Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in Patients With Symptomatic Sickle Cell Disease. (BMTCTN1507)
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: Medical College of Wisconsin

CONFIDENTIAL 
 
 
Reduced Intensity Conditioning for Haploidentical Bone Marrow 
Transplantation in Patients with Symptomatic Sickle Cell Disease 
(Posted on clinicaltrials.gov as NCT03263559) 
BMT CTN PROTOCOL 1507 
Version 5.0 
 
Study Chairpersons 
Robert Brodsky, MD1, Michael DeBaun, MD2, Adetola Kassim, MD2, and Mark Walters, MD3 
 
 
 
Allistair Abraham, MD4 
Brianne Allison5 
Kenneth Cooke, MD1 
Josu de la Fuente, MD6 
Mary Eapen, MD7 
Hilary Haines, MD8 
Rabi Hanna, MD13 
Mary Horowitz, MD7 
Shalini Shenoy, MD9 
Protocol Team 
 
Lori Jordan, MD2 
Lakshmanan Krishnamurti, MD10 
Eric Leifer, PhD12 
Kris Mahadeo, MD11 
Adam Mendizabal, PhD5 
Dinma Ahaiwe5 
Nicole Ritzau, RN5 
Lauren Nolley, MS5 
 
Sponsored by the National Institutes of Health  
National Heart, Lung, and Blood Institute National Cancer 
Institute 
 
1 Johns Hopkins University 
2 Vanderbilt University 
3 UCSF Benioff Children’s Hospital, Oakland 
4 Children’s National Medical Center 
5 The Emmes Company 
6 St. Mary’s of London Pediatric 
7 Medical College of Wisconsin 
8 University of Alabama Birmingham 
(Pediatrics) 
 
9 Washington University 
10 Children’s Healthcare of Atlanta 
11 MD Anderson Cancer Center 
12 National Heart, Lung, and Blood Institute, 
National Institutes of Health 
13 Cleveland Clinic Children’s Hospital 
_______________________________ 
 
_______________________________ 
*Approval Signature (Protocol Chair) 
 
*Approval Signature (Protocol Officer) 
 
* Please note, the cover page required updated signatures due to a technical issue with uploading the 
protocol onto the ClinicalTrials.gov website.  The protocol version number and date remain unchanged.  
Dr. Michael  Debaun
I am approving this document.
Dr. Michael Debaun
09/13/2021 12:56 PM EDT
Dr. Mary  Eapen
I am approving this document.
08/13/2021 12:59 PM
EDT
Dr. Mary Eapen

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Haplo Sickle Cell – Protocol 1507 
 
 
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Core Study Participants: 
Affiliate Study Participants: 
Baylor College of Medicine Consortium 
Texas Children’s Hospital 
Children’s National Medical Center 
Duke University 
Fred Hutchinson Cancer Research Center 
H. Lee Moffitt Cancer Center 
Johns Hopkins University 
Medical College of Wisconsin 
Mount Sinai Consortium 
Vanderbilt University 
Northside Hospital Atlanta Consortium 
Levine Cancer Institute/Carolinas Healthcare 
Northside Hospital Atlanta 
Ohio State Consortium 
Roswell Park Cancer Institute 
University of North Carolina 
Oregon Health Sciences University Consortium 
Case Western/U Hosp Cleveland 
Pediatric BMT Consortium 
Cardinal Glennon Children’s Hospital 
Children’s Hospital of Los Angeles 
Children’s Hospital of Michigan 
Cleveland Clinic 
Helen DeVos Children’s Hospital 
Lurie Children’s Hospital 
Medical University of South Carolina 
Nationwide Children’s Hospital 
North Shore University Children’s Hospital 
Riley Children’s Hospital at Indiana University 
St. Jude Children’s Research Hospital 
St. Louis University Hospital 
USCF Benioff Children’s Hospital Oakland 
University of Miami Children’s Hospital 
University of Colorado Denver Children’s 
University of Florida Consortium 
University of Florida 
University of Michigan Consortium 
University of Michigan 
Indiana University Medical Center 
Washington University, Barnes Jewish Hospital 
Hackensack University 
Methodist Healthcare BMT Center MD 
Anderson Cancer Center North Shore 
University Hospital Texas Transplant 
Institute University of Alabama 
University of Illinois University of 
Maryland University of Pittsburgh 

