A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Haploidentical Related, Partially HLA-Mismatched, or Matched Unrelated Bone Marrow for Newly Diagnosed Patients With Severe Aplastic Anemia
Phase: PHASE2
Conditions: Severe Aplastic Anemia
Sponsor: Medical College of Wisconsin

 
CureAA: Clinical Trial of Upfront Haploidentical or Unrelated Donor BMT 
to Restore Normal Hematopoiesis in Aplastic Anemia 
A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Haploidentical 
Related, Partially HLA-Mismatched, or Matched Unrelated Bone Marrow for Newly 
Diagnosed Patients with Severe Aplastic Anemia 
Version 2.0 
 
Study Chairpersons 
Sally Arai, MD, MS1, Amy DeZern, MD, MHS2 
 
Protocol Team:
Brian Ball, MD3 
Daria Babushok, MD, PhD4 
Anna Bellach, PhD5 
Larisa Broglie, MD, MS6 
Blachy Davila, MD7 
Steven Devine, MD8 
Nancy DiFronzo, PhD5 
Amber Fritz, PhD9 
Nancy Geller, PhD5 
Sara Hammad, PharmD10 
Lori Henderson, PhD11 
 
 
Mary Horowitz, MD, MS6 
Adetola Kassim, MD, MS12 
Craig Malmberg, BS8 
Abhishek Mangaonkar, MBBS13 
Michael Martens, PhD6 
Manu Pandey, MD14 
Sagar Patel, MD15 
Nicole Ritzau, RN, BSN9 
Srinivasa Sanikommu, MD16 
Akshay Sharma, MBBS, MSc17 
Steven Tsai, MD, PhD18 
  
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute, in collaboration with Sanofi US Services Inc 
 
1Stanford University 
 
 
 
 
 10Sanofi US Services 
2Johns Hopkins University 
 
 
 
 11National Cancer Institute 
3City of Hope 
 
 
 
 
  
 12Vanderbilt University 
4University of Pennsylvania 
 
 
 
 13Mayo Clinic 
5National Heart, Lung, and Blood Institute 
 
 14University of Oklahoma 
6Medical College of Wisconsin  
 
  
 15Huntsman Cancer Institute 
7Children’s National Hospital 
 
 
  
 16Levine Cancer Institute 
8NMDP 
 
 
 
 
 
 
 17St. Jude’s Children’s Research Hospital 
9The Emmes Company   
 
 
 
 18University of California, Los Angeles 
 
 
 
Approval Signature (Protocol Chair) 
Approval Signature (Protocol Chair) 
 
 
 
 
           Approval Signature (Protocol Officer) 
Amy  DeZern
I am approving this
document.
Amy DeZern
15/Oct/2024 01:57 PM EDT
Sally  Arai
Sally Arai
I am approving this
document.
16/Oct/2024 12:28 PM EDT
Larisa  Broglie
I am approving this document.
15/Oct/2024 01:14 PM EDT
Larisa Broglie

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PROTOCOL SYNOPSIS 
Clinical Trial of Upfront Haploidentical or Unrelated Donor BMT 
 to Restore Normal Hematopoiesis in Aplastic Anemia 
(CureAA) 
 
Co-Principal Investigators: 
Amy DeZern and Sally Arai 
 
Study Design: 
This study is a prospective, multicenter Phase II study with participants 
receiving 
haploidentical 
transplantation 
or 
unrelated 
donor 
transplantation for previously untreated severe aplastic anemia (SAA). 
 
Primary Objective: 
The primary objective is to estimate graft versus host disease (GVHD)-
free failure-free survival (GFFS) (a composite endpoint of survival 
without Grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) 
requiring immunosuppression, or primary or secondary graft failure 
requiring second definitive therapy) at 1 year after initiation of 
conditioning. GFFS will be evaluated separately for each transplant 
cohort.  
 
Secondary Objectives: 
Secondary objectives are the following: 
1. Estimate overall survival (OS) at 1 year after initiation of 
conditioning. 
2. Estimate FFS (a composite end point of survival without initiation 
of treatment with a second definitive therapy for curative intent) at 
1 year after initiation of conditioning. 
3. Estimate the probability of being engrafted (i.e., without primary or 
secondary graft failure) and alive at 1 year after initiation of 
conditioning. 
4. Estimate the cumulative incidences of neutrophil recovery at Day 
+28 and Day +56 post-hematopoietic stem cell transplantation 
(HSCT), platelet recovery at Day +100 post-HSCT, and red blood 
cell recovery at Day +100, Day +180, and Day +365 post-HSCT. 
5. Estimate the cumulative incidences of primary, secondary, and any 
graft failure at 1 year post-HSCT. 
6. Estimate the hematologic response classification according to the 
NIH criteria at Day +100, Day +180, and Day +365 post-HSCT. 
7. Estimate the cumulative incidences of Grade II-IV and Grade III-IV 
aGVHD at Day +100 post-HSCT. 
8. Estimate the cumulative incidences of all cGVHD and cGVHD 
requiring immunosuppression at 1 year post-HSCT. 
Exploratory Objectives: 
Exploratory objectives are the following: 
1. Describe the pace and quality of immune reconstitution by 
measuring CD4, CD19, and CD56 counts pre-HSCT and at Day 
+100, Day +180, and Day +365 post-HSCT. 
2. Describe the rates of specific infectious complications (CMV 
viremia and disease, EBV viremia, and PTLD) within the first year 
after HSCT. 

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3. Quantify how many available donors each patient has, including 
8/10, 9/10, and 10/10 unrelated donors and all haploidentical 
donors. 
4. Describe the time to enrollment after HLA typing of the recipient. 
5. Describe the time from diagnosis of SAA until 1) start of 
conditioning and 2) until HSCT. 
6. Describe total and CD34+ cell doses for haploidentical and 
unrelated donors. 
7. Describe times to donor activation, donor selection, start of 
conditioning, and transplant from enrollment. 
8. Describe the quality of life for SAA participants treated on this 
protocol. 
 
Eligibility Criteria: 
Diagnosis of SAA, without a fully matched related sibling donor 
available, but with a haploidentical or unrelated marrow donor 
available. Exclusions include inherited bone marrow failure syndrome, 
previous treatment for SAA including high-dose immunosuppressive 
therapy or hematopoietic stem cell transplantation (HSCT), history of 
solid organ transplant, uncontrolled infection, inadequate organ 
function, pregnancy, and performance score < 60. 
 
Treatment Description: 
Participants will be treated with a preparative regimen of fludarabine 
(150 mg/m2), cyclophosphamide (29 mg/kg), low dose total body 
irradiation (TBI, 400 cGy), and Thymoglobulin® (4.5 mg/kg). GVHD 
prophylaxis will be with post-HSCT cyclophosphamide (100 mg/kg), 
tacrolimus, and mycophenolate mofetil (MMF). 
 
Accrual Objective: 
The goal is 60 participants in total who initiate the protocol-specified 
conditioning regimen, 30 in each of the haploidentical and unrelated 
donor transplant cohorts. Additional participants may be screened, 
consented, and registered in order to reach accrual goals. 
 
Accrual Period: 
The estimated accrual period is 3 years. 
 
Study Duration: 
Participants will be followed for 1 year post-HSCT. 
 
Correlative Studies: 
Samples will be banked pre- and post-HSCT for future submitted 
protocols for use of specimens. 
 
Stopping Guidelines: 
Key safety endpoints for the study are graft failure, early mortality, and 
Grade III-IV acute GVHD. The rates of graft failure by Day 56 post-
HSCT, Grade III-IV acute GVHD by Day 100 post-HSCT, and mortality 
by Day 115 post-ATG preparation will be monitored on a daily basis 
using truncated sequential probability ratio tests (SPRT) for binary 
data. The SPRTs will test the null hypotheses that the graft failure rate 
does not exceed 10%, that the Grade III-IV acute GVHD rate does not 
exceed 15%, and that the early mortality rate does not exceed 10%. 
 
 
 

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TREATMENT SCHEMA 
 
Days -9  
 Thymoglobulin® 0.5 mg/kg intravenous (IV) with pre-meds 
↓ 
Days -8,-7 
Thymoglobulin® 2 mg/kg IV daily with pre-meds 
↓ 
Days -6, -5 
Fludarabine 30 mg/m2 IV daily (adjusted for renal function) 
 
Cyclophosphamide (CTX) 14.5 mg/kg IV daily 
 
Start steroid taper per institutional practice from Thymoglobulin® 
↓ 
Days –4à -2 Fludarabine 30 mg/m2 IV daily (adjusted for renal function) 
Day –1 
Total body irradiation (TBI) 400 cGy delivered in a single fraction 
↓ 
Day 0 
Infuse bone marrow per institutional standards 
 
 
↓ 
Days 3, 4 
Cyclophosphamide (PTCy) 50 mg/kg IV daily 
 
Mesna per institutional practice 
(First dose of PTCy must be administered 60-72 hrs after START of infusion of marrow) 
 
↓ 
Day 5  
Begin Tacrolimus 
Begin mycophenolate mofetil (MMF) 15 mg/kg (PO) 3 times a day (TID) (maximum daily dose 3 g/day) 
Begin G-CSF at 5 mcg/kg/day until absolute neutrophil count (ANC) is > 1500 for 3 days 
 
 
(At least 24 hours after the last dose of PTCy) 
 
↓ 
Day 28   Assess Chimerism in peripheral blood, assess graft versus host disease (GVHD) 
 
↓ 
Day 35  
 
 
 
Discontinue MMF 
 
↓ 
Day 56  Assess Chimerism in peripheral blood and bone marrow (with biopsy) 
 
Assess GVHD 
 
↓ 
 
Day 180 
Discontinue tacrolimus if no GVHD and full chimera 
 
Evaluate disease 
 
 
  
Assess Chimerism in peripheral blood, assess GVHD 
 
↓ 
Day 365  
 
 
Evaluate disease 
 
 
 
 Assess Chimerism in peripheral blood and bone marrow 

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TABLE OF CONTENTS 
1 
BACKGROUND ................................................................................................................. 1 
1.1 
Bone Marrow Transplantation (HSCT) and Immunosuppressive Therapy for SAA ......... 1 
1.2 
Regimen for HSCT in SAA ............................................................................................. 2 
1.3 
Supportive Pilot Data ...................................................................................................... 2 
1.4 
Summary ........................................................................................................................ 4 
2 
STUDY DESIGN ................................................................................................................. 5 
2.1 
Study Overview .............................................................................................................. 5 
2.2 
Hypotheses and Objectives ............................................................................................ 5 
2.2.1 Hypotheses ................................................................................................................ 5 
2.2.2 Objectives .................................................................................................................. 5 
2.3 
Participant Eligibility Criteria for Enrollment .................................................................... 6 
2.3.1 Participant Inclusion Criteria ....................................................................................... 6 
2.3.2 Participant Exclusion Criteria ..................................................................................... 7 
2.4 
Donor Selection Criteria ................................................................................................. 8 
2.5 
Site Eligibility .................................................................................................................11 
2.6 
Treatment Plan ..............................................................................................................11 
2.6.1 Conditioning and GVHD Prophylaxis .........................................................................11 
2.6.2 GVHD Treatment ......................................................................................................13 
2.6.3 Supportive Care ........................................................................................................13 
2.6.4 Risks and Toxicities ..................................................................................................15 
2.7 
Study Conduct ...............................................................................................................19 
3 
STUDY ENDPOINTS AND DEFINITIONS .........................................................................20 
3.1 
Primary Endpoint: GVHD-free, Failure-Free Survival (GFFS) ........................................20 
3.2 
Secondary Endpoints ....................................................................................................20 
3.2.1 Overall Survival (OS) ................................................................................................20 
3.2.2 Failure-Free Survival (FFS) .......................................................................................20 
3.2.3 Being Alive and Engrafted .........................................................................................20 
3.2.4 Neutrophil Recovery ..................................................................................................20 
3.2.5 Red Blood Cell Recovery ..........................................................................................20 
3.2.6 Platelet Recovery ......................................................................................................21 
3.2.7 Primary Graft Failure .................................................................................................21 
3.2.8 Secondary Graft Failure ............................................................................................21 
3.2.9 Hematologic Response .............................................................................................21 
3.2.10 GVHD .......................................................................................................................21 
3.3 
Exploratory Endpoints ...................................................................................................22 
3.3.1 Time to Enrollment ....................................................................................................22 

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3.3.2 Time from Diagnosis of SAA to Conditioning and to Transplant ................................22 
3.3.3 Time to Donor Activation, Donor Selection, Start of Conditioning, and Transplant.....22 
3.3.4 Donor Availability ......................................................................................................22 
3.3.5 HSCT Cell Dose ........................................................................................................22 
3.3.6 Immune Reconstitution .............................................................................................22 
3.3.7 Infection ....................................................................................................................22 
3.3.8 Health Related Quality of Life (HR-QoL) ...................................................................22 
4 
PARTICIPANT ENROLLMENT AND EVALUATION ........................................................23 
4.1 
Cohort Selection ............................................................................................................23 
4.2 
Enrollment Procedures ..................................................................................................23 
4.3 
Study Monitoring ...........................................................................................................23 
4.3.1 Follow-up Schedule ...................................................................................................23 
4.3.2 Data Capture Forms ..................................................................................................24 
4.3.3 Adverse Event Reporting ..........................................................................................25 
4.3.4 Classification of Adverse Events by Severity .............................................................26 
4.3.5 Classification of Adverse Events by Relationship to Study Intervention .....................26 
4.3.6 Required Adverse Event Reporting ...........................................................................26 
4.3.7 Procedure in Case of Pregnancy ...............................................................................27 
4.3.8 Participant Evaluations ..............................................................................................27 
5 
STATISTICAL CONSIDERATIONS ..................................................................................35 
5.1 
Study Overview .............................................................................................................35 
5.1.1 Accrual Duration .......................................................................................................35 
5.1.2 Primary Objective and Endpoint ................................................................................35 
5.1.3 Randomization and Blinding ......................................................................................35 
5.2 
Sample Size and Power Considerations ........................................................................35 
5.3 
Interim Analysis and Stopping Guidelines ......................................................................36 
5.3.1 Graft Failure by Day 56 Post-HSCT ..........................................................................37 
5.3.2 Grade 3-4 Acute GVHD through Day +100 Post-HSCT .............................................37 
5.3.3 Mortality by Day 115 After Initiation of Conditioning ..................................................38 
5.4 
Demographic and Baseline Characteristics ...................................................................39 
5.5 
Statistical Analysis Plan .................................................................................................40 
5.5.1 Analysis Populations .................................................................................................40 
5.5.2 Analysis of the Primary Endpoint ...............................................................................40 
5.5.3 Analysis of Secondary Endpoints ..............................................................................42 
5.5.4 Analysis of Exploratory Endpoints .............................................................................44 
5.5.5 Analysis of Safety Endpoints .....................................................................................46 
 
 

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APPENDIX A  HUMAN SUBJECTS .........................................................................................47 
APPENDIX B  LABORATORY PROCEDURES .......................................................................48 
APPENDIX C  WEIGHT CALCULATIONS ...............................................................................50 
APPENDIX D  CAMITTA [56] CRITERIA FOR SAA ................................................................51 
APPENDIX E  ABBREVIATIONS .............................................................................................52 
APPENDIX F  BONE MARROW HARVEST GUIDELINES [57] ...............................................56 
APPENDIX G  GUIDANCE FOR MIXED CHIMERISM .............................................................57 
APPENDIX H BMT CTN INFECTION GRADING TABLE AND RECURRENCE INTERVAL 
DEFINITIONS ....................................................................................................................58 
APPENDIX I  DIAGNOSIS AND SEVERITY SCORING FOR ACUTE AND CHRONIC GVHD 68 
APPENDIX J  PATIENT-REPORTED OUTCOME (PRO) QUESTIONS ...................................75 
APPENDIX K  CYTOKINE RELEASE SYNDROME GUIDANCE AND MANAGEMENT ..........90 
APPENDIX L  REFERENCES ..................................................................................................92 
 
 

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LIST OF TABLES 
Table 2.4.1: Donor Selection ......................................................................................... 10 
Table 2.6.1: Suggested Preemptive Dose Reduction of Tacrolimus when Azoles are 
Initiated at Steady State Levels of Tacrolimus .............................................................. 18 
Table 4.3.1: Follow-Up Schedule .................................................................................. 24 
Table 4.3.2: Pediatric (Age 5-7) PRO Assessments...................................................... 31 
Table 4.3.3: Pediatric (Age 8-17) PRO Assessments.................................................... 32 
Table 4.3.4: Adult (Age 18+) PRO Assessments .......................................................... 32 
Table 4.3.5: Summary of Assessments ......................................................................... 33 
Table 5.2.1: Possible Confidence Intervals for GFFS Probability at 1 Year After Initiation 
of Conditioning in a 30-Participant Cohort ..................................................................... 36 
Table 5.3.1: Stopping Guideline for Graft Failure through Day +56 Post-HSCT in a 30-
Participant Cohort.......................................................................................................... 37 
Table 5.3.2: Operating Characteristics of Sequential Monitoring Procedure for Graft 
Failure through Day +56 Post-HSCT in a 30-Participant Cohort ................................... 37 
Table 5.3.3: Stopping Guideline for Grade 3-4 Acute GVHD through Day +100 Post-
HSCT in a 30-Participant Cohort ................................................................................... 38 
Table 5.3.4: Operating Characteristics of Sequential Monitoring Procedure for Grade 3-4 
Acute GVHD through Day +100 Post-HSCT in a 30-Participant Cohort ........................ 38 
Table 5.3.5: Stopping Guideline for Mortality through Day +115 After Initiation of 
Conditioning in a 30-Participant Cohort ......................................................................... 39 
Table 5.3.6: Operating Characteristics of Sequential Monitoring Procedure for Mortality 
through Day +115 After Initiation of Conditioning in a 30-Participant Cohort ................ 39 
 
LIST OF FIGURES 
 
Figure 2.6.1: Conditioning and GVHD Prophylaxis Schematic ........................................ 11 
Figure 5.5.1: Coverage Probabilities of Nominal 90% Confidence Intervals from Test-
Then-Pool Procedure for Cohort 1 Estimated from 100000 Simulated Trials ................ 42 
 
 

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CHAPTER 1 
1 
BACKGROUND 
1.1 Bone Marrow Transplantation (HSCT) and Immunosuppressive Therapy for 
SAA 
Acquired severe aplastic anemia (SAA) is a rare, life-threatening hematopoietic stem cell disorder 
that manifests with pancytopenia.[1, 2] Bone marrow failure results from autoimmune destruction 
of hematopoietic stem cells.[1] Without definitive treatment, mortality from SAA approaches 70% 
at 2 years. Fungal infections are the leading cause of death; however, hemorrhage, evolution to 
clonal disease (myelodysplastic syndromes [MDS], leukemia, and paroxysmal nocturnal 
hemoglobinuria [PNH]), and transfusional iron overload are other causes of severe morbidity and 
mortality. 
Immunosuppressive therapy (IST) has been the standard front-line treatment for SAA for 
decades, except for patients aged < 40 years with a suitable human leukocyte antigen 
(HLA)-matched sibling donor (MSD) where bone marrow transplantation (hematopoietic stem cell 
transplantation [HSCT]) is standard first-line therapy.[3, 4] The standard IST regimen (ATG and 
cyclosporine) has undergone modest improvements to decrease the time to hematologic 
response, [4, 5] but longer-term durability remains relatively unchanged even with the addition of 
eltrombopag. The hematopoietic response after IST is ~ 70% - 80% even with recent 
augmentation of IST by eltrombopag.[3, 4, 6] Failure-free survival, defined as patients alive and 
in remission without clonal disease more than 10 years after IST, remains < 40% in most series.[1, 
3, 7-10] In the Phase 3 RACE trial (A prospective Randomized multicenter study comparing horse 
antithymocyte globulin (hATG) + Cyclosporine A (CsA) with or without eltrombopag as front-line 
therapy for SAA), event-free survival (defined as time from start of treatment to either relapse, 
death, treatment failure or clonal evolution [whichever occurs first]) for the ATG, cyclosporine, 
eltrombopag regimen was only 56% at 1 year and 46% at 2 years.[5] When IST fails, patients 
often require HSCT. 
Unfortunately, complications following IST may negatively affect HSCT utilization, donor options, 
and post-HSCT outcomes. Among patients receiving IST, clonal evolution to MDS or acute 
myeloid leukemia (AML) occurs in about 13%.[11] The most common MDS-associated clonal 
cytogenetic abnormality after IST for SAA is monosomy 7, which has notoriously poor outcomes 
with HSCT.[12] IST failure can also lead to higher rates of donor specific antibodies and therefore, 
limit the availability of suitable mismatched donor (related or unrelated) options. Long-term 
immunosuppressive use with cyclosporine can also limit quality of life post-IST with orthopedic 
complications such as avascular necrosis, organ complications including renal failure, or 
pulmonary fungal infections.[13] All of these issues could preclude HSCT as an option for an 
individual patient with SAA. Although 90 out of 197 patients enrolled in the RACE Trial were 
non-responders after IST, only 23 patients proceeded to HSCT.[5] In contrast, successful 
allogeneic bone marrow transplantation (alloBMT) in SAA not only overcomes the complications 
of the disease, but also eliminates the risk of relapse and secondary clonal disease. Innovations 
in recent decades have steadily reduced the morbidity and mortality of adult patients undergoing 
transplantation from donors other than MSDs (alternative donor HSCT). Standard platforms exist 
that allow rapid hematopoietic reconstitution-- representing a cure in SAA.[14] Long-term 
historical survival after HSCT is ~ 90% in patients aged < 20 years, [15, 16] and 75% in older 
patients.[14, 16] Due to concerns for morbidity and mortality, HSCT with an unrelated or 
HLA-haploidentical (haplo) related donor is currently reserved following failure of IST in most 
centers.[17-23] However, whether alternative donor HSCT should be reserved only as salvage 
therapy following failure of IST or performed upfront is currently unknown. This multicenter clinical 
trial is intended to bring alternative donor HSCT to the forefront of therapy for all HSCT-eligible 
SAA patients. 

