Appendix E. 
 
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations separately for both malignant and nonmalignant disease cohorts.  The SPRT can be 
represented graphically.  At each monthly interim analysis, the total time on study (e.g. in months 
or years, x axis) is plotted against the total number of endpoints (e.g., patients experiencing death, 
y axis).  The continuation region of the SPRT is defined by two parallel lines.  Only the upper 
boundary will be used for monitoring to protect against excessive 100-day mortality.  If the graph 
falls above the upper boundary, the SPRT rejects the null hypothesis, and concludes that there are 
more events than predicted by the observed time on study.  Otherwise, the SPRT continues until 
enrollment is closed. 
 
This procedure assumes a censored exponential distribution for the time until death during the first 
100 days, and censors follow-up time after 100 days.  Only deaths that occur on or before the 
patient has been followed for 100 days are counted.  Total time on study is computed as time from 
transplant to death, or to 100 days, whichever comes first, summed for all patients on study. 
 

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The usual measures of performance of an SPRT are the error probabilities α and β of rejecting H0 
when θ = θ0 and of accepting H1 when θ = θ1, respectively, and the expected sample size E(N|θi).  
The tests to be used in this protocol were developed from the following SPRTs:   
• Malignant disease: A SPRT contrasting 15% versus 25% 100-day rate of mortality results 
in decision boundaries with a common slope of 0.067 and an upper intercept of 4.372, with 
nominal type I and II errors of 7% and 15%, respectively. 
• Non-malignant disease: A SPRT contrasting 10% versus 30% 100-day rate of mortality 
results in decision boundaries with a common slope of 0.063 and an upper intercept of 
1.938, with nominal type I and II errors of 8% and 15%, respectively. 
 
The actual operating characteristics of the truncated tests, shown in Table 5.3a and 5.3b for the 
malignant and non-malignant cohorts respectively, were determined in a simulation study that 
assumed uniform accrual of 292 Very Unlikely to find a MUD individuals (approximately 260 
malignant and 32 nonmalignant) over a three-year time period, and exponential time to failure 
after transplant.  Deviations from these expected distributions of malignant vs. nonmalignant 
sample sizes may lead to small changes in the rejection probabilities and other operating 
characteristics.   
 
TABLE 5.3a:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
  
Day 100 MORTALITY (MALIGNANT COHORT) 
 
True 100-Day Rate 
15% 
20% 
25% 
Probability Reject Null 
0.053 
0.523 
0.963 
Mean Month Stopped 
37.9 
27.5 
13.7 
Mean # Endpoints in 100 Days 
37.6 
36.3 
21.9 
Mean # Patients Enrolled 
251.2 
187.1 
98.3 
 
For example, the testing procedure for the malignant cohort rejects the null hypothesis in favor of 
the alternative 5% of the time when the true 100-day mortality rate is 15%, and 96% 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 = 0.04.  When the true 100-day mortality rate is 25%, on average, the DSMB will be consulted 
14 months after opening, when 22 events have been observed in 98 patients. 
 

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 TABLE 5.3b:  OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FROM A SIMULATION STUDY WITH 10,000 REPLICATIONS 
  
Day 100 MORTALITY (NON-MALIGNANT COHORT) 
 
True 100-Day Rate 
10% 
20% 
30% 
Probability Reject Null 
0.049 
0.428 
0.853 
Mean Month Stopped 
38.1 
30.4 
19.6 
Mean # Endpoints in 100 Days 
3.1 
5.0 
4.9 
Mean # Patients Enrolled 
31.1 
25.5 
17.3 
 
For example, the testing procedure for the non-malignant cohort rejects the null hypothesis in favor 
of the alternative 5% of the time when the true 100-day mortality rate is 10%, and 85% of the time 
when the rate is 30%.  This corresponds to a type I error rate of α = 0.05 and a type II error rate of 
β = 0.15.  When the true 100-day mortality rate is 30%, on average, the DSMB will be consulted 
20 months after opening, when 5 events have been observed in 17 patients. 
  
5.4. Analysis Populations 
 
Primary Analysis Population: The primary analysis population will include all patients registered 
who meet study eligibility, do not have a suitable matched or 1 allele or antigen mismatched family 
donor, and who are Very Likely to find a MUD or are Very Unlikely to find a MUD.  Outcomes 
will be analyzed according to the donor search prognosis, regardless of the alternative donor 
prioritized, as an Intention-to-Treat analysis.  Outcomes will be measured from the time the patient 
is deemed evaluable by virtue of needing to pursue alternative donors.   
Less Likely to find a MUD group: Patients who are registered and meet study eligibility but have 
a donor search prognosis of Less Likely to find a MUD will not be included in the primary analysis 
population, but rather will be analyzed separately in a descriptive analysis, both overall and 
according to the specified alternative donor preference.  Outcomes will be measured from the time 
the patient is deemed evaluable.   
Transplant population: Several secondary analyses will be done on the subset of patients in all 
three search prognosis groups who receive a transplant.  Here patients will be analyzed according 
to both their initial search prognosis score and by the type of alternative donor transplant received, 
and outcomes will be measured from the time of transplant. Outcomes will be measured from the 
start of transplant.   
QOL Substudy population: A substudy will be conducted on a homogeneous group of AML and 
ALL patients who are transplanted in first complete remission and early stage MDS patients, in 
order to collect more detailed post-transplant outcome data.  Based on the eligibility for the QOL 
Substudy and transplant activity in 2016, we anticipate having 286 patients across the 3 search 
prognostic groups. This estimate is based on an enrollment of 1732 evaluable patients, 50% of 
whom are transplanted and 33% of those meet the eligibility criteria for the Substudy. Patients will 
be analyzed according to the type of alternative donor transplant received (matched unrelated 
donor vs. haploidentical), and outcomes will be measured from the time of transplant. These 

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analyses will be exploratory in nature, and hypothesis-generating for future studies. Although these 
are primarily exploratory analyses, we calculated the detectable mean difference with 85% power 
in the physical subscale of the PROMIS global health measure to be 5.1.  This assumes that 90% 
of the 286 patients would have baseline QOL, 60% would be alive at 2 years, and 70% of those 
would have complete 2 year QOL data, for an evaluable sample size of n=108.  It is based on a 
two-sample t-test with two-sided significance level of 5%, standard deviation of 8, and a sample 
size ratio of 2.5 to 1.   
 
5.5. Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for each of the analysis 
populations.  Characteristics to be examined for the primary analysis population and Less Likely 
to find a MUD group are: age, race/ethnicity, socioeconomic status as determined by zip code, 
disease (including known high risk cytogenetics or molecular markers), disease stage and duration, 
performance score, number of siblings, preferred alternative donor, and transplant center. 
Characteristics to be examined for the transplant population also include disease risk index, donor 
type, graft source (peripheral blood vs. bone marrow vs. cord blood), donor age and gender, CMV 
matching, co-morbidity index, time to transplant, preferred alternative donor identified, preferred 
alternative donor available, transplant center.  Characteristics of interest for the QOL Substudy 
include: all of the variables listed above plus baseline QOL, and self-reported socioeconomic 
status. 
 
5.6. General Analysis Considerations 
 
As this is a biologic assignment study where there may be potential biases in donor search 
prognosis groups or alternative donor transplant groups being compared, all analysis will include 
summary univariate measures as well as multivariate analyses whenever feasible with sufficient 
numbers to adjust for confounding.  Proportional hazards assumption will be assessed for all Cox 
models using graphical methods or time-dependent covariates.  Interactions between patient 
characteristics and donor search prognosis group or alternative donor transplant group will also be 
investigated but will be considered exploratory.   
 
