Optimizing Haploidentical Aplastic Anemia Transplantation (CHAMP) (BMT CTN 1502)
Phase: PHASE2
Conditions: Severe Aplastic Anemia
Sponsor: Medical College of Wisconsin

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
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Optimizing Haploidentical Aplastic 
Anemia Transplantation (CHAMP) 
 
(Posted on ClinicalTrials.gov as NCT02918292) 
 
BMT CTN PROTOCOL 1502 
VERSION 4.0 
 
Study Chairpersons 
Amy E. DeZern, M.D., M.H.S.1 
Michael A. Pulsipher, M.D.2 
 
Protocol Team 
Joseph Antin, M.D. 3 
Robert Brodsky, M.D.1 
Lauri Burroughs, M.D.4 
H. Joachim Deeg, M.D. 4 
Nancy DiFronzo, Ph.D. 5 
Eric Leifer, Ph.D. 5 
Mary Eapen, M.D. 6,7 
Iris Gersten, M.S.8 
 
Alfred Gillio, M.D.9 
Mitchell Horwitz, M.D. 10 
Chatchada Karanes, M.D.11 
Brent Logan, Ph.D.7 
Julie Talano, M.D.7 
Alyssa Ramirez8 
Juan Wu, M.S.8 
 
 
 
 
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
1 Johns Hopkins 
2 University of Southern California, CHLA 
3 Dana Farber Cancer Institute 
4 Fred Hutchinson Cancer Research Center 
5 National Heart, Lung, and Blood Institute 
6 CIBMTR 
7 Medical College of Wisconsin 
8 Emmes 
9 Hackensack University 
10 Duke University 
11 City of Hope National Medical Center 
12 National Marrow Donor Program 
 

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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL #1502 
 
Optimizing Haploidentical Aplastic Anemia Transplantation (CHAMP) 
 
Study Chairpersons: 
Amy E. DeZern, M.D., M.H.S. and Michael A. Pulsipher, M.D. 
 
Primary Objective: 
Assess overall survival (OS) at 1 year post-hematopoietic stem cell 
transplantation (HSCT) from a haploidentical marrow donor in 
patients with severe aplastic anemia (SAA). 
 
Secondary Objectives: 
Assess the proportion of patients alive and engrafted; neutrophil 
and platelet recovery; graft failure (primary and secondary); grades 
II-IV acute GVHD and chronic GVHD; immune reconstitution; 
incidence of CMV viremia/disease and EBV viremia/post-
transplant lymphoproliferative disease (PTLD). 
 
Correlative Studies: 
ATG pharmacokinetic (PK) profile in transplant recipients; pre-
HSCT telomere length in all consenting patients and consenting 
haplo donors. 
 
Study Design: 
 
This study is a prospective, multicenter phase II study with patients 
receiving haploidentical transplantation for SAA. 
 
Accrual Objective:  
The goal is to transplant 30 patients on the protocol.  Additional 
patients may be screened, consented, and registered in order to 
reach accrual goals. 
 
Accrual Period: 
 
The estimated accrual period is 3 years. 
 
Eligibility Criteria: 
Diagnosis of SAA, without a fully matched related sibling donor 
available, but with a haplo marrow donor available.  Exclusions 
include inherited bone marrow failure syndrome, previous 
hematopoietic stem cell or solid organ transplant, uncontrolled 
infection, inadequate organ function, and performance score < 60. 
 
Treatment Description: 
Patients will be treated with a preparative regimen of fludarabine 
(150 mg/m2), cyclophosphamide (29 mg/kg, low dose TBI (200 
cGy), and Thymoglobulin® (4.5 mg/kg).  GVHD prophylaxis will 
be with post-HSCT cyclophosphamide (100 mg/kg), tacrolimus, 
and mycophenolate mofetil (MMF). 
 
Study Duration: 
 
Patients will be followed for 1 year post-transplant. 
 
Interim Analysis: 
            No formal interim analyses for efficacy or futility will be used. 
 

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Safety Monitoring: 
Graft failure and mortality are the key safety endpoints to be 
monitored on the study so that if rates significantly exceed pre-set 
thresholds, the NHLBI will be notified in order that the DSMB can 
be advised.  The rate of graft failure including both primary graft 
failure and secondary graft failure by Day 56 post-transplant and 
the rate of mortality by Day 115 post ATG preparation will be 
monitored using a truncated Sequential Probability Ratio Test 
(SPRT) based on a binomial test of proportions. The safety 
boundary for graft failure was developed from an SPRT 
contrasting 15% versus 35% graft failure rate and the safety 
boundary for mortality was developed from an SPRT contrasting 
10% versus 30% mortality rate. 
 
 
 
 
 

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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
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TABLE OF CONTENTS 
 
1 
BACKGROUND AND STUDY RATIONALE ............................................................... 1-1 
1.1 
Objectives ............................................................................................................... 1-1 
1.2 
Background ............................................................................................................ 1-1 
1.2.1 
The Current Role of HSCT in SAA ....................................................................... 1-1 
1.2.2 
Haplo Donor Transplants in SAA .......................................................................... 1-2 
1.2.3 
Evolving Role of ATG Exposure in HSCT ............................................................ 1-4 
1.2.4 
Summary ................................................................................................................ 1-7 
1.2.5 
Protocol History ..................................................................................................... 1-7 
2 
STUDY DESIGN ................................................................................................................ 2-1 
2.1 
Study Overview ...................................................................................................... 2-1 
2.2 
Hypotheses and Objectives .................................................................................... 2-1 
2.2.1 
Hypotheses ............................................................................................................. 2-1 
2.2.2 
Objectives ............................................................................................................... 2-1 
2.3 
Eligibility Criteria for Enrollment .......................................................................... 2-1 
2.3.1 
Patient Inclusion Criteria ........................................................................................ 2-1 
2.3.2 
Patient Exclusion Criteria ....................................................................................... 2-3 
2.4 
Donor Selection Criteria ......................................................................................... 2-4 
2.5 
Treatment Plan ....................................................................................................... 2-5 
2.5.1 
Conditioning and GVHD Prophylaxis ................................................................... 2-5 
2.5.2 
GVHD Treatment ................................................................................................... 2-7 
2.5.3 
Supportive Care ...................................................................................................... 2-7 
2.5.4 
Risks and Toxicities ............................................................................................... 2-9 
2.5.5 
Health Related Quality of Life (HR-QoL) Assessments ...................................... 2-12 
3 
STUDY ENDPOINTS AND DEFINITIONS................................................................... 3-1 
3.1 
Primary Endpoint ................................................................................................... 3-1 
3.1.1 
Overall Survival (OS) ............................................................................................. 3-1 
3.2 
Secondary Endpoints .............................................................................................. 3-1 
3.2.1 
Neutrophil Recovery .............................................................................................. 3-1 
3.2.2 
Platelet Recovery .................................................................................................... 3-1 
3.2.3 
Alive with Sustained Engraftment ......................................................................... 3-1 
3.2.4 
GVHD .................................................................................................................... 3-2 
3.2.5 
Immune Reconstitution .......................................................................................... 3-2 
3.2.6 
Infection ................................................................................................................. 3-2 

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3.2.7 
Health Related Quality of Life (HR-QoL) ............................................................. 3-2 
4 
PATIENT ENROLLMENT AND EVALUATION ........................................................ 4-1 
4.1 
Enrollment Procedures ........................................................................................... 4-1 
4.2 
Study Monitoring ................................................................................................... 4-1 
4.2.1 
Follow-up Schedule ................................................................................................ 4-1 
4.2.2 
Case Report Forms ................................................................................................. 4-2 
4.2.3 
Adverse Event Reporting ....................................................................................... 4-2 
4.2.4 
Patient Evaluations ................................................................................................. 4-4 
5 
STATISTICAL CONSIDERATIONS ............................................................................. 5-1 
5.1 
Study Overview ...................................................................................................... 5-1 
5.1.1 
Accrual ................................................................................................................... 5-1 
5.1.2 
Primary Endpoint ................................................................................................... 5-1 
5.2 
Sample Size Calculations ....................................................................................... 5-1 
5.3 
Interim Analysis and Pausing Guidelines .............................................................. 5-2 
5.3.1 Graft Failure by Day 56 Post Transplant .................................................................... 5-2 
5.4 
Demographic and Baseline Characteristics ............................................................ 5-4 
5.5 
Analysis Plan .......................................................................................................... 5-4 
5.5.1 
Analysis of the Primary Endpoint .......................................................................... 5-4 
5.5.2 
Analysis of Secondary Endpoints .......................................................................... 5-4 
 
LIST OF APPENDICES 
 
APPENDIX A:  HUMAN SUBJECTS 
APPENDIX B:  CONSENT FORMS 
APPENDIX C:  LABORATORY PROCEDURES 
APPENDIX D:  WEIGHT CALCULATIONS 
APPENDIX E:  CAMITTA CRITERIA FOR SAA 
APPENDIX F:  ABBREVIATIONS 
APPENDIX G: BONE MARROW HARVEST GUIDELINES 
APPENDIX H: GUIDANCE FOR MIXED CHIMERISM 
APPENDIX I: REFERENCES 

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CHAPTER 1 
1 
BACKGROUND AND STUDY RATIONALE 
1.1 
Objectives 
 
The primary objective of this phase II study is to assess overall survival in recipients of 
haploidentical (haplo) donor grafts at 1 year post-hematopoietic stem cell transplantation 
(HSCT) in patients with severe aplastic anemia (SAA). 
 
Secondary endpoints include assessment of overall survival, rejection free survival, neutrophil 
and platelet engraftment, graft failure, grade II-IV acute GVHD, chronic GVHD, immune 
reconstitution, and infectious complications.  Additional biological correlative studies include 
measurement of antithymocyte globulin (ATG) pharmacokinetics (PK) for correlation with 
engraftment, GVHD, immune reconstitution, and survival as well as measurement of telomere 
length for correlation with disease phenotype, engraftment, and survival. 
1.2 
Background 
1.2.1 The Current Role of HSCT in SAA 
 
Acquired SAA is a rare bone marrow failure disorder with an estimated annual incidence of 2 
cases per million and with over 600 new cases in the United States each year.1, 2  The majority of 
cases are thought to be related to autoimmune destruction of marrow microenvironment or 
hematopoietic stem cells; accordingly, the disease can be treated and often cured by either 
immune suppression or marrow replacement through transplantation.3  HSCT from a human 
leukocyte antigen (HLA) matched sibling donor (MSD) has become the standard of care for 
younger, newly diagnosed patients3, 4 with long-term survival rates close to 90% in patients 
under 20,5, 6 and around 76% for patients older than 20.6  However, if the patient has siblings, 
each of them only has a 25% chance of being a match based on HLA inheritance patterns.   
 
Horse ATG and cyclosporine (CSA) immunosuppressive therapy (IST) is generally front-line 
treatment for SAA patients who lack matched sibling donors or are not good candidates for 
HSCT.7  The hematopoietic response rate is 60-70%.2  However, up to 40% of patients 
eventually relapse8 and an additional 10-40% develop a secondary clonal disease.9  For those 
whose disease is primary refractory or who relapse within 4-6 months after IST, most groups 
recommend unrelated donor HSCT if an appropriately matched unrelated donor is available.10  
Up to half of patients who initially respond to IST subsequently recur and either require long-
term immune suppression or are refractory to subsequent courses of IST.  Unrelated donor HSCT 
can be considered as a reasonable alternative for SAA patients in these clinical scenarios. 
 
Recent improvements in survival after unrelated donor transplant for SAA have been noted using 
reduced doses of total body irradiation (TBI),11 the substitution of a portion of the 
cyclophosphamide dosing with fludarabine,12 and selecting donors who are better HLA-matched 
to patients.  These approaches have helped to lower graft failure, overall mortality, and graft 
versus host disease (GVHD).  Some studies suggest that outcomes using HSCT with a fully 
matched unrelated donor (MUD) are similar to HSCT using a MSD.13-17 Results of the BMT 

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CTN 0301 trial for unrelated donor HSCT in SAA shows that of the 4 cyclophosphamide dose 
levels tested, 50 and 100 mg/kg in combination with ATG, fludarabine, and TBI (200 cGy) lead 
to better outcomes than the 0 mg/kg or 150 mg/kg dose.12  Additionally, it is well-recognized that 
bone marrow (BM) is the preferred source of stem cells over peripheral blood stem cells (PBSC) 
in the unrelated donor setting, similar to MSD HSCT for SAA.18-20   
 
Unfortunately, fully matched unrelated donors (HLA-A, B, C, DRB1) from worldwide registries 
can be identified for about 80% of Caucasians and for much lower percentages of persons of 
other races and/or ethnicities.21 Outcomes using unrelated adult donors mismatched at a single 
HLA-locus (7/8 HLA-matched) have proven inferior to outcomes with fully matched unrelated 
donors (MUD), though allowing a single HLA-locus mismatched transplant greatly expands 
donor availability.21, 22 With a sizable population of SAA patients who could benefit from 
unrelated donor HSCT who do not have fully matched donors, the need for improved alternative 
donor approaches has been identified as a key priority by an international working group on 
SAA convened by the BMT CTN in 2010.23 
 
Registry data for alternative donor HSCT for SAA shows inadequate outcomes.  Unpublished 
data from the CIBMTR for transplants performed between 2009 and 2013 in the US are 
summarized in Table 1 and show overall survival for each type of alternative donor transplant 
utilized for patients with SAA.  The following sections will show more promising data 
associated with specific approaches to haplo HSCT that inform our proposal. 
 
Table 1: Overall Survival in SAA by Donor Source  
MUD BM 
1-year OS 
MUD PBSC 
1-year OS 
MMURD 
1-year OS 
UCB 
1-year OS 
Haplo* 
 
 
Number=260 
85% 
(95% CI 80-89%) 
 
Number=72 
72% 
(95% CI 61-82%) 
 
Number=121 
66% 
(95% CI 56-74%) 
 
Number=45 
58% 
(95% CI 43-72%) 
 
Number=19 
12 alive 
(12 of 19; 63%) 
MUD = matched unrelated donor, MMURD = mismatched unrelated donor, MMRD = mismatched 
related donor (1 HLA-locus), Haplo = Haplo, UCB = unrelated cord blood, BM = bone marrow, PBSC = 
peripheral blood stem cells, OS = overall survival (95% CI = 95% confidence interval) 
*Too few patients to calculate 1-year overall survival using the Kaplan-Meier estimator 
1.2.2 Haplo Donor Transplants in SAA 
 
The use of haplo donors for SAA transplantation has only more recently been attempted and 
accordingly there are only limited published data regarding outcomes with this approach. In 
small case series, rejection has been between 6% and 25%, acute GVHD between 12% and 30%, 
chronic GVHD between 20% and 40%, and overall survival between 62.5% and 84.6%.24-26   
 
We pooled newer, unpublished data from Brazil, Johns Hopkins, and the Fred Hutchinson 
Cancer Research Center using a reduced intensity regimen with post-transplant 
cyclophosphamide in 29 patients.  Results are promising and are shown below. All patients 
received a uniform conditioning regimen of TBI 200, fludarabine 150 mg/m2 and Cy 29 mg/kg.  
Ten patients received ATG.  Patients received Cy 100 mg/kg post-transplant in addition to 
methotrexate or calcineurin inhibitors for GVHD prophylaxis.  There were 4 graft failures and 6 

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deaths.  Twenty-three of 29 patients are alive with variable follow up: 10 patients were followed 
for less than 6 months after transplantation, 4 patients have been followed between 6 and 12 
months, and 9 patients have been followed for longer than 12 months.  
 
Table 2: Haplo Donor Transplants in SAA 
Patient # 
Conditioning 
Engraftment 
Last 
Follow-
Up 
Status 
1 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
36 
months 
Alive 
2 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
13 
months 
Alive 
3 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
18 
months 
Alive 
4 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
7 months 
Alive 
5 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
17 
months 
Alive 
6 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
3 months 
Alive 
7 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
44 
months 
Alive 
8 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
6 months 
Alive 
9 
Cy29/Flu150/TBI200 
Primary Graft 
Failure 
2 months 
Died 
10 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
28 
months 
Alive 
11 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
9 months 
Alive 
12 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
24 
months 
Alive 
13 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
17 
months 
Alive 
14 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
11 
months 
Died 
15 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
6 months 
Alive 
16 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
3 months 
Alive 
17 
Cy29/Flu150/TBI200 
Primary Graft 
Failure 
4 months 
Died 
18 
Cy29/Flu150/TBI200 
Primary Graft 
Failure 
1 month 
Alive 
19 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
3 months 
Died 

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20 
Cy29/Flu150/TBI200 
Primary Graft 
Failure 
1 month 
Died 
21 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
29 
months 
Alive 
22 
Cy29/Flu150/TBI200 
Yes,  
94% donor 
2 months 
Alive 
23 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
5 months 
Died 
24 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
3 months 
Alive 
25 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
1 month 
Alive 
26 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
2 months 
Alive 
27 
Cy29/Flu150/TBI200 
Yes,  
100% donor 
1 month 
Alive 
28 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
4 months 
Alive 
29 
Cy29/Flu150/TBI200/ATG 
Yes,  
100% donor 
3 months 
Alive 
 
Eight of the 29 patients received early low dose ATG (4.5mg/kg starting on Day -9). The eight 
patients had documented acquired disease and received grafts from 5/10 HLA-A, B, C, DR, DQ 
matched related donors.  Six had failed ATG-containing regimens previously and two had 
relapsed after high dose cyclophosphamide as IST. Two additional patients had inherited 
syndromes: one with Diamond Blackfan who received a graft from a 5/10 related donor and one 
with telomeres less than the first percentile in length with a presumed familial syndrome who 
received a 9/10 unrelated graft.  Median follow-up time is 17.5 months (range 5-49). The median 
age was 34 years (range 17-54) with 6 patients greater than age 30 years and 50% were males. 
Median time to neutrophil engraftment was 18 days (range 16-24).  Median time to red cell 
engraftment was 25 days (range 16-48). Median time to platelet engraftment was 27.5 days 
(range 22-108).  At the time of BMT, six patients had PNH clones and all were eliminated. All 
patients are alive and well, fully engrafted with 100% donor chimerism in blood and marrow. 
Two patients had grade I-II skin acute GVHD.  These two patients also had mild chronic GVHD 
of the skin/mouth requiring systemic steroids.  One patient was able to come off all 
immunosuppression by 15 months and the other by 17 months. Based on these results, early low 
dose ATG will be used in this protocol.2 
 
1.2.3 Evolving Role of ATG Exposure in HSCT 
 
ATG is commonly used in HSCT regimens to prevent graft failure and GVHD, especially for 
nonmalignant diseases.27-30  There are data to suggest that the rabbit preparation of ATG (rATG 
– Thymoglobulin®) results in improved outcomes compared to the horse preparation (hATG – 
Atgam®) when used in HSCT for SAA.  In a CIBMTR study presented in abstract form, grades 
II-IV acute GVHD at Day 100 were lower with rATG compared to hATG for unrelated donor 

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transplants.  This advantage was not seen for hematopoietic recovery, chronic GVHD, or overall 
survival.31 
 
We know a great deal about pharmacokinetics (PK) of medications in HSCT, such as busulfan, 
where doses are individualized based on levels.32  Less is known about the PK and 
pharmacodynamic interactions of ATG in the HSCT setting, which can be even more variable in 
children and adolescents.33  Some reports show that prolonged exposure may lead to delayed 
immune reconstitution and more infections, while short exposure may lead to limited protection 
against GVHD.34, 35  Recently, a population PK model has been created for the Thymoglobulin® 
preparation of ATG.  This model allows for individualized dosing that can achieve target area 
under the curve (AUC) ATG exposures pre- and post-HSCT.  Dosing is based upon body weight 
and absolute lymphocyte count measured just prior to starting the HSCT preparative regimen.33   
 
Recent publications have demonstrated a link between pre-HSCT and post-HSCT AUC of ATG 
and outcomes.  Admiraal and colleagues in the Netherlands demonstrated in 251 patients (mostly 
children, n = 116 malignant disease, n = 69 benign disease, n = 15 marrow failure, and n = 51 
immune deficiency) that when the post-HSCT AUC was < 20 AU*day/mL there was improved 
immune reconstitution as shown by recovery of CD4 counts (p < 0.0001 on logistic regression 
fitting).36   One hundred and eighteen patients received bone marrow grafts, 36 received 
peripheral blood, and 96 received cord blood.  Successful immune reconstitution was in turn 
associated with improved overall survival compared to unsuccessful immune reconstitution (56% 
vs. 75%, p < 0.001).  A low ATG post-HSCT AUC (< 20 AU*day/mL in UCB or < 50 
AU*day/mL in marrow) was itself associated with improved overall survival for patients with 
benign diseases receiving a cord blood graft (91% vs. 57%, p = 0.013) and for all patients that 
received matched bone marrow or PBSC graft (93% vs. 76%, p = 0.014) as seen in Figure 1.   
 