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1.2 Regimen for HSCT in SAA 
For nearly 40 years, the treatment of choice for young patients with SAA has been MSD HSCT. 
This medical preference was related to rapid recovery of hematopoiesis, minimal complications, 
mitigation of clonal evolution rates, and impressive rates of overall survival (OS).[24] 
Cyclophosphamide (50 mg/kg/day × 4 days) with or without ATG, has traditionally been used as 
conditioning before these MSD HSCTs. Although this regimen is non-myeloablative, the 
immunosuppression is sufficient to allow engraftment in most cases. TBI and busulfan are 
avoided for MSD HSCT to reduce transplant-related complications such as mucositis, GVHD, 
second malignancies, and infertility. Survival rates following MSD allogeneic HSCT steadily 
improved since the 1970s largely because of improved supportive care, refined HLA typing, and 
better GVHD prophylaxis.[25] However, late HSCT-related complications such as chronic GVHD 
(cGVHD) occur in up to one-third of patients, with many of these patients requiring long-term 
therapy for their GVHD. In patients under 30 years of age, the event-free survival after 
HLA-matched sibling HSCT ranges from 70% to 90%. These reduced rates are predominantly 
due to GVHD (the rates of which steadily increase with age) and late graft failures.[26] 
Patients without a MSD must choose an alternative donor – haploidentical relatives (siblings, 
parents, cousins, aunt, uncles, etc.), or HLA-matched or mismatched unrelated donors. Mixed 
chimerism or late secondary graft failure and GVHD remain obstacles to longer-term successful 
outcomes after alternative donor HSCT for SAA. These outcomes are ripe for improvement. 
More recent research efforts in SAA HSCT have focused on transplant feasibility using 
mismatched donors to expand the donor pool. The most promising approach to facilitate 
engraftment and mitigate the risk of GVHD is the use of post-transplant cyclophosphamide (PTCy) 
for GVHD prophylaxis. These regimens have also augmented the TBI dosing from 200 cGy to 
400 cGy in 2019 to enhance engraftment, as learned from studies in sickle disease and MDS 
patients. These studies demonstrated success with haploidentical donors with > 90% full donor 
chimerism and < 10% GVHD.[27, 28] The use of PTCy has also resulted in decreased GVHD in 
the matched unrelated donor setting, with wide adoption of this GVHD prevention strategy for 
patients with both hematologic malignancies and non-malignant diseases.[29, 30] 
There is prior experience with PTCY. In the BMT CTN 1502 trial, NCT02918292, reported the 
outcomes of 31 pediatric and adult patients transplanted using reduced-intensity conditioning, 
related HLA-haploidentical (haplo) donors, and post-transplantation cyclophosphamide-based 
graft versus host (GVHD) prophylaxis. Because the trial offered an alternative to individuals 
without fully matched unrelated donors, over 60% of the enrollment was from underrepresented 
race/ethnicity patients. Twenty-four patients were alive with engraftment at 1 year with an 
additional patient alive with autologous recovery of hematopoiesis. Patients experienced low rates 
of graft versus host disease, with no severe chronic GVHD. Key post hoc analysis showed higher 
cell doses from bone marrow harvests are crucial to the success of this approach. This practice 
changing study expands the donor pool and access to BMT across all populations. This 
successful trial led to the obvious next step of this upfront trial. The trial did, however, only use 
200 cGY TBI. Given the rarity of SAA, there have been no comparative studies of conditioning or 
GVHD prophylaxis regimens. 
1.3  Supportive Pilot Data 
Haploidentical Transplantation 
In a single-center study published in 2023, [28] the authors demonstrated an OS rate of 92% at 
3 years using HLA-haplo HSCT for pediatric and adult participants with treatment-naïve SAA. The 
OS for those receiving 400 cGy was 100%. This pilot study opened for enrollment in August 2016 
and continued through July 2020. Twenty participants were treated on trial, and thereafter 
7 participants were treated identically for further pilot data in the recent publication. Median 
follow-up for all patients was 40.9 months (95% confidence interval [CI]: 29.4, 55.7 months). The 
minimum follow-up was 6.0 months, and the maximal follow-up was 73.8 months. Of the 

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27 transplanted participants, 14 (52%) were male, with 37% of the cohort self-reported as 
non-white. There were 3 (11%) participants who were Asian/ Pacific Islander, 6 (21%) were Black, 
and 1 (3%) was mixed or other race with 1 (3%) reporting as Hispanic. The median age at 
enrollment was 25 (range, 3-63, interquartile range [IQR], 17-52) years. The median age of the 
haplo donors was 30 years (range, 13-56, IQR, 26-44). Twenty-five participants were alive, of 
whom 24 had sustained engraftment at 1 year, showing a feasibility of 88.9% (95% CI: 70.8%, 
97.7%) of getting to BMT, engrafting and having graft present at 1 year. The OS for the 
27 participants was 92% (95% CI: 83%,100%) at 1, 2, and 3 years. 
The proportion of participants alive and engrafted at one year (graft failure-free survival) was 89% 
(95% CI: 77%, 100%). In this trial, the TBI dose was increased from 200 to 400 cGy to reduce 
graft failure after graft loss in 3 of the first 7 patients. All 20 consecutive participants who received 
400 cGy are alive and well with > 95% donor engraftment in whole blood and CD3 compartments. 
Two (6%) deaths were reported post-transplant. Two participants died of infection 
(cytomegalovirus [CMV] in an adult patient with secondary graft failure and Epstein-Barr virus 
[EBV] in a pediatric participant with primary graft failure). A third participant had secondary graft 
failure but later became 100% chimeric using the identical conditioning platform and a second 
HLA-haplo HSCT. 
Twenty-six of 27 participants achieved neutrophil recovery by Day 28. The median time to 
neutrophil recovery was 17 (range 14-88) days. The Day 28 cumulative incidence of neutrophil 
recovery was 96% (95% CI: 87%-100%). The median time to platelet recovery was 25.5 days 
with 90% transfusion independence by Day 100. The Day 100 incidence of platelet recovery was 
88% (95% CI: 74%-100%). The median time to red cell recovery was 25.5 days with 90% 
transfusion independence by Day 60. 
Eighteen (67%) individual participants experienced infections post-transplant. Of a total of 
39 infection events, 37 were Grade 2 and 2 were Grade 5 by Common Terminology Criteria for 
Adverse Events (CTCAE) grading. Both of the documented Grade 5 infections occurred in the 
2 participants who lost grafts and died of viral infection in that setting. The majority of documented 
infections were viral reactivation documented by polymerase chain reaction (PCR), followed by 
bacterial infections. Four (4) participants had documented fungal infections and 2 were in 
participants with graft failure. These participants did not pursue a 2nd transplant. Eleven (11) 
participants experienced CMV reactivation with 6 (55%) requiring therapy. One (1) participant had 
documented EBV-associated post-transplant lymphoproliferative disease (PTLD) that developed 
following secondary graft failure. 
Rates of acute GVHD (aGVHD) and cGVHD were both less than 10%, and no participant 
developed Grade 3-4 acute nor moderate/severe cGVHD. The cumulative incidence of 
Grade II-IV aGVHD at Day 100 was 7% (95% CI: not applicable [NA], 17%) and cGVHD at 2 years 
was 4% (95% CI: NA, 11%). 
Unrelated Donor Transplantation 
The identical regimen published in the haplo setting [28] as above has also been used in the 
unrelated donor setting. Also in the single-center setting, 11 adult participants (median age: 
25 years; range: 24 to 38 years) with treatment-naïve or refractory SAA were transplanted with 
matched donor marrow grafts (related and unrelated) with the Baltimore regimen as previously 
published.[31, 32] 
The median follow-up of this 11-participant cohort was 53.8 (range: 6-99) months. The OS for 
11 participants is 100% at 1 and 2 years, and 90% (95% CI: 73%, 100%) at 3 years. The median 
time to neutrophil recovery was 17 (range: 14-41) days. The Day 28 cumulative incidence of 
neutrophil recovery was 91% (95% CI: 69%-100%). The median time to platelet recovery was 
26 days with 91% transfusion independence by Day 100. The median time to red cell recovery 
was 31 days with 91% transfusion independence by Day 100. This is quite consistent with 
published timelines from other donor sources.[31] Ten (10) of the 11 participants had sustained 

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> 95% donor chimerism in both whole blood and CD3 compartments through one year. Nine 
(81%) participants experienced infections post-transplant. Of a total of 14 infection events, 
11 were Grade 2 and 3 were Grade 3, again by CTCAE grading. Two (2) of the documented 
Grade 3 infections occurred in a participant with secondary graft failure from adenovirus. Two (2) 
participants experienced CMV reactivation evidenced by viremia treated to undetectable by Day 
100, and no patients had EBV. The cumulative incidence of Grade II-IV aGVHD at Day 100 was 
9% (95% CI: NA, 27%), while the cumulative incidence of cGVHD at 2 years was 19% (95% CI: 
NA, 45%); no case of GVHD was beyond Grade 2 skin and mouth, and all lacked any other organ 
involvement.[31] Additionally, the standard of care for GVHD prophylaxis in patients receiving 
matched unrelated donor and mismatched donor HSCT has also recently shifted with a rapid rise 
in the use of PTCy.[33] This shift is due in part to the work of the BMT- CTN and others with 
studies showing superior outcomes with lower rates of GVHD utilizing PTCy-based GVHD 
prophylaxis.[34-37] 
Other groups have reported comparably low GVHD rates when PTCy is used for GVHD 
prophylaxis in the setting of mismatched unrelated donors.[38, 39] An NMDP study reported on 
80 patients that received mismatched unrelated donor bone marrow transplantation for 
hematologic malignancies (7/8 HLA match in 61%, 6/8 HLA-matched in 24%, remaining 4-5/8 
HLA-matched). Overall survival at 1-year was 76% (90%CI 67.3-83.3) and did not differ by HLA 
match grade (7/8 vs 6/8 or less). Survival outcomes were compared to contemporary 
haploidentical controls reported to the Center for International Blood and Marrow Transplant 
Research (CIBMTR) and found to be similar. The results of this study prompted a larger phase II 
clinical trial that is ongoing (NCT 04904588) utilizing peripheral blood stem cell grafts. 
1.4 Summary 
In conclusion, a major challenge in treating acquired SAA is the management of patients who 
desire a path to a cure but do not have a MSD. Although IST produces hematologic recovery in 
a substantial proportion of patients, in many of those patients, recovery is not complete, and all 
remain at risk for subsequent hematologic disorders such as MDS or AML. Many patients have 
historically been deemed ineligible for HSCT simply because they lack a suitable donor. Here, we 
seek to increase options for these patients, allowing HSCT to be considered as a potential 
treatment by using a novel GVHD prophylaxis strategy with PTCy that allows expansion of the 
donor pool to include haplo donors and unrelated donors (URDs). We have chosen age 3 years 
to start this protocol as this was the youngest patient in the pilot. We hypothesize that this 
approach will improve survival without transplant-associated morbidity by demonstrating low 
toxicity, reducing rates of GVHD and showing rapid hematologic recovery without graft failure 
making HSCT a viable option for upfront treatment of all patients. Additionally, we will evaluate 
key secondary endpoints traditionally used to evaluate success of upfront IST such as overall 
survival (OS), failure-free survival (FFS) and hematologic response according to the National 
Institutes of Health (NIH) criteria.[40] Clinical comparison of these endpoint measures with current 
results achieved with upfront IST will help in determining if a future randomized trial comparing 
IST with this approach to HSCT is warranted. 

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CHAPTER 2 
2 
STUDY DESIGN 
2.1 Study Overview 
This study is a prospective Phase II trial to assess if it is effective for previously untreated SAA 
participants to be transplanted using non-myeloablative conditioning and PTCy. This is a parallel 
cohort study comprised of two cohorts: haplo transplant and URD transplant. The accrual goal is 
30 participants enrolled and starting protocol-specified conditioning in each cohort, yielding 
60 participants in total. 
2.2 Hypotheses and Objectives 
2.2.1 Hypotheses 
Primary Hypothesis: 
Using the regimen described below, the point estimate of GVHD-free, failure-free survival 
(GFFS) at 1 year after initiation of conditioning will be greater than or equal to 75% in 
participants who receive a bone marrow transplant from a haplo donor or URD for first-line 
therapy in SAA. 
2.2.2 Objectives 
Primary Objective: 
Estimate GVHD-free failure-free survival (GFFS) (a composite end point of survival without Grade 
III-IV aGVHD, cGVHD requiring immunosuppression, or primary or secondary graft failure 
requiring second definitive therapy) at 1 year after initiation of conditioning. GFFS will be 
evaluated separately for each transplant cohort. 
Secondary Objectives: 
1. Estimate OS at 1 year after initiation of conditioning. 
2. Estimate FFS (a composite end point of survival without initiation of treatment with a 
second definitive therapy for curative intent) at 1 year after initiation of conditioning. 
3. Estimate the probability of being engrafted (i.e., without primary or secondary graft failure) 
and alive at 1 year after initiation of conditioning. 
4. Estimate the cumulative incidences of neutrophil recovery at Day +28 and Day +56 
post-HSCT, platelet recovery at Day +100 post-HSCT, and red blood cell recovery at 
Day +100, Day +180, and Day +365 post-HSCT. 
5. Estimate the cumulative incidences of primary, secondary, and any graft failure at 1 year 
post-HSCT. 
6. Estimate the hematologic response classification according to the NIH criteria at 
Day +100, Day +180, and Day +365 post-HSCT. 
7. Estimate the cumulative incidences of Grade II-IV and Grade III-IV aGVHD at Day +100 
post-HSCT. 
8. Estimate 
the 
cumulative 
incidences 
of 
all 
cGVHD 
and 
cGVHD 
requiring 
immunosuppression at 1 year post-HSCT. 

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Exploratory Objectives: 
1. Describe the pace and quality of immune reconstitution by measuring CD4, CD19, and 
CD56 counts pre-HSCT and at Day +100, Day +180, and Day +365 post-HSCT. 
2. Describe the rates of specific infectious complications (CMV viremia and disease, EBV 
viremia, and PTLD) within the first year after HSCT. 
3. Quantify how many available donors each patient has, including 8/10, 9/10, and 10/10 
unrelated donors and all haploidentical donors. 
4. Describe the time to enrollment after HLA typing of the recipient. 
5. Describe the time from diagnosis of SAA until 1) start of conditioning and 2) until HSCT. 
6. Describe total and CD34+ cell doses for haploidentical and unrelated donors. 
7. Describe times to donor activation, donor selection, start of conditioning, and transplant 
from enrollment. 
8. Describe the quality of life for SAA participants treated on this protocol. 
2.3 Participant Eligibility Criteria for Enrollment 
2.3.1 Participant Inclusion Criteria 
1. Age 3 years to 75 years (see Section 2.5). 
2. Confirmed diagnosis of acquired SAA defined as:[41] 
a. Bone marrow cellularity < 25% or variable marrow cellularity but with < 30% 
residual hematopoietic cells deemed HYPOcellular for age AND 
b. Two (2) out of 3 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 donor as per Investigator’s discretion (6/6 match for 
HLA-A and B at intermediate or high-resolution and DRB1 at high-resolution using 
deoxyribonucleic acid [DNA]-based typing) available. 
4. Available donor per Section 2.4. 
5. Participant and/or legal guardian must sign informed consent. 
6. Adequate organ function defined by institutional transplant standards or defined as below: 
a. Cardiac: Left ventricular ejection fraction (LVEF) at rest > 40% with no clinical signs 
of cardiac failure. For participants aged<13years,shorteningfraction(SF)≥26%
by echocardiogram or multigated acquisition (MUGA) may be substituted for LVEF. 
b. Hepatic: Total bilirubin < 2.0 mg/dL unless Gilbert’s disease is present 
c. Renal: 
i. For participants > 13.0 years of age at the time of enrollment: estimated 
creatinine clearance (CrCl) > 60 mL/minute (per institutional standard). 
Please refer to Body Weight calculations in Appendix C. 

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ii. For participants < 13.0 years of age at enrollment: glomerular filtration rate 
(GFR) estimated by the updated Schwartz formula1 ≥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 participants > 13.0 years of age: 
• 
Diffusing capacity of the lung for carbon monoxide (DLCO, 
corrected/adjusted for hemoglobin [Hb]) > 50%, or 
• 
Spirometry with forced expiratory volume 1 (FEV1) > 50% predicted 
(without administration of bronchodilator) and forced vital capacity 
(FVC) > 50% predicted. 
ii. For participants < 13.0 years of age unable to perform pulmonary function 
tests (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%]). 
7. Karnofsky or Lansky performance status ≥60%. 
8. 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 Participant Exclusion Criteria 
1. Inherited bone marrow failure syndromes such as Fanconi anemia and short telomere 
syndromes must be ruled out according to center standards. It is recommended that 
functional testing for Fanconi Anemia (di-epoxybutane [DEB] chromosomal breakage 
analysis) and telomere length assessment be performed. If available, genetic panels for 
inherited bone marrow failure syndromes can be considered as an alternative to functional 
testing. 
2. Clonal cytogenetic abnormalities consistent with pre-MDS or MDS on marrow examination 
(e.g., monosomy 7 and other MDS-defining changes per recent pathology guidelines).[42, 
43] 
3. Formal diagnosis of MDS by World Health Organization (WHO) 2022 or International 
Consensus Classification (ICC).[42, 43] 
4. Recipient positive for HLA antibodies against a mismatched HLA in the selected donor 
determined by the presence of donor specific HLA antibodies (DSA) to any mismatched 
HLA allele/antigen at any of the following loci (HLA-A, -B, -C, –DRB1, DRB3, DRB4, 
DRB5, -DQA1, -DQB1, -DPA1, -DPB1) with median fluorescence intensity (MFI) >3000 
by microarray-based single antigen bead testing. In patients receiving red blood cell or 
platelet transfusions, DSA evaluation must be performed or repeated post-transfusion and 
 
1 Schwartz formula: 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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immediately prior to initiation of recipient preparative regimen to ensure there is 
confirmation of no DSA to the selected donor when conditioning starts. 
5. Prior desensitization attempt for HLA antibodies to chosen donor. Any intervention with 
the sole intent to reduce the level of HLA DSA, (e.g., plasmapheresis, intravenous 
immunoglobulin [IVIG], MMF, etc.) would constitute a desensitization attempt. 
6. Prior treatment for SAA (e.g., immunosuppressive therapy using ATG, calcineurin 
inhibitors [CNIs], thrombopoietin receptor agonists or androgens). Short courses of 
steroids or IVIG that were not explicitly administered for SAA therapy will be allowed. 
7. Prior allogeneic stem cell transplant. 
8. Prior solid organ transplant. 
9. Known life-threatening reaction (i.e., anaphylaxis) to Thymoglobulin® (Sanofi) that would 
prohibit use for the participant as this study requires use of the Thymoglobulin® (Sanofi) 
preparation of ATG. 
10. 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. 
11. Female participants who are pregnant, as detected using a pregnancy test as 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. 
Of note, participants with seropositivity for the human immunodeficiency virus (HIV) may be 
considered if viral load is undetectable. Similarly, carriers of hepatitis B (HepB) or hepatitis C 
(HepC) may not have a detectable viral load of HepB virus or HepC virus. 
Participants with HIV that is well-controlled on combination antiretroviral therapy and no 
AIDS-related complications within the past 12 months are eligible. 
Infections other than HIV: 
• 
Prior infections must be controlled 
• 
HepB participants are eligible if on effective suppressive therapy and otherwise meet 
inclusion/exclusion criteria 
• 
HepC participants are eligible if otherwise meet inclusion/exclusion criteria 
2.4 Donor Selection Criteria 
1. Donor selection is based on HLA typing and relationship to recipient (Table 2.4.1). 
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 incompatibility due to HLA antibodies or a 
medical reason. 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 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.[44] 

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3. All Donors must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DRB1,  
-DQB1, and -DPB1 and recommend -DQA1 and DPA1 for cases with possible participant 
–DQA1 or DPA1 anti-HLA antibodies. 
a. For URDs, must be unrelated to the participant and high-resolution HLA-matched 
at 8/10, 9/10, or 10/10 (HLA-A, -B, -C, -DRB1, -DQB1) with up to one mismatch 
allowed at HLA-A, -B, -C, or -DRB1. 
b. For Haplo Donors, 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. 
4. Age > 18 years at the time of signing informed consent. 
5. Meet the medical suitability requirements of donor registries’ (unrelated) or individual 
sites’ (haploidentical) for bone marrow (BM) donation. 
6. Must undergo eligibility screening according to current Food and Drug Administration 
(FDA) requirements. Donors who do not meet one or more of the donor screening 
requirements may donate under urgent medical need. 
7. Must agree to donate BM. 
8. Additional considerations for donor selection should be given to: 
a. Prioritize donors under 35 years of age but depends on clinical situation, e.g., BM 
and size of donor 
b. Avoid donors where the estimated cell dose (total nucleated cells [TNC]) will be 
<2.5x108/kg recipient weight. Cell dose can be estimated using the following 
NMDP formula:[45] Estimated maximum donor volume2 x 0.183e8/mL = Estimated 
total nucleated cells 
c. ABO compatibility 
d. CMV matching 
e. B-Leader genotype for HLA-B mismatched donors 
f. Male over female for larger donor weight or donor weight if known 
g. Domestic donors over international donors for speed of acquisition 
 
2Estimated maximum donor volume (mL) = Donor weight (in kg) x 20 mL/kg 

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Table 2.4.1: Donor Selection 
Suggested Haplo Donor Selection Algorithm 
NOTE: Any donor chosen must be medically and psychologically fit and consent to donation. The list 
below are considerations and are not a hierarchy. Direct questions may be addressed to the protocol 
chairs. 
• 
No anti-donor specific HLA antibody as described in Section 2.3.2, criterion 4
• 
Younger donor over older donor
-- Degree of HLA match or degree of kinship are not prioritized 
• 
ABO compatible over minor incompatible over major incompatible
• 
CMV-compatible (seronegative into seronegative or seropositive into seropositive) over CMV-
incompatible 
Suggested Unrelated Donor Selection Algorithm[46] 
• 
High-resolution matches for Antigen Recognition Domain matching level (ARD), for 7 matched 
alleles if applicable 
• 
Select HLA-C*03.03 vs C*03:04 mismatch, if present 
• 
No other preference for mismatched loci (HLA-A/B/C/DRB1) or other allele combinations
• 
Younger donor over older donor
 
• 
Select matched/permissive DPB1 mismatch based on the algorithm developed by Crivello et al
[47, 48] (https://www.ebi.ac.uk/ipd/imgt/hla/matching/dpb_v2/)  
• 
Minimize mismatches at HLA-DRB3/4/5 and HLA-DQB1
• 
Select donor with single allele mismatched at patient’s homozygous locus (HLA-A/B/C/DRB1), 
if applicable 
• 
Avoid mismatches of allotypes targeted by DSAs, including DQA1 and DPA1 as described in 
Section 2.3.2, criterion 4 
• 
Avoid donors where estimated cell dose will be <2.5x108/kg. Cell dose can be estimated using 
the following NMDP formula: [45] Estimated maximum donor volume1 x 0.183e8/mL = 
Estimated total nucleated cells
• 
Prioritize domestic donors over international donors
Transplant center practice may differ in additional considerations to use in the selection among multiple 
donors equivalent for the characteristics above. 
Abbreviations: ARD: Antigen Recognition Domain; CMV: cytomegalovirus; DSA: donor specific HLA antibodies; 
HLA: human leukocyte antigen; URD: unrelated donor 
1Estimated maximum donor volume (mL) = Donor weight (in kg) x 20 mL/kg 
 
 
 
 
 
 

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2.5 Site Eligibility 
1. PTCTC sites who currently have the TransIT Trial open (or planned to open) and are 
Pediatric-only sites will not open this trial until TransIT completes enrollment. 
2. PTCTC TransIT sites that have an adult HSCT program may activate this trial for 
participants older than 25 years. 
2.6 Treatment Plan 
2.6.1 Conditioning and GVHD Prophylaxis 
The conditioning and GVHD prophylaxis schematic is provided in Figure 2.6.1. Refer to 
Appendix C for weight-based dosing adjustments as outlined in this section by medication. 
Figure 2.6.1: Conditioning and GVHD Prophylaxis Schematic 
 
 
2.6.1.1 
Conditioning for Bone Marrow Recipients 
2.6.1.1.1 Fludarabine 
The fludarabine dose will be 30 mg/m2 intravenously (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 participant is < 125% of ideal body weight (IBW). For 
participants > 125% of IBW, fludarabine will be dosed based upon the recipient’s adjusted ideal 
body weight (AIBW) as per Appendix C. For participants who have an estimated or measured 
creatinine clearance < 70 mL/min/1.73 m2, prior brain radiation, or prior intrathecal chemotherapy, 
the fludarabine dose should be reduced by 20%. Fludarabine dosing is based on the last 
creatinine clearance prior to the start of conditioning. The fludarabine dose should be the same 
on Days -6 to -2, even if the participant’s creatinine changes. 

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2.6.1.1.2 Pre-HSCT Cyclophosphamide 
The 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 hr infusion (total dose received 29 mg/kg). Cyclophosphamide dosing 
should be based on recipient’s actual body weight in all participants < 125% of IBW. For 
participants > 125% of IBW, cyclophosphamide will be dosed based upon the recipient’s adjusted 
ideal body weight (AIBW) as per Appendix C. 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. 
2.6.1.1.3 Total Body Irradiation 
TBI is to be delivered in a single fraction of 400 cGy on Day -1. TBI may be delivered from either 
linear accelerator or Cobalt sources (per institutional practice). 
2.6.1.1.4 Thymoglobulin® 
The Thymoglobulin® (Sanofi) preparation of rabbit ATG will be dosed upon actual body weight. 
The dose will be 0.5 mg/kg IV on Day -9 over 6 hrs and 2 mg/kg IV on Days -8 and -7 over 4 hrs. 
Premedication should be administered per institutional protocol. Note: Thymoglobulin® (Sanofi) 
is the required preparation of ATG for this study and will be provided by Sanofi. Other 
supplies of ATG may not be used. 
2.6.1.2 
Marrow Product Handling & Infusion 
Participants 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 BM will be harvested with a target yield of 4 x 108 nucleated cells per kilogram of recipient 
IBW, and a recommended minimum yield of 2.5 x 108 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 TNC 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 F for additional BM harvesting guidelines. 
The infusion will be done per institutional standards. 
Note: The participant 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 a medical emergency 
(e.g., treatment of anaphylaxis). Guidelines for management of suspected cytokine release 
syndrome (CRS) are provided in Appendix K. In the event that a participant requires 
steroids, please notify the Emmes Protocol Coordinator. 

