Conditions: Acute Leukemia Chronic Myelogenous Leukemia (CML) Myelodysplasia Lymphoma
Keywords: Acute Leukemia Chronic Myelogenous Leukemia (CML) Myelodysplasia (MDS) Lymphoma GVHD prophylaxis Acute GVHD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 431
Healthy volunteers: no

Brief summary:
1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation.

1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Detailed description:
1703: Graft-versus-Host Disease (GVHD) is a complication that affects many hematopoietic stem cell transplant (HSCT) patients; it occurs when the new cells from a transplant attack the recipient's body. The current standard GVHD prophylaxis regimen for patients with hematologic malignancies undergoing HSCT involves a combination of immunosuppressive agents given for the first 6 months after transplant.

The standard strategy of Tacrolimus/Methotrexate will be used as a control arm in comparison to one other treatment plan utilizing Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide. Study participants will receive an infusion of mobilized peripheral blood stem cell grafts on both arms. Study participants will be randomized to one of these two treatment arms.

1801: A relationship between the intestinal microbiota and graft-versus-host disease (GVHD) has long been appreciated but is still not well understood. Mice transplanted in germ-free conditions or treated with gut-decontaminating antibiotics developed less severe GVHD. Clinical studies initially suggested a benefit from near-total bacterial decontamination, but later showed no clear benefit and this approach was discontinued in the early 1990s. Partial gut decontamination continues to be practiced at many centers. More recently, the advent of next-generation sequencing (NGS) has resulted in cheaper and easier characterization of complex microbial mixtures. This has led to a renewed interest in evaluating the relationship between the microbiota and human health and disease, including recipients of hematopoietic cell transplantation (HCT). Similarly, NGS has also contributed to significant advancements in the investigator's understanding of immune reconstitution in HCT patients and how this may impact clinica outcomes.

The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

Arms:
arm 1: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate arm 2: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide

Interventions: intervention 1: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Methotrexate intervention 2: Tacrolimus intervention 3: Methotrexate intervention 4: Mobilized Peripheral Blood Stem Cell graft with Tacrolimus/Mycophenolate Mofetil/Post-Transplant Cyclophosphamide intervention 5: Tacrolimus intervention 6: Mycophenolate Mofetil intervention 7: Cyclophosphamide
Intervention descriptions: intervention 1: Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated. intervention 2: Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting on Day -3. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels per institutional guidelines with a suggested range of 5-15. If patients are on medications which alter the metabolism of tacrolimus (e.g.concurrent CYP3A4 inhibitors), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices and patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD. intervention 3: Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1, and 10 mg/m2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. Methotrexate should be dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per institutional guidelines. intervention 4: Mobilized PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated. intervention 5: Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of tapering will be done according to institutional practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of active GVHD intervention 6: MMF will be given at a dose of 15 mg/kg/dose ter in die (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day +5 and discontinue after the last dose on Day +35, or may be continued if active GVHD is present. intervention 7: Cyclophosphamide \[50 mg/kg ideal body weight (IBW); if actual body weight (ABW) \< IBW, use ABW\] will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day +4 post-transplant (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).

Protocol document:
SAP_002.pdf: 
 
 
 
 
 
 
 
 
BMT CTN 1703/ PROGRESS III 
NCT#: 03959241 
Statistical Analysis Plan  
Version 1.0 
July 26, 2021 
 
Effective by: August 6, 2021 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
 
THIS DOCUMENT IS CONFIDENTIAL AND PRIVILEGED


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VERSION HISTORY 
This table is updated whenever a change to this document occurs.  Record the new version 
date/number and summarize the changes to the document. 
Version 
# 
Creation/ 
Revision 
Date 
(DDMMMYYYY) 
Approved 
By 
Approval 
Date 
(DDMMMYYYY) 
Reason for Change 
1.0 
26Jul2021 
Brent Logan 
26Jul2021 
Initial version 
 
 
 


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List of Abbreviations 
Abbreviations  
Description of abbreviations 
aGVHD 
Acute graft-versus-host disease 
AE 
Adverse event 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
CBC 
Complete blood count 
CI 
Confidence interval 
cGVHD 
Chronic graft-versus-host disease 
CMV 
Cytomegalovirus 
CTCAE  
Common Terminology Criteria for Adverse Events 
DSMB  
Data and Safety Monitoring Board 
GRFS 
GVHD-Free, Relapse-Free Survival 
GVHD 
Graft-versus-host disease 
HCT 
Hematopoietic cell transplantation 
IPCW-GEE 
Inverse Probability of Censoring-Weighted Generalized Estimating 
Equation 
IV 
Intravenous 
MDS 
Myelodysplastic syndromes 
MOP 
Manual of Procedures 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health 
TRM 
Treatment-related mortality 
OS 
Overall survival 
DFS 
Disease-free survival 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
SAE 
Serious adverse events 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
 
 


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PROTOCOL SYNOPSIS 
A Randomized, Multicenter Phase III Trial of Tacrolimus/Methotrexate versus Post-
Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative / 
Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation 
 
Co-Principal Investigators:  
Javier Bolaños-Meade, MD and Shernan Holtan, MD  
Study Design:  
The study is designed as a randomized, phase III, multicenter 
trial comparing two acute graft-versus-host disease 
(aGVHD) prophylaxis regimens: tacrolimus / methotrexate 
(Tac/MTX) versus post-transplant cyclophosphamide / 
tacrolimus / mycophenolate mofetil (PTCy/Tac/MMF) in 
the setting of reduced intensity conditioning (RIC) 
allogeneic 
peripheral 
blood 
stem 
cell 
(PBSC) 
transplantation.  
Primary Objective:  
The primary objective of the trial is to compare 1 year 
GVHD-free, relapse-free survival (GRFS) between the two 
GVHD prophylaxis regimens. An event for this time—to-
event outcome is defined as grade III-IV aGVHD, chronic 
GVHD requiring systemic immune suppression, disease 
relapse or progression, or death by any cause.  
Secondary Objective:  
Secondary objectives are to describe for each treatment arm 
rates of grade II-IV and III-IV aGVHD, rates of Minnesota 
high risk aGVHD, chronic GVHD, immunosuppression-free 
survival at 1 year, hematologic recovery (neutrophil and 
platelet), donor cell engraftment, disease relapse or 
progression, transplant-related mortality, rates of grade 3+ 
toxicity according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0, incidence of grade 2-
3 infections, immune reconstitution, and overall survival.  
Eligibility Criteria:  
Eligible patients are at least 18.0 years of age undergoing 
allogeneic PBSC transplant for the treatment of acute 
leukemia and chronic myelogenous leukemia with no 
circulating blasts and less than 5% blasts in the bone 
marrow; 
or 
myelodysplasia/chronic 
myelomonocytic 
leukemia with no circulating blasts and less than 10% blasts 
in the bone marrow; chronic lymphocytic leukemia/small 


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lymphocytic lymphoma, follicular lymphoma, Hodgkin 
lymphoma, diffuse large B cell lymphoma, mantle cell 
lymphoma, 
peripheral 
T-cell 
lymphoma, 
angioimmunoblastic T-cell lymphoma and anaplastic large 
cell lymphoma sensitive to chemotherapy who are eligible 
for an allogeneic hematopoietic cell transplantation (HCT). 
Patients are eligible only if receiving a RIC regimen.  
Patients must have a related or unrelated PBSC donor. 
Sibling donor must be a 6/6 match for HLA-A and HLA-B 
at intermediate or higher resolution, and DRB1 at high 
resolution using DNA-based typing; must be willing to 
donate peripheral blood stem cells; and meet institutional 
criteria for donation. Unrelated donor must be a 7/8 or 8/8 
match at HLA-A, -B, -C, and -DRB1 at high resolution using 
DNA-based typing; must be willing to donate PBSCs; and 
be medically eligible to donate stem cells according to 
NMDP criteria.  
Treatment Description:  
Patients will be randomized to receive one of 2 specified 
GVHD 
prophylaxis 
regimens: 
Tac/MTX 
or 
PTCy/Tac/MMF. MTX will be dosed at 15 mg/m2 Day +1, 
and 10 mg/m2 Days +3, +6, and +11. PTCy will be dosed at 
50 mg/kg on Days +3 and +4, followed by Tac/MMF. MMF 
will be dosed at 15 mg/kg every 8 hours from Day +5 to Day 
+35.  
Accrual Objective:   
 
The clinical trial will enroll 428 patients, or 214 per arm.  
Accrual Period:  
 
 
The estimated accrual period is 36 months.  
Study Duration:  
 
 
Patients will be followed for 1 year post-PBSC transplant.  
Interim Analysis:  
The study will include one interim analysis for efficacy, for 
the primary endpoint at the time when the required total 
number of events is reached. Z test statistic for comparing 
the two treatment arms will be compared to the critical 
values and results will be reviewed by the NHLBI-appointed 
Data and Safety Monitoring Board (DSMB). If the test 
statistic is outside the continuation range, the DSMB will be 
consulted on the discontinuation of the trial.  


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Stopping Guidelines:  
Monitoring of the key safety endpoint of death will be 
conducted. The rate of overall mortality will be monitored 
up to Day 100 post-transplant separately in each of the 2 
treatment arms. Each month, the null hypothesis that the Day 
100 mortality rate is less than or equal to 15% is tested using 
a truncated Sequential Probability Ratio Test (SPRT) for 
censored exponential data. 


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Appendix A:  Plan Approval Signature Page..............................................................................................30
Appendix B – Tables and Figures...............................................................................................................33


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INTRODUCTION
This Statistical Analysis Plan (SAP) elaborates upon the analysis strategy introduced in the study 
protocol and includes detailed procedures for completing the statistical analysis of efficacy and 
safety endpoints. 
The content herein is based on BMT CTN Protocol 1703 version 4.0.  In order  to prevent bias 
from arising in the analysis, Version 0.5 of the SAP will be finalized and signed before the interim 
analysis for efficacy, for the primary endpoint at the time when the required total number of events 
is reached.  If required, revisions to the approved SAP may be made prior to the database hard 
lock. Revisions will be version controlled.
Any changes to the analyses described in the SAP will be detailed and justified in the final analysis 
report.
STUDY SCHEMA AND ASSESSMENT SCHEDULE
Study Schema
Outline of Treatment Plan
Age 18.0 years and older 
Controlled Malignant Diseases 
RIC
Related or Unrelated PBSC Donor
Tac/MTX
Tac/MMF/ 
Cyclophosphamide
Figure 1. Outline of Treatment Plan


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Schedule of Assessments
Pre-
Conditioning
Pre-
infusion
0
7
14
21
28
35
42
49
56
63
70
77
84
98
180
270
365
730
History, physical exam, weight
and height10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Karnofsky performance status
(see Appendix D)
X
X
X
X
X
HCT-Specific Comorbidity
Index score (see Appendix E)
X
Disease Risk Index (see
Appendix F)
X
Donor and recipient HLA
typing
X
CBC1, differential, platelet
count, and blood chemistries2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Infectious disease titers3
X
EKG and LVEF
X
DLCOcorr and FEV1predicted
X
Disease evaluation4
X
X
X
Chest x-ray or chest CT
X
Pregnancy test5
X
GVHD assessments6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Toxicity assessments7
X
X
X
X
X
X
Infection assessments11
X
X
X
X
X
X
X
X
X
X
X
X
Chimerism8
X
X
X
Table 1. Patient and Donor Clinical Assesment


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Pre- 
Conditioning 
Pre- 
infusion 
0 
 7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
98 
180 
270 
365 
730 
Patient Mi-Immune research 
samples (see Appendix J)9 
 
9 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Related donor CBC12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Related donor Mi-Immune 
research samples 
(see Appendix J) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
(see Appendix H) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X  
X  
Notes: 
1CBC with differential performed three times weekly from Day 0 until ANC at least 500/mcLor greater for three days and platelet count at least 20,000/mcL or greater after nadir, 
while hospitalized. CBC then performed weekly through Day 84 post-transplant, then at Days 98, 180, 270, 365 and 730 post-transplant (if patient consented to Mi-Immune 
study). For those patients participating in the Mi-Immune study, a CBC needs to be collected at the same time as the scheduled Mi-Immune research samples and 
reported in Advantage eClinical.  
2Blood chemistries include: serum creatinine, albumin, bilirubin, alkaline phosphatase, AST and ALT. Blood chemistries performed twice weekly until hospital 
discharge. Blood chemistries performed weekly after hospital discharge until Day 84 post-transplant, then at Days 98, 180, 270 and 365 post-transplant.  
3Infectious disease titers should be performed per institutional guidelines and may include: CMV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core 
Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV I/II antibody, and varicella zoster.  
4Evaluation of disease: (A) For acute leukemia, CML, and MDS, evaluation for malignant disease includes a bone marrow aspirate and biopsy for pathology and 
cytogenetics. A bone marrow biopsy must be performed no more than 44 days prior to the initiation of conditioning. (B) For lymphomas, bone marrow 
biopsy and/or imaging studies are appropriate for disease evaluation and will be done according to institutional practices. Patients with lymphomas should 
undergo the same post-transplant testing as their pre-transplant evaluation for matter of subsequent comparison. Imaging studies must be done no more than 
60 days prior to patient randomization.  
5Pregnancy test must be performed < 30 days before the start of the transplant conditioning regimen. Pregnancy test is required for females of child-bearing 
potential and may be performed per institutional practices.  
6GVHD assessments performed weekly from Day 7 until Day 84 post-transplant, and then at Days 98, 180, 270 and 365. The GVHD assessment will include a 
review of all abnormalities experienced during the entire assessment period and the highest grade for each abnormality during the assessment period will be 
recorded on the Acute GVHD form and the Follow-up/Chronic GVHD form in eClinical. The Chronic GVHD Provider Survey will record GVHD symptoms 
present in the last week (whether attributed to GVHD or not) and must be completed by a clinician on the day of the assessment.  
7The toxicity assessment will include a review of all toxicities experienced during the entire assessment period and the highest grade for each toxicity during 
the assessment period will be recorded on the Toxicity form in eClinical.  


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8Chimerism may be evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 or CD15 fraction, according to institutional 
practice. The actual measurement dates may be within +/- 7 days of the recommended time points.  
9The pre-conditioning baseline sample must be collected prior to the initiation of the transplant conditioning regimen and pre-antibiotic prophylaxis. These 
samples are to be collected from those patients who have consented to the Mi-Immune research samples. For patients, stool samples at Pre-Conditioning, Day 0, 
Day 7, Day 14, Day 21, and Day 28 are mandatory. Starting day 35 through day 77, then at day 98, 180, 270, 1 year, and 2 years, the stool samples are optional. 
Weekly urine sample collection for microbiome assays starting Pre-conditioning through Day 270, then at 1 year, and 2 years are ALL OPTIONAL. Pre-
transplant donor samples are to be collected from those donors who have signed the Mi-Immune consent.  
10Height is only required at baseline. It is not required to be repeated at the other time points.  
11The additional infection assessments will be performed for patients who have consented to the Mi-Immune research samples.  
12The related donor’s CBC needs to be collected at the same time as the scheduled Mi-Immune research samples and reported in Advantage eClinical from those 
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STUDY OBJECTIVES AND DESIGN
Study Objectives
The BMT CTN 1703 study is a Phase III randomized, open label, multicenter trial comparing post-
transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) versus 
tacrolimus/methotrexate (Tac/MTX) for GVHD prophylaxis in patients with controlled malignant 
diseases receiving an allogeneic PBSC transplant after a RIC regimen. The primary endpoint is 
GRFS at 1 year. 
3.1.1
Primary Objective
The primary objective of the randomized trial is to compare 1-year GRFS after HCT between 
PTCy/Tac/MMF versus Tac/MTX. An event for this time to event outcome is defined as grade III-
IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or 
progression, or death by any cause.
3.1.2
Secondary Objectives
Secondary objectives of the study are to assess the following:
1. Incidence of aGVHD grade II-IV and grade III-IV per the NIH Consensus Conference Criteria 
and Minnesota standard and high risk on aGVHD Grading at Days 100, 180 and at 1 year post-
transplant.
2. Incidence of chronic GVHD at 1 year post-transplant.
3. Systemic immunosuppression-free survival at 1 year post-transplant.
4. Probabilities of neutrophil recovery by Day 28 and Day 100. Probabilities of platelet recovery 
by Day 60 and Day 100. Probabilities of lymphocyte recovery by Day 60 and Day 100.
5. Donor chimerism at Day 28 and Day 100.
6. Incidence of disease relapse or progression at 1 year post-transplant.
7. Incidence of treatment-related mortality (TRM) at 1 year post-transplant.
8. Toxicity frequencies, grades 3-5, up to 1 year.
9. Incidence of systemic infections at 1 year.
10. Overall survival (OS) and disease-free survival (DFS) at 1 year post-transplant.
11. Probabilities of post-transplant lymphoproliferative disease (PRLD) at 1-year.


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12. Patient-Reported Outcomes at Day 0 (baseline) followed by Days 100, 180 and 1 year post-
transplant.
Study Design
The study is designed as a Phase III randomized, open label, multicenter trial to compare 
PTCy/Tac/MMF versus Tac/MTX for GVHD prophylaxis in patients with controlled malignant 
disease receiving an allogeneic PBSC transplant after a RIC regimen. The primary endpoint is 
GRFS at 1 year. The target enrollment is 428 patients in total, with 214 patients on each of the two 
treatment arms. 
The primary endpoint is GRFS as a time to event endpoint from the time of transplant. All 
transplanted patients will be followed for the primary endpoint for one year; however the primary 
endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the 
ITT population. The primary null hypothesis is that the hazard ratio for PTCy/Tac/MMF 
vsTac/MTX for the GRFS endpoint is equal to one versus an alternative hypothesis that the hazard 
ratio is not equal to one. A hazard ratio equal to one indicates no difference between the two 
treatments, while a hazard ratio less than one implies that the hazard of GRFS is lower for patients 
receiving PTCy/Tac/MMF compared with those in the Tac/MTX patient group. A hazard ratio 
greater than one would indicate an opposite treatment effect. This null hypothesis will be tested 
using a two-sided significance level of 5%.
One interim analysis for efficacy is included, to be performed once there are 147 cumulative GRFS 
events for the primary endpoint.  There will be no interim analyses for futility.
Site feasibility, selection, and qualification activities will not be performed for this project by 
Emmes. Please refer to the Project Management Plan for additional details.
Randomization
All patients will be randomized within 14 days prior to the initiation of conditioning therapy. 
Randomization will be performed in a 1:1 ratio using random block sizes for the two arms. 
Randomization will be stratified by centers and disease risk index (DRI Low, Intermediate and 
High). The DRI level “High” will include patients classified as both “High” and “Very High.”
SAMPLE SIZE AND POWER CONSIDERATIONS
Sample Size and Power
Sample size and power considerations are based on the comparison of PTCy/Tac/MMF to 
Tac/MTX using a Cox proportional hazards model. We assume an accrual period of 36 months 
and a 12-month follow-up period with a 5% drop-out rate. We further assume that the drop-out 
rate is exponentially distributed and that the GRFS endpoint matches the results of the BMT 
CTN 1203 trial control group. That is, the targeted effect size, HR of 0.66 is based on the 


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survival probabilities for GRFS of PTCy and Tac/MTX. Therefore, a sample size of 428 patients 
(214 per arm) is required to sufficiently maintain a two-sided type I error of 5% while providing 
90% statistical power for a two-sided test to detect a HR of 0.66.
InterimAnalysis and Stopping Guidelines
The study will consist of one interim analysis for efficacy after the required total number of events 
is reached in all evaluable patients for the primary endpoint to be reviewed by the NHLBI-
appointed Data and Safety Monitoring Board (DSMB). An interim analysis for efficacy will be 
conducted after reaching a total of 147 events at a 60% information fraction. The final analysis 
will be conducted when the targeted number of events of 244 occurs, or 1 year after the last patient 
is randomized. Policies and composition of the DSMB are described in the BMT CTN’s Manual 
of Procedures.
Analyses will be performed as described below for the primary endpoint. At the interim analysis 
time point, a Z test statistic for comparing the two treatments will be compared to the critical values
shown in Table 2. All patients with follow-up post randomization prior to the time of the interim 
analyses will be used to compute this statistic. If the test statistic is outside the continuation range, 
the DSMB will discuss the continuation of the trial. 
Efficacy stopping rules are based on the Wang and Tsiatis boundary family with shape parameters 
P=1.44, A=0, R=0 and G=1.9618. Higher values of P, with A and R fixed at zero, and G fixed at 
1.9618 will cause the group sequential test to be increasingly conservative at the earliest analyses 
times. This boundary corresponds approximately to a hazard ratio less than 0.5918 or greater than 
1.6898 and Z statistics less than -3.1710 or greater than 3.1710, respectively. A P-value less than 
0.00152 at the interim analysis would indicate a statistically significant result.
Table 2. Efficacy Stopping Thresholds
Info. 
Fraction
Sample 
Size
Cumulative 
GRFS 
Events
Nominal 
Cumulative 
Type I Error 
Rate
Hazard Ratio 
Efficacy 
Boundary 
Efficacy 
Boundary for Z 
Statistic
0.6
334
147
0.152%
(0.592, 1.690)
(-3.171, 3.171)
1.0
428
244
5.000%
(0.778, 1.286)
(-1.962, 1.962)
ANALYSIS POPULATIONS 
Intention-to-Treat Population
The intention-to-treat (ITT) population consists of all randomized subjects, classified according 
to their randomized treatment assignments. All randomized subjects are included, regardless of 
whether the assigned study treatment was truly administered.
Transplant Population


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The transplant population will include all subjects who have received a transplant after 
randomization. 
Safety Analysis Population
The safety analysis population is comprise of all subjects “as treated” in the study. This population 
will be used for the analysis of safety data. The “as treated” population consists of all randomized 
patients who received a HCT with one of the two randomized GVHD prophylaxis regimens. 
Patients will be included in the treatment group corresponding to the study treatment (GVHD 
prophylaxis) they actually received for the analysis of safety data using the “as treated” population. 
For most patients this will be the treatment group to which they are randomized.
STUDY OUTCOMES
Primary Endpoint
The primary endpoint is GVHD/relapse or progression-free survival (GRFS). An event for this 
time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD requiring systemic 
immune suppression, disease relapse or progression, or death by any cause. 
Use of systemic immunosuppressive therapy for treatment of chronic GVHD is at the discretion 
of the treating physicians. The event of interest is the development of chronic GVHD severe 
enough to warrant any additional systemic treatment(s). Also, continuation of study-mandated 
GVHD prophylaxis beyond Day 180 in the presence of chronic GVHD will also be considered an 
event with time to event determined as date of chronic GVHD onset. 
Secondary Endpoints
Specific information regarding study supplies will be outlined in the BMT CTN 2001 
Manufacturing MOO.
6.2.1
Acute GVHD
Cumulative incidences of grade II-IV and III-IV acute GVHD will be determined. Acute GVHD 
will be graded according to Mount Sinai Acute GVHD International Consortium (MAGIC) 
Criteria (Harris et al. 2016). The time of onset of acute grades II-IV and III-IV acute GVHD will 
be recorded, as well as the maximum grade achieved. Within the acute GVHD endpoint, the 
proportion of patients with visceral involvement (liver or gut) will be described. Cumulative 
incidences of Minnesota standard and high risk acute GVHD will also be determined.  
6.2.2
Chronic GVHD
The cumulative incidence of chronic GVHD will be determined. Data will be collected directly 
from providers and chart review as defined by the NIH Consensus Conference Criteria. Eight 
organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and 


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pulmonary function test results, and use of systemic therapy for treatment of chronic GVHD will 
also be recorded. These data will allow calculation of the NIH global severity scores of mild, 
moderate and severe chronic GVHD, which has been associated with transplant related mortality 
and overall survival. Assessment of chronic GVHD will occur up to 1 year post-transplant. 
6.2.3 Systemic Immunosuppression-free Survival 
Patients who are alive, relapse-free, and do not need ongoing immune suppression to control 
GVHD at one year post-transplant are considered successes for this endpoint. Immune suppression 
is defined as any systemic agents used to control or suppress GVHD. Corticosteroid doses greater 
than 10 mg will be considered active systemic immune suppression treatment. Patients who 
discontinued immune suppression within 15 days or less prior to the 1-year time point will be 
considered to be on immune suppression for this endpoint. 
6.2.4 Hematologic Recovery 
Hematologic recovery will be assessed according to neutrophil and platelet counts recovery after 
transplant. Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) 
greater than or equal to 500/mm3 for three consecutive measurements on three different days. 
The first of the three days will be designated the day of neutrophil recovery. The competing 
event is death without neutrophil recovery. For patients who never drop ANC below 500/mm3, 
the date of neutrophil recovery will be Day +1 post-transplant.  
Platelet recovery is defined by two different metrics: the first day of a sustained platelet count 
greater than or equal to 20,000/mm3 or greater than or equal to 50,000/mm3 with no platelet 
transfusions in the preceding seven days. The first day of sustained platelet count above these 
thresholds will be designated the day of platelet engraftment. For patients who never drop their 
platelet count below 20,000/mm3 or 50,000/mm3, the date of platelet recovery will be Day +1 
post HCT.  
Lymphocyte recovery will be defined as the first day of sustained absolute lymphocyte count 
greater than or equal to 1000/mm3. 
6.2.5 Donor Cell Engraftment  
Donor cell engraftment will be assessed with donor/recipient chimerism studies. Chimerism may 
be evaluated in bone marrow, whole unfractionated blood or blood cell fractions, including CD3 
and CD33 or CD15 fraction. For the purpose of this protocol, mixed chimerism is defined as the 
presence of donor cells, as a proportion of total cells to be less than 95% but at least 5% in the 
bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 
95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor 
cells of less than 5% will be considered as graft rejection. The proportion of patients with each 
level of chimerism described above will be described as part of this outcome. For sorted blood 


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cell fractions, CD3+ donor cell chimerism will be used to define the donor/recipient chimerism 
status. 
6.2.6 Disease Relapse or Progression  
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy. Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation. The 
event is defined as increase in size of prior sites of disease or evidence of new sites of disease, 
documented or not by biopsy. 
6.2.7 Transplant-Related Mortality  
The cumulative incidence of TRM will be estimated at Days 100, 180 and 1 year after HCT. An 
event for this endpoint is death without evidence of disease progression or recurrence. Disease 
progression or recurrence will be considered competing events. 
6.2.8 Toxicity 
All grade 3-5 toxicities according to CTCAE, version 5.0 will be tabulated for each intervention 
arm up to 1 year post-transplant. The proportion of patients developing at least a grade 3 or more 
AE across intervention arms will be compared. 
6.2.9 Infections 
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for 
each intervention arm. The cumulative incidence of treated CMV reactivation in the first 100 
days post-transplant will be described. All Grade 2 and 3 infections will be reported according to 
the BMT CTN Technical MOP up to 1 year post-transplant. 
6.2.10 Disease-Free Survival (DFS) 
Disease-free survival is the time from date of transplant to death or relapse/progression, 
whichever comes first. The event for this endpoint is relapse/progression or death. Patients alive 
and disease free will be censored at last follow-up. 
6.2.11 Overall Survival (OS) 
Overall survival is defined as the time interval between date of transplant and death from any 
cause. The event for this endpoint is death from any cause. Surviving patients will be censored at 
last follow-up. 
6.2.12 Post-Transplant Lymphoproliferative Disease 
The incidence of post-transplant lymphoproliferative disease (PTLD) will be measured at one 
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6.2.13 Patient-Reported Outcomes (PRO) 
PRO will be measured at Baseline and then at Day 100, Day 180 and 1 year post-transplant using 
the Lee Chronic GVHD Symptom Scale, Hemorrhagic Cystitis symptom questions, and selected 
PROMIS subscales for gastrointestinal symptoms, physical function and satisfaction with 
participation in social roles. The instruments will be scored according to the recommendations of 
the developers. PRO data will be collected electronically, or on paper vial mail if requested by 
the patient. Whether collected electronically or on paper, PRO data will be entered in the 
CIBMTR’s ePRO system. The PRO instruments will only be offered to English and Spanish 
speaking patients.
Adverse Event Reporting Requirements
6.3.1
Definitions
Safety outcomes of interest include adverse events (AEs), serious adverse events (SAEs), and 
deaths.  SAEs are defined as AEs that resulted in one of the following outcomes: death, a threat 
to life, requiring or prolonging inpatient hospitalization, causing persistent or significant 
disability, causing a congenital anomaly or birth defect, or requiring intervention to prevent any 
of the aforementioned outcomes.
Adverse Event: An Adverse Event (AE) is defined as any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease that is temporally associated 
with the use of a medical treatment or procedure regardless of whether it is considered related to 
the medical treatment or procedure.
Expectedness: An adverse event can be Expected or Unexpected 
x
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk. 
x
Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
Serious Adverse Event: A serious adverse event (SAE), as defined by per 21 CFR 312.32, is any 
adverse event that results in one of the following outcomes, regardless of causality and 
expectedness: 
x
Results in death 
x
Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
x
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
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Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned).  
x Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.  
x Is a congenital anomaly or birth defect; or  
x Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical events 
may not be immediately life threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the outcomes listed in the definition above 
(eg, suspected transmission of an infectious agent by a medicinal product is considered a Serious 
Adverse Event). Any event is considered a Serious Adverse Event if it is associated with clinical 
signs or symptoms judged by the investigator to have a significant clinical impact. 
6.3.2 BMT CTN Adverse Event Reporting Guidelines  
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN Administrative 
Manual of Procedures, Chapter 6). It is BMT CTN policy that AEs must be reported even if the 
investigator is unsure whether a relationship exists between the adverse event and the use of study 
treatment.  
Unexpected, serious adverse events (SAEs) will be reported through an expedited AE reporting 
system via Advantage eClinical. Unexpected, life-threatening and fatal SAEs must be reported 
within 24 hours of knowledge of the event. All other unexpected SAEs must be reported 
within three business days of knowledge of the event. Events entered in Advantage eClinical 
will be reported using NCI’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0.  
Expected AEs will be reported using NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 at regular intervals as defined on the Form Submission Schedule, including 
calendar-driven case report forms (e.g., Toxicity and GVHD) or event-driven case report forms 
(e.g., Relapse/Progression, Infection, and Death). Any expected life-threatening SAE not 
collected on another study form must be reported through the expedited AE reporting 
system via Advantage eClinical.  


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The Data and Safety Monitoring Board will receive summary reports of all unexpected SAEs on a 
semi-annual basis.
STATISTICAL METHODOLOGY
General Guidelines
Counts and percentages will be used to describe categorical variables, while the number of subjects 
(N), median, mean, standard deviation, and range will be used to summarize continuous variables.
The study day for most efficacy and safety assessments will be computed in reference to the date 
of randomization, with the date of randomization defined as Study Day 0 for each patient.  For all 
assessments, the (Study) Day will be calculated as (assessment date – randomization date). For 
outcomes where data is summarized in reference to other date, such as treatment initiation, the 
assessment time point will be clarified explicitly.
For all variables, the baseline value is defined as the last available measurement before 
randomization.
The primary null hypothesis is that the hazard ratio between PTCy/Tac/MMF and Tac/MTX for 
GRFS endpoint is equal to one versus an alternative hypothesis that the hazard ratio is not equal 
to one. A hazard ratio equal to one indicates no difference between the two treatments, while a 
hazard ratio less than one implies that the hazard of GRFS is lower for patients receiving 
PTCy/Tac/MMF compared with those in the Tac/MTX patient group. A hazard ratio greater than 
one would indicate an opposite treatment effect. 
All statistical analyses including primary and secondary outcomes will use the ITT population 
unless stated otherwise. All hypothesis tests will be two-sided with a type I error rate of 5% unless 
stated otherwise.
All data processing, summarization, and analyses will be performed using SAS Version 9.4 or 
higher, or R version 4.0 or higher.  Specifications for the table, figure, and data listing formats can 
be found in the templates created for this SAP.
Demographics and Disposition
7.2.1
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized using descriptive statistics. 
Categorical variables to be examined include age, gender, race/ethnicity, Karnofsky/Lansky 
performance status (<90 vs. >=90) at transplant, primary disease at transplant, disease-specific risk 
categories, disease risk index (DRI), hematopoietic cell transplant comorbidity index (HCT CI), 
donor type and HLA matching, donor/recipient CMV status, donor/recipient sex match, 
donor/recipient ABO match, and conditioning regimen. If a categorical variable has missing data 


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for some patient(s), a “Missing” category will be included as well for that variable with its 
frequency and percentage. Continuous characteristics to be considered include age, time from 
disease diagnosis to transplant, and.  If a continuous variable has missing data for some patient(s), 
the number missing will also be described.
7.2.2
Participant Disposition
The summary of subject disposition for the ITT population will include:
x
Number and percent of patients in ITT population
x
Number and percent initiating GVHD prophylaxis
x
Number and percent initiating GVHD prophylaxis as randomized
x
Number and percent withdrawn from study after initiating study drug
x
Number and percent who completed planned study follow-up (i.e. died before 12 months or 
survived on study up to 12 months post-transplant)
In addition, the reasons for patients withdrawing from the study will be tabulated.
7.2.3
Protocol Deviations
The number and percentage of patients in the ITT population with any protocol deviation will be 
tabulated by the deviation category.  A listing of all protocol deviations will be provided.
Statisitcal Analysis
7.3.1
Primary Endpoint – GRFS
7.3.1.1
Primary Analysis
The primary analysis will consist of a comparison of the treatment arms (PTCy/Tac/MMF vs 
Tac/MTX) in the ITT population using a multivariate Cox regression model. The following 
covariates will be included in the regression model: age, DRI, planned RIC regimen, donor 
type/HLA matching, and planned use of post-transplant maintenance therapy. A significance level 
of 0.05 (two-sided) will be used to test the null hypothesis of no difference between the treatments. 
Ninety-five percent confidence intervals for the hazard ratio of the PTCy/Tac/MMF treatment will 
also be constructed. 
7.3.2
Secondary Endpoints
For analyses of secondary endpoints, adverse events will be evaluated in the safety population. All 
other endpoints will be evaluated in the ITT or transplant population as appropriate.
7.3.2.1
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Time to acute GVHD is defined as the time from transplant until time of onset of acute grades II-
IV and III-IV acute GVHD. Cumulative incidence of acute GVHD grade II-IV and grade III-IV at 
Days 100, 180 and 1 year will be estimated using the Aalen-Johansen estimator for each treatment 
group, treating death prior to aGVHD as a competing event. Cumulative incidences of Minnesota 
standard and high risk acute GVHD at 1 year will also be determined. 95% confidence intervals 
will also be constructed from this estimator using the complementary log-log transformation.  
A multivariate Cox regression model for the cause-specific hazard of aGVHD will be used to 
compare the treatment groups, after adjustment for baseline characteristics as described for the 
primary endpoint. The Cox regression model will be used to evaluate the adjusted hazard ratio of 
treatment (PTCy/Tac/MMF vs Tac/MTX) using a point estimate and a 95% confidence interval. 
A corresponding adjusted Kaplan-Meier plot comparing treatment groups will be produced. 
The maximum severity of acute GVHD and the proportion of patients with visceral involvement 
(liver or gut) through 1 year post-transplant will be tabulated by treatment arm. 
7.3.2.2 
Chronic GVHD 
The time from transplant until the onset of chronic GVHD of any severity (mild, moderate, or 
severe per 2014 NIH Consensus Criteria) will be described graphically using the Aalen-Johansen 
estimator (Aalen and Johansen 1978), with death prior to chronic GVHD onset treated as a 
competing risk.  Estimates of the cumulative incidence of chronic GVHD will be provided at 6 
and 12 months post-transplant along with 95% CIs computed using the complementary log-log 
transformation.  
A multivariate Cox regression model for the cause-specific hazards of cGVHD will be used to 
compare the treatment groups, after adjustment for baseline characteristics as described for the 
primary endpoint. The Cox regression model will be used to evaluate the adjusted hazard ratio of 
treatment (PTCy/Tac/MMF vs Tac/MTX) using a point estimate and a 95% confidence interval. 
A corresponding adjusted Kaplan-Meier plot comparing treatment groups will be produced. 
The maximum severity of chronic GVHD through 12 months post-transplant will be tabulated by 
treatment arm. 
7.3.2.3 
Systemic Immunosuppression-Free Survival 
Proportions of patients alive, relapse free, and off immune suppression at 1 year post-transplant 
will be described for each treatment group, along with 95% Clopper-Pearson confidence intervals. 
If there is substantial censoring (more than 10%) prior to one year, multistate models will be 
constructed to estimate these probabilities by treatment groups. Agreement between this endpoint 
and the primary endpoint of GRFS will be described using cross-tabulation frequencies and 
assessed using the Kappa statistic. 
7.3.2.4 
Hematologic Recovery 


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The time from transplant until neutrophil recovery and platelet recovery will be described 
graphically for each treatment arm using the Aalen-Johansen estimator (Aalen and Johansen 1978). 
The cumulative incidence of neutrophil recovery by Day 28 and Day 100 will be described for 
each treatment group with point estimates and 95% confidence intervals using the complementary 
log-log transformation and treating death as a competing event. Similarly, cumulative incidence 
estimate of platelet recovery by Day 60 and Day 100 will be described by treatment group with 
95% confidence intervals (complementary log-log transformation), treating death as a competing 
event. These cumulative incidence curves will be compared between arms using Gray’s test. 
7.3.2.5 
Donor Cell Engraftment 
Donor chimerism at Day 28 and Day 100 after transplantation in each of the randomized treatment 
arms will be described numerically as the median and range among those evaluable as well as by 
the proportions with full (>95% donor cell), mixed (5.0-94.9% donor cells), graft rejection (<5%), 
or death prior to assessment of donor chimerism. Incidence of secondary graft failure (chimerism 
<5% after initial donor cell engraftment) will be described for each arm using frequencies. 
Comparisons between arms of quantitative donor chimerism will be done using Wilcoxon rank 
sum tests, while treatment comparisons of categorical donor chimerism groups will be done using 
a chi-square tests.  
7.3.2.6 
Disease Relapse or Progression 
Disease relapse or progression is defined as being alive and free of relapse/progression of the 
primary disease. The time from transplant until relapse/progression of the primary disease will be 
described graphically for each treatment arm using the Aalen-Johansen estimator, treating death 
prior to disease relapse as a competing event.  Estimates of disease relapse or progression at 1 year 
post-transplant will be provided along with 95% CIs computed using the complementary log-log 
transformation as detailed in Kalbfleisch and Prentice 1980. Gray’s test will be used to compare 
disease relapse or progression within 1 year of randomization between arms. 
A multivariate Cox regression model for the cause-specific hazard of relapse or progression will 
be used to compare the treatment groups, after adjustment for baseline characteristics as described 
for the primary endpoint. The Cox regression model will be used to evaluate the adjusted hazard 
ratio of treatment (PTCy/Tac/MMF vs Tac/MTX) using a point estimate and a 95% confidence 
interval. A corresponding adjusted Kaplan-Meier plot comparing treatment groups will be 
produced. 
7.3.2.7 
Treatment-Related Mortality (TRM) 
The time from transplant until TRM will be described graphically for each treatment arm using 
the Aalen-Johansen estimator (Aalen and Johansen 1978), with numbers of subjects at risk at 
specific time points presented for each treatment group and relapse/progression of the primary 
disease treated as a competing risk.  Estimates of the cumulative incidence of TRM will be 


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provided at Days 100, 180 and 1 year post-transplant along with 95% CIs computed using the 
complementary log-log transformation.  
A multivariate Cox regression model for the cause-specific hazard of TRM will be used to compare 
the treatment groups, after adjustment for baseline characteristics as described for the primary 
endpoint. The Cox regression model will be used to evaluate the adjusted hazard ratio of treatment 
(PTCy/Tac/MMF vs Tac/MTX) using a point estimate and a 95% confidence interval. A 
corresponding adjusted Kaplan-Meier plot comparing treatment groups will be produced. 
7.3.2.8 
Adverse Events (Toxicity) 
The frequency of Grade 3-5 adverse events per CTCAE version 5.0 occurring through 1 year post-
transplant will be tabulated by the organ system for each treatment arm. This analysis will use the 
safety population. 
The proportions of patients experiencing a Grade 3-5 adverse event,  through 1 year post-
transplantation, will be described by 95% Wilson score or Clopper-Pearson CIs and compared 
between treatment arms using Barnard’s exact test or a chi-squared test. 
7.3.2.9 
Infections 
The frequency of Grade 2-3 infections and the number of patients experiencing infections 
occurring within 1 year post-transplant, will be tabulated by treatment arm, disease site, date of 
onset, and severity, with Grade defined per the BMT CTN Technical MOP. 
The time from transplant until the first Grade 2-3 infection will be described graphically using the 
Aalen-Johansen estimator, with death before infection treated as a competing risk.  Provided there 
is sufficient data, estimates of the cumulative incidence of Grade 2-3 infection will be provided at 
6 and 12 months post-transplant along with 95% CIs computed using the complementary log-log 
transformation. Gray’s test will be used to compare the cumulative incidence of Grade 2-3 
infection within 12 months of randomization between arms. 
Among patients with previous CMV exposure (either donor or recipient was previously CMV 
positive), the cumulative incidence of initiation of systemic treatment for CMV reactivation will 
be described graphically using the Aalen-Johansen estimator, with death treated as a competing 
risk.  Estimates of the cumulative incidence of CMV reactivation will be provided at Day 100 post-
transplant for each arm along with 95% CIs computed using the complementary log-log 
transformation.  Gray’s test will be used to compare the cumulative incidence of CMV reactivation 
within 100 days of randomization between arms. 
7.3.2.10 
Disease-Free Survival (DFS) 
DFS is defined as being alive and free of relapse/progression of the primary disease. The time from 
transplant until death or relapse/progression (DFS failure) will be described graphically for each 
treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time 
points presented for each treatment group.  Estimates of DFS at 1 year post-transplant will be 


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provided along with 95% CIs computed using the complementary log-log transformation as 
detailed in Kalbfleisch and Prentice 1980.  
A multivariate Cox regression model for the hazards of DFS will be used to compare the treatment 
groups, after adjustment for baseline characteristics as described for the primary endpoint. The 
Cox regression model will be used to evaluate the adjusted hazard ratio of treatment 
(PTCy/Tac/MMF vs Tac/MTX) using a point estimate and 95% confidence interval. A 
corresponding adjusted Kaplan-Meier plot comparing treatment groups will be produced. 
7.3.2.11 
Overall Survival (OS) 
The time from transplant until death from any cause will be described graphically for each 
treatment arm using the Kaplan-Meier estimator, with numbers of subjects at risk at specific time 
points presented for each treatment group. 
Estimates of OS at 1 year post-transplant will be provided along with 95% CIs computed using the 
complementary log-log transformation as detailed in Kalbfleisch and Prentice 1980.  
A multivariate Cox regression model for the hazard of death will be used to compare the treatment 
groups, after adjustment for baseline characteristics as described for the primary endpoint. The 
Cox regression model will be used to evaluate the adjusted hazard ratio of treatment 
(PTCy/Tac/MMF vs Tac/MTX) using a point estimate and a 95% confidence interval. A 
corresponding adjusted Kaplan-Meier plot comparing treatment groups will be produced 
7.3.2.12 
Post-Transplant Lymphoproliferative Disease (PTLD) 
The cumulative incidence of lymphoproliferative disease at 1-year post-transplant will be 
described with 95% confidence intervals for each treatment group using the Aalen-Johansen 
estimator, treating death as a competing event. These estimates will be compared between groups 
using Gray’s test. This analysis will use the transplant population. 
7.3.2.13 
Patient-Reported Outcomes (PRO) 
Patient-Reported Outcomes will be measured at baseline then at Days 100, 180 and 1 year post-
transplant. All subjetcs with at least one post HCT PRO assessment will be incorporated within 
the relevant analysis, whether they completed or discontinued the study. Descriptive statistics of 
PROs will be provided. These will include the mean, standard deviation, number of observation, 
percentage missing, change and percent change from baseline, at all scheduled visits including 
baseline visits. 
Of the three PROMIS subscales ("Health Measures: Transforming How Health Is Measured.", 
2021), only physical function will be analyzed in a multivariate model. The analysis for PROMIS 
subscales for gastrointestinal symptoms and satisfaction with participation in social roles will be 
descriptive since these are based on two questions each. Additionally, the Lee chronic GHHD 
symptom scale (Lee et al, 2002) will be analyzed in a multivariate model. 