Figure 1: Overall Survival According to Post-HSCT Thymoglobulin® AUC 
 
 
With all stem cell sources included, the ATG post-HSCT AUC did not have an influence on 
GVHD.  When looking at cord blood transplants alone, with lower ATG post-HSCT AUC there 
was a higher rate of grades II-IV acute GVHD, but no difference in grades III-IV acute GVHD 

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and no difference in extensive chronic GVHD.  This increase in only grade II acute GVHD is 
balanced with the benefits of high ATG pre-HSCT exposure, which reduced grades II-IV acute 
GVHD (10% vs. 23%, p < 0.01), chronic GVHD (4% vs. 12%, p = 0.02), and graft failure (8% 
vs. 18%, p < 0.05) as shown in Figure 2.36 
 
Figure 2: GVHD and Graft Failure According to Pre-HSCT Thymoglobulin® AUC 
 
These results suggest that early and targeted ATG could improve outcomes in HSCT as depicted 
in Figure 3, although these data are primarily in children and with a limited population of SAA 
patients. Given that haplo donors have been a very small part of the data set to date and with the 
encouraging outcomes to date using a fixed ATG dose level of 4.5mg/kg in the Johns Hopkins 
single center experience, we will use a fixed ATG dosing in this haplo cohort study.  However, 
we will perform ATG PK testing on the haplo cohort as well to assess whether the pre- and post-
AUC levels achieved with fixed dosing correlate with outcomes.   
 
 
 
 
 
 
 
 
 
 

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Figure 3: Depiction of Thymoglobulin® Exposure and Impact on HSCT 
 
 
1.2.4 Summary 
 
In conclusion, a major challenge in treating acquired SAA is the management of patients who are 
refractory to IST or have relapsed after IST.  HSCT is the only curative option for these patients 
but many are ineligible because they lack a suitable donor.  Here we seek to increase options for 
these patients by using novel therapeutic strategies of GVHD prophylaxis with PTCY to expand 
the donor pool to include haploidentical donors.  We hypothesize that this approach will result in 
improved survival through reduction of transplant complications including graft failure and 
GVHD.  
 
1.2.5 Protocol History 
 
Version 1.0 of the protocol included a cord blood cohort in addition to the haploidentical cohort, 
and sites chose which cohort they would enroll their patients on. The intent was for these two 
cohorts to accrue in parallel and be evaluated separately.  Six months after accrual had begun, 
only a few sites expressed interest in the cord blood cohort and no cord blood patients had been 
enrolled. As a result, the cord blood cohort was removed from the protocol for Version 2.0, 
which was released on June 19, 2018.

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CHAPTER 2 
2 
STUDY DESIGN 
2.1 
Study Overview 
 
This study is a phase II study of haploidentical transplant to assess overall survival (OS) at one-
year post-HSCT in patients with SAA. 
2.2 
Hypotheses and Objectives 
2.2.1 Hypotheses 
 
Primary Hypothesis:  
 
Using the regimens described below, OS at one-year post-HSCT will be ≥ 75% in patients who 
receive a bone marrow transplant from a haplo donor for SAA. 
2.2.2 Objectives 
 
Primary Objective:  
 
Assess OS at one year post-HSCT in patients who receive haploidentical transplant for SAA. 
 
Secondary Objectives: 
 
1) Estimate the probability of being engrafted (i.e., without primary or secondary graft 
failure) and alive at 1-year post-HSCT.   
 
2) Estimate neutrophil recovery at Day 28 and Day 56 and platelet recovery at Day 100. 
 
3) Estimate the probability of primary or secondary graft failure at 1-year post-HSCT. 
 
4) Estimate grades II-IV and grade III-IV acute GVHD at Day 100 and chronic GVHD at 1-
year post-HSCT. 
 
5) Determine the pace and quality of immune reconstitution by measuring CD4, CD19, and 
CD56 counts pre-HSCT and at Day 91, Day 180, and Day 365 post-HSCT.  
 
6) Determine the rate of specific infectious complications (CMV viremia and disease, EBV 
viremia, and PTLD) within the first year after HSCT. 
2.3 
Eligibility Criteria for Enrollment 
2.3.1 Patient Inclusion Criteria  
1. Patient is < 75 years of age at time of enrollment. 
2. Confirmed diagnosis of SAA defined as:37 

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a. Bone marrow cellularity < 25% or marrow cellularity < 50% but with < 30% 
residual hematopoietic cells. 
b. Two out of three of the following (in peripheral blood):  
i. Neutrophils < 0.5 x109/L 
ii. Platelets < 20 x109/L 
iii. Reticulocyte count < 20 x109/L (< 60 x 109/L using an automated 
analysis) 
3. No suitable fully matched related sibling donor (6/6 match for HLA-A and B at 
intermediate or high resolution and DRB1 at high resolution using DNA-based typing) 
available. 
4. Failed at least one trial of immunosuppressive therapy (IST) by being refractory 
(persistence of severe cytopenias and fulfillment of SAA disease criteria at least 3 months 
after initial IST)41 or having relapsed (initial improvement of cytopenias after first-line 
IST but then a later return to fulfillment of SAA disease criteria when IST is decreased or 
ceased)41.  IST could have included ATG based regimens, calcineurin inhibitors and/or 
other higher dose therapy directed at the treatment of primary SAA. 
5. Available relative of the patient who is a haploidentical match, including biological 
parents, siblings or half siblings, children, uncles/aunts, first cousins, etc. Eligible 
haploidentical donors will have 2-4 mismatches if HLA-A, -B, -C, and -DRB1 typing is 
used; 2-5 mismatches if HLA-A, -B, -C, -DRB1, and -DQB1 typing is used; and 2-6 
mismatches if HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 typing is used. A 
unidirectional mismatch in either the graft versus host or host versus graft direction is 
considered a mismatch.  The donor and recipient must demonstrate that they are a full 
haplotype match by being identical at a minimum of one allele (at high resolution DNA-
based typing) at the following genetic loci: HLA-A, -B, -C, and DRB1 if 8 allele typing 
is used; HLA-A, -B, -C, -DRB1, and -DQB1 if 10 allele typing is used; and HLA-A, -B, -
C, -DRB1-, DQB1, and -DPB1 is 12 allele typing is used by the local center.  See Section 
2.4 for additional information.   
6. Patient and/or legal guardian must sign informed consent for HSCT.   
7. The haplo donor and/or legal guardian must be able to sign informed consent documents. 
8. The potential haplo donor must be willing and able to donate bone marrow. 
9. The weight of the haplo donor must be ≥ 20 kg. 
10. Adequate organ function defined as: 
a. Cardiac: Left ventricular ejection fraction (LVEF) at rest ≥ 40%.  For patients 
aged < 13 years, shortening fraction (SF) ≥ 26% by echocardiogram or MUGA 
may be substituted for LVEF. 
b. Hepatic: Total bilirubin < 3.0 x the upper limit of normal (ULN) for age (patients 
who have been diagnosed with Gilbert’s Disease are allowed to exceed this limit) 
and AST and ALT < 5.0 x ULN for age. 
c. Renal: 

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i. For patients > 13.0 years of age at the time of enrollment: estimated 
creatinine clearance > 50 mL/minute (using the Cockcroft-Gault formula1 
and actual body weight). Please refer to Body Weight calculations in 
Appendix E. 
ii. For patients < 13.0 years of age at enrollment: GFR estimated by the 
updated Schwartz formula2 ≥ 90 mL/min/1.73 m2.  If the estimated GFR is 
< 90 mL/min/1.73 m2, then renal function must be measured by 24-hour 
creatinine clearance or nuclear GFR, and must be > 50 mL/min/1.73 m2. 
d. Pulmonary: 
i. For patients > 13.0 years of age: DLCO (corrected/adjusted for 
hemoglobin) > 40% and FEV1 > 50% predicted (without administration 
of bronchodilator) and FVC > 50% predicted.   
ii. For patients < 13.0 years of age unable to perform PFTs due to age or 
developmental ability: (1) no evidence of dyspnea at rest and (2) no need 
for supplemental oxygen and (3) O2 saturation > 92% on room air at sea 
level (with lower levels allowed at higher elevations per established center 
standard of care (e.g., Utah, 4,200 feet above sea level, does not give 
supplemental oxygen unless below 90%)). 
11. Karnofsky or Lansky performance status ≥ 60%. 
12. Females and males of childbearing potential must agree to practice 2 effective methods of 
contraception at the same time or agree to abstinence.   
2.3.2 Patient Exclusion Criteria 
 
1. Inherited bone marrow failure syndromes such as Fanconi anemia must be ruled out 
according to center standards. 
2. Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-
MDS) or MDS on marrow examination (e.g. Monosomy 7). 
3. Diagnosis of myelodysplastic syndrome (MDS). 
4. Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a 
positive cross-match test of any titer by complement-dependent cytotoxicity or flow 
cytometric testing or the presence of anti-donor HLA antibody to the high expression loci 
HLA-A, B, C, DRB1, or DPB1 with mean fluorescence intensity (MFI) > 1000 by solid 
phase immunoassay). 
5. Prior allogeneic stem cell transplant. 
 
1 Cockcroft-Gault formula, based on ideal body weight (IBW): CrCl = (140 – age) x IBW (kg)   x   0.85 for females 
                                        
 
 
 
 
          PCr x 72 
2 Schwartz equation: CrCl (mL/min/1.73m2) = [length (cm) x k] / serum creatinine 
 
k = 0.45 for infants 1 to 52 weeks old 
 
k = 0.55 for children 1 to 13 years old 
 
k = 0.55 for adolescent females 13-18 years old 
 
k = 0.7 for adolescent males 13-18 years old 

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6. Prior solid organ transplant. 
7. Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® that would 
prohibit use for the patient as this study requires use of the Thymoglobulin® preparation 
of ATG. 
8. Uncontrolled bacterial, viral, or fungal infection at the time of enrollment.  Uncontrolled 
is defined as currently taking medication and with progression or no clinical 
improvement on adequate medical treatment. 
9. Seropositive for the human immunodeficiency virus (HIV). 
10. Active Hepatitis B or C determined by a detectable viral load of HBV or HCV. 
11. Female patients who are pregnant (per institutional practice) or breast-feeding. 
12. Prior malignancies except resected basal cell carcinoma 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 will not be allowed unless approved by 
the Protocol Chairs and/or Protocol Officer. 
13. Alemtuzumab or ATG within 2 weeks of enrollment. 
2.4 
Donor Selection Criteria 
1. Haplo donor selection is based on HLA typing and relationship to recipient (Section 
2.3.1).  
2. When more than one donor is available, the donor with the lowest number of HLA allele 
mismatches will be chosen unless there is HLA cross-match incompatibility or a medical 
reason to select otherwise.  In cases where there is more than one donor with the least 
degree of mismatch, donors will be selected based on the most favorable combination of 
HLA compatibility in cross-match testing and ABO compatibility.  Prioritization is given 
to the lowest number of mismatches in the host-versus-graft (HVG) direction to minimize 
the risk of graft failure.38 
3. If there is more than one donor with the least amount of HVG allele mismatches, the 
suggested prioritization in order of importance includes ABO compatibility, CMV status 
(use a sero-negative donor for a sero-negative recipient or use a sero-positive donor for a 
sero-positive recipient), younger age and lighter weight (this rule applies down to the age 
of 18, however, children may also be used as donors if appropriate), and sex of the donor 
(if all else is equal, males are preferred over nulliparous females over multiparous 
females).  

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2.5 
Treatment Plan 
2.5.1 Conditioning and GVHD Prophylaxis 
 
2.5.1.1 Conditioning for Haplo Bone Marrow Recipients 
2.5.1.1.1 Fludarabine 
Fludarabine dose will be 30 mg/m2 IV daily for 5 days from Day -6 to Day -2 (total dose 
received 150 mg/m2).   Fludarabine will be dosed on body surface area based upon the 
recipient’s actual body weight if the patient is < 125% of ideal body weight (IBW). For patients 
> 125% of IBW, fludarabine will be dosed on body surface area based upon the recipient’s 
adjusted ideal body weight (AIBW).  For patients who have an estimated or measured creatinine 
clearance < 70 mL/min/1.73 m2, or prior brain radiation, or prior intrathecal chemotherapy, the 
fludarabine dose should be reduced by 20%.  Fludarabine dosing is based on the last creatinine 
clearance prior to the start of conditioning. Fludarabine dose should be the same on Days -6 to -
2, even if the patient’s creatinine changes.   
2.5.1.1.2 Pre-HSCT Cyclophosphamide 
Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days from Day -6 to Day -5 and 
administered as a 1-2 hour infusion (total dose received 29 mg/kg). Cyclophosphamide dosing 
should be based on recipient’s total body weight (TBW) in all patients < 125% of IBW, and 
adjusted ideal body weight (AIBW) in all patients ≥ 125% of IBW as per Appendix E. 
Hydration, as well as doses and schedule for uroprotective agents (i.e., mesna), may be 
administered per institutional practice.  Mesna has generally been utilized for the Day +3 and 
Day +4 post-HSCT cyclophosphamide doses but not for the lower pre-HSCT doses. 
2.5.1.1.3 Total Body Irradiation 
TBI is to be delivered in a single dose of 200 cGy on Day -1.  TBI may be delivered from either 
linear accelerator or Cobalt sources (per institutional practice).  

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2.5.1.1.4 Thymoglobulin® 
Thymoglobulin® preparation of ATG will be dosed upon actual body weight. The dose will be 
0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours. 
Premedication should follow local institutional practice with suggested minimum of 1 mg/kg 
methylprednisolone in children and up to 100 mg in adults prior to the infusion (equivalent 
steroid allowed), preferably repeated in 3-4 hours during the infusion.  Note: Thymoglobulin® is 
the required preparation of ATG for this study. Patients will not be eligible if the treating 
center plans to use other preparations of ATG.   Pharmacokinetic corollary labs should be 
drawn as outlined in Appendix C. 
2.5.1.2 Haplo Marrow Product Handling & Infusion 
Patients will receive unprocessed marrow unless there is a major ABO incompatibility, in which 
case red blood cells will be depleted from the donor marrow using institutional practices.  
Institutional practices will determine if there will be processing for minor ABO incompatibilities.  
Donor bone marrow will be harvested with a target yield of 4 x108 nucleated cells per kilogram 
of recipient IBW, and a recommended minimum yield of 2.5 x108 nucleated cells per kilogram 
of recipient IBW.  It is recommended that no more than 10 mL per aspirate be taken.  In addition 
to calculating the total nucleated cell dose per kilogram, a sample of the product to be infused 
will be sent for flow cytometry to determine the content of CD34+ cells.  The use of 
cryopreserved marrow is not permitted. Please refer to Appendix G for additional bone marrow 
harvesting guidelines. 
The protocol team will begin implementing a review process in regards to bone marrow 
harvesting at participating sites. As a requirement for site activation, a copy of the site’s SOP for 
bone marrow harvest will be collected along with total nucleated cell dose/kilogram patient 
weight and product volume for the last 2 harvests performed at the site. This is to ensure that 
participating sites are experienced in bone marrow harvesting and the recommended TNC can be 
attained for all patients enrolled on 1502. 
Note: The patient is not to receive steroids as an antiemetic or any other 
immunosuppressive agent from Day 0 until at least 24 hours after completion of Day +4 
cyclophosphamide dose unless used for adrenal support or during medical emergency (e.g., 
treatment of anaphylaxis). In the event that a patient requires steroids, please notify the 
Emmes Protocol Coordinator. 
2.5.1.3 GVHD Prophylaxis for Haplo Recipients 
2.5.1.3.1 Post-HSCT Cyclophosphamide 
Cyclophosphamide 50 mg/kg IV daily will be given for 2 days, Days +3 to +4 (total dose 
received 100 mg/kg) after transplantation. Cyclophosphamide and mesna given post transplant 
will be dosed based on IBW, unless actual body weight is less than IBW, in which case use 
actual body weight.  If the patient weighs > 125% of IBW, cyclophosphamide will be dosed 
according to the adjusted IBW.  Hydration, as well as doses and schedule for uroprotective 
agents (i.e., mesna), should follow local institutional practice.  Mesna has generally been utilized 
for the Day +3 and Day +4 post-HSCT cyclophosphamide doses but not for the lower pre-HSCT 
doses.   
 

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Recommended Ideal Body Weight Calculation for Children Age 1-17 Years (who are less 
than 60 inches in height): 
IBW = ((Height in cm)2 x 1.65)/1000 
 
Recommended Ideal Body Weight Calculation for Adults Age > 18 Years: 
IBW (females) = (cm ÷ 2.54 – 60) x 2.3 kg + 45.5 kg 
IBW (males) = (cm ÷ 2.54 – 60) x 2.3 kg + 50 kg 
 
Dose Adjustment for Patients Weighing More Than 125% of IBW: 
Adjusted ideal body weight = IBW + 0.25(Actual weight – IBW)  
2.5.1.3.2 Tacrolimus  
Tacrolimus IV or PO should be started on Day +5 (24 hours after the end of the infusion of post-
HSCT cyclophosphamide) and administered per institutional standards to maintain a level of 10-
15 ng/mL.  The recommended IV starting dose is 0.03 mg/kg/day based on actual body weight 
with PO equivalent acceptable. May change to oral dosing once therapeutic levels are achieved 
or per institutional standards.  If tacrolimus is not tolerated, cyclosporine may be substituted IV 
or PO starting on Day +5 and administered per institutional standards to maintain a level of 200-
400 ng/mL by HPLC method or 250-500 ng/mL by TDX method.  Recommended starting doses 
range from 3-6 mg/kg/day IV bolus dosing q12 hours or 6 mg/kg/day PO divided BID.  The 
calcineurin inhibitor will be continued at therapeutic doses until at minimum Day +180 or longer 
per institutional preference.  If there is no evidence of GVHD, then taper as per institutional 
standard. 
2.5.1.3.3 MMF 
MMF dose will be 15 mg/kg PO TID up to 1 gm TID (or IV equivalent) starting on Day +5 (max 
dose 3000mg/day) and will be discontinued after the last dose on Day +35 or may continue if 
active GVHD is present. 
2.5.2.3.4 Growth factor  
G-CSF will be given IV or SQ starting on Day +5 for the haplo cohort at 5 mcg/kg/day (rounded 
to nearest vial size) until ANC is > 1500 for 3 days.  Additional G-CSF may be administered as 
warranted.  Pegfilgrastim (Neulasta®) and GM-CSF are not permitted. 
2.5.2 GVHD Treatment 
In the event of the development of either acute or chronic GVHD, therapy will be at the 
discretion of treating centers. 
2.5.3 Supportive Care 
2.5.3.1 Infectious disease prophylaxis 
Antifungal prophylaxis will be administered according to institutional practices.  It is important 
to follow levels of cyclosporine and tacrolimus for patients receiving one of the azole antifungal 
medications.  The combination of both drugs can raise the levels of the immunosuppressant to 
toxic levels.  If a patient on cyclosporine or tacrolimus is started on an azole antifungal 

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medication, a dose reduction of the cyclosporine or tacrolimus is required and levels should be 
obtained to ensure they are not in the toxic range. 
Pneumocystis jiroveci pneumonia (PJP) prophylaxis will be administered according to 
institutional practices.  Recommendations include starting approximately one month post-HSCT 
(or later if WBC not recovering) and continuing until at least three months off of all 
immunosuppressive medications. 
Viral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) will be 
administered according to institutional practices.  Recommendations include continuation for at 
least one year post-HSCT and while on immunosuppressive medications. 
Prophylactic and empiric antibiotics as well as intravenous immunoglobulin (IVIG) will be 
administered according to institutional practices.  Re-immunization may be performed according 
to institutional practices. 
2.5.3.2 Infectious disease monitoring 
CMV viremia as tested by DNA PCR will be monitored at minimum weekly after transplant 
until Day +100.  Patients who are viremic or show evidence of end organ CMV disease may be 
treated according to institutional practices. 
EBV viremia as tested by DNA PCR will be monitored at minimum weekly after transplant until 
Day +100.  If the patient becomes viremic with a DNA PCR level of 1000 copies/mL or higher 
on two consecutive occasions, the recommendation is to use Rituximab (375 mg/m2 IV x1) or 
treat according to institutional practice.  If the patient develops persistent EBV viremia or 
signs/symptoms of EBV-related post-transplant lymphoproliferative disease (PTLD) despite 
rituximab administration, treatment is recommended according to institutional practice. 
HHV-6 viremia as tested by DNA PCR is recommended to be monitored weekly until Day +60.  
If the patient becomes viremic they are treated according to institutional practices. 
In addition, all Grade 2 and 3 infections will be reported according to the BMT CTN MOP. 
2.5.3.3 Management of graft failure 
Patients experiencing primary or secondary graft failure are managed according to institutional 
practices. 
For this protocol, lineage-specific, myeloid and T cell chimerisms are required. Myeloid 
engraftment might not proceed at the same rate as T cell engraftment. If myeloid has greater than 
or equal to 5% donor, even if T cell compartment does not, this is not considered primary graft 
failure.  
In the event that Day 100 chimerism results at less than 50% donor in either myeloid or T cell 
compartment, additional chimerism testing of the same compartment should be performed every 
4 weeks or as clinically indicated until the chimerism is greater than or equal to 50% donor 
and/or stabilizes. 
Management of graft failure as defined in this protocol is per institutional standards. Fixed 
chimerism not defined as graft failure should be managed per Appendix H. 