5.6.1. Analysis of the Primary Endpoints 
 
The primary endpoint of the trial is overall survival from the time of evaluability determination in 
the primary analysis population, analyzed according to the donor search prognosis group (Very 
Likely vs. Very Unlikely to find a MUD), in an intent-to-treat fashion. The primary null hypothesis 
of the study is that there is no difference in overall survival between the Very Likely and Very 
Unlikely to find a MUD groups. Because of the potential bias resulting from this biologic 
assignment mechanism (using donor search prognosis as a surrogate for prioritization of 
alternative donor types),76 the comparisons of overall survival between groups will be done using 
a Cox proportional hazards model adjusted for the following pre-specified patient characteristics: 
age, sex, race, ethnicity, disease, and disease stage, if applicable.  A Cox model stratified on 
alternative donor type will be used to provide adjusted overall survival probabilities at two years 
for each alternative donor type, using the method of Zhang et al.77 It is not possible to adjust this 

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model for co-morbidities or disease risk index because this information is not available for all 
patients in the intention-to-treat analysis.  
 
5.6.2. Analysis of Secondary Endpoints for Primary Analysis Population 
 
Transplantation 
 
Cumulative incidence of transplant, treating death prior to transplant as a competing risk, will be 
plotted over time for each donor search prognosis group as a descriptive summary, and will be 
compared between the groups using a Fine-Gray model, adjusting for the following pre-specified 
patient characteristics at the time of registration: age, sex, race, ethnicity, disease and disease stage.  
Adjusted cumulative incidence curves using the method of Xu and Zhang may also be provided to 
supplement the univariate estimates.78 This analysis will be conducted as early as 6 months after 
the last evaluable participant is enrolled, since this analysis will not affect the primary endpoint. 
 
Barriers to Transplantation 
 
Barriers to transplantation will be summarized with descriptive statistics (number, frequencies) in 
each group, and compared between groups using chi-square tests. This analysis may be conducted 
as early as 6 months after the last participant is enrolled, since this analysis will not affect the 
primary endpoint. 
 
5.6.3. Analysis of Secondary Endpoints for Less Likely to find a MUD Population 
 
Cumulative incidence of transplant, Kaplan-Meier estimates of overall survival, and descriptive 
summaries of frequencies of barriers to transplantation will be provided both overall and by 
alternative donor preference group.    
 
5.6.4. Analysis of Secondary Endpoints for Transplant Population 
 
Overall Survival (OS) 
 
OS will be analyzed in the transplant population, and in the patients enrolled in the QOL Substudy.  
OS will be summarized in each alternative donor group using the Kaplan-Meier estimate, and 
compared between donor search prognosis groups and by type of alternative donor transplant 
received using a Cox proportional hazards model adjusted for the following pre-specified patient 
characteristics: age, race/ethnicity, performance status, CMV serostatus, disease risk index,79 co-
morbidity index,80,81 conditioning regimen intensity, donor age, graft type (bone marrow vs. 
peripheral blood), and GVHD prophylaxis regimen. A Cox model stratified on alternative donor 
type will be used to provide adjusted overall OS probabilities at two years for each alternative 
donor type, using the method of Zhang et al.77  
 
Disease-free Survival 
 
Disease-free survival will be analyzed in the malignant disease patients in the transplant 
population, and in the patients enrolled in the QOL substudy. Disease-free survival will not be 

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reported for non-malignant patients. Disease-free survival will be summarized in each alternative 
donor group using the Kaplan-Meier estimate, and compared between alternative donor groups 
using a Cox proportional hazards model adjusted for the same pre-specified patient characteristics 
as above. A Cox model stratified on alternative donor type will be used to provide adjusted overall 
disease-free survival probabilities at two years for each alternative donor type, using the method 
of Zhang et al.77   
 
Relapse 
 
Relapse will be analyzed in the malignant disease patients in the transplant population, and in the 
patients enrolled in the QOL Substudy. Relapse is not applicable to patients with non-malignant 
diseases. The cumulative incidence of relapse will be estimated and plotted over time for each 
alternative donor group, treating death as a competing event.  The cause specific hazard rate for 
relapse will be compared between alternative donor groups using the Cox proportional hazards 
model, adjusted for the same pre-specified patient characteristics as above.   
 
Treatment-Related Mortality 
 
Treatment-related mortality will be analyzed in the malignant disease patients in the transplant 
population, and in the patients enrolled in the QOL Substudy. Treatment-related mortality will not 
be reported for non-malignant diseases. The cumulative incidence of treatment-related mortality 
will be estimated and plotted over time for each alternative donor group, treating relapse as a 
competing event.  The cause specific hazard rate for treatment-related mortality will be compared 
between alternative donor groups using the Cox proportional hazards model, adjusted for same 
pre-specified patient characteristics as above.   
 
Acute GVHD 
 
Acute GVHD will be analyzed in the entire transplant population.  The cumulative incidence of 
grade II-IV and grade III-IV acute GVHD will be estimated and plotted over time for each 
alternative donor group, treating death as a competing risk.  The cause specific hazard rate for 
acute GVHD will be compared between alternative donor groups using the Cox proportional 
hazards model, adjusted for the same pre-specified patient characteristics as above.  
 
Chronic GVHD 
 
Chronic GVHD will be analyzed in the entire transplant population.  The cumulative incidence of 
chronic GVHD will be estimated and plotted over time for each alternative donor group, treating 
death as a competing risk. Relapse will not be considered a competing risk. The cause specific 
hazard rate for chronic GVHD will be compared between alternative donor groups using the Cox 
proportional hazards model, adjusted for the same pre-specified patient characteristics as above.  
 
5.6.5. Analysis of Secondary Endpoints for QOL Substudy participants 
 

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Chronic GVHD 
 
The cumulative incidence of moderate-severe chronic GVHD according to the NIH consensus 
criteria75,82 will be estimated and plotted over time for HLA-matched unrelated donor and 
haploidentical transplant groups, treating death as a competing risk.  The cause specific hazard rate 
for cGVHD will be compared between alternative donor groups using the Cox proportional 
hazards model, adjusted for the same pre-specified patient characteristics as above.  
 
Time until off immunosuppression for patients diagnosed with acute or chronic GVHD 
 
The cumulative incidence of stopping immunosuppression for patients diagnosed with acute or 
chronic GVHD will be estimated and plotted over time for HLA-matched unrelated donor and 
haploidentical transplant groups, treating death as a competing risk. The cause specific hazard rate 
for stopping immunosuppression will be compared between alternative donor groups using the 
Cox proportional hazards model, adjusted for age, race/ethnicity, sex matching, graft type (bone 
marrow vs. peripheral blood), and GVHD prophylaxis regimen. 
 
Chronic GVHD-free, Relapse-free Survival  
 
Probabilities of GRFS and CRFS will be estimated and plotted over time for each alternative donor 
group using the Kaplan-Meier method.  GRFS and CRFS will be compared between alternative 
donor groups using a Cox proportional hazards model adjusted for the same pre-specified patient 
characteristics as above for the secondary analysis of overall survival. Current CRFS will be 
described using simple frequencies, or by multistate model techniques if needed due to censoring.   
 