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Patterns of missing PRO data will be examined using graphical techniques and logistic regression 
models. At each time point, the effect of baseline characteristics as described for the primary 
endpoint on PROs conditional on being alive at that time point will be estimated using the inverse 
probability of censoring-weighted generalized estimating equations (IPCW-GEE) with 
independent working correlation model of Kurland and Heagerty. Multiple imputation methods 
may also be used ID (Schafer, 1997; Brand, 1999; Van Buuren, 2007). These methods will provide 
adjusted comparisons of mean PROs between treatment groups at each time point conditional on 
being alive at that time point.
Missing Data and Sensitivity Analysis
For time-to-event outcomes such as GRFS, TRM, OS, DFS, and relapse/progression, patients 
that withdraw or are lost to follow-up are assumed to be censored at random.
For other endpoints, the occurrence of missing data, whether due to the patient’s missing 
assessment(s) or withdrawal from the study, is assumed to be missing at random (MAR).
Safety Analysis
All AEs and SAEs reported on the study according to the NCI Common Terminology Criteria for 
Adverse Events Version 5.0.  The number of each type of event and number of patients affected 
will be described using descriptive statistics by treatment groups. These events will be reported 
using the safety analysis population.
Interim Analysis
The study will consist of one interim analysis for efficacy after the required total number of events 
is reached in all evaluable patients for the primary endpoint; the interim analysis will be reviewed 
by the NHLBI-appointed Data and Safety Monitoring Board (DSMB). An interim analysis for 
efficacy will be conducted after reaching a total of 147 events, at a 60% information fraction. The 
final analysis will be conducted when either the targeted number of events of 244 has occured or 
all randomized patients complete 1 year of follow-up post-transplant. Policies and composition of 
the DSMB are described in the BMT CTN’s Manual of Procedures.
Analyses will be performed as described below for the primary endpoint. At the interim analysis 
time point, a Z test statistic for comparing the two treatments will be compared to the critical values 
shown in Table 3. All patients with follow-up post randomization prior to the time of the interim 
analyses will be used to compute this statistic. If the test statistic is outside the continuation range, 
the DSMB will discuss the continuation of the trial. Should the DSMB stop the trial for efficacy, 
all patients receiving the inferior treatment arm will be switched to the superior treatment arm 
where the study will proceed until the targeted sample size for Mi-Immune is reached. 
Efficacy stopping rules are based on the Wang and Tsiatis boundary family with shape parameters 
P=1.44, A=0, R=0 and G=1.9618.25 Higher values of P, with A and R fixed at zero, and G fixed 
at 1.9618 will cause the group sequential test to be increasingly conservative at the earliest analyses 


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times. This boundary corresponds approximately to a hazard ratio less than 0.5918 or greater than 
1.6898 and Z statistics less than -3.1710 or greater than 3.1710, respectively. A P-value less than 
0.00152 at the interim analysis would indicate a statistically significant result. 
These stopping guidelines serve as triggers for consultation with the DSMB for guidance and are 
not formal “stopping rules” that would mandate automatic closure of study enrollment.  The 
monitoring scheme is detailed in section 5.3.3 of the study protocol. 
Assessment of Impact of COVID-19 on Trial Results
The BMT CTN considers the COVID-19 era to have potentially impacted its trials effective March 
10, 2020 unless otherwise specified.  Data collection was adjusted and guidance was given to 
centers to track the impact of COVID-19.  Specifically, the following modifications were made:
x
Impact of COVID-19 on scheduled visits and assessments: Collection of information about 
whether visits were missed or scheduled out of the assessment window; the type of visit (clinic 
visit, telemedicine visit, phone contact, or combination); and if the visit was missed, what the 
reason for the missed visit was (which included COVID-19 as an option)
x
COVID-19 infections: Guidance on the collection of COVID-19 infection occurrences was 
incorporated into the infection data collection form
x
COVID-19 related deaths: Addition of COVID-19 as a potential primary cause of death
Summary data will be provided on visits that were missed during the COVID era and their 
potential attribution to COVID-related concerns.  Infections and death attributed to COVID-19 
will also be described by treatment arm.  Sensitivity analyses will be performed for key study 
endpoints to evaluate the impact of COVID-19 related disruptions to study conduct on the 
results. Additional details will be added in a supplemental file for the SAP or described in the 
final analysis report.


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CHANGES TO PROTOCOL-SPECIFIED ANALYSIS
The current SAP elaborates on the protocol-specified analysis and makes no deviation from it.  
Any future changes made to the protocol-specified analysis, and the justification for these changes, 
will be documented in the amendment to this SAP.
REFERENCES
T Aalen, O. O. and S. Johansen (1978). An empirical transition matrix for non-homogeneous 
Markov chains based on censored observations. Scand J Stat 141-150.
Brand, J. P. L. (1999). “Development, Implementation, and Evaluation of Multiple Imputation 
Strategies for the Statistical Analysis of Incomplete Data Sets.” Ph.D. thesis, Erasmus 
University.
Clopper, C. J., and E. S. Pearson. (1934). The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika 26: 404-413.
"Health Measures: Transforming How Health Is Measured." . PROMIS Scoring Manuals. 
Retrieved from https://tinyurl.com/2t3rdya5 Accessed 16 Apr. 2021.
Kalbfleisch, J. D. and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New 
York: John Wiley & Sons.
Kittelson, J. M. and Emerson, S. S. (1999). A unifying family of group sequential test designs. 
Biometrics 55(3), 874-882.
Lee, S.J., Cook, E.F., Soiffer, R. and Antin, J.H., 2002. Development and validation of a scale to 
measure symptoms of chronic graft-versus-host disease. Biology of Blood and Marrow 
Transplantation, 8(8), pp.444-452.
Schafer, J. L. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall.
Van Buuren, S. (2007). “Multiple Imputation of Discrete and Continuous Data by Fully 
Conditional Specification.” Statistical Methods in Medical Research 16:219–242.


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Appendix A:  
Plan Approval Signature Page 
BMT CTN 1703 STATISTICAL ANLAYSIS PLAN 
Prepared and Accepted by: 
Protocol Chair: 
Signature: 
 
Date: 
 
Print Name: 
Mehdi Hamadani 
 
MMDDYYYY 
Title: 
Protocol Chair - Officer 
 
 
Attestation: 
I am approving this document. 
 
 
 
 
 
Mehdi  Hamadani
07/26/2021 05:41 PM EDT
Mehdi Hamadani
I am approving this document.


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Appendix A: 
Plan Approval Signature Page 
BMT CTN 1703 STATISTICAL ANLAYSIS PLAN 
Prepared and Accepted by: 
Protocol Statistician: 
Signature: 
 
Date: 
 
Print Name: 
Raphael Fraser 
 
MMDDYYYY 
Title: 
BMT CTN Protocol Statistician 
 
 
Attestation: 
I am approving this document. 
 
 
Raphael  Fraser
I am approving this document.
07/27/2021 09:44 AM EDT
Raphael Fraser


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Appendix A: 
Plan Approval Signature Page 
BMT CTN 1703 STATISTICAL ANLAYSIS PLAN 
Prepared and Accepted by: 
BMT CTN Statistician Leadership: 
Signature: 
 
Date: 
 
Print Name: 
Brent Logan 
 
MMDDYYYY 
Title: 
BMT CTN Statistician Leadership 
 
 
Attestation: 
I am approving this document. 
 
 
Brent  Logan
07/28/2021 03:43 PM EDT
I am approving this document.
Brent Logan


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Appendix B – Tables and Figures 
List of Tables: 
TABLE 1. PATIENT AND DONOR CLINICAL ASSESMENT ............................................................................. 10 
TABLE 2. EFFICACY STOPPING THRESHOLDS ............................................................................................. 15 
TABLE 3. STUDY ENROLLMENT OVER TIME ............................................................................................... 35 
TABLE 4. ACTUAL VS. PROJECTED ENROLLMENT ...................................................................................... 35 
TABLE 5. ANALYSIS POPULATIONS ............................................................................................................. 37 
TABLE 6. DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................................................................... 38 
TABLE 7. PRIMARY ANALYSIS—MULTIVARIATE COX PH MODEL FOR HAZARD OF GRFS ...................... 41 
TABLE 8. SENSITIVITY ANALYSIS #1 RE COVID-19 .................................................................................. 42 
TABLE 9. SENSITIVITY ANALYSIS #2 RE COVID-19 .................................................................................. 42 
TABLE 10. CUMULATIVE INCIDENCE OF ACUTE GVHD ............................................................................. 45 
TABLE 11. CUMULATIVE INCIDENCES OF MINNESOTA ACUTE GVHD ...................................................... 45 
TABLE 12. ACUTE GVHD SUMMARY ......................................................................................................... 46 
TABLE 13. ACUTE GVHD—COX PH MODEL ............................................................................................. 47 
TABLE 14. CUMULATIVE INCIDENCE OF CHRONIC GVHD ......................................................................... 48 
TABLE 15. CHRONIC GVHD—COX PH MODEL ......................................................................................... 49 
TABLE 16. MAXIMUM SEVERITY OF CHRONIC GVHD THROUGH 12 MONTHS POST-TRANSPLANT ........... 49 
TABLE 17. SYSTEMIC IMMUNOSUPPRESSION-FREE SURVIVAL AT 12 MONTHS POST-TRANSPLANT ......... 50 
TABLE 18. MEASURE OF AGREEMENT BETWEEN GRFS EVENTS AND SYSTEMIC IMMUNOSUPPRESSION-
FREE SURVIVAL .................................................................................................................................. 50 
TABLE 19. PROBABILITY OF NEUTROPHIL RECOVERY ............................................................................... 53 
TABLE 20. PROBABILITY OF PLATELET RECOVERY .................................................................................... 53 
TABLE 21. PROBABILITY OF LYMPHOCYTE RECOVERY.............................................................................. 53 
TABLE 22. DONOR CELL ENGRAFTMENT .................................................................................................... 54 
TABLE 23. INCIDENCE OF SECONDARY GRAFT FAILURE ............................................................................ 54 
TABLE 24. RELAPSE/PROGRESSION—COX PH MODEL .............................................................................. 55 
TABLE 25. CUMULATIVE INCIDENCE OF RELAPSE/PROGRESSION .............................................................. 56 
TABLE 26. TREATMENT-RELATED MORTALITY—COX PH MODEL ........................................................... 57 
TABLE 27. CUMULATIVE INCIDENCE OF TREATMENT-RELATED MORTALITY ........................................... 58 
TABLE 28. ADVERSE EVENTS (AES) OCCURRING THROUGH 12 MONTHS POST-TRANSPLANT BY SYSTEM 
ORGAN CLASS .................................................................................................................................... 59 
TABLE 29. ADVERSE EVENTS (AES) OCCURRING THROUGH 12 MONTHS POST-TRANSPLANT ................. 59 
TABLE 30. ADVERSE EVENTS SUMMARY THROUGH 12 MONTHS POST-TRANSPLANT .............................. 59 
TABLE 31. ADVERSE EVENTS REPORTED THROUGH 12 MONTHS POST-TRANSPLANT .............................. 60 
TABLE 32. SEVERE ADVERSE EVENTS REPORTED THROUGH 12 MONTHS POST-TRANSPLANT ................ 60 
TABLE 33. TOXICITIES THROUGH 12 MONTHS POST-TRANSPLANT ........................................................... 61 
TABLE 34. INFECTIONS ................................................................................................................................ 62 
TABLE 35. CUMULATIVE INCIDENCE OF INFECTIONS ................................................................................. 63 
TABLE 36. DISEASE-FREE SURVIVAL (DFS) PROBABILITY AT 1 YEAR ...................................................... 64 
TABLE 37. DISEASE-FREE SURVIVAL (DFS)—COX PH MODEL ................................................................ 65 
TABLE 38. OVERALL SURVIVAL (OS) PROBABILITY AT 1 YEAR ................................................................ 66 
TABLE 39. OVERALL SURVIVAL (OS)—COX PH MODEL........................................................................... 67 


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TABLE 40. CUMULATIVE INCIDENCE OF PTLD AT 1 YEAR ........................................................................ 68 
TABLE 41. PATIENT-REPORTED OUTCOMES FOR HEMORRHAGIC CYSTITIS ............................................... 69 
TABLE 42. PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM (PROMIS) DOMAIN 
SCORES FOR GASTROINTESTINAL SYMPTOMS ................................................................................... 70 
TABLE 43. PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM (PROMIS) FOR 
SATISFACTION WITH PARTICIPATION IN SOCIAL ROLES .................................................................... 70 
TABLE 44. PATIENT-REPORTED OUTCOMES SCORES FOR CHRONIC GVHD SYMPTOM SCALE ................. 71 
TABLE 45. PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION SYSTEM (PROMIS) DOMAIN 
SCORES FOR PHYSICAL FUNCTION ..................................................................................................... 71 
TABLE 46. IPCW-GEE MODEL OF CHANGE IN CHRONIC GVHD SYMPTOM SCALE FROM BASELINE 
ASSUMING EQUAL MEAN DOMIAN T-SCORE AT BASELINE (DAY 0) IN EACH TREATMENT ARM. .... 72 
TABLE 47. IPCW-GEE MODEL OF CHANGE IN PROMIS DOMAIN PHYSICAL FUNCTION T-SCORE FROM 
BASELINE ASSUMING EQUAL MEAN DOMIAN T-SCORE AT BASELINE (DAY 0) IN EACH TREATMENT 
ARM .................................................................................................................................................... 72 
TABLE 48. PRIMARY CAUSE OF DEATH ...................................................................................................... 73 
TABLE 49. PARTICIPANT DISPOSITION ........................................................................................................ 75 
TABLE 50. REASONS THAT PARTICIPANTS DID NOT COMPLETE STUDY TREATMENT PLAN AND/OR 
WITHDREW FROM STUDY ................................................................................................................... 75 
TABLE 51. SIGNIFICANT PROTOCOL DEVIATIONS ...................................................................................... 76 
 
List of Figures: 
FIGURE 1. OUTLINE OF TREATMENT PLAN ................................................................................................... 9 
FIGURE 2. ACCRUAL VS. PROJECTED ENROLLMENT .................................................................................. 36 
FIGURE 3. GVHD/RELAPSE OR PROGRESSION-FREE SURVIVAL (GRFS) ................................................... 42 
FIGURE 4. ACUTE GVHD GRADE II-IV ...................................................................................................... 43 
FIGURE 5. ACUTE GVHD GRADE III-IV ..................................................................................................... 44 
FIGURE 6. CHRONIC GVHD ........................................................................................................................ 48 
FIGURE 7. CUMULATIVE INCIDENCE OF NEUTROPHIL RECOVERY ............................................................. 51 
FIGURE 8. CUMULATIVE INCIDENCE OF PLATELET RECOVERY .................................................................. 52 
FIGURE 9. CUMULATIVE INCIDENCE OF RELAPSE/PROGRESSION ............................................................... 56 
FIGURE 10. CUMULATIVE INCIDENCE OF TREATMENT-RELATED MORTALITY .......................................... 58 
FIGURE 11. CUMULATIVE INCIDENCE OF INFECTIONS ................................................................................ 63 
FIGURE 12. DISEASE-FREE SURVIVAL (DFS).............................................................................................. 64 
FIGURE 13. OVERALL SURVIVAL (OS) ........................................................................................................ 66 
FIGURE 14. CUMULATIVE INCIDENCE OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE ............. 68 
FIGURE 15. CONSORT DIAGRAM .............................................................................................................. 74 
 
 


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Table 3. Study Enrollment Over Time 
Center 
Year 
Total 
2019 
2020 
2021 
2022 
2023 
Center 1 
XX 
XX 
XX 
XX 
XX 
XX 
Center 2 
XX 
XX 
XX 
XX 
XX 
XX 
… 
 
 
 
 
 
 
Center K 
XX 
XX 
XX 
XX 
XX 
XX 
All Centers 
XX 
XX 
XX 
XX 
XX 
XX 
 
Table 4. Actual vs. Projected Enrollment 
Months After Study 
Initiation 
Projected 
Cumulative 
Projected 
Actual 
Cumulative 
Actual 
0 – 3 
2 
2 
XX 
XX 
3 – 6 
5 
7 
XX 
XX 
6 – 9 
8 
15 
XX 
XX 
9 – 12 
11 
26 
XX 
XX 
12 – 15 
12 
38 
XX 
XX 
15 – 18 
12 
50 
XX 
XX 
18 – 21 
12 
62 
XX 
XX 
21 – 24 
12 
74 
XX 
XX 
24 – 27 
12 
86 
XX 
XX 
27 – 30 
12 
98 
XX 
XX 
30 – 33 
12 
110 
XX 
XX 
33 – 36 
12 
122 
XX 
XX 
 
 
 
 
 
 


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Figure 2. Accrual Vs. Projected Enrollment 
 
 
 


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Table 5. Analysis Populations 
Analysis Set 
N 
Description 
Intention-to-Treat 
(ITT) 
XX 
All randomized patients are included in this set, classified by their 
randomized treatment assignments. All randomized subjects are 
included, regardless of whether the assigned study treatment was truly 
administered. 
Transplant 
XX 
The transplant population will include all subjects who have received a 
transplant after randomization. This population is a subset of the ITT 
population. 
Safety Analysis 
XX 
The safety analysis population is comprise of all subjects “as treated” 
in the study. This population will be used for the analysis of safety data. 
The “as treated” population consists of all randomized patients who 
received a HCT with one of the two randomized GVHD prophylaxis 
regimens. Patients will be included in the treatment group 
corresponding to the study treatment (GVHD prophylaxis) they 
actually received for the analysis of safety data using the “as treated” 
population. For most patients this will be the treatment group to which 
they are randomized. 
Reasons for Not Receiving Study Drug: 
Reason 1 (N=X) 
Reason 2 (N=X) 
… 
 
 


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Table 6. Demographic and Baseline Characteristics 
 
Treatment Arm 
 
Variable 
PTCy/Tac/
MMF 
(N=XX) 
N (XX.X%) 
Tac/MTX 
(N=XX) 
N (XX.X%) 
Total 
(N=XXX) 
N (100%) 
Gender 
 
 
 
Male 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Female 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Ethnicity 
 
 
 
Hispanic or Latino 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Not Hispanic or Latino 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Unknown 
 
 
 
Not Answered 
 
 
 
Race 
 
 
 
American Indian/Alaska Native 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Asian 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Hawaiian/Pacific Islander 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Black or African American 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
White 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
More than One Race 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Other, Specify 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Unknown 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Not Answered 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Age (years) 
 
 
 
Median (range) 
XX.X (XX.X, 
XX.X) 
XX.X (XX.X, 
XX.X) 
XX.X (XX.X, 
XX.X) 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 
XX.X (XX.X) 
18-65 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
65 or Older 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Karnofsky / Lansky Performance Score 
 
 
 
At least 90 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Less Than 90 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Primary Disease 
 
 
 


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Table 6. Demographic and Baseline Characteristics (CONT’D) 
Variable 
PTCy/Tac/
MMF 
(N=XX) 
N (XX.X%) 
Tac/MTX 
(N=XX) 
N (XX.X%) 
Total 
(N=XXX) 
N (100%) 
Acute Myelogeneous Leukemia 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Acute Lymphoblastic Leukemia 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Chronic Myelogeneous Leukemia  
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Chronic Lymphocytic Leukemia 
 
 
 
Myelodysplastic Syndrome 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Follicular Lymphoma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Diffuse Large B-Cell Lymphoma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Mantle Cell Lymphoma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Marginal B-cell Cell Lymphoma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Hodgkin’s Lymphoma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Lymphoma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Lymphoproliferative Disease 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Multiple Myeloma 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Myeloproliferative Neoplasm 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Time from Disease Diagnosis to Transplant 
 
 
 
Median (range) 
XX.X (XX.X, 
XX.X) 
XX.X (XX.X, 
XX.X) 
XX.X (XX.X, 
XX.X) 
Mean (SD) 
XX.X (XX.X) 
XX.X (XX.X) 
XX.X (XX.X) 
Disease Risk Index 
 
 
 
Low 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
IM 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
High/ Very High 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
HCT-CI 
 
 
 
0 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
1 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
2 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
3 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
4+ 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
HLA Match and Donor Type 
 
 
 
Matched Related Donor (6/6) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Matched Unrelated Donor (8/8) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 


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Table 6.  Demographic and Baseline Characteristics (CONT’D) 
Variable 
PTCy/Tac/
MMF 
(N=XX) 
N (XX.X%) 
Tac/MTX 
(N=XX) 
N (XX.X%) 
Total 
(N=XXX) 
N (100%) 
     Mismatched Unrelated Donor (7/8) 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Donor/Recipient CMV Status 
 
 
 
Pos/Pos 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Pos/Neg 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Neg/Pos 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Neg/Neg 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Donor/Recipient Sex Match 
 
 
 
M-M 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
M-F 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
F-M 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
F-F 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Donor/Recipient ABO Match 
 
 
 
Match 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Minor Match 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Bidirectional Mismatch 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Major Mismatch 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Planned RIC Regimen 
 
 
 
Flu + Bu 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Flu + Mel 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Flu + Cy 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Flu + TBI 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Flu + Cy + TBI 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
     No 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
     Yes 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
           Tyrosine Kinase Inhibitor 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
           FLT3 Inhibitor 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
           Monoclonal Antibody 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
           Clinical Trial 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
           Other 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
 


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Table 7. Primary Analysis—Multivariate Cox PH Model for Hazard of GRFS 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
 
 
 


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Table 8. Sensitivity Analysis #1 Re COVID-19 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
 
 
 
 
 
 
 
Table 9. Sensitivity Analysis #2 Re COVID-19 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
 
 
 
 
 
 
Figure 3. GVHD/Relapse or Progression-Free Survival (GRFS) 
 
 
 


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Figure 4. Acute GVHD Grade II-IV 
 
 
 


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Figure 5. Acute GVHD Grade III-IV 
 
 
 
 
 
 


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Table 10. Cumulative Incidence of Acute GVHD 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Events 
Estimate 
95% CI 
#  Events 
Estimate 
95% CI 
MAGIC 
aGVHD 
Grade II-IV 
 
 
 
 
 
 
Day 100 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Day 180 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
MAGIC 
aGVHD 
Grade III-IV 
 
 
 
 
 
 
Day 100 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Day 180 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Table 11. Cumulative Incidences of Minnesota Acute GVHD 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Events 
Estimate 
95% CI 
#  Events 
Estimate 
95% CI 
Standard risk 
aGVHD  
 
 
 
 
 
 
Day 100 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Day 180 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
High risk 
aGVHD  
 
 
 
 
 
 
Day 100 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Day 180 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 


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Table 12. Acute GVHD Summary 
 
 
 
Treatment Arm 
 
Variable 
PTCy/Tac/MMF 
N=XXX (XX.X%) 
Tac/MTX  
N=XXX (XX.X%) 
Total 
N=XXX ( 
XX.X%) 
MAGIC Acute GVHD Maximum 
Grade 
 
 
 
I 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
II 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
III 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
IV 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
MAGIC Acute GVHD Skin Stage 
 
 
 
0 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
1 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
2 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
3 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
4 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
MAGIC Acute GVHD Upper GI 
Stage 
 
 
 
0 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
1 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
MAGIC Acute GVHD Lower GI 
Stage 
 
 
 
0 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
1 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
2 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
3 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
4 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
MAGIC Acute GVHD Liver Stage 
 
 
 
0 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
1 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
2 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
3 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 
4 
XX (XX.X) 
XX (XX.X) 
XX (XX.X) 


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Table 13. Acute GVHD—Cox PH Model 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
 
 
 


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Figure 6. Chronic GVHD 
 
 
Table 14. Cumulative Incidence of Chronic GVHD 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Events 
Estimate 
95% CI 
#  Events 
Estimate 
95% CI 
6 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
 
 


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Table 15. Chronic GVHD—Cox PH Model 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Table 16. Maximum Severity of Chronic GVHD through 12 Months Post-transplant 
 
PTCy/Tac/MMF 
(N=XXX) 
Tac/MTX (N=XXX) 
Maximum Chronic GVHD Severity 
N 
% 
N 
% 
None 
XX 
XX.X 
XX 
XX.X 
Mild 
XX 
XX.X 
XX 
XX.X 
Moderate 
XX 
XX.X 
XX 
XX.X 
Severe 
XX 
XX.X 
XX 
XX.X 
 
 
 


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Table 17. Systemic Immunosuppression-Free Survival at 12 Months Post-
Transplant 
Treatment Arm 
N 
# Events 
Estimate 
95% CI 
PTCy/Tac/MMF 
XXX 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Tac/MTX  
XXX 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
Table 18. Measure of Agreement between GRFS Events and Systemic 
Immunosuppression-Free Survival 
Treatment Arm 
N 
Kappa 
Coefficient 
95% CI 
PTCy/Tac/MMF 
XXX 
0.XXX 
(0.XXX, 0.XXX) 
Tac/MTX  
XXX 
0.XXX 
(0.XXX, 0.XXX) 


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Figure 7. Cumulative Incidence of Neutrophil Recovery 
Note: Label on the horizontal axis should be “Days Post-transplant” range 0 to 100. 
 
 
 


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Figure 8. Cumulative Incidence of Platelet Recovery 
Note: Label on the horizontal axis should be “Days Post-transplant” range 0 to 100. 
 
 
 


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Table 19. Probability of Neutrophil Recovery 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
Probability of Neutrophil 
Recovery (95% CI) 
Probability of Neutrophil 
Recovery (95% CI) 
Day 28 
XX.X% (XX.X%, XX.X%) 
XX.X% (XX.X%, XX.X%) 
Day 100 
XX.X% (XX.X%, XX.X%) 
XX.X% (XX.X%, XX.X%) 
 
 
Table 20. Probability of Platelet Recovery 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
Probability of Platelet 
Recovery (95% CI) 
Probability of Platelet 
Recovery (95% CI) 
Day 60 
XX.X% (XX.X%, XX.X%) 
XX.X% (XX.X%, XX.X%) 
Day 100 
XX.X% (XX.X%, XX.X%) 
XX.X% (XX.X%, XX.X%) 
 
 
Table 21. Probability of Lymphocyte Recovery 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
Probability of Lymphocyte 
Recovery (95% CI) 
Probability of Lymphocyte 
Recovery (95% CI) 
Day 60 
XX.X% (XX.X%, XX.X%) 
XX.X% (XX.X%, XX.X%) 
Day 100 
XX.X% (XX.X%, XX.X%) 
XX.X% (XX.X%, XX.X%) 
 
 
 


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Table 22. Donor Cell Engraftment 
Assessment Time 
Day 28 
Day 100 
Total 
 
Treatment Arm 
P-value 
Treatment Arm 
P-value 
 
 
PTCy/Tac/MMF 
(N=XXX) 
Tac/MTX 
(N=XXX) 
 
PTCy/Tac/MMF 
(N=XXX) 
Tac/MTX 
(N=XXX) 
 
 
Chimerism 
 
 
 
 
 
 
 
Full (>95% Donor 
Cells) 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX 
(XX.X%) 
Mixed (5-95% 
Donor Cells) 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX 
(XX.X%) 
Graft Rejection 
(<5% Donor 
Cells) 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX 
(XX.X%) 
Death Prior To 
Assessment 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX (XX.X%) 
XX 
(XX.X%) 
0.XXX 
XX 
(XX.X%) 
 
Table 23. Incidence of Secondary Graft Failure 
 
Treatment Arm 
P-value 
 
PTCy/Tac/MMF 
(N=XXX) 
Tac/MTX 
(N=XXX) 
 
Incidence of Secondary Graft 
Failure 
XX (XX.X%) 
XX (XX.X%) 
0.XXX 
 
 
 


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Table 24. Relapse/Progression—Cox PH Model 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
 
 
 


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Figure 9. Cumulative Incidence of Relapse/Progression 
 
 
Table 25. Cumulative Incidence of Relapse/Progression 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# R/Ps 
Estimate 
95% CI 
# R/Ps 
Estimate 
95% CI 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
 
 


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Table 26. Treatment-Related Mortality—Cox PH Model 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
 
 
 


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Figure 10. Cumulative Incidence of Treatment-Related Mortality 
 
 
Table 27. Cumulative Incidence of Treatment-Related Mortality 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# 
TRMs 
Estimate 
95% CI 
# 
TRMs 
Estimate 
95% CI 
Day 100 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
Day 180 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
 
 


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Table 28. Adverse Events (AEs) Occurring Through 12 Months Post-Transplant by 
System Organ Class 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
 
# Events (%) 
# Participants 
Affected (%) 
# Events (%) 
# Participants 
Affected (%) 
System Organ Class1 
 
 
 
 
Class 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Class 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
… 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Class K 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
1 Classified per MedDRA coding. 
 
 
Table 29. Adverse Events (AEs) Occurring Through 12 Months Post-Transplant 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
 
# Participants 
Affected 
% Participants Affected 
(95% CI) 
# Participants 
Affected 
% Participants Affected 
(95% CI) 
p-value1 
XX 
XX.X% (XX.X%, XX.X%) 
XX 
XX.X% (XX.X%, XX.X%) 
0.xxx 
 
 
Table 30. Adverse Events Summary Through 12 Months Post-Transplant 
Adverse Events – Number of Participants Affected 
 
PTCy/Tac/MMF 
(N=XXX) 
Tac/MTX 
 (N=XXX) 
Category 
N 
% 
N 
% 
Adverse Events (AEs) 
XX 
XX.X 
XX 
XX.X 
Severe Adverse Events (SAEs) 
XX 
XX.X 
XX 
XX.X 
 
 
 


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Table 31. Adverse Events Reported Through 12 Months Post-Transplant 
 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
System Organ 
Class 
Preferred 
Term 
# 
Events 
Participants 
Affected 
% of 
participants 
# 
Events 
Participants 
Affected 
% of 
participants 
SOC #1 
Category 1 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
Category 2 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
… 
 
 
 
 
 
 
Category K 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
SOC #2 
Category 1 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
Category 2 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
… 
 
 
 
 
 
 
Category K 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
… 
 
 
 
 
 
 
 
Total 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
 
 
 
Table 32. Severe Adverse Events Reported Through 12 Months Post-Transplant 
 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
System Organ 
Class 
Preferred 
Term 
# 
Events 
Participants 
Affected 
% of 
participants 
# 
Events 
Participants 
Affected 
% of 
participants 
SOC #1 
Category 1 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
Category 2 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
… 
 
 
 
 
 
 
Category K 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
SOC #2 
Category 1 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
Category 2 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
… 
 
 
 
 
 
 
Category K 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
… 
 
 
 
 
 
 
 
Total 
XX 
XX 
XX.X 
XX 
XX 
XX.X 
 
 
 
 


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Table 33. Toxicities Through 12 Months Post-Transplant 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
 
N 
% 
N 
% 
Maximum Toxicity Grade 
 
 
 
 
Grade 0 - 2 
XX 
XX.X 
XX 
XX.X 
Grade 3 
XX 
XX.X 
XX 
XX.X 
Grade 4 
XX 
XX.X 
XX 
XX.X 
Grade 5 
XX 
XX.X 
XX 
XX.X 
Toxicity Type 1 
 
 
 
 
Grade 0 – 2 
XX 
XX.X 
XX 
XX.X 
Grade 3 
XX 
XX.X 
XX 
XX.X 
Grade 4 
XX 
XX.X 
XX 
XX.X 
Grade 5 
XX 
XX.X 
XX 
XX.X 
Toxicity Type 2 
 
 
 
 
Grade 0 – 2 
XX 
XX.X 
XX 
XX.X 
Grade 3 
XX 
XX.X 
XX 
XX.X 
Grade 4 
XX 
XX.X 
XX 
XX.X 
Grade 5 
XX 
XX.X 
XX 
XX.X 
… 
 
 
 
 
Toxicity Type K 
 
 
 
 
Grade 0 – 2 
XX 
XX.X 
XX 
XX.X 
Grade 3 
XX 
XX.X 
XX 
XX.X 
Grade 4 
XX 
XX.X 
XX 
XX.X 
Grade 5 
XX 
XX.X 
XX 
XX.X 
 
1 Classified per CTCAE version 5.0 
 
 


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Table 34. Infections 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
 
# Infections (%) 
# Participants 
Affected (%) 
# Infections (%) 
# Participants 
Affected (%) 
Total Number of Infections 
XX (100.0%) 
XX (100.0%) 
XX (100.0%) 
XX (100.0%) 
Infection Site 
 
 
 
 
Site 1 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Site 2 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
… 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Site K 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Time of Onset Post-transplant 
 
 
 
 
000 -100 days 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
101 – 180 days 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
181 – 365 days 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Infection Severity 
 
 
 
 
Grade 2  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
Grade 3  
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
XX (XX.X%) 
 
 
 


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Figure 11. Cumulative Incidence of Infections 
 
Note: Include Grade 2 and grade 3 infections. 
Table 35. Cumulative Incidence of Infections 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Events 
Estimate 
95% CI 
#  Events 
Estimate 
95% CI 
6 Months 
XX 
XX.X% 
(XX.X%, XX.X%) 
XX 
XX.X% 
(XX.X%, XX.X%) 
12 Months 
XX 
XX.X% 
(XX.X%, XX.X%) 
XX 
XX.X% 
(XX.X%, XX.X%) 
 
 
 


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Figure 12. Disease-Free Survival (DFS) 
 
 
Table 36. Disease-Free Survival (DFS) Probability at 1 Year 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Events 
Estimate 
95% CI 
# Events 
Estimate 
95% CI 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
 
 


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Table 37. Disease-Free Survival (DFS)—Cox PH Model 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
 
 
 


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Figure 13. Overall Survival (OS) 
 
Table 38. Overall Survival (OS) Probability at 1 year 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Died 
Estimate 
95% CI 
# Died 
Estimate 
95% CI 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
 
 


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Table 39. Overall Survival (OS)—Cox PH Model 
Variable 
N 
# Events 
Hazard Ratio 
95% CI 
p-value 
Treatment Arm  
 
 
 
 
0.XXX 
Tac/MTX 
XX 
XX 
1.00 
 
 
PTCy/Tac/MMF 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Disease Risk Index 
 
 
 
 
0.XXX 
Low 
XX 
XX 
1.00 
 
 
IM 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
High/ Very High 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Age (years) 
 
 
 
 
0.XXX 
18-65 
XX 
XX 
1.00 
 
 
65 or Older 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned RIC Regimen 
 
 
 
 
0.XXX 
     Flu + Bu 
XX 
XX 
1.00 
 
 
     Flu + Mel 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
     Flu + Cy + TBI 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
HLA Match and Donor Type 
 
 
 
 
0.XXX 
    Matched Related Donor (6/6) 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
    Matched Unrelated Donor (8/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
    Mismatched Unrelated Donor (7/8) 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
Planned Post-Transplant Maintenance 
Therapy 
 
 
 
 
0.XXX 
No 
XX 
XX 
1.00 
(X.XX, X.XX) 
 
Yes 
XX 
XX 
X.XX 
(X.XX, X.XX) 
0.XXX 
 
 
 


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Figure 14. Cumulative Incidence of Post-Transplant Lymphoproliferative Disease 
 
 
Table 40. Cumulative Incidence of PTLD at 1 Year 
 
PTCy/Tac/MMF (N=XXX) 
Tac/MTX (N=XXX) 
Assessment 
Time 
# Events 
Estimate 
95% CI 
#  Events 
Estimate 
95% CI 
12 Months 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
XX 
XX.X% 
(XX.X%, 
XX.X%) 
 
 
 


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Table 41. Patient-Reported Outcomes for Hemorrhagic Cystitis 
Question/Response 
PTCy/Tac/MMF 
Tac/MTX 
During the past 7 days, 
how many days did you 
see blood in your urine? 
Day  
0 
Day 
100 
Day 
180 
Day 
365 
Day  
0 
Day 
100 
Day 
180 
Day 
365 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
No days 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
1 day 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
2 days 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
3-5 days 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
6-7 days 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
Missing 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
How often did you feel 
like you needed to empty 
your bladder right away 
or else you would have an 
accident? 
 