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2.5.3.4 Management of ATG Intolerance 
Patients experiencing a new, severe, or life-threatening reaction to ATG and therefore unable or 
unwilling to receive the full planned cumulative dose will continue to be evaluated for the study, 
but their conditioning regimen may then be altered as per local institutional preference or 
practice with documentation of the deviation. 
2.5.4 Risks and Toxicities 
2.5.4.1 General 
The agents being used in the study are used extensively in the HSCT setting and have well-
defined toxicity profiles.  In addition, there are many expected toxicities of allogeneic HSCT.  
The following are examples of toxicities that are serious but not unexpected: Grade 4 cytopenias; 
neutropenic fever and sepsis; bacterial, fungal, or viral (including CMV, BK virus) infection; 
severe mucositis; severe GVHD; hepatic veno-occlusive disease; pulmonary toxicities; 
hemorrhagic cystitis; bleeding without hemodynamic compromise. 
2.5.4.2 Drug Information 
2.5.4.2.1 Fludarabine 
Fludarabine is a purine analog antimetabolite.  Side effects of fludarabine include: 
1) Neurotoxicity: Agitation or confusion, blurred vision, loss of hearing, peripheral 
neuropathy, or weakness have been reported.  Severe neurologic effects, including 
blindness, coma, and death may occur; severe CNS toxicity is rarely seen with doses in 
the recommended range for non-transplant therapy. The dose used in this study is 
approximately 1.5 times the usual one-course dose given in non-transplant settings.  
Doses and schedules similar to those used in this study have been used in adult and 
pediatric patients without observed increase in neurotoxicity. 
2) Anemia: Life-threatening and sometimes fatal autoimmune hemolytic anemia has been 
reported after one or more cycles of therapy in patients with or without a previous history 
of autoimmune hemolytic anemia or a positive Coombs’ test and who may or may not be 
in remission.  Corticosteroids may or may not be effective in controlling these episodes.  
The majority of patients re-challenged developed a recurrence of the hemolytic process. 
3) Cardiovascular: Deep venous thrombosis, phlebitis, transient ischemic attack, and 
aneurysm (1%) are reported.    
4) Fever: 60% develop fever. 
5) Rash: 15% develop a rash, which may be pruritic.  
6) Digestive: Gastrointestinal side effects include: nausea/vomiting (36%), diarrhea (15%), 
stomatitis (9%), anorexia (7%), GI bleeding and esophagitis (3%), mucositis (2%), liver 
failure, abnormal liver function test, constipation, dysphagia (1%) and mouth sores.  
7) Some other side effects include: Chills (11%), peripheral edema (8%), myalgias (4%), 
osteoporosis (2%), pancytopenia, arthralgias (1%), dysuria (4%), urinary tract infection 
and hematuria (2%); renal failure, abnormal renal function test, and proteinuria (1%); 
and, very rarely, hemorrhagic cystitis and pulmonary toxicity.  

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Dose adjustments of fludarabine are required for renal insufficiency (Sections 2.5.1 and 2.5.2). 
2.5.4.3 Cyclophosphamide & Mesna 
Cyclophosphamide is an alkylating agent whose metabolites form cross-links with DNA 
resulting in cell cycle-nonspecific inhibition of DNA synthesis and function.  Cyclophosphamide 
side effects include: nausea, vomiting, diarrhea, headache, dizziness, hemorrhagic cystitis, fluid 
weight gain/edema, SIADH, transaminitis, cardiomyopathy, pericarditis, rash, mucositis, 
alopecia, cytopenias, sterility, and, rarely, secondary myelodysplastic syndrome and anaphylaxis. 
Dose adjustments for cyclophosphamide will not be made. 
Mesna (sodium-2-mercapto ethane sulphonate) is a prophylactic agent used to prevent 
hemorrhagic cystitis induced by the oxasophosphorines (cyclophosphamide and ifosfamide).  It 
has no intrinsic cytotoxicity and no antagonistic effects on chemotherapy.  Mesna binds with 
acrolein, the urotoxic metabolite produced by the oxasophosphorines, to produce a non-toxic 
thioether and slows the rate of acrolein formation by combining with 4-hydroxy metabolites of 
oxasophosphorines. 
The total daily dose of mesna is equal to 80% of the total daily dose of cyclophosphamide. 
At the doses used for uroprotection, mesna is virtually non-toxic.  However, potential adverse 
effects include nausea and vomiting, diarrhea, abdominal pain, altered taste, rash, urticaria, 
headache, joint or limb pain, hypotension, and fatigue. 
2.5.4.4 Thymoglobulin® 
Thymoglobulin® is a rabbit preparation of anti-thymocyte globulin (ATG).  Common side effects 
include nausea, fever, chills, diarrhea, rash, dizziness, headache, and tiredness.  More serious 
side effects can include severe allergic reaction, serum sickness, easy bleeding/bruising, 
fast/irregular heartbeat, joint/muscle pain, stomach/abdominal pain, and weakness.  Because this 
drug works by weakening the immune system, it lowers the ability to fight infections, including 
some viral infections such as cytomegalovirus (CMV) Epstein Barr virus (EBV), and Human 
Herpes Virus 6 (HHV-6).  No dose adjustments are required. 
2.5.4.5 Mycophenolate Mofetil (MMF) 
MMF is an ester prodrug of the active immunosuppressant mycophenolic acid (MPA).  
Side effects include: pancytopenia, infection (including sepsis, CMV, HSV, VZV, and Candida), 
nausea, vomiting, diarrhea, allergic reactions, hypertension, headache, dizziness, insomnia, 
hyperglycemia, electrolyte imbalances, rash, and leg cramps/bone pain.  
Drug interactions: MMF activity is decreased with oral antacids and cholestyramine. There are 
no pharmacokinetic interactions with cotrimoxazole, oral contraceptives, or cyclosporine.  
Acyclovir or ganciclovir blood levels may increase due to competition for tubular secretion. 
High doses of salicylates or other highly protein-bound drugs may increase the free fraction of 
MPA and exaggerate the potential for myelosuppression. 
Dose adjustments: No dose adjustments are required for liver dysfunction.  For renal 
insufficiency, MMF dosing should not be modified unless dialysis is needed, in which case 
MMF can be reduced to 25-50% of the starting dose. If toxicity is suspected, a trough 
mycophenolic acid (MPA) level should be checked. If the level is greater than 2, it will require a 

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dose reduction. 
2.5.4.6 Cyclosporine (CSA):  
Cyclosporine (CSA) is a calcineurin inhibitor used for immunosuppression.  Administration may 
cause nephrotoxicity, seizures, tremors, headaches, abdominal pain or indigestion, edema, 
confusion, muscle cramps, dizziness, hemolytic anemia, hypertension, hirsutism, thrombotic 
microangiopathy, electrolyte imbalances, paresthesia/neuropathy, gingival hyperplasia, 
hypertriglyceridemia, diarrhea, transient blindness, renal dysfunction, and hepatic dysfunction. 
Drug interactions & Dose adjustments: CSA is adjusted to maintain a serum trough level of 200-
400 ng/mL by HPLC method or 250-500 ng/mL by TDX method.  Patients with hepatic or renal 
insufficiency should receive doses at the lower end of therapeutic concentrations.  No dose 
adjustments are required in patients undergoing hemodialysis.  There are interactions between 
the azole antifungal medications and CSA such that the dose of CSA should be empirically 
lowered when an azole medication is initiated and levels of CSA should be checked to ensure it 
remains in the proper therapeutic window. 
2.5.4.7 Tacrolimus 
Tacrolimus is a macrolide immunosuppressant that inhibits lymphocytes through calcineurin 
inhibition.   
Toxicities: There is a spectrum of well-described toxicities of tacrolimus. Toxicities include 
renal insufficiency, hypertension, hyperglycemia, hypomagnesemia, hypokalemia, nausea, 
diarrhea, headache, neurologic toxicity including tremor and leukoencephalopathy, infection, and 
rarely thrombotic thrombocytopenic purpura (TTP). 
Drug interactions: Tacrolimus is well-absorbed orally.  Tacrolimus is extensively metabolized by 
the cytochrome P-450 (CYP3A4) system and metabolized products are excreted in the urine.  
Drugs that may increase tacrolimus levels include tri-azole drugs (especially voriconazole, 
isavuconazonium sulfate, and posaconazole), nephrotoxic drugs, calcium channel blockers, 
cimetidine and omeprazole, metoclopramide, macrolide antibiotics, quinupristin/dalfopristin, 
danazol, ethinyl estradiol, methylprednisolone, and HIV protease inhibitors.  Drugs that may 
decrease tacrolimus levels include some anticonvulsants (phenobarbital, phenytoin, 
carbamazepine), caspofungin, rifamycins, and St. John’s wort.   
Dose adjustments: The tacrolimus dose is adjusted to maintain a serum trough level of 5-15 
ng/mL, with a target of 10-15 ng/mL.  Patients with hepatic or renal insufficiency should receive 
doses at the lower end of concentrations (5-10ng/mL).  No dose adjustments are required in 
patients undergoing hemodialysis. 
Due to extreme interactions with voriconazole and posaconazole, the tacrolimus dose 
should be empirically lowered when these azoles are initiated at steady state levels of 
tacrolimus.  Guidelines are provided in the table below.  Dose adjustments for therapy with 
other azoles may be indicated.  However, the initial tacrolimus dose (on Day 5) remains fixed.  
Dosing considerations with concurrent azole therapy: Triazole antifungal medications are 
expected to increase serum CNI levels; therefore, dosages of CNIs should be adjusted 
accordingly. Guidelines are provided in the table below.  Of note, reversal of azole-mediated 
inhibition of CYP3A4 (and others) and P-glycoprotein is gradual when azoles are stopped.  
Therefore, immediate significant dose increases in tacrolimus are not advised when azoles are 

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stopped. Rather, tacrolimus dose increases should be cautious and based on more frequent 
monitoring of levels as appropriate. 
Table 2.1: Suggested preemptive dose reduction of tacrolimus when azoles are initiated at 
steady state levels of tacrolimus 
Antifungal 
Tacrolimus 
 
Dose ↓ 
Comment 
Voriconazole  
67% 
Strongly advised 
Posaconazole 
67% 
Advised 
Itraconazole 
50% 
Advised 
Fluconazole 
25% 
Consider 
2.5.4.8 Filgrastim (G-CSF) 
Administration of G-CSF can cause bone pain, increased levels of liver enzymes and uric acid in 
the blood, thrombocytopenia, headaches, fatigue, local irritation at injection site, nausea, 
bleeding, fever, allergic reaction, splenomegaly or rupture of the spleen, worsening of pre-
existing skin rashes, temporary hair loss, and inflammation of a blood vessel in the skin. 
2.5.4.9 Total Body Irradiation 
TBI can cause nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, usually 
self-limited), generalized mild erythema (usually within 24 hours, resolving in 48-72 hours), 
hyperpigmentation, fever, mucositis, alopecia, and pancytopenia. Late effects include: cataracts 
(10-20%), hypothyroidism, nephropathy, interstitial pneumonitis, veno-occlusive disease, 
carcinogenesis, and sterility.  
2.5.4.10 
Toxicity Grading 
Toxicities are graded using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
2.5.5 Health Related Quality of Life (HR-QoL) Assessments 
2.5.5.1 Instruments 
MOS SF-36: The Medical Outcomes Study Short Form 36 is a 36-item general assessment of 
HR-QoL with eight components: Physical Functioning, Role Physical, Pain Index, General 
Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index.  
Each domain is positively scored, indicating that higher scores are associated with positive 
outcome.  This scale has been widely applied in a variety of outcome studies and is being used in 
this protocol as a generic measure of HR-QoL.  To facilitate comparison of the results with 
published norms, the Physical Component Summary (PCS) and Mental Component Summary 
(MCS) will be used as the outcome measures in summarizing the SF-36 data.  These summary 
scores are derived by multiplying the z-score for each scale by its respective physical or mental 
factor score coefficient and summing the products.  Resulting scores are then transformed into T-
scores (mean = 50; standard deviation = 10).  The SF-36 takes 6 minutes to complete.  

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PedsQL: The PedsQLTM Stem Cell Transplant Module is a 46-item instrument that measures 
HR-QoL in children and adolescents undergoing hematopoietic stem cell transplant, and is 
developmentally appropriate for self-report in ages 8 through 18 years. 
2.5.5.2 Administration 
The self-report questionnaires will be completed at Baseline, then at Day 100, Day 180, and Day 
365 post-transplant or until death.  Only English- and Spanish-speaking adult patients and 
English-speaking pediatric patients are eligible to participate in the HR-QoL component of this 
trial.  Patients >18 years will complete the MOS SF-36.  Patients 8 years through 18 years will 
complete the PedsQLTM Stem Cell Transplant Module.  Surveys are completed by participants 
using self-completed instruments as a first choice.  If this method of data collection is not 
possible, then surveys and response options may be read verbatim to participants, either in 
person or over the phone, to collect data.  The method of survey completion, the date, and the 
language will be recorded in the database.  Surveys may not be completed by surrogates.   
Table 2.2 – Required Patient-Reported Outcomes Data Collection 
Instrument 
Number of Items 
Baseline 
Day 100 
Day 180 
Day 365 
MOS SF-36 
36 
X 
X 
X 
X 
PedsQLTM SCT Module 
46 
X 
X 
X 
X 
 

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CHAPTER 3 
3 
STUDY ENDPOINTS AND DEFINITIONS 
3.1 
Primary Endpoint 
3.1.1 Overall Survival (OS) 
The primary endpoint is overall survival (OS) at 1 year post-HSCT in patients with SAA.  OS is 
defined as the time interval from date of transplant to death or to last follow-up, whichever 
occurs first. 
3.2 
Secondary Endpoints 
3.2.1 Neutrophil Recovery 
Neutrophil recovery is achieving an ANC > 0.5 x109/L for three consecutive measurements on 
different days, with the first of the three days being defined as the day of neutrophil engraftment. 
3.2.2 Platelet Recovery 
Platelet recovery is defined by achieving a platelet count > 20 x 109/L with no platelet 
transfusions in the preceding seven days.  The first day of the sustained platelet count will be 
defined as the day of platelet engraftment. 
3.2.3 Alive with Sustained Engraftment 
Being alive and engrafted is defined as not having experienced death, primary graft failure, or 
secondary graft failure.  
Donor cell engraftment is defined as donor chimerism greater than or equal to 5% on or after 
Day 56 after transplantation. Chimerism may be evaluated in whole blood or blood cell fractions, 
including CD3 and CD33 or CD15 fractions. For this protocol, lineage-specific, myeloid, and T 
cell chimerisms are required. 
3.2.3.1 Primary Graft Failure 
Primary graft failure is defined by the lack of neutrophil engraftment by Day +56 post-HSCT or 
failure to achieve at least 5% donor chimerism (whole blood or marrow) on any measurement up 
to and including Day +56.   
For this protocol, lineage-specific, myeloid, and T cell chimerisms are required. Myeloid 
engraftment might not proceed at the same rate as T cell engraftment. If myeloid has greater than 
or equal to 5% donor, even if T cell compartment does not, this is not considered primary graft 
failure.  
3.2.3.2 Secondary Graft Failure 
Secondary graft failure is defined as any one of the following:  
1. Initial neutrophil engraftment (ANC greater than or equal to 0.5 x109/L measured for 
three consecutive measurements on different days) followed by sustained subsequent 

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decline in ANC to less than 0.5 x 109/L for three consecutive measurements on different 
days; 
2. Initial whole blood or marrow donor chimerism greater than or equal to 5%, but then 
declining to less than 5% on subsequent measurements; 
3. Second infusion/transplant given for graft failure. 
3.2.3.3 Alive with Autologous Recovery 
Autologous recovery is defined as ANC > 0.5 x 109/L and transfusion independence but with < 
5% donor chimerism (whole blood or marrow).  
3.2.4 GVHD 
Acute and chronic GVHD are graded according to the BMT CTN Manual of Procedures (MOP). 
3.2.5 Immune Reconstitution 
Quantitative assessments of peripheral blood CD4, CD19, and CD56 positive lymphocytes will 
be done through flow cytometric analysis at baseline, Day 100, Day 180, and Day 365 post-
transplant.   
3.2.6 Infection 
All Grade 2 and 3 infections will be reported according to the BMT CTN MOP.  CMV viremia 
and disease, EBV viremia, HHV-6, and PTLD will be collected as per section 2.5.4.2. 
3.2.7 Health Related Quality of Life (HR-QoL) 
HR-QoL will be measured at Baseline and then at Day 100, Day 180, and Day 365 post-
transplant using two instruments: the MOS SF-36 for adult patients (> 18 years), and the 
PedsQLTM Stem Cell Transplant Module for pediatric patients (8 years through 18 years).  The 
instruments will be scored according to the recommendations of the developers.  See Section 
2.5.6 for detailed descriptions of the instruments.  The SF-36 will be summarized by the Physical 
Component Summary (PCS) and Mental Component Summary (MCS).  HR-QoL will be 
described for each treatment arm over time.  Only adult patients able to read and speak in 
English or Spanish and pediatric patients able to read and speak in English are eligible to 
participate in the HR-QoL component of this trial.  
 
 

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CHAPTER 4 
4 
PATIENT ENROLLMENT AND EVALUATION 
4.1 
Enrollment Procedures 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCTM).  The following procedures should be followed: 
1. Prior to initiation of the conditioning regimen, an authorized user at the transplant center 
completes the Demographics Form and Segment 0 Enrollment Form in AdvantageEDC, 
at which point a study number will be generated. After patient is enrolled on Segment 0, 
the authorized user should complete the HLA Forms to verify an eligible HLA match 
score. This eligibility screening includes a question confirming that the patient (or legally 
authorized representative) signed informed consent.  The eligibility screening also 
includes a question confirming that the donor (or legal guardian) signed informed 
consent, agrees to provide marrow, and weighs at least 20 kg. 
2. After filling out the HLA Forms, the authorized user will be able to enroll the patient on 
Segment A using the Segment A Enrollment Form. The patient is not officially enrolled 
on study and may not begin study treatment until they are enrolled on Segment A.   
3. A visit schedule based on transplant date is displayed for printing and is referred to as 
“Segment A Follow-up”. 
4.2 
Study Monitoring 
4.2.1 Follow-up Schedule 
The follow-up schedule for study visits is outlined in Table 4.2.1.  A detailed description of each 
of the forms and the procedures required for forms completion and submission can be found in 
the BMT CTN 1502 Forms Guide. 
 