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Haplo Sickle Cell – Protocol 1507 
 
 
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PROTOCOL SYNOPSIS – BMT CTN 
PROTOCOL 1507 
 
Reduced Intensity Conditioning for Haploidentical Bone Marrow 
Transplantation in Patients with Symptomatic Sickle Cell Disease 
 
Co-Chairs: 
Robert Brodsky MD, Michael DeBaun, MD, Adetola Kassim, MD, 
and Mark Walters, MD 
Study Design: 
This is a Phase II, single arm, multi-center trial, designed to estimate 
the efficacy and toxicity of haploidentical bone marrow 
transplantation (BMT) in patients with sickle cell disease (SCD). 
Patients are stratified into two groups: (1) children with SCD with 
strokes; and (2) adults with severe SCD. Based on their age and entry 
criteria, participants are enrolled in 2 strata as defined below. The 
primary endpoint of event-free survival (EFS) will be estimated in each 
age-specific stratum. 
Primary Objective: 
The   primary  objective   is   to   estimate   EFS   at   2   years after 
haploidentical BMT in patients with SCD enrolled in 2 strata – 
children 5.00 – 14.99 years of age at enrollment with SCD and adults 
15.00 - 45.99 years of age at enrollment with severe SCD. Primary or 
secondary graft rejection, second transplant, or death will count as 
events for this endpoint. Stratum-specific estimates will be provided. 
If the protocol implements the planned treatment change in response 
to safety monitoring for graft failure, then the analysis will be based 
on the stratum participants under the active treatment plan at the close 
of the study and results for the other participants will be described. 
Secondary Objectives:      Secondary    objectives     include     determining     the     effect of 
haploidentical BMT on clinical and laboratory manifestations of SCD 
by 2 years after transplantation and determining the incidence of other 
transplant-related outcomes. Secondary outcomes include: overall 
survival post-haplo BMT at 1 and 2 years post-enrollment; EFS at 1 
year; graft rejection; disease progression; donor chimerism; grades II-
IV and III-IV acute graft-versus-host disease (GVHD); chronic 
GVHD, severe chronic GVHD; neutrophil, and platelet recovery; 
hepatic veno-occlusive disease (VOD); idiopathic pneumonia 
syndrome (IPS); central nervous system (CNS) toxicity (reversible 
posterior leukoencephalopathy syndrome [RPLS], hemorrhage, and 
seizures); cytomegalovirus (CMV) infection; adenovirus infection; 
Epstein Barr virus post-transplant lymphoproliferative disease (EBV 
PTLD); invasive fungal infection; CNS outcomes; 28 day e-pain diary 
assessments; health- 