 
 
 
 
 
 
 
 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
N=XX 
Never 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
One time during the       
past 7 days 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
2-6 times during the past 7 
days 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
Often once a day 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
More than once a day 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
Missing 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
XX 
(XX.X%) 
 
 
 


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Table 42. Patient-Reported Outcomes Measurement Information System (PROMIS) 
Domain Scores for Gastrointestinal Symptoms 
 
 
 
PROMIS Domain T-score 
Treatment Arm 
Assessment 
Time 
N 
Mean 
Median 
Interquartile 
Range 
Range 
PTCy/Tac/MMF 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Tac/MTX 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
 
Table 43. Patient-Reported Outcomes Measurement Information System (PROMIS) 
for Satisfaction with Participation in Social Roles 
 
 
 
PROMIS Domain T-score 
Treatment Arm 
Assessment 
Time 
N 
Mean 
Median 
Interquartile 
Range 
Range 
PTCy/Tac/MMF 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Tac/MTX 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
 
 
 


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Table 44. Patient-Reported Outcomes Scores for Chronic GVHD Symptom Scale 
 
 
 
cGVHD Score 
Treatment Arm 
Assessment 
Time 
N 
Mean 
Median 
Interquartile 
Range 
Range 
PTCy/Tac/MMF 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Tac/MTX 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
 
 
Table 45. Patient-Reported Outcomes Measurement Information System (PROMIS) 
Domain Scores for Physical Function 
 
 
 
PROMIS Domain T-Score of Physical Function 
Treatment Arm 
Assessment 
Time 
N 
Mean 
Median 
Interquartile 
Range 
Range 
PTCy/Tac/MMF 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Tac/MTX 
(N=XXX) 
Day 0 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 100 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 180 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
Day 365 
XX 
XX.X 
XX.X 
(XX.X, XX.X) 
(XX.X, XX.X) 
 
 
 
 
 
 
 


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Table 46. IPCW-GEE Model of Change in Chronic GVHD Symptom Scale from 
Baseline Assuming Equal Mean Domian T-Score at Baseline (Day 0) in each 
Treatment Arm. 
Variable 
N 
Parameter 
Estimate 
95% CI 
p-value 
Intercept 
- 
XX.X 
(XX.X, XX.X) 
- 
Assessment Time 
 
 
 
 
Day 0 
XX 
0.00 
- 
- 
Day 100 
XX 
XX.X 
(XX.X, XX.X) 
0.XXX 
Day 180 
XX 
XX.X 
(XX.X, XX.X) 
0.XXX 
Day 365 
XX 
XX.X 
(XX.X, XX.X) 
0.XXX 
Treatment by  
Assessment Time 
 
 
 
 
PTCy/Tac/MMF, Day 100 
- 
XX.X 
(XX.X, XX.X) 
0.XXX 
PTCy/Tac/MMF, Day 180 
- 
XX.X 
(XX.X, XX.X) 
0.XXX 
PTCy/Tac/MMF, Day 365 
- 
XX.X 
(XX.X, XX.X) 
0.XXX 
Note: This model does not include a treatment effect, allowing us to assume equal baseline scores 
 
Table 47. IPCW-GEE Model of Change in PROMIS Domain Physical Function T-
Score from Baseline Assuming Equal Mean Domian T-Score at Baseline (Day 0) in 
each Treatment Arm 
Variable 
N 
Parameter 
Estimate 
95% CI 
p-value 
Intercept 
- 
XX.X 
(XX.X, XX.X) 
- 
Assessment Time 
 
 
 
 
Day 0 
XX 
0.00 
- 
- 
Day 100 
XX 
XX.X 
(XX.X, XX.X) 
0.XXX 
Day 180 
XX 
XX.X 
(XX.X, XX.X) 
0.XXX 
Day 365 
XX 
XX.X 
(XX.X, XX.X) 
0.XXX 
Treatment by  
Assessment Time 
 
 
 
 
PTCy/Tac/MMF, Day 100 
- 
XX.X 
(XX.X, XX.X) 
0.XXX 
PTCy/Tac/MMF, Day 180 
- 
XX.X 
(XX.X, XX.X) 
0.XXX 
PTCy/Tac/MMF, Day 365 
- 
XX.X 
(XX.X, XX.X) 
0.XXX 
Note: This model does not include a treatment effect, allowing us to assume equal baseline scores 
 
 


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Table 48. Primary Cause of Death 
 
PTCy/Tac/MMF 
(N=XXX) 
Tac/MTX 
 (N=XXX) 
Cause of Death 
N 
% 
N 
% 
Cause 1 
XX 
XX.X 
XX 
XX.X 
Cause 2 
XX 
XX.X 
XX 
XX.X 
… 
 
 
 
 
Cause K 
XX 
XX.X 
XX 
XX.X 
Total 
XX 
100.0 
XX 
100.0 
 
 
 
Total Deaths 
XX 
XX.X 
XX 
XX.X 
Total Enrolled 
XX 
100.0 
XX 
100.0 
 
 
 


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Figure 15. CONSORT Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analyzed (n=xx) 
x
Excluded from analysis (give 
reasons) (n=xx) 
Lost to follow-up (give reasons) 
(n=xx) 
Discontinued intervention (give 
reasons) (n=xx) 
Lost to follow-up (give reasons) 
(n=xx) 
Discontinued intervention (give 
reasons) (n=xx) 
Analyzed (n=xx) 
x
Excluded from analysis (give 
reasons) (n=xx) 
Allocation 
Analysis 
Follow-Up 
Enrollment 
Enrolled/Randomized (n=xxx) 
Allocated to PTCy/Tac/MMF (n=xx) 
x
Received PTCy/Tac/MMF (n=xx) 
x
Did not receive PTCy/Tac/MMF 
(give reasons) (n=xx) 
Allocated to Tac/MTX (n=xx) 
x
Received Tac/MTX (n=xx) 
x
Did not receive Tac/MTX (give 
reasons) (n=xx) 


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Table 49. Participant Disposition 
 
PTCy/Tac/MMF 
(N=XX) 
Tac/MTX 
(N=XX) 
Study Progress 
N 
% 
N 
% 
Intention to Treat Population 
 
 
 
 
Initiated Study Drug 
XX 
XX.X 
XX 
XX.X 
Completed Study Drug as Planned 
XX 
XX.X 
XX 
XX.X 
Discontinued Study Drug Treatment After Initiation 
XX 
XX.X 
XX 
XX.X 
Withdrawn from Study After Initiating Study Drug 
XX 
XX.X 
XX 
XX.X 
Completed Planned Study Follow-up (i.e. died before 12 months or 
survived on study up to 12 months post-transplant) 
XX 
XX.X 
XX 
XX.X 
 
 
Table 50. Reasons That Participants Did Not Complete Study Treatment Plan 
and/or Withdrew from Study 
Reason for Failure to Complete Study Treatment and/or 
Withdrawal from Study 
PTCy/Tac/MMF 
Tac/MTX 
Reason 1 
X 
X 
Reason 2 
X 
X 
… 
 
 
Reason K 
X 
X 
Total 
X 
X 
 
 
 


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Table 51. Significant Protocol Deviations 
Center 
Patient ID 
Treatment Group 
Deviation Description 
 
 
 
 
 
 
 
 
 
 
 
 
 

Prot_001.pdf: 
 
 
A Randomized, Multicenter, Phase III Trial of 
Tacrolimus/Methotrexate versus Post-Transplant 
Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in 
Non-Myeloablative/Reduced Intensity Conditioning 
Allogeneic Peripheral Blood Stem Cell Transplantation 
Study Chairpersons 
Javier Bolaños-Meade, MD1 and Shernan Holtan, MD2 
 
 
Companion Study: Microbiome and Immune Reconstitution 
in Cellular Therapies and Hematopoietic Stem Cell 
Transplantation (Mi-Immune) 
Study Chairpersons 
Leslie S. Kean MD, PhD15, Miguel-Angel Perales, MD13, and Ami Bhatt MD, PhD12 
 
 
(Posted on ClinicalTrials.gov as NCT #03959241) 
BMT CTN Protocol 1703/1801 
Version 4.0 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
 
 
 


 
1703 Protocol Team:
Monzr M. Al Malki, MD3 
Kristy Applegate, MBA4 
Nancy DiFronzo, PhD5 
Yvonne Efebera, MD, MPH6 
Raphael Fraser, PhD7 
Mahasweta Gooptu, MD8 
Lori A. Henderson, PhD 10 
Mehdi Hamadani, MD7 
Carrie Kitko, MD9 
Eric Leifer, PhD5 
Michael Martens, PhD4 
 
Viji Ramachandran4 
Ran Reshef, MD11 
Andrew Rezvani, MD12 
Brian Shaffer, MD13 
Melhem Solh, MD14 
Janny Yao3?
 
 
1801 Protocol Team:
Merav Bar, MD16 
 
 
 
 
John Levine, MD20 
Brandi Bratrude, PMP, CCRP15 
 
 
Brent Logan, PhD7 
Saurabh Chhabra, MD7 
 
 
 
Hemant Murthy, MD21 
Sung Choi, MD17 
 
 
 
 
Armin Rashidi, MD, PhD2 
William Clark, MD, MS18 
 
 
 
Marcie Riches, MD, MS22 
Suman R. Das, PhD9  
 
 
 
Wael Saber, MD, MS7 
Mary Horowitz, MD, MS7 
 
 
 
Karamjeet Sandhu, MD3 
Rob Jenq, MD19 
 
 
 
 
Ashley Spahn23 
Rick Jones, MD1 
 
 
 
 
Anthony Sung, MD24 
 
 
1Johns Hopkins University 
2University of Minnesota 
3City of Hope 
4The Emmes Company 
5National, Heart, Lung and Blood 
Institute 
6Ohio State University 
7Medical College of Wisconsin 
8Dana Farber Cancer Institute 
13Memorial Sloan Kettering Cancer Center 
14 Northside Hospital 
15Boston Children’s Hospital 
16Fred Hutchinson Cancer Research 
Center 
17University of Michigan 
   18Virginia Commonwealth University 
  19MD Anderson Cancer Center 
  20Mount Sinai
 
9Vanderbilt University 
 
 
   21Mayo Clinic - Florida 
 
10National Cancer Institute 
 
 
   22University of North Carolina 
 
11Columbia University 
 
 
   23National Marrow Donor Program 
 
12Stanford University  
 
 
   24Duke University 
 
 
 
 
_________________________________ 
 
___________________________________ 
Approval Signature (Protocol Chair/Officer) 
 
Approval Signature (Protocol Chair/Officer) 


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ii 
PROTOCOL SYNOPSIS 
 
A Randomized, Multicenter Phase III Trial of Tacrolimus/Methotrexate versus Post-Transplant 
Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-Myeloablative / Reduced 
Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation 
 
Co-Principal Investigators: 
Javier Bolaños-Meade, MD and Shernan Holtan, MD 
 
Study Design: 
The study is designed as a randomized, phase III, multicenter trial 
comparing two acute graft-versus-host disease (aGVHD) 
prophylaxis regimens: tacrolimus / methotrexate (Tac/MTX) 
versus post-transplant cyclophosphamide / tacrolimus / 
mycophenolate mofetil (PTCy/Tac/MMF) in the setting of 
reduced intensity conditioning (RIC) allogeneic peripheral blood 
stem cell (PBSC) transplantation. 
 
Primary Objective: 
The primary objective of the trial is to compare 1 year GVHD-
free, relapse-free survival (GRFS) between the two GVHD 
prophylaxis regimens. An event for this time—to-event outcome 
is defined as grade III-IV aGVHD, chronic GVHD requiring 
systemic immune suppression, disease relapse or progression, or 
death by any cause.  
 
Secondary Objective: 
Secondary objectives are to describe for each treatment arm rates 
of grade II-IV and III-IV aGVHD, rates of Minnesota high risk 
aGVHD, chronic GVHD, immunosuppression-free survival at 1 
year, hematologic recovery (neutrophil and platelet), donor cell 
engraftment, disease relapse or progression, transplant-related 
mortality, rates of grade 3+ toxicity according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0, 
incidence of grade 2-3 infections, immune reconstitution, and 
overall survival.  
 
Eligibility Criteria: 
 
Eligible patients are at least 18.0 years of age undergoing 
allogeneic PBSC transplant for the treatment of acute leukemia 
and chronic myelogenous leukemia with no circulating blasts and 
less 
than 
5% 
blasts 
in 
the 
bone 
marrow; 
or 
myelodysplasia/chronic myelomonocytic leukemia with no 
circulating blasts and less than 10% blasts in the bone marrow; 
chronic lymphocytic leukemia/small lymphocytic lymphoma, 
follicular lymphoma, Hodgkin lymphoma, diffuse large B cell 
lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, 


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iii 
angioimmunoblastic T-cell lymphoma and anaplastic large cell 
lymphoma sensitive to chemotherapy who are eligible for an 
allogeneic hematopoietic cell transplantation (HCT). Patients are 
eligible only if receiving a RIC regimen. 
 
 
 
Patients must have a related or unrelated PBSC donor. Sibling 
donor must be a 6/6 match for HLA-A and HLA-B at 
intermediate or higher resolution, and DRB1 at high resolution 
using DNA-based typing; must be willing to donate peripheral 
blood stem cells; and meet institutional criteria for donation. 
Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C, 
and -DRB1 at high resolution using DNA-based typing; must be 
willing to donate PBSCs; and be medically eligible to donate 
stem cells according to NMDP criteria.  
 
Treatment Description: 
Patients will be randomized to receive one of 2 specified GVHD 
prophylaxis regimens: Tac/MTX or PTCy/Tac/MMF. MTX will 
be dosed at 15 mg/m2 Day +1, and 10 mg/m2 Days +3, +6, and 
+11. PTCy will be dosed at 50 mg/kg on Days +3 and +4, 
followed by Tac/MMF. MMF will be dosed at 15 mg/kg every 8 
hours from Day +5 to Day +35. 
 
Accrual Objective: 
The clinical trial will enroll 428 patients, or 214 per arm. 
 
Accrual Period: 
The estimated accrual period is 36 months. 
 
Study Duration: 
Patients will be followed for 1 year post-PBSC transplant. 
 
Interim Analysis: 
The study will include one interim analysis for efficacy, for the 
primary endpoint at the time when the required total number of 
events is reached. Z test statistic for comparing the two treatment 
arms will be compared to the critical values and results will be 
reviewed by the NHLBI-appointed Data and Safety Monitoring 
Board (DSMB). If the test statistic is outside the continuation 
range, the DSMB will be consulted on the discontinuation of the 
trial. 
 
Stopping Guidelines: 
Monitoring of the key safety endpoint of death will be conducted. 
The rate of overall mortality will be monitored up to Day 100 
post-randomization separately in each of the 2 treatment arms. 
Each month, the null hypothesis that the Day 100 mortality rate 


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is less than or equal to 15% is tested using a truncated Sequential 
Probability Ratio Test (SPRT) for censored exponential data. 
 
Correlative Studies: 
Completed through the Mi-Immune study (Appendix J), with 
additional blood samples processed and stored for future 
research. 
 
Companion Study: 
Microbiome and Immune Reconstitution in Cellular 
Therapies and Hematopoietic Stem Cell Transplantation 
(Mi-Immune) 
 
Co-Principal Investigator: 
Leslie S. Kean MD, PhD, Miguel-Angel Perales, MD, and Ami 
Bhatt MD, PhD 
Primary Objective: 
The goal of this protocol is to test the primary hypothesis that the 
engraftment stool microbiome diversity predicts one-year non-
relapse mortality in patients undergoing reduced intensity 
allogeneic HCT.  Our study will be powered to test this 
hypothesis. Patients will be primarily recruited through co-
enrollment on BMT CTN 1703. 
Secondary Objectives: 
To establish a cohort of biologic samples and a linked clinical 
and molecular dataset from patients and donors from BMT CTN 
1703. The product of this study will be a shared biospecimen and 
data resource for conducting future allogeneic HCT mechanistic 
studies.  
To study the diversity of the immune repertoire post-transplant 
and correlate with clinical outcomes, as well as study the impact 
on immune recovery of the method of GVHD prophylaxis and 
other patient and transplant factors. 
 
To study the diversity and composition of the gut microbiome 
post-transplant and correlate with clinical outcomes, as well as 
study the impact on the microbiome of the method of GVHD 
prophylaxis and other patient and transplant factors. 
Eligibility Criteria: 
Eligible patients are at least 18 years of age and enrolled on the 
BMT CTN 1703 PROGRESS III study. Eligible donors are at 
least 18 years of age. 
Treatment Description: 
Conditioning regimens, GVHD prophylaxis, and other 
supportive care will be those described in BMT CTN 1703. 
Accrual Objective: 
A minimum of 300 patients will be enrolled (in collaboration 
with protocol BMT CTN 1703). 


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Accrual Period: 
The estimated accrual period is 36 months. 
Study Duration: 
Patients will be followed clinically for 12 months post-HCT; 
long-term follow-up data will be collected through usual 
procedures of the Center for International Blood and Marrow 
Transplant Research (CIBMTR). A 24-month biological sample 
will be collected as well.  
 
 
 


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Outline of Treatment Plan 
 
 
 
 
 
 
 
Age 18.0 years and older 
Controlled Malignant Diseases 
RIC 
Related or Unrelated PBSC Donor 
Tac/MTX 
Tac/MMF/ 
Cyclophosphamide 


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TABLE OF CONTENTS 
1 
BACKGROUND AND RATIONALE .............................................................................. 1-1 
1.1 
Introduction ................................................................................................................. 1-1 
1.2 
Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil (PTCy/Tac/MMF) 1-2 
1.2.1 
Rationale of Post-transplant Cyclophosphamide ................................................... 1-2 
1.2.2 
Post-transplant Cyclophosphamide in Alternative Donor Transplantation ........... 1-2 
1.2.3 
Post-transplant Cyclophosphamide as GVHD Prophylaxis after PBSC 
transplantation ....................................................................................................... 1-3 
1.3 
Benchmark Analysis and Composite Endpoint ........................................................ 1-3 
1.4 
Studies of the Microbiome and Immune Reconstitution in Transplant Patients .. 1-6 
1.4.1 
Microbiome Studies ............................................................................................... 1-6 
1.4.2 
Protective Immunity............................................................................................... 1-7 
1.4.3 
Microbiome and Immune Reconstitution in Cellular Therapies and Hematopoietic 
Stem Cell Transplantation (Mi-Immune) .............................................................. 1-8 
1.5 
Rationale for a Randomized Trial ............................................................................. 1-8 
2 
sTudy design ........................................................................................................................ 2-1 
2.1 
Study Overview ........................................................................................................... 2-1 
2.2 
Hypothesis and Specific Objectives ........................................................................... 2-1 
2.2.1 
Primary Hypothesis ................................................................................................ 2-1 
2.2.2 
Study Objectives .................................................................................................... 2-1 
2.3 
Patient Eligibility ......................................................................................................... 2-2 
2.3.1 
Inclusion Criteria ................................................................................................... 2-2 
2.3.2 
Exclusion Criteria .................................................................................................. 2-3 
2.4 
Treatment Plans .......................................................................................................... 2-3 
2.4.1 
Conditioning Regimens ......................................................................................... 2-4 
2.4.2 
Hematopoietic Stem Cell Transplantation (HCT) ................................................. 2-7 
2.4.3 
Tacrolimus/Methotrexate ....................................................................................... 2-7 
2.4.4 
Tacrolimus/Mycophenolate Mofetil/Cyclophosphamide ...................................... 2-8 
2.5 
Supportive Care........................................................................................................... 2-9 
2.5.1 
Growth Factors....................................................................................................... 2-9 
2.5.2 
Blood Products ....................................................................................................... 2-9 
2.5.3 
Prophylaxis Against Infections .............................................................................. 2-9 
2.5.4 
Intravenous Immune Globulin (IVIG) ................................................................... 2-9 


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2.6 
Participant Risks ......................................................................................................... 2-9 
2.6.1 
Therapy Toxicities ................................................................................................. 2-9 
2.6.2 
Tacrolimus ............................................................................................................. 2-9 
2.6.3 
Methotrexate ........................................................................................................ 2-10 
2.6.4 
Mycophenolate mofetil (MMF) ........................................................................... 2-10 
2.6.5 
Cyclophosphamide ............................................................................................... 2-11 
2.6.6 
Busulfan ............................................................................................................... 2-11 
2.6.7 
Fludarabine .......................................................................................................... 2-12 
2.6.8 
Melphalan ............................................................................................................ 2-12 
2.6.9 
Total Body Irradiation (TBI) ............................................................................... 2-12 
2.7 
Study Drug Supply .................................................................................................... 2-13 
3 
STUDY ENDPOINTS ........................................................................................................ 3-1 
3.1 
Primary Endpoint ....................................................................................................... 3-1 
3.2 
Secondary Endpoints .................................................................................................. 3-1 
3.2.1 
Acute GVHD ......................................................................................................... 3-1 
3.2.2 
Chronic GVHD ...................................................................................................... 3-1 
3.2.3 
Systemic Immunosuppression-free Survival ......................................................... 3-1 
3.2.4 
Hematologic Recovery........................................................................................... 3-2 
3.2.5 
Donor Cell Engraftment ......................................................................................... 3-2 
3.2.6 
Disease Relapse or Progression ............................................................................. 3-2 
3.2.7 
Transplant-related Mortality .................................................................................. 3-3 
3.2.8 
Toxicity .................................................................................................................. 3-3 
3.2.9 
Infections................................................................................................................ 3-3 
3.2.10 
Disease-Free Survival ............................................................................................ 3-4 
3.2.11 
Overall Survival ..................................................................................................... 3-4 
3.2.12 
PTLD...................................................................................................................... 3-4 
3.2.13 
Patient-Reported Outcomes (PRO) ........................................................................ 3-4 
3.3 
Endpoint Review Process ........................................................................................... 3-4 
4 
PATIENT ENROLLMENT AND EVALUATION ......................................................... 4-1 
4.1 
Approaching Patients, Eligibility Screening and Obtaining Consent .................... 4-1 
4.2 
Transplant Protocol Registration .............................................................................. 4-1 
4.3 
Randomization ............................................................................................................. 4-1 


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4.4 
Treatment Scheduling ................................................................................................. 4-2 
4.5 
Patient Evaluation ....................................................................................................... 4-2 
4.6 
Study Monitoring ........................................................................................................ 4-2 
4.6.1 
Patient Assessments ............................................................................................... 4-3 
4.6.2 
Pre-transplant Evaluations ..................................................................................... 4-5 
4.6.3 
Post-transplant Evaluations .................................................................................... 4-6 
4.6.4 
Criteria for Forms Submission ............................................................................... 4-7 
4.6.5 
Reporting Patient Deaths ....................................................................................... 4-7 
4.7 
Adverse Event Reporting Requirements .................................................................. 4-7 
4.7.1 
Definitions.............................................................................................................. 4-7 
4.7.2 
BMT CTN Adverse Event Reporting Guidelines .................................................. 4-8 
4.8 
CIBMTR Data Reporting ........................................................................................... 4-9 
5 
STATISTICAL CONSIDERATIONS ............................................................................ 5-10 
5.1 
Study Design .............................................................................................................. 5-10 
5.1.1 
Accrual ................................................................................................................. 5-10 
5.1.2 
Randomization ..................................................................................................... 5-10 
5.1.3 
Primary Endpoint ................................................................................................. 5-10 
5.1.4 
Primary Hypothesis .............................................................................................. 5-10 
5.2 
Sample Size and Power Considerations .................................................................. 5-11 
5.3 
Interim Analysis and Stopping Guidelines ............................................................. 5-11 
5.3.1 
Interim Analysis for Efficacy ............................................................................... 5-11 
5.3.2 
Operating Characteristics of the Design .............................................................. 5-12 
5.3.3 
Guidelines for Safety Monitoring ........................................................................ 5-13 
5.4 
Demographic and Baseline Characteristics ............................................................ 5-14 
5.5 
Analysis Populations ................................................................................................. 5-14 
5.5.1 
Primary Population .............................................................................................. 5-14 
5.5.2 
Safety Population ................................................................................................. 5-15 
5.5.3 
Transplant Population .......................................................................................... 5-15 
5.6 
Analysis of Primary Endpoint .................................................................................. 5-15 
5.7 
Analysis of Secondary Endpoints ............................................................................ 5-15 
5.7.1 
Acute GVHD ....................................................................................................... 5-15 
5.7.2 
Chronic GVHD .................................................................................................... 5-15 


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5.7.3 
Systemic Immunosuppression-Free Survival ...................................................... 5-16 
5.7.4 
Hematologic Recovery......................................................................................... 5-16 
5.7.5 
Donor Cell Engraftment ....................................................................................... 5-16 
5.7.6 
Disease Relapse or Progression ........................................................................... 5-16 
5.7.7 
Transplant-related Mortality ................................................................................ 5-16 
5.7.8 
Toxicity ................................................................................................................ 5-16 
5.7.9 
Infections.............................................................................................................. 5-17 
5.7.10 
Disease-free Survival ........................................................................................... 5-17 
5.7.11 
Overall Survival ................................................................................................... 5-17 
5.7.12 
Post-Transplant Lymphoproliferative Disease (PTLD) ....................................... 5-17 
5.7.13 
Patient-Reported Outcomes (PRO) ...................................................................... 5-17 
5.8 
Safety Analysis ........................................................................................................... 5-17 
APPENDIX A: Human Subjects 
APPENDIX B: Chimerism Assessment 
APPENDIX C: Derivation of a Sequential Test Statistic for Censored Exponential Data 
APPENDIX D: Karnofsky Performance Status Scale 
APPENDIX E: HCT-Specific Comorbidity Index Score 
APPENDIX F: Disease Risk Index 
APPENDIX G: Diagnosis and Severity Scoring for Acute and Chronic GVHD 
APPENDIX H: Patient Reported Outcome Questions 
APPENDIX I: References 
APPENDIX J: Mi-Immune Study  
 
BMT CTN 1801 
1 
Background and Significance ............................................................................................... 1 
2 
Study Design ........................................................................................................................... 2 
2.1 
Study Overview .............................................................................................................. 2 
2.2 
Hypothesis and Objectives............................................................................................. 2 
2.2.1 
Hypothesis................................................................................................................. 2 
2.2.2 
Objectives ................................................................................................................. 2 
2.3 
Eligibility Criteria for Enrollment................................................................................ 3 
2.4 
Treatment Plan ............................................................................................................... 4 
3 
Study Endpoints and Definitions ......................................................................................... 5 
3.1 
Primary Endpoint .......................................................................................................... 5 
3.2 
Secondary Endpoints ..................................................................................................... 5 


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3.2.1 
Clinical Endpoints ..................................................................................................... 5 
3.2.2 
Infection .................................................................................................................... 5 
3.2.3 
Correlative endpoints ................................................................................................ 5 
3.2.3.1 Microbiome ............................................................................................................... 5 
3.2.3.2 T cell Repertoire ....................................................................................................... 5 
4 
Patient Evaluation ................................................................................................................. 6 
4.3 
Collection of Research Samples ........................................................................... 10 
4.3.1 
Study Blood Draws ................................................................................................. 10 
4.3.2     Stool Samples ........................................................................................................... 10 
4.3.3     Urine Samples .......................................................................................................... 10 
5 
Statistical Considerations.................................................................................................... 11 
5.1 
Study Overview ............................................................................................................ 11 
5.1.1 
Accrual .................................................................................................................... 11 
5.1.2 
Randomization ........................................................................................................ 11 
5.1.3 
Primary Endpoint .................................................................................................... 11 
5.1.4 
Primary Objective ................................................................................................... 11 
5.1.5 
Sample Size and Power Considerations .................................................................. 11 
5.2 
Interim Analysis and Pausing Guidelines .................................................................. 12 
5.3 
Demographic and Baseline Characteristics ............................................................... 12 
5.4 
Analysis Populations .................................................................................................... 12 
5.5 
Analysis Plan ................................................................................................................. 13 
5.5.1 
Analysis of the Primary Objective:  Compare NRM within 1 year between groups 
defined by engraftment stool microbiome diversity. .............................................. 13 
5.5.2 
Analysis of the Secondary Objectives .................................................................... 13 
 


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CHAPTER 1 
 
1 BACKGROUND AND RATIONALE 
1.1 
Introduction 
Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after 
allogeneic hematopoietic cell transplantation (HCT). Clinically significant grade II-IV acute 
GVHD occurs in 34-40% of patients undergoing HLA-matched related donor HCT, 47-52% of 
HLA-matched unrelated donor 
HCT, and is 
further increased in 
those lacking  
HLA-matched donors.1,2,3,4 
Acute GVHD is mediated by donor-derived T cells that are reactive against recipient antigens 
expressed in the context of the major histocompatibility complex (MHC or HLA). These antigens, 
termed minor histocompatibility antigens (mHA), are small peptides with immunogenic single 
nucleotide polymorphisms (SNPs) capable of eliciting potent T cell immune responses upon 
presentation by antigen presenting cells (APCs). A number of these mHAs have been identified.5 
In fact, mismatches of known mHA among HLA identical donor-recipient pairs have been 
associated with the development of acute GVHD after stem cell transplantation.6  
Approximately 40% of patients with acute GVHD will have durable responses to corticosteroid 
therapy.7 The prognosis of the 60% of patients without long-lasting response is poor.8 A strategy 
that minimizes the incidence of acute GVHD, without other adverse effects, would be an effective 
approach to improve survival after allogeneic transplantation. 
Acute GVHD incidence can be decreased with various pharmacologic agents. Early transplants 
were done using post-transplant methotrexate to prevent GVHD; in the 1980s cyclosporine was 
shown to be superior to methotrexate and in 1986 the combined use of cyclosporine and 
methotrexate was shown to be superior to single agent prophylaxis.9 More recently, other 
calcineurin-inhibitors, such as tacrolimus have been developed as acute GVHD prophylactic 
agents due to favorable toxicity profiles in comparison with cyclosporine.10,11 
Phase III trials comparing tacrolimus/methotrexate (Tac/MTX) versus cyclosporine/methotrexate 
for related and unrelated donors have been performed. In the unrelated donor setting, the incidence 
of grade II-IV acute GVHD was 56% among the 46 patients randomized to tacrolimus arm versus 
74% among the 63 patients randomized to cyclosporine arm.12 The combination of 
tacrolimus/methotrexate remains the standard for acute GVHD prophylaxis, despite its limited 
efficacy. Hence for many years, a calcineurin inhibitor-based doublet has been considered the 
standard of care for acute GVHD prophylaxis.  
In order to test novel regimens incorporating agents promising in the phase II setting, BMT CTN 
1203 was completed. This phase II multicenter trial randomly assigned patients (pts) 1:1:1 to 
Tac/MTX /maraviroc 300mg PO BID Day -3 to +30; Tac/MTX/bortezomib 1.3mg/m2 on Days 
+1, +4, and +7; or post-transplant cyclophosphamide (PTCy) 50mg/kg/day on Days +3 and +4 
plus Tac/MMF(mycophenolate mofetil), each compared with a nonrandomized prospective 


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contemporaneous Tac/MTX treated control cohort. Pts aged 18-75 with hematologic malignancies 
eligible for RIC alloHCT were accrued. All pts received peripheral blood stem cell (PBSC) grafts 
from 6/6 HLA matched related or 7-8/8 HLA matched unrelated donors. Controls had the same 
eligibility, but enrollment was done at centers not participating in the trial.  
In BMT CTN 1203, the regimen of PTCy/Tac/MMF was the most promising compared to controls 
(detailed in later paragraphs) and thus has been selected for a randomized phase III study in 
comparison with Tac/MTX in BMT CTN 1703. 
1.2 
Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil 
(PTCy/Tac/MMF)  
1.2.1 
Rationale of Post-transplant Cyclophosphamide 
High dose cyclophosphamide is a potent immunosuppressor that has been successfully used to 
prevent GVHD in unrelated, HLA-matched sibling and haploidentical bone marrow/PBSC 
transplants in single center as well as in multicenter studies.13,14,15,16,17,50 Cyclophosphamide 
administered early post HCT preferentially kills allo-reactive T cells while sparing resting, non 
allo-reactive T cells leading to suppression of GVHD as well as graft rejection.18 The paragraphs 
that follow highlight the growing experience with PTCy as GVHD prophylaxis. 
1.2.2 
Post-transplant Cyclophosphamide in Alternative Donor Transplantation 
Based on promising pre-clinical results at Johns Hopkins, a Phase I/II clinical trial of 
haploidentical BMT to treat high-risk hematologic malignancies was initiated in 1999. Following 
a non-myeloablative regimen of fludarabine, cyclophosphamide, and low-dose total body 
irradiation (TBI), GVHD prophylaxis consisted of cyclophosphamide (Cy) given on Days +3 and 
+4 post-transplant, tacrolimus, and mycophenolate mofetil (MMF).15 Primary graft failure 
occurred in 13% of patients, and was fatal due to infection in one patient in whom autologous 
hematopoiesis failed to occur. In general, complete T-cell engraftment was observed by Day +28 
or the grafts were rejected. Cumulative incidences of grades II-IV and grades III-IV acute GVHD 
by Day 200 were 34% and 6%, respectively. There was lower incidence of extensive chronic 
GVHD among recipients of two versus one dose of post-transplantation Cy (5% versus 25%; 
p=.05). There was no difference in the incidence of severe acute GVHD with one or two doses of 
post-transplant Cy. The cumulative incidences of non-relapse mortality and relapse at 1 year were 
15% and 51%, respectively. Actuarial overall and event-free survivals (EFS) at two years after 
transplantation were 36% and 26%, respectively. Patients with lymphoid malignancies appeared 
to have an improved EFS compared to those with myeloid malignancies (p=.02). 
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) sponsored a multicenter 
Phase II trial of haploidentical BMT (BMT CTN 0603) for high-risk hematologic malignancies 
modeled after the Hopkins approach. This was published along with a similar study using cord 
grafts without post-transplant Cy (BMT CTN 0604).13 The 1-year probabilities of overall and 
progression-free survival were 54% and 46% after cord transplantation and 62% and 48% after 
haploidentical bone marrow transplantation. The Day +56 cumulative incidence of neutrophil 
recovery was 94% after dUCB and 96% after haploidentical marrow. The 100-day cumulative 


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incidence of grade II-IV acute GVHD was 40% with cord blood and 32% with haploidentical bone 
marrow. The 1-year cumulative incidences of non-relapse mortality and relapse after cord 
transplantation were 24% and 31%, respectively; corresponding rates after haploidentical bone 
marrow transplantation were 7% and 45%. 
1.2.3 
Post-transplant Cyclophosphamide as GVHD Prophylaxis after PBSC transplantation 
Post-transplant Cy as GVHD prophylaxis was developed initially for haploidentical BM 
transplantation after nonmyeloablative conditioning but, recently, several studies have extended 
the approach to PBSC transplantation. To date, haploidentical nonablative transplantation with 
post-transplant Cy has used bone marrow as the graft source. Use of PBSC instead of marrow may 
allow wider applicability of this approach but there is concern about higher risks of acute and 
chronic GVHD due to the 5-10-fold higher number of T-cells in the allograft. Groups in Houston 
and Seattle/London reported small studies in which PBSC were substituted for BM with post-
transplant Cy in the haploidentical donor setting.16,19  In both studies, the incidences of severe 
acute GVHD, chronic GVHD and non-relapse mortality at 1 year with PBSC were comparable to 
the rates seen with BM. A recent large series compared clinical outcomes in 481 patients receiving 
haploidentical bone marrow (BM) grafts versus 190 patients receiving haploidentical PBSC grafts. 
There were no significant differences in OS or NRM, but leukemia patients receiving BM had a 
lower risk of acute and chronic GVHD (HR = 0.45, p<0.001 and HR = 0.35, p<0.001 respectively), 
and patients with leukemia receiving BM had a higher risk of relapse (HR 1.73, p=0.002).20  
PTCy has been extended beyond haploidentical donor grafts and into matched related/unrelated 
PBSC transplantation in recent reports. The Seattle group published experience with 
PTCy/cyclosporine/MMF as GVHD prophylaxis in the myeloablative transplantation setting, with 
previously tested regimen that showed excellent rates of engraftment (>97%), low relapse at 2 
years (17%), low 2-year non-relapse mortality (14%), no grade III-IV acute GVHD, and low rates 
of chronic GVHD (16%).21 Moiseev et al described similar outcomes in a prospective study, with 
<10% grade III-IV acute GVHD and non-relapse mortality <20%.50  In BMT CTN 1203, a reduced 
intensity setting, PTCy/Tac/MMF showed the most favorable results compared to controls (details 
in 1.3). Thus, experience and interest in extending PTCy in to the matched PBSC transplantation 
setting continues to grow. 
1.3 
Benchmark Analysis and Composite Endpoint 
In order to better evaluate the efficacy of novel approaches for GVHD prophylaxis, a benchmark 
analysis was performed using data from the Center for International Blood and Marrow Transplant 
Research (CIBMTR) for patients who received a RIC HCT.  
The CIBMTR maintains an outcomes registry that prospectively collects data from all centers 
performing allogeneic HCTs and almost all centers performing autologous HCTs in the United 
States and about 100 non-US centers. Centers must report all consecutive patients and provide 
longitudinal follow-up on those patients according to set timelines that include a pre-transplant 
report, a 100-day report, a 6-month report and an annual report through 6 years post-transplant 
followed by a biannual report in perpetuity. Data are reported on two tracks: a “Transplant 
Essential Data” track and a “Comprehensive Report Form” track. Centers provide a pretransplant 


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Transplant Essential Data form for all patients. Data from this form are used to select patients for 
the Comprehensive Report Form track using a weighted random selection that over selects patients 
with rare diseases or procedures or for the purposes of specific studies. For example, most patients 
on BMT CTN trials are selected for the Comprehensive Report Form track so that data collected 
by the CIBMTR can supplement clinical trial data collected through AdvantageEDC or Advantage 
eClinical and can allow for long-term follow-up of trial patients for specific late effects of 
treatment. Longitudinal data are collected for patients on both the Transplant Essential Data and 
Comprehensive Report Form Track; the data differ in quantity and granularity. Data quality is 
ensured by computerized error checks and on-site audits. 
The objective of the benchmark analysis was to select promising approaches to be further studied 
and to explore novel endpoints that could not only assess GVHD, but also the complex 
relationships between relapse and GVHD as well as prolonged use of immune suppression. The 
control population selected from the CIBMTR database was comprised of patients who received 
HCT in a US center from 2006 to 2009 and who received tacrolimus and methotrexate as their sole 
GVHD prophylaxis. Data from single institution studies of the two agents to be tested in this 
protocol were also studied. Populations differed according to disease, donor, conditioning 
intensity, disease risk and patient age. Each institutional cohort was compared with the CIBMTR 
controls, adjusting for differences in baseline populations using multivariate regression techniques. 
Table 1.3A summarizes the results of both univariate and multivariate analyses for the 2 arms 
proposed in BMT CTN 1703.  
Table 1.3A: Univariate and Multivariate Results from the Benchmark Analysis 
Outcome 
Tac+MTX Control 
(95%CI) 
PTCy 
(95%CI) 
Grade III-IV Acute 
GVHD  
HR 
 
1.00 
0.90 
(0.58-1.4) 
Incidence at 6 mo 
(95%CI) 
25% 
(23-26%) 
23% 
(15-33%) 
CGVHD 
HR 
 
1.00 
0.24 
(0.14-0.41) 
Incidence at 12 mo 
(95%CI) 
45% 
(43-46%) 
13% 
(7-20%) 
Overall Survival 
HR 
 
1.00 
1.07 
(0.82-1.4) 
Probability at 12 mo 
(95%CI) 
60% 
(58-61%) 
57% 
(47-66%) 
Disease free survival 
HR 
1.00 
1.21 
(0.94-1.56) 
Probability at 12 mo 
(95%CI) 
52% 
(51-53%) 
46% 
(37-55%) 
HR=Hazard Ratio, CI=Confidence Interval. The event for overall survival was death and the event for disease free survival was death or 
relapse. A hazard ratio (HR) greater than 1 implies that a specific group has more events at any time compared to the Tac+MTX Control 
reference group (indicated by a HR of 1.00). 
 