Table 4.2.1: Follow-Up Schedule 
Study Visit 
Target Day Post-
Transplant 
1 week 
7 ± 3 days 
2 week 
14 ± 3 days 
3 week 
21 ± 3 days 
4 week 
28 ± 3 days 
5 week 
35 ± 3 days 
6 week 
42 ± 3 days 
7 week 
49 ± 3 days 
8 week 
56 ± 3 days 
9 week 
63 ± 3 days 
10 week 
70 ± 3 days 
11 week 
77 ± 3 days 

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12 week 
84 ± 3 days 
13 week 
91 ± 3 days 
100 day 
100 ± 3 days 
6 month 
180 ± 28 days 
12 month 
365 ± 45 days 
4.2.2 Case Report Forms 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Forms Guide.  Forms that are not entered into AdvantageEDCTM within the 
specified time will be considered delinquent.  A missing form will continue to be requested 
either until the form is entered into AdvantageEDC TM and integrated into the Data Coordinating 
Center’s (DCC) master database, or until an exception is granted and entered into the Missing 
Form Exception File, as detailed in the Forms Guide. 
Reporting Patient Deaths: Recipient death information must be entered into AdvantageEDC TM 
within 24 business hours of knowledge of the patient’s death.  If the cause of death is unknown 
at that time, it does not need to be recorded at that time.  However, once the cause of death is 
determined, the Death Form must be updated in AdvantageEDC TM. 
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 on BMT CTN #1502 must be 
indicated on the SCTOD pre-transplant registration form.  Additionally, CIBMTR pre- and post-
transplant 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.  Patients not undergoing HCT are not required to have their information reported to 
the CIBMTR. 
Weekly GVHD Monitoring:  GVHD should be monitored in accordance with BMT CTN 
guidelines as specified in the Manual of Procedures.  Patients should be assessed weekly until 
Day +100 post-transplant for GVHD.  After Day +100, patients will be assessed at each follow-
up visit through 12 months for the presence of GVHD.  For scheduling, a target day range has 
been provided in Table 4.2.1. 
4.2.3 Adverse Event Reporting 
4.2.3.1 Definitions 
Adverse Event: An adverse event (AE) is any undesirable sign, symptom or medical condition 
or experience that develops or worsens in severity after starting the first dose of study treatment 
or any procedure specified in the protocol, even if the event is not considered to be related to the 
study.   
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 

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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 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 subject 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. 
4.2.3.2 Required Adverse Event Reporting 
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 AdvantageEDC.  Unexpected, life-

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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 AdvantageEDC will be reported using NCI’s Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0.  Expected AEs will be reported using NCI’s Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on 
the Form Submission Schedule. Any expected life-threatening SAE not collected on another 
study form must be reported through the expedited AE reporting system via AdvantageEDC. 
The Data and Safety Monitoring Board will receive summary reports of all unexpected SAEs on 
a semi-annual basis. 
4.2.4 Patient Evaluations 
Table 4.2.4 summarizes patient clinical assessments over the course of the study. 
4.2.4.1 Pre-transplant evaluations 
The following observations must be performed within 30 days prior to enrollment (unless noted 
otherwise): 
1. History, physical examination, height, and weight (weight within 7 days prior to planned 
ATG infusion to ascertain ATG dosing). 
2. Karnofsky or Lansky performance status. 
3. Hematopoietic cell transplantation- comorbidity index (HCT-CI) 
4. CBC with differential and platelet count and chemistries (creatinine, bilirubin, alkaline 
phosphatase, AST, ALT, ferritin).  Please note that the absolute lymphocyte count is 
required within 7 days prior to planned ATG infusion to ascertain ATG dosing for UCB 
transplant recipients. 
5. HLA typing (patient and donor) and anti-donor antibody testing (if not already 
performed). HLA typing may be done more than 30 days prior to enrollment. 
6. Infectious disease titer for human immunodeficiency virus (HIV) by local standard of 
care. 
7. Hepatitis B and C determined by serology and/or NAT. 
8. LVEF or, for patients aged < 13.0 years, shortening fraction measurement by 
echocardiogram or MUGA. 
9. Pulmonary function testing: FEV1, FVC, and DLCO (corrected for Hb).  For patients 
aged < 13.0 years and patients unable to perform PFTs due to age or developmental 
ability, pulse oximetry is an acceptable alternative. 
10. Bone marrow aspirate/biopsy with cytogenetics within 60 days prior to enrollment. 
11. Diepoxybutane (DEB) testing on peripheral blood or comparable testing on marrow for 
Fanconi Anemia (at any time prior to enrollment). 
12. Pregnancy test for females of childbearing potential (testing per institutional practice).  
13. Study-required blood samples as described in Appendix C (all patients):  
a. Thymoglobulin pharmacokinetics (5 time points, 5 mL each time):  

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i. Upon completion of 1st dose of ATG (within 60 minutes) 
ii. Prior to infusion of 2nd dose (within 60 minutes) 
iii. Upon completion of 2nd dose of ATG (within 60 minutes) 
iv. Upon completion of 3rd dose of ATG (within 60 minutes) 
v. Day 0 (any time prior to infusion of graft) 
CBC including absolute lymphocyte count should also be collected 
on Day 0 (if possible) along with this PK sample and results 
documented in AdvantageEDC; the timing of the sample (d-m-y 
hh:mm) should also be documented 
14. Optional blood samples as described in Appendix C: 
a. Telomere length assay (all patients and haplo donors; collected pre-conditioning 
for patients, pre-donation for donors) 
i. Children < 20 kg: 12 mL in EDTA tubes 
ii. Adults: 24 mL in EDTA tubes 
b. Future research (all patients): 3mL whole blood prior to conditioning 
15. Absolute lymphocyte numbers by flow cytometry for lymphocyte subpopulations to 
include CD4, CD19, and CD56. 
16. Serum quantification of IgG, IgM, and IgA.  
17. Baseline peripheral blood samples for chimerism analysis by molecular methods (patient 
and donor). 
18. Health Related Quality of Life (HR-QoL): Patient ‘self-reported’ assessments to include 
the Medical Outcomes Study Short Form 36 (MOS SF-36) for English and Spanish 
speaking adult patients (> 18 years).  English-speaking pediatric patients (ages 8 through 
18 years) will complete the PedsQLTM Stem Cell Transplant Module.  
4.2.4.2 Post-transplant evaluations 
1. History and physical exam to assess GVHD and other morbidities weekly until Day 
+100, then at Day +180 and Day +365.  GVHD evaluation and grading to be in keeping 
with the BMT CTN MOP.  Chronic GVHD Provider Survey to be completed by an MD, 
NP, or PA at the time of patient assessment. For scheduling purposes, a target day range 
has been provided in Table 4.2.1. 
2. Karnofsky or Lansky performance status at Day +365. 
3. CBC at least three times a week (or as per institution’s standard practice) from Day 0 
until ANC > 0.5 x 109/L for 3 consecutive measurements over 3 or more days.  
Thereafter, CBC at least twice per week (or as per institution’s standard practice) until 
Day +28, then weekly until Day +100, then at Day +180 and Day +365. 
4. Chemistries (creatinine, bilirubin, alkaline phosphatase, AST, ALT) twice a week until 
Day +28 and then weekly until Day +100, then at Day +180 and Day +365 (or as per 
institution’s standard practice).  Cyclosporine or tacrolimus levels will be measured at 

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least once weekly until Day +100, and then at each follow-up visit until the drug is 
tapered off (or as per institution’s standard practice). 
5. Toxicity assessments at Day +28, +56, +100, +180, and +365. 
6. Absolute lymphocyte numbers by flow cytometry for lymphocyte subpopulations to 
include at minimum CD4, CD19, and CD56 at Day +100, +180, and +365. 
7. Serum quantification of IgG, IgM, and IgA at Day +365. 
8. Quantification of peripheral blood (whole blood and CD3) or marrow chimerism 
(including lineage-specific, myeloid, and T cell chimerisms) at Day +28, Day +56, Day 
+100, Day +180, and Day +365.  In the event that Day 100 chimerism results at less 
than 50% donor in either myeloid or T cell compartment, additional chimerism 
testing of the same compartment should be performed every 4 weeks or as clinically 
indicated until the chimerism is greater than or equal to 50% donor and/or 
stabilizes.  
9. EBV DNA quantitative PCR testing and CMV DNA quantitative PCR testing on 
peripheral blood at least weekly until Day +100 and then per institutional practice.  It is 
recommended to continue weekly or every other week until the patient is off of all 
immunosuppression. 
10. Study-required blood samples as described in Appendix C (all patients): 
a. Thymoglobulin pharmacokinetics (1 time point, 5 mL): 
i. Day +7 (no time restrictions) 
11. Health Related Quality of Life (HR-QoL): Patient ‘self-reported’ assessments at Day 
+100, Day +180, and Day +365 post-transplant to include the Medical Outcomes Study 
Short Form 36 (MOS SF-36) for English- and Spanish-speaking adult patients (> 18 
years).  English-speaking pediatric patients (ages 8 through 18 years) will complete the 
PedsQLTM Stem Cell Transplant Module.  

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Table 4.2.4: Summary of Assessments 
 
Study Assessments / Testing 
Baseline 
(Pre-
conditioning) 
 
 
 
 
 
 
 
 
During 
conditi-
oning 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
100 
180 
365 
History, Physical Exam, Weight, and Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky/Lansky Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
HLA Typing & Anti-Donor Antibody Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious Disease Titers3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LVEF or Shortening Fraction for < 13 years 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Tests4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate for Pathology and 
Cytogenetics5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Testing for Fanconi Anemia6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (females only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study-required Blood Samples7 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Blood Samples8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4, CD19, and CD56 Counts 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Serum Quantification of IgG, IgM, and IgA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Peripheral Blood Chimerism9 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
CMV & EBV DNA Quantitative PCR Testing10 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Toxicity Assessments 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Acute GVHD 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chronic GVHD (including Provider surveys)11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Comprehensive CIBMTR Forms & HR-QoL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
1  
CBC performed three times weekly from Day 0 until ANC > 0.5 x 109/L for three consecutive measurements on different days.  CBC then performed twice per week until Day +28, then weekly until Day +100, then 
at Day +180 and Day +365. CBC including absolute lymphocyte count should be collected on Day 0 along with the PK sample (if possible). 
2  
Blood chemistries include: creatinine, bilirubin, alkaline phosphatase, AST, ALT, Ferritin (baseline only) and cyclosporine or tacrolimus level.  Cyclosporine or tacrolimus levels will be measured at least once 
weekly until Day +100 and then at each follow-up visit until tapered off.  Blood chemistries performed twice weekly until Day +28 and then weekly until Day +100, then at Day +180 and Day +365.  
3  
Infectious disease titers include: hepatitis panel (HepB SAb, HepB SAg, HepB Core Ab, HepC Ab) and HIV. 
4 
DLCO (corrected for Hb), FEV1, and FVC or pulse oximetry for patients aged < 13.0 years if unable to perform standard PFT. 
5  
Bone marrow aspirate and biopsy (cytogenetics is required, local MDS panel recommended) within 60 days prior to enrollment. 
6 
Results of Diepoxybutane (DEB) testing on peripheral blood or comparable testing on marrow for Fanconi anemia at any time prior to enrollment. 
7 
Study-required blood draws include 6 samples for Thymoglobulin® pharmacokinetics in all patients (4 samples during ATG dose days, 1 sample on Day 0, and 1 sample on Day +7). 
8 
Optional blood draws include a baseline sample for telomere length assay collected from all consenting patients pre-conditioning and consenting haplo donors pre-donation as well as 1 sample for future 
research collected from all consenting patients pre-conditioning. 
9 
Chimerism to be measured by standard molecular testing of a peripheral blood (whole blood and CD3) sample or marrow chimerism (including lineage-specific, myeloid, and T cell chimerisms). 
10 
EBV and CMV monitoring is required weekly until Day +100, and then per institutional practices. It is recommended to continue monitoring weekly or every other week until off all immunosuppression. 
11    Chronic GVHD Provider Survey to be completed by an MD, NP, or PA at the time of patient assessment.

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CHAPTER 5 
5 
STATISTICAL CONSIDERATIONS 
5.1 
 Study Overview 
This study is designed as a multi-center, Phase II trial to assess the safety and efficacy of HSCT 
using haploidentical bone marrow with Thymoglobulin® (ATG)-containing preparative regimens 
in patients with severe aplastic anemia.  The target enrollment is to get 30 transplanted patients.   
5.1.1  Accrual 
It is estimated that 36 months of accrual will be necessary to enroll the targeted sample size.  
5.1.2  Primary Endpoint 
The primary objective is to assess overall survival probability at one year post-transplant.  Death 
from any cause is the event for this endpoint.  The time to event is time from transplant to death 
or last follow-up, whichever occurs first. 
5.2 
Sample Size Calculations 
The sample size for this study is 30 patients. Overall survival probability will be estimated.  
Ninety-five percent confidence intervals were calculated for varying probabilities based on a 
sample size of 30.  Table 5.2 provides confidence intervals for a variety of underlying 
proportions.  Of particular interest is where the OS probability is 75%, which is our targeted one-
year survival probability.  For this setting, the confidence interval length is 31% with the lower 
limit of 59.5%, which is above previous estimates.  As presented in the background, CIBMTR 
one year survival of patients using haplo was 63%, very close to the 59.5% 95% confidence 
interval if the OS probability is 75%.  If we achieve survival > 75%, we will have high 
confidence (p = 0.05) that outcomes have improved compared to this historical control.  The 
percentages above and below 75% are meant to represent other plausible survival rates. 
TABLE 5.2 POSSIBLE 95% CONFIDENCE INTERVAL FOR VARIOUS 
UNDERLYING OVERALL SURVIVAL RATES WITH N = 30 
Overall Survival 
Rate (%) 
Possible 95% Confidence 
Intervals (%) 
Length of 95% 
Confidence Interval 
85 
72.2 
97.8 
25.6 
80 
65.7 
94.3 
28.6 
75 
59.5 
90.5 
31.0 
70 
53.6 
86.4 
32.8 
65 
47.9 
82.1 
34.1 
60 
42.5 
77.5 
35.0 
55 
37.2 
72.8 
35.6 
50 
32.1 
67.9 
35.8 
 
The OS probability estimate will be based on the Kaplan-Meier product limit estimator.  In the 
absence of censoring, the Kaplan-Meier estimate reduces to the binomial proportion.  

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5.3 
Interim Analysis and Pausing Guidelines 
There will be no interim analyses for efficacy or futility.  Patients will be monitored for key 
safety endpoints including graft failure and mortality.  Graft failure will be monitored including 
both primary graft failure and secondary graft failure.  Primary graft failure will be determined 
by Day 56 post-transplant in all patients receiving a transplant. Secondary graft failure will be 
determined by Day 56 post-transplant in all patients achieving the initial engraftment.  Mortality 
will be monitored up to 115 days from the first day of preparative regimen (Day -9) in all 
patients receiving the first dose of ATG.  The rationale for monitoring mortality from the first 
day of ATG preparation in all patients receiving the first dose of ATG is to guard against 
excessive early mortality including death due to the intervention in patients who never proceed to 
transplant, although this event is expected to be extremely uncommon.  The monitoring period 
for mortality is set to 115 days from the first day of ATG preparation to ensure that this time 
point aligns with the Day-100 post-transplant evaluation for patients receiving a transplant.   
Graft failure and mortality will be monitored so that 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 pausing 
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. 
A truncated Sequential Probability Ratio Test (SPRT) based on a binomial test of proportions 
will be used to monitor each safety endpoint as described below.  This sequential testing 
procedure conserves type I error across all of the monitoring looks for each endpoint, but not 
across endpoints.  The SPRT can be represented graphically.  At each interim analysis, the 
number of patients evaluable for the endpoint is plotted against the total number of patients who 
have experienced the event.  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 graft 
failure or mortality.  If the graph falls above the upper boundary, the SPRT rejects the null 
hypothesis, and concludes that graft failure or mortality is higher than predicted by the number of 
patients on study.  Otherwise, the SPRT continues until enrollment reaches the target goal. 
The usual measures of performance of an SPRT are the error probabilities α and β of rejecting 
H0 when θ = θ0 and of accepting H1 when θ = θ1, respectively, and the expected sample size 
E(N|θi).  Note that since the test uses only the upper boundary, and is truncated by a finite 
sample size, the size of the test will be slightly lower than the nominal level.   
5.3.1 Graft Failure by Day 56 Post Transplant 
Graft failure will be monitored up to Day 56 post-transplant in all patients who proceed to 
transplant.  Events for this safety endpoint include both primary graft failure and secondary graft 
failure. The safety boundary for graft failure was developed from an SPRT contrasting 15% 
versus 35% graft failure by Day 56 post-transplant, with nominal type I and II errors of 10% and 
14%, respectively.  The slope of the line for monitoring excessive graft failure is 0.240 and the 
intercept is 1.929.  The stopping rule is summarized in Table 5.3.1A.   
 
 
 

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TABLE 5.3.1A PAUSING GUIDELINES FOR DAY-56 GRAFT FAILURE 
Number of Patients Proceed to Transplant  
Pause if Graft Failure 
Occurs in  
3 – 4 
3 
5 – 8 
4 
9 – 12 
5 
13 – 16 
6 
17 – 21 
7 
22 – 25 
8 
26 – 29 
9 
30 
10 
The actual operating characteristics of the truncated test, shown in Table 5.3.1B, were 
determined in a simulation study with 10,000 replications.  The simulation assumed uniform 
accrual of 30 patients over a three-year time period.   
TABLE 5.3.1B OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING PROCEDURE 
FOR DAY-56 GRAFT FAILURE FROM A SIMULATION STUDY WITH 10,000 
REPLICATIONS 
True Day-56 rate 
15% 
20% 
25% 
30% 
35% 
Probability reject the null hypothesis 
0.07 
0.20 
0.41 
0.63 
0.80 
Mean month stopped 
36.6 
34.1 
30.2 
25.6 
21.0 
Mean # endpoints in 56 days 
4.4 
5.4 
6.0 
6.0 
5.7 
Mean patients evaluable for endpoints 
28.9 
26.9 
23.7 
20.0 
16.3 
Graft failure will be monitored in all patients who actually receive a BM infusion.  The SPRT 
rejects the null hypothesis in favor of the alternative 7% of the time when the true Day-56 
rejection rate is 15%, and 80% of the time when the true Day-56 rejection rate is 35%.  This 
corresponds to a type I error rate α = 0.07 and a type II error rate β = 0.20.  When the true Day-
56 rejection rate is 35%, on average, the DSMB will be consulted 21 months after opening, when 
6 events have been observed in 17 patients.  Note that the SPRT procedure is adequately 
powered to distinguish between a rejection rate of 15% and 35%. 
5.3.2 Mortality by Day 115 Post ATG Preparation 
Mortality will be monitored up to 115 days from the first day of ATG preparation (~100 days 
post-transplant for patients receiving a transplant).  Mortality will be monitored in all patients 
receiving the first dose of ATG.  The safety boundary for mortality was developed from an 
SPRT contrasting 10% versus 30% mortality rate, with nominal type I and type II errors of 8% 
and 15%, respectively.  The slope of the line for monitoring excessive mortality is 0.186 and the 
intercept is 1.751.  The stopping rule is summarized in Table 5.3.2A.   
TABLE 5.3.2A PAUSING GUIDELINES FOR 115 DAY MORTALITY 
Number of Patients Started ATG Preparation 
and Evaluable for Mortality by 115 Days 
Pause if Mortality 
Occurs in  
3 – 6 
3 
7 – 12 
4 

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13 – 17 
5 
18 – 22 
6 
23 – 28 
7 
29 – 30 
8 
The actual operating characteristics of the truncated test, shown in Table 5.3.2B, were 
determined in a simulation study with 10,000 replications.  The simulation assumed uniform 
accrual of 30 patients over a three-year time period.   
TABLE 5.3.2B OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR DAY 115 MORTALITY FROM A SIMULATION 
STUDY WITH 10,000 REPLICATIONS 
True Day-115 rate 
10% 
15% 
20% 
25% 
30% 
Probability reject the null hypothesis 
0.05 
0.20 
0.43 
0.67 
0.84 
Mean month stopped 
38.7 
35.9 
31.4 
26.0 
21.4 
Mean # endpoints 
2.9 
4.1 
4.6 
4.8 
4.6 
Mean patients with 115 days follow-up 
29.1 
26.9 
23.2 
18.9 
15.2 
Mortality will be monitored in all patients starting the preparative regimen.  The SPRT rejects 
the null hypothesis in favor of the alternative 5% of the time when the true Day-115 mortality is 
10%, and 84% of the time when the true Day-115 mortality is 30%.  This corresponds to a type I 
error rate α = 0.05 and a type II error rate β = 0.16.  When the true Day-115 mortality is 30%, on 
average, the DSMB will be consulted 21.4 months after opening, when 5 events have been 
observed in 16 patients.  Note that the SPRT procedure is adequately powered to distinguish 
between a mortality rate of 10% and 30%. 
5.4 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be described for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, serum bilirubin level, serum 
creatinine level, graft type, HLA match, donor age, donor gender, donor ethnicity, donor and 
recipient blood types, and cell dose infused (TNC per kg recipient body weight and if available 
CD34 count per kg recipient body weight). 
5.5 
Analysis Plan  
Analysis of all endpoints will be conducted for transplanted patients. 
5.5.1 Analysis of the Primary Endpoint 
The primary analysis will consist of estimating the one-year overall survival probability using 
the Kaplan-Meier estimator.  The event for this endpoint is death from any cause.  The time to 
this event is the time from transplant to death or last follow-up, whichever occurs first.  The one-
year OS probability and its 95% confidence interval will be estimated.   
5.5.2 Analysis of Secondary Endpoints 
Proportion of Patients Alive and Engrafted 
The proportion of patients alive and engrafted at one year will be estimated along with a 95% 
confidence interval. 
 