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2.6.1.3 
GVHD Prophylaxis 
2.6.1.3.1 Post-HSCT Cyclophosphamide 
Cyclophosphamide 50 mg/kg IV daily will be given for 2 days on Days +3 and +4 (total dose 
received 100 mg/kg) after transplantation. The first dose of cyclophosphamide must be 
administered 60-72 hours after the start of the marrow infusion. Cyclophosphamide and mesna 
will be given post-transplant and dosed based on IBW or actual body weight, whichever is less. 
For participants > 125% of IBW, cyclophosphamide will be dosed based upon the recipient’s 
adjusted ideal body weight (AIBW), as per Appendix C. 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 cyclophosphamide doses. 
2.6.1.3.2 Tacrolimus 
Tacrolimus IV or by mouth (per os, 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 trough level of 10-15 ng/mL. The recommended IV starting dose is 0.03 mg/kg/day 
either as a continuous infusion or divided into q12 hour IV bolus dosing based on actual body 
weight. PO equivalent dosing is acceptable at a suggested starting dose of 0.05-0.1 mg/kg/dose 
PO BID. If the participant converts from IV to PO once therapeutic levels are achieved, a 
suggested IV to PO conversion of 1:3 can be used or per institutional standards. Tacrolimus 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. Please see 
Section 2.6.4.2.5 on Tacrolimus for further information. 
2.6.1.3.3 Mycophenolate Mofetil 
The MMF dose will be 15 mg/kg PO TID up to 1 g TID (or IV equivalent) starting on Day +5 
(24 hours after the end of the infusion of post-HSCT cyclophosphamide; max dose 3000 mg/day) 
and will be discontinued after the last dose on Day +35 or may continue if active GVHD is present. 
2.6.1.3.4 Growth Factor 
Granulocyte colony stimulating factor (G-CSF) will be given IV or subcutaneously (SQ) starting 
on Day +5 (24 hours after the end of the infusion of post-HSCT cyclophosphamide) at 
5 mcg/kg/day (rounded to nearest vial size) until absolute neutrophil count (ANC) is > 1500 for 
3 days. Pegfilgrastim (Neulasta®) and granulocyte macrophage colony stimulating factor 
(GM-CSF) are not permitted. 
2.6.2 GVHD Treatment 
In the event of the development of either aGVHD or cGVHD, therapy will be at the discretion of 
treating centers. For participants with aGVHD or cGVHD refractory to standard of care treatments, 
investigational agents may be considered. Discussion with the protocol chair or protocol officer is 
encouraged. 
2.6.3 Supportive Care 
2.6.3.1 
Infectious Disease Prophylaxis 
Antifungal prophylaxis will be administered according to institutional practices. It is important to 
follow levels of cyclosporine and tacrolimus for participants receiving one of the azole antifungal 
medications. Please see Section 2.6.4.2.5. 

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Pneumocystis jiroveci pneumonia (PJP) prophylaxis will be administered according to institutional 
practices. Recommendations include starting approximately 1-month post-HSCT (or later if white 
blood cells [WBCs] not recovering) and continuing until the participant has been off of all 
immunosuppressive medications for at least 3 months. 
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 1 year post-HSCT and while on immunosuppressive medications. 
Prophylaxis for CMV with letermovir or institutional standards for participants at risk of CMV 
reactivation, defined as either CMV immunoglobulin G (IgG) positive pre-transplant, or CMV 
negative but receiving a CMV positive stem cell product as well as continuation of CMV monitoring 
through weaning of all immunosuppression is strongly recommended. Viral prophylaxis for EBV 
(including use of rituximab) may be administered according to institutional practices. 
Prophylactic and empiric antibiotics as well as IVIG will be administered according to institutional 
practices. Re-immunization may be performed according to institutional practices. 
2.6.3.2 
Infectious Disease Monitoring 
CMV viremia as tested by DNA PCR will be monitored at minimum weekly after transplant until 
Day +100. Participants who are viremic or show evidence of end organ CMV disease may be 
treated according to institutional practices. For participants at risk of CMV reactivation, defined as 
either CMV immunoglobulin G (IgG) positive pre transplant, or CMV negative but receiving a CMV 
positive stem cell product, prophylaxis with letermovir or institutional standards as well as 
continuation of CMV monitoring though weaning of all immunosuppression is strongly 
recommended. 
EBV viremia as tested by DNA PCR will be monitored at minimum weekly after transplant until 
Day +100. If the participant becomes viremic, as determined by the treating provider, the 
recommendation is to use rituximab (375 mg/m2 IV x 1) or treat according to institutional practice. 
If the participant develops persistent EBV viremia or signs/symptoms of EBV-related PTLD 
despite rituximab administration, treatment is recommended according to institutional practice. 
Adenovirus viremia as tested by DNA PCR will be monitored at minimum weekly after transplant 
until Day +100. Participants who are viremic or show evidence of adenovirus disease may be 
treated according to institutional practices. 
Screening for additional infections, including HHV-6, may be done per institutional practice but is 
not mandated by protocol. In addition, all Grade 2 and 3 infections, according to the BMT CTN 
Technical Guideline (see Appendix H for infection grading), will be reported on the infection data 
capture form up to 1 year post HSCT. 
2.6.3.3 
Management of Graft Failure 
Participants experiencing primary or secondary graft failure or poor graft function are managed 
according to institutional practices. 
For this protocol, lineage-specific, myeloid, and T cell chimerism measurements are required. 
Myeloid engraftment might not proceed at the same rate as T cell engraftment. In the presence 
of neutrophil recovery, a participant who achieved a myeloid chimerism greater than or equal to 
5% donor with < 5% donor chimerism in the T cell compartment is not considered a primary graft 
failure as recovery of the myeloid compartment has priority in aplastic anemia. 
In the event that Day 100 chimerism results in less than 50% donor in either myeloid or T cell 
compartment, additional lineage-specific chimerism testing should be performed every 4 weeks 
or as clinically indicated until the chimerism is greater than or equal to 50% donor and/or remains 
at a constant range for 3 consecutive tests. 

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Patients not meeting graft failure but having sustained cytopenia of 2 or 3 lineages for over 
2 weeks and meeting the following criteria may be treated as having poor graft function (based 
on the combined European Society for Blood and Marrow Transplantation [EBMT] and American 
Society for Transplantation and Cellular Therapy [ASTCT] definitions):[49, 50] 
• 
frequent dependence on blood/platelet/growth factor support, and 
• 
with full donor chimerism of > 95%, and 
• 
hypoplastic-aplastic BM, if performed, and 
• 
absence of other explanations, such as drugs or infections. 
Management of graft failure and poor graft function is per institutional standards. Mixed chimerism 
not fitting the definition of graft failure should be managed per Appendix G. 
2.6.3.4 
Management of ATG Intolerance 
Participants who experience a new, severe, or life-threatening reaction to ATG and are 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 per local Investigator discretion with 
documentation of the deviation in the data system. 
2.6.4 Risks and Toxicities 
2.6.4.1 
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, and viral (including CMV, Polyomavirus [BK virus]) 
infection; severe mucositis; severe GVHD; hepatic veno-occlusive disease; pulmonary toxicities; 
hemorrhagic cystitis; transplant-associated thrombotic microangiopathy (TA-TMA), renal 
insufficiency; bleeding without hemodynamic compromise. 
2.6.4.2 
Drug Information 
2.6.4.2.1 Fludarabine 
Fludarabine is a purine analog antimetabolite. Side effects of fludarabine include: 
• 
Cardiac: edema 
• 
Gastrointestinal: vomiting, anorexia, nausea, mucositis 
• 
General: fatigue, fever, chills 
• 
Hematologic: anemia, thrombocytopenia, neutropenia 
• 
Hepatic: increased liver function tests 
• 
Neurologic: paresthesia, confusion, seizure, agitation, visual disturbances, pain, coma 
• 
Pulmonary: cough, shortness of breath 
• 
Renal: renal impairment, hematuria 
• 
Miscellaneous: infection, general organ damage, hearing loss, rash, allergic reaction 
Dose adjustments: Dose adjustments of fludarabine are required for renal insufficiency, prior brain 
radiation, prior intrathecal chemotherapy, and weight (see Section 2.6.1.1.1). 

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2.6.4.2.2 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: 
• 
Cardiac and vascular: heart failure (which can result in edema, effusion, dyspnea) 
• 
Cutaneous: alopecia, rash, hyperpigmentation of skin and nails 
• 
Gastrointestinal: nausea, vomiting, diarrhea, anorexia, abdominal pain, mucositis, 
stomatitis 
• 
General: lethargy 
• 
Hematologic: leukopenia, thrombocytopenia, anemia 
• 
Pulmonary: pulmonary fibrosis 
• 
Renal: renal impairment 
• 
Endocrine: amenorrhea, gonadal function impairment, sterility, syndrome of inappropriate 
antidiuretic hormone secretion (SIADH) - with associated cerebral edema 
• 
Genitourinary: hemorrhagic cystitis 
• 
Miscellaneous: infection, allergic reaction, secondary malignancy 
Dose adjustments: Dose adjustments for cyclophosphamide will be made for weight  (see Section 
2.6.1.3.1). 
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 determined per institutional practice. 
At the doses used for uroprotection, mesna is virtually non-toxic. However, potential adverse 
effects include nausea, vomiting, diarrhea, abdominal pain, altered taste, rash, itching, headache, 
joint or limb pain, hypotension, and fatigue. 
2.6.4.2.3 Thymoglobulin® 
Thymoglobulin® (Sanofi) is a rabbit preparation of ATG. Thymoglobulin side effects include: 
• 
Cardiovascular: tachycardia, hypertension, hypotension 
• 
Cutaneous: rash, itching 
• 
Endocrine: hyperkalemia, hyperphosphatemia, hypokalemia, acidosis 
• 
Gastrointestinal: nausea, vomiting, abdominal pain, diarrhea, constipation 
• 
Hematologic: anemia, thrombocytopenia, leukopenia, febrile neutropenia 
• 
Hepatobiliary: transaminases increased 
• 
Musculoskeletal: myalgia, arthralgia, weakness 
• 
Neurologic: headache, insomnia, anxiety, pain 
• 
Respiratory: dyspnea 
• 
Miscellaneous: infection, fever, infusion reaction, allergic reaction including anaphylaxis 
and anaphylactic shock, CRS (please see Appendix K for guidelines on grading and 
management of suspected CRS), sweating, chills, edema, serum sickness, malignancy 
(lymphoma or lymphoproliferative disorders) 
Dose adjustments: Dose adjustments for Thymoglobulin will not be made. 

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2.6.4.2.4 Mycophenolate Mofetil 
Mycophenolate mofetil (MMF) is an ester prodrug of the active immunosuppressant mycophenolic 
acid (MPA). Side effects of MMF include: 
• 
Cardiac and vascular: hypertension, hypotension, tachycardia, edema 
• 
Cutaneous: rash 
• 
Endocrine and metabolic: hypocalcemia, hypokalemia, hyperuricemia, hyperkalemia, 
hypomagnesemia 
• 
Gastrointestinal: nausea, vomiting, dyspepsia, abdominal pain, diarrhea 
• 
Genitourinary: teratogenicity, miscarriage, limited effectiveness of birth control 
• 
Hematologic: leukopenia, thrombocytopenia, anemia 
• 
Neurologic: 
headache, 
tremors, 
insomnia, 
dizziness, 
progressive 
multifocal 
leukoencephalopathy (PML) 
• 
Pulmonary: dyspnea, cough, interstitial lung disease 
• 
Miscellaneous: change in vision, infection, secondary malignancy, arthralgia, myalgia 
Drug interactions: MMF activity is decreased with oral antacids and cholestyramine. There are no 
pharmacokinetic (PK) 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 MPA level should be checked. If 
the level is greater than 2 mcg/mL, it will require a dose reduction. 
2.6.4.2.5 Tacrolimus 
Tacrolimus is a macrolide immunosuppressant that inhibits lymphocytes through calcineurin 
inhibition. 
Tacrolimus side effects include: 
• 
Cardiovascular: pericardial effusion, hypertension (which may cause arrhythmia, angina, 
myocardial infarction) 
• 
Cutaneous: itching, rash 
• 
Endocrine and metabolic: hyperglycemia, hypomagnesemia, hypokalemia, hyperkalemia, 
hypophosphatemia, hyperlipidemia 
• 
Gastrointestinal: constipation, diarrhea, nausea, vomiting, anorexia, bowel perforation, 
dyspepsia 
• 
General: fever, fatigue 
• 
Hematologic: anemia, thrombocytopenia, leukopenia, thrombotic microangiopathy 
• 
Hepatic: liver dysfunction 
• 
Neurologic: paresthesia, headache, tremor, posterior reversible encephalopathy 
syndrome (PRES), dizziness, insomnia, confusion, altered mental status, seizure, 
blindness 
• 
Pulmonary: pleural effusion, dyspnea 
• 
Renal: renal impairment which may require dialysis, peripheral edema 
• 
Miscellaneous: infection, post-transplant lymphoproliferative disorders, allergic reaction, 
secondary malignancy 

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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. Participants with hepatic or renal insufficiency should 
receive doses at the lower end of concentrations (5-10 ng/mL). No dose adjustments are required 
in participants 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 Table 2.6.1 below. Dose adjustments for therapy with 
other azoles may be indicated. However, the initial tacrolimus dose (on Day 5) remains fixed to 
ensure participants become therapeutic initially. 
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 Table 2.6.1 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 
stopped. Rather, tacrolimus dose increases should be cautious and based on more frequent 
monitoring of levels as appropriate. 
 
Table 2.6.1: Suggested Preemptive Dose Reduction of Tacrolimus when Azoles 
are Initiated at Steady State Levels of Tacrolimus 
Antifungal
Tacrolimus
Dose↓
Comment
Voriconazole 
67%
At least 50% reduction strongly advised
Posaconazole
67%
At least 50% reduction strongly advised
Itraconazole
50%
At least 50% reduction strongly advised
Fluconazole 
25%
No reduction suggested/Consider mold-
active azole as above
2.6.4.2.6 Filgrastim (G-CSF) 
Filgrastim side effects include: 
• 
Cardiovascular: chest pain, hypertension 
• 
Dermatologic: rash, erythema, alopecia, irritation at injection site 
• 
Endocrine and metabolic: increased lactate dehydrogenase 
• 
Gastrointestinal: diarrhea, nausea 
• 
Genitourinary: urinary tract infection 
• 
Hematologic: anemia, thrombocytopenia, leukocytosis, vasculitis 
• 
Hepatic: increased liver enzymes 
• 
Musculoskeletal: myalgia, arthralgia, muscle spasms 
• 
Neurologic: headache, dizziness, fatigue, generalized pain, hypoesthesia 
• 
Renal: glomerulonephritis 

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• 
Respiratory: cough, dyspnea, upper respiratory tract infections, acute respiratory 
distress syndrome 
• 
Miscellaneous: bone pain, fever, allergic reaction, splenomegaly, splenic rupture, 
capillary leak syndrome 
Dosing considerations: Dose reduction or interruption of therapy should be considered if 
glomerulonephritis due to filgrastim occurs. 
2.6.4.2.7 Total Body Irradiation 
TBI side effects include: 
• 
Cutaneous: erythema, hyperpigmentation, alopecia 
• 
Gastrointestinal: nausea, vomiting, diarrhea, parotitis, mucositis, abdominal cramping 
• 
General: fever, fatigue 
• 
Genitourinary: gonadal impairment 
• 
Hepatic: hepatic sinusoidal obstruction syndrome 
• 
Hematologic: myelosuppression, anemia, thrombocytopenia 
• 
Pulmonary: interstitial pneumonitis 
• 
Renal: nephropathy 
• 
Miscellaneous: infection, short stature, vertebral deformities, cataracts, secondary 
malignancy, hormonal impairment 
2.6.4.3 
Toxicity Grading 
Toxicities are graded using the National Cancer Institute (NCI) CTCAE Version 5.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
2.7 Study Conduct 
This study will be conducted in accordance with the protocol, the BMT CTN Administrative Manual 
of Procedures (MOP, located on the BMT CTN Website), and the following: a) Consensus ethical 
principles derived from international guidelines including the Declaration of Helsinki; b) Applicable 
International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines and 
c) Applicable laws and regulations. The NMDP single Institutional Review Board (IRB) of Record 
will oversee this study and conduct the study-specific reviews as required by federal regulations 
and per the NMDP IRB SOPs. Site personnel will enter data in the electronic data capture system 
as described in the BMT CTN 2207 forms guide. 
Source documentation should be made available for monitoring visits, audits, and regulatory 
inspections as described in the BMT CTN Administrative MOP. Participating Principal 
Investigators (PIs) bear ultimate responsibility for training of site staff as well as the scientific, 
technical, and administrative aspects of conduct of the protocol, even when certain tasks have 
been delegated to coinvestigators, sub-investigators, or staff. The PIs have a responsibility to 
protect the rights and welfare of participants and comply with all requirements regarding the 
clinical obligations and all other pertinent requirements in 21 Code of Federal Regulations (CFR) 
part 312. In addition to following applicable federal, state, and local regulations, Investigators are 
expected to follow ethical principles and standards and receive training in GCP every 3 years and 
human subjects training within the past 3 years and thereafter as per institutional requirements. 
 

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CHAPTER 3 
3 
STUDY ENDPOINTS AND DEFINITIONS 
3.1 Primary Endpoint: GVHD-free, Failure-Free Survival (GFFS) 
The primary endpoint is GFFS at 1 year after initiation of conditioning. Events for GFFS include 
Grade III-IV aGVHD, cGVHD requiring immunosuppression, primary or secondary graft failure 
requiring second definitive therapy, failure to receive an HSCT infusion, and death. GFFS is 
defined as the time interval from start of conditioning until the first of these events occurs. For 
failure to receive an HSCT infusion, the date will be at the time the decision not to proceed to 
HSCT is made. 
3.2 Secondary Endpoints 
3.2.1 Overall Survival (OS) 
Events for OS include death from any cause. OS is defined as the time interval from initiation of 
conditioning until death. The OS probability will be assessed at 1 year after initiation of 
conditioning. 
3.2.2 Failure-Free Survival (FFS) 
Events for FFS include treatment failure or death. Treatment failure is defined as the initiation of 
treatment with a second definitive therapy. FFS is defined as the time interval from start of 
conditioning until the start date of a second definitive therapy or death, whichever occurs first. 
The FFS probability will be assessed at 1 year after initiation of conditioning. 
3.2.3 Being Alive and Engrafted  
The proportion of patients who are alive with donor cells present at 1 year after initiation of 
conditioning will be described, where the presence of donor cells is defined as achieving at least 
5% myeloid donor chimerism (whole blood or marrow) in the most recent measurement through 
1 year. 
3.2.4 Neutrophil Recovery 
Neutrophil recovery is achieving an ANC ≥ 0.5 x109/L for 3 consecutive measurements on 
different days, with the first of the 3 days being defined as the day of neutrophil recovery. The 
cumulative incidences of neutrophil recovery at Day +28 and Day +56 post-HSCT will be 
estimated. 
3.2.5 Red Blood Cell Recovery 
Redbloodcell(RBC)recoveryisdefinedasHblevel≥7g/dLwithnoredcelltransfusioninthe
preceding 7 days. The first day of the 7 days will be defined as the day of RBC recovery. The 
cumulative incidences of RBC recovery at Day +100, Day +180, and Day +365 post-HSCT will 
be estimated. 

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3.2.6 Platelet Recovery 
Plateletrecoveryisdefinedbyachievingaplateletcount≥20x109/L with no platelet transfusions 
in the preceding 7 days. The first 7 days of the sustained platelet count will be defined as the day 
of platelet recovery. The cumulative incidence of platelet recovery at Day +100 post-HSCT will be 
estimated. 
3.2.7 Primary Graft Failure 
Primary graft failure is defined as the occurrence of any of the following: 
1. Lack of neutrophil recovery by Day +56 post-HSCT. 
2. Failure to achieve at least 5% myeloid donor chimerism (whole blood or marrow) on any 
measurement up to and including Day +56 post-HSCT. 
3. Administration of a second definitive therapy, which is defined as a second transplant 
(following conditioning regimen) or a course of ATG. A CD34+ boost or use of growth 
factors will NOT be considered as a second definitive therapy. 
The proportion of patients with primary graft failure through Day +56 post-HSCT will be 
estimated. 
3.2.8 Secondary Graft Failure 
Secondary graft failure is defined as the occurrence of any of the following: 
1. Initial neutrophil recovery (ANC greater than or equal to 0.5 x109/L measured for 
3 consecutive measurements on different days) with whole blood or marrow donor 
chimerism greater than or equal to 5%, followed by sustained subsequent decline in ANC 
to less than 0.5 x 109/L with whole blood or marrow donor chimerism declining to less than 
5%. 
2. Administration of a second definitive therapy, which is defined as a second transplant 
(following conditioning regimen) or a course of ATG. A CD34+ boost or use of growth 
factors will NOT be considered as a second definitive therapy. 
The cumulative incidence of secondary graft failure at 1 year post-HSCT will be estimated. 
3.2.9 Hematologic Response 
Hematologic response will be assessed according to the modified NIH criteria [40] determined at 
Day +100, Day +180, and Day +365 post-HSCT. Complete response (CR) is defined as meeting 
all 3 peripheral blood count criteria: 1) ANC > 1x 109/L; 2) Hb > 10g/dL; and 3) platelet count 
> 100 x 109/L. Partial response (PR) is defined as blood counts no longer satisfying criteria for 
SAA and having transfusion independence (defined as no need for packed red blood cell [PRBC] 
or platelet transfusions) but insufficient for a CR. 
3.2.10 GVHD 
Acute and chronic GVHD are graded according to the BMT CTN Technical Guideline. See 
Appendix I for guidance in grading, with detailed grading direction in the Technical Guideline 
document. 
The cumulative incidences of Grade II-IV and Grade III-IV aGVHD at Day +100 post-HSCT and 
the cumulative incidences of all cGVHD and of cGVHD requiring immunosuppression will be 
estimated at 1 year post-HSCT. 

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3.3 Exploratory Endpoints 
3.3.1 Time to Enrollment 
The median time to enrollment in days after HLA typing of the recipient will be estimated. 
3.3.2 Time from Diagnosis of SAA to Conditioning and to Transplant 
The median time from SAA diagnosis to conditioning start and to HSCT will be estimated. 
3.3.3 Time to Donor Activation, Donor Selection, Start of Conditioning, and 
Transplant  
The median times in days from enrollment to the day of donor activation, day of donor selection, 
day conditioning is initiated, and day of transplant will be estimated. 
3.3.4 Donor Availability 
The number and types (haploidentical and 8/10, 9/10, and 10/10 URDs) of available donors for 
participants will be described. 
3.3.5 HSCT Cell Dose 
The total nucleated cell dose and CD34+ cell doses received by transplanted participants will be 
described. 
3.3.6 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-HSCT. 
3.3.7 Infection 
All Grade 2 and 3 infections will be reported according to the BMT CTN Technical Guideline. See 
Appendix H for guidance in infection grading. CMV viremia and disease, EBV viremia, and PTLD 
will be collected as per Section 2.6.3.2. 
3.3.8 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-HSCT 
using the following instruments/questionnaires: Patient-Reported Outcomes Measurement 
Information System (PROMIS; anxiety, depression, anger, fatigue, physical function, cognitive 
function, ability to participate in social roles & activities subscales), Comprehensive Score of 
Financial Toxicity (COST), occupational function items, and sociodemographic/social 
determinants of health items. The scales will be scored according to the recommendations of the 
developers. See Section 4.3.8.3 for detailed descriptions of the instruments. HR-QoL will be 
described for each treatment arm over time. Participants aged 8+, and parents/guardians of 
participants aged 5-7, who are able to read and speak in English or Spanish are eligible to 
participate in the HR-QoL component of this trial. 
 

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CHAPTER 4 
4 
PARTICIPANT ENROLLMENT AND EVALUATION 
4.1 Cohort Selection 
1. Each participating institution declares a preferred donor source (URD or haplo) to the Data 
Coordinating Center (DCC)/Emmes at the time of site activation. 
2. If the preferred donor source is not available for a given participant, the center may use 
the other donor source and document it in the data capture system. 
4.2 Enrollment Procedures 
Participants will be registered using the Advantage eClinical Electronic Data Capture System. 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 Enrollment Form in Advantage eClinical, at which 
point a study number will be generated. After the participant is enrolled in the screening 
segment, the authorized user should complete the HLA Forms to verify an eligible HLA 
match score. This eligibility screening includes a question confirming that the participant 
(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 participant in 
the transplant segment. The participant is not officially enrolled on study and may 
not begin study treatment until they are enrolled in the transplant segment. 
4.3 Study Monitoring 
4.3.1 Follow-up Schedule 
The follow-up schedule for study visits is outlined in Table 4.3.1. A detailed description of each of 
the forms and the procedures required for forms completion and submission can be found in the 
BMT CTN 2207 forms guide. 

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Table 4.3.1: Follow-Up Schedule 
Study Visit 
Target Day Post-
Transplant
week 1
7 ± 3 days
week 2
14 ± 3 days
week 3
21 ± 3 days
week 4
28 ± 3 days
week 5
35 ± 3 days
week 6
42 ± 3 days
week 7
49 ± 3 days
week 8
56 ± 3 days
week 9
63 ± 3 days
week 10 
70 ± 3 days
week 11 
77 ± 3 days
week 12 
84 ± 3 days
Day 100 
100 ± 7 days
6 months
180 ± 28 days
12 months 
365 ± 45 days
4.3.2 Data Capture Forms 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the study forms guide. Forms that are not entered into the data capture system within 
the specified time will be considered delinquent. A missing form will continue to be requested 
either until the form is entered into the data capture system and integrated into the DCC’s master 
database, or until an exception is granted. 
Reporting Participant Deaths: Recipient death information must be entered into the data 
capture system within 24 business hours of knowledge of the participant’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 the data capture system. 
CIBMTR Data Reporting: Centers participating in BMT CTN trials must register pre- and post-
transplant outcomes on all consecutive HSCTs 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 United States [US] 
allotransplant recipients.) Enrollment on BMT CTN #2207 must be indicated on the SCTOD 
pre-transplant registration form. Additionally, CIBMTR pre- and post-transplant Report Forms 
must also be submitted for all participants enrolled on this trial. CIBMTR forms will be submitted 
directly to the CIBMTR at the times specified on the Form Submission Schedule. 
Weekly GVHD Monitoring: GVHD should be monitored in accordance with BMT CTN guidelines 
as specified in the Technical Guideline. Participants should be assessed weekly until Day +100 
post-transplant for GVHD. After Day +100, participants 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 4.3.1. 