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We remain interested in evaluating a composite endpoint that would better reflect reductions in 
either or both acute and chronic GVHD as well as the sometimes opposite effects of reducing 
GVHD on transplant-related mortality and relapse. In BMT CTN 1203, PTCy/Tac/MMF was the 
only study arm that showed an improved GVHD- Free-Relapse-Free Survival (GRFS) relative to 
controls. The study design provided an 81-87% power to identify a superior treatment if 1-year 
GRFS was 15% better than control. One-sided testing was used. 92 pts were assigned to 
PTCy/Tac/MMF; 89 to Tac/MTX/bortezomib; 92 to MTX/Tac/maraviroc; and 224 controls 
received Tac/MTX. For the primary 1-year GRFS endpoint, only the MMF/Tac/PTCy arm was 
superior to control (p 0.04, Table 1.3B). The cumulative incidence of grade II-IV aGvHD through 
Day 180 was not different for each arm vs. control; however, for grade III-IV aGvHD and GVHD-
free survival, PTCy/Tac/MMF was superior to control (p 0.006, p 0.01 respectively). While there 
was no difference in overall cGvHD incidence, for cGVHD requiring SIS, the PTCy/Tac/MMF 
arm was superior to control (p 0.04). Treatment-related mortality at 1 year was 11% for 
PTCy/Tac/MMF vs 16% in controls and 17% in the other 2 arms, but was not statistically different. 
There were no differences in engraftment, relapse/progression, and overall survival. 
Table 1.3B: Multivariate Outcomes 
s 
Controls 
Bortezomib 
Maraviroc 
PTCy 
GRFS 
HR (90% CI) 
1 
0.82 (0.62-1.08) 
1.02 (0.79-1.32) 
0.72 (0.54-0.94) 
P 
  
0.2407 
0.8689 
0.0467 
Adjusted 1 yr KM 
estimates 
0.32 (0.26-0.39) 
0.42 (0.33-0.54) 
0.32 (0.23-0.43) 
0.46 (0.37-0.57) 
aGvHD II-IV 
HR (90% CI) 
1 
0.80 (0.53-1.20) 
0.98 (0.68-1.43) 
0.83 (0.56-1.22) 
P 
  
0.3694 
0.9578 
0.4334 
CuI at 180 days 
(90% CI) 
31 (26-36)% 
26 (19-34)% 
32 (24-40)% 
27 (20-35)% 
aGvHD III-IV 
HR (90% CI) 
1 
0.51 (0.25-1.04) 
0.58 (0.29-1.15) 
0.13 (0.03-0.44) 
P 
  
0.1204 
0.1945 
0.0066 
CuI at 180 days 
(90% CI) 
13 (9-16)% 
8 (4-13)% 
9 (4-14)% 
2 (0-5)% 
cGvHD 
HR (90% CI) 
1 
1.07 (0.76-1.51) 
1.23 (0.90-1.70) 
0.74 (0.51-1.08) 
P 
  
0.7352 
0.2717 
0.2029 
CuI at 1 yr (90% CI) 
38 (32-43)% 
39 (30-47)% 
44 (35-53) 
37 (20-36)% 
cGvHD requiring 
immunosuppression 
HR (90% CI) 
1 
0.70 (0.45-1.07) 
0.85 (0.57-1.26) 
0.57 (0.36-0.89) 
P 
  
0.1749 
0.5063 
0.0413 
CuI at 1 yr (90% CI) 
32 (27-37)% 
22 (16-30)% 
27 (20-35)% 
19 (12-26)% 
Relapse/progression 
HR (90% CI) 
1 
0.94 (0.60-1.46) 
1.209 (0.80-1.81) 
1.24 (0.84-1.83) 
P 
  
0.8188 
0.4415 
0.3458 
CuI at 1 yr (90% CI) 
25 (20-30)% 
22 (15-30)% 
28 (20-36)% 
27 (20-35)% 
Treatment related 
mortality 
HR (90% CI) 
1 
1.06 (0.63-1.78) 
0.97 (0.57-1.65) 
0.62 (0.34-1.11) 
P 
  
0.8465 
0.9327 
0.1799 
CuI at 1 yr (90% CI) 
16 (12-21)% 
17 (11-24)% 
17 (11-24)% 
11 (6-17)% 
Disease-free 
survival 
HR (90% CI) 
1 
0.97 (0.70-1.35) 
1.14 (0.83-1.57) 
0.93 (0.68-1.29) 
P 
  
0.9086 
0.4685 
0.7449 
1 yr KM estimates 
59 (53-64)% 
60 (52-69)% 
56 (47-64)% 
62 (53-70)% 
GvHD free survival 
HR (90% CI) 
1 
0.83 (0.62-1.11) 
0.98 (0.75-1.28) 
0.63 (0.46-0.85) 


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P 
  
0.3078 
0.9130 
0.0121 
Adjusted 1 yr 
estimates (90% CI) 
0.39 (0.33-0.46) 
0.46 (0.37-0.58) 
0.40 (0.31-0.51) 
0.56 (0.47-0.67) 
 
1.4 Studies of the Microbiome and Immune Reconstitution in Transplant Patients 
1.4.1 
Microbiome Studies 
The microbiome, consisting of a varied community of microbes (bacteria, viruses, fungi, 
microeukaryotes, and sometimes multicellular parasites), exists in niches across the human body. 
The skin, lung, nares, vagina, and gastrointestinal tract are among the most heavily colonized, with 
the largest number of microorganisms inhabiting the colonic lumen. Intestinal microbiota interact 
with and regulate host immunity.26 While the majority of the over trillion organisms that live within 
a healthy human colon are nonpathogenic members of the phyla Firmicutes, Bacteroidetes, 
Actinobacteria, and Proteobacteria, alterations in the balance of these microorganisms have been 
associated with adverse outcomes ranging from GVHD and infection to relapse post-HCT.27 This 
clinical association between intestinal microorganisms and HCT outcomes has been investigated 
for decades – and has informed the still controversial practices of infection prophylaxis, gut 
decontamination, the “neutropenic diet,” and isolation of patients in laminar air flow rooms. 
Single-institution studies have demonstrated that low microbial diversity in the stool after 
allogeneic HCT is associated with poor survival .28,29 Additionally, specific alterations have been 
associated with increased risk of acute GVHD, infectious outcomes and most recently, relapse.30-
32 While these findings are compelling, most studies have been carried out in single institutions 
and thus the generalizability of these proposed microbial biomarkers is unclear. This is particularly 
important as there is known geographic variation of the intestinal microbiome and practice 
variability in antibiotic use for prophylaxis and treatment from institution to institution, in part due 
to different antibiograms.  
Growing understanding of the positive roles of the microbiome in regulating immune maturation 
in developing humans, maintenance of host barriers against pathogens, and nutrition suggest that 
the health of the microbiome must be carefully considered in allogeneic HCT patients.  
 
While a substantial investment was made by the NIH Common Fund in characterizing the “normal 
human microbiome” in the Human Microbiome Project (HMP) phase I and diseased human 
microbiome in the HMP phase II, no broad scale microbiome characterization effort has yet been 
made in the setting of cancer. Indeed, iHMP (or HMP2) prioritized multi-omic characterization of 
longitudinal samples from diseased individuals from three categories: pre-term birth, type 2 
diabetes mellitus, and inflammatory bowel disease. As recently outlined in the NIH Emerging 
Themes workshop on microbiome research (NIH, Bethesda, MD; August 15 – 18, 2018), the field 
has recognized the strong importance of longitudinal sampling, high quality metadata collection, 
and simultaneous microbial and immunologic characterization.  
Novel methods being pioneered and perfected in microbiome research are likely to facilitate 
translational breakthroughs – these methods allow (1) detailed taxonomic classification of 
microorganisms at the strain level, (2) metabolic characterization of the small molecules and 
proteins that a microbial community makes, (3) measurement of microbial genomic evolution in 
clinical time courses, and (4) culturing of previously fastidious organisms from the microbiome 


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for in vitro investigation and cultivation as potential therapeutic/adjuvant live bacterial clinical 
interventions. A well-curated, longitudinal biospecimen collection will facilitate validation of 
existing microbial biomarkers of disease and discovery of novel microbial biomarkers of disease 
that are generalizable. Particularly compelling is the fact that both preclinical and clinical studies 
support the role of the microbiome as a potentially modifiable biomarker of disease.33 In fact, the 
microbiome has already been causally associated with opportunistic infections such as C. difficile 
colitis, in which fecal microbiota transplantation is highly safe and effective.34 Furthermore, 
inflammatory diseases, such as IBD, are clearly modulated by the microbiome.35  
Given recent reports suggesting that alterations in the microbiome can impact the efficacy of 
immunologic therapies, there is a clear imperative that the strong and growing link between the 
microbiome and cancer outcomes be investigated.36,37 As the BMT CTN carries out a multitude of 
interventional clinical trials and has a strong track record for longitudinal sampling, high quality 
metadata collection, and immunologic characterization of patients post-HCT, the BMT CTN is 
ideally suited to lead the first cancer-associated effort in this space.  
 
1.4.2 
Protective Immunity 
The reconstitution and regain of function of a donor-derived immune system is of utmost 
importance for the recovery and long-term survival of patients after allogeneic HCT. 
Dysfunctional immune reconstitution after transplant is associated with several transplant-related 
complications and adverse transplant outcome. However, although the phenomenology of the 
many defects in protective immunity (both against infectious pathogens and against leukemia 
relapse) is well-documented, the causative molecular mechanisms remain unknown.38 To address 
these questions, several groups, including investigators at FHCRC, MSKCC, and Stanford, have 
begun to perform detailed assessments of immunologic reconstitution after allogeneic HCT 
including the application of new T Cell Receptor (TCR) and B Cell Receptor (BCR) deep-
sequencing technologies39-46 These technologies allow the investigation of the breadth and depth 
of post-transplant immune reconstitution at a level of molecular detail not previously possible and 
hold the promise of deepening our understanding of the impact of infectious pathogens on global 
immune health and immune reconstitution. The widespread application of these technologies, and 
their intersection with detailed assessment of immune phenotype and function can provide novel 
insights about the state of immune health in transplant patients, and holds the promise of 
identifying patients in need of novel interventions to improve their post-transplant immune 
reconstitution. 
Accumulating evidence in recent years have indicated that the host microbiome has a tremendous 
influence on the generation and shaping of immune cell repertoire.47 Additionally, the microbiota 
affects the immune response against cancer. For example, there are studies demonstrating the 
association between intestinal microbiota and relapse after HCT32, or studies demonstrating that 
immune responses against cancer triggered by immune checkpoint inhibition are associated with 
the abundance of distinct members of intestinal microbiota.48,49 
 


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1.4.3 
Microbiome and Immune Reconstitution in Cellular Therapies and Hematopoietic 
Stem Cell Transplantation (Mi-Immune) 
Mi-Immune represents a companion study, where additional key precision medicine and systems 
biology questions will be explored. The goal of this companion study is several-fold:  First, it is to 
test the primary hypothesis that the engraftment stool microbiome diversity (determined by 16s 
rRNA sequencing analysis of the sample closest after, but within 14 days of neutrophil 
engraftment) predicts 1-year non-relapse mortality in patients undergoing reduced-intensity 
allogeneic HCT.  Second, it is to perform additional analyses on patient samples to answer key 
questions concerning: a)  the impact of the stool microbiome on transplant outcome as well as the 
impact of transplant on the microbiome and the associated downstream impact on patient health; 
and b) reconstitution of the T cell repertoire after transplant.  Third, it is to establish a cohort of 
biologic samples collected prospectively from patients treated on BMT CTN 1703 that will be a 
shared biospecimen resource for conducting future allogeneic HCT correlative studies.  The 
resulting dataset will become an additional resource generated by the trial and will be made 
available to the biomedical community. Mi-Immune is designed to link molecular data and 
biospecimens with high quality clinical phenotype and outcomes data to identify risk factors for 
development and severity of key complications after allogeneic HCT.  
 
1.5 
Rationale for a Randomized Trial 
This multicenter Phase III clinical trial will evaluate 2 acute GVHD prophylaxis approaches for 
their efficacies in improving the proportion of patients who do not develop severe acute GVHD, 
chronic GVHD that requires systemic therapy, disease progression, or relapse by one year post-
transplant. Selection of the most promising therapy will be made based on the magnitude of 
difference in the primary endpoint.


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CHAPTER 2 
2 STUDY DESIGN 
2.1 
Study Overview 
The BMT CTN 1703 study is a Phase III randomized, open label, multicenter trial comparing 
PTCy/Tac/MMF versus Tac/MTX for GVHD prophylaxis in patients with controlled malignant 
diseases receiving an allogeneic PBSC transplant after a RIC regimen. The primary endpoint is 
GRFS at 1 year. 
The study will collect stool, urine, and blood biospecimens, as well as detailed clinical data on 
infections and antibiotic exposures in an attempt to understand the microbial and immune recovery 
predictors of HCT outcomes. Mi-Immune component of the study will form the correlative science 
arm of the BMT CTN 1703 study (PROGRESS III), which will compare two acute GVHD 
prophylaxis regimens: Tac/MTX versus PTCy/Tac/MMF in the setting of RIC allogeneic PBSC 
transplantation.  
2.2 
Hypothesis and Specific Objectives 
2.2.1 
Primary Hypothesis  
BMT CTN 1703: At 1 year, PTCy/Tac/MMF GRFS will be 15% or greater compared to Tac/MTX 
GRFS. 
Mi-Immune study: The engraftment stool microbiome diversity (determined within 14 days after 
neutrophil engraftment) predicts 1-year non-relapse mortality. 
2.2.2 
Study Objectives  
BMT CTN 1703: The primary objective of the randomized trial is to compare 1-year GRFS after 
HCT between PTCy/Tac/MMF versus Tac/MTX. An event for this time to event outcome is 
defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, 
disease relapse or progression, or death by any cause. Secondary objectives are grade II-IV and 
III-IV acute GVHD per the NIH Consensus Conference Criteria on Acute GVHD Grading by Day 
+180, rates of Minnesota standard and high risk acute GVHD by Day +180, rates of NIH mild, 
moderate, and severe chronic GVHD (defined by the NIH Consensus Conference Criteria) at 1 
year, systemic immunosuppression-free survival at 1 year, hematologic recovery including 
neutrophil engraftment (first day of ANC greater than or equal to 500 for 3 consecutive days), 
platelet engraftment (first day of sustained platelet greater than or equal to 20,000, or greater than 
or equal to 50,000 with no platelet transfusion in preceding 7 days), lymphocyte recovery (first 
day of sustained absolute lymphocyte count greater than or equal to 1000), proportion of patients 
with full (at least 95% or more) or mixed (5.0-94.9%) total donor chimerism or graft rejection (less 
than 5% total donor chimerism) at Day +100, disease relapse or progression at 1 year, non-relapse 
mortality at 1 year, incidence of biopsy-confirmed PTLD at 1 year, incidence of infections at 1 
year, overall survival at 1 year, and patient-reported outcomes (PRO) at baseline, Day 100, Day 
180, 1 year. 


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Mi-Immune study: The goal of this protocol is to test the primary hypothesis that the engraftment 
stool microbiome diversity (determined by 16s rRNA sequencing analysis of the sample closest 
after, but within 14 days of neutrophil engraftment) predicts 1-year non-relapse mortality in 
patients undergoing reduced-intensity allogeneic HCT.  Mi-Immune secondary and exploratory 
objectives are addressed in Chapter 2 of Appendix J.  
2.3 
Patient Eligibility 
2.3.1 
Inclusion Criteria 
1. Age 18.0 years or older at the time of enrollment on Segment A  
2. Patients with acute leukemia or chronic myelogenous leukemia with no circulating blasts 
and with less than 5% blasts in the bone marrow  
3. Patients with myelodysplasia/chronic myelomonocytic leukemia with no circulating blasts 
and with less than 10% blasts in the bone marrow (higher blast percentage allowed in MDS 
due to lack of differences in outcomes with <5% vs. 5-10% blasts in this disease)  
4. Patients with relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma with 
chemosensitive disease at time of transplantation 
5. Patients with lymphoma [follicular lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, 
mantle cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and 
anaplastic large cell lymphoma] with chemosensitive disease at the time of transplantation  
6. Planned reduced intensity conditioning regimen (see eligible regimens in Table 2.4a) 
7. Patients must have a related or unrelated peripheral blood stem cell donor as follows: 
a. Sibling donor must be a 6/6 match for HLA-A and -B at intermediate (or higher) 
resolution, and -DRB1 at high resolution using DNA-based typing and must be 
willing to donate peripheral blood stem cells and meet institutional criteria for 
donation. 
b. Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C and –DRB1 at high 
resolution using DNA-based typing. Unrelated donor must be willing to donate 
peripheral blood stem cells and meet NMDP criteria for donation. 
8. Cardiac function: Left ventricular ejection fraction at least 45% 
9. Estimated creatinine clearance acceptable per institutional guidelines 
10. Pulmonary function: DLCO corrected for hemoglobin at least 40% and FEV1 predicted 
at least 50%  
11. Liver function acceptable per institutional guidelines 
12. Karnofsky Performance Score at least 60% 
13. Female patients (unless postmenopausal for at least 1 year before the screening visit, or 
surgically sterilized), agree to practice two (2) effective methods of contraception at the 
same time, or agree to completely abstain from heterosexual intercourse, from the time of 
signing the informed consent through 12 months post-transplant.  


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14. Male patients (even if surgically sterilized), of partners of women of childbearing potential 
must agree to one of the following: practice effective barrier contraception, or abstain from 
heterosexual intercourse from the time of signing the informed consent through 12 months 
post-transplant. 
15. Plans for the use of post-transplant maintenance therapy must be disclosed upon 
enrollment and must be used irrespective of the outcome of the randomization.  
Please note that THIS DOES NOT INCLUDE INVESTIGATIONAL AGENTS and 
maintenance therapy with investigational treatment requires approval by the study chairs.   
16. Voluntary written consent obtained prior to the performance of any study-related 
procedure that is not a part of standard medical care, with the understanding that consent 
may be withdrawn by the patient at any time without prejudice to future medical care 
 
2.3.2 
Exclusion Criteria 
1. Prior allogeneic transplant 
2. Active CNS involvement by malignant cells 
3. Patients with secondary acute myeloid leukemia arising from myeloproliferative disease, 
including CMML 
4. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication 
and with progression or no clinical improvement) at time of enrollment. 
5. Presence of clinically significant fluid collection (ascites, pleural or pericardial effusion) 
that interferes with methotrexate clearance or makes methotrexate use contraindicated 
6. Patients seropositive for human immunodeficiency virus (HIV) with detectable viral load. 
HIV+ patients with an undetectable viral load on antiviral therapy are eligible.  
7. Myocardial infarction within 6 months prior to enrollment or New York Heart Association 
(NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia. 
8. Female patients who are pregnant (as per institutional practice) or lactating 
9. Patients with a serious medical or psychiatric illness likely to interfere with participation 
in this clinical study 
10. Patients with prior malignancies except resected non-melanoma skin cancer or treated 
cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be 
allowed. Cancer treated with curative intent < 5 years previously must be reviewed and 
approved by the Protocol Officer or Chairs. 
11. Planned use of ATG or alemtuzumab in conditioning regimen 
 
2.4 
Treatment Plans 
It is recommended that adjusted ideal body weight be used when calculating conditioning 
regimen chemotherapy doses. 


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Ideal Body Weight (IBW) Formulas: 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
 
Adjusted Ideal Body Weight Formula: 
 
AIBW = IBW + [(0.25) x (ABW* - IBW)] 
 
2.4.1 
Conditioning Regimens 
Eligible patients will receive a reduced intensity or nonmyeloablative conditioning regimen 
according to Table 2.4A. Other regimens deemed to be RIC by the transplant center and not 
included in Table 2.4A should be submitted to the Protocol Coordinator for consideration by the 
Protocol Chairs and/or Officer. 
*ABW: Actual Body Weight 
 


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Table 2.4A: Conditioning Regimens1 
Reduced Intensity Conditioning 
Nonmyeloablative Conditioning 
Fludarabine/Busulfan (Flu/Bu) 
• Fludarabine (120-180 mg/m2) 
• Busulfan (less than or equal to 8 
mg/kg PO or 6.4 mg/kg IV) 
 Fludarabine/Cyclophosphamide (Flu/Cy) 
• Fludarabine (90-120 mg/m2) 
• Cyclophosphamide (120 mg/kg or 2250 
mg/m2) 
Fludarabine/Melphalan ( Flu/Mel) 
• Fludarabine (120-180 mg/m2) 
• Melphalan (less than or equal to 150 
mg/m2) 
Fludarabine /Total Body Irradiation 
(Flu/TBI) 
• Fludarabine (90 mg/m2) 
• TBI (200 cGy) 
 
Fludarabine/ Cyclophosphamide/TBI 
(Flu/Cy/TBI) 
• Fludarabine (150 mg/m2) 
• TBI (200 cGy) 
• Cyclophosphamide (29-50 mg/kg)  
1Addition of antithymocyte globulin or alemtuzumab is not allowed.  
 
Fludarabine and busulfan (Flu/Bu) 
The recommended Flu/Bu regimen is the following:  
• Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) 
Busulfan Options 
Busulfan without PK - Days -5 to -4: Busulfan (4 mg/kg/day PO or 3.2 mg/kg/day IV or 
130 mg/m2/day IV; total dose of 8 mg/kg PO or 6.4 mg/kg IV or 260 mg/m2 IV 
respectively) 
Busulfan with PK – target doses to area under the curve of 4000μMol/min (course AUC 
16000μMol/min) or less is allowed. 
The sequence of fludarabine and busulfan administration may follow institutional 
practice.  
 
Fludarabine and melphalan (Flu/Mel) 
The recommended Flu/Mel regimen is the following: 
• Days -5 to -2: Flu (30 mg/m2/day, total dose of 120 mg/m2) 


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• Day -1: Mel (140 mg/m2) 
The sequence of fludarabine and melphalan administration will be done according to institutional 
standards as long as the prescribed doses are the same as the recommended regimen above. 
Dividing the dose of melphalan into two days is allowed.  
Fludarabine and cyclophosphamide (Flu/Cy) 
The recommended Flu/Cy regimen is the following:  
• Days -5 to -3: Flu (30 mg/m2/day, total dose of 90 mg/m2) 
• Days -4 to -2: Cyclophosphamide (750 mg/m2/day, total dose of 2250 mg/m2) 
Alternatively: 
• Days -3 to -2: Cyclophosphamide (60 mg/kg/day, total dose of 120 mg/kg) 
The sequence of fludarabine and cyclophosphamide administration will be done according to 
institutional standards as long as the prescribed doses are the same as the recommended regimen 
above. Hydration and Mesna may be administered per institutional guidelines. Addition of 
rituximab conditioning in patients with lymphoproliferative disease is allowed. Dose and intervals 
of rituximab conditioning can be determined according to institutional guidelines. However, 
rituximab use after stem cell infusion is not permitted.  
 
Fludarabine and total body irradiation (Flu/TBI) 
The recommended Flu/TBI regimen is the following:  
• Days -5 to -3: Flu (30 mg/m2/day, total dose of 90 mg/m2) 
• Day -1 or 0: TBI 200 cGY (pre-stem cell infusion) 
 
Fludarabine, total body irradiation and cyclophosphamide (Flu/Cy/TBI) 
The recommend Flu/Cy/TBI regimen is the following: 
• Days -6 to -5: Cy (14.5 mg/kg/day, total dose of 29 mg/kg, or single dose 50 mg/kg on day 
-6 [Minnesota regimen]) 
• Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) 
• Day -1: TBI 200 cGY 
 
Hydration and Mesna may be administered per institutional standards.  Fludarabine can be dose 
adjusted per institutional standards.   
 
 


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2.4.2 
Hematopoietic Stem Cell Transplantation (HCT) 
Mobilized PBSC is the only allowed graft source for patients enrolled in this clinical trial. 
Donors will undergo G-CSF and/or plerixafor mobilization according to local institutional and 
donor center practices. PBSC will be collected by apheresis according to local institutional 
guidelines. Plasma and red cell depletion are allowed for volume reduction or ABO incompatibility 
but any other form of graft manipulation (including ex-vivo T cell depletion) is not permitted. 
The target stem cell dose is a minimum of 2 x 106/kg and a maximum 10 x 106/kg (actual body 
weight) CD34+ cells. The maximum CD34+ cell dose is 10 x 106/kg.   
Up to two leukapheresis procedures may be performed to obtain the minimum CD34+ cell target. 
If, after two leukapheresis procedures, fewer than 2 x 106/kg CD34+ cells have been collected, 
transplant centers will have the discretion to continue PBSC cell harvesting or to proceed to bone 
marrow harvesting to obtain sufficient cells. A third leukapheresis procedure is discouraged. If 
bone marrow harvesting is needed in order to meet the desired cell dose, the transplant center needs 
to notify the Protocol Coordinator, in addition to the Protocol Chairs and/or Officer.  
If more than 10 x 106/kg CD34+ stem cells are collected, the excess will either be discarded or 
cryopreserved for future use, but will not be administered to the patient.  PBSC will be 
administered on Day 0 to all patients according to individual institutional guidelines after 
appropriate processing and quantification has been performed by the local laboratory. If two 
leukapheresis procedures are performed to obtain the minimum CD34+ cell dose target, the two 
products must be combined and infused together on one day. Stem cells are administered through 
an indwelling central venous catheter.  
2.4.3 
Tacrolimus/Methotrexate 
Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or 
intravenously at a dose of 0.02-0.03 mg/kg/day starting on Day –3. The dose of tacrolimus may be 
rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood 
levels per institutional guidelines with a suggested range of 5-15. If patients are on medications 
which alter the metabolism of tacrolimus (e.g. concurrent CYP3A4 inhibitors), the initial starting 
dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper can be 
initiated at a minimum of 90 days post HCT if there is no evidence of active GVHD. The rate of 
tapering will be done according institutional practices and patients should be off tacrolimus by 
Day 180 post HCT if there is no evidence of active GVHD.  
Dose reductions should be made if toxicity is present or whole blood levels are above the 
recommended range, in the absence of toxicity. Patients with severe intolerance of tacrolimus may 
be placed on cyclosporine (trough level of 200-400 ng/mL) or sirolimus (trough level of 5-10 
ng/mL). 
Methotrexate will be administered at the doses of 15 mg/m2 IV bolus on Day +1 and 10 mg/m2 IV 
bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion.  Methotrexate should be 
dose reduced, given with leucovorin rescue, or held for complications such as severe mucositis per 
institutional guidelines. 


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2.4.4 
Tacrolimus/Mycophenolate Mofetil/Cyclophosphamide 
Tacrolimus 
Tacrolimus will be given per institutional practices, orally at a dose of 0.05-0.06 mg/kg/day or 
intravenously at a dose of 0.02-0.03 mg/kg/day starting Day +5. Starting tacrolimus dose can be 
modified to account for possible drug interactions (e.g. concurrent CYP3A4 inhibitor use) 
according to institutional guides. Serum levels of tacrolimus will be measured at Day +7 and then 
should be checked weekly thereafter, and the dose adjusted accordingly to maintain a suggested 
level of 5-15 ng/mL. Tacrolimus taper can be initiated at a minimum of 90 days post HCT if there 
is no evidence of active GVHD.  The rate of tapering will be done according to institutional 
practices but patients should be off tacrolimus by Day 180 post HCT if there is no evidence of 
active GVHD.  
Dose reductions should be made if toxicity is present or whole blood levels are above the 
recommended range, in the absence of toxicity. Patients with severe intolerance of tacrolimus may 
be placed on cyclosporine (trough level of 200-400 ng/mL) or sirolimus (trough level of 5-10 
ng/mL). 
Mycophenolate mofetil (MMF) 
MMF will be given at a dose of 15 mg/kg/dose TID (based upon actual body weight) with the 
maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start 
Day +5 and discontinue after the last dose on Day +35 or may be continued if active GVHD is 
present.  
Cyclophosphamide 
Hydration prior to cyclophosphamide may be given according to institutional standards. A 
recommended approach is as follows: Patients are instructed to increase fluids overnight before 
cyclophosphamide administration. Hydration with normal saline at 3 ml/kg/hr IV will be started 2 
hours prior to cyclophosphamide, then the rate will be reduced to 2 ml/kg/hr for 1 hour pre-
cyclophosphamide and continued at 2 ml/kg/hr for 8 hours post-cyclophosphamide. 
Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-
cyclophosphamide or administered per institutional standards. Mesna dose will be based on the 
cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80%-100% of the 
total daily dose of cyclophosphamide.  
Cyclophosphamide [50 mg/kg IBW; if ABW < IBW, use ABW] will be given on Day +3 (between 
60 and 72 hours after the start of the PBSC infusion) and on Day +4 post-transplant (approximately 
24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 
1-2 hours (depending on volume). 
It is crucial that no systemic immunosuppressive agents, such as corticosteroids, are given from 
day 0 until 24 hours after the completion of the post-transplant cyclophosphamide (Day +5). This 


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rule applies only to the post-transplant cyclophosphamide arm of the studyThis includes 
corticosteroids as anti-emetics, however, replacement doses of chronic glucocorticoids for 
adrenal insufficiency are allowed. 
2.5 
Supportive Care 
All supportive care will be given in keeping with local institutional practice. Supportive care will 
be administered in a similar fashion to patients randomized to both arms of the study.  
2.5.1 
Growth Factors 
G-CSF may be given per institutional guidelines. 
2.5.2 
Blood Products 
Transfusion thresholds for blood product support will be consistent with standard institutional 
guidelines. All blood products will be irradiated. 
2.5.3 
Prophylaxis Against Infections 
Patients will receive infection prophylaxis according to institutional guidelines. Infection 
prophylaxis will include, but is not limited to, agents or strategies (e.g., PCR screening and 
preemptive therapy) to reduce the risk of bacterial, herpes simplex, CMV, HHV-6, EBV, 
Pneumocystis jirovecii, and fungal infections: 
• Antifungal therapy: Prophylaxis with fluconazole or other antifungal agents can be given 
as per local institutional guidelines.  
o Fluconazole, voriconazole and other azoles (CYP3A4 inhibitors) are expected to 
increase serum tacrolimus levels, therefore, dosages of tacrolimus should be 
adjusted accordingly.  
• CMV: CMV monitoring will be done according to institutional guidelines. It is 
recommended that weekly assessment for CMV be done through Day 60 post-transplant. 
Use of letermovir is allowed. Any reactivation and/or CMV disease will be captured in this 
study. An Infection form must be submitted in Advantage eClinical.  
 
2.5.4 
Intravenous Immune Globulin (IVIG) 
IVIG administration will be according to local institutional standard practice. 
2.6 
Participant Risks 
2.6.1 
Therapy Toxicities 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0. 
2.6.2 
Tacrolimus 
Tacrolimus side effects include: 


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• Cardiovascular: pericardial effusion, hypertension (which may cause arrhythmia, angina, 
myocardial infarction) 
• Cutaneous: itching, rash 
• Endocrine and metabolic: hyperglycemia, hypomagnesemia, hypokalemia, hyperkalemia, 
hypophosphatemia, hyperlipidemia 
• Gastrointestinal: constipation, diarrhea, nausea, vomiting, anorexia, bowel perforation, 
dyspepsia 
• General: fatigue 
• Hematologic: anemia, thrombocytopenia, leukopenia, thrombotic microangiopathy  
• Hepatic: liver dysfunction 
• Neurologic: 
paresthesia, 
headache, 
tremor, 
encephalopathy/posterior 
reversible 
encephalopathy syndrome (PRES), dizziness, insomnia, confusion, altered mental status, 
seizure, blindness 
• Pulmonary: pleural effusion, dyspnea 
• Renal: renal impairment which may require dialysis, peripheral edema 
• Miscellaneous: infection, post-transplant lymphoproliferative disorders, allergic reaction, 
secondary malignancy  
 
2.6.3 
Methotrexate 
Methotrexate side effects include: 
• Cardiac and vascular: thrombosis 
• Cutaneous: photosensitivity, rash, alopecia, erythema multiforme 
• Gastroinstestinal: nausea, vomiting, diarrhea, pain, anorexia, ulcers, gastrointestinal 
bleeding, mucositis 
• General: fatigue 
• Hematologic: anemia, thrombocytopenia, leukopenia 
• Pulmonary: pulmonary fibrosis 
• Renal: nephrotoxicity 
• Miscellaneous: secondary malignancy, infection 
 
2.6.4 
Mycophenolate mofetil (MMF) 
MMF side effects include: 
• Cardiac and vascular: hypertension, hypotension, tachycardia, edema 
• Cutaneous: rash 


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• Endocrine and metabolic: hypocalcemia, hypokalemia, hyperuricemia, hyperkalemia, 
hypomagnesemia 
• Gastrointestinal: nausea, vomiting, dyspepsia, abdominal pain, diarrhea 
• Hematologic: leukopenia, thrombocytopenia, anemia 
• Neurologic: 
headache, 
tremors, 
insomnia, 
dizziness, 
progressive 
multifocal 
leukoencephalopathy (PML) 
• Pulmonary: dyspnea, cough, interstitial lung disease 
• Miscellaneous: change in vision, infection, secondary malignancy, arthralgia, myalgia 
 
2.6.5 
Cyclophosphamide 
Cyclophosphamide side effects include: 
• Cardiac and vascular: heart failure (which can result in edema, effusion, dyspnea) 
• Cutaneous: alopecia, rash, hyperpigmentation of skin and nails 
• Gastrointestinal: nausea, vomiting, anorexia, mucositis, stomatitis, abdominal pain, 
diarrhea 
• General: lethargy 
• Hematologic: leukopenia, thrombocytopenia, anemia 
• Pulmonary: pulmonary fibrosis 
• Endocrine: amenorrhea, gonadal function impairment, sterility, syndrome of inappropriate 
antidiuretic hormone secretion (SIADH) – with associated cerebral edema  
• Genitourinary: hemorrhagic cystitis 
• Miscellaneous: infection, allergic reaction including anaphylaxis, secondary malignancy 
 
2.6.6 
Busulfan 
Busulfan side effects include: 
• Cardiac: arrhythmia, edema, hypertension, tachycardia, pericardial effusion, heart failure, 
hypotension 
• Cutaneous: rash, hyperpigmentation, pruritis 
• Gastrointestinal: constipation, diarrhea, dyspepsia, nausea, vomiting, anorexia, mucositis, 
dysphagia 
• General: chills, fever, pain, fatigue 
• Genitourinary: gonadal function impairment, menopause 
• Endocrine: hypomagnesemia, hyperglycemia, hypokalemia, hypocalcemia 
• Hematologic: anemia, thrombocytopenia, leukopenia 
• Hepatic: hepatic impairment, hepatic sinusoidal obstruction syndrome 


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• Neurologic: dizziness, headache, insomnia, seizure, anxiety, depression 
• Pulmonary: cough, nasal congestion, hemoptysis, interstitial pulmonary fibrosis 
• Renal: hematuria, renal impairment 
• Miscellaneous: infection, allergic reaction including anaphylaxis, visual impairment 
2.6.7 
Fludarabine 
Fludarabine side effects include: 
• Gastrointestinal: vomiting, anorexia, nausea, mucositis 
• General: fatigue, fever, chills 
• Hematologic: anemia, thrombocytopenia, neutropenia 
• Hepatic: increased liver function tests  
• Neurologic: paresthesia, confusion, seizure, agitation, visual disturbances, pain 
• Pulmonary: cough, shortness of breath 
• Renal: renal impairment, hematuria 
• Miscellaneous: infection, general organ damage 
2.6.8 
Melphalan 
Melphalan side effects include: 
• Cardiac and vascular: edema, heart failure, vasculitis 
• Gastrointestinal: mucositis, nausea, vomiting, diarrhea 
• General: fatigue 
• Hematologic: anemia, thrombocytopenia, neutropenia  
• Hepatic: abnormal liver function tests, hepatitis 
• Pulmonary: shortness of breath, pulmonary fibrosis 
• Renal: renal impairment  
• Miscellaneous: allergic reaction including anaphylaxis, secondary malignancy 
2.6.9 
Total Body Irradiation (TBI) 
Low Dose TBI side effects include: 
• Cutaneous: erythema, hyperpigmentation, alopecia 
• Gastrointestinal: nausea, vomiting, diarrhea, parotitis, mucositis, abdominal cramping 
• General: fever, fatigue 
• Genitourinary: gonadal impairment 
• Hepatic: hepatic sinusoidal obstruction syndrome 
• Hematologic: myelosuppression, anemia, thrombocytopenia 
• Pulmonary: interstitial pneumonitis 
• Renal: nephropathy 
• Miscellaneous: infection, short stature, vertebral deformities, cataracts, secondary 
malignancy, hormonal impairment  


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2.7 
Study Drug Supply  
Tacrolimus, methotrexate, cyclophosphamide and mycophenolate mofetil are commercially 
available agents and will not be provided by the study. Please administer as described in  
Section 2.4. 