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Neutrophil Engraftment 
Cumulative incidence of neutrophil engraftment at Day 28 will be estimated with a 95% 
confidence interval using the cumulative incidence function with death prior to neutrophil 
engraftment as the competing risk.   
Platelet Engraftment 
Cumulative incidence of platelet engraftment at Day 100 will be estimated with a 95% 
confidence interval using the cumulative incidence function with death prior to platelet 
engraftment as the competing risk.   
Primary and Secondary Graft Failure 
The frequency and proportion of patients experiencing primary graft failure by Day 56 and the 
proportion of patients who have engrafted and subsequently experience secondary graft failure 
will be described with 95% confidence interval. 
Grade II – IV Acute GVHD 
Cumulative incidence of Grade II – IV acute GVHD at Day 100 will be estimated with a 95% 
confidence interval using the cumulative incidence function with death prior to Grade II – IV 
acute GVHD as the competing risk.   
Chronic GVHD 
Cumulative incidence of chronic GVHD at one year will be estimated with a 95% confidence 
interval using the cumulative incidence function with death prior to chronic GVHD as the 
competing risk.  This will include analysis of the severity of chronic GVHD using the NIH 
criteria. 
Immunologic Reconstitution  
Immune reconstitution assays including CD4, CD19, and CD56 will be measured pre-HCT and 
at Day 91, Day 180, and Day 365 post-HCT.  These will be summarized at each time point using 
descriptive statistics.   
Incidence of Infectious Complications 
The number of specific infections (documented bacteremia with organism, CMV, and EBV) and 
the number of patients experiencing infections will be tabulated. Incidences of CMV viremia and 
disease, EBV viremia, and PTLD will be reported. 
Health Related Quality of Life (HR-QoL) 
HR-QoL will be measured at Baseline and then at Day 100, Day 180, and Day 365 post-
transplant using two instruments: the MOS SF-36 (both PCS and MCS) for English- and 
Spanish-speaking adult patients (> 18 years) and the PedsQLTM Stem Cell Transplant Module for 
English-speaking pediatric patients (8 years through 18 years).  HR-QoL at each time point will 
be summarized using simple descriptive statistics (mean, SD).  Analysis will be done separately 
for each instrument using a Bonferroni adjusted significance level (0.05/4).  All models will be 
adjusted for baseline HR-QoL.   

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APPENDIX A: 
 
HUMAN SUBJECTS

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APPENDIX A: 
 
HUMAN SUBJECTS 
 
 
1.  Subject Consent 
Candidates for the study will be identified as described in Chapter 4 of the protocol.  The 
Prinicipal Investigator or his/her designee at each transplant center will contact the candidates, 
provide the patient with information about the purpose of the study, and obtain consent.  The 
BMT CTN will provide a template of the consent form to each center.  Each center will 
customize the template according to their local requirements and submit it for review by the local 
Institutional Review Board (IRB).  The DCC will verify the adequacy of the consent forms prior 
to submission to the IRB.  Each center must provide evidence of IRB approval to the DCC. 
 
 
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 generated by and kept on file at the BMT CTN Data and 
Coordinating Center upon enrollment. 
 
 
3. Participation of Women and Minorities 
Women, 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 severe 
aplastic anemia in these groups.  Centers will be notified if their rates differ significantly from 
those expected and asked to develop appropriate recruitment reports. 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B: 
 
CONSENT FORMS 
 
 

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Patient Informed Consent Template for the BMT CTN 1502 Study 
 
 
Optimizing Haploidentical Aplastic Anemia Transplantation 
 
Your Name: 
       ________________________________ 
 
Study Title:  
Optimizing Haploidentical Aplastic Anemia Transplantation (CHAMP) 
 
Protocol: 
BMT CTN #1502 
 
Co-Investigator:     Amy E. DeZern, M.D., M.H.S.  
      Division of Hematologic Malignancies 
      1650 Orleans Street, CRBI Room 3M87 
      Baltimore, MD 21287-0013 
      (O) 410-502-7208 
      (F) 410-614-7279 
      adezern1@jhmi.edu  
 
Co-Investigator:    Michael A. Pulsipher, M.D.  
Division of Pediatrics, USC Keck School of Medicine 
Children's Hospital Los Angeles 
4650 Sunset Blvd, MS#54 
Los Angeles, CA 90027 
(O)  323-361-2546 
(F)   323-361-8068 
mpulsipher@chla.usc.edu 
 
Principal 
Investigator:  
Insert local PI information 
 
Sponsor:   
The National Institutes of Health (NIH) is sponsoring this study by providing 
financial support through the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN).  
 
1. 
Introduction 
We invite you to join this clinical trial, also known as a research study. You’re being asked to 
join because you: 
 Have a diagnosis of severe aplastic anemia (SAA), and  
 Your SAA can be treated with an allogeneic transplant.  You don’t have a completely 
matched related or unrelated donor, but you do have a half-matched family 
(haploidentical) bone marrow donor 
 

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This study will take at least 3 years and will include 30 participants. Your participation will last 
for 1 year after your transplant.  
This Consent Form will tell you about the purpose of the study, the possible risks and benefits, 
other options available to you, and your rights as a participant in the study.  
Everyone who takes part in research at [insert facility name] should know that: 
 Being in any research study is voluntary. 
 You may or may not benefit from being in the study.  Knowledge we gain from this study may 
benefit others. 
 If you join the study, you can quit the study at any time.  
 If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
 Please ask the study staff questions about anything that you do not understand, or if you would 
like to have more information. 
 You can ask questions now or any time during the study. 
 Please take the time you need to talk about the study with your doctor, study staff, and your 
family and friends. It is your decision to be in the study. If you decide to join, please sign and 
date the end of the Consent Form. 
You and your doctor will discuss other treatment choices if you do not want to participate in this 
study.  
2. 
Study Background 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), is providing staff support and money for this research study. The 
BMT CTN and the NIH will make decisions together about how to manage the study.  
An allogeneic transplant uses blood-making cells from a related donor (family member) or an 
unrelated donor (not a family member) to replace your diseased blood cells. Before your 
transplant, you will get chemotherapy with radiation to destroy the diseased cells.  
After chemotherapy, the healthy cells from your donor are given to you. The new cells go into 
your bloodstream through an intravenous (IV) catheter (or tube). It’s just like getting blood or 
medicine through an IV. The donor cells find their way into your marrow where most often they 
grow and start to make healthy new red blood cells, white blood cells, and platelets. 
For this study, the cells used for your transplant will come from bone marrow (related donor), 
which is soft, spongy tissue inside of bones. The bone marrow will come from a half-matched 
(haploidentical) family member such as a sister, brother, child or parent. This means that you and 

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the donor have one set of genes (out of two possible) that are the same, or are half-matched. This 
is called a haploidentical transplant. ‘Haplo’ means half.   
3. 
Study Purpose  
We invite you to take part in this study because you have severe aplastic anemia (SAA) and an 
allogeneic transplant is a treatment option for you. We’re doing this study to learn how well 
SAA patients do with transplants that use haploidentical bone marrow. 
4. 
Rights to Ask Questions and/or Withdraw 
You have the right to ask questions about the study at any time. If you have questions about your 
rights as a participant or if you want to leave the study, please contact:  
[insert contact info] 
Being in this study is voluntary. You can choose not to be in this study or leave this study at any 
time. If you choose not to take part or leave this study, it will not affect your regular medical care 
in any way.  
Your study doctor and study staff will be available to answer any questions that you may have 
about taking part in or leaving this study.  
5. 
Study Treatment and Tests 
If you join the study, we will check your health before you start treatment, while you receive 
treatment, and for 1 year after your transplant.  
Before Your Treatment  
You will need to have several check-ups and tests to see if you can be in the study. These check-
ups and tests are part of your regular care. They would be done even if you were not part of this 
study. These tests include: 
 Medical history 
 Physical exam, height, and weight 
 Blood and urine tests 
 Heart function tests 
 Lung (pulmonary) function tests; for children, pulse oximetry test to measure how much 
oxygen is in your blood.  
 Bone marrow tests. These tests are called aspirates or biopsies. Samples of your marrow 
will be taken from your hip bone with a large needle.  
 A pregnancy test if you are a woman and able to have children (if you are pregnant, you 
will not be able to join this study). 

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During Your Treatment   
If the check-ups and tests show that you can be in the study, you’ll get a bone marrow transplant 
from a half-matched (haplo-identical) family member. 
Before Your Transplant: 
The conditioning regimen is the combination of chemotherapy drugs (chemo) and radiation 
you’ll receive before you get your donor cells. This helps the donor cells start to grow and make 
new cells in your bone marrow (engraft).  
A common side effect of allogeneic transplant is Graft versus Host Disease (GVHD). It’s a 
medical condition that can be very serious (see Risks and Toxicities Related to Transplant under 
Section 6: Risks and Discomfort).   
GVHD happens because of differences in your immune cells (host) and your donor’s immune 
cells (graft). The donor cells might see your cells as foreign and attack them, causing GVHD to 
happen. Your doctor will give you drugs to help prevent GVHD from happening.  
Your doctor will use the following drugs and radiation to prepare your body for transplant:  
 Thymoglobulin®, also known as anti-thymocyte globulin, rabbit ATG and rATG 
(helps the donor cells engraft in your body and is also a GVHD prevention drug) 
 Fludarabine and Cyclophosphamide (chemotherapy drugs) 
 Total body irradiation, TBI (radiation therapy given to the whole body to help weaken 
your immune system and prevent rejection of transplanted stem cells) 
The schedule of drugs you will receive to prepare your body for transplant is as follows: 
 We’ll give you Thymoglobulin® each day for 3 days, starting 9 days before your transplant 
(Day -9 through Day -7).  
 Then we’ll give you Fludarabine each day for 5 days, starting 6 days before your transplant 
(Day -6 through Day -2). 
 You’ll also get Cyclophosphamide for 2 days, starting 6 days before your transplant (Day 
-6 and Day -5).   
 Last, you’ll get a low dose of TBI the day before your transplant (Day -1).  
After your transplant, you’ll also get drugs to help prevent GVHD: 
 You’ll get Cyclophosphamide for 2 days, starting 3 days after your transplant (Day +3 
and Day +4).  Your doctor will give you this drug in your vein (IV). 
 We’ll give you Tacrolimus daily starting 5 days after your transplant (Day +5). Your 
doctor will either give you this drug in your vein (IV) or you will take a pill.  

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 Then we’ll give you Mycophenolate mofetil (MMF) daily starting 5 days after your 
transplant (Day +5). Your doctor will either give you this drug in your vein (IV) or you 
will take a pill.  
 You will continue to take Tacrolimus (or a similar drug called Cyclosporine) for about 6 
to 12 months, and MMF for about 5 weeks after your transplant or until there are no signs 
of GVHD. 
After your transplant, you will also get drugs to help speed up the recovery of white blood 
cells.  
 We’ll give you Filgrastim (G-CSF) through your catheter or by injection under your skin 
5 days after your transplant (Day +5). You’ll get Filgrastim every day until your blood 
counts are at a safe level and then continue for three additional days before stopping.  
See Table 1 below for a schedule of when you’ll get these drugs. 
Table 1: Schedule of Drugs 
Drugs 
Days 
-9 to -7 
Days 
-6 to -
2 
Days   
-6 & -
5 
Day 
-1 
Day 0 
(Transplant 
day) 
Days 
+3 & 
+4 
Days 
+5 to 
+180 
Days 
+5 to 
+35 
Days 
+5 to 
+7 or 
more 
Thymoglobulin 
(ATG) 
X 
 
 
 
 
 
 
 
 
Fludarabine 
 
X 
 
 
 
 
 
 
 
Cyclophosphamide  
 
 
X 
 
 
 
 
 
 
Total body 
irradiation (TBI) 
 
 
 
X 
 
 
 
 
 
Transplant day 
(infusion of bone 
marrow)  
 
 
 
 
X 
 
 
 
 
Cyclophosphamide 
 
 
 
 
 
X 
 
 
 
Tacrolimus or 
cyclosporine 
 
 
 
 
 
 
X 
 
 
Mycophenolate 
mofetil (MMF) 
 
 
 
 
 
 
 
X 
 

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Filgrastim 
 
 
 
 
 
 
 
 
X 
 
Your Transplant:  
On your transplant day (Day 0), the donor cells from your haploidentical family member will be 
given to you through your catheter just like a blood transfusion. The cells will travel to your bone 
marrow where they will start to make new, healthy blood cells. 
Health Evaluations: 
We will test (evaluate) your health during the study. These tests and how often they are 
scheduled are standard care for patients receiving an allogeneic transplant. They would be done 
even if you were not part of this study. You will be watched closely for any signs and symptoms 
of GVHD.  
After Your Treatment 
Health Evaluations after Transplant: 
 Routine blood tests (cell counts and liver and kidney function) two or three times per week 
until Day 28, then weekly until Day 100, and then at Days 180 and 365. 
 One of six protocol-required 5 mL (~1 teaspoon) blood samples from a vein in your arm 
on Day 7 (4 of the other protocol-required samples will be taken pre-transplant on the days 
you receive ATG and 1 will be taken on the day of your transplant). 
 Blood tests to see how well your immune system is working at Day 100, 180, and 365. 
 Blood tests to find the amount of donor cells in your body on Days 28, 56, 100, 180, and 
365.  This is called chimerism. 
 Blood tests to find out if you have any infections weekly until Day 100. 
 Physical exam to look for toxicities on Days 28, 56, 100, 180, and 365. 
 Physical exam to look for GVHD weekly until Day 100 and then at Days 180 and 365. 
 Health-Related Quality of Life Questionnaires: If you speak English and are 8 years of age 
or older or if you speak Spanish and are 19 years of age or older, you will be asked to 
complete a questionnaire about your quality of life before your transplant and then at Day 
100, Day 180, and Day 365. 
6. 
Risks and Discomforts 
You will have side effects while on the study. Side effects can range from mild to very serious. 
The risks listed in this section might happen from transplant. These risks might happen if you 
have a transplant as part of this study or as standard care. Your doctor will give you drugs to help 
lower the side effects, such as feeling sick to your stomach (nausea). In some cases, side effects 

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can be long lasting or may never go away. The chemotherapy drugs can cause leukemia years 
later, but this is rare. These “secondary cancers” are often very hard to treat and can cause death. 
Risks and Toxicities Related to Transplant: 
The following problems may happen because of your transplant. These risks may happen if a 
transplant was done as part of the study or not. The risks are:  
Death due to infection or transplant complications:  Patients undergoing transplant for severe 
aplastic anemia are at risk of fatal complications due to several complications listed below 
(infection, organ damage, graft versus host disease, etc.).  Although approaches to haploidentical 
transplant included in this study may improve outcomes, in past studies, as many as 20-40% of 
patients have had fatal complications using this stem cell source. 
Slow recovery of blood counts: The red blood cells, white blood cells, and platelets can be slow 
to recover after a bone marrow transplant. Until your blood counts recover, you will need blood 
and platelet transfusions and you will be at risk for bleeding and infections. You’ll receive 
Filgrastim to speed the recovery of the white cells as much as possible.   
Graft failure: The stem cells (the “graft”) may fail to grow inside your body. Past experience 
suggests that there can be up to a 10 - 15% chance of graft failure. If graft failure occurs, you could 
have low blood counts for a long period of time. If your counts don’t recover, you may need to 
receive a second transplant. Graft failure can be fatal. 
Graft-Versus-Host Disease (GVHD): GVHD happens when the donor cells recognize your body 
as foreign and attack it. In most cases, GVHD can be successfully treated. Sometimes GVHD is 
severe or difficult to treat and may lead to death. You will be watched closely for this complication 
and given drugs to prevent and/or treat it.  
Acute GVHD, which can happen 0 – 3 months after transplant, may produce skin rash, nausea, 
vomiting, diarrhea, abdominal pain, abnormalities of liver function, and an increased risk of 
infection. Chronic GVHD, which can happen 3 months or later after transplant,  may produce skin 
rashes, hair loss, thickened dry skin, dry eyes, dry mouth, liver disease, weight loss, diarrhea, and an 
increased risk of infection. To confirm the diagnosis of acute or chronic GVHD, you may be asked 
to have a biopsy (a small sample of your tissue to look at under the microscope) of your skin, gut, 
or, rarely, your liver.  
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, bladder, or brain. The kidneys and the liver are most 
likely to be damaged. Some patients will experience serious lung problems from infections or the 
chemotherapy and radiation.  
Serious infections: Full and complete recovery of your immune system may take many months. 
During this time, there is an increased risk of infections. You will be prescribed certain drugs to 
reduce the chance of those infections. However, these treatments do not always work. If you have 
an infection, you may have to stay in the hospital longer or be re-hospitalized after transplant. 

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Although most infections can be successfully treated, some infections may result in death.  
Recurrence of disease or a new blood cancer: Your severe aplastic anemia may come back even 
if the transplant is successful at first. 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). These blood 
cancers usually develop 2 - 10 years after treatment, or 6 years on average. The risk of 
developing a new blood cancer after allogeneic transplant is probably less than 2%. If cancer 
develops in your blood cells, you may require additional treatment with chemotherapy or another 
blood or marrow transplant. 
Risk to the unborn: The treatments in this study have not been proven to be safe at any stage of 
pregnancy. Therefore, if you are pregnant or nursing, you are not eligible for this study. Women 
who can become pregnant must 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. 
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. Women may also want to talk to their doctors about freezing eggs prior 
to transplant. 
 If you are a woman and can become pregnant:  
You will need to take a pregnancy test before you start the study. You should discuss 
ways to prevent pregnancy while you are in the study. Women who have gone through 
puberty may find that their menstrual cycle becomes irregular or stops permanently. This 
does not mean that you cannot become pregnant. You must still use an effective method 
of birth control during your transplant and continue until 1 year after transplant.  
Additional Information about MMF: 
o MMF could be damaging to an unborn baby if you are pregnant or become pregnant 

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while receiving the drug.  
o MMF can make birth control pills less effective and increase your chances of 
becoming pregnant while you are taking it. 
o If you can become pregnant, you must use 2 effective forms of birth control for 4 
weeks before starting MMF, during treatment, and for 6 weeks after stopping MMF. 
o In this study, you will be assigned to receive MMF for about 5 weeks, so you should 
not become pregnant during that time. If you think you might become pregnant or 
could become pregnant during the upcoming 5 weeks, you should not join the study. 
 If you are a man: 
Your body may not be able to produce sperm (become sterile). You should talk with your 
doctor about banking your sperm before having a transplant. You must still use an 
effective method of birth control during your transplant and continue until 1 year after 
transplant. 
Please check with your doctor to understand more about these risks. 
Unforeseen Risks:  
New risks might appear at any time during the study. These risks might be different from what is 
listed in this Consent Form. We will promptly tell you about new information that may affect 
your decision to take part in the study. We may learn new things about these types of 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.  
Other Treatments or Medications: 
Some medicines react with each other, and it is important that you tell the study doctor or staff 
about any other drugs, treatments, or medicines you are taking.  This includes over-the-counter 
drugs, vitamins, and herbal treatments.  
It is also important that you tell the study staff about any changes to these medications during 
your participation in the study. 
For more information about risks and side effects, ask your study doctor. 
 