Primary Graft Failure 
 
The cumulative incidence of primary graft failure for patients who survive at least 28 days after 
transplant will be estimated and plotted over time for HLA-matched unrelated donor and 
haploidentical transplant groups, treating death as a competing risk. The cause specific hazard rate 
for graft failure will be compared between alternative donor groups using the Cox proportional 
hazards model, adjusted for the same pre-specified patient characteristics as above. 
 
Quality of Life 
 
QOL will be described and compared between alternative donor groups for the primary QOL 
endpoints: the PROMIS general health physical summary score, the fatigue, sleep and pain scales, 
and the LSS summary score. The questionnaires will be scored according to standard procedures.  
The self-report questionnaires will be completed prior to HCT and subsequently at 1, 2 years and 
5 years, and the first analysis will be conducted at 2 years adjusting for pre-transplant scores.  
 
Differences in QOL will be assessed in several ways.  For the descriptive analysis only, QOL 
scores for survivors at specific time points will be compared between treatment arms using analysis 
of covariance adjusted for baseline values of QOL.  In addition, pattern of missing QOL data will 
be examined using graphical techniques and logistic regression models.  At each time point, the 
difference in QOL between the treatment arms conditional on being alive at that time point will be 

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estimated using the inverse probability of censoring-weighted generalized estimating equations 
with independent working correlation model of Kurland and Heagerty.83 Imputation methods may 
also be used. 
 
Hospital Days 
 
Total hospital days in the first 100 days post-transplant will be described.  To account for patient 
death in the first 100 days, two analyses will be conducted; either normalizing the hospital days 
out of the number of days alive, or using the number of days alive and out of the hospital in the 
first 100 days.  Nonparametric Mann-Whitney tests will be used to compare the median values 
between groups in both cases.   
 
Infection 
 
The number of infections and the number of patients experiencing infections will be tabulated for 
the two groups by type of infection and time period after transplant. 
 
Immune Reconstitution 
 
The distribution of the following laboratory markers will be described in the two groups: absolute 
neutrophil count, absolute lymphocyte count, IgG level, and absolute numbers of T-cell subsets 
and B cells. Research blood samples will be banked for future studies, not conducted as part of 
this protocol. 
 
Late Effects  
 
The number and types of late effects will be tabulated for each group at 1 and 2 years after 
transplant 
 
 

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6. 
APPENDICES 
 
6.1. APPENDIX A.  LIST OF ABBREVIATIONS 
 
AA – Acquired Aplastic Anemia 
aGVHD – Acute Graft versus Host Disease 
ALL – Acute Lymphoblastic Leukemia 
AML – Acute Myeloid Leukemia 
ATG – Antithymocyte Globulin 
BMT CTN – Blood and Marrow Transplant 
Clinical Trials Network 
CAT – Computer Adaptive Tests 
cGVHD – Chronic Graft versus Host 
Disease 
CIBMTR – Center for International Blood 
and Marrow Transplant Research 
CMV – Cytomegalovirus  
CRF – Comprehensive Report Form 
CRFS – Moderate-Severe Chronic GVHD 
Relapse-free Survival  
CRID – CIMBTR Research Identification 
Cy – Cyclophosphamide 
DCC – Data and Coordinating Center 
DSA – Donor-Specific Antibodies 
DSP – Donor Search Prognosis 
ePRO – Electronic Patient Reported 
Outcomes 
Flu – Fludarabine 
GRFS – Acute Grade III-IV and Chronic 
GVHD Requiring Immunosuppression-free, 
Relapse-free Survival 
GVHD – Graft versus Host Disease 
HCT – Hematopoietic Cell Transplantation 
HL – Hodgkin Lymphoma 
HLA – Human Leucocyte Antigen 
HPC – Hematopoietic Progenitor Cell 
HR – Hazard Ratio 
ICU – Intensive Care Unit 
IRB – Institutional Review Board 
LSS – Lee Chronic GVHD Symptom Scale 
MDS – Myelodysplastic Syndromes 
MMF – Mycophenolate Mofetil 
MRD – Matched Related Donor 
NHL – Non-Hodgkin Lymphoma 
NHLBI – National Heart, Lung, and Blood 
Institute 
NK – Natural Killer 
NMDP – National Marrow Donor Program 
PROMIS – Patient-Reported Outcomes 
Measurement Information System 
PTCy – Post Transplant Cyclophosphamide 
PTLD – Post-Transplant 
Lymphoproliferative Disorder 
PUVA – Psoralen and Ultraviolet A 
QOL – Quality of Life 
SCD – Sickle Cell Disease 
SCTOD – US Stem Cell Therapeutic 
Outcomes Database 
SRG – CIBMTR Survey Research Group 
TBI – Total body irradiation 
TED – Transplant Essential Data 
UCBT – Umbilical Cord Blood Transplant 
 
 

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6.2. APPENDIX B.  HUMAN SUBJECTS 
Subject Consent 
Candidates for the study will be identified as described in Chapter 4 of the protocol.  The Principal 
Investigator or his/her designee at each transplant center will contact the candidates, provide them 
with information about the purpose of the study and obtain voluntary consent if the candidates 
agree to participate.  The BMT CTN will provide a template of the consent form to each 
center.  Each center will add their NMDP IRB approved boiler-plate language to the consent and 
submit for review by the NMDP IRB.  The DCC will verify the adequacy of the consent forms 
prior to submission to the IRB.  The NMDP IRB will provide evidence of IRB approval. 
 
Confidentiality 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code relaying the patient’s identity with the ID code will be kept separately 
at the center.  The ID code will be transmitted to the network.  
 
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 AML, ALL, MDS, 
NHL, HL, AA, or SCD in these groups.  Centers will be notified if their rates differ significantly 
from those expected and asked to develop appropriate recruitment reports. 
 
 

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6.3. APPENDIX C. LIKELIHOOD OF A MATCHED UNRELATED DONOR TRANSPLANT BY DONOR SEARCH 
PROGNOSIS  
 
REANALYSIS OF THE WADSWORTH ET AL PAPER  
 
African American, Hispanic, Asian-Pacific Islander 
Transplants 
  
Donor 
Category 
Total Formal   
Work-
ups 
  
Transplants   
Cord 
10/10 
9/10 
8/10 or less 
Very Likely 
86 
64 
74% 42 
49% 34 
40% 2 
2% 
32 
37% 0 
0% 
0 
0% 
Less Likely 
318 
211 
66% 85 
27% 88 
28% 28 
9% 
22 
7% 
30 
9% 
8 
3% 
Very Unlikely 104 
63 
61% 16 
15% 22 
21% 14 
13% 0 
0% 
6 
6% 
2 
2% 
Total 
508 
338 
67% 138 
27% 144 
28% 44 
9% 
54 
11% 36 
7% 
10 
2% 
 
 
 
Caucasian 
Transplants 
  
Donor 
Category 
Total Formal   
Work-
ups 
  
Transplants   
Cord 
10/10 
9/10 
8/10 
Very Likely 
313 
244 
78% 170 
54% 154 
49% 7 
2% 
141 45% 6 
2% 
0 
0% 
Less Likely 
130 
88 
68% 48 
37% 54 
42% 10 
8% 
26 
20% 18 
14% 0 
0% 
Very Unlikely 88 
57 
65% 14 
16% 22 
25% 13 
15% 2 
2% 
7 
8% 
0 
0% 
Total 
531 
389 
73% 231 
44% 230 
43% 30 
6% 
169 32% 31 
6% 
0 
0% 
 