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CHAPTER 3 
3 STUDY ENDPOINTS 
3.1 
Primary Endpoint 
BMT CTN 1703: The primary endpoint is GVHD/relapse or progression-free survival (GRFS). 
An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD 
requiring systemic immune suppression, disease relapse or progression, or death by any cause.  
Use of systemic immunosuppressive therapy for treatment of chronic GVHD is at the discretion 
of the treating physicians. The event of interest is the development of chronic GVHD severe 
enough to warrant any additional systemic treatment(s). Also, continuation of study-mandated 
GVHD prophylaxis beyond Day 180 in the presence of chronic GVHD will also be considered an 
event with time to event determined as date of chronic GVHD onset.  
Mi-Immune: The primary endpoint is non-relapse mortality within one year.  This endpoint is 
defined according to the BMT CTN 1703 protocol.  This primary endpoint will be associated with 
the engraftment stool microbiome diversity (grouped by tertiles) for the primary analysis of this 
study.  Mi-Immune secondary endpoints are addressed in Chapter 3 of Appendix J. 
3.2 
Secondary Endpoints 
3.2.1 
Acute GVHD 
Cumulative incidences of grade II-IV and III-IV acute GVHD will be determined. Acute GVHD 
will be graded according to the BMT CTN Technical MOP (see Appendix G). The time of onset 
of acute grades II-IV and III-IV acute GVHD will be recorded, as well as the maximum grade 
achieved. Within the acute GVHD endpoint, the proportion of patients with visceral involvement 
(liver or gut) will be described.  
Cumulative incidences of Minnesota standard and high risk acute GVHD will also be determined.  
3.2.2 
Chronic GVHD 
The cumulative incidence of chronic GVHD will be determined. Data will be collected directly 
from providers and chart review as defined by the NIH Consensus Conference Criteria. Eight 
organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and 
pulmonary function test results, and use of systemic therapy for treatment of chronic GVHD will 
also be recorded. These data will allow calculation of the NIH global severity scores of mild, 
moderate and severe chronic GVHD, which has been associated with transplant related mortality 
and overall survival. Assessment of chronic GVHD will occur up to 1 year post-transplant.  
3.2.3 
Systemic Immunosuppression-free Survival 
Patients who are alive, relapse-free, and do not need ongoing immune suppression to control 
GVHD at one year post-transplant are considered successes for this endpoint. Immune suppression 
is defined as any systemic agents used to control or suppress GVHD. Corticosteroid doses greater 
than 10 mg will be considered active systemic immune suppression treatment. Patients who 


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discontinued immune suppression within 15 days or less prior to the 1-year time point will be 
considered to be on immune suppression for this endpoint.  
3.2.4 
Hematologic Recovery 
Hematologic recovery will be assessed according to neutrophil and platelet counts recovery after 
transplant. Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC)  
greater than or equal to 500/mm3 for three consecutive measurements on three different days. The 
first of the three days will be designated the day of neutrophil recovery. The competing event is 
death without neutrophil recovery. For patients who never drop ANC below 500/mm3, the date of 
neutrophil recovery will be Day +1 post-transplant.  
Platelet recovery is defined by two different metrics: the first day of a sustained platelet count 
greater than or equal to 20,000/mm3 or greater than or equal to 50,000/mm3 with no platelet 
transfusions in the preceding seven days. The first day of sustained platelet count above these 
thresholds will be designated the day of platelet engraftment. For patients who never drop their 
platelet count below 20,000/mm3 or 50,000/mm3, the date of platelet recovery will be Day +1 post 
HCT.  
Lymphocyte recovery will be defined as the first day of sustained absolute lymphocyte count 
greater than or equal to 1000/mm3. 
3.2.5 
Donor Cell Engraftment 
Donor cell engraftment will be assessed with donor/recipient chimerism studies. Chimerism may 
be evaluated in bone marrow, whole unfractionated blood or blood cell fractions, including CD3 
and CD33 or CD15 fraction. For the purpose of this protocol, mixed chimerism is defined as the 
presence of donor cells, as a proportion of total cells to be less than 95% but at least 5% in the 
bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% 
of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells 
of less than 5% will be considered as graft rejection. The proportion of patients with each level of 
chimerism described above will be described as part of this outcome. For sorted blood cell 
fractions, CD3+ donor cell chimerism will be used to define the donor/recipient chimerism status.  
3.2.6 
Disease Relapse or Progression 
Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS 
consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not 
by biopsy. Progression of disease applies to patients with lymphoproliferative diseases (lymphoma 
or chronic lymphocytic leukemia) not in remission prior to transplantation. The event is defined 
as increase in size of prior sites of disease or evidence of new sites of disease, documented or not 
by biopsy.  
Acute leukemia and MDS – Relapse will be diagnosed when there is: 
- 
Reappearance of leukemia blast cells in the peripheral blood; or, 
- 
Greater than 5% blasts in the bone marrow, not attributable to another cause (e.g. bone 
marrow regeneration) 


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- 
The appearance of previous or new dysplastic changes (MDS specific) within the bone 
marrow with or without falling donor chimerism; or  
- 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal fluid 
or 
- 
The reappearance of cytogenetic abnormalities present prior to transplantation 
 
Lymphoproliferative Diseases – Relapse or progression will be diagnosed when there is: 
- 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size. Increased FDG uptake in a previously 
unaffected site will only be considered relapsed or progressive disease after confirmation 
with other modalities. In patients with no prior history of pulmonary lymphoma, new lung 
nodules identified by CT are mostly benign. Thus, a therapeutic decision should not be 
made solely on the basis of the PET without histologic confirmation. 
- 
At least a 50% increase from nadir in the sum of the product diameters of any previously 
involved nodes, or in a single involved node, or the size of other lesions (e.g., splenic or 
hepatic nodules). To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1.0 cm must increase by at least 50% or more and to a size of 1.5 
x 1.5 cm or more than 1.5 cm in the long axis.  
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion 
was PET positive before therapy unless the lesion is too small to be detected with current 
PET systems (less than 1.5 cm in its long axis by CT). 
- 
In addition to the criteria above, patients with CLL who present in complete remission prior 
to transplantation may fulfill the relapse definition if there is reappearance of circulating 
malignant cells that are phenotypically characteristic of CLL.  
 
Institution of any therapy to treat persistent, progressive or relapsed disease, including the 
withdrawal of immunosuppressive therapy or donor lymphocyte infusion, will be considered 
evidence of relapse/progression regardless of whether the criteria described above were met.  
3.2.7 
Transplant-related Mortality 
The cumulative incidence of TRM will be estimated at Days 100, 180 and 1 year after HCT. An 
event for this endpoint is death without evidence of disease progression or recurrence. Disease 
progression or recurrence will be considered competing events. 
3.2.8 
Toxicity 
All grade 3-5 toxicities according to CTCAE, version 5.0 will be tabulated for each intervention 
arm. The proportion of patients developing at least a grade 3 or more AE across intervention arms 
will be compared.  
3.2.9 
Infections 
The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for 
each intervention arm. The cumulative incidence of treated CMV reactivation in the first 100 days 


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post-transplant will be described. All Grade 2 and 3 infections will be reported according to the 
BMT CTN Technical MOP up to 1 year posttransplant.  
3.2.10 
Disease-Free Survival 
Disease-free survival is the time from date of transplant to death or relapse/progression, whichever 
comes first. The event for this endpoint is relapse/progression or death. Patients alive and disease 
free will be censored at last follow-up.  
3.2.11 
Overall Survival 
Overall survival is defined as the time interval between date of transplant and death from any 
cause. The event for this endpoint is death from any cause. Surviving patients will be censored at 
last follow-up.  
3.2.12 
PTLD 
The incidence of post-transplant lymphoproliferative disease (PTLD) will be measured at one year 
post-transplant. 
3.2.13 
Patient-Reported Outcomes (PRO)  
PRO will be measured at Baseline and then at Day 100, Day 180 and 1 year post-transplant using 
the Lee Chronic GVHD Symptom Scale, Hemorrhagic Cystitis symptom questions, and selected 
PROMIS subscales for gastrointestinal symptoms, physical function and satisfaction with 
participation in social roles. The instruments will be scored according to the recommendations of 
the developers. PRO data will be collected electronically, or on paper vial mail if requested by the 
patient.  Whether collected electronically or on paper, PRO data will be entered in the CIBMTR’s 
ePRO system.  The PRO instruments will only be offered to English and Spanish speaking patients.  
3.3 
Endpoint Review Process 
Upon completion of participant follow-up, an Endpoint Review Committee (ERC) will conduct an 
independent review of site-reported data on key study endpoints to determine the endpoint data to 
be presented in the primary manuscript and final analysis.  This Committee will consist of members 
of the protocol team, including the Protocol Chairs, Protocol Officer, Operational Statistician, and 
Protocol Coordinator.  Each participant’s data will be reviewed by ERC clinicians.  The 
adjudicated endpoint data for each participant will be determined by consensus of their reviewers.   
The ERC will employ a risk-based strategy to the data review.  First, a random sample of 20% of 
the total study population will be chosen.  The key endpoints will be determined in two ways: 
using ERC adjudications and using the site-reported data.  The concordance between the ERC 
adjudicated and site-reported endpoints will be computed.  If the concordance is 90% or above, 
the ERC will end and site-reported endpoints will be used for all statistical analyses.  If the 
concordance falls below 90%, a second random subset of 20% of study participants will be drawn 
from the unadjudicated participants.  Then, the concordance between ERC adjudicated and site-
reported endpoints in the combined first and second subsets will be computed.  If the concordance 
is 90% or above, the ERC will end and site-reported data will be used for all statistical analyses.  
Otherwise, all remaining, unadjudicated participants will undergo review and the ERC adjudicated 
endpoints for the entire study population will be used in all statistical analyses. 


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Data will be obtained from the relevant case report forms and source documents and will be 
provided to reviewers in a blinded manner with respect to treatment assignment, treatment center, 
and participant identifier.  These data will be kept confidential and will not be discussed outside 
the Committee or presented in a public forum.


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CHAPTER 4 
4 PATIENT ENROLLMENT AND EVALUATION 
4.1 
Approaching Patients, Eligibility Screening and Obtaining Consent 
Patients will be approached for this study after the decision to proceed with transplantation is 
made and an HLA-matched PBSC donor is identified. Patients willing to participate in the trial 
will sign an NMDP IRB-approved consent form. Transplant physicians will evaluate the patient 
eligibility for randomization onto this study (see Section 2.2). Eligibility criteria will be verified, 
and ineligible patients will not be randomized, and no further follow-up will be obtained. 
Transplant center personnel will record the documentation of patient consent and register the 
patient in Segment 0 of the study in Advantage eClinical (Electronic Data Capture, an Internet-
based data entry system).  Patients also need to sign the CIBMTR “Protocol for a Research 
Database for Hematopoietic Cell Transplantation and Marrow Toxic Injuries” consent form 
because future laboratory correlative studies using any remaining stored research samples will 
require linking with clinical data collected CIBMTR.     In cases where the HLA-matched donor 
is a related donor, the patient’s donor who is 18 years of age or older should be approached to 
provide consent for the Mi-Immune study samples. Unrelated donors will be approached for 
consent for the Mi-Immune study by the NMDP. 
4.2 
Transplant Protocol Registration 
Before randomization occurs, the transplant center must state through Advantage eClinical 
which conditioning regimen and which maintenance regimen (if any) will be used for the 
enrolled patient. Such a registration step will avoid potential biases that preferential use of a 
certain regimen on one treatment arm could confer to the study. At this stage, the transplant 
center will also verify that the patient is still a candidate for transplantation, and eligible for the 
trial. The transplant center will also record the donor’s willingness to participate in the Mi-
Immune study.  At this point the patient is enrolled into Segment A of the study.   
At the time of enrollment in Segment A, transplant center personnel will securely email or fax 
patient contact information to the CIBMTR Survey Research Group for purpose of contacting 
patients for PRO administration.  
4.3 
Randomization 
Once the patient is deemed eligible and has given written informed consent, and the transplant 
center has confirmed patient eligibility and registered the patient’s conditioning and 
maintenance regimen, randomization occurs. Patients should not be randomized more than 14 
days prior to the planned initiation of conditioning. If initiation of conditioning has not started 
within 14 days of randomization, the Protocol Coordinator and Protocol Chairs and Officer must 
be notified. Refer to section 4.6.1 Patient Assessments-pre-transplant evaluations. 


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4.4 
Treatment Scheduling 
Treatment should be initiated as soon as possible after randomization. This will prevent patient 
attrition prior to transplant for reasons such as disease progression. Consequently, all treatments 
related to the transplant should be scheduled prior to randomization. This includes planning an 
admission date and ensuring that the PBSC donor can be mobilized and undergo apheresis in a 
coordinated fashion with the planned transplant. 
4.5 
Patient Evaluation 
The patient pre-transplant evaluation must be completed within 60 days of randomization 
(exceptions noted in the Study Calendar). See section 4.6.1 Patient Assessments-pre-transplant 
evaluations. This step is necessary because patient organ function, infection status, and status of 
malignancy may vary over time. This evaluation will protect patients with a new 
contraindication to transplant from initiating transplant therapy at an unsafe time. 
4.6 
Study Monitoring 
The follow-up schedule for scheduled study visits is outlined in Table 4.6A. A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide. 
TABLE 4.6A: FOLLOW-UP SCHEDULE 
Study Visit 
Target Day Post-Transplant 
Day of Transplant 
Day 0* 
1 week 
7  3 days 
2 weeks 
14  3 days 
3 weeks 
21  3 days 
4 weeks 
28  3 days 
5 weeks 
35  3 days 
6 weeks 
42  3 days 
7 weeks 
49  3 days 
8 weeks 
56  3 days 
9 weeks 
63  3 days 
10 weeks 
70  3 days 
11 weeks 
77  3 days 
12 weeks 
84  3 days 
14 weeks 
98  7 days 
6 months 
180  28 days 
9 months 
270  28 days 
12 months 
365  28 days 
24 months 
730  60 days 
*If infusion occurs over 2 days, the day of transplant should be recorded as the day 
the first infusion occurred. 


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4.6.1 
Patient Assessments 
Table 4.6B summarizes patient clinical assessments over the course of the study. 


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TABLE 4.6B: PATIENT AND DONOR CLINICAL ASSESSMENTS 
Pre-
Conditioning  
Pre-
infusion 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
98 
180 
270 
365 
730 
History, physical exam, weight 
and height10 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Karnofsky performance status 
(see Appendix D) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
HCT-Specific Comorbidity 
Index score (see Appendix E) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Risk Index (see 
Appendix F) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor and recipient HLA 
typing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC1, differential, platelet 
count, and blood chemistries2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infectious disease titers3 
X 
EKG and LVEF  
X 
DLCOcorr and FEV1predicted  
X 
 
Disease evaluation4 
X 
 
 
 
X 
 
X 
Chest x-ray or chest CT 
X 
Pregnancy test5 
X 
GVHD assessments6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity assessments7 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
Infection assessments 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Chimerism8 
X 
X 
 
 
 
X 
Patient Mi-Immune research 
samples (see Appendix J)9 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Related donor CBC11 
 
X 
 
 
 
 
 
 
 
 
Related donor Mi-Immune 
research samples  
(see Appendix J) 
 
X 
 
 
 
 
 
 
 
 
Patient Reported Outcomes 
(see Appendix H) 
X 
 
 
 
 
X 
X 
X 
 


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1CBC with differential performed three times weekly from Day 0 until ANC at least 500/mcLor greater for three days and platelet count at least 20,000/mcL or 
greater after nadir, while hospitalized. CBC then performed weekly through Day 84 post-transplant, then at Days 98, 180, 270, 365 and 730 post-transplant.  A 
CBC needs to be collected at the same time as the scheduled Mi-Immune research samples and reported in Advantage eClinical.  
2Blood chemistries include: serum creatinine, albumin, bilirubin, alkaline phosphatase, AST and ALT. Blood chemistries performed twice weekly until hospital 
discharge. Blood chemistries performed weekly after hospital discharge until Day 84 post-transplant, then at Days 98, 180, 270 and 365 post-transplant. 
3Infectious disease titers should be performed per institutional guidelines and may include: CMV, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core 
Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV I/II antibody, and varicella zoster. 
4Evaluation of disease: (A) For acute leukemia, CML, and MDS, evaluation for malignant disease includes a bone marrow aspirate and biopsy for pathology and 
cytogenetics. A bone marrow biopsy must be performed no more than 44 days prior to the initiation of conditioning.  (B) For lymphomas, bone marrow 
biopsy and/or imaging studies are appropriate for disease evaluation and will be done according to institutional practices.  Patients with lymphomas should 
undergo the same post-transplant testing as their pre-transplant evaluation for matter of subsequent comparison.  Imaging studies must be done no more than 
60 days prior to patient randomization.  
5Pregnancy test must be performed < 30 days before the start of the transplant conditioning regimen. Pregnancy test is required for females of child-bearing 
potential and may be performed per institutional practices. 
6GVHD assessments performed weekly from Day 7 until Day 84 post-transplant, and then at Days 98, 180, 270 and 365. The GVHD assessment will include a 
review of all abnormalities experienced during the entire assessment period and the highest grade for each abnormality during the assessment period will be 
recorded on the Acute GVHD form and the Follow-up/Chronic GVHD form in eClinical.  The Chronic GVHD Provider Survey will record GVHD symptoms 
present in the last week (whether attributed to GVHD or not) and must be completed by a clinician on the day of the assessment. 
7The toxicity assessment will include a review of all toxicities experienced during the entire assessment period and the highest grade for each toxicity during 
the assessment period will be recorded on the Toxicity form in eClinical. 
8Chimerism may be evaluated in bone marrow, whole blood or blood cell fractions, including CD3 and CD33 or CD15 fraction, according to institutional 
practice. The actual measurement dates may be within +/- 7 days of the recommended time points. 
9The pre-conditioning baseline sample must be collected prior to the initiation of the transplant conditioning regimen and pre-antibiotic prophylaxis.  For 
patients, stool samples at Pre-Conditioning, Day 0, Day 7, Day 14, Day 21, and Day 28 are mandatory.  Starting day 35 through day 77, then at day 98, 180, 
270, 1 year, and 2 years, the stool samples are optional.  Weekly urine sample collection for microbiome assays starting Pre-conditioning through Day 270, then 
at 1 year, and 2 years are ALL OPTIONAL.   Pre-transplant donor samples are to be collected from those donors who have signed the Mi-Immune consent.  
 
10Height is only required at baseline. It is not required to be repeated at the other time points.  
11The related donor’s CBC needs to be collected at the same time as the scheduled Mi-Immune research samples and reported in Advantage eClinical from those 
donors who have signed the Mi-Immune consent. 
 
 


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4.6.2 
Pre-transplant Evaluations 
The following observations must be completed within 60 days prior to patient randomization, or 
74 days prior to initiation of conditioning regimen unless otherwise indicated.  
• History, physical examination, height and weight. 
• Karnofsky performance status 
• HCT-Specific Comorbidity Index score. 
• CBC with differential and platelet count, serum creatinine, bilirubin, alkaline 
phosphatase, AST and ALT.   
• Infectious disease titers should be performed per institutional guidelines and may 
include: CMV antibody, Hepatitis panel (HepA Ab, HepB SAb, HepB SAg, HepB Core 
Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV I/II antibody, and 
varicella zoster. 
• EKG and LVEF – can be performed within 90 days prior to patient randomization. 
• Pulmonary function tests, including DLCO and FEV1 - can be performed within 90 
days prior to patient randomization. 
• HLA typing of patient and donor. HLA typing can be performed at any time prior to 
randomization. 
• 
Sibling donors must be HLA typed for HLA-A and -B at intermediate (or 
higher) resolution, and -DRB1 at high resolution using DNA-based typing. 
• 
Unrelated donors must be HLA typed for HLA-A, -B, -C and -DRB1 at high 
resolution using DNA-based typing.  
• Disease evaluation for patients with acute leukemia, CML or MDS includes a bone 
marrow aspirate and biopsy for pathology and cytogenetics. A bone marrow biopsy 
must be performed no more than 44 days prior to the initiation of conditioning. 
• Disease evaluation for patients with lymphomas includes imaging studies for matters of 
comparison post-transplant, the types of which may be determined according to the 
center’s institutional practices. Imaging studies must be done no more than 60 days 
prior to patient randomization. 
• Chest X-ray or chest CT. 
• Pregnancy test per institutional practices for females of child-bearing potential. NOTE: 
pregnancy test must be performed no more than 30 days prior to randomization 
and must be repeated if not within 30 days prior to the initiation of conditioning.  
• Patient Reported Outcomes (PRO) to be completed by English or Spanish speaking study 
patients. 
• Pre-transplant donor and recipient samples for post-transplant chimerism studies. 
• Related donor and recipient blood, urine and stool samples for Mi-Immune study 
(Appendix J). CBCs need to be collected at the same time as the scheduled Mi-Immune 
research samples. 


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4.6.3 
Post-transplant Evaluations 
The following observations will be made according to Table 4.6B: 
• History and physical exam to assess GVHD and other morbidity weekly through Day 84 
post-transplant, then at Days 98, 180, 270 and 365 post-transplant. GVHD will be 
monitored in accordance with BMT CTN guidelines as specified in the BMT CTN 
Technical Manual of Procedures (BMT CTN MOP). GVHD assessments weekly from 
Day +7 through Day +84 post-transplant, and then at Days 98, 180, 270 and 365 post- 
transplant. 
• Assessment for toxicities at Days 28, 56, 98, 180, 270 and 365 post-transplant. 
• CBC with differential performed at least three times a week from Day 0 until ANC at 
least 500/μL for 3 consecutive measurements over 3 days and platelet count at least 
20,000/μL for 3 days without platelet transfusion in the prior 7 days (while hospitalized 
only) after nadir is reached. Thereafter, CBC weekly until Day 84 post-transplant, then 
at Days 98, 180, 270, 365 and 730 post-transplant.  CBCs need to be collected at the 
same time as the scheduled Mi-Immune research samples. 
• Serum creatinine, bilirubin, alkaline phosphatase, ALT and AST, twice a week until 
hospital discharge and then weekly until Day 84 post-transplant, then at Days 98, 180, 
270 and 365 post-transplant. 
• Chimerism studies performed at Days 28 and 98 post-transplant. Chimerism may be 
evaluated in bone marrow, whole unfractionated blood or blood cell fractions, including 
CD3 and CD33 or CD15 fraction. The actual measurement dates may be within +/- 7 
days of the recommended time points. (see Appendix B) 
• Disease evaluation of the malignant disease at Days 98 and 365 post-transplant: For acute 
leukemia, CML and MDS this includes a bone marrow aspirate and biopsy for pathology 
and cytogenetics. For lymphomas this includes imaging studies, which will be done 
according to institutional practices and the same as prior to transplant, for matter of 
comparison. 
• Data on occurrence of Grade 2 and 3 infections and recorded as per the BMT CTN 
Technical MOP. 
• Blood, urine and stool samples for Mi-Immune study to be collected Days 7, 14, 21, 28, 
35, 42, 49, 56, 63, 70, 77, 84, 98, 180, 270, 365 and 730. (see Appendix J) 
• Patient Reported Outcomes (PRO) to be completed by English or Spanish speaking study 
participant at Days 98, 180 and 365.  The CIBMTR Survey Research Group will contact 
patients via email, phone or mail to collect the PRO instruments online, or on paper.  The 
Survey Research Group 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.  
 


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4.6.4 
Criteria for Forms Submission 
Criteria for timeliness of submission for all study forms are detailed in the Data Management 
Handbook and User’s Guide. Forms that are not entered into Advantage eClinical within the 
specified time will be considered delinquent. A missing form will continue to be requested either 
until the form is entered into the Advantage eClinical and integrated into the eClincal master 
database, or until an exception is granted and entered into the Missing Form Exception File, as 
detailed in the Data Management Handbook. 
4.6.5 
Reporting Patient Deaths 
Recipient death information must be entered into Advantage eClinical within 24 business hours 
of knowledge of the patient’s death. If the cause of death is unknown at that time, it need not be 
recorded at that time. However, once the cause of death is determined, the form must be updated 
in Advantage eClinical. 
4.7 
Adverse Event Reporting Requirements 
4.7.1 
Definitions 
Adverse Event: An Adverse Event (AE) is defined as any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease that is temporally associated with 
the use of a medical treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure. 
Expectedness: An adverse event can be Expected or Unexpected 
• Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk. 
• Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, the package 
insert, or when it is not included in the informed consent document as a potential risk. 
 
Serious Adverse Event: A serious adverse event (SAE), as defined by per 21 CFR 312.32, is 
any adverse event that results in one of the following outcomes, regardless of causality and 
expectedness:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-
hour hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period, but planned prior to study entry are not considered SAEs if the illness or 
disease existed before the person was enrolled in the trial, provided that it did not 


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deteriorate in an unexpected manner during the trial (e.g., surgery performed earlier than 
planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical events 
may not be immediately life threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the outcomes listed in the definition above 
(eg, suspected transmission of an infectious agent by a medicinal product is considered a Serious 
Adverse Event). Any event is considered a Serious Adverse Event if it is associated with clinical 
signs or symptoms judged by the investigator to have a significant clinical impact. 
4.7.2 
BMT CTN Adverse Event Reporting Guidelines 
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN Administrative 
Manual of Procedures, Chapter 6). It is BMT CTN policy that AEs must be reported even if the 
investigator is unsure whether a relationship exists between the adverse event and the use of study 
treatment.  
Unexpected, serious adverse events (SAEs) will be reported through an expedited AE reporting 
system via Advantage eClinical. Unexpected, life-threatening and fatal SAEs must be reported 
within 24 hours of knowledge of the event. All other unexpected SAEs must be reported 
within three business days of knowledge of the event. Events entered in Advantage eClinical 
will be reported using NCI’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0.  
Expected AEs will be reported using NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 at regular intervals as defined on the Form Submission Schedule, including 
calendar-driven case report forms (e.g., Toxicity and GVHD) or event-driven case report forms 
(e.g., Relapse/Progression, Infection, and Death). Any expected life-threatening SAE not 
collected on another study form must be reported through the expedited AE reporting 
system via Advantage eClinical. 
The Data and Safety Monitoring Board will receive summary reports of all unexpected SAEs on 
a semi-annual basis. 


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4.8 
CIBMTR Data Reporting 
Centers participating in BMT CTN trials must register pre- and post-transplant outcomes on all 
consecutive hematopoietic stem cell transplants done at their institution during their time of 
participation to the Center for International Blood and Marrow Transplant Research (CIBMTR). 
Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database 
(SCTOD). (Note: Federal legislation requires submission of these forms for all US allotransplant 
recipients.) Enrollment in BMT CTN 1703 must be indicated on the SCTOD pre-transplant 
registration form. Additionally, CIBMTR pre- and post- transplant Comprehensive Report 
Forms must also be submitted for all patients enrolled on this trial. CIBMTR forms will be 
submitted directly to the CIBMTR at the times specified on the Form Submission Schedule. 
 


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CHAPTER 5 
5 STATISTICAL CONSIDERATIONS 
5.1 
Study Design 
The study is designed as a Phase III randomized, open label, multicenter trial to compare 
PTCy/Tac/MMF versus Tac/MTX for GVHD prophylaxis in patients with controlled malignant 
disease receiving an allogeneic PBSC transplant after a RIC regimen. The primary endpoint is 
GRFS at 1 year. The target enrollment is 428 patients in total, with 214 patients on each of the two 
treatment arms. 
Of note, all statistical considerations for the Mi-Immune study are addressed in Chapter 5 of 
Appendix J. 
5.1.1 
Accrual 
It is estimated that 36 months of accrual will be necessary to enroll the targeted sample size with 
an accrual rate of approximately 12 patients per month. Both Core and Affiliate Centers will enroll 
patients on this study. Accrual will be reported by race, ethnicity, gender, and age. 
5.1.2 
Randomization 
All patients will be randomized within 14 days prior to the initiation of conditioning therapy. 
Randomization will be performed in a 1:1 ratio using random block sizes for the two arms. 
Randomization will be stratified by centers and by disease risk using Disease Risk Index (DRI 
Low, Intermediate and High). The DRI level “High” will include patients classified as both “High” 
and “Very High”. 
5.1.3 
Primary Endpoint 
The primary endpoint is GRFS as a time to event endpoint from the time of randomization. All 
transplanted patients will be followed for the primary endpoint for one year; however, the primary 
endpoint will be analyzed as a time to event endpoint. The primary analysis will be done using the 
intent-to-treat principle.  
5.1.4 
Primary Hypothesis 
The primary null hypothesis is that the hazard ratio between PTCy/Tac/MMF vsTac/MTX for 
GRFS endpoint is equal to one versus an alternative hypothesis that the hazard ratio not equal to 
one. A hazard ratio equal to one indicates no difference between the two treatments, while a hazard 
ratio less than one implies that the hazard of GRFS is lower for patients receiving PTCy/Tac/MMF 
compared with those in the Tac/MTX patient group. A hazard ratio greater than one would indicate 
an opposite treatment effect. This null hypothesis will be tested using a two-sided significance 
level of 5% 


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5.2 
Sample Size and Power Considerations 
Sample size and power considerations are based on the comparison of PTCy/Tac/MMF to 
Tac/MTX using a Cox proportional hazards model. We assume an accrual period of 36 months 
and a 12-month follow-up period with a 5% drop-out rate. We further assume that the drop-out 
rate is exponentially distributed and that the GRFS endpoint matches the results of the BMT CTN 
1203 trial control group. The survival probabilities for GRFS are based on data collected from the 
BMT CTN 1203 study. Therefore, a sample size of 428 patients (214 per arm) is required to 
sufficiently maintain a two-sided type I error of 5% while providing 90% statistical power for a 
two-sided test to detect a HR of 0.66.   
5.3 
Interim Analysis and Stopping Guidelines 
The study will consist of one interim analysis for efficacy after the required total number of events 
is reached in all evaluable patients for the primary endpoint to be reviewed by the NHLBI-
appointed Data and Safety Monitoring Board (DSMB). An interim analysis for efficacy will be 
conducted after reaching a total of 147 events, at a 60% information fraction. The final analysis 
will be conducted when the targeted number of events of 244 occurs, or 1 year after the last patient 
is randomized. Policies and composition of the DSMB are described in the BMT CTN’s Manual 
of Procedures.  
5.3.1 
Interim Analysis for Efficacy 
Analyses will be performed as described below for the primary endpoint. At the interim analysis 
time point, a Z test for comparing the two treatments will be compared to the critical values shown 
in Table 5.3A. All patients with follow-up post randomization prior to the time of the interim 
analyses will be used to compute this statistic. If the test statistic is outside the continuation range, 
the DSMB will discuss the continuation of the trial. Should the DSMB stop the trial for efficacy, 
all patients receiving the inferior treatment arm will be switched to the superior treatment arm 
where the study will proceed until the targeted sample size for Mi-Immune is reached.  
Efficacy stopping rules are based on Wang and Tsiatis boundary family with shape parameters 
P=1.44, A=0, R=0 and G=1.9618.25 Higher values of P, with A and R fixed at zero, and G fixed at 
1.9618 will cause the group sequential test to be increasingly conservative at the earliest analyses 
times. This boundary corresponds approximately to a hazard ratio less than 0.5918 or greater than 
1.6898 and Z statistics less than -3.1710 or greater than 3.1710, respectively. A P-value less than 
0.00152 at the interim analysis would indicate a statistically significant result. 
 
 
 
 
 


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Table 5.3A: Efficacy Stopping Thresholds with Type I Error 0.05,  
Power 90% and an Effect Size of 15% or Hazard Ratio 0.66 
Analysis 
Time 
Information 
Fraction 
Total 
Cumulative 
Sample Size Under 
Alternative 
 
Cumulative Events 
Under 
Alternative 
Hazard Ratio 
Efficacy  
Boundary 
Z-Statistic  
Efficacy  
Boundary 
Cumulative 
Type I Error 
 
 
 
 
Lower 
Upper 
Lower 
Upper 
 
Interim 
0.60 
334 
147 
0.5918 
1.6898 
-3.1710 
3.1710 
0.152% 
Final 
1.00 
428 
244 
0.7777 
1.2858 
-1.9618 
1.9618 
5.000% 
 
 
5.3.2 
Operating Characteristics of the Design 
The statistical power to reject the null hypothesis under various treatment effect sizes using the Z 
test for comparing treatments is shown in Table 5.3A. This table shows that the target sample size 
of 428 patients has 90% power to detect a 0.66 hazard ratio. 


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Table 5.3B: Summary of Operating Characteristics 
Hazard 
Ratio 
Corresponding 
Approximate Effect Size 
for GRFS Endpoint 
Expected 
Number of 
GRFS Events 
Overall  
Cumulative 
Power 
Probability of 
Stopping Early at 
Interim Analysis 
0.57 
20% 
186 
99.24% 
0.5897 
0.66 
15% 
219 
90.00% 
0.2548 
0.68 
14% 
224 
85.28% 
0.2005 
 0.72 
12% 
232 
72.66% 
0.1179 
0.76 
10% 
237 
57.17% 
0.0652 
1.00 
0.0 
243 
5.00% 
0.0015 
 
5.3.3 
Guidelines for Safety Monitoring 
Monitoring of a key safety endpoint will be conducted monthly, and if rates significantly exceed 
pre-set thresholds, the NHLBI will be notified in order that the DSMB can be advised. Policies 
and composition of the DSMB are described in the BMT CTN's Manual of Procedures. The 
stopping guidelines serve as a trigger for consultation with the DSMB for additional review and 
are not formal “stopping rules” that would mandate automatic closure of study enrollment. 
Toxicity, adverse events, and other safety endpoints will be monitored regularly and reported to 
the DSMB at each meeting and sooner if there are concerns. 
The key safety endpoint for this study is Day 100 mortality. The rate of mortality will be monitored 
up to Day 100 post-randomization separately in each of the two treatment arms. The expected 
probability of Day 100 mortality after a reduced intensity conditioning transplant is 10-15%, based 
on CIBMTR data. Each month, the null hypothesis that the Day 100 mortality rate is less than or 
equal to 15% is tested separately in each treatment arm using an extension of the sequential 
probability ratio test (SPRT) for censored exponential data—See Appendix C for more details on 
SPRT.  
This sequential testing procedure conserves type I error at 5% across all of the monthly 
examinations for a treatment arm. The censored exponential SPRT can be represented graphically. 
At each monthly examination, the total patient time at risk is plotted against the cumulative number 
of events. 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 Day 100 mortality. If the 
cumulative number of events falls above the upper boundary, the SPRT rejects the null hypothesis, 
and concludes that there are more events than predicted by the total time at risk. Otherwise, the 
SPRT continues until enrollment reaches the target sample size of 214 patients per arm.  
 
 


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This procedure assumes an exponential distribution for the time until death during the first 100 
days and censors follow-up time at Day 100. 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 
randomization to death or to Day 100, whichever comes first, summed for all patients on study. A 
SPRT contrasting 15% versus 25% Day 100 mortality rate results in decision boundaries with a 
common slope of 0.8005 and an upper intercept of 4.8015 with nominal type I and II errors of 
5.8% and 10%, respectively. Because of truncation of the SPRT at a finite sample size the actual 
type I and II errors will usually be lower than nominal levels. 
The actual operating characteristics of the truncated test were determined in a simulation study 
that assumed uniform accrual of 428 participants over a 36-month period. The actual error rates 
are shown in Table 5.3C. 
Table 5.3C: Operating Characteristics of the Sequential Probability Ratio Test  
for Day 100 Mortality with 100,000 Simulation Replicates 
True Day 100 Mortality Rate 
15% 
17% 
20% 
23% 
25% 
Probability Reject Null 
0.050 
0.152 
0.474 
0.813 
0.935 
Mean Month Stopped 
36 
34 
27 
19 
15 
Mean Number of Day 100 Mortality Events 
31 
33 
31 
25 
20 
Mean Number of Patients Enrolled 
207 
195 
157 
108 
82 
 
For example, the testing procedure rejects the null hypothesis in favor of the alternative 5.0% of 
the time when the true Day 100 mortality rate is 15%, and 93.5% of the time when the rate is 25%. 
This corresponds to a type I error rate of  = 0.050 and a type II error rate of  = 0.065. When the 
true Day 100 mortality rate is 25%, on average, the DSMB will be consulted 15 months after 
opening, when 20 events have been observed in 82 patients. 
5.4 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all patients. Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, primary disease, disease-specific 
risk categories, DRI, hematopoietic cell transplant comorbidity index (HCT CI), donor type and 
HLA matching, donor/recipient CMV status, donor/recipient sex match, donor/recipient ABO 
match, and conditioning regimen. Between group comparisons will be performed for continuous 
variables via a Kruskal-Wallis test and for categorical variables, via the chi-square test. 
5.5 
Analysis Populations 
5.5.1 
Primary Population  
The intention-to-treat population will serve as the population for the primary analysis. All 
randomized patients will be included in this population. Patients will be included in the treatment 


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group to which they are randomized. Intention-to-treat population consists of all randomized 
patients whether or not treatment was administered. 
5.5.2 
Safety Population 
The safety analysis population in this study will comprise of all patients “as treated” in the study. 
This population will be used for the analysis of safety data. The “as treated” population consists 
of all randomized patients who received a HCT with one of the two randomized GVHD 
prophylaxis regimens. Patients will be included in the treatment group corresponding to the study 
treatment (GVHD prophylaxis) they actually received for the analysis of safety data using the “as 
treated” population. For most patients this will be the treatment group to which they are 
randomized.  
5.5.3 
Transplant Population 
The transplant population will include all patients who have received a transplant after 
randomization. 
5.6 
Analysis of Primary Endpoint 
Kaplan-Meier curves along with 95% confidence intervals will be constructed to estimate GRFS 
probabilities at 1 year for each treatment group. The primary analysis will consist of a comparison 
of GRFS in the ITT population by treatment arm based on a multivariate Cox regression model. 
The following covariates will be adjusted for in the regression model: age, DRI, planned RIC 
regimen, donor type/HLA matching, and planned use of post-transplant maintenance therapy. A 
significance level of 0.05 (two-sided) will be used to test the null hypothesis of no difference 
between the treatments. Ninety-five percent confidence intervals for the hazard ratio of the 
PTCy/Tac/MMF treatment will also be constructed.  
5.7 
Analysis of Secondary Endpoints 
5.7.1 
Acute GVHD 
Incidence of acute GVHD grade II-IV and grade III-IV at Days 100, 180 and 1 year will be 
estimated with 95% confidence intervals for each treatment group - using the cumulative incidence 
estimate, treating death prior to aGVHD as a competing event. Comparison of cumulative 
incidence will be done using Gray’s test. A multivariate Cox regression model for the cause-
specific hazard of aGVHD will be used to compare the treatment groups, after adjustment for 
baseline characteristics as described for the primary endpoint. 
5.7.2 
Chronic GVHD 
Incidence of chronic GVHD at 1 year will be estimated with 95% confidence intervals for each 
treatment group using the cumulative incidence estimate, treating death prior to chronic GVHD as 
a competing event. Comparison of cumulative incidence will be done using Gray’s test. A 
multivariate Cox regression model for the cause-specific hazard of chronic GVHD will be used to 
compare the treatment groups, after adjustment for baseline characteristics as described for the 
primary endpoint. 