 

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Risks and Toxicities Related to Medications:
 
Possible Side Effects of Study Drugs 
The most common side effects of the treatments used in this study are listed below. There is also 
the risk of very uncommon or unknown side effects. All chemotherapy drugs in this study are 
commonly used in transplant. 
Fludarabine (Fludara®) – Chemotherapy drug 
Likely 
Less Likely 
Rare, but Serious 
 
Infection  
 
Anemia (low red blood cell 
count) 
 
Tiredness 
 
Nausea 
 
Vomiting 
 
Pneumonia  
 
Mouth sores 
 
Fever 
 
Swelling of hands and feet 
 
Weakened immune system 
 
Pain 
 
Low number of white blood 
cells 
 
Low number of platelets in 
the blood 
 
Electrolyte imbalances 
 
Diarrhea 
 
Numbness and tingling in 
hands and/or feet  
 
Changes in vision 
 
Skin rash 
 
Cough 
 
Changes in heartbeat 
 
Loss of appetite 
 
Chills 
 
Lung inflammation 
 
Agitation or nervousness 
 
Confusion 
 
Difficulty breathing 
 
Weakness 
 
Severe brain injury and 
death 
 
Bleeding due to decreased 
number of platelets 
 
Kidney damage that could 
require dialysis 
 
Coma 
 
New (secondary) cancers 
 
Likely 
What it means: This type of 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 
What it means: This type of 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 
What it means: This type of side effect does not happen often – in fewer 
than 2% of patients – but is serious when it happens. This means that 1 or 
2 patients (or fewer) out of 100 might get this side effect. 

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Thymoglobulin® (rabbit ATG, antithymocyte globulin rabbit) - Helps engraft cells and prevent 
GVHD  
Likely 
Less Likely 
Rare, but Serious 
 
Fever/chills 
 
Hives 
 
Nausea 
 
Headache 
 
Body swelling 
 
Skin rash, joint aches and 
pain 
 
Shivering 
 
Serum sickness 
 
Low white blood cell count  
 
Severe or life-threatening 
allergic reaction 
 
Lymphomas (i.e., cancers of 
the immune system)  
 
Anaphylaxis 
 
Acute kidney failure 
 
High potassium  
 
Cyclophosphamide (Cytoxan®) - Chemotherapy drug, helps prevent GVHD 
Likely 
Less Likely 
Rare, but Serious 
 
Decreased white blood cell 
count with increased risk of 
infection 
 
Temporary hair loss 
 
Nausea 
 
Vomiting 
 
Loss of appetite 
 
Sores in mouth or on lips 
 
Diarrhea 
 
Stopping of menstrual 
periods in women 
 
Decreased sperm production 
in men 
 
Decreased platelet count 
(mild) with increased risk of 
bleeding 
 
Blood in urine 
 
Low red blood cell count 
(anemia) 
 
Temporary tiredness 
 
Damage to the fetus if you 
become pregnant while 
taking drug 
 
Scarring of lung tissue, with 
cough and shortness of 
breath 
 
Severe heart muscle injury 
and death at very high doses 
 
New (secondary) cancers 
 
 
Filgrastim (G-CSF; Neupogen®) – helps speed up recovery of white blood cells 
Likely 
Less Likely 
Rare, but Serious 
 
Ache or pain inside of bones 
 
Increased levels of liver 
enzymes and uric acid in the 
blood 
 
Low number of platelets in 
the blood 
 
Headache 
 
Tiredness  
 
Local irritation (skin) at the 
injection site 
 
Nausea 
 
Bleeding 
 
Fever 
 
Allergic reaction 
 
Enlargement or rupture of 
the spleen 
 
Worsening of pre-existing 
rashes 
 
Temporary hair loss 
 
Inflammation of a blood 
vessel in the skin 

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Mycophenolate Mofetil (MMF: CellCept®) – helps prevent GVHD  
Likely 
Less Likely 
Rare, but Serious 
 
Miscarriage 
 
Birth defects 
 
Diarrhea 
 
Damage to unborn baby 
 
Limited effectiveness of birth 
control 
 
Stomach pain 
 
Nausea 
 
Vomiting 
 
Headache 
 
Tremors 
 
Low white blood cell count with 
increased risk of infection 
 
Swelling of the hands, feet, 
ankles or lower legs 
 
 
Low red blood cell count 
(anemia) 
 
Rash 
 
Difficulty falling asleep 
or staying asleep 
 
Dizziness 
 
Uncontrollable hand 
shakes 
 
Difficulty breathing 
 
Unusual bruising 
 
Fast heartbeat 
 
Excessive tiredness 
 
Weakness 
 
Blood in stool 
 
Bloody vomit 
 
Change in vision 
 
New (secondary) cancers  
 
Progressive Multifocal 
Leukoencephalopathy (a 
disease that damages the 
white/gray parts of the 
brain) 

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Total Body Radiation (TBI) – helps to weaken your immune system and prevent rejection of 
transplanted stem cells 
Likely 
Less Likely 
Rare, but Serious 
 
Fever 
 
Fatigue 
 
Hair loss 
 
Loss of appetite 
 
Mouth sores 
 
Nausea 
 
Diarrhea 
 
Stomach cramps 
 
Vomiting (throwing up) 
 
Painful swelling of the salivary 
glands under the ears for a few 
days 
 
Low red blood cell count 
(anemia) 
 
Infection 
 
Bleeding 
 
Cataracts 
 
Hormone problems (such as 
thyroid disease or diabetes) 
 
Mouth sores 
 
Skin pigmentation 
(reversible) 
 
Sterility (inability to 
have children) 
 
Slow growth 
 
 
Lung fibrosis 
 
New (secondary) cancers 
 
Tacrolimus (FK506, Prograf®) – GVHD drug 
Likely 
Less Likely 
Rare, but Serious 
 High blood pressure 
 High blood sugar 
 Low red blood cell count 
(anemia) 
 High or low potassium levels 
 Low magnesium and calcium 
levels 
 Loss of appetite 
 Diarrhea 
 Nausea 
 Fever 
 Headache 
 Hair loss 
 Vomiting 
 Tingling sensation in the 
extremities 
 Itching 
 Rash 
 Abdominal pain 
 
 
 
 
Confusion 
 
Painful joints 
 
Increased sensitivity to 
light 
 
Change in vision 
 
Insomnia (trouble 
sleeping) 
 
Infection 
 
Jaundice (skin 
yellowing) 
 
Kidney injury 
 
Seizures 
 
RPLS/PRES1 
1 Reversible posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible 
encephalopathy syndrome (PRES). In transplant patients, it can be caused by some of the drugs used to 
prevent or treat GVHD. It can often, but not always, be prevented by very careful control of blood 
pressure.   

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It is very important that you DO NOT eat grapefruit or drink grapefruit juice while taking 
Tacrolimus. Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs used in this study. Common soft drinks that have bergamottin are Fresca, 
Squirt, and Sunny Delight.  
7. 
Other Treatments
It’s optional to join this study. If you choose not to take part, you may still receive treatment with 
alternative immune suppressing therapy, new agents, or an allogeneic transplant to treat your 
disease. The transplant treatment and evaluations you would receive could be very similar to 
what you 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 a partially-matched related or unrelated donor or another alternative 
donor source 
 Treatment with other drugs to suppress the immune system without a transplant 
 Treatment with drugs aimed at temporarily boosting your blood counts or other new 
agents under investigation 
 Treatment with blood transfusions only 
 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.
8. 
Possible Benefits 
 
Taking part in this study may or may not make your health better. The information from this 
study will help doctors learn more about transplants for SAA. It could also help people with 
SAA that may need a transplant in the future.
9. 
New Information Available During the Study 
 
During this research study, the study doctors may learn about new information about the study 
drugs or the risks and benefits of the study. If this happens, they will tell you about the new 
information.  The new information may mean that you can no longer participate in the study, or that 
you may not want to continue in the study.  

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If this happens, the study doctor will stop your participation in the study and will offer you all 
available care to meet your needs and medical conditions. 
10. 
Privacy, Confidentiality, and Use of Information 
Your confidentiality is one of our main concerns. Study records that have your name will be kept 
private as required by law. You will not be identified by name in the central study records. Your 
records will be given a unique code number. The key to the code will be kept in a locked file in the 
Principal Investigator’s office. 
All necessary steps will be taken to avoid you being identified in any public presentations.  The 
results of this study treatment may be published in scientific journals in the future, but no patients 
(including you) will be identified.  
Information about your transplant course may be reviewed or transmitted to national and 
international transplant registries, including: 
 [Institution] 
 The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
 U.S. government agencies that are responsible for overseeing research such as The Food and 
Drug Administration (FDA) and the Office of Human Research Protection (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 
 The Data and Safety Monitoring Board (DSMB), not part of [Institution] 
 Institutional Review Boards (IRBs) responsible for this study 
 Blood and Marrow Transplant Clinical Trials Network Data and Coordinating Center (BMT 
CTN DCC), including: 
 The Center for International Blood and Marrow Transplant Research (CIBMTR) 
 The National Marrow Donor Program (NMDP) 
 Emmes, who are coordinating the studies of the BMT CTN 
 Study investigators: 
 Dr. Amy DeZern, Co-Principal Investigator 
 Dr. Michael Pulsipher, Co-Principal Investigator 
We will not identify you by name in any publications or reports that come from these organizations 
or groups. 

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Information that does not include personally identifiable information about this clinical trial has 
been or will be submitted, at the appropriate and required time, to the government-operated 
clinical trial registry data bank, which contains registration, results, and other information about 
registered studies.   
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.  
Your privacy is very important to us.  The study doctors will make every effort to protect it. 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 who you are. 
Data regarding your clinical situation, including follow-up after 1 year, may be obtained from the 
CIBMTR, which captures information on all U.S. transplants. 
For questions about access to your medical records, please contact: 
[Insert name and phone number]. 
Expiration date for retention of records: 
Information about the study results will stay in your research file at [insert institution] for at least 6 
years or until after the study is completed, whichever is longer. At that time, either the research 
information not already in your medical record will be destroyed or your name and other identifying 
information will be removed from such study results. Research information in your medical record 
will be kept indefinitely.
11.   Ending Your Participation
Being in this study is voluntary. You can choose to not be in this study or to leave this study at 
any time. If you choose not to take part in or leave this study, your regular medical care will not 
be affected in any way. Tell your doctor in writing if you are thinking about stopping or decide 
to stop. He or she will tell you how to stop safely. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing will be most helpful to you. 
The study doctor or the study sponsor may stop the study at any time and we may ask you to 
leave the study. We may ask you to leave the study if you do not follow directions or if you 
suffer from side effects of the 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. 

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 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. 
If you decide to leave this study after taking the study treatment or are asked to leave by your 
doctor for medical reasons, you’ll need to come back to the doctor’s office for tests for your 
safety. Even if you leave the study, the information collected from your participation will be 
included in the study evaluation.
12.   Physical Injury as a Result of Participation  
It is important that you tell your doctor, [investigator's name(s)], or study staff if you feel that 
you have been injured because of taking part in this study. You can tell the doctor in person or 
call him/her at [telephone number]. 
You will get medical treatment if you’re injured as a result of taking part in this study. You 
and/or your health plan will be charged for this treatment. The study will not pay for medical 
treatment.  
In case 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 your participation in this research study. You will not be compensated or 
reimbursed for any extra costs (travel, meals, etc.) from taking part in this study. 
14.   Costs and Reimbursements 
Most of the visits for this research study are standard medical care for your allogeneic transplant and 
will be billed to your insurance company. You and/or your health plan/insurance company will need 
to pay for some or all of the costs of standard treatment in this study.   
You or your insurance will not be charged for tests that are only done for research on this study. 
Some health plans will not pay these costs for people taking part in studies. Check with your health 
plan or insurance company to find out if they will pay.  
For questions about your costs, financial responsibilities, and/or medical insurance coverage for 
your transplant and this study, please contact /Center/Financial Counselor at /Number/. 

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For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
15.   Ethical Review
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 
16.   For More Information
If you need more information about this study, or if you have problems while taking part in this 
study, you can contact the study doctor or his/her staff.  They can be reached at the telephone 
numbers listed here: 
[Insert names and contact details] 
17.   Contact Someone about Your Rights 
If you wish to speak to someone not directly involved in this study, or if you have any complaints 
about any aspect of the study, the way it is being conducted, or any questions about your rights as a 
research participant, you may contact:  
[Insert appropriate contact details] 
For questions about your rights while taking part in this study, call the [name of center] 
Institutional Review Board (a group of people who review the research to protect your rights) at 
[telephone number]. 
 
 
 
 
 
 
 
 
 

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18.   OPTIONAL Blood Samples for Trial-Related and Future Research 
Studies 
This section of the Consent Form is about collection of optional blood samples for trial-
specific and future research studies from people who are taking part in the study.  
You can choose to give blood samples for optional trial-specific and future research studies if 
you want to. You can still be a part of the main study even if you say “no” to giving optional 
blood samples for these studies. Please mark your choice at the end of this section. 
Researchers are trying to learn more about how the human body processes the drugs used for 
transplant and how the body recovers after transplant. This research is meant to gain knowledge 
that may help people in the future and make transplants even more successful.  
If you agree to provide optional blood samples, here is what will happen: 
 We’ll take 24 mL (about 5 teaspoons) from your catheter or by a vein in your arm if you are 
an adult , or 12 mL (about 2.5 teaspoons) if you’re a child (< 20kg). We’ll collect this sample 
when you have your 1st check-up, before treatment starts. 
o This blood sample will be shipped on the day of collection to a qualified research 
laboratory that is partnering with the clinical trial team physicians for an important 
study related to this trial. This study wants to look at your telomeres, which are caps at 
the end of DNA strands to protect them. DNA is in your blood, so we can study 
telomeres using blood samples. 
 At the same time, we will collect one additional 3 mL (about ⅔ teaspoon) blood sample. 
o This blood sample will be sent to the BMT CTN Biorepository for processing and 
storage for future genomic research studies. A repository is a place that protects, stores, 
and sends out samples for approved research studies. All research samples will be given 
a bar code that cannot be linked to you by future researchers testing your samples. 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. 
o These samples will be kept and may be used in research to learn more about immune 
recovery, GVHD, severe aplastic anemia, cancer, and other diseases. When the samples 
are given to investigators for research, no information about your name, address, phone 
number, or other information that will let the researchers know who you are will be 
provided. 
o DNA from your stored blood samples and your health information might be used in 
genome-wide association (GWA) studies for a future project either done or supported 

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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. 
o If your coded samples are used in such a study, the researchers are 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. However, the results of genetic studies could, in theory, include identifying 
information about you. 
Your name and other information that could directly identify you (such as address or 
social security number) will not be placed into any scientific database. However, 
because your genetic information is unique to you, there is a small chance that someone 
could trace it back to you. The risk of this happening is small, but may grow in the 
future. Researchers have a duty to protect your privacy and to keep your information 
confidential. 
Benefits 
The research that may be done with your blood samples is not designed specifically to help you. 
The benefits of research using blood samples include learning more about what causes GVHD, 
severe aplastic anemia, 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.  
A possible risk is the loss of confidentiality about your medical information. We will do our best 
to make sure that your personal information is kept private. The chance that this information will 
be given to someone else is very small.  
Some general things to think about when letting us store your blood samples for research are:  
 The choice to let us collect and/or store blood samples 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 samples can be collected and stored for research, you 
can change your mind at any time. Just contact your study doctor in writing and let him or 
her know that you do not want us to continue storing your blood samples. His/her mailing 
address is on the first page of this form. Then any unused blood samples that remain will 
no longer be stored for research. However, samples and information that have already been 
shared with researchers cannot be taken back or destroyed. 
 In the future, people who do research on these blood samples may need to know more about 
your health. While the study doctor or others involved in running this study may give the 

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researchers reports about your health, they will not give them your name, address, phone 
number, or any other information that will let the researchers know who you are.  
Sometimes blood is used for genetic research (about diseases that are passed on in 
families). Even if your blood is used for this kind of research, you will not be told of the 
results and the results will not be put in your health records. 
 Your blood will be used only for research and will not be sold. The research done with 
your blood may help to develop new products in the future. You will not get paid for any 
samples or for any products that may be developed from current or future research. 
 Reports about research done with your blood 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.  
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 about your 
insurance. 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. 
Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, 
please indicate your choice below. If you have any questions, please talk to your doctor or nurse, 
or call our research review board at [telephone number]. 
No matter what you decide to do, it will not affect your care. 
You can change your mind at any time about allowing us to use your samples and health 
information for research. However, samples and information that have already been 
shared with researchers cannot be taken back or destroyed. 
 
 

BMT CLINICAL TRIALS NETWORK 
 
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Statement of Consent for Optional Blood Samples for Trial-Related 
and Future Research Studies 
The purpose of collecting, storing optional blood samples, the procedures involved, and the risks 
and benefits have been explained to me. I have asked all the questions I have at this time and I 
have been told whom to contact if I have more questions. I have been told that I will be given a 
signed copy of this consent form to keep. I understand that I do not have to allow the collection 
and storage of my blood samples for study-specific and future research studies. If I decide to not 
let you store research samples now or in the future, it will not affect my medical care in any way. 
I voluntarily agree that optional blood samples may be collected and that my blood samples and 
related information can be stored indefinitely by the BMT CTN Biorepository for research to 
learn about, prevent, or treat GVHD, severe aplastic anemia, cancer, or other health problems. I 
also understand that my DNA and health information may or may not be used in genome-wide 
association studies.  
Telomere Research Study 
 I do agree to give blood samples for a telomere research study. 
 I do not agree to give blood samples for a telomere research study. 
Future Genomic Research Studies 
 I do agree to give blood samples for future genomic research. 
 I do not agree to give blood samples for future genomic research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 

BMT CLINICAL TRIALS NETWORK 
 
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B-23 
Health Insurance Portability and Accountability Act 1 (HIPAA)13 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, Optimizing Cord Blood and Haploidentical Aplastic Anemia Transplantation. 
B. Individual Health Information to be Used or Disclosed:  
My individual health information that may be used or disclosed for 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 I 
disclose during the course of the research may be received and used by the following parties: 
 Principal Investigators and the researcher’s staff: 
o Dr. Amy DeZern, Co-Principal Investigator  
o Dr. Michael Pulsipher, Co-Principal Investigator 
 Study Sponsors: 
o National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer 
Institute (NCI), both of the National Institutes of Health (NIH); 
o Blood and Marrow Transplant Clinical Trials Network Data and Coordinating 
Center (BMT CTN DCC), including the National Marrow Donor Program 
(NMDP), the Center for International Blood and Marrow Transplant Research 
(CIBMTR), and Emmes; 
 
3 HIPAA is the Health Insurance Portability and Accountability Act of 1906, a federal law related to privacy of health 
information. 

BMT CLINICAL TRIALS NETWORK 
 
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 U.S. government agencies that are responsible for overseeing research such as the Food 
and Drug Administration (FDA) and the Office of Human Research Protections 
(OHRP); 
 U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state, and local health 
departments. 
 The 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 this 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 for 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 
H. This authorization does not have an expiration date. 