 

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6-4 
Unknown 
Transplants 
  
Donor 
Category 
Total Formal   
Work-
ups 
  
Transplants   
Cord 
10/10 
9/10 
8/10 
Very Likely 
47 
27 
57% 18 
38% 15 
32% 2 
4% 
13 
28% 0 
0% 
0 
0% 
Less Likely 
54 
38 
70% 21 
39% 22 
41% 7 
13% 4 
7% 
9 
17% 2 
4% 
Very Unlikely 79 
51 
65% 18 
23% 21 
27% 7 
9% 
9 
11% 3 
4% 
2 
3% 
Total 
180 
116 
64% 55 
31% 58 
32% 16 
9% 
26 
14% 12 
7% 
4 
2% 
Total 
Transplants 
  
Donor 
Category 
Total Formal   
Work-
ups 
  
Transplants   
Cord 
10/10 
9/10 
8/10 
Very Likely 
446 
335 
75% 230 
52% 203 
46% 11 
2% 
186 42% 6 
1% 
0 
0% 
Less Likely 
502 
337 
67% 154 
31% 164 
33% 45 
9% 
52 
10% 57 
11% 
10 
2% 
Very Unlikely 271 
171 
63% 48 
18% 65 
24% 34 
13% 11 
4% 
16 
6% 
4 
1% 
Total 
1219 843 
69% 432 
35% 432 
35% 90 
7% 
249 20% 79 
6% 
14 
1% 
 
 
 

BMT CLINICAL TRIALS NETWORK 
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Version 1.0 – December 10, 2018 
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6.4. APPENDIX D. CURRENT 1 YEAR AND 100 DAY SURVIVAL FOR VARIOUS PATIENT AND DONOR GROUPS 
BASED ON 2012-2015 CIBMTR DATA 
 
Table 1. OS at 1 year for all diseases for first allogeneic transplants in 2012-2015 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ 
Locus 
Mismatched Related 
Donor 
Unrelated 
Umbilical 
Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
6782 
72 (71-73)  
10596 
69 (68-70)  
1918 
61 (59-63)  
708 
68 (65-72)  
1555 
63 (61-66)  
Black/African American 
855 
79 (77-82)  
351 
71 (66-76)  
351 
58 (53-63)  
296 
75 (70-80)  
456 
55 (51-60)  
Non-black Hispanic 
1122 
76 (74-79)  
731 
74 (71-77)  
427 
65 (60-70)  
133 
61 (52-70)  
524 
64 (61-69)  
Asian/Pacific Islander 
531 
75 (71-79)  
341 
70 (66-76)  
155 
67 (59-75)  
71 
59 (47-71)  
207 
66 (60-73)  
Missing race 
565 
77 (74-81)  
226 
76 (70-82) 
129 
67 (59-76) 
82 
71 (60-81) 
174 
65 (58-72) 
Total 
9855 
74 (73-75)  
12245 
69 (69-70) 
2980 
62 (60-64) 
1290 
69 (66-71) 
2916 
63 (61-64) 
 
 
Table 2. OS at 1 year for malignant diseasesa for first allogeneic transplants in 2012-2015 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ 
Locus 
Mismatched Related 
Donor 
Unrelated 
Umbilical 
Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
6055 
71 (70-72)  
9586 
68 (67-69)  
1701 
59 (57-62)  
621 
69 (66-73)  
1312 
61 (58-63)  
Black/African American 
509 
71 (67-75)  
246 
67 (61-73)  
268 
53 (47-60)  
228 
72 (66-78)  
349 
51 (45-56)  
Non-black Hispanic 
963 
71 (71-77)  
608 
72 (68-76)  
344 
64 (59-69)  
121 
59 (49-68)  
413 
61 (56-66)  
Asian/Pacific Islander 
442 
72 (68-76)  
272 
68 (63-74)  
126 
66 (57-75)  
61 
57 (44-71)  
171 
64 (56-71)  
Missing race 
453 
74 (70-78) 
166 
75 (68-82) 
126 
63 (53-73) 
61 
67 (54-79) 
124 
57 (48-66) 
Total 
8422 
71 (71-73) 
10878 
68 (67-69) 
2538 
60 (58-62) 
1094 
68 (65-71) 
2369 
59 (57-61) 
aExcludes multiple myeloma and solid tumor 

BMT CLINICAL TRIALS NETWORK 
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Table 3. OS at 1 year for non-malignant diseases for first allogeneic transplants in 2012-2015 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ Locus Mismatched 
Related Donor 
Unrelated 
Umbilical 
Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
507 
89 (87-92)  
771 
84 (81-86)  
169 
80 (74-86)  
43 
65 (50-81)  
232 
78 (73-84)  
Black/African American 
313 
95 (92-97)  
98 
82 (73-90)  
75 
75 (64-85)  
54 
89 (80-98)  
102 
72 (62-81)  
Non-black Hispanic 
125 
94 (89-98)  
113 
84 (77-91)  
75 
73 (63-84)  
9 
89 (63-100)  
108 
80 (72-88)  
Asian/Pacific Islander 
74 
97 (93-100)  
64 
81 (71-92)  
27 
74 (56-92)  
7 
71 (31-100)  
35 
83 (69-97)  
Missing race 
102 
94 (89-99)  
55 
80 (69-91)  
29 
86 (72-100)  
15 
87 (66-100)  
47 
87 (77-98)  
Total 
1121 
92 (91-94)  
1101 
83 (81-85)  
375 
78 (73-82)  
128 
80 (72-87)  
524 
78 (75-82)  
 
Table 4. OS at 1 year for Severe Aplastic Anemia for first allogeneic transplants in 2012-2015 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ 
Locus 
Mismatched 
Related Donor 
Unrelated 
Umbilical 
Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
239 
92 (88-96)  
278 
85 (81-89)  
57 
79 (67-90)  
17 
65 (39-90)  
10 
50 (14-86)  
Black/African American 
40 
90 (79-100)  
12 
83 (58-100)  
20 
65 (42-88)  
10 
70 (37-100)  
14 
79 (54-100)  
Non-black Hispanic 
64 
92 (85-100)  
43 
91 (81-100)  
24 
67 (46-88)  
1 
100 (50-100)  
12 
83 (58-100)  
Asian/Pacific Islander 
34 
100 (99-100)  
17 
76 (53-100)  
7 
71 (31-100)  
2 
100 (75-100)  
6 
100 (92-100)  
Missing race 
43 
93 (84-100)  
10 
100 (95-100)  
10 
70 (37-100)  
8 
75 (39-100)  
3 
100 (83-100)  
Total 
420 
93 (90-95)  
360 
86 (82-89)  
118 
73 (64-81)  
38 
71 (55-87)  
45 
78 (65-91)  
 
 

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Table 5. OS at 1 year for sickle cell anemia for first allogeneic transplants in 2012-2015 
 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ 
Locus 
Mismatched Related 
Donor 
Unrelated Umbilical 
Cord Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
11 
100 (95-100)  
1 
100 (50-100)  
0 
 
1 
100 (50-100)  
0 
 
Black/African American 
240 
96 (94-99)  
61 
80 (70-91)  
21 
81 (62-100)  
37 
97 (91-100)  
24 
83 (66-100)  
Non-black Hispanic 
14 
100 (96-100)  
1 
100 (50-100)  
4 
75 (20-100)  
0 
 