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5.7.3 
Systemic Immunosuppression-Free Survival 
Proportions of patients alive, relapse free, and off immune suppression at 1 year will be described 
for each treatment group, along with 95% confidence intervals. If there is substantial censoring 
prior to one year, multistate models will be constructed to estimate these probabilities. Agreement 
between this endpoint and the primary endpoint of GRFS will be described using cross-tabulation 
frequencies and assessed using the Kappa statistic.  
5.7.4 
Hematologic Recovery 
Probabilities of neutrophil recovery by Day 28 and Day 100 will be described with 95% confidence 
intervals for each treatment group using the cumulative incidence estimate, treating death as a 
competing event. Similarly, probabilities of platelet recovery by Day 60 and Day 100 will be 
described with 95% confidence intervals for each treatment group using the cumulative incidence 
estimate, treating death as a competing event. These cumulative incidence curves will be compared 
using Gray’s test. 
5.7.5 
Donor Cell Engraftment 
Donor chimerism at Day 28 and Day 100 after transplantation in each of the randomized treatment 
arms will be described numerically as median and range for those evaluable as well as according 
to proportions with full (>95% donor cell), mixed (5.0-94.9% donor cells), graft rejection (<5%), 
or death prior to assessment of donor chimerism. Incidence of secondary graft failure (chimerism 
<5% after initial donor cell engraftment) will be described for each arm using frequencies. 
Comparisons between quantitative donor chimerism will be done using Wilcoxon rank sum test, 
while comparisons between categorical donor chimerism groups will be done using chi-square 
tests. 
5.7.6 
Disease Relapse or Progression 
Incidence of disease relapse or progression at 1 year will be estimated with 95% confidence 
intervals for each treatment group using the cumulative incidence estimate, treating death prior to 
disease relapse as a competing event. A multivariate Cox regression model for the cause-specific 
hazard of relapse or progression will be used to compare the treatment groups with the control 
group, after adjustment for baseline characteristics as described for the primary endpoint.  
5.7.7 
Transplant-related Mortality 
Incidence of transplant-related mortality (TRM) at Days 100, 180 and 1 year will be estimated for 
each treatment group using the cumulative incidence estimate, treating disease relapse or 
progression as a competing event. A multivariate Cox regression model for the cause-specific 
hazard of TRM will be used to compare the treatment groups with the control group, after 
adjustment for baseline characteristics as described for the primary endpoint.  
5.7.8 
Toxicity 
All Grade 3-5 toxicities will be tabulated by grade for each randomized treatment arm, by type of 
toxicity as well as the peak grade overall. Toxicity frequencies up to 1 year will be described for 
each time interval as well as cumulative over time.  


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5.7.9 
Infections 
The number of infections and the number of patients experiencing infections will be tabulated for 
each randomized treatment arm by type of infection, severity, and time period after transplant.  
5.7.10 
Disease-free Survival 
Kaplan-Meier curves will be constructed to estimate 1 year disease free survival probabilities for 
each treatment group. A multivariate Cox regression model for the risk of death or 
relapse/progression will be used to compare the treatment groups, after adjustment for baseline 
characteristics as described for the primary endpoint.  
5.7.11 
Overall Survival 
Kaplan-Meier curves will be constructed to estimate 1 year overall survival probabilities for each 
treatment group. A multivariate Cox regression model for the risk of death will be used to compare 
the treatment group, after adjustment for baseline characteristics as described for the primary 
endpoint.  
5.7.12 
Post-Transplant Lymphoproliferative Disease (PTLD)  
Probabilities of PTLD at 1-year post transplant will be described with 95% confidence intervals 
for each treatment group using the cumulative incidence estimate, treating death as a competing 
event. These estimates will be compared between groups using Gray’s test.   
5.7.13 
Patient-Reported Outcomes (PRO) 
Patient-Reported Outcomes will be measured at baseline then at Days 100, 180 and one year post 
HCT. Using a repeated measures model, we will compute PRO composite scores and compare 
treatments after adjustment for baseline characteristics as described for the primary endpoint. 
All patients with at least one post HCT PRO assessment will be incorporated within the relevant 
repeated measures analysis, whether they completed or discontinued the study. Missing 
assessments will not be imputed, as we assume these data are missing at random. 
5.8 
Safety Analysis 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse 
Events Version 5.0.  
 


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Page A-1 
APPENDIX A 
HUMAN SUBJECTS 
 
1. 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 
it for review by the NMDP Internal Review Board (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. 
 
2. 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.  
 
3. Participation of Women and Minorities 
Women and ethnic minorities and other populations will be included in this study. Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities expected 
from data reported to the CIBMTR and from published data on incidence of leukemia and 
lymphoma in these groups. Centers will be notified if their rates differ significantly from those 
expected and asked to develop appropriate recruitment reports. 
Patients under the age of 18 years will not be eligible to enroll on this study.  Reduced Intensity 
Conditioning (RIC) is not a standard therapy for patients in this age group.  PBSC grafts are not 
used standardly in this age group for allogeneic transplants either.   
 


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Page B-1 
 
 
 
 
 
 
 
 
APPENDIX B 
CHIMERISM ASSESSMENT 
We will study the proportion of patients with full (at least 95% or more) or mixed (5.0-94.9%) 
total donor chimerism or graft rejection (less than 5% total donor chimerism). 
 
Chimerism analysis will be performed according to institutional practice, with the following as 
prioritization for analysis: 
1. Sorted peripheral blood lymphocyte and myeloid populations 
2. Unsorted peripheral blood mononuclear cell populations 
3. Whole (unsorted) bone marrow 
 
 


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APPENDIX C 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA 
 
Background – The Sequential Probability Ratio Test 
Let 
)
(.,
f
be the density function for random variable X. According to Neyman and Pearson, the 
most powerful test of 
o
H

=
:
0
 versus
1
1 :

=
H
 decides in favor of 
1
H  or 
0
H if 
c
Ln 
 or 
c
Ln 
, respectively, where 

=
n
i
i
i
n
x
f
x
f
L
)
;
(
/)
;
(
0
1


is the likelihood ratio, and 

c is 
determined to have the size 
. 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 
and
of 
rejecting 
0
H when 
0

=
, and of accepting 
0
H when 
1
=
, respectively, and the expected 
sample size 
)
(
)
|
(
N
E
N
E
j
j


. Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 


)
reject 
(
Pr
0
0
H
 and 


)
reject 
(
Pr
0
1
H
, and for which 
)
(N
E j
 are finite, j=0,1, 
the SPRT with error probabilities  and 
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 
)
,
(

x
f
, with 
monotone likelihood ratio in 
)
(x

, then any SPRT for testing 
0
against 
)
(
0
1


 has non-
decreasing power function. 
 
For the SPRT with error probabilities 
and
, the SPRT boundaries are given approximately 
by 

/)
1( −
=
A
 and 
)
1
/(


−
=
B
. The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O
−
−
=
 where 
)
(
h
is the non-trivial solution to the equation 

=1
)
;
(
))
,
(
/
)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.  
 
The formula 
)
;
(
/]
log
)
(
log
)]
(
1
[[(
)
;
(




z
E
B
O
A
O
N
E
+
−
=
provides the average sample number 
for an arbitrary . 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. 


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Derivation of the SPRT for Uncensored Exponential Survival Times 
For example, we wish to construct a sequential test for the composite null hypothesis that the rate 
of TRM at 180 days is less than or equal to 5% versus the alternative hypothesis that it is greater 
than or equal to 5%. For the derivation of the uncensored SPRT, we will require that the type I 
error of the test be less than 10%, and that the test provide 90% power to reject the null hypothesis 
under a specified alternative that the true rate is 10%. A maximum sample size of 250 patients will 
be permitted. 
Let us assume that the survival times, 
nT
T
T
,...,
,
2
1
, are completely observed (uncensored) and are 
i.i.d. with exponential density function 
T
e
T
f



−
=
)
,
(
. These assumptions will be relaxed to 
incompletely observed data subsequently. In the exponential parameterization, a 180-day survival 
rate of 95% translates into a mean survival of 9.747 years (
=
0
.1026), and 90% translates into a 
mean survival of 4.746 years (
=
1
.2107). 
The SPRT is derived with reference to a simple null and alternative hypothesis, in this case, 
=
=
o
H


:
0
 .1026 versus
1
1 :

=
H
 = .2107. However, since the log-likelihood ratio for the 
exponential, 



−
−
−
=
−
n
i
n
i
n
i
i
i
i
T
n
x
f
x
f
)
(
))
log(
)
(log(
)
,
(
log
)
;
(
log
0
1
0
1
0
1






, 
is 
a 
monotone function of 
n
i
iT , the power of the test is non-decreasing in . Thus the SPRT is a 
one-sided level .10 test of a composite null (
1026
.
:
0
=

o
H


) versus a composite alternative (
2107
.
:
1
=

o
H


), with power of 
90
.
1
=
−
 at the selected alternative 
=
=
1


.2107. 
The SPRT can be represented graphically. The continuation region is bounded by two parallel lines 
with common slope 
=
−
−
)
log
/(log
)
(
0
1
0
1




0.150, and intercepts 
=
−
)
log
/(log
log
0
1


A
3.05 
and 
=
−
)
log
/(log
log
0
1


B
-3.05 for the lower and upper bounds, respectively. As each individual 
unit is put on trial and observed to fail, the current sample size, n, is plotted against the cumulative 
sum of failure times. When this graph crosses the upper boundary, the null hypothesis is rejected. 
The maximum sample size of 250 patients requires that the SPRT be truncated. We choose to 
truncate the SPRT by declaring that if the test has failed to terminate after 250 patients, that the 
null hypothesis will be accepted. Since the probability that the untruncated SPRT would reject the 
null at a sample size of 250 is negligible, it makes little difference how the final boundary value is 
selected, and this rule is chosen for simplicity.  
Derivation of a Modified SPRT for Censored Exponential Data 
The assumption of uncensored exponential survival times is flawed. However, we consider it 
reasonable to assume the hazard for TRM is constant over the first 180 days post-transplant, and 
we will restrict our attention to this time interval. Furthermore, it is not practical to conduct a 


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clinical study by putting each individual on trial, and waiting until that individual is observed to 
fail. We relax our assumptions as follows. Firstly, each individual’s time on study will be computed 
as time from transplant to failure, or to the 180 day time point, whichever comes first. Secondly, 
we will put individuals on trial as soon as they become available, without waiting for the previous 
individual to fail. 
Let us consider the impact of relaxing these assumptions one at a time. In a fixed sample size trial 
with uncensored exponential failure times, mean survival time is estimated by the sample mean of 
the failure times, or total time on study divided by the number of individuals enrolled. When 
censoring is introduced, the estimate becomes the total time on study divided by the number of 
observed (non-censored) failures. This suggests that in an exponential SPRT test modified to 
incorporate censoring, we replace the observed failure times, 
nT
T
T
,...,
,
2
1
, with censored failures 
times, 
nx
x
x
,...,
,
2
1
, and the current sample size, n, with the number of observed failures, d .  
Now we relax the second assumption, and put individuals on trial as soon as they become available, 
without waiting for the previous individual to fail. Assume that three years are required for accrual 
of 250 patients to the study, and that the final analysis takes place 180 days after the last patient is 
entered. Putting all of this together, we propose a modified truncated SPRT, where at any interim 
time point, s, ranging from 0 to 3 years 180 days, the number of observed failures, d(s), is plotted 
against the sum of observed time on study, 
n
i
i s
X
)
(
. In practice, monitoring will be scheduled 
monthly after the start of enrollment to the study. A further modification to the SPRT was to only 
use the upper boundary for stopping since the primary focus of the monitoring is to protect against 
unacceptable 180-day TRM rates. 
Operating Characteristics of the Modified SPRT Test for Censored Exponential Data 
Recall that the uncensored SPRT targeted a drop in TRM-free survival at Day 180 from 95% to 
90%, with type I and II errors of 10% and 10%. Since only the upper boundary is used for 
monitoring, the continuation region of the test was bounded above by a line with a slope of 0.150 
and intercept of 3.05. In our example, the sample size is large enough that the reduction in power 
due to truncation of the test is negligible compared to the increase in power because the modified 
SPRT, lacking a lower boundary, cannot stop early to “accept” the null hypothesis. In order to 
maintain type I error, we raise the upper boundary to make it harder to cross. Under the further 
assumption of uniform accrual over a three year period, and monthly interim analyses over the 
course of the study, the operating characteristics of the modified SPRT were obtained from a 
simulation study. These simulation show that an intercept of 4.02, corresponding to setting 
parameters 
 and 
to 10% and 10%, result in empirical type I and II error rates of 10% and 
10%.  


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Table C.1: Operating Characteristics of Sequential Testing Procedures 
  
from a Simulation Study with 100,000 Replications 
True 180-Day Rate 
5% 
10% 
Probability Reject Null 
0.095 
0.903 
Mean Month Stopped 
41.0 
20.2 
Mean # Endpoints in 180 days 
11.8 
11.6 
Mean # Patients Enrolled 
240.8 
135.4 
 
While the motivation for this testing procedure is largely heuristic rather than theoretical, the 
simulation results validate the approach. When the true rate of TRM on or before Day 180 was 
5%, the test crossed the lower boundary in 9484 of 100,000 replications, for an estimated type I 
error rate of 9.5%. When the true rate of TRM on or before Day 180 was 10%, the test failed to 
cross the boundary in the in 9742 of 100,000 replications, for an estimated type II error rate of 
9.7%. In this setting, on average, the boundary will be crossed at 20.2 months. 
It is interesting to note that the SPRT derived above for exponential failure times with censoring 
at 180 days, has operating characteristics which are similar to those of a more traditional SPRT, 
derived for binomial variates with success probability equal to the 180 day failure rate. Using time 
to failure rather than a simple binary indicator of failure, leads to little improvement in power when 
failure times are censored relatively soon after entry on study. We speculate that if the constant 
hazard rate over the first 180 days were high, the exponential test would reject faster than the 
binomial test, but have not conducted simulation studies to demonstrate this. 


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Page D-1 
APPENDIX D 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of 
disease. 
 
Able to carry on normal activity; 
no special care needed. 
90 
Able to carry on normal activity, minor signs 
or symptoms of disease. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Care for self, unable to carry on normal 
activity or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, varying amount of 
assistance needed. 
60 
Requires occasional assistance from others but 
able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, requires special care and assistance. 
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
 
30 
Severely disabled, hospitalization indicated, 
but death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead 


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APPENDIX E 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
Comorbidities 
Definition 
Score 
Migraine/headache 
 
0 
Osteoporosis 
 
0 
Osteoarthritis 
 
0 
Hypertension 
 
0 
Gastrointestinal 
Including inflammatory bowel disease 
0 
Mild pulmonary 
DLCo and/or FEV1 >80% or 
Dyspnea on moderate activity 
0 
Mild renal 
Serum creatinine 1.2-2 mg/dl 
0 
Endocrine 
 
0 
Bleeding 
 
0 
Coagulopathy 
Deep venous thrombosis or pulmonary embolism 
0 
Asthma 
 
0 
Arrhythmia 
 
1 
Myocardial 
Coronary artery disease, congestive HF, history of 
medically documented MI, EF50% 
1 
Mild hepatic 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN 
1 
Cerebro-vascular 
accident 
History of transient ischemic attack or cerebro-vascular 
accident 
1 
Morbid obesity 
 
1 
Diabetes 
Requiring treatment 
1 
Depression/anxiety 
 
1 
Infection 
Requiring continuation of treatment after Day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica 
 
2 
Moderate pulmonary 
DLCo and/or FEV1 66-80% or 
Dyspnea on slight activity 
2 
Peptic ulcer 
Patients who have required treatment 
2 
Moderate-severe renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation 
2 
Valvular heart disease 
Except mitral valve prolapse 
3 
Prior solid tumor 
Requiring treatment with chemotherapy 
3 
Moderate-severe hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN 
3 
Severe pulmonary 
DLCo and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen 
3 
Total score is the sum of all comorbidities present at time of transplantation. 


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APPENDIX F 
2014 REFINED DISEASE RISK INDEX24 
Participating sites to use column labeled as “New DRI Group” to report DRI of enrolled 
patient. 
 
 
 


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APPENDIX G 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE AND CHRONIC GVHD  
 
1. Acute GVHD organ staging and grading22 
 
 
 
 
 
 
 
 
 


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2. Grading of Chronic GVHD (NIH Criteria)23 
 
 
 
Organ scoring of chronic GVHD. ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; LPS, Lansky 
Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, alanine 
aminotransferase; ULN, normal upper limit. *Weight loss within 3 months. Skin scoring should use both percentage of BSA involved by disease 
signs and the cutaneous features scales. When a discrepancy exists between the percentage of total body surface (BSA) score and the skin feature 
score, OR if superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the higher level should be 
used for the final skin scoring. To be completed by specialist or trained medical providers. **Lung scoring should be performed using both the 
symptoms and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and 
FEV1 scores. 
 
 


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3. Categories of Acute and Chronic GVHD 
 
Categories of Acute and Chronic GVHD 
Category 
Time of 
Symptoms 
after HCT  
Presence 
of Acute 
GVHD 
Features 
Presence of 
Chronic 
GVHD 
Features* 
Acute GVHD 
Classic acute GVHD 
≤100 d 
Yes 
No 
Late-onset acute GVHD 
>100 d 
Yes 
No 
Chronic GVHD 
Classic chronic GVHD 
No time 
limit 
No 
Yes 
Overlap syndrome 
No time 
limit 
Yes 
Yes 
*As defined in section 4 (below) 
 
 


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4. Signs and Symptoms of Chronic GVHD23 
 


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APPENDIX H 
PATIENT REPORTED OUTCOME QUESTIONS 
BMT CTN 1703 Hemorrhagic Cystitis questions 
During the past 7 days, how many days did you see blood in your urine? 
1. No days 
2. 1 day 
3. 2 days 
4. 3-5 days 
5. 6-7 days 
How often did you feel like you needed to empty your bladder right away or else you would have 
an accident? 
1. Never 
2. One time during the past 7 days 
3. 2-6 times during the past 7 days 
4. Often once a day 
5. More than once a day 
 
PROMIS questions 
[GISX38] During the past 7 days, how many days did you have loose or watery stools? 
1. No days 
2. 1 day 
3. 2 days 
4. 3-5 days 
5. 6-7 days 
 
[GISX42] How often did you feel like you needed to empty your bowels right away or else you 
would have an accident? 
1. Never 
2. One time during the past 7 days 
3. 2-6 times during the past 7 days 
4. Often once a day 
5. More than once a day 
 
[PFA6] Does your health now limit you in bathing or dressing yourself? 
1. Not at all 
2. Very little 
3. Somewhat 
4. Quite a lot 
5. Cannot do 


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[PFA53] Are you able to run errands and shop? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
[PFA21] Are you able to go up and down stairs at a normal pace? 
1. Without any difficulty 
2. With a little difficulty 
3. With some difficulty 
4. With much difficulty 
5. Unable to do 
PSRPSAT06r1] I am satisfied with my ability to do things for my family.  
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
[SRPSAT49r1] I am satisfied with my ability to perform my daily routines. 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
[SRPSAT09r1] I am satisfied with my ability to do the work that is really important to me 
(include work at home). 
1. Not at all 
2. A little bit 
3. Somewhat 
4. Quite a bit 
5. Very much 
6.  
LEE CHRONIC GVHD SYMPTOM SCALE questions 
On a scale of 0 to 4, indicate how much you have been bothered by the following problems in the 
past month: 
 


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Skin: 
• Abnormal skin color 
• Rashes 
• Thickened skin 
• Sores on skin 
• Itchy skin 
 
Eyes and Mouth: 
• Dry eyes 
• Need to use eye drops frequently 
• Difficulty seeing clearly 
• Need to avoid certain foods due to mouth pain 
• Ulcers in mouth 
• Receiving nutrition from an intravenous line or feeding tube 
 
Breathing: 
• Frequent cough 
• Colored sputum 
• Shortness of breath with exercise 
• Shortness of breath at rest 
• Need to use oxygen 
 
Eating and Digestion: 
• Difficulty swallowing solid foods 
• Difficult swallowing liquids 
• Vomiting 
• Weight loss 
 
Muscles and Joints: 
• Joint and muscle aches 
• Limited joint movement 
• Muscle cramps 
• Weak muscles 
 
Energy: 
• Loss of energy 
• Need to sleep more/take naps 
• Fevers 


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Mental and Emotional: 
• Depression 
• Anxiety 
• Difficulty sleeping 
 
 
 


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APPENDIX I 
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1;334(5):281-5. 
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8Martin PJ, Schoch G, Fisher L, Byers V, Appelbaum FR, McDonald GB, et al. A retrospective 
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9Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and 
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11Przepiorka D, Devine S, Fay J, Uberti J, Wingard J. Practical considerations in the use of 
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12Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing 
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versus-host disease after marrow transplantation from unrelated donors. Blood. 2000 Sep 
15;96(6):2062-8. 
13Brunstein 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 
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14Luznik L, Fuchs EJ, Chen AR et al. Post-transplantation high-dose cyclophosphamide (Cy) is 
effective single agent GVHD prophylaxis that permits prompt immune reconstitution after 
myeloablative HLA matched related and unrelated bone marrow transplantation (BMT). Biology 
of Blood and Marrow Transplantation. 2007;13:4. 
15Luznik 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;14:641-650. 
16Raj, K., Streetly, M., Kazmi, M., Harringon, E., Getzendaner, L. C., Lee, S. J., and O'Donnell, P. 
V. Peripheral Blood Progenitor Cell (PBPC) Transplantation from Haploidentical Donors 
Following Reduced Intensity Conditioning (RIC) for High-Risk Hematologic Malignancies. 
Biology of blood and marrow transplantation : journal of the American Society for Blood and 
Marrow Transplantation 18[2], S331. 2-1-2012. 
17Bolaños-Meade J, Fuchs EJ, Luznik L et al. HLA-haploidentical bone marrow transplantation 
with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell 
disease. Blood. 2012;120:4285-4291. 
18Luznik L, Fuchs EJ. High-dose, post-transplantation cyclophosphamide to promote graft-host 
tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. 2010;47:65-77. 
19Ciurea SO, Mulanovich V, Saliba RM et al. Improved early outcomes using a T cell replete graft 
compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol 
Blood Marrow Transplant. 2012;18:1835-1844. 
20Bashay A, Zhang MJ, McCurdy SR, St. Martin A, Argall T, Anasetti C, et al. Mobilized 
Peripheral Blood Stem Cells versus Unstimulated Bone Marrow as a Graft Source for T-Cell 
Replete Haploididentical Donor Transplantation Using Post-Transplant Cyclophosphamide. J 
Clin Oncol. 2017;35(26):3002-9. 
21Mielcarek M, Furlong T, O’Donnell PV, Storer BE, McCune JS, Storb R, et al. 
Postransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-
matched mobilized blood cell transplantation. Blood. 2016;127(11):1502-8. 
22Harris AC, Young R, Decine S, et al. International, Multicenter Standardization of Acute Graft-
versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD 
International Consortium. Biology of Blood and Marrow Transplantation 2016;22:4-10.  
23Jagasia MH, Hildegard TG, 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. Biology of Blood and Marrow Transplantation; 
Journal of the American Society for Blood and Marrow Transplantation 2015;21:389-401. 
24Armand P, Haesook TK, Logan B, et al. Validation and refinement of the Disease Risk Index for 
allogeneic stem cell transplantation. Blood 2014;123(23):3664-3671 


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25Kittelson, J.M. and Emerson, S.S., 1999. A unifying family of group sequential test designs. Biometrics, 
55(3), pp.874-882.26Belkaid Y and Hand TW. Role of the microbiota in immunity and 
inflammation. Cell 2014;157(1):121-41. 
 
27Andermann TM, Peled JU, Ho C, et al. The microbiome and hematopoietic cell transplantation: 
past, present, and future. Biol Blood Marrow Transplant 2018;24(7):1322-40. 
28Holler E, Butzhammer P, Schmid K, et al. Metagenomic analysis of the stool microbiome in 
patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of 
systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol 
Blood Marrow Transplant 2014;20(5):640-5. 
29Weber D, Jenq RR, Peled JU, et al. Microbiota disruption induced by early use of broad 
spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell 
transplantation. Biol Blood Marrow Transplant 2017;23(5):845-852. 
30Jenq RR, Taur Y, Devlin SM, et al. Intestinal blautia is associated with reduced death from 
graft-versus-host disease. Biol Blood Marrow Transplant 2015;21(8):1373-83. 
31Shono Y, Docampo MD, Peled JU, et al. Intestinal microbiota-related effects on graft-versus-
host disease. Int J Hematol 2015;101(5):428-37. 
32Peled JU, Devlin SM, Staffas A, et al. Intestinal microbiota and relapse after hematopoietic-cell 
transplantation. J Clin Oncol 2017;35(15):1650-59. 
33Kashyap PC, Chia N, Nelson H, et al. Microbiome at the Frontier of Personalized Medicine. 
Mayo Clin Proc 2017;92(12):1855-64. 
34Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for clostridium 
difficile infection: a systematic review. Ann Intern Med 2015;162(9):630-8. 
35Kostic AD, Xavier RJ, and Gevers D. The microbiome in inflammatory bowel disease: current 
status and the future ahead. Gastroenterology 2014;146(6):1489-99. 
36Wilkinson EM, Ilhan ZE, and Herbst-Kralovetz MM. Microbiota-drug interactions: impact on 
metabolism and efficacy of therapeutics. Maturitas 2018;112:53-63. 
37Kroemer G and Zitvogel L. Cancer immunotherapy in 2017: the breakthrough of the 
microbiota. Nat Rev Immunol 2018;18(2):87-88. 
38Ogonek J, Kralj Juric M, Ghimire S, et al. Immune reconstitution after allogeneic 
hematopoietic stem cell transplantation. Front Immunol 2016;7:507. 
39Suessmuth Y, Mukherjee R, Watkins B, et al. CMV reactivation drives posttransplant T-cell 
reconstitution and results in defects in the underlying TCRbeta repertoire. Blood 2015;125:3835-
50. 
40van Heijst JW, Ceberio I, Lipuma LB, et al. Quantitative assessment of T cell repertoire recovery 
after hematopoietic stem cell transplantation. Nature medicine 2013;19:372-7. 


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41Perales MA, Goldberg JD, Yuan J, et al. Recombinant human interleukin-7 (CYT107) promotes 
T-cell recovery after allogeneic stem cell transplantation. Blood 2012;120:4882-91. 
 
42Meyer EH, Hsu AR, Liliental J, et al. A distinct evolution of the T-cell repertoire categorizes 
treatment refractory gastrointestinal acute graft-versus-host disease. Blood 2013;121:4955-62. 
 
43Emerson R, Sherwood A, Desmarais C, Malhotra S, Phippard D, Robins H. Estimating the ratio 
of CD4+ to CD8+ T cells using high-throughput sequence data. Journal of immunological methods 
2013;391:14-21. 
 
44Wu D, Sherwood A, Fromm JR, et al. High-throughput sequencing detects minimal residual 
disease in acute T lymphoblastic leukemia. Science translational medicine 2012;4:134ra63. 
 
45Wu D, Emerson RO, Sherwood A, et al. Detection of minimal residual disease in B 
lymphoblastic leukemia by high-throughput sequencing of IGH. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2014;20:4540-8. 
 
46Rawstron AC, Fazi C, Agathangelidis A, et al. A complementary role of multiparameter flow 
cytometry and high-throughput sequencing for minimal residual disease detection in chronic 
lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia 2016;30:929-
36. 
 
47Honda K and Littman DR. The microbiota in adaptive immune homeostasis and disease. 
Nature 2016;535(7610:75-84. 
48Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-
1 immunotherapy in melanoma patients. Science 2018;359(6371):97-103. 
49Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based 
immunotherapy against epithelial tumors. Science 2018;359(6371):91-97.  
50Moissev I, Pirogova O, Alyanski A, et al. Graft-versus-Host Disease Prophylaxis in Unrelated 
Peripheral Blood Stem cell Transplantation with Post-Transplantation Cyclophosphamide, 
Tacrolimus, and Mycophenolate Mofetil. BBMT 2016;22(6):1037-1042. 


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APPENDIX J 
Mi-Immune Study 


 
Page J-0 
  
Microbiome and Immune Reconstitution in Cellular 
Therapies and Hematopoietic Stem Cell Transplantation 
(Mi-Immune) 
 
BMT CTN Protocol 1801 
 
Principal Investigators 
Ami Bhatt, MD, PhD1 
Leslie S. Kean MD, PhD18 
Miguel-Angel Perales, MD3 
 
Companion Study Protocol Team:
Merav Bar, MD2 
Brandi Bratrude, PNP, CCRP18 
Saurabh Chhabra, MD4 
Sung Choi, MD5 
William Clark, MD, MS6 
Suman R. Das, PhD7 
Mary Horowitz, MD, MS4 
Rob Jenq, MD8 
Rick Jones, MD9 
John Levine, MD10 
Brent Logan, PhD4 
Hemant Murthy, MD12 
Armin Rashidi, MD, PhD13 
Marcie Riches, MD, MS14 
Wael Saber, MD, MS4 
Karamjeet Sandhu, MD15 
Ashley Spahn16 
Anthony Sung, MD17
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
1Stanford University 
2Fred Hutchinson Cancer Research 
Center 
3Memorial Sloan Kettering Cancer 
Center 
4Medical College of Wisconsin 
5University of Michigan 
6Virginia Commonwealth University 
7Vanderbilt University 
                8MD Anderson Cancer Center 
9Johns Hopkins University 
 10Mount Sinai 
11Emmes 
12University of Florida 
13University of Minnesota 
14University of North Carolina 
15City of Hope 
16National Marrow Donor Program 
17Duke University 
18Boston Children’s Hospital 


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CHAPTER 1 
1 
BACKGROUND AND SIGNIFICANCE 
Allogeneic HCT is an effective treatment for patients with malignant and non-malignant 
hematologic diseases. However, this treatment is complicated by high rates of morbidity and 
mortality limiting its broader application. The leading causes of post-transplant morbidity and 
mortality include acute and chronic GVHD, relapse and infectious disease.  The goal of the trial is 
to apply a systems biology approach to understanding the mechanisms driving these complications, 
such that evidence-based treatment strategies can be devised. Results of this study may also inform 
the development of accurate and predictive surrogate markers of clinically relevant endpoints that 
may be informative for future BMT clinical trial design.  
The sample repository and molecular and clinical databases established through the trial will be 
made available to the biomedical community and are expected to facilitate studies that will 
establish the utility of molecular biomarkers for risk assessment, diagnosis and monitoring, and 
allow more rational treatment strategies to be developed for patients undergoing allogeneic HCT.  
These studies are also likely to provide mechanistic insights and to identify new therapeutic targets 
leading to development of more targeted and effective therapies. 
The goal of this protocol is several-fold:  First, it is to test the primary hypothesis that the 
engraftment stool microbiome diversity (determined by 16s rRNA sequencing analysis of the 
sample closest after, but within 14 days of neutrophil engraftment) predicts 1-year non-relapse 
mortality in patients undergoing reduced-intensity allogeneic HCT.  Second, it is to perform 
additional analyses on patient samples to answer key questions concerning: a) the impact of the 
stool microbiome on transplant outcome as well as the impact of transplant on the microbiome and 
the associated downstream impact on patient health; and b) reconstitution of the T cell repertoire 
after transplant.  Third, it is to establish a cohort of biologic samples collected prospectively from 
patients treated on BMT CTN 1703 that will be a shared biospecimen resource for conducting 
future allogeneic HCT correlative studies.  The resulting dataset will become an additional 
resource generated by the trial and will be made available to the biomedical community. Mi-
Immune is designed to link molecular data and biospecimens with high quality clinical phenotype 
and outcomes data to identify risk factors for development and severity of key complications after 
allogeneic HCT.  
To achieve this goal, patients and donors will be recruited and consent will be obtained at the time 
that they enroll on BMT CTN protocol 1703.  Samples will be collected: (1) from patients and 
donors pre-transplant; and, (2) from patients post-transplant on a calendar-driven schedule through 
the first year post-HCT.  Shared clinical data will be collected in the context of the primary 
transplant protocol, BMT CTN 1703, and Mi-Immune-specific data will be collected using Case 
Report Forms (CRFs).  Additional clinical data will be available from data submitted to the Center 
for International Blood and Marrow Transplant Research (CIBMTR) using the CIBMTR CRFs. 


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CHAPTER 2 
2 
STUDY DESIGN 
2.1 
Study Overview 
In this study, we will collect stool, urine, and blood biospecimens, as well as detailed clinical data 
on infections and antibiotic exposures in an attempt to understand the microbial and immune 
recovery predictors of HCT outcomes. This study will form the correlative science arm of the BMT 
CTN 1703 study (PROGRESS III), which will compare two acute graft-versus-host disease 
(aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant 
cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced 
intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation.  
2.2 
Hypothesis and Objectives 
2.2.1 Hypothesis 
The engraftment stool microbiome diversity (determined within 14 days after neutrophil 
engraftment) predicts 1-year non-relapse mortality. 
2.2.2 Objectives 
Primary Objective: 
The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome 
diversity (determined by 16s rRNA sequencing analysis of the sample closest after, but within 14 
days of neutrophil engraftment) predicts 1-year non-relapse mortality in patients undergoing 
reduced-intensity allogeneic HCT. 
Secondary Objectives: 
Microbiome, Infection, and Antimicrobial Exposure: 
1) Association of engraftment microbiome diversity with development of aGVHD, cGVHD, 
and overall survival (corrected for GVHD prophylaxis). 
2) Association of baseline microbiome diversity with development of aGVHD, cGVHD, and 
overall survival (corrected for GVHD prophylaxis). 
3) Effect of GVHD prophylaxis on microbiome diversity: Difference in the level of 
microbiome diversity detected at 6, 12, and 24 months in the 2 arms. 
4) Association of microbiome oligodomination at the time of engraftment (>30% of 
microbiome being a single operational taxonomic unit) with increased subsequent risk of 
bloodstream infection. 
5) Association of volume of antimicrobial exposure (number and duration of drugs) in first 
30 days after transplant with rates of aGVHD, cGVHD, and overall survival. 


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6) Association between urine metabolites (such as indoxyl sulfate) at the time of engraftment 
and rate of acute GVHD. 
Immune Repertoire: 
1) Effect of GVHD prophylaxis on TCR diversity: Difference in the level of TCR diversity 
detected at 3, 6, 12 and 24 months in the 2 arms. 
2) Effect of TCR diversity at 3 months, 6 months, 12 months and 24 months  on subsequent 
non-relapse mortality, overall survival, and relapse, using landmark analyses and time-
dependent covariates. 
Biorepository: 
1) To establish a cohort of biologic samples and a linked clinical and molecular dataset from 
patients treated on BMT CTN 1703. The product of this study will be a shared biospecimen 
and data resource for conducting future allogeneic HCT mechanistic studies.  Examples of 
future exploratory objectives that can be addressed with this biorepository are the 
following: 
Exploratory Objectives: 
1) Effect of antibiotic use (length of exposure, anaerobic sparing vs. not) on level of 
microbiome diversity at 6, 12, and 24 months. 
2) Effect of aGVHD and/or its treatment on microbiome at 6, 12 and 24 months.  
3) Effect of cGVHD and/or its treatment on microbiome at 12 and 24 months. 
4) Effect of CMV and BK reactivation on TCR diversity at 3, 6, 12 and 24 months. 
5) Effect of patient age on TCR diversity at 3, 6, 12, and 24 months. 
6) Effect of donor age on TCR diversity at 3, 6, 12, and 24 months. 
7) Effect of aGVHD and/or its treatment on TCR diversity at 3, 6, 12 and 24 months. 
8) Effect of cGVHD and/or its treatment on TCR diversity at 12 and 24 months. 
9) Correlation of microbiome diversity and TCR diversity at 3, 6, 12, and 24 months. 
2.3 
Eligibility Criteria for Enrollment 
 
The primary intention of the Mi-Immune protocol is to co-enroll patients on BMT CTN 1703.  
Patient inclusion and exclusion criteria are those of BMT CTN 1703.  Related and unrelated donors 
must be at least 18 years of age.  


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2.4 
Treatment Plan 
The conditioning, GVHD prophylaxis, and supportive care are described in BMT CTN 1703. 


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CHAPTER 3 
3 
STUDY ENDPOINTS AND DEFINITIONS 
3.1 
Primary Endpoint 
The primary endpoint is non-relapse mortality within one year.  This endpoint is defined according 
to the BMT CTN 1703 protocol.  This primary endpoint will be associated with the engraftment 
stool microbiome diversity (grouped by tertiles) for the primary analysis of this study.   
3.2 
Secondary Endpoints 
3.2.1 Clinical Endpoints 
Standard transplant endpoints and clinical outcomes, with the exception of infections and 
antimicrobial use, will be collected according to BMT CTN 1703, including long-term follow-up 
data collection through CIBMTR. The endpoints collected on BMT CTN 1703 include acute 
GVHD, chronic GVHD, non-relapse mortality, relapse, death and cause of death.  In addition, a 
feasibility endpoint (i.e., proportion of samples successfully collected on schedule), and 
exploratory analyses of donor/recipient pairs will be included. 
3.2.2 Infection 
Data on infections and antimicrobial agent administration occurring through Day 365 will be 
collected specifically for patients with Mi-Immune samples collected.  The incidence of definite 
and probable viral, fungal and bacterial infections will be tabulated.  The infections will be reported 
using the BMT CTN Advantage eClinical data reporting system. 
3.2.3 Correlative endpoints 
3.2.3.1 Microbiome 
The microbiome will be analyzed in two ways:  
First, the microbiome taxonomic diversity will be evaluated using 16S ribosomal RNA amplicon 
sequencing. Data will be generated per standard protocols, as previously described.5 Resultant 
sequencing data will be quality filtered, adapter sequences will be trimmed, and sequences will be 
analyzed using the QIIME pipeline.6 Shannon diversity will be calculated, as previously 
described.7  
Second, urinary indoxyl sulfate has been used as a biomarker of microbiome composition.8 We 
will measure urinary indoxyl sulfate using liquid chromatography followed by mass spectrometry, 
as previously described.9 
3.2.3.2 T cell Repertoire 
T cell repertoire will be analyzed using next generation sequencing on the Adaptive 
Biotechnologies ImmunoSEQ platform.  PBMCs from patients will be collected at 3, 6, 12 and 24 
months post HCT.  TCR diversity will be assessed using the inverse Simpson's diversity index 
(1/Ds), which sums the frequency of each clonotype1. 