BMT CLINICAL TRIALS NETWORK 
 
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B-25 
TITLE: BMT CTN 1502: Optimizing Haploidentical Aplastic Anemia Transplantation  
Principal Investigator: 
Name: 
 
 
 
Phone:  
Address 1: 
 
 
 
 
 
 
 
Fax: 
Address 2: 
 
 
 
 
 
 
 
Email:  
For patients under 18, consent must be provided by the Legally Authorized Representative and 
Patient Assent is required (see Assent Section on the next page). 
 I have had the chance to ask questions and understand the answers I have been given. I 
understand that I may ask questions at any time during the study. 
 I freely agree to be a participant in the study. 
 I understand that I may not directly benefit from taking part in the study. 
 I understand that, while information gained during the study may be published, I will not be 
identified and my personal results will stay confidential. 
 I have had the chance to discuss my participation in this research study with a family member 
or friend. 
 I understand that I can leave this study at any time, and doing so will not affect my current care 
or prevent me from receiving future treatment. 
 I understand that I will be given a copy of this signed consent form. 
 
 
 
 
 
______ 
 
_________________________________ 
Participant Name 
 
 
 
 
Date 
___________________________________  
_____________ 
 
 
___ 
Participant’s Signature (if 14 years or older)  
Date 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
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I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided.  
 
___________________________________   
_________________________________ 
Name of Counseling Physician/Staff   
 
Date 
 
 
___________________________________  
_____________ 
 
 
___ 
Signature of Counseling Physician/Staff 
 
Date 
 
 
___________________________________  
_________________________________ 
Name of Interpreter 
 
 
 
 
Date 
 
 
___________________________________  
_________________________________ 
Signature of Interpreter 
 
 
 
Date 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
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B-27 
Pediatric Patient Assent 
Study Title: 
Optimizing Haploidentical Aplastic Anemia Transplantation  
Protocol: 
BMT CTN 1502 
 Why am I here? 
We invite you to join this research study because you need a transplant to treat your severe 
aplastic anemia. We will replace your unhealthy blood cells with blood cells from one of 
your family members. The new cells will travel to your bones and start making healthy cells 
in your body.  
For this study, we will ask you for information about your health (health information) and for 
extra blood samples.   
 Why are you doing this study? 
We’re doing this study to learn how well patients with severe aplastic anemia do with 
transplants that use haploidentical bone marrow. 
 What will happen to me if I join the study? 
If you say you want to be in the study, we will:  
 Before your transplant:  
o Give you drugs to help your body get ready for the transplant. The drugs might 
make you feel sick. Your doctor will watch your health closely.  
o We will collect extra blood (about 1 teaspoon) 4 times before your transplant 
and 1 time on the day of your transplant. We will use a small needle to collect 
the blood from a vein in your arm, unless you have a central line in which case 
the samples will be collected through that central line. We will try to collect the 
extra samples at the same time as you have other blood tests done.  
 After your transplant:  
o We will collect extra blood (about 1 teaspoon) one week after your transplant. 
o We will also give you drugs to help your body adjust to the new cells. The drugs 
might make you feel sick. Your doctor will keep watching your health after 
your transplant.  
You will be in the study for 1 year after your transplant. About 30 people will be in the study. 

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 Will the blood draw hurt? 
When we collect your blood from a vein in your arm, it may feel like a pinch. It will hurt for 
a minute and the place where the needle went might be red and sore. You might get a little 
bruise from the needle, but it goes away in a few days. 
 What if I have questions? 
You can ask any questions that you have about the study. If you forget to ask a question and 
think of it later, you can call me: 
 [insert office number].   
You can also ask your question the next time you see me.  
You can call the study office at any time to ask questions about the study. 
 How will you use my health information and blood samples? 
Your health information and blood samples will be used for this study and for future research 
about transplant in patients with severe aplastic anemia. 
 How will you store my health information and blood samples? 
Your blood samples will be sent to a qualified research lab for an important study.  
All research samples will be tied to a number. This number will not be linked to your name or 
other identifying information.  
A. Will the study help me? 
We don’t know if this study will help you or not. It may help other people who need a 
transplant in the future. 
B. Will I be paid to be in the study? 
No, you will not be paid to be in the study. It will not cost you anything to be in the study. 
C. Do I have to be in this study? 
If you don’t want to be in this study, you need to tell us and your parent or guardian.  
Your doctor will not be angry or upset if you do not want to join. You will still need to have 
treatment for your disease.  
You can say yes now and change your mind at any time.   
Please talk this over with your parents before you decide if you want to be in the study. We 
will also ask your parents to give their permission for you to join this study.  
 
 

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B-29 
 
TITLE: BMT CTN 1502: Optimizing Haploidentical Aplastic Anemia Transplantation  
Writing your name on this page means that you agree to join this study and know what will 
happen to you.  
 I’ve been told what I will be asked to do if I am in this study.  
 I’ve been told that I don’t have to be in this study. I may quit the study at any time, and no 
one will be mad at me.   
 If I want to quit the study, all I have to do is tell the person in charge. 
 I’ve had a chance to discuss the study and ask questions. My questions have been answered.   
 I agree to be in the study and do what I am asked to do for as long as I am in the study. 
 My parents and I will get a copy of this form after I sign it. 
 
 
 
 
 
 
 
_______ 
 
 
 
 
Patient’s Name (if less than 14 years) 
Date 
 
    
 
Age (years) 
 
 
 
 
 
 
 
_______ 
 
 
 
 
Signature of Child  
 
        
Date 
 
    
 
Age (years) 
I have explained the purposes, procedures, and risks involved in this research study in detail to: 
 
 
 
 
 
 
 
 
 
 
 
          
Print name(s) of Parents/Authorized Consenting Party  
AND 
________________________________________________________________________ 
Print child’s name 
Who in my opinion:  ______IS    
__IS NOT capable of assenting to participate in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Conducting Assent  
 
 
Date 
 

BMT CLINICAL TRIALS NETWORK 
 
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B-30 
Donor Informed Consent to Participate in Research 
Optimizing Haploidentical Aplastic Anemia Transplantation 
 
Your Name: 
_____________________________________ 
Study Title:  
Optimizing Haploidentical Aplastic Anemia Transplantation (CHAMP) 
Protocol: 
BMT CTN #1502 
Co-Investigator:   Amy E. DeZern, M.D., M.H.S. 
 
Division of Hematologic Malignancies 
 
1650 Orleans Street, CRBI Room 3M87 
 
Baltimore, MD 21287-0013 
 
(O) 410-502-7208 
 
(F) 410-614-7279 
 
adezern1@jhmi.edu  
Co-Investigator:   Michael A. Pulsipher, M.D. 
 
Division of Pediatrics, USC Keck School of Medicine 
 
Children’s Hospital Los Angeles 
 
4650 Sunset Blvd, MS#54 
 
Los Angeles, CA 90027 
 
(O) 323-361-2546 
 
(F) 323-361-8068 
 
mpulsipher@chla.usc.edu 
  
Principal 
Investigator:  
[Insert local PI information] 
 
Sponsor: 
The National Institutes of Health (NIH) is sponsoring this study by providing financial 
support through the Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN). 
1.   Introduction 
We invite you to join this clinical trial, also known as a research study. You’re being asked to 
join because you’re a bone marrow donor for a family member who is going to receive a 
haploidentical (half-matched) transplant in the main study, BMT CTN 1502.  
This consent form is about a research study to learn how patients’ DNA changes after they get 
cells from a donor (transplant). We will compare your DNA to your family member’s DNA 

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before and after their transplant. In order to do this study, we will need extra blood samples from 
you. 
It’s your choice to give blood samples. Even if you say 'no' to giving samples for this research 
study, your family member can still receive a transplant from you as part of the main study. If 
you agree to give blood samples, we will collect them at the same time you have routine blood 
tests done.   
This Consent Form will tell you about the purpose of the samples for research, the possible risks 
and benefits, other options available to you, and your rights as a research participant.  
Everyone who takes part in research at [insert facility name] should know that: 
 Being in any research study is voluntary. 
 You will not directly benefit from being in the study. Knowledge we gain from this study may 
benefit others. 
 If you give blood samples for future research, you can change your mind at any time.  
 If you decide to quit the study, it will not affect your care or the care of your family member 
at [insert name of facility or institution]. 
 Please ask the study staff questions about anything that you do not understand, or if you would 
like to have more information. 
 You can ask questions now or any time during the study. 
 Please take the time you need to talk about the study with your doctor, study staff, and your 
family and friends. It is your decision to provide blood samples for future research. If you 
decide to join, please sign and date the end of the Consent Form. 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), are giving staff support and money for this research study.  
The BMT CTN will lead the research study and, along with the NIH, will make decisions about 
how to manage the study. 
2.   
Study Purpose  
We are collecting extra blood samples because we want to learn more about telomere length in 
donors and how it relates to outcomes (results) for transplant recipients, including engraftment 
and survival. Telomeres are caps at the end of DNA strands to protect them. DNA is in your 
blood, so we can study telomeres using blood samples. 
 
 

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3.   
Right to Ask Questions and/or Withdraw
You have the right to ask questions about the study at any time. If you have questions about your 
rights as a study participant or you want to leave the study, please contact:  
[insert contact info] 
Giving blood samples for research is voluntary. You can choose not to give samples or change 
your mind at any time. 
If you choose not to take part or change your mind, it will not affect your donation process or the 
treatment of your family member in the main study in any way.  
If you change your mind, any unused blood samples will be destroyed. However, samples and 
information that have already been shared with researchers cannot be taken back or destroyed. 
Your study doctor and study staff will be available to answer any questions that you may have.
4.   
Study Treatments and Tests
If you agree to give blood samples, here is what will happen: 
a.) We will collect an extra blood sample at the same time you have routine blood tests done. 
For adults and children who weigh 44 pounds (20kg) or more: 
 We will collect 4 extra blood samples at one time prior to your donation to look at your 
telomeres. The amount of blood collected from you will be about 24 mL (about 5 
teaspoons).   
For children who weigh less than 44 pounds (20 kg): 
 We will collect 2 extra blood samples at one time prior to your donation to look at your 
telomeres. The amount of blood collected from you will be 12 mL (about 2.5 teaspoons).   
b.) The blood samples will be sent to the Johns Hopkins laboratory for processing and storage. 
All samples will be given a unique bar code that cannot be linked to you by researchers 
testing your samples. 
5.   
Risks and Discomforts 
There are no major risks to having your blood drawn. It can be uncomfortable to have your blood 
taken and it can sometimes leave a bruise. You might faint, but this is unlikely to happen. Only 
trained people will take your blood.   
Information about the bone marrow donation process for this study can be found in a separate 
consent form. The transplant doctor or study coordinator will give you a copy of the donation 
consent form. 

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6.   
Possible Benefits
You will not directly benefit from taking part in this study. The information from this study will 
help doctors learn more about how well transplant recipients do with a haploidentical (half-
matched) donor. 
This information could help other people with blood cancers and disorders who may need a 
transplant in the future. 
7.   
Privacy, Confidentiality and Use of Information 
Your confidentiality is one of our main concerns. We will do our best to make sure that the 
personal information in your medical record is kept private. However, we cannot guarantee total 
privacy. All your medical and demographic information (such as race and ethnicity, gender and 
household income) will be kept private and confidential.  
[Name of Transplant Center] and the organizations listed below will not disclose your 
participation by any means of communication to any person or organization, except by your 
written request, or permission, or unless required by federal, state or local laws, or regulatory 
agencies.  
 The National Institutes of Health (NIH), which include the National Heart, Lung, and 
Blood Institute (NHLBI) and the National Cancer Institute (NCI) 
 U.S. government agencies that are responsible for overseeing research such as The Food 
and Drug Administration (FDA) and the Office of Human Research Protection (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 
 The Data and Safety Monitoring Board (DSMB), not part of [Institution] 
 Institutional Review Boards (IRBs) responsible for this study 
 Blood and Marrow Transplant Clinical Trials Network Data and Coordinating Center 
(BMT CTN DCC), including: 
 The Center for International Blood and Marrow Transplant Research (CIBMTR) 
 The National Marrow Donor Program (NMDP) 
 Emmes, who is coordinating the studies of the BMT CTN 
 Study investigators: 
 Dr. Amy DeZern, Co-Principal Investigator 
 Dr. Michael Pulsipher, Co-Principal Investigator 

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Individuals authorized by the organizations above will have access to your research and medical 
information. They may use this information for inspections or audits to study the outcomes of 
your treatment. In agreeing to participate, you consent to these inspections. You also consent to 
allow authorized individuals to copy parts of your records, if required by these organizations. 
We may give out your personal information if required by law. If information from this study is 
published or presented at scientific meetings, your name and other personal information will not 
be used.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.  
Your privacy is very important to us. The study doctors will make every effort to protect it. 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 who you are. 
For questions about access to your medical records, please contact [name] at [number].
8.   
Ending Your Participation 
The study doctor or the study sponsor may stop the study at any time, and we may ask you to 
leave the study. We may ask you to leave the study if you do not follow directions or if you 
suffer from side effects of the blood draw. The study sponsor may decide to end the study at any 
time. If we ask you to leave the study, the reasons will be discussed with you.  
Possible reasons to end your participation in this study include: 
 You do not meet the study requirements.  
 You become unable to donate bone marrow to your family member. 
 The study is stopped for any reason.
9.   
Physical Injury as a Result of Participation 
It’s important that you tell your doctor, [investigator's name(s)], or study staff if you feel that you 
have been injured because you provided blood samples for research. You can tell the doctor in 
person or call him/her at [telephone number]. 
You will get all available medical treatment if you are injured as a result of providing blood 
samples for future research. 
You, your health plan, or your family member’s health plan will be charged for this treatment for 
injury. The study will not pay for medical treatment.  

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B-36 
In case of injury resulting from providing blood samples for this study, you do not lose any of 
your legal rights to seek payment by signing this form. 
10.   Payment and Study Costs 
You will not be paid for your participation in the research study or for providing blood samples for 
research.  
You will not be compensated or reimbursed for any extra costs (for example, travel and meals) from 
taking part in this study. 
The visits at which these samples will be collected are standard for bone marrow donors and will be 
billed to your family member’s insurance company.  
Your family member’s insurance will not be charged for the collection of these optional samples or 
for the research tests done with these samples. The costs of shipping and storing your blood samples 
will be paid by the BMT CTN. 
For questions about your costs, financial responsibilities, and/or medical insurance coverage for 
your transplant and this study, please contact /Center/ Financial Counselor at /Number.
11.   For More Study Information 
If you need more information about providing blood samples for research, or if you have problems 
while you are participating in this study, you can contact the study doctor or his/her staff. They can 
be reached at the telephone numbers listed here: 
[Insert name and contact details]. 
12.   Contact Someone About Your Rights 
If you wish to speak to someone not directly involved in the study, if you have any complaints about 
the study, or would like more information about your rights as a research participant, you may 
contact:  
[Insert appropriate contact details]. 
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 
For more information about your rights when providing blood samples for research, call the 
[name of center] Institutional Review Board (a group of people who review the research to 
protect your rights) at [telephone number].

BMT CLINICAL TRIALS NETWORK 
 
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Health Insurance Portability and Accountability Act (HIPAA)4 Authorization 
to use and disclose 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, 
Optimizing Cord Blood and Haploidentical Aplastic Anemia Transplantation. 
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. 
 Findings from physical exams. 
 Laboratory test results obtained at the time of work up  
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 researcher’s staff: 
o Dr. Amy DeZern, Co-Principal Investigator 
o Dr. Michael Pulsipher, Co-Principal Investigator 
 Study Sponsors: 
o National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer 
Institute (NCI), both of the National Institutes of Health (NIH),  
o Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data 
coordinating center 
 
4 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information. 

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 U.S. government agencies that are responsible for overseeing research such as the Food 
and Drug Administration (FDA) and the Office of Human Research Protections (OHRP) 
 U.S. government agencies that are responsible for overseeing public health concerns such 
as the Centers for Disease Control (CDC) and federal, state, and local health departments.  
 The 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 for 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 
H. Genetic Information Nondiscrimination Act (GINA)  
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA) 
generally makes it illegal for health insurance companies, group health plans, and employers of 
15 or more persons to discriminate against you based on your genetic information.  
Health insurance companies and group health plans may not request your genetic information 
that we get from this research. This means that they must not use your genetic information when 
making decisions regarding insurability. Be aware that this new federal law will not protect you 
against genetic discrimination by companies that sell life insurance, disability insurance, or long-
term care insurance. 
I. This authorization does not have an expiration date.

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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TITLE: BMT CTN 1502: Optimizing and Haploidentical Aplastic Anemia Transplantation  
Principal Investigator: Name: 
 
 
 
Phone:  
Address 1: 
 
 
 
 
 
 
 
Fax: 
Address 2: 
 
 
 
 
 
 
 
Email:  
For donors under 18, consent must be provided by the Legally Authorized Representative and 
Donor Assent is required (see Assent Section on the next page). 
 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 will 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 family 
member’s current care or prevent my family member from receiving future treatment. 
 I understand that I will be given a copy of this signed consent form. 
 
 
 
 
 
 
 
____________________________ 
Participant Name 
 
 
 
 
Date 
 
___________________________________  
____________________________  
 
Participant’s Signature (if 18 years or older)  
Date 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided.
 
___________________________________   
____________________ 
Name of Counseling Physician/Staff   
 
Date 
 
___________________________________  
____________________ 
Signature of Counseling Physician/Staff 
 
Date 
 
 
___________________________________  
____________________ 
Name of Interpreter 
 
 
 
 
Date 
 
 
___________________________________  
____________________ 
Signature of Interpreter 
 
 
 
Date 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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Pediatric Donor Assent to Participate in Research 
Study Title: 
Optimizing Haploidentical Aplastic Anemia Transplantation  
Protocol: 
BMT CTN 1502 
D. Why am I here? 
If you give us your permission, we would like to have an extra sample of your blood. We 
would collect the extra sample at the same time you have other blood tests done. 
E. Why are you doing this study? 
We are collecting blood samples from donors, like you, to learn more about how the ends of 
DNA in donors affects how patients do after their transplants. DNA is in your cells and 
carries all the information about how your body works. We will keep all of the extra samples 
private and store them in a place called a biorepository. Your name will not be on the 
samples.  
F. What will happen to me if I join the study? 
If you say you want to be in the study, we will ask you for:  
o 1 extra blood sample: We’ll collect about 2.5 teaspoons of blood (if you weigh less 
than 20kg) or 5 teaspoons of blood (if you weigh 20kg or more) 1 time. 
We will use a small needle to collect the blood from a vein in your arm.  
G. Will the blood draw hurt? 
When we collect your blood from a vein in your arm, it may feel like a pinch. It will hurt for 
a minute and the place where the needle went might be red and sore. You might get a little 
bruise from the needle but it goes away in a few days. We will collect the extra samples at 
the same time as you have other blood tests done. 
 
H. What if I have questions? 
You can ask any questions that you have about this study. If you forget to ask a question and 
think of it later, you can call me at: [insert office number].   
You can also ask your question the next time you see me. You can call the study office at any 
time to ask questions about the study. 
 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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I. How will you use my health information and blood samples? 
Your health information and blood samples will be used for a study about transplant in 
patients with severe aplastic anemia. 
J. How will you store my health information and blood samples? 
Your blood samples will be kept at a laboratory at Johns Hopkins  
All research samples will be tied to a number. This number will not be linked to your name 
or other identifying information.  
K. Will the study help me? 
This study will not help you or your family member, but it may help other people who need a 
transplant in the future. 
L. Will I be paid to be in the study? 
No, you will not be paid to be in the study. It will not cost you anything to be in the study. 
M. Do I have to be in this study? 
If you don’t want to be in this study, you need to tell us and your parent or guardian.  
Your doctor will not be angry or upset if you do not want to join. You can still give bone 
marrow to your family member who needs it. They will still get the exact same care.  
You can say yes now and change your mind at any time.   
Please talk this over with your parents before you decide if you want to give an extra blood 
sample for research. We will also ask your parents to give their permission for you to give an 
extra sample for research.  
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
B-44 
 
TITLE: BMT CTN 1502: Optimizing Haploidentical Aplastic Anemia Transplantation  
Principal Investigator:  
Name:  
 
 
 
 
 
 
 
Phone:  
Address 1: 
 
 
 
 
 
 
 
Fax: 
Address 2: 
 
 
 
 
 
 
 
Email:  
 
Writing your name on this page means that you agree to give an extra blood sample and know 
what will happen.  
If you want to quit the study, all you have to do is tell the person in charge.  
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Child 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Conducting Assent 
 
 
Date 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX C: 
 
LABORATORY PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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APPENDIX C: 
 
PROTOCOL-BASED LABORATORY PROCEDURES 
 
There is one protocol-required correlative laboratory study associated with the BMT CTN 1502 
trial. Study patients and consenting haplo-donors will also be provided the opportunity to 
participate in an optional correlative study. And finally, an optional opportunity will be offered 
to study patients to provide a single sample to be stored and used for future research.   
 