0 
 
Asian/Pacific Islander 
3 
100 (83-100)  
0 
 
0 
 
0 
 
0 
 
Missing race 
18 
94 (81-100)  
4 
100 (88-100)  
1 
100 (50-100)  
0 
 
2 
100 (75-100)  
Total 
286 
97 (94-99)  
67 
82 (72-92)  
26 
81 (64-98)  
38 
97 (91-100)  
26 
85 (69-100)  
 
Table 6. OS at 100 days for all diseases for first allogeneic transplants in 2012-2015 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ Locus Mismatched 
Related Donor 
Unrelated 
Umbilical Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
6782 
92 (91-93)  
10596 
89 (89-90)  
1918 
85 (83-87)  
708 
90 (88-93)  
1555 
85 (83-87)  
Black/African American 
855 
94 (93-96)  
351 
86 (83-90)  
351 
83 (79-88)  
296 
89 (85-93)  
456 
80 (77-84)  
Non-black Hispanic 
1122 
95 (93-96)  
731 
91 (89-93)  
427 
88 (85-91)  
133 
89 (84-95)  
524 
84 (81-87)  
Asian/Pacific Islander 
531 
93 (91-96)  
341 
88 (85-92)  
155 
88 (82-93)  
71 
73 (62-84)  
207 
86 (82-91)  
Missing race 
565 
93 (90-95)  
226 
91 (87-95)  
129 
87 (81-93)  
82 
95 (90-100)  
174 
85 (79-91)  
Total 
9855 
93 (92-93)  
12245 
89 (89-90)  
2980 
85 (84-87)  
1290 
89 (87-91)  
2916 
84 (83-85)  
 
 
 
 

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Version 1.0 – December 10, 2018 
6-8 
Table 7. OS at 100 days for malignant diseasesa for first allogeneic transplants in 2012-2015 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ Locus Mismatched 
Related Donor 
Unrelated 
Umbilical Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
6055 
92 (91-92)  
9586 
89 (89-90)  
1701 
84 (82-86)  
621 
91 (89-93)  
1312 
84 (82-86)  
Black/African American 
509 
92 (90-95)  
246 
84 (79-89)  
268 
81 (76-86)  
228 
89 (84-93)  
349 
79 (75-83)  
Non-black Hispanic 
963 
94 (93-96)  
608 
90 (88-93)  
344 
88 (85-92)  
121 
88 (82-95)  
413 
83 (79-87)  
Asian/Pacific Islander 
442 
92 (89-95)  
272 
88 (84-92)  
126 
74 (82-94)  
61 
74 (62-86)  
171 
87 (81-92)  
Missing race 
453 
92 (90-95)  
166 
92 (88-97)  
99 
95 (78-93)  
63 
95 (89-100)  
124 
80 (72-87)  
Total 
8422 
92 (92-93)  
10878 
89 (89-90)  
2538 
90 (83-86)  
1094 
90 (88-91)  
2369 
83 (81-84)  
aExcludes multiple myeloma and solid tumor 
 
 
 
Table 8. OS at 100 days for non-malignant diseases for first allogeneic transplants in 2012-2015 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ Locus 
Mismatched Related 
Donor 
Unrelated 
Umbilical Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
507 
95 (93-97)  
771 
92 (90-94)  
169 
92 (88-97)  
43 
81 (69-94)  
232 
91 (88-95)  
Black/African American 
313 
97 (96-99)  
98 
92 (86-98)  
75 
92 (85-99)  
54 
93 (85-100)  
102 
83 (76-91)  
Non-black Hispanic 
125 
97 (93-100)  
113 
93 (88-98)  
75 
89 (82-97)  
9 
100 (94-100)  
108 
87 (80-94)  
Asian/Pacific Islander 
74 
100 (99-100)  
64 
89 (81-97)  
27 
85 (70-100)  
7 
71 (31-100)  
35 
89 (77-100)  
Missing race 
102 
96 (92-100)  
55 
87 (78-97)  
29 
90 (77-100)  
15 
93 (77-100)  
47 
98 (93-100)  
Total 
1121 
96 (95-98)  1101 
92 (90-93)  
375 
91 (88-94)  
128 
88 (82-94)  
524 
89 (87-92)  
 

BMT CLINICAL TRIALS NETWORK 
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6-9 
Table 9. OS at 100 days for Severe Aplastic Anemia for first allogeneic transplants in 2012-2015 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ Locus 
Mismatched 
Related Donor 
Unrelated 
Umbilical Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
239 
97 (94-99)  
278 
93 (90-96)  
57 
93 (85-100)  
17 
82 (61-100)  
10 
90 (66-100)  
Black/African American 
40 
95 (87-100)  
12 
83 (58-100)  
20 
85 (67-100)  
10 
80 (50-100)  
14 
86 (64-100)  
Non-black Hispanic 
64 
94 (87-100)  
43 
93 (84-100)  
24 
79 (61-97)  
1 
100 (50-100)  
12 
92 (72-100)  
Asian/Pacific Islander 
34 
100 (99-100)  
17 
82 (61-100)  
7 
100 (93-100)  
2 
100 (75-100)  
6 
100 (92-100)  
Missing race 
43 
95 (88-100)  
10 
100 (95-100)  
10 
70 (37-100)  
8 
88 (58-100)  
3 
100 (83-100)  
Total 
420 
96 (94-98)  
360 
92 (89-95)  
118 
87 (81-94)  
38 
84 (71-97)  
45 
91 (82-100)  
 
Table 10. OS at 100 days for sickle cell anemia for first allogeneic transplants in 2012-2015 
 
 
HLA-id sib 
MUD 
Mismatched UD 
2+ Locus 
Mismatched 
Related Donor 
Unrelated 
Umbilical Cord 
Blood 
 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
N 
Prob  
(95% CI) 
White  
11 
100 (95-100)  
1 
100 (50-100)  
0 
 
1 
100 (50-100)  
0 
 
Black/African American 
240 
98 (97-100)  
61 
95 (89-100)  
21 
95 (84-100)  
37 
100 (99-100)  
24 
96 (86-100)  
Non-black Hispanic 
14 
100 (96-100)  
1 
100 (50-100)  
4 
100 (88-100)  
0 
 
0 
 
Asian/Pacific Islander 
3 
100 (83-100)  
0 
 
0 
 
0 
 
0 
 
Missing race 
18 
100 (97-100)  
4 
100 (88-100)  
1 
100 (50-100)  
0 
 
2 
100 (75-100)  
Total 
286 
99 (97-100)  
67 
96 (90-100)  
26 
96 (87-100)  
38 
100 (99-100)  
26 
96 (87-100)  
 
 
 

BMT CLINICAL TRIALS NETWORK 
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6-1 
6.5. APPENDIX E. DERIVATION OF A SQUENTIAL TEST STATISTIC FOR 
CENSORED EXPOENTIAL DATA 
 
Background – The Sequential Probability Ratio Test 
 
Let 
)
(.,θ
f
be the density function for random variable X. According to Neyman and Pearson, the 
most powerful test of 
o
H
θ
θ =
:
0
 versus
1
1 :
θ
θ =
H
 decides in favor of 
1
H  or 
0
H if 
αc
Ln >
 or
αc
Ln <
, respectively, where 
∏
=
n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1
θ
θ
is the likelihood ratio, and 
αc is 
determined to have the size α . When the sample size is not fixed in advance, further improvement 
is possible by using Wald’s Sequential Probability Ratio Test (SPRT). The SPRT continues to 
sample as long as 
A
L
B
n <
<
 for some constant 
A
B
<
<1
, stops sampling and decides in favor of 
1
H as soon as 
A
Ln >
, and stops sampling and decides in favor of 
0
H as soon as 
B
Ln <
. 
 