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4.3.3 Adverse Event Reporting 
4.3.3.1 
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. 
Serious Adverse Event: A serious adverse event (SAE), as defined by per 21 CFR 312.32, is 
any AE 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 and convulsions that do not result in inpatient hospitalization, and 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 participant or may require intervention to prevent one of the outcomes listed in the 
definition above (e.g., suspected transmission of an infectious agent by a medicinal product is 
considered an SAE). Any event is considered an SAE if it is associated with clinical signs or 
symptoms judged by the investigator to have a significant clinical impact. 
Anticipation: 
• 
Anticipated AEs are those that are listed in the protocol, the informed consent document, 
package inserts, or have been previously identified as resulting from the underlying disease 
or the transplant process. In non-Investigational New Drug (IND) trials such as this one, 
anticipated is often referred to as expected. 
• 
Unanticipated AEs would include those that have not been listed in the protocol, the 
informed consent document, package inserts, or have not been previously identified as 
resulting from the underlying disease or the transplant process. Unanticipated events also 
include events that would normally be anticipated, but vary in nature, intensity, or 
frequency, as determined by the investigator. In non-IND trials such as this one, 
unanticipated is often referred to as unexpected. 

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4.3.4 Classification of Adverse Events by Severity 
The severity refers to the intensity of the reported event. The Investigator must categorize the 
severity of each reportable SAE according to the NCI CTCAE Version 5.0. CTCAE guidelines can 
be referenced at the following website: http://ctep.cancer.gov/reporting/ctc.html. For any term that 
is not specifically listed in the CTCAE scale, intensity will be assigned a grade of 1 through 5 using 
the following CTCAE guidelines: 
• 
Grade 1: Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
4.3.5 Classification of Adverse Events by Relationship to Study Intervention 
The relationship of each reported event to the study treatment will be assessed by the Investigator 
after careful consideration of all relevant factors such as (but not limited to) the underlying study 
indication, coexisting disease, concomitant medication, relevant history, pattern of the SAE, 
temporal relationship to any study treatment interventions and de-challenge or re-challenge 
according to the following guidelines: 
• 
Possibly, Probably, or Definitely Related: there is a reasonable possibility that the study 
treatment caused the event. A relationship of possibly, probably, or definitely related to 
the investigational product is considered related for the purposes of regulatory authority 
reporting. 
• 
Unlikely, or Not Related: There is no reasonable possibility that the investigational 
product caused the event. An unlikely or not related relationship to the investigational 
product is not considered related for the purposes of regulatory authority reporting 
4.3.6 Required Adverse Event Reporting 
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN Administrative 
MOP, Chapter 6). It is BMT CTN policy that events meeting reporting requirements must be 
reported even if the Investigator is unsure whether a relationship exists between the adverse 
event and the use of study treatment. 
Unanticipated SAEs will be reported through an expedited AE reporting system via the Advantage 
eClinical data capture system. Unanticipated life-threatening and fatal SAEs must be reported 
within 24 hours of knowledge of the event. All other unanticipated SAEs must be reported within 
3 business days of knowledge of the event. Events entered in the data capture system will be 
reported using NCI’s CTCAE Version 5.0. 
Anticipated AEs will be reported using NCI’s CTCAE Version 5.0 at regular intervals as defined 
on the Form Submission Schedule, including calendar-driven case report forms (e.g., Toxicity and 
GVHD forms) and event-driven case report forms (e.g., Relapse/Progression, Infection, and 
Death forms). Any anticipated life-threatening SAE not collected on another study form must be 
reported through the expedited AE reporting system via the data capture system within 24 hours 
of knowledge of the event. 

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This trial will also have 3 adverse events of special interest (AESIs): pregnancy, medication error 
related to Thymoglobulin® and overdose of Thymoglobulin®. If any of these AESIs occur, this 
event should be reported on the AE data capture forms as an expedited event within 24 hours of 
knowledge of the event, whether it is considered a non-serious event or an SAE, and regardless 
of anticipation assessment. 
The National Heart, Lung, and Blood Institute (NHLBI)/Data and Safety Monitoring Board (DSMB) 
will receive unanticipated SAEs within 7 days of Medical Monitor assessment that it meets 
reporting guidelines. The DSMB will also review summary reports of all unanticipated SAEs on 
an annual basis. 
4.3.7 Procedure in Case of Pregnancy 
If a female participant becomes pregnant during the study intervention period or within 30 days 
from the study intervention, the Investigator should report the information through an expedited 
AE reporting system via the data capture system. If a partner of a male participant becomes 
pregnant during the study intervention period or within 90 days from the last study intervention, 
the Investigator should report the information through an expedited AE reporting system via the 
data capture system. In the event of a pregnancy, the pregnant study participant or pregnant 
partner of a male participant will be approached by the Investigator to obtain the study-specific 
pregnancy consent. The expected date of delivery or expected date of the end of the pregnancy, 
last menstruation, estimated conception date, pregnancy result, neonatal data, and other related 
information will be requested. 
The Investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome. Additional information regarding the outcome 
of a pregnancy (which is categorized as an SAE) are mentioned below. 
• 
“Spontaneous abortion” includes miscarriage, abortion, and missed abortion. 
• 
Death of an infant within 30 days after birth should be reported as an SAE regardless of 
its relationship with the study intervention. 
• 
If an infant dies more than 30 days after birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study intervention is judged as 
“possible” by the Investigator. 
• 
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at 
the birth. 
• 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination. 
Information will be collected at the time of delivery/birth and 180 and 360 days after birth. 
4.3.8 Participant Evaluations 
Table 4.3.5 summarizes participant clinical assessments over the course of the study. Table 4.3.1 
outlines the timing windows of assessments. 
4.3.8.1 
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. 
2. Karnofsky or Lansky performance status (Karnofsky for patients age 16 and older; Lansky 
for patients age <15.99 at the time of enrollment) 
3. Hematopoietic cell transplantation-comorbidity index (HCT-CI). 

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4. Complete blood count (CBC) with differential, reticulocyte count and chemistries 
(creatinine, bilirubin, alkaline phosphatase, AST, ALT, ferritin, magnesium). 
5. Calculation of estimated CrCl, and GFR by radionucleotide scan or urine collection, if 
indicated. 
6. Chest x-ray or chest computerized tomography (CT) scan (contrast not required for CT 
chest). 
7. HLA typing by high-resolution methodology at HLA -A, -B, -C, DPB1, and DRB1 loci, ABO 
and Rh typing. Confirmatory donor typing must be completed < 100 days prior to 
enrollment. 
8. Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as the 
presence of donor specific HLA antibodies [DSA] to any mismatched HLA allele/antigen 
at any of the following loci [HLA-A, -B, -C, –DRB1, DRB3, DRB4, DRB5, -DQA1, -DQB1, 
-DPA1, -DPB1] with MFI >3000 by microarray-based single antigen bead testing). 
9. CMV antibody test, hepatitis panel (hepatitis A [HepA] antibody [Ab], HepB surface Ab 
[sAb], HepB surface antigen [sAg], HepB Core Ab [IgG or total with IgG], HepC Ab), HSV, 
syphilis, HIV and human T-lymphotropic virus type 1 (HTLV1) I/II Ab, VZV Ab, and EBV 
serostatus. 
10. LVEF or, for participants aged < 13.0 years, shortening fraction measurement by 
echocardiogram or MUGA. 
11. Pulmonary function testing: FEV1, FVC, and DLCO (corrected for Hb). For participants 
aged < 13.0 years and participants unable to perform PFTs due to age or developmental 
ability, pulse oximetry is an acceptable alternative. 
12. Baseline electrocardiogram (EKG). 
13. BM aspirate/biopsy with cytogenetics or fluorescence in situ hybridization (FISH, if failed 
cytogenetics) within 60 days prior to enrollment. 
14. Testing for telomere biology studies per institution standards to rule out short telomere 
disorders. Genetic panels for inherited bone marrow failure syndromes can be considered 
as an alternative to telomere length testing. 
15. Recommend diepoxybutane (DEB) testing on peripheral blood to rule out Fanconi Anemia 
(at any time prior to enrollment). Genetic panels for inherited bone marrow failure 
syndromes (IBMFS) can be considered as an alternative to functional testing. If patients 
have clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder 
should be excluded by pancreatic isoamylase testing or gene mutation analysis. Other 
testing per center may be performed to exclude IBMFS. 
16. Pregnancy test for females of childbearing potential (testing per institutional practice). 
17. Optional blood samples as described in Appendix B: 
a. Future research (all participants who consent): 38 mL whole blood prior to 
conditioning. 
18. Optional donor sample as described in Appendix B. 
a. Future research: 20 mL whole blood prior to collection. 
19. Absolute lymphocyte numbers by flow cytometry for lymphocyte subpopulations to include 
CD4, CD19, and CD56. 
20. Serum quantification of IgG, immunoglobulin M (IgM), and immunoglobulin A (IgA). 

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21. Baseline peripheral blood samples for chimerism analysis by molecular methods 
(participant and donor). 
22. HR-QoL: Patient-Reported Outcome (PRO) assessments for participants able to complete 
surveys in English or Spanish (see Section 3.3.8). 
4.3.8.2 
Post-transplant Evaluations 
1. History, physical exam, and weight weekly until Day +28, then at Day +100, Day +180, 
and Day +365. 
2. 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 per BMT CTN Technical 
Guideline. Chronic GVHD Provider Survey to be completed by a clinician at the time of 
participant assessment. For scheduling purposes, a target day range has been provided 
in Table 4.3.1. 
3. Karnofsky or Lansky performance status at Day +365 (Karnofsky for patients age 16 and 
older; Lansky for patients age <15.99 at the time of enrollment). 
4. CBC with differential at least 2 times a week from Day 0 until ANC > 0.5 x 109/L for 
3 consecutive measurements over 3 or more days. CBC performed at least twice per week 
until Day +28, then weekly until Day +100, then at Day +180 and Day +365. 
5. Reticulocyte count for assessment of hematologic response on Day +100, Day +180, and 
Day +365. 
6. 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. Cyclosporine 
or tacrolimus levels will be measured at least once weekly until Day +100, and then at 
each follow-up visit until the drug is tapered off. 
7. Toxicity assessments at Day +28, Day +56, Day +100, Day +180, and Day +365. 
8. Absolute lymphocyte numbers by flow cytometry for lymphocyte subpopulations to include 
at minimum CD4, CD19, and CD56 at Day +100, Day +180, and Day +365. 
9. Serum quantification of IgG, IgM, and IgA at Day +365. 
10. Quantification of peripheral blood (whole blood and CD3) or marrow chimerism (including 
lineage-specific, myeloid, and T cell chimerisms per institutional standards) 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. Bone marrow testing is optional per institutional standards. 
11. EBV DNA quantitative PCR testing, CMV DNA quantitative PCR testing, and adenovirus 
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 participant is off of all immunosuppression. 
12. HR-QoL: PRO assessments at Day +100, Day +180, and Day +365 post-transplant for 
participants able to complete surveys in English or Spanish. 
13. Organ function testing post-HSCT per institutional standards – PFT, echocardiogram, 
renal function testing at Day +365 are recommended. 

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14. Screening for TA-TMA is recommended as this complication can lead to anemia and 
thrombocytopenia post-HSCT. Screening may include monitoring LDH, urinalysis for 
proteinuria, urine quantification of protein/creatinine ratio, or other institutional guidelines 
[51]. 
15. BM aspirate/biopsy with cytogenetics or fluorescence in situ hybridization (FISH, if failed 
cytogenetics) Day +100. If the institutional standard is not to perform a Day +100 BM 
aspirate/biopsy, then collection is optional. 
16. Optional blood samples as described in Appendix B: 
a. Future research (all participants who consent): 38 mL whole blood at Day +28, 
Day +56, Day +100, Day +180 and Day +365. 
4.3.8.3 
Patient-Reported Outcome (PRO) Surveys 
The CIBMTR Survey Research Group (SRG) centrally coordinates all PRO survey assessments. 
At the time a participant is enrolled in the study, the SRG receives an email notification and adds 
that participant to CIBMTR’s electronic Patient-Reported Outcomes (ePRO) system for data 
collection tracking. Transplant Centers provide participant contact information securely to the 
SRG. 
Age-appropriate PROs will be collected using PROMIS® domains, COST, occupational 
functioning items, and sociodemographic/social determinants of health items (See Appendix J for 
sample questions). 
Participants and/or their parent/guardian will complete PRO measures at baseline (before the 
start of conditioning) and at Day +100, Day +180 and Day +365 post-transplant. 
Respondents may choose to complete PRO surveys on paper or electronically, and in English or 
Spanish. The same survey items will be used in paper and electronic versions of the surveys. If 
participants or parent/guardians are unable to complete the PRO surveys in these modes and 
languages, they are still eligible for study enrollment and will complete all other study 
assessments and tests. 
Baseline PRO surveys will be collected by the center electronically or on paper forms after 
consent and before randomization. Centers will be provided with paper PDFs of the baseline 
survey and a set of unique electronic survey links in both English and Spanish for each age group. 
Surveys may also be administered verbally if needed. Centers will record participant responses 
on a paper copy of the survey contemporaneously while reading survey questions and response 
choices to the participant. Electronically collected PRO surveys are directly entered in the ePRO 
system via the unique links. 
The SRG will centrally collect all post-treatment PRO surveys starting at Day +100. Centers will 
securely provide participant contact information to the SRG upon enrollment. At Day +100, the 
SRG will attempt to contact the participant by phone to confirm contact information, remind them 
of survey assessment time points and confirm how they want to complete PRO surveys (paper or 
electronic). After speaking by phone with the participant, or if they are unreachable by phone, the 
SRG will send the Day +100 survey assessment by email and/or mail. The SRG will continue to 
contact the participant via email, phone and/or mail to collect survey assessments at Day +180 
and Day +365. The SRG will follow-up by phone and email with non-responders up to 
approximately six contact attempts or until the visit window closes, to minimize missing surveys. 
The SRG may also administer surveys verbally by phone if needed. The SRG will record 
participant responses in the electronic version of the survey contemporaneously while reading 
questions and response choices to the patient. If the SRG is unable to get response from enrolled 
participants, they may request that local study coordinators remind participants or administer the 
PRO surveys at clinical visits. 

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The participant or their parent/guardian will be asked to complete the PRO surveys, depending 
on the age of the participant at the time of each PRO survey time point. 
• 
Under age 5 – PRO surveys not completed. 
• 
Age 5-7 – Pediatric versions of PRO surveys completed by the parent/guardian (see 
Table 4.3.2) 
• 
Age 8-17 – Pediatric versions of PRO surveys completed by the participant, with 
occupational function, sociodemographic and social determinants of health items 
completed by the parent/guardian (see Table 4.3.3). 
• 
Age 18 and older – Adult versions of PRO surveys completed by the participant (see 
Table 4.3.4). 
4.3.8.4 
Patient-Reported Outcomes Measurement Information System 
(PROMIS) Domains 
Seven PROMIS domains will be used to measure detailed functioning and symptom burden for 
participants. PROMIS measures utilize T-score metrics, with higher scores indicating more of the 
concept (i.e., physical function or depression). Scores are normalized to 50 with a standard 
deviation of 10, and scores greater than 0.5 times standard deviation (i.e., < 45 or > 55, compared 
to the general population) are considered clinically meaningful. 
The PROMIS domains for adult patients are Anxiety, Depression, Anger, Fatigue, Physical 
Function, Cognition, Ability to Participate in Social Roles & Activities. The PROMIS domains for 
pediatric participants are Anxiety, Depressive Symptoms, Anger, Fatigue, Mobility, Cognition, 
Peer relationships. 
4.3.8.5 
 Financial Impact Scales 
The COST, and items about return to work/school, income, insurance, and household burden 
measure the impacts of treatment on finances and economic status of the patient households.  
4.3.8.6 
PRO Compensation 
To compensate participants for their effort and time and ensure high compliance on PRO surveys, 
participants will receive $20 for each completed PRO survey timepoint. The SRG will track all 
completed surveys and coordinate remuneration. 
Table 4.3.2: Pediatric (Age 5-7) PRO Assessments 
Assessment 
# items 
Estimated 
completion 
time
Respondent 
Baseline 
Day 
100 
Day 
180 
Day 
365 
PROMIS® domains
 
Anxiety
8
1-2 minutes
Parent/Guardian
X
X
X
X
Depressive Symptoms
8
1-2 minutes
Parent/Guardian
X
X
X
X
Anger
5
1-2 minutes
Parent/Guardian
X
X
X
X
Fatigue
10
1-2 minutes
Parent/Guardian
X
X
X
X
Mobility
8
1-2 minutes
Parent/Guardian
X
X
X
X
Cognition 
 
7
1-2 minutes
Parent/Guardian
X
X
X
X
Peer relationships 
8
1-2 minutes
Parent/Guardian
X
X
X
X
Occupational function 
items 
4
1 minute
Parent/Guardian
X
X
X
Sociodemographics/ 
social determinants of 
health 
9
1-2 minutes
Parent/Guardian
X
Total length 
67
9-17 min
7-14 
min
8-15
min
8-15
min

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Table 4.3.3: Pediatric (Age 8-17) PRO Assessments 
Assessment 
# items 
Estimated 
completion  
time
Respondent 
Baseline 
Day 
100 
Day 
180 
Day 
365 
PROMIS® domains
 
Anxiety
8
1-2 minutes
Participant
X
X
X
X
Depressive Symptoms
6
1-2 minutes
Participant
X
X
X
X
Anger
5
1-2 minutes
Participant
X
X
X
X
Fatigue
10
1-2 minutes
Participant
X
X
X
X
Mobility
8
1-2 minutes
Participant
X
X
X
X
Cognition 
7
1-2 minutes
Participant
X
X
X
X
Peer relationships 
7
1-2 minutes
Participant
X
X
X
X
Occupational function 
items 
4
1 minute
Parent/Guardian
X
X
X
Sociodemographics/ 
social determinants of 
health 
9
1-2 minutes
Parent/Guardian
X
Total length 
64
9-17 min
7-14 
min
8-15 
min
8-15 
min
 
Table 4.3.4: Adult (Age 18+) PRO Assessments 
Assessment 
# 
items 
Estimated 
completion 
time
Respondent 
Baseline 
Day 
100 
Day 
180 
Day 
365 
PROMIS® domains
 
Anxiety
8
1-2 minutes
Participant
X
X
X
X
Depression
8
1-2 minutes
Participant
X
X
X
X
Anger
7
1-2 minutes
Participant
X
X
X
X
Fatigue
8
1-2 minutes
Participant
X
X
X
X
Physical Function
8
1-2 minutes
Participant
X
X
X
X
Cognition 
8
1-2 minutes
Participant
X
X
X
X
Ability to Participate in 
Social Roles & Activities
8
1-2 minutes
Participant
X
X
X
X
Comprehensive Score of 
Financial Toxicity (COST) 
12
2-3 minutes
Participant
X
X
X
Occupational function 
items 
8
1 minute
Participant
X
X
X
Sociodemographics/ 
social determinants of 
health 
16
2 minutes
Participant
X
Total length 
91
12-20 min
7-14
min
10-18 
min
10-18
min
 

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Table 4.3.5: Summary of Assessments 
Study Assessments / Testing 
Baseline 
(Pre-
conditioning) 
 
 
 
 
 
 
 
 
During 
conditi-
oning14 
0  
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
100 
180 
365 
History, Physical Exam, Weight, and Height16 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Karnofsky/Lansky Performance Status15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
HCT-CI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC1, Differential, and Blood Chemistries2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte Count 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
CrCl and GFR Assessment3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA Typing & Anti-Donor Antibody Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious Disease Titers4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LVEF or Shortening Fraction for < 13 years 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or Chest CT Scan5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Tests6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM Aspirate for Pathology and Cytogenetics7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Testing for Fanconi Anemia/telomere 
disorders8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test (females of childbearing 
potential only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4, CD19, and CD56 Counts 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Serum Quantification of IgG, IgM, and IgA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chimerism9 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
CMV, EBV, and Adenovirus DNA Quantitative 
PCR Testing10 
 
 
 
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 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
HR-QoL 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Optional Research Blood Draw for 
Biorepository12 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Organ Function Testing post-HSCT (per 
Institutional Standards) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
1  CBC performed 2 times weekly from Day 0 until ANC > 0.5 x 109/L for 3 consecutive measurements on different days. CBC performed twice per week until Day +28, then weekly until Day +100, 
then at Day +180 and Day +365.  
2  Blood chemistries include: creatinine, bilirubin, alkaline phosphatase, AST, ALT, ferritin (baseline only), magnesium (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 
Calculation of estimated CrCl, and GFR by radionucleotide scan or urine collection, if indicated. 

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4  Infectious disease titers include: hepatitis panel (HepA Ab, HepB Sab, HepB Sag, HepB Core Ab [IgG or total with IgG], HepC Ab), CMV Ab, HIV, HSV, syphilis, HTLV1 I/II Ab, VZV Ab, and EBV 
serostatus. 
5 
Contrast not required for chest CT scan. 
6 
DLCO (corrected for Hb), FEV1, and FVC or pulse oximetry for participants aged < 13.0 years if unable to perform standard PFT. 
7 
BM aspirate and biopsy (cytogenetics is required, local MDS panel recommended) within 60 days prior to enrollment. Day +100 marrow is optional per institutional standards. 
8 
Results of DEB testing on peripheral blood or comparable testing on marrow to rule out Fanconi anemia at any time prior to enrollment. Testing for telomere biology studies per institution 
standards to rule out short telomere disorders. Genetic panels for inherited bone marrow failure syndromes (IBMFS) can be considered as an alternative to functional testing. If patients have 
clinical characteristics suspicious for Shwachman-Diamond syndrome, this disorder should be excluded by pancreatic isoamylase testing or gene mutation analysis. 
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). 
Peripheral blood samples for chimerism assessment at baseline should be collected from the participant and the donor. 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. 
10 
EBV, CMV, and adenovirus 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 a clinician at the time of participant assessment. 
12 Optional research blood draws as outlined in Appendix B. 
13 
Recommended: PFT, echocardiogram, renal function testing 
14 Window of assessments: see Table 4.3.1. 
15 Karnofsky for patients age 16 and older; Lansky for patients age 12-15.99 at the time of enrollment 
16    Height only required at baseline

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CHAPTER 5 
5 
STATISTICAL CONSIDERATIONS 
5.1 
Study Overview 
This study is a multicenter, Phase II, parallel cohort trial to assess the safety and efficacy of HSCT 
using haploidentical or URD BM with Thymoglobulin® (Sanofi)(ATG)-containing preparative 
regimens in participants with previously untreated SAA. The two cohorts are: (1) haplo transplant 
and (2) URD transplant. The accrual goal for each cohort is 30 participants who have enrolled 
and initiated protocol-specified conditioning in each cohort, yielding 60 participants in total. 
5.1.1 Accrual Duration 
It is estimated that 36 months of accrual will be necessary to enroll the targeted sample size. 
5.1.2 Primary Objective and Endpoint 
The primary endpoint is GFFS. Events contributing to this endpoint are defined in Section 3.1. 
The primary objective is to assess the GFFS probability at 1 year after initiation of conditioning 
for each cohort. 
5.1.3 Randomization and Blinding 
This is a parallel cohort trial in which each participant’s transplant cohort is determined by the 
donor type that they receive (haplo or URD) or, for those not proceeding to transplant, by the 
selected donor type at start of conditioning. The donor type is expected to match the center’s 
donor preference in most cases. Outcomes will not be compared between the two transplant 
cohorts. Therefore, no randomization or blinding will be performed. 
5.2 
Sample Size and Power Considerations 
The sample size of 30 participants per cohort was determined to provide estimates of GFFS 
probabilities at 1 year after initiation of conditioning for each cohort with CIs that are sufficiently 
narrow. A 1-year GFFS rate of 75% or higher is particularly desirable. Table 5.2.1 displays 
possible 90% CIs for GFFS, under an assumption of complete follow-up on all participants and 
using exact Clopper-Pearson binomial CIs. If a cohort has an observed 1-year GFFS rate of 
76.7% or higher, the CI will be no wider than 27.9% and will rule out GFFS rates less than 60%. 
There is expected to be minimal, if any, withdrawal or loss to follow-up before 1 year; in the event 
that some participant(s) withdraw or are lost to follow-up before 1 year, their GFFS time will be 
censored, and the Kaplan-Meier estimator will be used for estimation. 