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related quality of life (HRQoL) in the adult stratum; lung function; 
TRJV; 6 minute walk distance; hematological outcomes; viral mold 
infections/bacterial 
or 
fungal 
sepsis; 
and 
proportion 
on 
immunosuppression. All objectives are within each stratum. 
Eligibility: 
Eligibility criteria differ by age. 
1. 
Children with SCD (Hb SS or Sß° Thalassemia) aged 5.00 – 
14.99 years at Segment A enrollment who have one or more of 
the following: 
a. A neurological event resulting in focal neurologic deficits 
WKDWODVWHGKRXUVFODVVLFDOFOLQLFDOGHILQLWLRQRIVWURNH
not requiring imaging studies of the brain) OR a focal 
neurological event resulting in abnormalities on T2- 
weighted or FLAIR images using a MRI scan, indicative of 
an acute infarct, with no other reasonable medical 
explanation (definition of a stroke supported with MRI 
imaging scans of the brain), OR both. 
b. Abnormal transcranial Doppler (TCD) measurement with a 
timed average maximum mean velocity of  200 cm/sec in 
the terminal portion of the internal carotid or proximal 
portion of middle cerebral artery1 or if the imaging TCD 
method is used > 185 cm/sec2 plus evidence of intracranial 
vasculopathy. 
c. Silent Cerebral Infarct defined as an infarct-like lesion based 
on an MRI signal abnormality at least 3 mm in one 
dimension and visible in two planes on FLAIR or T2- 
weighted images (or similar image with 3D imaging) and 
documented neurological examination performed by a 
neurologist demonstrating the participant has a normal 
neurologic examination or an abnormality on examination 
that could not be explained by the location of the brain 
lesion(s). 
d. Acute severe vaso-occlusive pain episodes requiring 
hospitalization and recalcitrant to maximum medical 
therapy. Episodes of pain to be adjudicated by selected 
committee.  
e. One acute chest syndrome episode resulting in intensive care 
admission requiring non-mechanical ventilatory support: 
simple nasal cannula, face mask that requires oxygen content 
(venti mask, non-rebreather), simple nasal cannula, face 
mask O2(e.g. ventimask, rebreather), CPAP, SiPAP, BiPAP, 

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high flow nasal cannula (HFNC) or invasive mechanical 
ventilatory support (delivered by ETT or trach).  
f. Right heart catheterization confirmed pulmonary artery 
pressure >25 mmHG or mean pulmonary vascular resistance 
206(57-421) dyn·s·cmí 
g. Essential hypertension on antihypertensive medications 
>95% upper limit of normal age (as defined according to the 
American Academy of Pediatrics) 
h. Recurrent priapism (episodes lasting at least 4 hours at least 
twice in the last 12 months or 3 times in the last 24 months) 
recalcitrant to medical treatment or unable to use 
hydroxyurea due to SCD phenotype with the approval of the 
adjudication committee 
2. Participants with SCD (any clinically significant sickle 
JHQRW\SHIRUH[DPSOH+E666&6'6ȕ7KDODVVHPLD6ȕ+ 
Thalassemia, S-OArab) aged 15.00 – 45.99 years at Segment A 
enrollment who have one or more of the following: 
a. 
A neurological event resulting in focal neurologic deficits 
that lasted  24 hours (classical clinical definition of stroke, 
not requiring imaging studies of the brain) OR a focal 
neurological event resulting in abnormalities on T2- 
weighted or FLAIR images using a MRI scan, indicative of 
an acute infarct, with no other reasonable medical 
explanation (definition of a stroke supported with MRI 
imaging scans of the brain), OR both. 
b. History of two or more episodes of acute chest syndrome 
(ACS) in the 2-year period preceding enrollment despite the 
institution of supportive care measures (i.e. asthma therapy 
and/or hydroxyurea); 
c. History of three or more severe vaso-occlusive pain crises 
per year in the 2-year period preceding enrollment despite 
the institution of supportive care measures (i.e. a pain 
management plan and/or treatment with hydroxyurea); 
painful episodes related to priapism, osteonecrosis or any 
sickle-related complication are acceptable; 
d. Administration of regular red blood cell (RBC) transfusion 
therapy, defined as 8 or more transfusion events per year (in 
the 12 months before enrollment) to prevent vaso-occlusive 
clinical complications (i.e. pain, stroke, or acute chest 
syndrome); 