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CHAPTER 4 
4 
PATIENT EVALUATION 
4.1 
Pre-transplant Evaluations 
All pre-transplant evaluations occur as dictated by BMT CTN 1703.  The data will be captured in 
the BMT CTN 1703 forms and not re-entered for Mi-Immune.   
Additional Pre-transplant requirements for Mi-Immune to be collected no sooner than 7 days prior 
to the start of conditioning regimen: 
1. Specimen Collection: Urine, stool, and blood will be collected pre-conditioning (Day -14 
to Day -7) and pre-infusion (Day -1 to Day 0).  Please note that stool sample collection at 
pre-conditioning is MANDATORY and urine sample collection is OPTIONAL.   
2. A CBC will be performed pre-conditioning (Day -14 to Day -7) and pre-infusion (Day -1 
to Day 0). 
3. Infection data collection at baseline. 
 
4.2 
Post-transplant Evaluations 
1. For all enrolled HCT patients, the empty bag or syringe in which the stem cell product was 
infused will be retrieved by the study team and sent to the Central Reference Laboratory at 
ambient temperature where it will be washed to obtain donor cells for analysis. 
2. Toxicities associated with specimen collection for Mi-Immune will be collected and 
reported on days 28, 56, 98, 180, 270, and 365 post-transplant.  All other toxicities will be 
reported for BMT CTN 1703. 
3. Specimen collection (blood, urine, and stool) for microbiome assays will occur weekly 
starting on day 0 through day 77 (through day 84 for blood), then at day 98, day 180, day 
270, 1 year, and 2 years.   
• Weekly stool sample collection for microbiome assays starting Day 0 weekly 
through Day 28 is MANDATORY.   
• Weekly stool sample collection for microbiome assays starting day 35 through 
day 77, then at day 98, 180, 270, 1 year, and 2 years are OPTIONAL.   
• 
Weekly urine sample collection for microbiome assays starting Pre-conditioning 
through Day 270, then at 1 year, and 2 years are ALL OPTIONAL.   
4. A CBC will be performed weekly from day 0 through day 77 (through day 84 for blood), 
then day 98, 180, 270, 365, And 730. 
5. Infection data: This will occur every 14 days from day 0 until day 98, then on day 180, 
270, and 365 post-transplant. 
6. Antimicrobial medications:  Specific medications including route of administration, start 
date, and stop date will be collected every 14 days from day 0 to day 98. Medications prior 
to start of conditioning and on day 180, 270, and 365 post-transplant will be listed with 
route of administration for the 7 days prior to the form date. 


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Table 4.2: Patient and Donor Evaluations 
 
 
 
Pre-
conditioning 
(Day -14 to -7) 
Pre-
infusion 
(Day -1 to 
0) 
0 
7 
+ 3 
14 
+ 3 
21 
+ 3 
28 
+ 3 
35 
+ 3 
42 
+ 3 
49 
+ 3 
56 
+ 3 
63 
+ 3 
70 
+ 3 
77 
+ 3 
84 
+ 3 
98 
+ 7 
180 
+ 
28 
270 
+ 
28 
365 
+ 
28 
730 
+ 
60 
Patient 
Data 
CBC 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infections 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Antimicrobial 
medications 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Toxicities 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
 
Patient 
Samples 
Peripheral 
Blood 
X*** 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine1 
X*** 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Stool2 
X*** 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Related 
Donor 
Samples 
CBC 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral 
Blood 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematopoietic 
Stem Cell 
Product Cells 
 
 
X** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unrelated 
Donor 
Samples 
Hematopoietic 
Stem Cell 
Product Cells 
 
 
X** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Pre-donation. 
**Empty bag or syringe in which the stem cell product was infused. 
***Samples should be collected Pre-conditioning, pre-antibiotic prophylaxis on Day -14 to Day -7.  
1 Weekly urine sample collection for microbiome assays starting Pre-conditioning through Day 270, then at 1 year, and 2 years are ALL OPTIONAL  
2 Weekly stool sample collection for microbiome assays at Pre-conditioning, Pre-infusion/Day 0 weekly through Day 28 is MANDATORY.  Weekly stool sample 
collection for microbiome assays starting day 35 through day 77, then at day 98, 180, 270, 1 year, and 2 years are OPTIONAL.   
 


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4.3 
Collection of Research Samples 
Blood, stool, urine and biopsy research samples will be collected in this study. The majority of 
study samples will be collected on a calendar driven schedule. Based on historical experience with 
BMT CTN 1202, we anticipate high compliance (1202 calendar-driven samples were collected at 
a rate of 96% completeness).  
4.3.1 Study Blood Draws 
For transplant patients, the blood sample collections will occur at baseline (defined as pre-
conditioning, pre-antibiotic prophylaxis) at day -7 to day -14 prior to start of conditioning. Samples 
will then be collected weekly from day 0 (pre-infusion) through day 84 (+/- 3 days), then on day 
+98 +/- 7 days, day +180 +/- 28 days, day +270 +/- 28 days, day +365 +/- 28 days, day +730 +/- 
60 days as outlined in Table 4.2.  Related donor samples will be drawn prior to the peripheral 
blood stem cell collection.   
4.3.2     Stool Samples 
Stool samples will be collected according to standard operating procedures modified from the NIH 
Human Microbiome Project protocols. Briefly, samples will be stored at 4oC within 30 minutes of 
collection and then will be shipped to NMDP within 24-48 hours. At NMDP, the samples will be 
aliquoted and stored at -80oC. Samples will be collected with and without preservative solutions 
to enable downstream DNA, RNA and mass spectrometry (metabolite and metaproteome) 
analysis. Selected centers with substantial microbiome sampling experience will collect and 
process samples for additional downstream transcriptome and volatile metabolite sampling, which 
requires rapid processing. For transplant patients, the stool sample collections will occur at 
baseline (defined as pre-conditioning, pre-antibiotic prophylaxis) at day -7 to day -14 prior to start 
of conditioning. Samples will then be collected weekly from day 0 through day 77 (+/- 3 days), 
then on day +98 +/- 7 days, day +180 +/- 28 days, day +270 +/- 28 days, day +365 +/- 28 days, 
day +730 +/- 60 days as outlined in Table 4.2.1 (see Laboratory Procedures Table for inpatient and 
outpatient stool collection schedule). 5-10ml of stool will be obtained at each timepoint and placed 
into a sterile container. Stool sample will then be placed on ice (4oC) and transferred to the lab. 
4.3.3     Urine Samples 
Urine metabolites such as indoxyl sulfate are associated with GVHD and specific intestinal 
microbiome compositions. Urine collections will be performed according to the standard operating 
procedures outlined in the Laboratory Procedures Table. For transplant patients, the urine sample 
collections will occur at baseline (defined as pre-conditioning, pre-antibiotic prophylaxis) at day -
7 to day -14 prior to start of conditioning. Samples will then be collected weekly from day 0 
through day 77 (+/- 3 days), then on day +98 +/- 7 days, day +180 +/- 28 days, day +270 +/- 28 
days, day +365 +/- 28 days, day +730 +/- 60 days as outlined in Table 4.2. Samples will be placed 
at 4oC within 30 minutes of collection and for no more than 48 hours prior to aliquoting and deep 
freeze storage.  
 


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CHAPTER 5 
5 
STATISTICAL CONSIDERATIONS 
5.1 
Study Overview 
This study is designed as a companion study to the BMT CTN 1703 Phase III randomized, open 
label, multicenter trial to compare PTCy/Tac/MMF versus Tac/MTX for GVHD prophylaxis in 
patients with controlled malignant disease receiving an allogeneic PBSC transplant after a RIC 
regimen. Patients enrolled on this study will be asked to provide additional study samples which 
will be linked with the clinical data collected on the parent protocol, in order to address specific 
research questions associated with those study samples and to provide banked samples for future 
studies.   
5.1.1 Accrual 
Accrual will occur in conjunction with the BMT CTN 1703 trial. The target enrollment of the 
parent trial is 428 patients; we plan to enroll approximately 70%, or n=300 patients, on this 
companion protocol.   It is estimated that 36 months of accrual will be necessary to enroll the 
targeted sample size. The study will remain open until the last recipient enrolled has been followed 
for two years post-transplant. 
5.1.2 Randomization 
Patients on the BMT CTN 1703 trial will be randomized at a ratio of 1:1 between the treatment 
arms; no further randomization will be done on this companion protocol. 
5.1.3 Primary Endpoint 
The primary endpoint for this study is non-relapse mortality within 1 year of transplant.   
5.1.4 Primary Objective 
The primary objective of Mi-Immune is to compare NRM within 1 year between groups defined 
by engraftment stool microbiome diversity.  Tertiles will be used to define 3 approximately equal 
sized groups.   
5.1.5 Sample Size and Power Considerations 
The primary analysis will be done using a Fine and Gray model comparing the non-relapse 
mortality within 1 year between the three groups.  Non-relapse mortality by 1 year is expected to 
be approximately 15% overall based on BMT CTN 1203 trial data. Using the method of Latouche 
(2004), we computed power to detect differences of 20% in the 1 year NRM between any two 
pairs of groups, using a Bonferroni adjusted type I error of 0.05/3 to account for pairwise 
comparisons2.  The table below shows various comparisons of this difference in NRM over an 
expected range of NRM for this protocol; the targeted sample size of 300 evaluable patients would 
have at least 85% power to detect a 20% difference in 1 year NRM between any two microbiome 
diversity groups.   


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Table: Power to detect 20% differences in 1 year NRM between any two microbiome diversity 
groups: 
 
NRM difference 
Power 
5% vs. 25% 
99% 
10% vs. 30% 
93% 
15% vs. 35% 
85% 
5.2 
Interim Analysis and Pausing Guidelines 
As this is a non-interventional correlative study, no interim analyses will be included specifically 
as part of this protocol, separate from those used in BMT CTN 1703. 
5.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be described for all patients and separately for each 
cohort.  Characteristics to be examined are: age, gender, race/ethnicity, performance status, 
primary disease, disease-specific risk categories, DRI, hematopoietic cell transplant comorbidity 
index (HCT CI), donor type and HLA matching, donor/recipient CMV status, donor/recipient sex 
match, donor/recipient ABO match, and conditioning regimen.  Between group comparisons will 
be performed for continuous variables via a Kruskal-Wallis test and for categorical variables, via 
the chi-square test.  Additionally, we will compare the distributions of these characteristics 
between patients with Mi-Immune samples collected vs. those enrolled on BMT CTN 1703 but 
who did not provide Mi-Immune samples, to assess whether the Mi-Immune cohort appears 
representative of the larger trial.   
5.4 
Analysis Populations 
5.4.1 Engraftment stool Microbiome Population 
All enrolled patients with an available engraftment stool microbiome diversity measure will be 
included in this population.  The primary analysis as well as secondary analyses focusing on the 
impact of the engraftment stool microbiome diversity on clinical outcomes will use this population.  
Outcomes are determined from the time of the engraftment stool sample collection. 
5.4.2 Baseline Microbiome Population 
All enrolled patients with an available baseline stool microbiome diversity measure will be 
included in this population.  This population will be used for secondary analyses looking at the 
impact of baseline microbiome diversity on subsequent clinical outcomes.  Outcomes will be 
determined from the time of transplant.   
5.4.3 Landmark Microbiome Populations 
Various landmark microbiome populations will be used to examine the impact of microbiome 
diversity measures at that timepoint on subsequent clinical outcomes, or to compare microbiome 


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diversity measures at that timepoint between groups such as randomized GVHD prophylaxis 
strategy.  In each case, patients will be included if they are still at risk for the clinical outcome at 
the landmark time, and have an available microbiome diversity measure at that timepoint.  Clinical 
outcomes will be assessed starting at that landmark timepoint. 
5.4.4 Antimicrobial exposure population 
All enrolled patients with complete data collection on antimicrobial exposure within the first 30 
days and who are still at risk for the clinical outcome at day 30 will be included in this landmark 
antimicrobial exposure cohort.  The antimicrobial exposure population will be used to examine the 
impact of antimicrobial exposure within 30 days on subsequent clinical outcomes.  Clinical 
outcomes will be assessed starting at 30 days. 
5.4.5 Landmark TCR diversity Populations. 
Various landmark TCR diversity populations will be used to examine the impact of TCR diversity 
measures at that timepoint on subsequent clinical outcomes, or to compare TCR diversity measures 
at that timepoint between groups such as randomized GVHD prophylaxis strategy.  In each case, 
patients will be included if they are still at risk for the clinical outcome at the landmark time, and 
have an available TCR diversity measure at that timepoint.  Clinical outcomes will be assessed 
starting at that landmark timepoint. 
5.5 
Analysis Plan 
5.5.1 Analysis of the Primary Objective:  Compare NRM within 1 year between groups defined 
by engraftment stool microbiome diversity.   
This analysis will use the engraftment stool microbiome cohort.  Microbiome diversity will be 
separated into three groups based on tertiles for the primary analysis.  Non-relapse mortality will 
be summarized for each group using cumulative incidence with relapse as a competing event and 
compared in a univariate manner between tertiles using Gray’s test.  A Fine and Gray model will 
be used to compare microbiome diversity groups after adjustment for baseline covariates; 
microbiome diversity as well as GVHD prophylaxis received will be forced into the model and 
stepwise selection will be used to identify additional variables associated with outcome.  
Interactions between GVHD prophylaxis received and microbiome diversity will be assessed.  A 
secondary analysis will further examine the functional form of the relationship between 
quantitative values of microbiome diversity and the subdistribution hazard for NRM using splines, 
and if appropriate, an optimal cutpoint will be determined.   
5.5.2 Analysis of the Secondary Objectives 
Microbiome, Infection, and Antimicrobial Exposure: 
1) Association of engraftment microbiome diversity with development of aGVHD, cGVHD, 
and overall survival (corrected for GVHD prophylaxis). 
This analysis will use the engraftment stool microbiome cohort; diversity will be grouped 
by tertiles or if a more appropriate classification is identified in the primary analysis, that 


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may be used instead.  aGVHD (grade 2-4 or 3-4) and chronic GVHD (any or moderate-
severe) will be described in each group using cumulative incidence with death or relapse 
as a competing event, and compared between groups using Gray’s test.  Overall survival 
will be described using the Kaplan-Meier estimator and compared between groups using 
the log-rank test.  Multivariate models will be constructed in a similar manner as for the 
primary endpoint using Fine and Gray models for aGVHD and cGVHD, and using Cox 
models for OS.   
2) Association of baseline microbiome diversity with development of aGVHD, cGVHD, and 
overall survival (corrected for GVHD prophylaxis). 
This analysis will use the baseline stool microbiome cohort; diversity at baseline will be 
separated into three groups based on tertiles for initial analysis. aGVHD (grade 2-4 or 3-4) 
and chronic GVHD (any or moderate-severe) will be described in each group using 
cumulative incidence with death or relapse as a competing event, and compared between 
groups using Gray’s test.  Overall survival will be described using the Kaplan-Meier 
estimator and compared between groups using the log-rank test.  Multivariate models will 
be constructed in a similar manner as for the primary endpoint using Fine and Gray models 
for aGVHD and cGVHD, and using Cox models for OS.  We will also consider further 
examination of the functional form of the relationship between quantitative values of 
baseline microbiome diversity and the risk of aGVHD, cGVHD, or death using splines, 
and if appropriate, an optimal cutpoint will be determined. 
3) Effect of GVHD prophylaxis on microbiome diversity: Difference in the level of 
microbiome diversity detected at 6, 12, and 24 months in the 2 arms. 
This analysis will use a series of landmark microbiome populations at each time point.  
Microbiome diversity will be compared between GVHD prophylaxis groups at each time 
point using Mann-Whitney tests; randomized GVHD prophylaxis groups will be used 
rather than GVHD prophylaxis received to maintain the ITT principle, however a 
secondary analysis using the GVHD prophylaxis received may also be performed.  
Transformation of diversity will be considered to induce normality.  If a normalizing 
transformation can be identified, analysis of covariance will be used to compare diversity 
at each time point, after adjustment for baseline diversity and other covariates; stepwise 
selection will be used to identify additional covariates associated with diversity.   
4) Association of microbiome oligodomination at the time of engraftment (>30% of 
microbiome being a single operational taxonomic unit) with increased subsequent risk of 
bloodstream infection. 
This analysis will use the engraftment stool microbiome population.  The number of 
bloodstream infections and the number of patients experiencing a bloodstream infection 
between engraftment and day 100 will be described by presence of microbiome 
oligodomination group.  Prevalence of active bloodstream infection will be described at 
subsequent visit times by microbiome oligodomination group, and compared using the chi-


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square test.   Additional details on organisms will also be summarized.  Bloodstream 
infection density in the first 100 days will be computed as infection frequencies over 100 
patient days at risk. If there are sufficient numbers of bloodstream infection events in the 
first 100 days, multivariate regression analyses will be performed to examine the 
association between microbiome oligodomination and infection density, while adjusting 
for other relevant covariates. Proportional rates/means models will be used to model the 
infection density, with a robust variance estimator to account for within patient correlation; 
microbiome oligodomination and GVHD prophylaxis received will be forced into the 
model, and additional variables will be added using stepwise regression3. Interaction 
between microbiome oligodomination and GVHD prophylaxis received will be assessed. 
5) Association of volume of antimicrobial exposure (number and duration of drugs) in first 
30 days after transplant with rates of aGVHD, cGVHD, and overall survival. 
This analysis will use the antimicrobial exposure population.  Volume of antimicrobial 
exposure will be computed by measuring the “daily defined dose” exposure for each 
individual. This value is calculated on a per antimicrobial basis. Each day that a patient is 
given a specific antimicrobial agent counts as one daily defined dose. Thus, if a patient 
receives two different antimicrobials for one day each, the patient has received 2 daily 
defined doses. Alternatively, if a patient receives one antimicrobial for three days, the 
patient has received 3 daily defined doses. For combination drugs, such as 
trimethoprim/sulfamethoxazole, the daily defined doses will be calculated individually for 
each of the two active antimicrobial components of the combination therapy4. Volume of 
antimicrobial exposure will be dichotomized at the median.  aGVHD (grade 2-4 or 3-4) 
and chronic GVHD (any or moderate-severe) will be described in each group using 
cumulative incidence with death or relapse as a competing event, and compared between 
groups using Gray’s test.  Overall survival will be described using the Kaplan-Meier 
estimator and compared between groups using the log-rank test.  Multivariate models will 
be constructed in a similar manner as for the primary endpoint using Fine and Gray models 
for aGVHD and cGVHD, and using Cox models for OS.   
6) Association between urine metabolites (such as indoxyl sulfate) at the time of engraftment 
and rate of acute GVHD. 
This analysis will use the engraftment stool microbiome cohort; urine metabolites at the 
time of engraftment will be dichotomized at the median.  aGVHD (grade 2-4 or 3-4) will 
be described in each group using cumulative incidence with death or relapse as a competing 
event, and compared between groups using Gray’s test.  Multivariate models will be 
constructed in a similar manner as for the primary endpoint using Fine and Gray models 
for aGVHD.   
Immune Repertoire: 
1) Effect of GVHD prophylaxis on TCR diversity: Difference in the level of TCR diversity 
detected at 3, 6, 12 and 24 months in the 2 arms. 


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This analysis will use a series of landmark TCR diversity populations at each time point.  
TCR diversity will be compared between GVHD prophylaxis groups at each time point 
using Mann-Whitney tests; randomized GVHD prophylaxis groups will be used rather than 
GVHD prophylaxis received to maintain the ITT principle, however a secondary analysis 
using the GVHD prophylaxis received may also be performed.  Transformation of diversity 
will be considered to induce normality.  If a normalizing transformation can be identified, 
analysis of covariance will be used to compare diversity at each time point, after adjustment 
for baseline diversity and other covariates; stepwise selection will be used to identify 
additional covariates associated with diversity.   
2) Effect of TCR diversity at 3 months, 6 months, 12 months and 24 months on subsequent 
non-relapse mortality, overall survival, and relapse, using landmark analyses and time-
dependent covariates 
This analysis will use a landmark TCR diversity population at each time point.  TCR 
diversity will be dichotomized as above or below the median at each corresponding 
landmark time point, and cumulative incidence of non-relapse mortality and relapse will 
be estimated in each group, with relapse and death in remission respectively as competing 
risks.  Survival will be estimated in each group using Kaplan-Meier method.  We will 
examine the impact of TCR diversity over time as a time-dependent covariate in Cox 
models for the cause specific hazard for NRM or relapse, or for the hazard of death; GVHD 
prophylaxis received will be forced into the models, and other covariates will be considered 
using stepwise variable selection.  We will also explore the functional form of the 
relationship between TCR diversity and outcome using splines and if appropriate will 
identify an optimal cutpoint.   
 
 


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LABORATORY PROCEDURES TABLE 
Study Subject 
Research 
Sample Type 
Time Points 
Sample 
Quantity 
Shipping 
Temperature 
to BMT CTN 
Biorepository  
Sample Collection 
or Shipping 
Container 
Processed Research 
Sample Material 
Research Sample 
Material Aliquots 
Storage 
Temperature 
Patient 
(N = 300) 
Peripheral 
Blood 
Pre-
conditioning, 
Day 14, 28, 98, 
180, 365, 730 
39 mL  
Insulated 
Ambient  
5 mL Clot Tube 
Serum 
5 - 0.5 mL aliquots 
-80⁰ C 
2 mL EDTA Tube 
Whole Blood 
2 - 1.0 mL aliquots 
32 mL in Sodium 
Heparin Tubes 
Heparin Plasma 
15 - 0.5 mL aliquots 
PBMC 
~3 - 5x106 / 1 mL 
aliqouts 
LN 
Day 7, 21, 35, 
42, 49, 56, 63, 
70, 77, 84, 270 
31 mL  
 Insulated 
Ambient 
5 mL Clot Tube 
Serum 
5 - 0.5 mL aliquots 
-80⁰ C 
2 mL EDTA Tube 
Whole Blood 
2 - 1.0 mL aliquots 
24 mL in Sodium 
Heparin Tubes 
Heparin Plasma 
15 - 0.5 mL aliquots 
PBMC 
~2 - 5x106 / 1 mL 
aliqouts 
LN 
Pre-infusion 
24 mL  
Insulated 
Ambient  
5 mL Clot Tube 
Serum 
5 - 0.5 mL aliquots 
-80⁰ C 
24 mL in Sodium 
Heparin Tubes 
Heparin Plasma 
15 - 0.5 mL aliquots 
PBMC 
~2 - 5x106 / 1 mL 
aliqouts 
LN 
Urine 
Pre-
conditioning, 
Weekly Day 0 
to Day 77, Day 
98, 180, 270, 
365, 730 
10-12 mL 
2-8⁰ C  
Sterile Specimen 
Container 
Urine - No Preservative 
10 - 1.0 mL aliquots 
-80⁰ C 
Stool 
Pre-
conditioning, 
Weekly Day 0 
to Day 77, Day 
98, 180, 270, 
365, 730 
10-12 mL 
2-8⁰ C  
Sterile Specimen 
Container 
Stool - No Preservative 
4 - 1 to 1.5 mL aliquots 
-80⁰ C 
Stool in RNAlater 
2 - 1.5 mL processed 
aliquots 
 
 


Blood and Marrow Transplant Clinical Trials Network 
PROGRESS III - PTCY vs. TAC/MTX Protocol – 1703 
 
Version 4.0 dated November 16, 2020 
 
Page J-18 
  
Study 
Subject 
Research 
Sample Type 
Time Points 
Sample 
Quantity 
Shipping 
Temperature 
to BMT CTN 
Biorepository 
Shipping 
Temperature 
to Leslie 
Kean Lab 
Sample 
Collection or 
Shipping 
Container 
Processed Research 
Sample Material 
Research Sample 
Material Aliquots 
Storage 
Temperature 
Related 
Donor 
(N= ~120) 
Peripheral 
Blood 
Pre-donation 
41 mL  
Insulated 
Ambient 
  
5 mL Clot Tube 
Serum 
5 - 0.5 mL aliquots 
-80⁰ C 
4 mL EDTA Tube 
Whole Blood 
4 - 1.0 mL aliquots 
32 mL Sodium 
Heparin Tubes 
Heparin Plasma 
15 - 0.5 mL aliquots 
PBMC 
~3 - 5x106 / 1 mL 
aliqouts 
LN 
Urine 
Pre-donation 
10-12 mL 
2-8⁰ C 
  
Sterile Specimen 
Container 
Urine - No Preservative 
10 - 1.0 mL aliquots 
-80⁰ C 
Stool 
Pre-donation 
10-20 mL 
2-8⁰ C 
  
Sterile Specimen 
Container 
Stool - No Preservative 
4 - 1 to 1.5 mL 
aliquots 
-80⁰ C 
Stool in RNAlater  
 
2 - 1.5 mL processed 
aliquots 
 
All 
Donors     
(Will need 
protocol-
specific 
donor 
consent) 
Hematopoietic 
Stem Cell 
Product Cells 
Day 0 
Product Bag 
or Syringe 
  
2-8⁰ C 
Empty bag or 
syringe in which 
the stem cell 
product was 
infused 
Viably Cryopreserved 
WBC 
2-4 - 10x106 / 1 mL 
aliqouts 
LN 
 
 


Blood and Marrow Transplant Clinical Trials Network 
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Version 4.0 dated November 16, 2020 
 
Page J-0 
 
Mi-Immune REFERENCES 
 
1Venturi, V., Kedzierska, K., Turner, S.J., Doherty, P.C. & Davenport, M.P. Methods 
for comparing the diversity of samples of the T cell receptor repertoire. J. Immunol. Methods 321, 
182–195 (2007). 
2Latouche A, Porcher R, Chevret S (2004).  Sample size formula for proportional hazards 
modelling of competing risks.  Statistics in Medicine, 23:3263-3274. 
3D. Lin, L. Wei, I. Yang, Z. Ying. Semiparametric regression for the mean and rate functions of 
recurrent events. J Royal Statist Soc, 62 (2000), pp. 711-730. 
 
4“Definition and General Considerations.” WHO Collaborating Centre for Drug Statistics 
Methodology, 
Norwegian 
Institute 
of 
Public 
Health, 
https://www.whocc.no/ddd/definition_and_general_considera/ 
 
5Walters W, Hyde ER, Berg-Lyons D, et al. Improved bacterial 16S rRNA gene (V4 and V4-5) 
and fungal internal transcribed spacer marker gene primers for microbial community surveys. 
mSystems 2015;1(1):pii:e00009-15. 
 
6Kuczynski J, Stombaugh J, Walter WA, et al. Using QIIME to analyze 16s rRNA gene 
sequences from microbial communities. Curr Protoc Microbiol 2012;Chapter 1. 
 
7Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on 
mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014;124(7):1174-
82. 
 
8Weber D, Oefner PJ, Hiergeist A, et al. Low urinary indoxyl sulfate levels early after 
transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood 
2015;126(14):1723-8. 
 
9Zhu W, Stevens AP, Dettmer K, et al. Quantitative profiling of tryptophan metabolites in serum, 
urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry. Anal 
Bioanal Chem 2011;401(10):3249-61. 
 

ICF_003.pdf: 
Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 4.0 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 1 of 34 
                                                                                
Informed Consent to Participate in Research 
 
BMT CTN 1703 
 
A Randomized, Multicenter, Phase III Trial of Tacrolimus/Methotrexate versus Post-
Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-
Myeloablative/Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell 
Transplantation 
 
 
BMT CTN 1801 
Companion Study: Microbiome and Immune Reconstitution in Cellular Therapies and 
Hematopoietic Stem Cell Transplantation (Mi-Immune) 
 
 
 
Your Name:  
________________________________ 
 
 
Study Title:  
A Randomized, Multi-Center, Phase III Trial of Tacrolimus/Methotrexate 
versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate 
Mofetil in Non-Myeloablative Reduced Intensity Conditioning Allogeneic 
Peripheral Blood Stem Cell Transplantation 
 
 
 
Companion Study: Microbiome and Immune Reconstitution in Cellular 
Therapies and Hematopoietic Stem Cell Transplantation (Mi-Immune) 
 
Protocol: 
 
BMT CTN 1703 / BMT CTN 1801 
 
Principal 
Investigator:   
Insert local PI information 
 
 
Sponsor:   
This study is sponsored by National Institutes of Health (NIH), through 
the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).  
 
 
 
 
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 4.0 dated December 16, 2020 
 
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SUMMARY 
 
The following is a consent form for research and a peripheral blood stem cell transplant for which 
you are eligible.   
 
The research involves 2 questions.  The first research question is whether one combination of 
medications designed to prevent graft-versus-host disease (GVHD) is better than another 
combination of medications.  This question will be answered by the procedures outlined in the 
BMT CTN 1703 study by comparing Tacrolimus/methotrexate (the standard treatment) versus 
Tacrolimus/mycophenolate mofetil/cyclophosphamide (the experimental treatment).  
 
The second research question is whether intestinal bacteria and proteins related to them influence 
transplant outcomes, including the risk of GVHD.  This question will be answered by procedures 
outlined in BMT CTN 1801 involving collection of samples of blood, urine, and stool during the 
course of this study. 
 
The peripheral blood stem cell transplant is considered standard of care.  
 
Both of these research questions and the transplant are outlined in greater detail below.  Your 
participation in these studies is completely voluntary.   
 
 
BMT CTN 1703 - A Randomized, Multi-Center, Phase III Trial of Tacrolimus/Methotrexate 
versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate Mofetil in Non-
Myeloablative Reduced Intensity Conditioning Allogeneic Peripheral Blood Stem Cell 
Transplantation 
 
Purpose: The purpose of this study is to compare 2 combinations of drugs to prevent graft-
versus-host disease (GVHD), a serious complication of a stem cell transplant.  These 
combinations are either Tacrolimus/methotrexate or Tacrolimus/mycophenolate 
mofetil/cyclophosphamide. Doctors want to know which combination is better or if they give the 
same results.  The study will help doctors decide which treatment is best at preventing GVHD 
for future transplant patients.  
 
Procedures: Before the transplant, you will have testing to see if you are a suitable candidate for 
this study and transplantation.  You will receive a conditioning regimen chosen by your doctor to 
prepare your body for transplant. A computer will randomly assign you to 1 of the 2 treatment 
groups.  The treatment will start either before or after you receive the donor’s stem cells.  
 
Risks: Most of the risks you may experience are from the medications you will receive and the 
transplant.  More details can be found in the following consent 
 
Benefits: Information from this study may help doctors learn more about medications used to 
prevent GVHD for future transplant patients.  
 
Duration: You will be in the study for 1 year after your transplant. 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 4.0 dated December 16, 2020 
 
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Page 3 of 34 
 
 
BMT CTN 1801 - Microbiome and Immune Reconstitution in Cellular Therapies and 
Hematopoietic Stem Cell Transplantation (Mi-Immune) 
Purpose: The purpose of this study is to understand if the bacteria and proteins in your gut and 
body fluids can help the doctors predict transplant outcomes.  
 
Procedures: We will collect blood, urine, and stool samples, as well as detailed health 
information about your infections and antibiotic use. The sample collections will happen before 
and after your transplant and at your regular clinic visits.  Some of these samples will be stored 
for future research.   
 
Risks: Main risk is loss of confidentiality, but study staff have in place many safeguards for 
your privacy.   
 
Benefits: Information from this study may help doctors learn more about how the bacteria and 
proteins in your body could affect a transplant patient’s outcome.  This information could help to 
improve the outcomes for future transplant patients. 
 
Duration: You will be in the study for 2 years after your transplant. 
 
1. 
Introduction  
We invite you to join this clinical trial, also known as a research study.  We are doing this study 
because we want to compare 2 combinations of drugs to see which is better at preventing Graft-
versus-Host Disease (GVHD). You are being asked to join this study because: 
1. You have a disease that can be treated by a peripheral blood stem cell transplant; and 
2. Your doctor plans to use a reduced-intensity conditioning regimen for your transplant. 
 
You will be in the study for 1 year after your transplant. This study will take at least 3 years and 
will include 428 participants. There will be 214 participants in each of the treatment groups.  
 
We are also doing a companion study called Mi-Immune with participants enrolled in the main 
study. We want to understand if the microorganisms and proteins in your immune system can 
help us predict transplant outcomes.   The companion study will take 2 years and will include 
300 participants. This study is explained in greater detail in Section 18: Mi-Immune Study 
Research Samples of this consent.  
 
This Consent Form will tell you about the purpose of the research, the possible risks and 
benefits, other options available to you, and your rights as a participant in the study.  Your study 
doctor or study nurse will go over this form with you.  


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 4.0 dated December 16, 2020 
 
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Everyone who takes part in this research at [insert facility name] should know that: 
▪ Being in any research study is voluntary. 
▪ You may or may not benefit from being in the study.  Knowledge we gain from this study 
may benefit others. 
▪ If you join the study, you can quit the study at any time.  
▪ If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
▪ Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 
▪ You can ask questions now or any time during the study. 
▪ Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends. It is your decision to be in the study. If you decide to join, please 
sign and date the end of the Consent Form.  You’ll be given a signed and dated copy to 
keep.  No once can force you to take part in this study.  
 
You and your doctor will discuss other treatment choices if you do not want to participate in this 
study. 
 
2. 
Study Background 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), are providing staff support and money for this research study. The 
BMT CTN will direct the research study.  The BMT CTN and the NIH will make decisions 
about how to manage the study.  
 
A blood stem cell transplant is a standard treatment for blood cancers such as acute and chronic 
leukemias, lymphoma and myelodysplastic disorders. It replaces the abnormal (or diseased) 
blood cells with healthy cells from a donor. It requires a close tissue match between you and the 
donor. Your donor could be a family member, or it could be an unrelated person. The 
chemotherapy and radiation you get to destroy the abnormal cells and prepare your body for 
transplant is called the conditioning regimen. When lower doses of chemotherapy and radiation 
than usual are given, it’s called a reduced-intensity conditioning regimen.  
A common problem that may occur after a blood stem cell transplant is a condition known as 
Graft-Versus-Host Disease (GVHD).  The “graft” is the donor blood cells that you will get 
during your transplant.  The “host” is the person (in this case, you) receiving the cells. GVHD is 
when the donor graft attacks and damages some of your (the transplant recipient's) tissues.   


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 4.0 dated December 16, 2020 
 
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• GVHD can cause skin rash, stomach (intestinal) problems such as nausea, vomiting, or 
diarrhea   
• It may also damage your liver and cause hepatitis or jaundice (yellowing of the skin).   
• GVHD may also increase your risk of infection. 
 
3. 
Study Purpose 
We are inviting you to take part in this study because you have a cancer of the blood or lymph 
glands and a blood stem cell transplant is a treatment option. 
The purpose of this study is to compare 2 combinations of drugs to prevent GVHD. These 
combinations are listed below.  
Group A (current standard of care) 
Group B (this is being used more often in stem 
cell transplant) 
Tacrolimus and methotrexate  
Tacrolimus, mycophenolate mofetil and 
cyclophosphamide  
 
Doctors want to know which combination (A or B) is better, or if they give the same results. The 
study will help doctors decide which treatment is best at preventing GVHD for future transplant 
patients. 
4. 
Right to Ask Questions and/or Withdraw  
You have the right to ask questions about the study at any time.  If you have questions about the 
study, please contact:  
[insert contact info for Principal Investigator or study team] 
Being in this study is voluntary. You can choose not to be in this study or leave this study at any 
time. If you choose not to take part or leave this study, it will not affect your regular medical care 
in any way.  
 
Your study doctor and study staff can answer your questions about joining or leaving this study.  
 
5. 
Study Treatment and Tests  
We will check your health before you start treatment, while you receive treatment, and for 1 year 
after transplant.   
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 4.0 dated December 16, 2020 
 
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Before You Begin the Study 
First, you will need to have several tests or check-ups to see if you can be in the study. These 
exams, tests or procedures are part of regular cancer care. They may be done even if you do not 
join the study. These include: 
• Medical history 
• Physical examination, including height and weight 
• Blood and urine tests 
• Heart function tests, including EKG and ejection fraction 
• Lung (pulmonary) function tests 
• Tests to evaluate your cancer, including a bone marrow aspirate/biopsy if you have acute 
leukemia, chronic myeloid leukemia or myelodysplastic syndrome. This is where samples 
of your bone marrow are taken from your hip bone with a needle.  
• Imaging studies if you have lymphoma   
• Chest X-ray or chest CT 
• A pregnancy test if you are a woman able to have children. If you are pregnant, you will 
not be able to take part in this study. 
• Blood, urine, and stool samples for a Mi-Immune Study (see Section 18: Mi-Immune 
Study Research Samples) 
 


Blood and Marrow Transplant Clinical Trials Network   
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Study Participation 
If you decide to join the study, your participation will last for 1 year after your transplant for the 
main study. The Mi-Immune study will collect research samples from you at 2 years after your 
transplant. We will ask you to sign this Consent Form and you will get a copy of the signed form 
to keep. Most of the tests and procedures used for this study are the same as those normally used 
for transplant patients. However, there will be some extra tests if you join the study: 
 
1) Questions about your health and how well you can do your normal everyday activities 
(Patient Reported Outcomes (PRO) surveys). The CIBMTR Survey Research Group will 
contact you by email, phone or mail to collect PRO surveys online or on paper.  Your 
transplant center will provide your name and contact information to the CIBMTR Survey 
Research Group when you enroll in the study, so that they may administer the survey to you.  
You will take the surveys before your conditioning regimen and on Days 98, 180, 365 after 
your transplant.    
2) Mi-Immune biological samples: blood, urine and stool samples  
Before the Transplant 
Before your transplant, your doctor will choose a conditioning regimen.  The conditioning 
regimen prepares your body for transplant. It uses chemotherapy and/or radiation to destroy the 
cancer cells and the cells that make up your immune system.  Your doctor will decide which 
regimen you will receive before you are assigned to 1 of the 2 GVHD treatment groups.  
 
Randomization  
We will use a computer to randomly assign you to 1 of 2 treatment groups. You will have an equal 
chance of being in either group.  It’s just like flipping a coin.  You or your doctor won’t choose your 
group.  Once you’re in a group, you or your doctor can’t change your group. Both you and your 
doctor will know which group you are in.   
 
During Your Transplant 
The treatments that are used to prevent GVHD start either before or after you receive the donor stem 
cells. These treatments are a combination of drugs that hold back (suppress) your immune system 
and a standard component of the transplant. 
Details on the drugs we will give you for both treatment groups are outlined below:  
Group A: Tacrolimus and methotrexate  
 
Group B: Tacrolimus, mycophenolate 
mofetil and cyclophosphamide 
• Tacrolimus: given daily as a pill by mouth 
or intravenously (IV) through your vein, 
• Tacrolimus: given daily as a pill by mouth 
or by intravenously (IV) through your 


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beginning 3 days before your transplant. 
We will slowly decrease the amount of 
drug given to you and eventually stop.  
This process occurs over several months.  
• Methotrexate: given intravenously (IV) 
through your vein on 4 different days (1, 
3, 6 and 11) after your transplant. 
 
vein, beginning on Day 5 after your 
transplant. We will slowly decrease the 
amount of drug given to you and 
eventually stop.  This process occurs over 
several months. 
• Mycophenolate mofetil: given daily 
intravenously (IV) through your vein or as 
a pill by mouth 3 times a day, beginning 
on Day 5 after your transplant, and will 
continue for 30 days. Your doctor may 
decide to continue this drug if you still 
have GVHD. 
• Cyclophosphamide: given intravenously 
(IV) through your vein, over 1-2 hours, on 
Day 3 and Day 4 after your transplant. 
 
Peripheral Blood Stem Cell Transplant 
On your transplant day, the stem cells will be given to you through your central line, like a blood 
transfusion. The cells will travel through your bloodstream to your bone marrow where they will 
start to make healthy, new blood cells after several weeks.  
 