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Table 5.2.1: Possible Confidence Intervals for GFFS Probability at 1 Year After 
Initiation of Conditioning in a 30-Participant Cohort 
Observed Rate (%) 
90% CI* for True Rate 
Width of 90% CI 
96.7% (29/30)
85.1% - 99.8%
14.7%
90.0% (27/30) 
76.1% - 97.2% 
21.1% 
83.3% (25/30)
68.1% - 93.2% 
25.1% 
76.7% (23/30)
60.6% - 88.5%
27.9%
70.0% (21/30) 
53.5% - 83.4% 
29.9% 
63.3% (19.30) 
46.7% - 77.9% 
31.2% 
56.7% (17/30) 
40.2% - 72.1% 
32.0% 
50.0% (15/30) 
33.9% - 66.1% 
32.2% 
* Clopper-Pearson CI 
5.3 
Interim Analysis and Stopping Guidelines 
Interim analyses will be performed for safety only, not for efficacy or futility. Participants will be 
monitored for key safety endpoints on a daily basis for evidence of excess risk. If rates significantly 
exceed pre-set thresholds (see Sections 5.3.1, 5.3.2, and 5.3.3), the NHLBI will be notified in 
order that the DSMB can be advised. The policies and composition of the DSMB are described in 
the BMT CTN MOP. The monitoring guidelines serve as a trigger for consultation with the DSMB 
and are not formal stopping rules that mandate automatic closure of study enrollment. 
Safety outcomes to be monitored include graft failure, Grade 3-4 aGVHD, and early mortality. 
Graft failure events to be considered include both primary and secondary graft failures occurring 
through Day +56 post-HSCT in all transplanted participants. Grade 3-4 aGVHD events to be 
monitored are those occurring through Day +100 post-HSCT in all transplanted participants. 
Mortality will be monitored up to 115 days from the first day of preparative regimen (Day -9) in all 
participants receiving the first dose of ATG. The rationale for monitoring mortality from the first 
day of ATG preparation in all participants receiving the first dose of ATG is to guard against 
excessive early mortality including death due to the intervention in participants 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-HSCT evaluation for participants receiving a transplant. 
A truncated sequential probability ratio test (SPRT) for binary data [52] will be used to monitor 
each safety endpoint. This sequential testing procedure preserves the type I error rate at a 
prespecified level across all of the daily examinations. The binary SPRT can be represented 
graphically, with the rejection boundary of the SPRT defined by a straight line. At each 
examination, the number of evaluable participants is plotted against the cumulative number of 
events; if the number of events meets or exceeds the boundary, the SPRT rejects the null 
hypothesis, concluding there is evidence of excessive risk. Otherwise, the SPRT continues until 
the targeted enrollment goal is reached. Each safety outcome will be monitored separately by 
transplant cohort to guard against excess risk for a specific transplant type. 

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5.3.1 Graft Failure by Day 56 Post-HSCT 
Graft failure will be monitored through Day +56 post-HSCT among participants who proceed to 
transplant. Events for this safety endpoint include both primary and secondary graft failure. A graft 
failure rate of up to 10% is anticipated based on prior experience with HSCT using haploidentical 
and URDs. A safety monitoring boundary was derived using a binary SPRT that compares a null 
graft failure rate of 10% to a targeted excessive rate of 30%. The type I error rate for this 
procedure is 3.7%, corresponding to a critical value of 14.354 for the probability ratio and a 
rejection boundary with intercept 1.973 and slope 0.159 for the number of events versus 
participants. The 2 transplant cohorts will be monitored separately using this stopping guideline. 
Table 5.3.1 displays the SPRT in a tabular form, showing the rejection boundary values for the 
number of Day +56 graft failures corresponding to the number of evaluable participants. At least 
3 events must be observed in order to trigger review. 
Additionally, if 2 Day +56 graft failures occur among the first 5 participants in a cohort, accrual to 
the cohort will be halted and will resume only when all other transplanted participants pending 
evaluation reach the Day +56 time point without flagging the stopping guideline. 
Table 5.3.1: Stopping Guideline for Graft Failure through Day +56 Post-HSCT in a 
30-Participant Cohort 
Number of Evaluable Participants*
Rejection Boundary for # Events
3 - 5
3
6 - 10 
4 
11 - 16 
5
17 - 21 
6 
22 - 26 
7 
27 - 30 
8 
* Evaluable participants are those who underwent HSCT. 
Table 5.3.2 shows the operating characteristics of this test over a range of true graft failure rates. 
Uniform accrual of 30 participants to the cohort over a 3-year period is assumed. The operating 
characteristics were computed exactly using procedures described in Jennison & Turnbull 1999, 
Chapter 12.[53] This procedure rejects the null hypothesis 3.6% of the time when the true Day 56 
graft failure rate is 10% and 80.1% of the time when the rate is 30%. If the true rate is 30%, the 
DSMB will be consulted at approximately 22 months after opening on average, when 5 events 
have been observed in 18 enrolled participants. 
Table 5.3.2: Operating Characteristics of Sequential Monitoring Procedure for 
Graft Failure through Day +56 Post-HSCT in a 30-Participant Cohort 
True Graft Failure Rate 
10%
15%
20%
25%
30%
Probability of Early Stopping 
0.036 
0.155 
0.368 
0.608 
0.801 
Mean Month Stopped
37.4
35.2
31.5
26.8
22.0
Mean # Events 
3.0 
4.2 
5.0 
5.3 
5.2 
Mean # Participants Enrolled
29.4
27.9
25.0
21.4
17.8
5.3.2 Grade 3-4 Acute GVHD through Day +100 Post-HSCT 
The occurrence of Grade 3-4 aGVHD onset will be monitored through Day +100 post-HSCT 
among participants who proceed to transplant. The Grade 3-4 aGVHD rate is expected not to 
exceed 15% based on prior experience with HSCT in this population. A safety stopping rule was 
constructed using a binary SPRT contrasting a null rate of 15% to a targeted excessive rate of 

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35%. The type I error rate for this procedure is 6.6%, corresponding to a critical value of 8.811 for 
the probability ratio and a rejection boundary with intercept 1.951 and slope 0.224 for the number 
of events versus participants. The 2 transplant cohorts will be monitored separately using this 
procedure. 
The stopping rule is tabulated in Table 5.3.3, showing the rejection boundary values for the 
number of Day +100 Grade 3-4 aGVHD events corresponding to the number of evaluable 
participants. At least 3 events must be observed in order to trigger review. 
Additionally, if 2 Day +100 Grade 3-4 aGVHD events occur among the first 4 participants in a 
cohort, accrual to the cohort will be halted and will resume only when all other transplanted 
participants pending evaluation reach the Day +100 time point without flagging the stopping 
guideline. 
Table 5.3.3: Stopping Guideline for Grade 3-4 Acute GVHD through Day +100 
Post-HSCT in a 30-Participant Cohort 
Number of Evaluable Participants* 
Rejection Boundary for # aGVHD Events
3 - 4 
3 
5 - 8
4
9 - 12 
5 
13 - 16 
6 
17 - 20 
7
21 - 25 
8
26 - 29 
9 
30 
10 
* Evaluable participants are those who underwent HSCT. 
Table 5.3.4 shows the operating characteristics of this test over a range of true Grade 3-4 aGVHD 
rates. Uniform accrual of 30 participants to the cohort over a 3-year period is assumed. The 
operating characteristics were computed exactly using procedures described in Jennison & 
Turnbull 1999, Chapter 12.[53] This procedure rejects the null hypothesis 6.5% of the time when 
the true Day +100 aGVHD rate is 15% and 80.2% of the time when the rate is 35%. If the true 
rate is 35%, the DSMB will be consulted at approximately 23 months after opening on average, 
when 6 events have been observed in 19 enrolled participants. 
 
Table 5.3.4: Operating Characteristics of Sequential Monitoring Procedure for 
Grade 3-4 Acute GVHD through Day +100 Post-HSCT in a 30-Participant Cohort 
True Acute GVHD Rate 
15%
20%
25%
30%
35%
Probability of Early Stopping 
0.065 
0.195 
0.398 
0.620 
0.802 
Mean Month Stopped 
38.3 
35.9 
32.3 
27.8 
23.3 
Mean # Events
4.4
5.5
6.1
6.2
6.0
Mean # Participants Enrolled 
29.1 
27.5 
25.0 
21.8 
18.6 
5.3.3 Mortality by Day 115 After Initiation of Conditioning 
Mortality will be monitored through 115 days from the first day of conditioning (approximately 100 
days post-HSCT for participants receiving a transplant) among participants who initiate the 
conditioning regimen. The mortality rate is not expected to exceed 10% in either cohort. A safety 
monitoring boundary for mortality was developed using an SPRT that contrasts a 10% null rate to 
a 30% targeted excessive rate. The type I error rate for this procedure is 3.7%, corresponding to 

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a critical value of 14.354 for the probability ratio and a rejection boundary with intercept 1.973 and 
slope 0.159 for the number of events versus participants. The 2 transplant cohorts will be 
monitored separately using this stopping guideline. 
Table 5.3.5 displays the stopping guideline for mortality, showing the rejection boundary values 
for the number of deaths through Day +115 after initiation of conditioning by the number of 
evaluable participants. At least 3 events must be observed in order to trigger review. 
Additionally, if 2 Day +115 deaths occur among the first five participants in a cohort, accrual to 
the cohort will be halted and will resume only when all other participants pending evaluation reach 
the Day +115 time point without flagging the stopping guideline. 
 
Table 5.3.5: Stopping Guideline for Mortality through Day +115 After Initiation of 
Conditioning in a 30-Participant Cohort 
Number of Evaluable Participants* 
Rejection Boundary for # Deaths
3 - 5
3
6 - 10
4
11 - 16 
5 
17 - 21 
6
22 - 26 
7 
27 - 30 
8 
* Evaluable participants are those who initiated conditioning. 
Table 5.3.6 shows the operating characteristics of this test over a range of true mortality rates. 
Uniform accrual of 30 participants to the cohort over a 3-year period is assumed. The operating 
characteristics were computed exactly using procedures described in Jennison & Turnbull 1999, 
Chapter 12.[53] This procedure rejects the null hypothesis 3.6% of the time when the true Day 
115 mortality rate is 10% and 80.1% of the time when the rate is 30%. If the true rate is 30%, the 
DSMB will be consulted at approximately 24 months after opening on average, when 5 events 
have been observed in 19 enrolled participants. 
 
Table 5.3.6: Operating Characteristics of Sequential Monitoring Procedure for 
Mortality through Day +115 After Initiation of Conditioning in a 30-Participant 
Cohort 
True Mortality Rate
10%
15%
20%
25%
30%
Probability of Early Stopping 
0.036
0.155
0.368
0.608
0.801
Mean Month Stopped 
39.1 
36.9 
33.2 
28.4 
23.7 
Mean # Events 
3.0 
4.2 
5.0 
5.3 
5.2 
Mean # Participants Enrolled
29.5
28.1
25.6
22.4
19.1
5.4 Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be described for all participants. 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 race and 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). 

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5.5 Statistical Analysis Plan 
5.5.1 Analysis Populations 
5.5.1.1 
Primary Analysis Population 
The primary analysis population will consist of all participants who initiate the protocol-specified 
conditioning regimen. Participants will be classified in the transplant cohort (haplo or URD) 
corresponding to the type of donor selected at the time conditioning is started, even if the infusion 
is not given. 
5.5.1.2 
Transplanted Population 
The transplanted population will consist of all participants who received a transplant, classified 
in the transplant cohort (haplo or URD) corresponding to the type of transplant received. 
5.5.1.3 
Safety Population 
The safety population will consist of all participants who initiate the preparative regimen and 
receive at least one dose of ATG. 
5.5.2 Analysis of the Primary Endpoint 
5.5.2.1 
Analysis Methods 
The primary endpoint analysis will focus upon estimating the GFFS probabilities at 1 year after 
initiation of conditioning for each of the two transplant cohorts. Events for GFFS include Grade 
III-IV aGVHD, cGVHD requiring immunosuppression, primary or secondary graft failure requiring 
second definitive therapy, and death. GFFS is defined as the time interval from start of 
conditioning until the first of these events occurs. Participants who are event-free and withdraw, 
are lost to follow-up, or complete study follow-up without experiencing an event will be censored 
at their last contact date. Kaplan-Meier curves will be used to display GFFS from start of 
conditioning to Day +365 after start of conditioning for each cohort. If no censoring occurs, sample 
proportions and 90% Clopper-Pearson CIs will be used to estimate 1-year GFFS probabilities. In 
the presence of censoring, the Kaplan-Meier estimator will give point estimates of GFFS and the 
beta product confidence procedure [54] will provide 90% exact CIs; the latter reduces to Clopper-
Pearson CIs when censoring is absent. GFFS will be analyzed using the primary analysis 
population. 
It is suspected that upfront HSCT using the protocol regimen will produce similar GFFS outcomes 
for both haplo and URD transplants. If true, data from both cohorts can be combined to obtain 
more precise estimates of GFFS. A test-then-pool procedure [55] will be employed to allow the 
possibility of pooling cohort data if their outcomes are similar. The procedure proceeds as follows: 
1. Estimate 1-year GFFS probabilities separately for the two cohorts. 
2. Compute the difference in GFFS estimates from Step 1. 
3. If the magnitude of the difference does not exceed a threshold value of 0.05, a 5% absolute 
difference in GFFS, combine cohort data and report GFFS point and interval estimates 
computed from pooled data analysis. Otherwise, only report GFFS estimates from 
separate analyses of the two cohorts. 
The estimates from separate analyses of the transplant cohorts will be reported, regardless of 
whether a pooled analysis is performed. 

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5.5.2.2 
Simulation Study of Test-Then-Pool Procedure 
A limitation of the test-then-pool procedure is that it can sometimes pool data sources in situations 
where the true GFFS probabilities are not similar and pooling is undesirable. This could result in 
biased estimation and CIs that have actual coverage probabilities falling short of their nominal 
levels. A simulation study was conducted to investigate this possibility under the proposed 
analysis method. The accuracy of estimates for cohort 1, haplo HSCT, is described; however, 
because each cohort will be analyzed in the same manner, the results apply identically to both 
cohorts. True 1-year GFFS probabilities of 65%, 70%, 75%, 80%, 85%, and 90% were considered 
for each cohort and 100000 trials were simulated for each pair of possible rates with no censoring. 
The test-then-pool procedure was applied for each simulated trial to obtain a point estimate and 
nominal 90% CI for GFFS in cohort 1. The true coverage probability was estimated using the 
proportion of simulated trials where the CI contained the true GFFS probability for cohort 1. Bias 
was similarly estimated by computing the average difference in the point estimates from the true 
probability in cohort 1. 
Figure 5.5.1 displays Monte Carlo estimates of the coverage probabilities for the CI for cohort 1 
at each pair of true GFFS rates considered for cohorts 1 and 2. The estimated coverage 
probabilities are 88% or higher across all configurations, lying close to or exceeding the nominal 
90% level. The coverage probabilities tend to meet or exceed 90% in situations where the cohorts’ 
GFFS rates are equal or within 5% of each other; coverage falls below 90% mainly in cases where 
the rates are not close. For instance, if the cohort 1 GFFS rate is 75%, coverage probabilities 
exceed 90% when the cohort 2 rate is 65-80% and are approximately 89% when cohort 2’s rate 
is 85-90%. The estimated bias was small across all scenarios, not exceeding 0.2% in magnitude 
for any configuration. These simulations support the ability of the test-then-pool procedure to 
provide GFFS estimates with small bias and nominal 90% CIs with accurate coverage rates. 

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Figure 5.5.1: Coverage Probabilities of Nominal 90% Confidence Intervals from 
Test-Then-Pool Procedure for Cohort 1 Estimated from 100000 Simulated Trials 
 
5.5.3 Analysis of Secondary Endpoints 
5.5.3.1 
Failure-free Survival (FFS) 
Events for FFS include death and the receipt of a second definitive therapy. FFS is defined as the 
time interval from initiation of conditioning until the first of these events occurs. Participants who 
are event-free and withdraw, are lost to follow-up, or complete study follow-up without 
experiencing an event will be censored at their last contact date. Kaplan-Meier curves will be used 
to display FFS from start of conditioning to Day +365 after the start of conditioning for each cohort. 
If no censoring occurs, sample proportions and 90% Clopper-Pearson CIs will be used to estimate 
1-year FFS probabilities. In the presence of censoring, the Kaplan-Meier estimator will give point 
estimates of FFS and the beta product confidence procedure [54] will provide 90% exact CIs. FFS 
will be analyzed using the primary analysis population. 
It is suspected that FFS outcomes may be similar for haplo and URD transplants. If true, data 
from both cohorts can be combined to obtain more precise estimates of FFS for them. A 
test-then-pool procedure [55] will be employed to allow the possibility of pooling cohort data if 
their outcomes are similar. The procedure proceeds as follows: 
1. Estimate 1 year FFS probabilities separately for the two cohorts. 
2. Compute the difference in FFS estimates from Step 1. 

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3. If the magnitude of the difference does not exceed a threshold value of 0.05, a 5% absolute 
difference in FFS, combine cohort data and report FFS point and interval estimates 
computed from pooled data analysis. Otherwise, only report FFS estimates from separate 
analyses of the two cohorts. 
The estimates from separate analyses of the transplant cohorts will be reported, regardless of 
whether a pooled analysis is performed. 
5.5.3.2 
Overall Survival (OS) 
OS is defined as the time interval from initiation of conditioning until death. Participants who 
withdraw, are lost to follow-up, or complete study follow-up alive will be censored at their last 
contact date. Kaplan-Meier curves will be used to display OS from start of conditioning initiation 
to Day +365 after the start of conditioning for each cohort. If no censoring occurs, sample 
proportions and 90% Clopper-Pearson CIs will be used to estimate 1-year OS probabilities. In the 
presence of censoring, the Kaplan-Meier estimator will give point estimates of OS and the beta 
product confidence procedure [54] will provide 90% exact CIs. OS will be analyzed using the 
primary analysis population. 
It is suspected that OS may be similar for haplo and URD transplants. If true, data from both 
cohorts can be combined to obtain more precise estimates of OS for them. A test-then-pool 
procedure [55] will be employed to allow the possibility of pooling cohort data if their outcomes 
are similar. The same procedure will be used as is described for the analysis of FFS in 
Section 5.5.3.1. 
5.5.3.3 
Neutrophil Recovery 
Neutrophil recovery will be analyzed using the transplanted population The time interval from 
transplant until neutrophil recovery will be described for each transplant cohort using the 
Aalen-Johansen estimator, with death prior to recovery treated as a competing risk. Estimates 
and 90% CIs of the cumulative incidence of neutrophil recovery will be provided at Day +28 and 
Day +56 post-HSCT for each cohort. 
5.5.3.4 
Red Blood Cell Recovery 
RBC recovery will be analyzed using the transplanted population. The time interval from 
transplant until RBC recovery will be described for each transplant cohort using the 
Aalen-Johansen estimator, with death prior to recovery treated as a competing risk. Estimates 
and 90% CIs of the cumulative incidence of RBC recovery will be provided at Day +100, 
Day +180, and Day +365 post-HSCT for each cohort. 
5.5.3.5 
Platelet Recovery 
Platelet recovery will be analyzed using the transplanted population The time interval from 
transplant until platelet recovery will be described for each transplant cohort using the 
Aalen-Johansen estimator, with death prior to recovery treated as a competing risk. Estimates 
and 90% CIs of the cumulative incidence of platelet recovery will be provided at Day +100 
post-HSCT for each cohort. 
5.5.3.6 
Graft Failure 
Graft failure will be analyzed using the transplanted population. The frequencies and proportions 
of participants with primary graft failure through Day +56 post-HSCT will be described for each 
transplant cohort. Participants who die before Day +56 without experiencing primary graft failure 

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will be classified as non-failures for this analysis. Proportions will be estimated using sample 
proportions and 90% CIs. 
The time interval from transplant until secondary graft failure will be described for each transplant 
cohort using the Aalen-Johansen estimator, with death prior to secondary failure treated as a 
competing risk. Estimates and 90% CIs of the cumulative incidence of secondary graft failure will 
be provided at Day +365 post-HSCT for each cohort. 
The time from transplant until any graft failure (primary or secondary) will be described for each 
transplant cohort using the Aalen-Johansen estimator, with death treated as a competing risk. 
Estimates and 90% CIs of the cumulative incidence of any graft failure will be provided at 
Day +365 post-HSCT for each cohort. 
5.5.3.7 
Hematologic Response 
Hematologic response will be analyzed using the transplanted population. The frequencies and 
proportions of participants with complete, partial, and no hematologic response will be described 
at Day +100, Day +180, and Day +365 post-HSCT for each transplant cohort. Proportions will be 
estimated using sample proportions and 90% CIs. 
5.5.3.8 
Acute GVHD 
Acute GVHD will be analyzed using the transplanted population. The time intervals from 
transplant until Grade II-IV and Grade III-IV aGVHD onset will be described for each transplant 
cohort using the Aalen-Johansen estimator, with death prior to aGVHD onset treated as a 
competing risk. Estimates and 90% CIs of the cumulative incidences of Grade II-IV and 
Grade III-IV aGVHD will be provided at Day +100 post-HSCT for each cohort. 
5.5.3.9 
Chronic GVHD 
Chronic GVHD will be analyzed using the transplanted population. The time intervals from 
transplant until any cGVHD onset and cGVHD onset requiring immunosuppression will be 
described for each transplant cohort using the Aalen-Johansen estimator, with death prior to onset 
treated as a competing risk for each outcome. Estimates and 90% CIs of the cumulative 
incidences of any cGVHD onset and cGVHD onset requiring immunosuppression will be provided 
at Day +365 post-HSCT for each cohort. The maximum severity of cGVHD will be tabulated for 
each cohort. 
5.5.3.10 
Being Alive and Engrafted 
This outcome will be analyzed using the primary analysis population. The frequencies and 
proportions of participants who are alive and engrafted at 1 year after initiation of conditioning will 
be described for each transplant cohort. Failures for this endpoint include death, failure to receive 
an HSCT infusion, and the failure to achieve at least 5% myeloid donor chimerism (whole blood 
or marrow) in the most recent measurement through 1 year. For failure to receive an HSCT 
infusion, the event time will be the day that the decision not to proceed to HSCT is made. 
Proportions will be estimated using sample proportions and 90% CIs. 
5.5.4 Analysis of Exploratory Endpoints 
5.5.4.1 
Time to Enrollment 
The time interval from HLA typing to enrollment will be described in the primary analysis 
population by transplant cohort using the sample median, quartiles, minimum, and maximum. 

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5.5.4.2 
Time from Diagnosis of SAA to Conditioning and to Transplant 
The time interval from SAA diagnosis to start of conditioning will be described in the primary 
analysis population by transplant cohort using the sample median, quartiles, minimum, and 
maximum. The time interval from SAA diagnosis to HSCT will be described in the transplanted 
population by transplant cohort using the sample median, quartiles, minimum, and maximum.  
5.5.4.3 
Times to Donor Activation, Donor Selection, Start of Conditioning, 
and Transplant 
The time intervals from enrollment to donor activation, donor selection, and start of conditioning 
will be described in the primary analysis population by transplant cohort using the sample median, 
quartiles, minimum, and maximum. The time interval from enrollment to HSCT will be described 
in the transplanted population by transplant cohort using the sample median, quartiles, minimum, 
and maximum. 
5.5.4.4 
Donor Availability 
The number of available donors will be described in the primary analysis population by transplant 
cohort using the sample median, quartiles, minimum, and maximum. Available donors will be 
described overall and separately by graft type for haploidentical and for 8/10, 9/10, and 10/10 
URDs. 
5.5.4.5 
HSCT Cell Dose 
The TNC and CD34+ cell doses received will be described in the transplanted population by 
transplant cohort using the sample median, quartiles, minimum, and maximum. 
5.5.4.6 
Immune Reconstitution 
Levels of peripheral blood CD4-, CD19-, and CD56-positive lymphocytes will be measured by 
flow cytometry analysis at baseline and Day +100, Day +180, and Day +365 post-HSCT. These 
cell populations will be analyzed in the transplanted population. 
The level of each cell population will be summarized for each transplant cohort using descriptive 
statistics at each assessment time considered. Changes in levels from baseline to each follow-up 
assessment time will be evaluated within each cohort. Logarithmic and other transformations will 
be applied to the cell levels to induce normality. If a normalizing transformation is identified, a 
linear mixed model will be used to assess changes in levels over time, with fixed effects for 
assessment times (Day +100, Day +180, and Day +365) and random effects to account for 
correlations of levels within each participant. If no normalizing transformation is found, a 
nonparametric analysis will be conducted using Wilcoxon signed rank tests to evaluate the 
changes in cell levels between each pair of assessment times. 
5.5.4.7 
Infection 
The number of Grade 2-3 infections and number of participants infected will be summarized by 
type, severity, and time period in the transplanted population by transplant cohort. The incidences 
of CMV viremia and disease, EBV viremia, and PTLD will be described for each cohort. 
5.5.4.8 
Health Related Quality of Life (HR-QoL)  
HR-QOL will be assessed at baseline and at Day +100, Day +180, and Day +365 post-HSCT 
using the PROMIS domains for anxiety, depression, anger, fatigue, physical function, cognitive 
function, and ability to participate in social roles & activities. The COST, occupational functioning 

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items, and sociodemographic/social determinants of health will be assessed at baseline and at 
Day +180 and Day +365 post-HSCT. These measures will be analyzed using the transplanted 
population. 
The distributions of scores for the PROMIS domains and COST will be described by descriptive 
statistics at each assessment time point for each transplant cohort. Responses to occupational 
functioning, and sociodemographic/social determinants of health items will be tabulated by 
frequency and percentages at each assessment time for each cohort. 
Changes in scores from baseline to each follow-up assessment time will be evaluated for the 
PROMIS domains and COST. A linear mixed model will be used for each score and cohort to 
assess changes over time, with fixed effects for assessment times and random effects to account 
for correlations of scores within each participant. 
5.5.5 Analysis of Safety Endpoints 
The frequency of Grade 3-5 AEs per CTCAE version 5.0 will be tabulated by system organ class 
(SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA®) 
dictionary for each transplant cohort. The frequency and proportion of participants having at least 
one Grade 3-5 AE will be summarized by SOC and PT. Detailed listings of unexpected SAEs, 
including grade and relationship to treatment, will be presented. Adverse events will be 
summarized using the safety population. 
 