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e. An echocardiographic finding of tricuspid valve regurgitant 
MHWYHORFLW\75-9 m/sec. 
3. Participants in either age group must have adequate physical 
function as measured by all of the following: 
a. Karnofsky or Lansky performance score  
b. Cardiac function: 
Left ventricular ejection fraction 
(LVEF) 
i. 40%; or LV shortening fraction > 26% by cardiac 
echocardiogram or by MUGA scan. 
c. Pulmonary function: Pulse oximetry with a baseline O2 
VDWXUDWLRQ RI  and DLCO > 40% (corrected for 
hemoglobin). 
i. Patients unable to perform DLCO due to young age or 
other inability are not required to have a specified 
threshold but must have no evidence of dyspnea at 
rest and O2 saturation level must be greater than 88% 
in room air at baseline. 
d. Renal function: Serum FUHDWLQLQH   [ XSSHU OLPLW RI
normal for age and estimated or measured creatinine 
FOHDUDQFHP/PLQ m2. 
e. Hepatic function: 
i. 6HUXPFRQMXJDWHGGLUHFWELOLUXELQ[XSSHUOLPLW
of normal for age as per local laboratory. Participants 
are not excluded if the serum conjugated (direct) 
bilirubin is >2x the upper limit of normal for age as 
per local laboratory and: 
1. There is evidence of a hyperhemolytic reaction 
after a recent RBC transfusion, OR 
2. There is evidence of moderate direct 
hyperbilirubinemia defined as direct serum 
bilirubin < 5 times ULN and not caused by 
underlying hepatic disease. 
ii. ALT and AST < 5x upper limit of normal as per local 
laboratory. 
f. Liver MRI using a validated methodology per institutional 
preference (T2* or R2* or by ferriscan [R2 MRI]) for 

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estimation of hepatic iron content is required for 
SDUWLFLSDQWV ZKR DUH FXUUHQWO\ UHFHLYLQJ  SDFNHG UHG
EORRGFHOOWUDQVIXVLRQVSHU\HDUIRU\HDURUKDYHUHFHLYHG
 SDFNHG UHG EORRG FHOO WUDQVIXVLRQV OLIHWLPH
cumulative). Participants who have hepatic iron content  
10 mg Fe/g liver dry weight by liver MRI must have a 
Gastroenterology/hepatology consultation with liver biopsy 
and histological examination including documentation of 
the absence of cirrhosis, bridging fibrosis[1], and active 
hepatitis. 
g. 
Participants must be HLA typed at high resolution using 
DNA based typing at HLA-A, -B, -C, DRB1, and have 
available: 
i. An HLA haploidentical first degree relative donor 
(parents, siblings or half siblings, or children) with 2, 
3, or 4 (out of 8) HLA-mismatches who is willing and 
able to donate bone marrow. A unidirectional 
mismatch in either the graft versus host or host versus 
graft direction is considered a mismatch. The donor 
and recipient must be HLA identical for at least one 
antigen (using high resolution DNA based typing) at 
the following genetic loci: HLA-A, HLA-B, HLA-C, 
and HLA- DRB1. Fulfillment of this criterion shall be 
considered sufficient evidence that the donor and 
recipient share one HLA haplotype and typing of 
additional family members is not required. 
Confirmatory donor HLA typing must be completed < 
100 days prior to Segment A enrollment 
 
h. 
Umbilical cord blood or peripheral blood stem cell donors 
will not be accepted. 
Exclusion criteria: 
1.  Participants who have an HLA-matched sibling  
 
who is able and willing to donate bone marrow. 
2. Participants with uncontrolled bacterial, viral or fungal infection 
in the 6 weeks before enrollment (currently taking medication 
with evidence of progression of clinical symptoms or radiologic 
findings). 
3. Participants with evidence of HIV infection or seropositivity for 
HIV. 
4. Participants who have received a previous Hematopoietic Cell 
Transplant (HCT) 

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5. Participants who have had an EDAS procedure within the 6 
months prior to enrollment (Section 2.4.6). 
6. Participants who have received a prior solid organ transplant. 
7. Participants who have participated in another clinical trial in 
which the participant received an investigational or off-label use 
of a drug or device within 3 months prior to enrollment. 
8. Females who are pregnant or breast feeding. 
9. Participants 
with 
clinically 
significant, 
uncontrolled 
autoimmune disease, requiring active medical management 
(immunosuppressive therapy or chemotherapy), which, in the 
judgment of the local Principal Investigator, indicates that the 
patient could not tolerate transplantation. 
 