The usual measures of performance of such a procedure are the error probabilities 
α
and β of 
rejecting 
0
H  when
0
θ
θ =
, and of accepting 
0
H  when 
1
θ
θ =
, respectively, and the expected sample 
size 
)
(
)
|
(
N
E
N
E
j
j ≡
θ
. Wald and Wolfowitz showed that among all tests, sequential or not, for 
which 
α
≤
)
reject 
(
Pr
0
0
H
 and
β
≤
)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, j=0,1, the 
SPRT with error probabilities 
α
 and β minimizes 
)
(
0 N
E
 and 
)
(
1 N
E
. If, in addition, the 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function
)
,
(
θ
x
f
, with 
monotone likelihood ratio in
)
(x
τ
, then any SPRT for testing 
0
θ against 
)
(
0
1
θ
θ >
 has non-
decreasing power function. 
 
For the SPRT with error probabilities 
α
and β , the SPRT boundaries are given approximately by 
α
β /)
1( −
=
A
 and 
)
1
/(
α
β
−
=
B
. The operating characteristics of the SPRT are given by 
)
/(
)
1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0
θ
θ
θ
θ
θ
β
α
θ
h
h
h
B
A
A
O
−
−
=
 where 
)
(θ
h
is the non-trivial solution to the equation 
∫
=1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h
θ
θ
θ
θ
.  
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(
θ
θ
θ
θ
z
E
B
O
A
O
N
E
+
−
=
provides the average sample number 
for an arbitrary θ . The sample size distribution is very highly skewed, 
2
)]
(
[
)
(
N
E
N
Var
≈
. Thus we 
will consider a truncated test with maximum sample size of 
0
N  and simulate to obtain the 
operating characteristics of the test. 
 

BMT CLINICAL TRIALS NETWORK 
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6-2 
Derivation of the SPRT for Censored Exponential Survival Times 
 
Suppose that we wish to construct a sequential test for the composite null hypothesis that the rate 
of overall mortality at an early time point t is less than or equal to p0 versus the alternative 
hypothesis that it is greater than or equal to p0. Let us assume that the survival times, 
n
T
T
T
,...,
,
2
1
, 
are i.i.d. with exponential density function 
T
e
T
f
θ
θ
θ
−
=
)
,
(
. Although an exponential model may 
not fit well for overall mortality, it usually provides a reasonable model over a short time frame 
for modeling toxicity, so in all discussion below we assume that exponential survival times are 
censored at time point t. In the exponential parameterization, a t-day survival rate of p0 translates 
into a mean survival of µ0=-t/ln(1-p0) (rate parameter 
=
0
θ
-ln(1-p0)/t). . 
 
The SPRT is derived with reference to a simple null and alternative hypothesis for the rate 
parameter, in this case, 
0 :
o
H
θ
θ
=
 versus
1
1 :
θ
θ =
H
 . The log-likelihood ratio for the exponential 
in 
the 
presence 
of 
censoring 
is 
1
0
1
0
1
0
log
( ;
)
log
( ,
)
(log( )
log(
))
(
)
n
n
n
i
i
i
i
i
i
f x
f x
d
T
θ
θ
θ
θ
θ
θ
−
=
−
−
−
∑
∏
∏
, where d is the number of 
events. The SPRT can be represented graphically when plotting the number of deaths (d) on the y 
axis against the total time on study ∑
n
i
iT  on the x axis. The continuation region in terms of d is 
bounded by two parallel lines given by 
1
0
1
0
1
0
1
0
1
0
1
0
(
)
(
)
log( )
log( )
(log
log
)
(log
log
)
(log
log
)
(log
log
)
n
n
i
i
i
i
B
A
T
d
T
θ
θ
θ
θ
θ
θ
θ
θ
θ
θ
θ
θ








−
−
+
<
<
+








−
−
−
−








∑
∑
 
with 
common 
slope 
1
0
1
0
(
) / (log
log
)
θ
θ
θ
θ
−
−
, 
and 
intercepts 
1
0
log
/ (ln
ln
)
A
θ
θ
−
 
and 
1
0
log
/ (ln
ln
)
B
θ
θ
−
, for the upper and lower bounds, respectively. For monitoring purposes, at an 
interim analysis calendar time point s, suppose that d(s) events have occurred and that the total 
time on study is 
( )
n
i
i
T s
∑
.The cumulative number of events d(s) is plotted on the y axis against the 
total time on study,
( )
n
i
i
T s
∑
. When this graph crosses the upper boundary, the null hypothesis is 
rejected. In practice, monitoring will be scheduled monthly after the start of enrollment to the 
study.  
 
A truncated version of the SPRT can be obtained by specifying a maximum sample size. We 
truncate the SPRT by declaring that if the test has failed to terminate after the maximum sample 
size, that the null hypothesis will be accepted. Since the probability that the untruncated SPRT 
would reject the null at the maximum sample size is negligible, it makes little difference how the 
final boundary value is selected, and this rule is chosen for simplicity. The operating characteristics 
of this proposed truncated SPRT for censored exponential data can be estimated by simulation. 
 
 
 

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6.6.  APPENDIX F.  REFERENCES 
 
 
1. Gratwohl A, Pasquini MC, Aljurf M, et al. One million haemopoietic stem-cell transplants: a 
retrospective observational study. Lancet Haematol. 2015;2(3):e91-100. 
2. Passweg JR, Baldomero H, Bader P, et al. Use of haploidentical stem cell transplantation 
continues to increase: the 2015 European Society for Blood and Marrow Transplant activity 
survey report. Bone Marrow Transplant. 2017;52(6):811-817. 
3. Ballen KK, King RJ, Chitphakdithai P, et al. The national marrow donor program 20 years of 
unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(9 
Suppl):2-7. 
4. Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching 
contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576-
4583. 
5. Horan J, Wang T, Haagenson M, et al. Evaluation of HLA matching in unrelated 
hematopoietic stem cell transplantation for nonmalignant disorders. Blood. 2012;120(14):2918-
2924. 
6. Appelbaum FR. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia 
when a matched related donor is not available. Hematology Am Soc Hematol Educ Program. 
2008:412-417. 
7. Brissot E, Labopin M, Stelljes M, et al. Comparison of matched sibling donors versus 
unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid 
leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. J Hematol 
Oncol. 2017;10(1):130. 
8. Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched 
unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute 
myelogenous leukemia. Blood. 2012;119(17):3908-3916. 
9. Segal E, Martens M, Wang HL, et al. Comparing outcomes of matched related donor and 
matched unrelated donor hematopoietic cell transplants in adults with B-Cell acute 
lymphoblastic leukemia. Cancer. 2017;123(17):3346-3355. 
10. Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell 
grafts in the U.S. registry. N Engl J Med. 2014;371(4):339-348. 
11. Pidala J, Kim J, Schell M, et al. Race/ethnicity affects the probability of finding an HLA-A, -
B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant 
utilization. Bone Marrow Transplant. 2013;48(3):346-350. 