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APPENDIX A 
 
HUMAN SUBJECTS 
 
1. Participant 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 
participant 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 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 participant 
identifier (ID) code. The code relaying the participant’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 DCC 
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 SAA 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 
 
LABORATORY PROCEDURES 
 
OPTIONAL RESEARCH SPECIMENS 
 
Participants and donors consenting to the optional future research will have samples 
collected for future research supporting the protocol. All research sample aliquots will be 
given unique bar code designations that cannot be linked back to the participant’s name 
or other identifying information. Laboratory test results, clinical information, etc., 
associated with the coded samples are provided to the Investigator only after completion 
of the protocol. Samples sent to researchers cannot be linked with any remaining samples 
at the repository. 
 
Patient samples will be collected both prior to the initiation of conditioning and at Day +28, 
Day +56, Day +100, Day +180 and Day +365 post-treatment as specified in the table on 
the next page. Donor samples will be collected at a single timepoint prior to marrow 
collection. All research samples will be collected and shipped same day to the BMT CTN 
Repository for processing and sample aliquot storage. Sample collection and shipping 
procedures are detailed in the BMT CTN 2207 Research Sample Information Guide. 
 
 
 

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Subjects 
Sample Type 
& Volume 
Sample 
Collection 
Time Points 
Sample Collection 
and Processing 
Summary 
Shipping Specifications 
Patients 
Peripheral Blood  
(SST Clot Tube) 
 
5 mL 
Pre-
Conditioning 
Day -9 
 
 
  
Post-
Treatment 
Day 28, 56, 
100, 180, and 
365 
Collect the blood 
sample and place into 
a SST Vacutainer tube 
containing clot 
activator. Allow blood 
samples to clot upright 
for 30-60 minutes in a 
tube rack prior to 
centrifugation. 
Centrifuged blood sample 
tube will be shipped at 
ambient temperature on the 
day of collection to the BMT 
CTN Biorepository, 
processed into five 0.5 mL 
serum aliquots, and stored 
at -80⁰C. 
Peripheral Blood 
(EDTA) 
 
3 mL 
Collect the blood 
sample and place into 
a Vacutainer tube 
containing EDTA 
anticoagulant. Gently 
mix sample by 
inversion 8-10 times to 
mix. 
Blood sample tubes will be 
shipped at ambient 
temperature on the day of 
collection, to the BMT CTN 
Biorepository, processed 
into three 1.0 mL whole 
blood aliquots, and stored 
and -80⁰C. 
Peripheral Blood 
(NaHep) 
 
30 mL 
Collect the blood 
sample and place 10 
mL into each of three 
Vacutainer tubes 
containing sodium 
heparin anticoagulant. 
Gently mix sample by 
inversion 8-10 times to 
mix. 
Blood sample tubes will be 
shipped at ambient 
temperature on the day of 
collection, to the BMT CTN 
Biorepository, processed 
into three 5x10^6 PBMC 
aliquots and ten 0.5 mL 
plasma aliquots, and stored 
in LN2 and -80⁰C
respectively.
Donors 
Peripheral Blood 
(EDTA) 
 
20 mL 
Prior to 
Marrow 
Collection 
Collect the blood 
sample and place into 
a Vacutainer tube 
containing EDTA 
anticoagulant. Gently 
mix sample by 
inversion 8-10 times to 
mix. 
Blood sample tubes will be 
shipped at ambient 
temperature on the day of 
collection, to the BMT CTN 
Biorepository, processed 
into three 1.0 mL whole 
blood aliquots, and stored 
and -80⁰C. 
 
Windows for Submitting Optional Research Samples 
Day -9 
Prior to initiation of conditioning
(Day -9 -7 days)
Pre-Collection 
(Donor)
Prior to marrow collection 
Day +28
Day 28 ± 3 days
Day +56
Day 56 ± 3 days
Day +100 
Day 100 ± 7 days
Day +180 
Day 180 ± 28 days
Day +365 
Day 365 ± 45 days

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APPENDIX C 
 
WEIGHT CALCULATIONS 
 
Use the following calculations according to medication specific instructions in Section 2.6.1.1: 
Adjusted IBW (AIBW) Formula: 
  AIBW = IBW + [(0.25) x (actual body weight – IBW)] 
IBWforParticipants≥18YearsofAge(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 participants 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 participants less than 152.4 cm feet, subtract 2.3 kg/2.54 cm 
IBW for Participants 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: 
A 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 
EXAMPLE CALCULATION 3: 
A 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 
 

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APPENDIX D 
 
CAMITTA [56] 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)
BM Cellularity 
< 25% 
< 25% 
< 25% 
ANC 
 
< 500 / mL 
< 200 / mL 
Platelet Count 
 
< 20,000 / mL 
 
Reticulocyte Count 
 
< 1.0% corrected 
or 
< 60,000 / mL 
 
 

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APPENDIX E 
 
ABBREVIATIONS 
Abbreviation
Definition 
Ab 
Antibody 
ADL
Activity of Daily Living
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest
aGVHD
Acute Graft Versus Host Disease 
AIBW 
Adjusted Ideal Body weight 
AIHA
Autoimmune hemolytic anemia
alloBMT 
Allogenic Bone Marrow Transplantation 
ALT
Alanine Aminotransferase
AML 
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
AP 
Alkaline Phosphatase
ARD
Antigen Recognition Domain
ASBMT
American Society for Blood and Marrow Transplantation
AST
Aspartate Aminotransferase
ASTCT 
American Society for Transplantation and Cellular Therapy
ATG 
Antithymocyte globulin 
BAL 
Bronchoalveolar Lavage 
BiPap
Bi-level positive airway pressure 
BM
Bone Marrow 
BMT
Bone Marrow Transplant 
BMT CTN
Blood and Marrow Transplant Clinical Trials Network 
BOS
Bronchiolitis Obliterans Syndrome
BSA 
Body Surface Area
CBC
Complete Blood Count
CD 
Cluster of Differentiation
CFR 
Code of Federal Regulations 
cGVHD 
Chronic Graft Versus Host Disease
cGY
Centigray 
CI
Confidence Interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research
CMV
Cytomegalovirus
CNI 
Calcineurin inhibitor
CNS
Central Nervous System 
CoNS
Coagulase-Negative Staphylococci 
COST
Comprehensive Score of Financial Toxicity
CPAP 
Continuous Positive Airway Pressure
CPK 
Creatine Phosphokinase
CR 
Complete Response
CrCl 
Creatinine Clearance
CRP
C-Reactive Protein
CRS
Cytokine Release Syndrome
CSA 
Cyclosporin A
CSF 
Cerebrospinal Fluid

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Abbreviation
Definition 
CT  
Computerized Tomography
CTCAE  
Common Terminology Criteria for Adverse Effects 
CTX 
Cyclophosphamide
CXR
Chest X-Ray 
CYP3A4  
Cytochrome P450 3A4
DCC 
Data Coordinating Center 
DEB 
Diepoxybutane 
DIC 
Disseminated Intravascular Coagulopathy
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide
DLI
Donor Lymphocyte Infusion 
DNA 
Deoxyribonucleic Acid 
DSA 
Donor Specific HLA Antibodies
DSMB 
Data and Safety Monitoring Board
EBV  
Epstein-Barr Virus
EBMT 
European Society for Blood and Marrow Transplantation
Echo 
Echocardiogram
ECOG 
Eastern Cooperative Oncology Group
EKG 
Electrocardiogram
ePRO  
electronic Patient-Reported Outcomes
FEV1 
Forced Expiratory Volume 1
FFP 
Fresh Frozen Plasma 
FFS  
Failure-Free Survival 
FISH  
Fluorescence In Situ Hybridization
FVC  
Forced Vital Capacity
GCP  
Good Clinical Practice 
G-CSF  
Granulocyte Colony Stimulating Factor
GFFS 
Graft Failure-Free Survival 
GFR 
Glomerular Filtration Rate
GI 
Gastrointestinal 
GM-CSF  
Granulocyte Macrophage Colony Stimulating Factor
GVHD 
Graft Versus Host Disease
hATG 
Horse Antithymocyte Globulin 
HCT 
Hematopoietic Cell Transplant
HCT-CI  
Hematopoietic Cell Transplant Comorbidity Index
HepA 
Hepatitis A 
HepB 
Hepatitis B 
HepC  
Hepatitis C
Hgb
Hemoglobin
HHV-6  
Human Herpesvirus 6 
HIV
Human Immunodeficiency Virus
HLA 
Human Lymphocyte Antigen
HLH 
Haemophagocytic Lymphohistiocytosis
Hr 
Hour
HR-QoL  
Health Related Quality of Life 
HSCT  
Hematopoietic Stem Cell Transplantation 
HSV 
Herpes Simplex Virus
HTLV1 
Human T-Lymphotropic Virus type 1
HVG  
Host Versus Graft

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Abbreviation
Definition 
HypoMg/Ca/Phos Hyopmagnesemia/Hypocalcemia/Hypophosphatemia
IBW  
Ideal Body Weight
ICC  
International Consensus Classification
ICH  
International Council for Harmonization
ICU 
Intensive Care Unit
ID 
Identifier
IFD  
Invasive Fungal Disease
IgA  
Immunoglobulin A
IgG  
Immunoglobulin G
IgM 
Immunoglobulin M 
IND  
Investigational New Drug 
INR 
International Normalized Ratio 
I&O 
Input and Output
IQR  
Interquartile Range
IRB 
Institutional Review Board
IST 
Immunosuppressive Therapy 
ITP 
Idiopathic Thrombocytopenic Purpura 
IV
Intravenous
IVIG  
Intravenous Immunoglobulin
KCS 
Keratoconjunctivitis sicca
KPS  
Karnofsky Performance Status
LDH 
Lactate Dehydrogenase
LFT  
Liver Function Test
LPS  
Lansky Performance Status
LSS  
Lee chronic GVHD Symptom Scale
LVEF 
Left Ventricular Ejection Fraction
MAS 
Macrophage Activation Syndrome
Max 
Maximum
MDS 
Myelodysplastic Syndrome
MedDRA 
Medical Dictionary for Regulatory Activities
MFI  
Mean Fluorescence Intensity 
MMF  
Mycophenolate Mofetil 
MOP  
Manual of Procedures
MPA  
Mycophenolic Acid 
MSD 
Matched Sibling Donor 
MUGA  
Multigated Acquisition
NA 
Not Applicable
NAT  
Nucleic Acid Testing
NCI 
National Cancer Institute 
Neuro 
Neurological 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH  
National Institutes of Health
NOS  
Not Otherwise Specified
OS  
Overall Survival
PBSC  
Peripheral Blood Stem Cell
PCR 
Polymerase Chain Reaction
PFT  
Pulmonary Function Test 
PI  
Principal Investigator 

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Abbreviation
Definition 
PJP (or PCP) 
Pneumocystis Jiroveci Pneumonia 
PK 
Pharmacokinetic(s)
PML 
Progressive Multifocal Leukoencephalopathy 
PNH
Paroxysmal Nocturnal Hemoglobinuria 
PO 
Per Os (by mouth) 
PR
Partial Response 
PRBC
Packet Red Blood Cell 
PRES 
Posterior Reversible Encephalopathy Syndrome
PRO 
Patient-Reported Outcome
P-ROM
Photographic Range of Motion
PROMIS 
Patient-Reported Outcomes Measurement Information System
PT
Preferred Termothrombin Time 
PTCTC
Pediatric Transplantation and Cellular Therapy Consortium
PTCy
Post-transplant Cyclophosphamide 
PTLD 
Post-Transplant Lymphoproliferative Disease 
PTT 
Partial Thromboplastin Time
q
Quaque (each) 
RACE
A prospective Randomized multicenter study comparing horse Antithymocyte 
globulin (hATG) + Cyclosporine A (CsA) with or without Eltrombopag as front-
line therapy for severe aplastic anemia
RBC
Red Blood Cell 
ROM
Range of Motion 
RSV 
Respiratory Syncytial Virus
SAA 
Severe Aplastic Anemia
sAb 
Surface Antibody 
SAE 
Serious Adverse Event
sAg 
Surface Antigen
SCTOD
Stem Cell Transplant Outcomes Database 
SD
Standard Deviation
SF
Shortening Fraction 
SIADH
Syndrome of Inappropriate Antidiuretic Hormone
SOC 
System Organ Class 
SOP
Standard Operating Procedure 
SOS
Sinusoidal Obstruction Syndrome/ 
SPRT
Sequential Probability Ratio Test
SRG 
Survey Research Group
SQ  
Subcutaneous 
STAT 
Immediately 
TA-TMA 
Transplant-Associated Thrombotic Microangiopathy
TBI 
Total Body Irradiation
TID 
Ter in Die (3 times a day) 
TNC 
Total Nucleated Cell 
US 
United States
VOD 
Veno-Occlusive Disease
VZV
Varicella Zoster Virus
WBC
White Blood Cell
WHO 
World Health Organization

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APPENDIX F 
 
BONE MARROW HARVEST GUIDELINES [57] 
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 
BM 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-BM 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 iIs 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 TNC: A x B = TNC. (Example: if marrow count is 27 and peripheral white cell 
count is 6, then the marrow mononuclear cell count would be 21 = B) 
3. TNC should then be divided by IBW to determine TNC/kg achieved (target 4 x 108 
nucleated cells/kg recipient IBW). 
 
(1.058 is the specific gravity that we use to convert weight to volume for BM) 

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APPENDIX G 
 
GUIDANCE FOR MIXED CHIMERISM 
 
Chimerism measurements should be assessed as per protocol requirements (Table 4.3.5). 
Primary and secondary graft failure are also defined (Section 3.2.6 and Section 3.2.7). There will 
be participants who meet criteria for mixed chimerism post-transplant who require special 
attention. 
Any donor chimerism below 95% 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 in 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 reduce the risk of mixed chimerism and to manage mixed chimerism, if it 
occurs: 
1. Optimize cell counts in the donor harvest to achieve at least a goal of 4 x 108 nucleated 
cells/kg recipient weight (minimum 2.5 x 108 nucleated cells/kg recipient weight) 
2. Ensure optimal compliance with all post-transplant immunosuppression. 
a. Mycophenolate mofetil should be given via IV in participants whom the oral 
preparation is not well tolerated. 
b. Monitor levels of tacrolimus (as often as daily) to ensure therapeutic troughs. 
3. If post-Day 28, Day 56, or Day 100 chimerism is low, increase frequency of monitoring 
per protocol (Table 4.3.5), with monthly chimerisms until stable or resolved. 
4. Do not stop immunosuppression. Consider up-titrating dose of calcineurin inhibitor to 
ensure trough in the upper end of goal range. 
5. In most situations, we do not advise donor lymphocyte infusion (DLI) as a first approach 
for reduced chimerism due to the risk of GVHD. For participants with poor graft function 
and established donor chimerism, CD34+ selected cell boosts or growth factors can be 
considered. 
6. Continue close clinical follow-up. 
7. Notify protocol chairs or medical monitor with questions or concerns. 
 

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APPENDIX H 
BMT CTN INFECTION GRADING TABLE AND RECURRENCE INTERVAL 
DEFINITIONS 
From BMT CTN Technical Document Infectious Diseases v2.0, dated September 9, 
2024 
 
Type of Infection/ 
Severity Grade 
 
Grade 1 
Grade 2 
Grade 3 
Bacterial infections
Bacteremia with skin flora 
[ex. Coag Neg Staph 
(CoNS, S. epi), 
Corynebacterium, or 
Cutibacterium 
(Proprioniobacterium)] 
requiringantibioticsfor≤
14 days of therapy for 
treatment 
 
Bacterial focus NOS 
requiringantibioticsfor≤
14 days of therapy for 
treatment (e.g urinary 
tract infection) Bacterial 
focus NOS requiring only 
topical, ocular, or otic 
treatments  
 
Cellulitis responding to 
initial therapy within 14 
days 
 
Any bacterial pneumonia 
not requiring 
supplemental oxygen 
 
C difficile toxin or PCR 
positive stool with 
diarrhea < 
1L/day without 
abdominal pain (child < 
20 mL/kg/day) 
Bacteremia due to other 
organisms (not skin flora) 
 
 
Bacterial focus (including 
bacteremia) with persistent 
signs/symptoms or persistent 
positive cultures requiring 
antibiotics for > 14 days of 
therapy  
 
 
Cellulitis requiring a change in 
therapy due to progression or 
systemic treatment for >14 
days 
 
Localized or diffuse infections 
requiring incision with or 
without drain placement but 
no debridement 
 
Any pneumonia documented 
or presumed to be bacterial 
requiring low flow oxygen 
 
C difficile toxin or PCR 
positive stool with diarrhea 
> 1L/day (child > 20 
mL/kg/day) or with 
abdominal pain   
Bacteremia with deep 
organ involvement (e.g. 
with new or worsening 
pulmonary infiltrates; 
endocarditis, brain 
abscess) 
 
Severe shock with 
bacteremia. 
 
Endocarditis 
 
Brain abscess or 
meningitis without 
bacteremia  
 
Active Tuberculosis 
infection 
 
Fasciitis or other skin and 
soft tissue infection 
requiring surgical 
debridement  
 
Bacterial pneumonia 
requiring high flow 
oxygen or positive 
pressure ventilation 
 
C difficile toxin or PCR 
positive stool with ileus, 
colon dilation, or toxic 
megacolon, or need for 
surgical bowel resection 
(colectomy, ileostomy)  

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Type of Infection/ 
Severity Grade 
 
Grade 1 
Grade 2 
Grade 3 
Fungal infections
Mucocutaneous 
candidiasis (excluding 
esophagitis) (e.g., oral 
thrush, vaginal 
candidiasis) and 
dermatophyte infections 
(tinea) 
Candida esophagitis 
diagnosed by endoscopy 
 
Fungal sinusitis confirmed 
radiologically without orbital, 
brain or bone involvement. 
 
Fungal pneumonia or 
pulmonary nodules (unless 
requiring high-flow oxygen or 
positive pressure ventilation) 
 
Fungal skin and soft tissue 
infection without fungemia, 
involvement of other sites, or 
need for debridement 
 
Pneumocystis jirovecii 
pneumonia (unless requiring 
high-flow oxygen or positive 
pressure ventilation) 
Fungemia including 
candidemia 
Fungal sinusitis confirmed 
radiologically with orbital, 
brain, or bone 
involvement 
 
Fungal pneumonia or 
pulmonary nodules 
presumed to be fungal 
requiring high-flow 
oxygen or positive 
pressure ventilation 
Disseminated infections 
(defined as multifocal 
pneumonia with 1 or more 
additional site of 
involvement, cutaneous 
spread, CNS 
involvement) with any 
fungus (yeast or mold) 
 
Pneumocystis jirovecii 
pneumonia requiring 
high-flow oxygen or 
positive pressure 
ventilation 
 
 

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Type of Infection/ 
Severity Grade 
 
Grade 1 
Grade 2 
Grade 3 
Viral infections
Mucosal (mouth, 
esophagus, vaginal, 
penile) HSV infection 
requiring oral antiviral 
therapy or observation 
 
Dermatomal zoster 
(shingles)affecting≤2
dermatomes 
 
Asymptomatic CMV 
viremia not requiring 
treatment 
 
EBV viremia not requiring 
treatment  
 
Adenoviral infection not 
requiring treatment   
 
HHV-6 viremia not 
requiring treatment 
 
BK viremia or viruria with 
cystitis not requiring 
intervention except anti-
spasmodics or pain 
medication 
 
Symptomatic upper and 
lower tract respiratory 
virus (excludes 
adenovirus, SARS-CoV-2 
[COVID]) not requiring 
oxygen 
 
Viremia (virus not 
otherwise specified) 
not requiring 
therapy 
Mucosal (mouth, esophagus, 
vaginal, penile) HSV infection 
requiring IV nutrition or IV 
antiviral therapy 
 
VZV infection involving 3 or 
more dermatomes  
 
CMV viremia requiring 
therapy or CMV viremia 
requiring a change in therapy 
due to resistance or with 
persistent viremia beyond 4 
weeks while on treatment 
 
EBV viremia requiring 
institution of therapy  
 
Adenoviral upper respiratory 
infection, viremia, or 
symptomatic viruria requiring 
treatment  
 
HHV-6 infection (e.g., 
symptoms, cytopenias) 
requiring treatment  
 
BK viremia or viruria with 
clinical consequence requiring 
therapy (continuous bladder 
irrigation, antiviral therapy) 
and/or surgical intervention 
 
Enterocolitis with enteric (GI) 
viruses  
 
Lower tract respiratory viruses 
(excludes adenovirus, SARS-
CoV-2 [COVID]) requiring low 
flow oxygen 
 
SARS-CoV-2 (COVID) 
infection requiring low flow 
oxygen 
Any viremia (virus not 
otherwise specified) requiring 
therapy  
HSV infection with end 
organ involvement 
(encephalitis, hepatic, 
lung) 
 
Severe VZV infection with 
end organ involvement 
(coagulopathy, 
encephalitis, hepatic, 
lung, eye) 
 
CMV end-organ 
involvement (lung, 
intestines, eye) 
 
EBV PTLD 
 
Adenovirus with end-
organ involvement, 
including pneumonitis, but 
excluding conjunctivitis 
and upper respiratory 
tract infections 
 
HHV-6 with end-organ 
involvement (such as 
encephalitis, hepatitis, 
pneumonitis) 
 
BK viremia or viruria with 
end organ damage (i.e., 
renal failure requiring 
dialysis) 
 
Lower tract respiratory 
viruses (excludes 
adenovirus, SARS-CoV-2 
[COVID]) requiring or high 
flow oxygen 
 Or positive pressure 
ventilation 
 
Any viral encephalitis, 
meningitis, or end organ 
disease 

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Type of Infection/ 
Severity Grade 
 
Grade 1 
Grade 2 
Grade 3 
Parasitic infections Giardiasis or other
parasitic 
gastrointestinal 
infection with diarrhea 
<1L / day (<5 episodes 
/ day) (child < 20 
mL/kg/day) 
 
 
Chronic strongyloidiasis 
treated with oral 
ivermectin or other oral 
therapies 
 
Toxoplasma DNAemia 
without organ 
involvement resolving 
spontaneously (without 
treatment)
Giardiasis or other parasitic
gastrointestinal infection 
with diarrhea > 1 L / day (5 
episodes/ day) (child > 20 
mL/kg/day) or with 
abdominal pain 
 
 
Toxoplasma DNAemia 
without organ involvement 
requiring treatment 
Strongyloides 
hyperinfection or 
disseminated infection 
 
 
 
CNS or other organ 
toxoplasmosis 
 
Nonmicrobiologica 
lly defined 
infections 
Pneumonia or 
bronchopneumonia not 
requiring supplemental 
oxygen 
 
Fever with negative 
cultures responding to 
treatment within 14 
days 
 
Clinically documented 
infection not requiring 
inpatient management 
Pneumonia or 
bronchopneumonia requiring 
low flow oxygen 
 
 
Sepsis without an identified 
organism (excluding patients 
receiving immune effector 
therapy diagnosed with 
cytokine release syndrome 
(CRS)) 
 
 
Typhlitis without severe 
sepsis, ileus, or need for 
surgical intervention 
Any acute pneumonia 
requiring high flow 
oxygen 
or positive pressure 
ventilation 
 
Septic shock without an 
identified organism 
(excluding patients 
receiving immune 
effector therapy 
diagnosed with CRS) 
 
 
 
Typhlitis requiring 
surgical indication as 
grade 3
 
 
Sepsis (Adult) based on CDC’s Sepsis Criteria:  
a. Sepsis: Life-threatening organ dysfunction caused by a dysregulated host response 
to infection.  
b. Hypotension: A systolic blood pressure of <100 mm Hg or a reduction of >40 mm hg 
from baseline in the absence of other causes for hypotension 
c. Organ Dysfunction defined by Sequential Organ Failure Assessment (eSOFA) score: 
Any of the following 
i. Initiation of new vasopressor infusion 
ii. Initiation of mechanical ventilation (invasive or non-invasive) 
iii. Acute renal failure (only for patients without end-stage renal failure) defined 
as Either: 
a. Doubling of serum creatinine compared to baseline OR 

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b. Decrease in estimated glomerular filtration rate (eGFR) by > 
50% compared to baseline 
iv. Hyperbilirubinemia defined as BOTH 
a. Total bilirubin > 2mg/dl, AND 
b. Total bilirubin increase of > 50% compared to baseline 
v. Thrombocytopenia (only for patients with baseline platelet count >100 cell/µL) 
defined as BOTH 
a. Platelet count <100 cell/µL, AND  
b. Decrease in platelet count >50% compared to baseline 
vi. Serum lactate >2 mg/dL 
d. Adult Sepsis Criteria: Any organ dysfunction PLUS a source and or suspected 
source of infection  
e. Adult Septic Shock: Sepsis plus vasopressors to maintain adequate blood pressure 
AND elevated lactate (>2mmol/L or >18 mg/dL). 
 