Females of child bearing potential (to include all female 
participants > 10 years of age, unless postmenopausal for a 
minimum of 1 year before the time of consent or surgically 
sterilized) who do not agree to practice two (2) effective 
methods of contraception at the same time, or who do not agree 
to practice true abstinence when this is in line with the 
preferred and usual lifestyle of the subject, from the time of 
signing of informed consent through 12 months post-transplant. 
10. Males (even if surgically sterilized) who do not agree to practice 
effective barrier contraception, or who do not agree to practice 
true abstinence from the time of signing informed consent 
through 12 months post-transplant. 
11. Presence of anti-donor specific HLA antibodies. HLA antibody 
presence and specificity will be determined by solid phase 
immunoassays. An anti-donor specific HLA antibody will be 
considered positive when the mean fluorescence intensity (MFI) 
is higher than the cut-off defined by each center. Recommended 
cut-off values are MFI >1000 for donor specific antibody to 
HLA-A, -B, and DRB1 and MFI >2000 for HLA-C, DQB1 and 
DPB1. This must be measured before the final donor selection, 
and < 100 days before enrollment in Segment A (preferably < 
30 days before Segment A enrollment). If MFI >1000 for donor 
specific antibody to HLA-A, -B, DRB1 and/or MFI >2000 for 
HLA-C, DQB1 and DPB1, documentation must be submitted to 
the DCC coordinator for review and approval by a Protocol 
Chair and/or Protocol Officer prior to enrollment. 
Treatment Description:         
The   BMT   preparative   regimen   will   start   on   Day   -70 
with hydroxyurea 30mg/kg daily through Day -10. The 

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conditioning regimen will also include Thymoglobulin (rATG) 
(0.5mg/kg on Day -9, 2mg/kg on Day -8, Day -7), Thiotepa 
10mg/kg on Day -7, Fludarabine (30mg/m2 on Day -6 to Day -
2), Cyclophosphamide 14.5mg/kg on Day -6 and Day -5, and 
TBI 200cGy on Day -1. Day 0 is the day of infusion with non T-
cell depleted bone marrow. Cyclophosphamide 50 mg/kg and 
Mesna 40mg/kg is given on Days +3 and +4, and GVHD 
prophylaxis (sirolimus and mycophenolate mofetil) begin on 
Day +5. 
If it is determined that the graft failure rate in a stratum has met 
the stopping rule within the first 12 evaluable participants in the 
stratum, and approval from the DSMB and Sponsor is provided, 
then the conditioning regimen with TBI 400cGy instead of TBI 
200cGy will be used for future participants in the stratum, and 
an additional 40 participants will be accrued to that stratum. 
Accrual Objective: 
The target sample size is 40 transplanted patients in each  
stratum; if the stopping rule for graft  failure  is  triggered  within  
the  first  12 evaluable participants in either stratum using the 
200cGy dose of TBI and the DSMB and sponsor approve the 
pre-defined switch in conditioning regimen, then accrual for that 
strata will restart under the modified conditioning regimen. 
Accrual Period: 
The estimated accrual period is 4 years. If the safety  
monitoring for graft  failure  passes  a   stopping   boundary    
within   the   first   12 evaluable participants, it is estimated that 
the accrual period will be extended up to an additional 15 
months. 
Study Duration: 
Participants will be followed for the 28-day pain diary  
(prior to 70-day conditioning period) and for 2 years from date 
of infusion (post-transplant). 
Safety Monitoring: 
The rate of overall mortality by Day 180 post start of 
hydroxyureatherapy pre-transplant, acute grade III-IV GVHD at 
100 days, and severe chronic GVHD at 18 months post-
transplant will be monitored by using a sequential probability 
ratio test (SPRT) for censored exponential data for  each  of  
these.  Graft  failure  at  100 days post-transplant will be 
monitored by using a sequential probability ratio test (SPRT) for 
binary data. 