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12. Ciurea SO, Zhang MJ, Bacigalupo AA, et al. Haploidentical transplant with posttransplant 
cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 
2015;126(8):1033-1040. 
13. Kanate AS, Mussetti A, Kharfan-Dabaja MA, et al. Reduced-intensity transplantation for 
lymphomas using haploidentical related donors vs HLA-matched unrelated donors. Blood. 
2016;127(7):938-947. 
14. Wadsworth K, Albrecht M, Fonstad R, Spellman S, Maiers M, Dehn J. Unrelated donor 
search prognostic score to support early HLA consultation and clinical decisions. Bone Marrow 
Transplant. 2016;51(11):1476-1481. 
15. Woolfrey A, Klein JP, Haagenson M, et al. HLA-C antigen mismatch is associated with 
worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow 
Transplant. 2011;17(6):885-892. 
16. Perkins J, Field T, Kim J, et al. A randomized phase II trial comparing tacrolimus and 
mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease 
prophylaxis. Biol Blood Marrow Transplant. 2010;16(7):937-947. 
17. Finke J, Schmoor C, Lang H, Potthoff K, Bertz H. Matched and mismatched allogeneic stem-
cell transplantation from unrelated donors using combined graft-versus-host disease prophylaxis 
including rabbit anti-T lymphocyte globulin. J Clin Oncol. 2003;21(3):506-513. 
18. Fuji S, Kanda J, Kato S, et al. A single high-resolution HLA mismatch has a similar adverse 
impact on the outcome of related hematopoietic stem cell transplantation as a single low-
resolution HLA mismatch. Am J Hematol. 2015;90(7):618-623. 
19. Bosch M, Dhadda M, Hoegh-Petersen M, et al. Immune reconstitution after anti-thymocyte 
globulin-conditioned hematopoietic cell transplantation. Cytotherapy. 2012;14(10):1258-1275. 
20. Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host 
disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo 
Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98(10):2942-2947. 
21. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with 
or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated 
donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855-864. 
22. Mehta RS, Saliba RM, Chen J, et al. Post-transplantation cyclophosphamide versus 
conventional graft-versus-host disease prophylaxis in mismatched unrelated donor 
haematopoietic cell transplantation. Br J Haematol. 2016;173(3):444-455. 
23. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient 
with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl 
J Med. 1989;321(17):1174-1178. 

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24. Total Number of Donors and Cord blood units. Vol. 2018: The World Marrow Donor 
Association (WMDA); 2018. 
25. Niederwieser D, Baldomero H, Szer J, et al. Hematopoietic stem cell transplantation activity 
worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow 
Transplantation Group including the global survey. Bone Marrow Transplant. 2016;51(6):778-
785. 
26. Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor 
umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. 
Lancet. 2007;369(9577):1947-1954. 
27. Ruggeri A, Eapen M, Scaravadou A, et al. Umbilical cord blood transplantation for children 
with thalassemia and sickle cell disease. Biol Blood Marrow Transplant. 2011;17(9):1375-1382. 
28. Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation 
for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood. 
2010;116(22):4693-4699. 
29. Brunstein CG, Eapen M, Ahn KW, et al. Reduced-intensity conditioning transplantation in 
acute leukemia: the effect of source of unrelated donor stem cells on outcomes. Blood. 
2012;119(23):5591-5598. 
30. Ponce DM, Hilden P, Devlin SM, et al. High Disease-Free Survival with Enhanced 
Protection against Relapse after Double-Unit Cord Blood Transplantation When Compared with 
T Cell-Depleted Unrelated Donor Transplantation in Patients with Acute Leukemia and Chronic 
Myelogenous Leukemia. Biol Blood Marrow Transplant. 2015;21(11):1985-1993. 
31. Warlick ED, Peffault de Latour R, Shanley R, et al. Allogeneic hematopoietic cell 
transplantation outcomes in acute myeloid leukemia: similar outcomes regardless of donor type. 
Biol Blood Marrow Transplant. 2015;21(2):357-363. 
32. Lou X, Zhao C, Chen H. Unrelated donor umbilical cord blood transplant versus unrelated 
hematopoietic stem cell transplant in patients with acute leukemia: A meta-analysis and 
systematic review. Blood Rev. 2018;32(3):192-202. 
33. Broxmeyer HE, Lee MR, Hangoc G, et al. Hematopoietic stem/progenitor cells, generation 
of induced pluripotent stem cells, and isolation of endothelial progenitors from 21- to 23.5-year 
cryopreserved cord blood. Blood. 2011;117(18):4773-4777. 
34. Gluckman E, Rocha V, Ionescu I, et al. Results of unrelated cord blood transplant in fanconi 
anemia patients: risk factor analysis for engraftment and survival. Biol Blood Marrow 
Transplant. 2007;13(9):1073-1082. 
35. Ooi J, Takahashi S, Tomonari A, et al. Unrelated cord blood transplantation after 
myeloablative conditioning in adults with acute myelogenous leukemia. Biol Blood Marrow 
Transplant. 2008;14(12):1341-1347. 

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36. Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of 2 partially HLA-matched 
umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. 
Blood. 2005;105(3):1343-1347. 
37. MacMillan ML, Weisdorf DJ, Brunstein CG, et al. Acute graft-versus-host disease after 
unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 
2009;113(11):2410-2415. 
38. Rodrigues CA, Sanz G, Brunstein CG, et al. Analysis of risk factors for outcomes after 
unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the 
Eurocord-Netcord and lymphoma working party of the European group for blood and marrow 
transplantation. J Clin Oncol. 2009;27(2):256-263. 
39. Kindwall-Keller TL, Hegerfeldt Y, Meyerson HJ, et al. Prospective study of one- vs two-unit 
umbilical cord blood transplantation following reduced intensity conditioning in adults with 
hematological malignancies. Bone Marrow Transplant. 2012;47(7):924-933. 
40. Shpall EJ, Quinones R, Giller R, et al. Transplantation of ex vivo expanded cord blood. Biol 
Blood Marrow Transplant. 2002;8(7):368-376. 
41. de Lima M, McMannis J, Gee A, et al. Transplantation of ex vivo expanded cord blood cells 
using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow 
Transplant. 2008;41(9):771-778. 
42. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-
mediated expansion of human cord blood progenitor cells capable of rapid myeloid 
reconstitution. Nat Med. 2010;16(2):232-236. 
43. de Lima M, McNiece I, Robinson SN, et al. Cord-blood engraftment with ex vivo 
mesenchymal-cell coculture. N Engl J Med. 2012;367(24):2305-2315. 
44. Horwitz ME, Chao NJ, Rizzieri DA, et al. Umbilical cord blood expansion with nicotinamide 
provides long-term multilineage engraftment. J Clin Invest. 2014;124(7):3121-3128. 
45. Brunstein CG, McKenna DH, DeFor TE, et al. Complement fragment 3a priming of 
umbilical cord blood progenitors: safety profile. Biol Blood Marrow Transplant. 
2013;19(10):1474-1479. 
46. Farag SS, Srivastava S, Messina-Graham S, et al. In vivo DPP-4 inhibition to enhance 
engraftment of single-unit cord blood transplants in adults with hematological malignancies. 
Stem Cells Dev. 2013;22(7):1007-1015. 
47. Cutler C, Multani P, Robbins D, et al. Prostaglandin-modulated umbilical cord blood 
hematopoietic stem cell transplantation. Blood. 2013;122(17):3074-3081. 
48. O'Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation 
from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. 
Biol Blood Marrow Transplant. 2002;8(7):377-386. 