 
Pediatric Sepsis based on International Pediatric Sepsis Consensus Conference 
(2005): 
a. Pediatric SIRS definition: Two or more of the following, one of which must be 
abnormal temperature or leukocyte count 
i. Core temperature >38.5C or < 36C 
ii. Tachycardia, otherwise unexplained and persistent in the absence of external 
stimulus, chronic drugs, or painful stimuli; or bradycardia, in < 1 year old, 
otherwise unexplained and persistent. 
iii. Tachypnea or mechanical ventilation for an acute process not related to 
underlying neuromuscular disease or general anesthesia 
iv. Leukocytosis or leukopenia for age (not secondary to chemotherapy) or 
>10% bands 
b. Pediatric Sepsis: Requires either Pediatric SIRS definition (supplemental table 2) 
plus suspected or proven infection 
c. Pediatric Severe Sepsis: Sepsis plus either 1) cardiovascular dysfunction or ARDS; 
or 2) two or more other organ dysfunctions. 
d. Pediatric Septic Shock: Sepsis and cardiovascular organ dysfunction (below)  
e. Pediatric organ dysfunction criteria: (hematological criteria excluded) 
I.Cardiovascular:  
Despite administration of fluid bolus >40 ml/kg in 1 hour presence of  
a. Hypotension <5th percentile for age (or per supplemental table 2) 
      OR 
b. Blood pressure elevation agents at any dose  
      OR 
c. Two of the following:  
I. 
Capillary refill > 5 secs  
II. 
Core to peripheral temperature gap > 3oC  
III. 
Urine output < 0.5 mL/kg/hr  
IV. 
Unexplained metabolic acidosis (Base deficit > 5.0 
mEq/L) 
V. 
Blood lactate > 2 x ULN  
II.Respiratory: 
a. ARDS  
   OR 
b. Intubated  

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  OR 
c. >50% FiO2 to maintain SaO2 or SpO2 > 92%  
III.Neurological: 
a. Glasgow Coma Score < 11 
      OR 
b. Acute change in mental status with a decrease in GSC >3 pts 
from abnormal baseline  
IV. 
Renal:  
a. Serum creatinine > 2 x ULN for age  
    OR 
b.  2-fold increase in baseline creatinine  
V. Hepatic: 
  a. Total bilirubin >4 mg/dL  
OR 
b.  ALT >2 x ULN for age  
 
 
Pediatric Systemic Inflammatory Response Syndrome Definitions and Laboratory Values 
Ranges for the four Pediatric Age Groups ϣ 
Age
Tachycardia 
(bpm)
Bradycardia 
(bpm)
Tachypnea 
(breaths/min)
Leukocytosis / 
Leukopenia ( 
103/mm3WBC) 
Hypotension
Systolic BP 
mmHg
1 mo to 1 yr
>180
<90 
>34
>17.5 to <5.0
<75
>1 yr to 5 yr 
>140
NA
>22
>15.5 to <6.0
<74
>5 yr to 12 yr 
>130
NA
>18
>13.5 to <4.5
<83
>12 yr to < 18 yr 
>110
NA
>14
>11 to <4.5
<90
Ϣ  Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis. 
International pediatric sepsis consensus conference: definitions for sepsis and organ 
dysfunction in pediatrics. Pediatr Crit Care Med. 2005 Jan;6(1):2-8. doi: 
10.1097/01.PCC.0000149131.72248.E6. PMID: 15636651. 
 
Disseminated Infections: 
Two or more non-contiguous sites infected with the same organisms. 
• 
For infections coded as “Disseminated” per the Infection Form, any previous infection with 
the same organism but different site within the recurrence interval for that organism will 
be counted as part of the disseminated infection. 
• 
It can occur at any level of severity, but most will be grade 2 or 3 
 
Oxygen Supplementation definitions:  
a. Low flow:  oxygenbynasalcannulaat≤6L/minute 
b. If patient requires supplemental oxygen at baseline (i.e., on 2L/minute) in the outpatient 
setting, an increase over the baseline oxygen needs (i.e increase to 3L/minute) is required 
to meet “low flow” definition 
c. High flow: oxygen by nasal cannula at >6L/minute 
d. Positive Pressure: Continuous positive airway pressure (CPAP), bilevel positive airway 
pressure (BPAP), intubation with mechanical ventilation 

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Recurrence Intervals to Determine Whether an Infection is the Same or New: 
 
Type of Infection
Recurrence Internal reflects a 
previously diagnosed Infection 
Cytomegalovirus, Herpes simplex virus, Epstein-Barr virus, and Human 
herpes virus 6 related infections 
2 months (< 60 days)
Varicella zoster virus
2 weeks (< 14 days)
Polyomavirus
2 months (< 60 days)
Bacterial, non-C. difficile 
1 week (< 7 days)
Bacterial, C. difficile
1 month (< 30 days)
Yeast infections (non-cryptococcal)
2 weeks (< 14 days)
Invasive mold infections, dimorphic fungal infection, and cryptococcal 
infection 
3 months (< 90 days)
Helicobacter pylori infection
1 year (< 365 days)
Respiratory viruses: Adenovirus, Enterovirus, Influenza A &B, 
Respiratory syncytial virus, Parainfluenza, Rhinovirus, and SARS-CoV-
2 infections 
3 months (<90 days)
Parasitic infections (excluding chronic strongyloidiasis)
3 months (< 90 days)
Chronic strongyloidiasis (defined as positive serologies without 
detection of larvae) 
2 years
 
 
 
 
 
 
 
 
 
 

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Invasive fungal disease (IFD) due to yeasts, yeast-like fungi, and dimorphic fungi 
IFD type 
Criteria for proven IFD 
 Criteria for evidence of IFD 
Endemic mycoses 
(for example 
Coccidioides, 
Blastomyces, 
Histoplasma) 
At least one of these criteria:
• 
Histopathology or direct microscopy 
of specimens obtained from an 
affected site showing the distinctive 
form of the fungus, or 
• 
Culture of the fungus from blood or 
specimens from an affected site 
Clinical diagnosis (pulmonary, 
cutaneous, osseous, GI, and/or 
CNS) and initiation of treatment 
for endemic mycosis 
 
Plus at least one of these 
criteria: 
• 
Histoplasma or 
Blastomyces antigen in 
urine, serum, or body 
fluid 
• 
Antibody to Coccidioides 
in cerebrospinal fluid 
• 
Two-fold rise of 
Coccidioides antibodies 
in 2 consecutive serum 
samples 
Pneumocystis 
jirovecii 
pneumonia (PJP 
or PCP) 
Detection of the organism microscopically in 
tissue, BAL fluid, or sputum using 
conventional or immunofluorescence staining 
Clinical diagnosis of PJP with 
initiation of treatment 
• 
Plus at least one of these 
criteria: 
• 
ß-D-glucan (Fungitell®) 
≥ 8 0 ng/L (pg/mL) from 
one serum sample (if 
other etiologies for 
elevated Fungitell have 
been excluded) 
• 
Detection of 
Pneumocystis jirovecii 
DNA by PCR from a 
respiratory tract 
specimen 
 

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IFD type
Criteria for proven IFD 
Criteria for evidence of IFD 
Cryptococcal 
infection 
At least one of these criteria:
• 
Histopathologic, cytopathologic, or 
direct microscopic examination of a 
specimen obtained by needle 
aspiration or biopsy from a normally 
sterile site (other than mucous 
membranes) showing yeast 
consistent with Cryptococcus species 
(based on morphology or PCR) 
• 
Recovery of Cryptococcus by culture 
of a sample obtained by a sterile 
procedure from a normally sterile site 
showing a clinical or radiological 
abnormality consistent with an 
infection 
• 
Blood culture with Cryptococcus 
• 
Positive cryptococcal antigen in 
cerebrospinal fluid or blood
Clinical diagnosis of cryptococcal 
infection (pulmonary, CNS, 
cutaneous, disseminated with 
initiation of treatment 
 
Plus at least one of these 
criteria: 
• 
Radiographic evidence 
of meningeal 
inflammation 
• 
Lesion on imaging 
consistent with 
cryptococcal disease 
Candida and other 
yeast infection 
At least one of these criteria:
• 
Histopathologic, cytopathologic, or 
direct microscopic examination of a 
specimen obtained by needle 
aspiration or biopsy from a normally 
sterile site (other than mucous 
membranes) showing yeast 
• 
Recovery of yeast by culture of a 
sample obtained by a sterile 
procedure from a normally sterile site 
showing a clinical or radiological 
abnormality consistent with an 
infection 
• 
Blood culture with yeast 
Applies to Candida only
Candidemia within the previous 
2 weeks with at least one of 
these criteria: 
• 
Radiographic findings 
consistent with 
abscesses in liver, 
spleen, or brain 
• 
Meningeal enhancement 
• 
Progressive retinal 
exudates or vitreal 
opacities on 
ophthalmologic 
examination 
 
Plus initiation of treatment and at 
least one of these criteria: 
• 
ß-D-glucan (Fungitell®) 
≥80ng/L(pg/mL)from
one serum sample (if 
other etiologies for 
elevated Fungitell® have 
been excluded) 
• 
Positive T2Candida® 
 
 

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IFD due to Aspergillus and other molds 
Proven 
mold 
infection 
At least one of these criteria:
• 
Histopathologic, cytopathologic, or direct microscopic examination of a tissue 
specimen obtained by needle aspiration or biopsy in which hyphae or melanized 
yeast-like forms are seen accompanied by evidence of associated tissue 
damage 
• 
Recovery of a mold by culture of a specimen obtained by a sterile procedure 
from a normally sterile site (with clinical or radiological evidence of an infection), 
excluding BAL fluid, sinus specimens, and urine 
• 
Blood culture that yields a mold in the context of a compatible infection 
• 
Identification of fungal DNA by PCR combined with DNA sequencing when molds 
are seen in formalin-fixed paraffin-embedded tissue
Probable 
mold 
infection 
Clinical feature
Pulmonary aspergillosis and 
other pulmonary mold infections 
At least one of these patterns are 
seen on CT imaging: 
• 
Dense, well-circumscribed 
lesions 
• 
Air crescent sign 
• 
Cavity 
• 
Wedge-shaped, 
segmental, or lobar 
consolidation 
• 
Reverse halo sign (for 
molds other than 
Aspergillus) 
Aspergillus or other mold 
tracheobronchitis 
Tracheobronchial ulceration, 
nodule, pseudomembrane, plaque, 
or eschar seen on bronchoscopy 
 
Aspergillus and other mold sino- 
nasal disease 
At least one of these criteria: 
• 
Acute localized pain 
• 
Nasal ulcer with black 
eschar 
• 
Extension from the 
paranasal sinus across 
bony barriers 
 
Aspergillus and other mold CNS 
infection 
Focal lesions or meningeal 
enhancement on imaging 
AND
Mycologic evidence
• 
Aspergillus or other mold 
recovered by culture from sputum, 
BAL, bronchial brush, or aspirate 
• 
Microscopic detection of mold from 
sputum, BAL, bronchial brush, or 
aspirate 
• 
At least one of these criteria 
applied to Aspergillus 
galactomannan antigen: 
o 
Single serum or plasma: ≥
1.0 
o 
BAL fluid: ≥ 1.0 
o 
Single serum or plasma: ≥ 
0.7 plus BAL fluid ≥ 0.8 
o 
CSF: ≥ 1.0 
• 
At least one of these criteria 
applied to organism specific PCR 
(e.g., Aspergillus or Mucor): 
o 
Plasma, serum, or whole 
blood: 2 or more 
consecutive PCR tests 
positive 
o 
BAL fluid: 2 or more PCR 
tests positive 
o 
At least 1 PCR test 
positive in plasma, serum, 
or whole blood and 1 PCR 
test positive in BAL fluid 

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APPENDIX I 
 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE AND CHRONIC GVHD 
 
1.  GvHD Clinical Staging 
GVHD clinical staging will be according to the MAGIC criteria below 
From BMT CTN Technical Document GvHD Guidance v1.0, dated March 13, 2023. 
 
 
 
Overall Clinical Grade: 
Grade 0  No stage 1-4 of any organ 
Grade I  Stage 1-2 skin and no liver or GI involvement  
Grade II  Stage 3 skin and/or Stage 1 liver and/or Stage 1 GI 
Grade III  Stage 0-3 skin with Stage 2-3 liver and/or Stage 2-3 GI  
Grade IV  Stage 4 in any target organ (skin, liver, GI) 
 
 
 
 
 
 
 
Stage 0 
Stage 1
Stage 2
Stage 3
Stage 4
 
Skin 
No rash 
Rash < 25% BSA 
25-50% 
> 50% 
Generalized 
erythroderma 
Generalized 
erythroderma (>50% 
BSA) plus bullae 
and/or desquamation 
Liver 
Bilirubin≤2
mg/dl 
2.1-3 mg/dl 
3.1-6mg/dl 
6.1-15mg/dl 
>15mg/dl 
 
GI 
tract 
Adult: < 500 
ml/day or <3 
episodes/day 
Child: < 10 
ml/kg/day or <4 
episodes/day 
Adult: 500–999 
ml/day or 3–4 
episodes/day 
Child: 10–19.9 
ml/kg/day or 4–6 
episodes/day 
Adult: 1000–1500 
ml/day or 5–7 
episodes/day 
Child: 20 – 30 
ml/kg/day or 7–10 
episodes/day 
Adult: 1000–1500 
ml/day or 5–7 
episodes/day 
Child: 20 – 30 
ml/kg/day or 7–10 
episodes/day 
Severe abdominal 
pain +/- ileus, frank 
blood or melena 
(regardless of stool 
volume) 
UGI 
 
Severe/persistent 
nausea/vomiting/  
anorexia 
 
 
 
• 
For GI GVHD, children is defined as <18 years of age and <50 kg weight 
• 
Upper GI GVHD: in the absenceofabiopsy,symptomseverityanddurationrequirenausea≥3days, and/or 
≥2vomitingepisodesperdayforatleasttwodays,and/oranorexiawithweightloss 
• 
For stage 4 GI GVHD, severe abdominal pain is defined as (1) pain that requires opioid use and (2) pain that 
significantly impacts on performance status as determined by the treating physician 

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

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

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4. Signs and Symptoms of Chronic GVHD 
 
 
 
Organ 
or Site 
Diagnostic
(sufficient to establish 
the diagnosis of chronic 
GvHD)
Distinctive
(seen in chronic GvHD, 
but insufficient alone to 
establish a diagnosis)
Other Features
(can be recognized as 
part of chronic GvHD if 
diagnosis is confirmed)
Common Features 
(seen with both 
acute and chronic 
GvHD)
Skin 
• Poikiloderma 
• Lichen planus-like 
features 
• Sclerotic features 
• Morphea-like features 
• Lichen sclerosus-
like features
• Depigmentation 
• Papulosquamous 
lesions 
• Sweat impairment 
• Ichthyosis 
• Keratosis pilaris 
• Hypopigmentation 
• Hyperpigmentation 
• Erythema 
• Maculopapular 
rash 
• Pruritus 
Nails 
• Dystrophy 
• Longitudinal 
ridging, splitting, or 
brittle features 
• Onycholysis 
• Pterygium unguis 
• Nail loss (usually 
symmetric)
Scalp 
and 
body 
hair 
• New onset of scarring 
or non- scarring scalp 
alopecia (after 
recovery from 
chemoradiotherapy) 
• Loss of body hair 
• Scaling
• Thinning scalp hair, 
typically patchy, 
coarse, or dull (not 
explained by other 
causes) 
• Premature gray hair 
Mouth 
• Lichen-planus like 
changes 
• Xerostomia 
• Mucocele 
• Mucosal atrophy 
• Pseudomembranes 
• Ulcers
• Gingivitis 
• Mucositis 
• Erythema 
• Pain 
Eyes 
• New onset dry, 
gritty, or painful 
eyes 
• Cicatricial conjunctivitis 
• Keratoconjunctivitis 
sicca 
• Confluent areas of 
punctate 
keratopathy
• Photophobia 
• Periorbital 
hyperpigmentation 
• Blepharitis (erythema 
of the eyelids with 
edema) 
Genitalia 
 
Females 
 
 
Males 
• Lichen  planus-like 
features 
• Lichen sclerosus-
like features 
• Vaginal scarring 
or stenosis 
• Phimosis or 
urethral/meatus 
scaring or stenosis
• Erosions 
• Fissures 
• Ulcers 

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Organ or 
Site 
Diagnostic 
(sufficient to establish the 
diagnosis of chronic 
GvHD) 
Distinctive
(seen in chronic 
GvHD, but 
insufficient alone to 
establish a 
diagnosis)
Other Features
(can be recognized as 
part of chronic GvHD if 
diagnosis is confirmed) 
Common Features 
(seen with both 
acute and chronic 
GvHD) 
GI tract 
• Esophageal web 
• Strictures or stenosis in 
the upper to mid third of 
the esophagus 
• Exocrine pancreatic 
insufficiency 
• Anorexia 
• Nausea, vomiting 
• Diarrhea 
• Weight loss 
• Failure to thrive
Liver 
• Total bilirubin, 
ALP >2 x ULN 
ALT> 2 x ULN
Lung 
• Bronchiolitis obliterans 
diagnosed lung biopsy 
• Bronchiolitis obliterans 
syndrome* 
• Air trapping 
and 
bronchiectasis 
on chest CT 
• Cryptogenic 
organizing 
pneumonia** 
• Restrictive lung 
disease**
Muscles, 
fascia, 
joints 
• Fasciitis 
• Joint stiffness or 
contractures secondary 
to fasciitis or sclerosis
• Myositis or 
polymyositis 
• Edema 
• Muscle cramps 
• Arthralgia or arthritis 
Hemato 
poietic and 
immune 
• Thrombocytopenia 
• Eosinophilia 
• Lymphopenia 
• Hypo- or hyper- 
gammaglobulinemia 
• AIHA and ITP 
• Raynaud’s 
phenomenon
Other 
• Pericardial or pleural 
effusions 
• Ascites 
• Peripheral neuropathy 
• Nephrotic syndrome 
• Myasthenia gravis 
• Cardiac conduction 
abnormality or 
cardiomyopathy
 

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APPENDIX J 
 
PATIENT-REPORTED OUTCOME (PRO) QUESTIONS 
Presented here are the individual question items for all PRO surveys. The schedule for each PRO domain 
or set of items is described in Sections 4.3.8.3 to 4.3.8.6. Patient-facing survey forms will be prepared for 
both electronic and paper survey administration. 
Patient-facing survey forms will be developed and approved by the NMDP IRB as separate documents 
from this protocol. This protocol appendix should not be printed and provided to patients. 
1. Pediatric (age 5-7) Parent/guardian proxy-report PROMIS assessments 
1.1. PROMIS Anxiety 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
My child felt nervous
▢
▢
▢
▢
▢
My child felt scared
▢
▢
▢
▢
▢
My child felt worried
▢
▢
▢
▢
▢
My child felt like something awful might happen 
▢
▢
▢
▢
▢
My child worried when he/she was at home
▢
▢
▢
▢
▢
My child got scared really easy 
▢
▢
▢
▢
▢
My child worried about what could happen to 
him/her
▢
▢
▢
▢
▢
My child worried when he/she went to bed at night
▢
▢
▢
▢
▢
1.2. PROMIS Depressive symptoms 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
My child could not stop feeling sad 
▢
▢
▢
▢
▢
My child felt everything in his/her life went wrong
▢
▢
▢
▢
▢
My child felt like he/she couldn’'t do anything right
▢
▢
▢
▢
▢
My child felt lonely 
▢
▢
▢
▢
▢
My child felt sad 
▢
▢
▢
▢
▢
It was hard for my child to have fun 
▢
▢
▢
▢
▢
 
1.3. PROMIS Anger 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
My child felt mad 
▢
▢
▢
▢
▢
My child was so angry he/she felt like yelling at 
somebody 
▢
▢
▢
▢
▢
My child was so angry he/she felt like throwing 
something 
▢
▢
▢
▢
▢
My child felt upset
▢
▢
▢
▢
▢
When my child got mad, he/she stayed mad
▢
▢
▢
▢
▢
 
 

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1.4. PROMIS Fatigue 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
Being tired made it hard for my child to play or go 
out with friends as much as he/she would like
▢
▢
▢
▢
▢
My child felt weak
▢
▢
▢
▢
▢
My child got tired easily
▢
▢
▢
▢
▢
Being tired made it hard for my child to keep up 
with schoolwork
▢
▢
▢
▢
▢
My child had trouble finishing things because 
he/she was too tired
▢
▢
▢
▢
▢
My child had trouble starting things because 
he/she was too tired
▢
▢
▢
▢
▢
My child was so tired it was hard for him/her to 
pay attention
▢
▢
▢
▢
▢
My child was too tired to do sports or exercise
▢
▢
▢
▢
▢
My child was too tired to do things outside
▢
▢
▢
▢
▢
My child was too tired to enjoy the things he/she 
likes to do 
▢
▢
▢
▢
▢
1.5. PROMIS Mobility 
In the past 7 days… 
With no 
trouble 
With a 
little 
trouble
With 
some 
trouble
With a lot 
of trouble 
Not able 
to do 
My child could do sports and exercise that other 
kids his/her age could do 
▢
▢
▢
▢
▢
My child could get up from the floor
▢
▢
▢
▢
▢
My child could keep up when he/she played with 
other kids
▢
▢
▢
▢
▢
My child could move his/her legs
▢
▢
▢
▢
▢
My child could stand up without help
▢
▢
▢
▢
▢
My child could stand up on his/her
tiptoes
▢
▢
▢
▢
▢
My child could walk up stairs without holding on to 
anything
▢
▢
▢
▢
▢
My child has been physically able to do the 
activities he/she enjoys most
▢
▢
▢
▢
▢
 

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1.6. PROMIS Cognition 
In the past 7 days… 
None of 
the time
A little of 
the time
Some of 
the time
Most of 
the time
All of the 
time
Your child has to use written lists more often than 
other people his/her age so he/she will not forget 
things 
▢
▢
▢
▢
▢
It is hard for your child to pay attention to one 
thing for more than 5-10 minutes
▢
▢
▢
▢
▢
Your child has trouble keeping track of what 
he/she is doing if he/she gets interrupted
▢
▢
▢
▢
▢
Your child has to read things several times to 
understand them 
▢
▢
▢
▢
▢
Your child forgets things easily 
▢
▢
▢
▢
▢
Your child has to work really hard to pay attention 
or he/she makes mistakes 
▢
▢
▢
▢
▢
Your child has trouble remembering to do things 
like school projects or chores
▢
▢
▢
▢
▢
1.7. PROMIS Peer relationships 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
My child felt accepted by other kids his/her age 
▢
▢
▢
▢
▢
My child was able to count on his/her friends
▢
▢
▢
▢
▢
My child was good at making friends
▢
▢
▢
▢
▢
My child and his/her friends helped each other 
out
▢
▢
▢
▢
▢
Other kids wanted to be my child’'s
friend
▢
▢
▢
▢
▢
Other kids wanted to be with my child 
▢
▢
▢
▢
▢
Other kids wanted to talk to my child
▢
▢
▢
▢
▢
 
2. Pediatric (age 5-17) Parent/guardian proxy-report Occupational Function and 
Sociodemographic/social determinant of health items 
 
2.1. Occupational function items 
How many days per week does your child attend school? 
    
Number of days attending school (please enter whole number): ___________ 
 
In the past 30 days, how many days did your child miss school because of illness or injury? 
 