Health Evaluations After the Transplant (see Table 1) 
We will test (evaluate) your health during the study. These tests and how often they are 
scheduled are standard care for patients receiving transplant except for the PRO questions and 
the Mi-Immune research samples. This means they would be done even if you were not part of 
this study. The exceptions to this are the PRO questions described above and the Mi-Immune 
research samples. You will be watched closely for any signs and symptoms of GVHD.  
• Physical exam to assess toxicities, and infections weekly until Day 84 and then at Days 
98, 180, 270 and 365. 
• Physical exam to assess GVHD weekly starting Day 7 until Day 84 and then at Days 98, 
180, 270 and 365. 
• Routine blood tests (cell counts, liver and kidney function) weekly until Day 84 and then 
at Days 98, 180, 270, 365 and 730. 
• Blood or bone marrow tests to find the amount of donor cells in your body on Days 28 
and 98. This is also called chimerism.  
• Disease evaluation tests to see how much cancer you have after treatment on Days 98 and 
365. 


Blood and Marrow Transplant Clinical Trials Network   
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• Mi-Immune research samples: Blood, urine, and stool samples for the Mi-Immune 
study and future research collected weekly through Day 84, then at Days 98, 180, 270, 
365 and 730 (see Section 18: Samples for Additional Research).  Mi-Immune research 
samples: the stool samples at Pre-Conditioning, Day 0, Day 7, Day 14, Day 21, and Day 
28 are mandatory.  Starting day 35 through day 77, then at day 98, 180, 270, 1 year, and 2 
years, the stool samples are optional.  Weekly urine sample collection for Pre-
conditioning through Day 270, then at 1 year, and 2 years are ALL OPTIONAL.  
 


Blood and Marrow Transplant Clinical Trials Network   
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Table 1: Schedule for Health Evaluations after Transplant 
 
Day 
7 
Day 
14 
Day 
21 
Day 
28 
Day 
35 
Day 
42 
Day 
49 
Day 
56 
Day 
63 
Day 
70 
Day 
77 
Day 
84 
Day 
98 
Day 
180 
Day 
270 
Day 
365 
Day 
730 
Medical history, 
physical exam, & 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC & chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete GVHD 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Infection 
assessment 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Disease evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Patient Reported 
Outcome surveys 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
Mi-Immune 
research samples 
(see Table 4) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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6. 
Risks and Discomforts  
You will have side effects while on the study.  Side effects can range from mild to life-
threatening.  The risks and discomforts from this study are similar to what you would have even 
if you do not join this study.  If you do, the effect on you might be better, worse or about the 
same.  Your health care team may give you medicines to help lessen side effects such as feeling 
sick to your stomach (nausea).  In some cases, side effects can be long lasting or may never go 
away.  
 
Risks of Medicines  
All of the immune suppressive and conditioning regimen drugs listed below are commonly used 
in blood stem cell transplant.  The tables below describe all conditioning regimens that are 
allowed to be used in this study.  The regimen you will receive depends on your doctor’s choice.  
 
Table 2: Conditioning Regimens 
Reduced Intensity Conditioning 
Nonmyeloablative Conditioning 
Fludarabine/Busulfan (Flu/Bu) 
• Fludarabine (120-180 mg/m2) 
• Busulfan (less than or equal to 8 
mg/kg PO or 6.4 mg/kg IV) 
 Fludarabine/Cyclophosphamide (Flu/Cy) 
• Fludarabine (90-120 mg/m2) 
• Cyclophosphamide (120 mg/kg or 2250 
mg/m2) 
Fludarabine/Melphalan ( Flu/Mel) 
• Fludarabine (120-180 mg/m2) 
• Melphalan (less than or equal to 150 
mg/m2) 
Fludarabine /Total Body Irradiation (Flu/TBI) 
• Fludarabine (90 mg/m2) 
• TBI (200 cGy) 
 
Fludarabine/ Cyclophosphamide/TBI 
(Flu/Cy/TBI) 
• Fludarabine (150 mg/m2) 
• TBI (200 cGy) 
• Cyclophosphamide (29-50 mg/kg)  
 
 


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Table 3: Risks and Side Effects  
Likely 
This side effect is expected to happen in more than 20% of patients. This 
means that 21 or more patients out of 100 might get this side effect. 
Less Likely 
This side effect is expected to happen in 20% of patients or fewer. This 
means that 20 patients or fewer out of 100 might get this side effect. 
Rare, but 
Serious 
This side effect does not happen often – in fewer than 3% of patients – but 
is serious when it happens. This means that 0, 1, 2 or 3 patients out of 100 
might get this side effect. 
 
 
 
Methotrexate 
Likely 
(May happen in more than 20% 
of patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% or 
fewer patients) 
▪ Increased risk of 
sunburn or rash 
▪ Nausea, vomiting, loss 
of appetite  
▪ Sores in mouth which 
may cause difficulty 
swallowing 
 
▪ Anemia from low red 
blood cell count which 
may cause tiredness, or 
may require transfusion 
▪ Blood clots which may 
cause swelling, pain, 
shortness of breath 
▪ Bruising, bleeding from 
low platelet count 
▪ Diarrhea, sores in the 
gastrointestinal tract 
▪ Fluid around the heart 
▪ Hair loss  
▪ Hepatitis or liver 
damage which may 
cause yellowing of eyes 
and skin, generalized 
swelling 
▪ Infection, especially 
when white blood cell 
count is low 
▪ Kidney damage  
 
▪ A new cancer 
▪ Internal bleeding 
which may cause 
belly pain, black 
tarry stool, blood 
in vomit 
▪ Scarring of the 
lungs which may 
cause shortness of 
breath, confusion 
▪ Severe skin rash 
with blisters and 
peeling which can 
involve mouth 
and other parts of 
the body  
 
 
 


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Mycophenolate Mofetil (MMF, Cellcept®) 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% or 
fewer patients) 
▪ Birth control may not 
work as well 
▪ Damage to unborn 
baby if you become 
pregnant while taking 
this medicine 
▪ Difficulty 
breathing, 
cough 
▪ Headache 
▪ High blood pressure 
▪ Low white blood cell 
count with increased 
risk of infection 
▪ Nausea, vomiting, 
diarrhea, stomach pain 
▪ Swelling of the hands, 
feet, ankles, or legs 
▪ Tremors 
▪ Anemia (low red blood 
cell count) 
▪ Change in the levels of 
salts in the blood 
▪ Decreased platelet 
count, may cause blood 
loss into stool or vomit, 
increased bruising 
▪ Difficulty falling asleep 
or staying asleep 
▪ Dizziness 
▪ Low blood pressure 
▪ Pain in joints or muscles 
▪ Rash 
▪ A new cancer 
▪ Change in vision 
▪ Encephalopathy or 
brain dysfunction that 
can lead to death 
▪ Excessive tiredness 
▪ Fast heartbeat 
▪ Progressive 
Multifocal 
Leukoencephalopathy 
– This is caused by a 
virus that damages 
the protective 
covering in the brain.  
▪ Severe difficulty 
breathing 
▪ Weakness 
 
 
 


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Tacrolimus (FK506, Prograf®) 
Likely 
(May happen in more than 20% of 
patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% 
or fewer patients) 
▪ Abnormal body movement, 
including tremors 
▪ Abnormal levels of sugar, 
fat, or minerals (like sodium 
or potassium) in your blood 
▪ Constipation, diarrhea, 
nausea, vomiting, reflux, 
lack of desire to eat 
▪ Difficulty sleeping  
▪ Dizziness 
▪ Feeling of "pins and 
needles" in arms and legs 
▪ Headache 
▪ High blood pressure which 
may cause dizziness, chest 
pain 
▪ Itching, rash 
▪ Kidney damage which may 
cause swelling, may require 
dialysis 
▪ Low red blood cell counts, 
which may cause tiredness, 
or may require blood 
transfusions 
▪ Low platelet levels, which 
may cause bruising, 
bleeding 
▪ Low white blood cell 
counts, which may lead to 
infection 
▪ Liver damage 
▪ Swelling of the body 
 
▪ A new cancer 
▪ A tear or a hole in your 
bowels which may cause 
belly pain and may 
require surgery 
▪ Allergic reaction which 
may cause rash, low 
blood pressure, 
wheezing, shortness of 
breath, swelling of the 
face or throat 
▪ Change in the heart 
rhythm, abnormal 
heartbeat, or heart stops 
beating 
▪ Damage to brain, which 
may cause headache, 
seizure, blindness 
▪ Damage to lungs, which 
may cause shortness of 
breath, fluid around lungs 
▪ Heart attack or heart 
failure which may cause 
chest pain, swelling of 
ankles, and tiredness 
 
▪ Damage to 
small blood 
vessels with 
resulting small 
blood clots and 
possible organ 
damage. 
It is very important that you do not eat grapefruit or drink grapefruit juice while taking 
Tacrolimus. Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs used in this study.  Common soft drinks that have bergamottin are Fresca, 
Squirt, Sundrop, and Sunny Delight.  
 


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Cyclophosphamide (Cytoxan®) 
Likely 
(May happen in more than 20% 
of patients) 
Less Likely 
(May happen in 20% or  
fewer patients, but more 
than 3%) 
Rare, but Serious 
(May happen in 3% or  
fewer patients) 
▪ Absence of menstrual 
cycles which may decrease 
the ability to have children 
▪ Blood in urine 
▪ Feeling tired 
▪ Hair loss, skin changes, 
rash, change in nails 
▪ Infection, especially when 
white blood cell count is 
low 
▪ Nausea, vomiting, 
diarrhea, loss of appetite, 
pain in belly 
▪ Sores in mouth 
 
▪ Allergic reaction 
which may cause 
rash, low blood 
pressure, wheezing, 
shortness of breath, 
swelling of the face 
or throat 
▪ Decrease in platelets 
which may cause 
bleeding 
▪ Decrease in red 
blood cells, which 
may require blood 
transfusions 
▪ Loss or absence of 
sperm which may 
lead to an inability 
to father children 
 
▪ A new cancer 
▪ Damage to the 
heart or heart 
failure which may 
cause shortness of 
breath, swelling, 
cough or tiredness 
▪ Scarring of the 
lungs which may 
cause shortness of 
breath, fluid 
arounds the lungs 
▪ Swelling of the 
brain which may 
cause dizziness, 
confusion 
 
 
 
 


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Busulfan 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% or fewer 
patients) 
• Abnormal or fast 
heartbeat 
• Abnormal salt and/or 
vitamin levels that 
may require IV fluids 
• Anemia (low red 
blood cells) which 
may require blood 
transfusions 
• Chills, fever 
• Constipation, 
diarrhea, heartburn, 
nausea, vomiting, loss 
of appetite, stomach 
pain 
• Cough, stuffy nose 
• Damage to the liver or 
kidneys 
• Difficulty sleeping 
• Dizziness, headache 
• Feeling tired 
• High blood pressure  
• Infection, especially 
when white blood cell 
count is low 
• Low platelet counts 
which may cause 
bruising or bleeding  
• Pain 
• Rash 
• Sadness, worry 
• Sores in mouth which 
may cause difficulty 
swallowing 
• Swelling of the body 
 
• Blood in the urine 
• Coughing up blood 
• Damage to or scarring 
of the lungs 
• Loss or absence of 
sperm 
• Menopause 
• Seizure 
• Visual disturbances 
• Allergic reaction 
which may cause rash, 
low blood pressure, 
wheezing, shortness 
of breath, swelling of 
the face or throat 
• Fluid around the heart 
• Heart failure which 
may cause shortness 
of breath, swelling of 
ankles, and tiredness 
• Low blood pressure 
which may cause 
feeling faint 
 
 


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Fludarabine 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% or fewer 
patients) 
• Anemia (low red 
blood cells) which 
may require blood 
transfusions 
• Cough 
• Feeling tired or 
irritable 
• Infection, especially 
when white blood cell 
count is low 
• Low platelet counts, 
which may cause 
bruising or bleeding 
• Pain 
 
• Chills 
• Confusion 
• Damage to brain, 
lungs, or other organs. 
This may cause 
tiredness, changes in 
thinking or shortness 
of breath 
• Feeling of "pins and 
needles" in arms and 
legs 
• Nausea, vomiting, 
loss of appetite  
• Sores in mouth which 
may cause difficulty 
swallowing 
 
• Blood in urine 
• Changes in vision 
• Kidney damage which 
may require dialysis 
• Liver damage 
• Seizures 
 
 
Melphalan 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% or fewer 
patients) 
 
• Anemia 
(low 
red 
blood 
cells) 
which 
may 
require 
blood 
transfusions 
• Diarrhea 
• Feeling tired 
• Infection, 
especially 
when white blood cell 
count is low 
• Nausea, vomiting 
• Sores in mouth which 
may cause difficulty 
swallowing 
• Swelling of the body 
 
• Inflammation of blood 
vessels 
• Kidney problems 
which may require 
dialysis 
• Liver problems which 
may cause yellow eyes 
or skin 
• Low platelet counts, 
which may cause 
bruising or bleeding 
• Scarring of the lungs 
which may cause 
shortness of breath 
 
• A new cancer 
• Allergic reaction 
which may cause 
rash, low blood 
pressure, wheezing, 
shortness of breath, 
swelling of the face 
or throat 
• Heart failure which 
may cause shortness 
of breath, swelling of 
ankles, and tiredness 


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Low Dose Total Body Irradiation (TBI) 
Likely 
(May happen in more than 
20% of patients) 
Less Likely 
(May happen in 20% or fewer 
patients, but more than 3%) 
Rare, but Serious 
(May happen in 3% or fewer 
patients) 
• Anemia (low red blood 
cells) which may 
require blood 
transfusions 
• Infection, especially 
when white blood cell 
count is low 
• Low platelet counts, 
which may cause 
bruising or bleeding 
• Mouth sores 
• Nausea, vomiting, 
stomach pain, diarrhea 
 
• Eye cloudiness 
• Hair loss 
• Inability to have 
children 
• Painful swelling of the 
salivary glands under 
the ears for a few days 
• Redness of the skin 
 
• A new cancer 
• Back pain  
• Difficulty swallowing 
• Hormone problems 
(such as thyroid 
disease or diabetes) 
• Kidney problems 
• Learning problems 
• Liver problems 
• Lung inflammation 
• Slow growth (for 
example, height)  
 
Risks and Toxicities Related to Transplant 
Everyone who has a stem cell transplant faces these risks.  These are serious, and in some cases 
can cause death.  These risks are not specific to this study.  
Slow recovery of blood counts: The red blood cells, white blood cells, and platelets can be slow 
to recover after blood or marrow transplant. Until your blood counts recover, you will need 
blood and platelet transfusions, and will be at risk for bleeding and infections. You may receive 
filgrastim, a medicine to help speed up the recovery of white blood cells.  
Graft failure: The stem cells from your donor (the “graft”) may fail to grow inside your body. Past 
experience suggests that there can be up to a 10-15% chance of graft failure. Graft failure may cause 
low blood counts for a long time. If your counts do not recover, you may need to receive a second 
transplant. Graft failure can be fatal. 
Graft-Versus-Host Disease (GVHD): GVHD happens when the donated cells see your body as 
foreign and attack it.  GVHD can be treated, but treatment can take months to years.  Sometimes 
GVHD is severe or difficult to treat and may lead to death. You will be watched closely for this 
complication and given drugs to prevent and/or treat it.  
Acute GVHD may produce skin rash, nausea, vomiting, diarrhea, abdominal pain, abnormalities of 
liver function, and an increased risk of infection. Chronic GVHD may produce skin rashes, hair 
loss, thickened dry skin, dry eyes, dry mouth, liver disease, weight loss, diarrhea, and an increased 
risk of infection. To confirm the diagnosis of acute or chronic GVHD, you may be asked to have a 


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biopsy (a small sample of your tissue to look at under the microscope) of your skin, gut, or, rarely, 
your liver.  
 
Other complications. Other complications may include: 
a. Damage to the vital organs in your body. The transplant could cause problems in any body 
organ such as the heart, lungs, liver, gut, kidneys and bladder, or brain. The kidneys and the 
liver are most likely to be damaged. Some patients will experience serious lung problems from 
infections, chemotherapy or radiation.  
b. Serious infections. Full and complete recovery of your immune system may take many months. 
During this time, there is an increased risk of infections.  You will take medicines to lower your 
risk of infections. However, these treatments do not always work. If you have an infection, you 
may have to stay in the hospital longer or be re-hospitalized after transplant. Although most 
infections can be successfully treated, some infections may result in death.  
c. Relapse of disease or a new blood cancer. Your leukemia or lymphoma may come back even 
if the transplant is initially successful. In rare cases, a new blood cancer may develop from the 
donor cells. Cyclophosphamide can cause damage to blood cells, which may result in a blood 
cancer such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The 
blood cancer usually develops 2-10 years after treatment, or 6 years on average. The risk of 
developing a new blood cancer after allogeneic blood or marrow transplant is probably less 
than 2%. If cancer develops in your donor’s blood cells, you may require additional treatment 
with chemotherapy or another blood or marrow transplant. 
d. Risk to the unborn. The treatments in this study have not been proven to be safe at any stage of 
pregnancy and could affect the health of infants exposed to them via mother’s milk. Therefore, 
if you are pregnant or nursing, you are not eligible for this study. Women who can become 
pregnant must use effective birth control while receiving chemotherapy, TBI, and drugs to 
prevent GVHD, and for 1 year after transplant. Effective birth control is defined as the 
following: 
1. Refraining from all acts of vaginal sex (abstinence)  
2. Consistent use of birth control pills 
3. Injectable birth control methods (Depo-Provera, Norplant) 
4. Tubal sterilization or male partner who has undergone a vasectomy 
5. Placement of an IUD (intrauterine device) 
6. Use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam 
every time you have sex. 
 


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Reproductive Risks 
The drugs used in this research study may damage your reproductive organs, affect your ability to 
have children or possibly cause birth defects if you take them while you are pregnant. It is 
important that a woman is not pregnant or breast-feeding and does not become pregnant during 
the course of the study.  
It is important that both women who can become pregnant and their male partners use 
birth control for 1 year after transplant while on this study. 
▪ If you’re female: 
If you can become pregnant, you will need to take a pregnancy test before you start the study. 
You should discuss ways to prevent pregnancy while you are in the study. Women who have 
gone through puberty may find that their menstrual cycle becomes irregular or stops 
permanently. This does not mean that you cannot become pregnant. You must still use an 
effective method of birth control during your transplant and continue until you are finished with 
your GVHD prevention treatment. You may want to talk with your doctor about ova banking 
before having a transplant.   
Effective birth control is defined as the following: 
1. Not have any vaginal sex (abstinence)  
2. Consistently use birth control pills or patch 
3. Use injectable birth control (for example, Depo-Provera or Norplant) 
4. Have tubal sterilization (tied tubes) 
5. Have placement of an IUD (intrauterine device) 
6. Use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam 
every time you have vaginal sex.  
Tell your doctor right away if you become pregnant during the study.  Your doctor will 
discuss the risks to your unborn child and options with you and will watch you closely if you 
become pregnant.  
▪ If you’re male: 
Your body may not be able to produce sperm (become sterile). You should talk with your doctor 
about banking your sperm before having a transplant.  Please check with your doctor to 
understand more about these risks. 


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You must use one of the following birth control methods: 
1. Not have any vaginal sex (abstinence)  
2. Vasectomy or female partner who had a tubal ligation (tied tubes) 
3. Use of condoms with contraceptive foam every time you have sex. 
Or your partner must use:  
1. Consistently use birth control pills or patch 
2. Use injectable birth control (for example, Depo-Provera or Norplant) 
3. Have placement of an IUD (intrauterine device) 
4. Use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam 
every time you have vaginal sex. 
Tell your doctor right away if your partner becomes pregnant during the study. Your doctor 
will discuss the risks to your unborn child and your options.  
Additional Information about MMF 
▪ MMF could be damaging to an unborn baby if you are pregnant or become pregnant 
while receiving the drug.  
▪ MMF can make birth control pills not work well.  So, you have a higher risk of 
becoming pregnant while you are taking it. 
▪ If you could become pregnant, you must use 2 effective forms of birth control for 4 
weeks before starting MMF, during treatment, and for one year after transplant. 
If you think you might be pregnant or could become pregnant prior to enrollment, you should 
not join this study. 
Unforeseen Risks  
Other new risks might appear at any time during the study. These risks might be different from 
what is listed in this Consent Form. We will promptly tell you about new information that may 
affect your decision to take part in the study. We may learn new things about reduced-intensity 
transplants that might make you want to stop being in the study. We will let you know if this 
happens and you can decide if you want to continue in the study. There may be some unknown or 
unanticipated discomforts or risks associated with this treatment in addition to those specified 
above, but every precaution will be taken to assure your personal safety and to minimize 
discomforts. 


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Other Treatments or Medications 
Some medicines react with each other, so it is important that you tell the study doctor or staff 
about any other drugs, treatments, or medicines you are taking.  This includes non-prescription 
or over-the-counter medicines, vitamins and herbal treatments.  
It is also important that you tell the study staff about any changes to these medicines while 
you’re in the study.  
For more information about risks and side effects, ask your study doctor. 
 
Patient Reported Outcomes surveys 
There are a few risks from completing the quality of life surveys. Some of the questions or topics 
may upset you. You may feel emotional or that your privacy is lost. Talk to your doctor about your 
privacy concerns. We can put you in touch with a counselor or trained support specialist, if needed. 
 
7. 
Alternative to Participation 
Participation in this study is optional. If you choose not to take part, you may still receive a 
transplant to treat your disease.  The treatment and evaluations you would receive could be very 
similar to what would receive if you join this study. Your study doctor will talk with you about 
your options. If you decide not to participate in this study, your medical care will not be affected 
in any way. 
Your other choices may include: 
▪ Treatment with other drugs, radiation, or a combination of drugs and radiation without a 
transplant. 
▪ A transplant that is not part of the study, or another type of transplant 
▪ Participation in another clinical trial, if available (check with your doctor) 
▪ No treatment for your blood cancer at this time 
▪ Comfort care 
 
Every treatment option has benefits and risks. Talk with your doctor about your treatment 
choices before you decide if you will take part in this study. 
 


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8. 
Possible Benefits 
Taking part in this study may or may not make your health better.  The information from this 
study could help doctors learn more about medications used to prevent GVHD. 
9. 
New Information Available During the Study 
During this study, the study doctors may learn about new information about the study drugs or the 
risks and benefits of taking part in the study.  If they learn new information, they’ll tell you as soon 
as it’s available.  The new information may mean that you can no longer participate in the study, or 
you may not want to continue.  
10. 
Privacy, Confidentiality, and Use of Information 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  
This study has a “Certificate of Confidentiality,” which means the study doctors have a privacy 
permit to help protect your records if there is a court case.  However, some of your medical 
information may be given out if required by law.  If this should happen, the study doctors will do 
their best to make sure that any information that goes out to others will not identify you.   
Representatives from government agencies, including the U.S. Food and Drug Administration 
(“FDA”), institutional review boards, the Sponsors and/or the Sponsors’ authorized representatives 
may need access to your original medical records and study records to check information collected 
for the study. By signing this Consent Form, you authorize this access. 
If information from this study is published or presented at scientific meetings, your name and other 
personal information will not be used. Your study number (code) is not related to your name, social 
security number, or medical record number at [insert facility name]. Coded study information may 
also be used for unexpected medical projects and research in the future. These projects could be 
related to your disease or similar diseases, and development of the study drug. At all times the 
projects will follow the law. 
You will not be able to access your personal health information related to this study until the study 
is done. This helps to maintain the scientific integrity of the study.  
After the study is complete, you can ask your study doctor for your health information. By signing 
this Consent Form, you agree to ask for your health information only after the study is done. 
Information about your transplant from your original medical records may be seen or sent to: 


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▪ Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN DCC), including the Center for International Blood and Marrow Transplant 
Research (CIBMTR), the National Marrow Donor Program (NMDP)/Be The Match registry 
and The Emmes Corporation, who are coordinating the studies of the BMT CTN 
▪ The Food and Drug Administration (FDA) and National Institutes of Health (NIH), which 
includes the National Heart, Lung and Blood Institute (NHLBI) and the National Cancer 
Institute (NCI) 
▪ Office of Human Research Protection (OHRP) 
▪ Data and Safety Monitoring Board (DSMB), not part of [Institution] 
▪ Institutional Review Boards (IRBs) responsible for this study 
  
Data about your clinical situation, including follow-up after 1 year, may be obtained by the BMT 
CTN from the CIBMTR. The CIBMTR collects information on all U.S. transplants. 
We won’t identify you by name in any publications or reports that come from these organizations or 
agencies. 
11. 
Ending Your Participation  
Being in this study is voluntary.  You can choose to not be in this study, or leave this study at 
any time.  If you choose not to take part or leave this study, your regular medical care will not be 
affected in any way.  Tell your doctor if you are thinking about stopping or decide to stop.  He or 
she will tell you how to stop safely. 
 
The study doctor or the study sponsor may stop the study at any time.  We may ask you to leave 
the study if you do not follow directions or if you suffer from side effects of the treatment.  If we 
ask you to leave the study, the reasons will be discussed with you.   
 
Possible reasons to end your participation in this study include: 
▪ You do not meet the study requirements.  
▪ You need a medical treatment not allowed in this study. 
▪ The study doctor decides that it would be harmful to you to stay in the study. 
▪ You are having serious side effects. 
▪ You become pregnant. 
▪ You cannot keep appointments or take study drugs as directed. 
▪ The study is stopped for any reason. 


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Even if you leave the study, the information collected from your participation will be included in 
the study evaluation.  If you don’t want any of your information to be used or if you want to 
cancel this authorization, you must let your study doctor know.  
 
12. 
Physical Injury as a Result of Participation 
It is important that you tell your doctor or study staff if you feel that you have been hurt or 
injured because of taking part in this study.   
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study sponsor will not pay for 
medical treatment.  
In case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
13. 
Compensation or Payment  
You will not be paid for participating in this study.  You will not get paid or reimbursed for any 
extra expenses (such as travel or meals) from your participation in this study. 
 
14. 
Cost and Reimbursement 
Most of the visits for this study are standard medical care for patients undergoing allogeneic 
transplants and will be billed to your insurance company.  You and/or your health insurance 
company will need to pay for some or all of the costs of standard treatment in this study. 
Some health/insurance plans will not pay for costs of care when you take part in a research study.  
Check with your health plan or insurance company to find out if they’ll pay.   
You or your health plan/insurance will not be charged for optional research samples on this study. 
For questions about your costs, financial responsibilities, and/or medical insurance coverage for 
your transplant and this study, please contact [Center/Financial Counselor at phone #]. 
 
15. 
Ethical Review 
The ethical aspects of this research study have been reviewed and approved by the National Marrow 
Donor Program IRB. 


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16. 
 For More Information 
If you would like more information about this study, or if you have problems while you are 
participating in this study, you can contact the study doctor or staff.   
 
[Insert name and contact details] 
 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This web site will not include information that can identify you.  At most, the web 
site will include a summary of the results.  You can search this web site at any time.  
17. 
 Independent Contact 
If you wish to speak to someone not directly involved in the study, or if you have any complaints or 
questions about your rights as a research participant, you may contact:  
[Insert appropriate contact details] 
 
18. 
Mi-Immune Study Research Samples 
For the Mi-Immune study, we are collecting health information and extra blood, urine and stool 
samples from transplant patients. We want to understand if the microorganisms and proteins in 
your immune system can help us predict transplant outcomes.   
The protocol-defined studies include testing the microorganisms in your stool, the metabolism 
waste in your urine and the proteins found on your white blood cells in your blood.  Some of the 
samples will be stored for future research.   
You will be in the study for 2 years after your transplant.  This study will include 300 
participants.  
 
Here is what will happen: 
a.) We will collect blood, urine, and stool samples before and after transplant (see Table 4).  The 
collections will happen at your regular visits. Stool samples at Pre-Conditioning, Day 0, Day 
7, Day 14, Day 21, and Day 28 are mandatory.  Starting day 35 through day 77, then at day 98, 
180, 270, 1 year, and 2 years, the stool samples are optional.  Weekly urine sample collection 
for Pre-conditioning through Day 270, then at 1 year, and 2 years are ALL OPTIONAL.  
b.) The samples will be sent to the BMT CTN Repository for processing and storage. A 
repository is a place that protects, stores and sends out samples for approved research studies. 


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All research samples will be coded with a unique code.  The codes themselves do not contain 
information that could identify you, however, a link to this code does exist.  The link is 
stored at the Data and Coordinating Center for the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN DCC).  The staff at the Repository where your sample is being 
stored does not have a link to this code.  Your research samples will continue to be stored at 
the BMT CTN Repository until they are used up for approved research.  
c.) We will use your health information from the main study BMT CTN 1703 and CIBMTR but 
will collect additional data, such as infection and medication information.  
Samples stored in the Repository will be used mainly by doctors and researchers in the BMT 
CTN network. In the future, the unused blood samples and health information will be made 
available outside of this network.  Researchers can apply to study the health information and 
samples in the Repository. The BMT CTN Steering Committee and/or the BMT CTN Executive 
Committee must approve each request before they will share samples or information with 
researchers. This is to make sure that the investigators requesting the samples are qualified and 
that the research is of high quality. 
Your samples will be used only for research and will not be sold. The research done with your 
samples may help to develop new products in the future. You will not get paid for any samples 
or for any products that may be developed from current or future research. 
 
Risks Related to Research Samples 
The risk of injury is small.  If your blood samples are collected from your arm (instead of 
your central line), you may bleed a little bit and/or develop a small bruise. Infection from 
blood draws is rare, but may happen. If you are uncomfortable at the sight of blood, you may 
feel light-headed or faint.  
 
There are no major risks to collecting your urine or stool samples. A possible risk is the loss 
of confidentiality about your medical information. We will use safety measures with both 
your samples and health information to make sure that your personal information will be kept 
private. It’s very unlikely that your personal information will be given to someone else (see 
the Privacy, Confidentiality and Use of Information section below). 
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 28 of 34 
Table 4. Timeline for Collection of Research Samples  
Tests and 
Samples 
during Study 
Before 
conditioning 
Pre-Infusion 
Day -1 or 0  
 
Weekly,  
Day 
7-77 
Day 84 
Day 
98 
Day 
180 
Day 
270 
Day 
365 
Day 
730 
Blood samples  
X 
39ML  
(8 TSPS*) 
X 
24ML  
(5 TSPS) 
X 
31ML OR 39ML 
(6 OR 8 TSPS) 
X 
31ML  
(6 TSPS) 
X 
39ML  
(8 TSPS) 
X 
39ML  
(8 TSPS) 
X 
31ML  
(6 TSPS) 
X 
39ML  
(8 TSPS) 
X 
39ML  
(8 TSPS) 
Urine samples1 
X1 
10-12ML  
(3 TSPS) 
X1 
10-12ML  
(3 TSPS) 
X1 
10-12ML  
(3 TSPS)  
 
X1 
10-12ML  
(3 TSPS) 
X1 
10-12ML  
(3 TSPS) 
X1 
10-12ML  
(3 TSPS) 
X1 
10-12ML  
(3 TSPS) 
X1 
10-12ML  
(3 TSPS) 
Stool samples2 
X2 
10-12ML  
(3 TSPS) 
X2 
10-12ML  
(3 TSPS) 
 X2 
10-12ML  
(3 TSPS) 
 
X2 
10-12ML  
(3 TSPS) 
X2 
10-12ML  
(3 TSPS) 
X2 
10-12ML  
(3 TSPS) 
X2 
10-12ML  
(3 TSPS) 
X2 
10-12ML  
(3 TSPS) 
*TSPS = Teaspoons 
1 Weekly urine sample collection for Pre-conditioning through Day 270, then at 1 year, and 2 years are ALL OPTIONAL.   
2Stool samples at Pre-Conditioning, Day 0, Day 7, Day 14, Day 21, and Day 28 are mandatory.  Starting day 35 through day 77, then at day 98, 180, 270, 1 
year, and 2 years, the stool samples are optional.   
 
 
 
 
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 29 of 34 
Genome-Wide Association Studies: 
DNA from your stored blood samples might be used in genome-wide association (GWA) 
studies for a future project either done or supported by the National Institutes of Health 
(NIH).  Genome-wide association studies are a way for scientists to find genes that have a 
role in human disease or treatment. Each study can look at hundreds of thousands of genetic 
changes at the same time. 
 
If your coded samples are used in such a study, the researcher is required to add your test 
results and sample information into a public research database.  This public database is called 
the NIH Genotype and Phenotype Database and it is managed by the National Center for 
Biotechnology Information (NCBI).  The NCBI will never have any information that would 
identify you, or link you to your information or research samples, although the results of 
genetic studies could theoretically include identifying information about you.  
 
Genetic Information Nondiscrimination Act: 
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA), 
generally makes it illegal for health insurance companies, group health plans, and employers of 
15 or more persons to discriminate against you based on your genetic information.  Health 
insurance companies and group health plans may not request your genetic information that we 
get from this research.  This means that they must not use your genetic information when making 
decisions regarding insurability.  Be aware that this new federal law will not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
 
Things to Think About:  
• The choice to let us have blood/urine/stool samples for protocol-defined studies and 
stored for future research is up to you.  No matter what you decide to do, it will not affect 
your care.  
 
• If you decide now that your blood/urine/stool can be kept for research, you can change 
your mind at any time.  Just contact your study doctor and let him or her know that you 
do not want us to use your blood/urine/stool sample.  Then any blood/urine/stool that 
remains will no longer be used for research.  
 
• In the future, people who do research on these blood/urine/stool samples may need to 
know more about your health.  While the study doctor or others involved in running this 
study may give the researchers reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who 
you are.  


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 30 of 34 
• Sometimes blood/urine/stool is used for genetic research (about diseases that are passed on 
in families).  Even if your blood is used for this kind of research, the results will not be put 
in your health records.  
 
• Your blood/urine/stool will be used only for research and will not be sold.  The research 
done with your blood/urine/stool may help to develop new products in the future.  
 
• Reports about research done with your blood/urine/stool will not be given to you or your 
doctor.  These reports will not be put in your health record.  The research will not have an 
effect on your care.  
 
Benefits: 
The research that may be done with your blood/urine/stool is not designed specifically to help 
you.  The benefits of research using blood/urine/stool include learning more about what causes 
GVHD, cancer and other diseases, how to prevent them, and how to treat them.  
 
Risks: 
There is a small risk of an infection or fainting from the blood draw.  
 
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
 
The results of this study will be published, but your personal information (for examples, name 
and address) will remain confidential (private).  BMT CTN may also use the information from 
this study for future medical research.   
 
⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ 
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 31 of 34 
Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purposes 
 
A. Purpose 
 
As a research participant, I authorize the Principal Investigators and the researcher’s staff to use 
and disclose my individual health information for the purpose of conducting the research study:  
[List PI and research staff] 
 
B. Individual Health Information to be Used or Disclosed 
 
My individual health information that may be used or disclosed to do this research includes:  
▪ Demographic information (for example: date of birth, sex, weight).  
▪ Medical history (for example: diagnosis, complications with prior treatment). 
▪ Findings from physical exams. 
▪ Laboratory test results obtained at the time of work up and after transplant (for example: 
blood tests, biopsy results).  
 
C. Parties Who May Disclose My Individual Health Information 
 
The researcher and the researcher’s staff may collect my individual health information from: 
 
[List hospitals, clinics or providers from which health care information can be requested]. 
 
D. Parties Who May Receive or Use My Individual Health Information 
 
The individual health information disclosed by parties listed in item c and information disclosed 
by me during the course of the research may be received and used by the following parties: 
 
Principal Investigators and the researchers’ staff 
BMT CTN 1703: Drs. Javier Bolaños-Meade and Shernan Holtan, Co-Principal 
Investigators  
BMT CTN 1801: Drs. Ami Bhatt, Leslie Kean and Miguel Perales, Co-Principal 
Investigators 
 
Study Sponsors  
▪ National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH),  
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 32 of 34 
▪ Blood and Marrow Transplant Clinical Trials Network (BMT CTN), including the 
Center for International Blood and Marrow Transplant Research (CIBMTR), the 
National Marrow Donor Program (NMDP) and The Emmes Corporation, who are 
coordinating the studies of the BMT CTN   
▪ U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP) 
▪ U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state and local health 
departments 
▪ Data and Safety Monitoring Board (DSMB), not part of [Institution] 
▪ Institutional Review Boards (IRBs) responsible for this study 
 
E. Right to Refuse to Sign this Authorization 
 
I do not have to sign this authorization.  If I decide not to sign the authorization, I will not be 
allowed to participate in this study or receive any treatment related to research that is provided 
through the study.   
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
 
F. Right to Revoke 
 
I can change my mind and withdraw this authorization at any time by sending a written notice to 
the Principal Investigator to inform the researcher of my decision.  
If I withdraw this authorization, the researcher may only use and disclose the protected health 
information already collected for this research study.  No further health information about me 
will be collected by or disclosed to the researcher for this study. 
 
G. Potential for Re-disclosure 
 
My individual health information disclosed under this authorization may be subject to re-
disclosure outside the research study and no longer protected. 
Examples include: potential disclosures for law enforcement purposes, mandated reporting or 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 
 
H. This authorization does not have an expiration date. 
 
 
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 33 of 34 
TITLE: BMT CTN 1703: A Randomized, Multicenter, Phase III Trial of 
Tacrolimus/Methotrexate versus Post-Transplant Cyclophosphamide/Tacrolimus/Mycophenolate 
Mofetil in Non-Myeloablative/Reduced Intensity Conditioning Allogeneic Hematopoietic Cell 
Peripheral Blood Stem Cell Transplantation 
 
COMPANION STUDY: BMT CTN 1801: Microbiome and Immune Reconstitution in Cellular 
Therapies and Hematopoietic Stem Cell Transplantation (Mi-Immune)    
 
Principal Investigator(s) 
Name:  
 
 
 
 
 
Phone: 
Address: 
 
 
 
 
 
Fax: 
Email: 
 
▪ I have read and understood this Consent Form.  The nature and purpose of the research 
study has been explained to me. 
▪ I have had the chance to ask questions and understand the answers I have been given.  I 
understand that I may ask questions at any time during the study. 
▪ I freely agree to be a participant in the study. 
▪ I understand that I may not directly benefit from taking part in the study. 
▪ I understand that, while information gained during the study may be published, I will not 
be identified, and my personal results will stay confidential. 
▪ I have had the chance to discuss my participation in this research study with a family 
member or friend. 
▪ I understand that I can leave this study at any time, and doing so will not affect my 
current care or prevent me from receiving future treatment. 
▪ I understand that I will be given a copy of this signed Consent Form. 
▪ I understand that I will be participating in the Companion Study – Mi-Immune and that I 
will have blood, stool and urine samples collected.  
 
 


Blood and Marrow Transplant Clinical Trials Network   
PROGRESS III – PTCY vs. TAC/MTX - 1703 
 
 
Version 3.2 dated December 16, 2020 
 
 Template NMDP IRB Approved January 24, 2021 
IRB-2019-0400 
Page 34 of 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks.  I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Person Obtaining Consent  
 
 
Date 
 
 
 
 
 
 
 
 
                                                                
Signature of Person Obtaining Consent 
    
 
Date