1) REQUIRED: Thymoglobulin® Pharmacokinetics (PK) 
 
The objective of the first lab correlate to the clinical trial will be to collect PK samples for 
Thymoglobulin® and to determine pre- and post-HSCT exposure levels (area under the curve, 
AUC) in all patients.  These exposure levels will then be correlated with clinically relevant 
metrics, including engraftment, rejection, GVHD, immune reconstitution, and survival.   
 
The PK assessment of Thymoglobulin® will be performed at UMC Utrecht in the laboratory of 
Jaap Jan Boelens and Rick Admiraal.  Thymoglobulin® concentrations will be determined from 
plasma samples. 
 
5 mL of blood for PK samples will be collected in an EDTA (lavender top) tube at 6 time points: 
 
1.) Upon completion of first dose infusion (within 60 minutes) 
With this draw, the start and end of the first Thymoglobulin® infusion (d-m-y 
hh:mm) and the timing of the sample (d-m-y hh:mm) must be documented 
 
2.) Prior to infusion of second dose (within 60 minutes) 
With this draw, the timing of the sample (d-m-y hh:mm) must be documented 
 
3.) Upon completion of second dose infusion (within 60 minutes) 
With this draw, the start and end of the second Thymoglobulin® infusion (d-m-y 
hh:mm) and the timing of the sample (d-m-y hh:mm) must be documented 
 
4.) Upon completion of third dose infusion (within 60 minutes) 
With this draw, the start and end of the second Thymoglobulin infusion (d-m-y 
hh:mm) and the timing of the sample (d-m-y hh:mm) must be documented 
 
5.) On day 0 (any time prior to stem cell infusion) 
CBC including absolute lymphocyte count should be collected on Day 0 (if 
possible) along with the PK sample and results documented in AdvantageEDC; 
the timing of the sample (d-m-y hh:mm) should also be documented 
 
6.) On day 7 (no time restrictions) 
With this draw, the timing of the sample (d-m-y hh:mm) must be documented 
 
All blood samples should be placed on ice after collection and promptly taken for processing into 

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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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plasma within 6 hours of collection.  Samples should be maintained cold while handling and 
final samples should be frozen.  Please see the protocol-specific Research Sample Information 
Guide for detailed processing, aliquot labeling, and frozen sample shipping procedures. 
 
Frozen samples will be batch-shipped on a biannual basis to the BMT CTN Biorepository 
managed by the NMDP.  Once the trial is complete and all PK samples obtained, they will then 
be transported together to UMC Utrecht for laboratory analysis. 
 
2) OPTIONAL:  Telomere Length Analysis  
 
The objective of the second lab correlate to the clinical trial will be to collect whole blood 
samples from consenting patients and each available consenting donor to measure leukocyte 
telomere length.  The telomere lengths will then be correlated with clinically relevant metrics, 
including disease phenotype, engraftment, and survival for research purposes.   
 
The telomere length will be measured by a CLIA-certified flow cytometry and FISH assay 
(Baerlocher Nature Protocols 2006) that is operated within the Johns Hopkins Pathology 
Laboratories (Armanios).  Subpopulations of leukocytes will include granulocytes and 
lymphocytes. 
 
The blood required from the patient (pre-HSCT conditioning) and donor (pre-donation) at a 
single time point will include: 
 
Adults: 4 EDTA purple tops (6cc mL, 24cc total)  
This will ensure yields for leukopenic patients especially if it will be shipped on Fridays. 
 
Children less than 20kg: 2 EDTA purple tops (6cc mL, 12cc total)  
 
Please see the protocol-specific Research Sample Information Guide for detailed sample labeling 
and same-day sample shipping procedures. 
 
The blood tubes will be shipped on the day of collection to the Johns Hopkins project laboratory 
by Priority Overnight FedEx courier.  No additional information will be provided to the patients 
or their treating physicians during the trial. Clinical correlations will be made in a retrospective 
fashion. 
 
3) OPTIONAL: Research Sample to Support Future Genomic Studies 
 
The objective of the optional research sample banking is to collect 3 mL of whole blood from all 
consenting patients pre-conditioning to support future genomic research.  Blood samples will be 
collected and processed at the clinical sites into three 1 mL cryovial aliquots and frozen. Please 
see the protocol-specific Research Sample Information Guide for detailed processing, aliquot 
labeling, and frozen sample shipping procedures. Frozen whole blood samples will be batch-
shipped on a biannual basis, along with the Thymoglobulin® PK samples, to the BMT CTN 
Biorepository managed by the NMDP. 
 

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Required - Thymoglobulin® Pharmacokinetics Correlative Study Research Samples 
Subjects 
Sample 
Type 
Sample Collection 
Time Points 
Stored 
Material 
Sample 
Processing 
& Storage Site 
Aliquots 
Stored 
Purpose 
Patients 
Peripheral 
Blood 
 
5 mL 
EDTA 
• Completion of first dose 
infusion 
• Prior to infusion of second dose 
• Completion of second dose 
infusion 
• Completion of third dose 
infusion 
• On Day 0 (prior to stem cell 
infusion) 
• On Day +7 post-stem cell 
infusion 
EDTA 
Plasma 
Samples processed 
on the day of 
collection by the 
clinical sites and 
frozen for future 
batch-shipment to 
the BMT CTN 
Biorepository. 
Four 0.5 mL 
EDTA plasma 
aliquots; stored 
at -80º C 
Thymoglobulin® 
Pharmacokinetics 
(PK) 
 
 
Optional - Telomere Length Analysis Correlative Study Research Samples 
Subjects 
Sample 
Type 
Sample Collection 
Time Point 
Sample Collection 
Summary 
Shipping 
Specifications 
Shipping and 
Testing 
Location 
Patients 
and 
Haplo-
Donors 
Peripheral 
Blood 
EDTA 
 
24 mL 
(adults) 
12 mL 
(children) 
Patient: pre-HSCT 
conditioning 
 
Haplo-donor: pre-
HSC donation 
Collect the peripheral blood 
sample and place into four (two 
for children) 6 mL Vacutainer 
tubes, containing EDTA 
anticoagulant. Gently mix 
sample by inversion 8-10 times 
to mix sample well with 
anticoagulant. 
Blood sample tubes 
will be shipped at 
ambient temperature, 
on the day of 
collection, to JHMI 
laboratory by priority 
overnight FedEx® 
delivery. 
Telomere Length 
Analysis 
 
Johns Hopkins 
Laboratory 
 
 
Optional - Future Research Samples 
Subjects 
Sample 
Type 
Sample 
Collection 
Time Point 
Stored 
Material 
Sample Processing 
& Storage Site 
Aliquots 
Stored 
Purpose 
Patients 
Peripheral 
Blood 
 
3 mL 
EDTA 
pre-HSCT 
conditioning 
 
Whole Blood 
EDTA 
Samples processed on 
the day of collection by 
the clinical sites and 
frozen for future batch-
shipment to the BMT 
CTN Biorepository. 
Three 1.0 mL 
whole blood 
aliquots; stored 
at -80º C 
Undefined Future 
Research 
(Genomic DNA 
Isolation) 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX D: 
WEIGHT CALCULATIONS 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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APPENDIX D: 
 
WEIGHT CALCULATIONS 
 
All chemotherapy doses will be calculated using weights determined as described below. 
 
Dosing should be based on total body weight (TBW), if < 125% of IBW, and adjusted ideal body 
weight (AIBW) in all patients ≥ 125% of IBW.  
 
Adjusted Ideal Body Weight (AIBW) Formula: 
     AIBW = IBW + [(0.25) x (actual body weight – IBW)] 
 
Ideal Body Weight (IBW) for Patients greater than 17 Years of Age and older (Devine 
equation): 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
For patients less than 5 feet, subtract 2.3 kg/inch 
  
Note for Centers using the metric system, the following equations can be used: 
Males IBW = 50 kg + [(cm ÷ 2.54 – 60) x 2.3 kg] 
Females IBW = 45.5 kg + [(cm ÷ 2.54 – 60) x 2.3 kg] 
For patients less than 152.4 cm feet, subtract 2.3 kg/2.54 cm 
 
Ideal Body Weight (IBW) for Patients 1 to 17 Years of Age: 
  
Less than 60 inches 
IBW = (ht2 x 1.65)/1000 where ht = cm, IBW = kg 
   
More than 60 inches 
Males IBW = 39.0 + [2.27 x (ht - 60)] where ht = inches, IBW = kg 
Females IBW = 42.2 + [2.27 x (ht - 60)] where ht = inches, IBW = kg 
 
Examples of calculations: 
  
EXAMPLE CALCULATION 1: 
A 62 year old female TBW 60 kg, height 64 inches   
IBW = 54.7 kg 
 
EXAMPLE CALCULATION 2: 
62 year old female  Weight 86 kg, height 64 inches 
IBW 54.7 kg 
TBW/IBW = 86/54.7 = 157% IBW 
AIBW  = IBW + 0..25(TBW – IBW) = 54.7 + 0.25(86 – 54.7) = 62.5 kg 
 
 

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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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EXAMPLE CALCULATION 3: 
62 year old Male  Weight 86 kg, height 68 inches 
IBW 68.4 kg 
TBW/IBW = 86/68.4 = 126% IBW 
AIBW  = IBW + 0..25(TBW – IBW) = 68.4 + 0.25(86 – 68.4) = 72.8 kg 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX E: 
 
CAMITTA CRITERIA FOR SAA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
APPENDIX E: 
 
CAMITTA CRITERIA FOR SAA 
 
Peripheral Blood 
Cytopenias 
Non-severe 
(Moderate) 
Aplastic Anemia 
(not meeting criteria for 
severe disease) 
Severe 
Aplastic Anemia 
(any 2 of 3) 
Very-severe 
Aplastic Anemia 
(meets criteria for severe 
disease and absolute 
neutrophils < 200) 
Bone Marrow 
Cellularity 
< 25% 
< 25% 
< 25% 
Absolute 
Neutrophil Count 
 
< 500 / ml 
< 200 / ml 
Platelet Count 
 
< 20,000 / ml 
 
Reticulocyte 
Count 
 
< 1.0% corrected 
or 
< 60,000 / ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX F: 
 
ABBREVIATIONS 
 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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APPENDIX F: 
 
ABBREVIATIONS 
 
AdvantageEDCTM – Proprietary electronic data capture system 
AE – Adverse Event 
AIBW: Adjusted Ideal Body weight 
aGVHD – Acute Graft Versus Host Disease 
ALT – Alanine Aminotransferase 
ANC – Absolute Neutrophil Count 
AST – Aspartate Aminotransferase 
ATG – Antithymocyte globulin 
AUC – Area under the curve 
BK – BK Virus 
BM – Bone Marrow 
BMT – Bone Marrow Transplant 
BMT CTN – Blood and Marrow Transplant Clinical Trials Network 
CBC – Complete Blood Count 
CD4 – Cluster of Differentiation 4 
CD34 – Cluster of Differentiation 34 
CD19 – Cluster of Differentiation 19 
CD56 – Cluster of Differentiation 56 
cGVHD – Chronic Graft Versus Host Disease 
cGY – Centigray 
CIBMTR – Center for International Blood and Marrow Transplant Research 
CMV – Cytomegalovirus 
CNI – Calcineurin inhibitor 
CNS – Central Nervous System 
CSA – Cyclosporin A 
CTCAE – Common Terminology Criteria for Adverse Effects 
CYP3A4 – Cytochrome P450 3A4 
DEB – Diepoxybutane 
DLCO – Diffusing Capacity of the Lung for Carbon Monoxide 
DMSO – Dimethyl Sulfoxide 
DNA – Deoxyribonucleic Acid 
EBV – Epstein Barr Virus 
FEV1 – Forced Expiratory Volume 1 
FVC – Forced Vital Capacity 
G-CSF – Granulocyte Colony Stimulating Factor 
GM-CSF – Granulocyte Macrophage Colony Stimulating Factor 
GVHD – Graft Versus Host Disease 
HCT-comorbidity – Hematopoietic Cell Transplant Comorbidity 
HIV – Human Immunodeficiency Virus 
HLA – Human Lymphocyte Antigen 
HSCT – Hematopoietic Stem Cell Transplantation 
HSV – Herpes Simplex Virus 

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HVG – Host Versus Graft 
IBW – Ideal Body Weight 
IST – Immunosuppressive Therapy 
IV – Intravenous 
IVIG – Intravenous Immunoglobulin 
MDS – Myelodysplastic Syndrome 
MMF – Mycophenolate Mofetil 
MMRD – Mismatched related Donor 
MMURD – Mismatched Unrelated Donor 
MOP – Manual of Procedures 
MPA – Mycophenolic Acid 
MSD – Matched Sibling Donor 
MUD – Matched Unrelated Donor 
NAT – Nucleic Acid Testing 
NCI – National Cancer Institute 
OS – Overall Survival 
PBSC – Peripheral Blood Stem Cells 
PCR – Polymerase Chain Reaction 
PFT – Pulmonary Function Testing 
PJP – Pneumocystis Jiroveci Pneumonia 
PK – Pharmacokinetics 
PO – Per Os (by mouth) 
PTLD – Post-Transplant Lymphoproliferative Disease 
SAA – Severe Aplastic Anemia 
SIADH – Syndrome of Inappropriate Antidiuretic Hormone 
SQ – Subcutaneous  
TBI – Total Body Irradiation 
VZV – Varicella Zoster Virus 
WBC – White Blood Cell 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX G: 
 
BONE MARROW HARVEST GUIDELINES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
APPENDIX G: 
 
BONE MARROW HARVEST GUIDELINES 39 
 
Bone marrow is usually harvested from the posterior iliac crests while the donor is under 
regional (spinal or epidural) or general anesthesia. Two individuals, usually a physician and a 
nurse practitioner or physician’s assistant, perform the harvest, one on each posterior iliac crest. 
The bone marrow cavity is entered through a skin puncture, after sterile prepping and draping. 
The posterior superior iliac spine is used as a starting anatomic landmark for the procedure. 
Large bore needles attached to 50 mL syringes rinsed with a heparinized solution are used for 
aspirating the marrow using a quick, vigorous suctioning technique. No more than 3-5 mL of a 
blood-bone marrow mixture should be withdrawn from a single aspirate, since aspirating more 
will dilute the marrow cells with peripheral blood. After 3-5 mL are aspirated, additional 
aspirates can by withdrawn from the same marrow puncture as long as the needle position is 
repositioned, i.e., withdrawing the needle 0.5 cm while changing the position of the bevel by 90o. 
Generally, 10-30 punctures into the marrow are made through a single skin puncture. Limiting 
any one skin puncture to 10-30 marrow punctures will also limit blood contamination as a result 
of local area bleeding. Thereafter, 2-3 additional skin punctures are made on each side of the 
iliac crest, each one several centimeters lateral to the previous, proceeding as far as necessary 
toward the anterior superior iliac spine to acquire sufficient marrow. The usual marrow harvest 
target for transplantation is 4 x 108 nucleated marrow cells per kg of the transplant recipient’s 
ideal weight, so that the volume collected (generally between 500 and 1500 mL) will vary on the 
size of the recipient and the marrow cell concentration (see below). The aspirated marrow is 
collected into semi-closed or closed system of filters and a bag containing anticoagulant 
(Fenwall, BioAcess). 
 
The collection is based on the target number of cells specified for the recipient. The nucleated 
cell/mL should be assessed during the procedure with a cell count that is called back to the 
operating room. Calculation of the total volume needed to achieve the target dose should then be 
used to clinically determine the final harvest volumes. Erring on the high end is preferred to 
underestimating doses. Equations used to calculate are as follows: 
 
1. Prior to the procedure, determine the weight of the collection bag or tare the scale.  The 
weight of the product (total weight minus bag or weight above the tared weight) is then 
divided by 1.058, the specific gravity of marrow.  This result (A) is the volume of the 
marrow. 
2. The marrow nucleated cell count (B) is determined by the nucleated cell count from the lab 
in cells/mL corrected by subtracting the number of peripheral blood white cells/mL 
presumed to be contaminating the marrow, and is then multiplied by the volume (A) to 
calculate the total nucleated cells:  A x B = TNC.   (Example: if marrow count is 27 and 
peripheral white cell count is 6, then the marrow mononuclear cell counts would be 21 = B) 
3. TNC should then be divided by ideal body weight to determine TNC/kg achieved (target 4 x 
108 nucleated cells/kg recipient ideal body weight). 
 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
(1.058 is the specific gravity that we use to convert weight to volume for bone marrow) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX H: 
 
GUIDANCE FOR MIXED CHIMERISM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
APPENDIX H: 
 
GUIDANCE FOR MIXED CHIMERISM 
 
Chimerism measurements should be assessed as per protocol requirements (Table 4.2.4). Primary 
and secondary graft failure are also defined (Section 3.2.3 and 4.2.4.2). There will be patients 
who meet criteria for mixed chimerism post-transplant who require special attention. 
 
Any donor chimerism below 99% in the myeloid or the T cell compartment should be considered 
mixed chimerism.  
 
Less than 50% donor CD3 chimerism in the early post-transplant period has correlated in 
malignant diseases with increased risk of graft loss or rejection. 
 
In aplastic anemia, a graft is considered functional if it results in correction of the underlying 
marrow failure with increase neutrophils and/or transfusion independence from baseline, even in 
the setting of mixed chimerism. 
 
Low early T-cell chimerism could be a harbinger of rejection or may improve spontaneously 
over time. 
 
Recommendations to avoid, and if it occurs, treat mixed chimerism:  
 
1. Optimize all possible cell counts in the donor harvest to achieve at least a goal of 3 x 108 
mononuclear cells/kg recipient weight. 
2. Ensure optimal compliance with all post-transplant immunosuppression. 
a. Mycophenolate mofetil should be given intravenously in patients in whom the 
oral preparation is not well tolerated 
b. Monitor levels of tacrolimus (as often as daily) to ensure therapeutic troughs of 
10-15ng/mL. 
3. If post-Day 28, Day 56, or Day 100 chimerism is low, increase frequency of monitoring 
per protocol (table 4.2.4), with monthly chimerisms until stable or resolved. 
4. Do not stop immunosuppression. Consider increasing levels to upper end of goal range 
for tacrolimus or CSP. 
5. Do not give DLI for chimerism. For patients with poor graft function and established 
donor chimerism, CD34+ selected cell boosts can be considered. 
6. Rule out additional immune phenomenon such as large granular lymphocytosis. 
7. Rule out contribution of infections or their treatments (e.g. valganciclovir for CMV, other 
treatments for EBV, HHV6, etc.). 
8. Continue close clinical follow up. 
9. Notify protocol chairs or medical monitor with questions or concerns. 
 
 
 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
NCT02918292 
Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX I: 
 
REFERENCES 
 
 
 

BMT CLINICAL TRIALS NETWORK 
 
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Optimizing Haplo for SAA – Protocol 1502                                                                   Version 4.0 – January 13, 2020 
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APPENDIX I: 
 
REFERENCES 
 
1. 
Young NS, Kaufman DW. The epidemiology of acquired aplastic anemia. Haematologica 
2008;93:489-492. 
2. 
DeZern AE, Zahurak M, Symons H, Cooke K, Jones RJ, Brodsky RA. Alternative Donor 
Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe 
Aplastic Anemia. Biol Blood Marrow Transplant 2017;23:498-504. 
3. 
Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012;120:1185-
1196. 
4. 
Eapen M, Horowitz MM. Alternative donor transplantation for aplastic anemia. 
Hematology Am Soc Hematol Educ Program 2010;2010:43-46. 
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Storb R, Blume KG, O'Donnell MR, et al. Cyclophosphamide and antithymocyte 
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