Number of days of school missed (please enter whole number): ___________ 
 
 
In the past 30 days, has your child attempted to go to school but found that he/she wasn’t able to? 
• 
Yes 
• 
No 
 
If yes, what prevents your child from going to school at the present time? 
 ______________________________________________________________________ 
 
_______________________________________________________________________ 

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2.2. Sociodemographics/social determinants of health 
What is your child’s zip code? ________________ 
 
Is your child Hispanic or Latino? (Select one response) 
□ Yes 
□ No 
□ Don’t know 
 
 
Which group(s) best describes your child? (Select all that apply) 
 
□ American Indian or Alaska Native 
□ Alaskan Native or Aleut 
□ North American Indian 
□ American Indian, South or 
Central America 
□ Caribbean Indian 
□ Asian 
□ South Asian 
□ Filipino (Pilipino) 
□ Japanese 
□ Korean 
□ Chinese 
□ Vietnamese 
□ Other Southeast Asian 
□ Black or African American 
□ African 
□ African American 
□ Black Caribbean 
□ Black South or Central American 
□ Other Black 
□ Native Hawaiian or Other Pacific 
Islander 
□ Guamanian 
□ Hawaiian 
□ Samoan 
□ Other Pacific Islander 
□ White 
□ Eastern European 
□ Mediterranean 
□ Middle Eastern 
□ North Coast of Africa 
□ North American 
□ Northern European 
□ Western European 
□ White Caribbean 
□ White South or Central American 
□ Other White 
□ Something else, please specify: 
________________________________ 
□ Don’t know 
 
What type of health insurance coverage does your child have? (Select all that apply) 
□ No insurance 
□ Medicaid 
□ Medicare 
□ Medigap 
□ Indian Health Service 
□ Military-related healthcare 
□ Private health insurance (including through 
your employer) 
□ Disability insurance Other government program (please describe): _____________________________ 
□ Other health insurance coverage (please describe): 
_____________________________________________ 
□ Don’t know 
 
 

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Was there any time during the past year when your child needed medical care but did not get it? 
□ Yes 
□ No 
 
 
Was there any time during the past year that your child delayed getting medical care you felt he/she 
needed? 
□ Yes 
□ No 
 
 
What is your family’s total yearly HOUSEHOLD income from all sources, before taxes? (Select one 
response) 
This includes money from jobs, disability benefits, social security payments, pensions or retirement, dividends and 
any other income received by ALL members of your household 
□ Less than $10,000 
□ $10,000 to $19,999 
□ $20,000 to $29,999 
□ $30,000 to $39,999 
□ $40,000 to $49,999 
□ $50,000 to $59,999 
□ $60,000 to $69,999 
□ $70,000 to $79,999 
□ $80,000 to $89,999 
□ $90,000 to $99,999 
□ $100,000 to $149,999 
□ $150,000 to $199,999 
□ $200,000 or more 
□ Don’t know 
 
What is your child’s living situation today? 
□ My child has a steady place to live 
□ My child has a place to live today, but I am worried about losing it in the future 
□ My child has does not have a steady place to live 
 
Think about the place your child lives. Are there problems with any of the following? (Select all that 
apply) 
□ Pests such as bugs, ants, or mice 
□ Mold 
□ Lead paint or pipes 
□ Lack of heat 
□ Oven or stove not working 
 
 
 
 
 
 
 
 
 
 
 

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3. Pediatric (age 8-17) Self-report PROMIS assessments 
3.1. PROMIS Anxiety 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
I felt like something awful might happen
▢
▢
▢
▢
▢
I felt nervous
▢
▢
▢
▢
▢
I felt scared
▢
▢
▢
▢
▢
I felt worried 
▢
▢
▢
▢
▢
I worried when I was at home
▢
▢
▢
▢
▢
I got scared really easy
▢
▢
▢
▢
▢
I worried about what could happen to me
▢
▢
▢
▢
▢
I worried when I went to bed at night
▢
▢
▢
▢
▢
3.2. PROMIS Depressive symptoms 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
I could not stop feeling sad
▢
▢
▢
▢
▢
I felt alone 
▢
▢
▢
▢
▢
I felt everything in my life went wrong
▢
▢
▢
▢
▢
I felt like I couldn’t do anything right
▢
▢
▢
▢
▢
I felt lonely
▢
▢
▢
▢
▢
I felt sad
▢
▢
▢
▢
▢
I felt unhappy 
▢
▢
▢
▢
▢
It was hard for me to have fun
▢
▢
▢
▢
▢
3.3. PROMIS Anger 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
I felt fed up
▢
▢
▢
▢
▢
I felt mad
▢
▢
▢
▢
▢
I felt upset 
▢
▢
▢
▢
▢
I was so angry I felt like throwing something
▢
▢
▢
▢
▢
I was so angry I felt like yelling at somebody
▢
▢
▢
▢
▢
3.4. PROMIS Fatigue 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
Being tired made it hard for me to keep up with my 
schoolwork
▢
▢
▢
▢
▢
Being tired made it hard for me to play or go out 
with my friends as much as 
I’'d like 
▢
▢
▢
▢
▢
I felt weak 
▢
▢
▢
▢
▢
I got tired easily
▢
▢
▢
▢
▢
I had trouble finishing things because I was too tired
▢
▢
▢
▢
▢
I had trouble starting things because I was too tired 
▢
▢
▢
▢
▢
I was so tired it was hard for me to pay attention
▢
▢
▢
▢
▢
I was too tired to do sports or exercise
▢
▢
▢
▢
▢
I was too tired to do things outside 
▢
▢
▢
▢
▢
I was too tired to enjoy the things I like to do
▢
▢
▢
▢
▢

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3.5. PROMIS Mobility 
In the past 7 days… 
With no 
trouble 
With a 
little 
trouble
With 
some 
trouble
With a 
lot of 
trouble
Not able 
to do 
I could do sports and exercise that other kids my 
age could do
▢
▢
▢
▢
▢
I could get up from the floor 
▢
▢
▢
▢
▢
I could keep up when I played with other kids
▢
▢
▢
▢
▢
I could move my legs
▢
▢
▢
▢
▢
I could stand up by myself
▢
▢
▢
▢
▢
I could stand up on my tiptoes
▢
▢
▢
▢
▢
I could walk up stairs without holding on to 
anything
▢
▢
▢
▢
▢
I have been physically able to do the activities I 
enjoy most
▢
▢
▢
▢
▢
 
3.6. PROMIS Cognition 
In the past 7 days… 
None of 
the time 
A little of 
the time
Some of 
the time
Most of 
the time
All of the 
time
I have to use written lists more often than other 
people my age so I will not forget things 
▢
▢
▢
▢
▢
It is hard for me to pay attention to one thing for 
more than 5-10 minutes
▢
▢
▢
▢
▢
I have trouble keeping track of what I am doing if I 
get interrupted
▢
▢
▢
▢
▢
I have to read things several times to understand 
them 
▢
▢
▢
▢
▢
I forget things easily
▢
▢
▢
▢
▢
I have to work really hard to pay attention or I make 
mistakes 
▢
▢
▢
▢
▢
I have trouble remembering to do things like school 
projects or chores 
▢
▢
▢
▢
▢
3.7. PROMIS Peer relationships 
In the past 7 days… 
Never
Almost 
Never
Sometimes
Often
Almost 
Always
I felt accepted by other kids my age 
▢
▢
▢
▢
▢
I was able to count on my friends.
▢
▢
▢
▢
▢
I was able to talk about everything with
my friends.
▢
▢
▢
▢
▢
I was good at making friends.
▢
▢
▢
▢
▢
My friends and I helped each other out
▢
▢
▢
▢
▢
Other kids wanted to be my friend 
▢
▢
▢
▢
▢
Other kids wanted to be with me
▢
▢
▢
▢
▢
Other kids wanted to talk to me 
▢
▢
▢
▢
▢
 
 
 

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4. Comprehensive Score of Financial Toxicity – COST (Adult self-report, Age 18+) 
 
Below is a list of statements that other people with your illness have said are important. Please mark one 
response per line to indicate your response as it applies to the past 7 days. 
Not at all
A little bit
Somewhat Quite a bit Very much
I know that I have enough money in savings, 
retirement, or assets to cover the cost of my 
treatment.
□ 
□ 
□ 
□ 
□ 
My out-of-pocket medical expenses are more 
than I thought they would be.
□ 
□ 
□ 
□ 
□ 
I worry about the financial problems I will have in 
the future as a result of my illness or treatment.
□ 
□ 
□ 
□ 
□ 
I feel I have no choice about the amount of 
money I spend on care.
□ 
□ 
□ 
□ 
□ 
I am frustrated that I cannot work or contribute as 
much as I usually do.
□ 
□ 
□ 
□ 
□ 
I am satisfied with my current financial situation.
□
□
□
□
□
I am able to meet my monthly expenses.
□
□
□
□
□
I feel financially stressed. 
□
□
□
□
□
I am concerned about keeping my job and 
income, including work at home. 
□ 
□ 
□ 
□ 
□ 
My cancer or treatment has reduced my 
satisfaction with my present financial situation.
□ 
□ 
□ 
□ 
□ 
I feel in control of my financial situation.
□
□
□
□
□
My illness has been a financial hardship to my 
family and me.
□ 
□ 
□ 
□ 
□ 
Copyright 2014, FACIT and the University of Chicago. 
 
 
5. Adult (age 18+) Self-report PROMIS assessments 
5.1. Anxiety 
In the past 7 days… 
Never
Rarely
Sometimes
Often
Always
I felt fearful
▢
▢
▢
▢
▢
I found it hard to focus on anything other than my 
anxiety 
▢
▢
▢
▢
▢
My worries overwhelmed me
▢
▢
▢
▢
▢
I felt uneasy
▢
▢
▢
▢
▢
I felt nervous
▢
▢
▢
▢
▢
I felt like I needed help for my anxiety
▢
▢
▢
▢
▢
I felt anxious
▢
▢
▢
▢
▢
I felt tense 
▢
▢
▢
▢
▢

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5.2. Depression 
In the past 7 days… 
Never
Rarely
Sometimes
Often
Always
I felt worthless
▢
▢
▢
▢
▢
I felt helpless
▢
▢
▢
▢
▢
I felt depressed
▢
▢
▢
▢
▢
I felt hopeless
▢
▢
▢
▢
▢
I felt like a failure 
▢
▢
▢
▢
▢
I felt unhappy.
▢
▢
▢
▢
▢
I felt that I had nothing to look forward to
▢
▢
▢
▢
▢
I felt that nothing could cheer me up
▢
▢
▢
▢
▢
5.3. Anger 
In the past 7 days… 
Never
Rarely
Sometimes
Often
Always
I was irritated more than people knew
▢
▢
▢
▢
▢
I felt angry
▢
▢
▢
▢
▢
I felt like I was ready to explode
▢
▢
▢
▢
▢
I was grouchy
▢
▢
▢
▢
▢
I felt annoyed 
▢
▢
▢
▢
▢
5.4. Fatigue 
During the past 7 days… 
Not at all
A little bit
Somewhat
Quite a 
bit
Very 
much
I feel fatigued 
▢
▢
▢
▢
▢
I have trouble starting things because I am tired
▢
▢
▢
▢
▢
In the past 7 days… 
Not at all
A little bit
Somewhat
Quite a 
bit
Very 
much
How run-down did you feel on average?
▢
▢
▢
▢
▢
How fatigued were you on average?
▢
▢
▢
▢
▢
How much were you bothered by your fatigue on 
average? 
▢
▢
▢
▢
▢
To what degree did your fatigue interfere with your 
physical functioning?
▢
▢
▢
▢
▢
In the past 7 days… 
Never
Rarely
Sometimes
Often
Always
How often did you have to push yourself to get 
things done because of your fatigue?
▢
▢
▢
▢
▢
How often did you have trouble finishing things 
because of your fatigue?
▢
▢
▢
▢
▢

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5.5. Physical function 
Without 
any 
difficulty
With a 
little 
difficulty
With 
some 
difficulty
With 
much 
difficulty
Unable 
to do 
Are you able to do chores such as vacuuming or 
yard work?
▢
▢
▢
▢
▢
Are you able to go up and down stairs at a normal 
pace?
▢
▢
▢
▢
▢
Are you able to go for a walk of at least 15 
minutes? 
▢
▢
▢
▢
▢
Are you able to run errands and shop?
▢
▢
▢
▢
▢
Does your health now limit you in doing two hours 
of physical labor?
▢
▢
▢
▢
▢
Does your health now limit you in doing moderate 
work around the house like vacuuming, sweeping 
floors or carrying in groceries? 
▢
▢
▢
▢
▢
Does your health now limit you in lifting or carrying 
groceries?
▢
▢
▢
▢
▢
Does your health now limit you in doing heavy work 
around the house like scrubbing floors, or lifting or 
moving heavy furniture?
▢
▢
▢
▢
▢
5.6. Cognition 
In the past 7 days… 
Never
Rarely 
(Once) 
Sometimes 
(Two or 
three 
times) 
Often 
(About 
once a 
day) 
Very 
often 
(Several 
times a 
day)
My thinking has been slow 
▢
▢
▢
▢
▢
It has seemed like my brain was not working as 
well as usual
▢
▢
▢
▢
▢
I have had to work harder than usual to keep track 
of what I was doing
▢
▢
▢
▢
▢
I have had trouble shifting back and forth between 
different activities that require thinking 
▢
▢
▢
▢
▢
I have had trouble concentrating
▢
▢
▢
▢
▢
I have had to work really hard to pay attention or I 
would make a mistake 
▢
▢
▢
▢
▢
I have had trouble forming thoughts 
▢
▢
▢
▢
▢
I have had trouble adding or subtracting numbers 
in my head
▢
▢
▢
▢
▢

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5.7. Ability to participate in social roles & activities 
Never 
Rarely
Sometimes
Usually
Always
I have trouble doing all of my regular leisure 
activities with others
▢
▢
▢
▢
▢
I have trouble doing all of the family activities that I 
want to do 
▢
▢
▢
▢
▢
I have trouble doing all of my usual work (include 
work at home).
▢
▢
▢
▢
▢
I have trouble doing all of the activities with friends 
that I want to do
▢
▢
▢
▢
▢
I have to limit the things I do for fun with others
▢
▢
▢
▢
▢
I have to limit my regular activities with friends
▢
▢
▢
▢
▢
I have to limit my regular family activities
▢
▢
▢
▢
▢
I have trouble doing all of the work that is really 
important to me (include work at home) 
▢
▢
▢
▢
▢
 
 
6. Adult (age 18+) Parent/guardian proxy-report Occupational Function and Sociodemographic/social 
determinant of health items 
 
6.1. Occupational Functioning 
 
Which of the following best describes your current job status? (Select all that apply) 
□ Working full-time (30 or more hours per week) 
□ Working part-time (less than 30 hours per week 
□ Caring for home or family (not seeking paid work) 
□ Unemployed and looking for work (including laid off or furloughed) 
□ Unable to work due to illness or disability 
□ Retired 
□ Student 
□ Other, please specify: _______________________ 
 
What kind of work do you do at the present time or in your previous employment? (Select all that apply) 
□ Management, Business and Financial 
Occupations 
□ Computer, Engineering, and Science 
Occupations 
□ Education, Legal, Community Service, Arts, 
and Media Occupations 
□ Healthcare Practitioners and Technical 
Occupations 
□ Service Occupations 
□ Sales and Related Occupations 
□ Office and Administrative Support 
Occupations 
□ Farming, Fishing, and Forestry Occupations 
□ Construction and Extraction Occupations 
□ Installation, Maintenance, and Repair 
Occupations 
□ Production Occupations 
□ Transportation and Material Moving 
Occupations 
□ Military Specific Occupations
 
 
□ Other, please specify: 
_______________________________ 
□ I am not currently and have not previously been employed 
 
 
 

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Please answer if you are currently a student: 
How many days per week do you attend school? 
 
 
Number of days attending school (please enter whole number): ___________ 
 
In the past 30 days, how many days did you miss school because of illness or injury? 
 
 
Number of days of school missed (please enter whole number): ___________ 
 
 
Please answer if you are currently working: 
At the present time, how many hours do you work each week (paid or unpaid)? 
 
  Number of hours worked (please enter whole number): ______________ 
 
In the past 30 days, about how many days did you miss work because of illness or injury? (Do not 
include work missed for maternity/paternity leave) 
 
Number of days missed (please enter whole number): _____________________  
 
In the past 30 days, have you attempted to work/go to school but found that you weren’t able to? 
□ Yes 
□ No 
 
If yes, what prevents you from working/going to school at the present time? 
___________________________________________________________________________ 
___________________________________________________________________________ 
 
How much have your disease and treatment experiences impacted your goals concerning work or 
school? (Select one response) 
□ Very negative impact 
□ Somewhat negative impact 
□ No impact 
□ Somewhat positive impact 
□ Very positive impact 
 
6.2. Sociodemographics/social determinants of health 
 
What is your zip code? ________________ 
 
 
Are you Hispanic or Latino? (Select one response) 
□ Yes 
□ No 
□ Don’t know 
 
 
 
 
 
 
 

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Which group(s) best describes you? (Select all that apply) 
 
□ American Indian or Alaska Native 
□ Alaskan Native or Aleut 
□ North American Indian 
□ American Indian, South or 
Central America 
□ Caribbean Indian 
□ Asian 
□ South Asian 
□ Filipino (Pilipino) 
□ Japanese 
□ Korean 
□ Chinese 
□ Vietnamese 
□ Other Southeast Asian 
□ Black or African American 
□ African 
□ African American 
□ Black Caribbean 
□ Black South or Central American 
□ Other Black 
□ Native Hawaiian or Other Pacific 
Islander 
□ Guamanian 
□ Hawaiian 
□ Samoan 
□ Other Pacific Islander 
□ White 
□ Eastern European 
□ Mediterranean 
□ Middle Eastern 
□ North Coast of Africa 
□ North American 
□ Northern European 
□ Western European 
□ White Caribbean 
□ White South or Central American 
□ Other White 
□ Something else, please specify: 
□ Don’t know 
 
 
What is your current relationship status? (Select the one response that best describes your current 
relationship status) 
□ Married 
□ Living with a partner 
□ Never married 
□ Separated 
□ Divorced 
□ Widowed 
□ Other, please describe: 
___________________________ 
 
 
What is the highest degree or level of school that you have completed? (Select one response) 
□ Up to 8th grade 
□ 9th –- 12th grade, no diploma 
□ High school diploma or equivalent (GED) 
□ Some college, no degree 
□ Vocational or Associate’s degree 
□ College degree (B.A./B.S.) 
□ Advanced degree (e.g., Master’s or Doctorate program) 
□ Don’t know 
 
 
 

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What type of health insurance coverage do you have? (Select all that apply) 
□ No insurance 
□ Medicaid 
□ Medicare 
□ Medigap 
□ Indian Health Service 
□ Military-related healthcare 
□ Private health insurance (including through your employer) 
□ Disability insurance 
□ Other government program (please describe): _____________________________ 
□ Other health insurance coverage (please describe): 
_____________________________________________ 
□ Don’t know 
 
 
 
Was there any time during the past year when you needed medical care but did not get it? 
□ Yes 
□ No 
 
Was there any time during the past year that you delayed getting medical care you felt you 
needed? 
□ Yes 
□ No 
 
 
What is your total yearly HOUSEHOLD income from all sources, before taxes? (Select one 
response) 
This includes money from jobs, disability benefits, social security payments, pensions or retirement, 
dividends and any other income received by ALL members of your household.
□ Less than $10,000 
□ $10,000 to $19,999 
□ $20,000 to $29,999 
□ $30,000 to $39,999 
□ $40,000 to $49,999 
□ $50,000 to $59,999 
□ $60,000 to $69,999 
□ $70,000 to $79,999 
□ $80,000 to $89,999 
□ $90,000 to $99,999 
□ $100,000 to $149,999 
□ $150,000 to $199,999 
□ $200,000 or more 
□ Don’t know

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What is your living situation today? 
□ I have a steady place to live 
□ I have a place to live today, but I am worried about losing it in the future 
□ I do not have a steady place to live 
 
Think about the place you live. Do you have problems with any of the following? (Select all that 
apply) 
□ Pests such as bugs, ants, or mice 
□ Mold 
□ Lead paint or pipes 
□ Lack of heat 
□ Oven or stove not working 
 
 
How confident are you filling out medical forms by yourself? 
□ Not at all 
□ A little bit 
□ Somewhat 
□ Quite a bit 
□ Extremely 
 
 
Do you currently need a caregiver (anyone who provides direct medical, financial or emotional 
support)? 
□ Yes 
□ No 
□ Don’t know 
 
Do you currently have a caregiver? 
□ Yes 
□ No 
 
[If yes] Does your caregiver live with you? 
□ Yes 
□ No  
 
 
 
 

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APPENDIX K 
 
CYTOKINE RELEASE SYNDROME GUIDANCE AND MANAGEMENT 
Guidelines for Grading and Management of Suspected Cytokine Release Syndrome 
Cytokine Release Syndrome (CRS): Transplantation of HLA-mismatched peripheral blood stem 
cells (PBSC) can be complicated by the development of CRS, usually within 7-10 days of 
transplantation. In many cases, clinical toxicities correlate with elevated inflammatory serum 
cytokine levels. The signs and symptoms most often experienced by patients include, but are not 
limited to, fever, fatigue, hypotension, tachycardia, acute renal failure, and neurological toxicities. 
Fever is usually the first toxicity to occur. Management of CRS should be per institutional practice. 
Steroids should be avoided. 
CRS Grading: Grading will be based on the American Society for Blood and Marrow 
Transplantation (ASBMT) CRS Consensus Guidelines.[58] Generalized treatment guidelines are 
as outlined in the Table K1 below. 
Table K1. Generalized Guidelines for Monitoring and Treatment of CRS 
CRS 
parameter
Grade 1 
Grade 2 
Grade 3 
Grade 4^ 
Fever
> 38
> 38 
> 38 
> 38 
With EITHER
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor 
with or without 
vasopressin 
 
Requiring multiple 
vasopressors 
(excluding vasopressin) 
 
And/or 
Hypoxia 
None 
Requiring low 
flow nasal 
cannula‡ or 
blow-by 
 
Requiring high
flow nasal 
cannula‡, 
facemask, 
nonrebreather 
mask, or 
Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
Potential 
Interventions 
(General) 
Supportive 
care, 
antipyretics. 
Consider 
Tocilizumab 
Fluid bolus, 
notify the ICU, 
consideration of 
low dose 
pressors for 
prevention of 
fluid overload, 
Echo/CXR. 
Consider 
Tocilizumab 
Tocilizumab 
with exception 
for grade 3 
CRS with 
hypotension 
alone which is 
well managed 
on low dose 
pressors.**  
Tocilizumab (per 
institutional standards) 
***  

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Abbreviations: BiPAP: Bi-level Positive Airway Pressure; CPAP; Continuous Positive Airway Pressure; 
CRS: Cytokine Release Syndrome; CXR: Chest X-Ray; Echo: Echocardiogram; ICU: Intensive Care 
Unit 
 
*Feverisdefinedastemperature≥38°Cnotattributabletoanyothercause.InpatientswhohaveCRS
then receive antipyretics or anticytokine therapy such as tocilizumab, fever is no longer required to 
grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
 
†CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any 
othercause.Forexample,apatientwithtemperatureof39.5°C,hypotensionrequiring1vasopressor,
and hypoxia requiring low flow nasal cannula is classified as grade 3 CRS. ‡Low flow nasal cannula is 
definedasoxygendeliveredat≤6L/minute.Lowflowalsoincludesblow-by oxygen delivery, 
sometimes used in pediatrics. High flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
 
^Intubation may be indicated in patients who have a degree of neurotoxicity where there is concern for 
their ability to maintain a patent airway. This may occur either in the setting of CRS or after CRS has 
resolved. The decision for intubation should not be captured as a grade 4 CRS when the other criteria 
for such are not met. Intubation of a patient without hypoxia for the possible neurologic compromise of 
a patent airway alone or for a procedure is not, by definition, grade 4 CRS. 
 
**The definition of “High dose” vasopressors requires > 3 hours of any of the following: norepinephrine 
monotherapy > 20 mcg/kg/min; dopamine monotherapy > 10 mcg/kg/min; phenylephrine monotherapy 
> 200 mcg/kg/min; epinephrine monotherapy > 10 mcg/kg/min; if on vasopressin: vasopressin + 
norepinephrine equivalent of > 10 mcg/kg/min; and if on combination vasopressors (excluding 
vasopressin) > norepinephrine equivalent (cumulative) > 20 mcg/kg/min. 
 
***Steroids should be avoided.

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APPENDIX L 
 
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