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Version 1.0 – December 10, 2018 
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49. Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation 
for hematologic malignancies using nonmyeloablative conditioning and high-dose, 
posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641-650. 
50. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced 
intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related 
bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282-288. 
51. Gaballa S, Ge I, El Fakih R, et al. Results of a 2-arm, phase 2 clinical trial using post-
transplantation cyclophosphamide for the prevention of graft-versus-host disease in 
haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation. 
Cancer. 2016;122(21):3316-3326. 
52. Baker M, Wang H, Rowley SD, et al. Comparative Outcomes after Haploidentical or 
Unrelated Donor Bone Marrow or Blood Stem Cell Transplantation in Adult Patients with 
Hematological Malignancies. Biol Blood Marrow Transplant. 2016;22(11):2047-2055. 
53. Bashey A, Zhang X, Sizemore CA, et al. T-cell-replete HLA-haploidentical hematopoietic 
transplantation for hematologic malignancies using post-transplantation cyclophosphamide 
results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated 
donor transplantation. J Clin Oncol. 2013;31(10):1310-1316. 
54. Blaise D, Furst S, Crocchiolo R, et al. Haploidentical T Cell-Replete Transplantation with 
Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age 
Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte 
Antigen-Matched Related or Unrelated Donor. Biol Blood Marrow Transplant. 2016;22(1):119-
124. 
55. Burroughs LM, O'Donnell PV, Sandmaier BM, et al. Comparison of outcomes of HLA-
matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation 
following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol 
Blood Marrow Transplant. 2008;14(11):1279-1287. 
56. Raiola AM, Dominietto A, di Grazia C, et al. Unmanipulated haploidentical transplants 
compared with other alternative donors and matched sibling grafts. Biol Blood Marrow 
Transplant. 2014;20(10):1573-1579. 
57. Rashidi A, Slade M, DiPersio JF, Westervelt P, Vij R, Romee R. Post-transplant high-dose 
cyclophosphamide after HLA-matched vs haploidentical hematopoietic cell transplantation for 
AML. Bone Marrow Transplant. 2016;51(12):1561-1564. 
58. Martinez C, Gayoso J, Canals C, et al. Post-Transplantation Cyclophosphamide-Based 
Haploidentical Transplantation as Alternative to Matched Sibling or Unrelated Donor 
Transplantation for Hodgkin Lymphoma: A Registry Study of the Lymphoma Working Party of 
the European Society for Blood and Marrow Transplantation. J Clin Oncol. 2017;35(30):3425-
3432. 

BMT CLINICAL TRIALS NETWORK 
CTRL-ALT-D – Protocol 1702 
 
 
Version 1.0 – December 10, 2018 
6-8 
59. Di Stasi A, Milton DR, Poon LM, et al. Similar transplantation outcomes for acute myeloid 
leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human 
leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant. 
2014;20(12):1975-1981. 
60. Altmaier EM, Gingrich RD, Fyfe MA. Two-year adjustment of bone marrow transplant 
survivors. Bone Marrow Transplant. 1991;7(4):311-316. 
61. Andrykowski MA. Psychosocial factors in bone marrow transplantation: a review and 
recommendations for research. Bone Marrow Transplant. 1994;13(4):357-375. 
62. Baker F, Wingard JR, Curbow B, et al. Quality of life of bone marrow transplant long-term 
survivors. Bone Marrow Transplant. 1994;13(5):589-596. 
63. Bush NE, Haberman M, Donaldson G, Sullivan KM. Quality of life of 125 adults surviving 
6-18 years after bone marrow transplantation. Soc Sci Med. 1995;40(4):479-490. 
64. Kiss TL, Abdolell M, Jamal N, Minden MD, Lipton JH, Messner HA. Long-term medical 
outcomes and quality-of-life assessment of patients with chronic myeloid leukemia followed at 
least 10 years after allogeneic bone marrow transplantation. J Clin Oncol. 2002;20(9):2334-
2343. 
65. Sutherland HJ, Fyles GM, Adams G, et al. Quality of life following bone marrow 
transplantation: a comparison of patient reports with population norms. Bone Marrow 
Transplant. 1997;19(11):1129-1136. 
66. Syrjala KL, Langer SL, Abrams JR, et al. Recovery and long-term function after 
hematopoietic cell transplantation for leukemia or lymphoma. JAMA. 2004;291(19):2335-2343. 
67. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and preventive practices for 
long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 
2012;18(3):348-371. 
68. Lee SJ, Onstad L, Chow EJ, et al. Patient-reported outcomes and health status associated 
with chronic graft-versus-host disease. Haematologica. 2018. 
69. Shaw BE, Syrjala KL, Onstad LE, et al. PROMIS measures can be used to assess symptoms 
and function in long-term hematopoietic cell transplantation survivors. Cancer. 
2018;124(4):841-849. 
70. Jensen RE, Potosky AL, Moinpour CM, et al. United States Population-Based Estimates of 
Patient-Reported Outcomes Measurement Information System Symptom and Functional Status 
Reference Values for Individuals With Cancer. J Clin Oncol. 2017;35(17):1913-1920. 
71. Cella D, Gershon R, Lai JS, Choi S. The future of outcomes measurement: item banking, 
tailored short-forms, and computerized adaptive assessment. Qual Life Res. 2007;16 Suppl 
1:133-141. 

BMT CLINICAL TRIALS NETWORK 
CTRL-ALT-D – Protocol 1702 
 
 
Version 1.0 – December 10, 2018 
6-9 
72. Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8(8):444-
452. 
73. Lee SJ, Logan B, Westervelt P, et al. Comparison of Patient-Reported Outcomes in 5-Year 
Survivors Who Received Bone Marrow vs Peripheral Blood Unrelated Donor Transplantation: 
Long-term Follow-up of a Randomized Clinical Trial. JAMA Oncol. 2016;2(12):1583-1589. 
74. Walker I, Panzarella T, Couban S, et al. Pretreatment with anti-thymocyte globulin versus no 
anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic 
cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, 
multicentre trial. Lancet Oncol. 2016;17(2):164-173. 
75. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 
2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 
2015;21(3):389-401 e381. 
76. Logan B, Leifer E, Bredeson C, et al. Use of biological assignment in hematopoietic stem 
cell transplantation clinical trials. Clin Trials. 2008;5(6):607-616. 
77. Zhang X, Loberiza FR, Klein JP, Zhang MJ. A SAS macro for estimation of direct adjusted 
survival curves based on a stratified Cox regression model. Comput Methods Programs Biomed. 
2007;88(2):95-101. 
78. Zhang X, Zhang MJ. SAS macros for estimation of direct adjusted cumulative incidence 
curves under proportional subdistribution hazards models. Comput Methods Programs Biomed. 
2011;101(1):87-93. 
79. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic 
stem cell transplantation. Blood. 2012;120(4):905-913. 
80. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 
2013;121(15):2854-2863. 
81. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific 
comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 
2005;106(8):2912-2919. 
82. Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129(1):30-
37. 
83. Kurland BF, Heagerty PJ. Directly parameterized regression conditioning on being alive: 
analysis of longitudinal data truncated by deaths. Biostatistics. 2005;6(2):241-258.