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TREATMENT SCHEMA 
 
Days –ĺ–10 
Hydroxyurea 30 mg/kg po daily 
 
Hgb S fraction < 35% prior to administration of Thymoglobulin. If Hbg S > 35%, 
automated exchange transfusion (RBC apheresis) is the preferred strategy to lower 
Hgb S with a goal of 20% and 
the maximum Hgb S fraction not to exceed 35%. 
Day –9*** 
Thymoglobulin 0.5 mg/kg IV with pre-meds 
Day –8*** 
Thymoglobulin 2 mg/kg IV qd with pre-meds 
Day –7*** 
Thymoglobulin 2 mg/kg IV qd with pre-meds 
Thiotepa 5 mg/kg IV q 12 h (10 mg/kg total) 
Days –6, –5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide (CY) 14.5 mg/kg IV over 1-2 hours* 
Days –4 ĺ–2 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day –1 
TBI 200 cGy with gonadal shielding** 
Day 0 
Non-T-cell depleted bone marrow 
Days +3, +4 
Cyclophosphamide 50 mg/kg IV 
Mesna 40 mg/kg IV* 
Day +5 
Begin sirolimus (section 2.4.5.1)**, mycophenolate mofetil (MMF) 
15 mg/kg pot id with maximum daily dose 3 gm/d 
Day +35 
Discontinue MMF 
*Uroprophylaxis may be altered per institutional preference (see below) 
    **See Section 2.4.2.10 and section 4.4.6 regarding planned protocol change in TBI dose if safety 
monitoring guideline for 100-day graft failure is passed in the first 12 evaluable participants per 
stratum. 
***If using corticosteroids as premedication, discontinue before Day -1. 

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ABBREVIATIONS 
 
 
ACS 
Acute Chest Syndrome 
IPS 
Idiopathic Pneumonia 
AE 
Adverse Event 
 
Syndrome 
AjBW 
Adjusted Body Weight 
IV 
Intravenous 
ANC 
Absolute Neutrophil Count 
6MWD 
6 Minute Walk Distance 
rATG 
rabbit Anti-thymocyte 
MMF 
Mycophenolate Mofetil 
 
Globulin (Thymoglobulin) 
NHLBI 
National Heart Lung & Blood 
BMT 
Bone Marrow Transplant 
 
Institute 
CBC 
Complete Blood Count 
NIH 
National Institutes of Health 
CIBMTR 
Center for International 
NMDP 
National Marrow Donor 
 
Blood and Marrow 
 
Program 
 
Transplant Research 
OS 
Overall Survival 
CMV 
Cytomegalovirus 
PCR 
Polymerase Chain Reaction 
CNS 
Central Nervous System 
PFT 
Pulmonary Function Test 
CNT 
Clinical Trials Network 
PI 
Principal Investigator 
CTCAE 
Common Terminology for 
PRES 
Posterior Reversible 
 
Adverse Events 
 
Encephalopathy Syndrome 
CY 
Cyclophosphamide 
PROMIS 
Patient Reported Outcomes 
DCC 
Data and Coordinating 
 
Measurement Information 
 
Center 
 
System 
EFS 
Event-Free Survival 
PTLD 
Post-transplant 
DSMB 
Data Safety Monitoring 
 
lymphoproliferative disease 
 
Committee 
SAE 
Serious Adverse Event 
EBV 
Epstein-Barr Virus 
SCD 
Sickle Cell Disease 
EDC 
Electronic Data Capture 
SCD-EOSI 
Sickle Cell Disease-related 
GVHD 
Graft-versus-Host Disease 
 
Event of Special Interest 
HCT 
Hematopoietic Cell 
SPRT 
Sequential Probability Ratio 
 
Transplantation 
 
Test 
HLA 
Human Leukocyte Antigen 
TBI 
Total Body Irradiation 
HRQoL 
Health-Related Quality of 
TLC 
Total Lung Capacity 
 
Life 
TRJV 
Tricuspid Regurgitant Jet 
HU 
Hydroxyurea 
 
Velocity 
IBW 
Ideal Body Weight 
VOD 
Veno-occlusive Disease 
 
 
 

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TABLE OF CONTENTS 
1 
BACKGROUND AND RATIONALE ....................................................................................... 15 
1.1 
Introduction .................................................................................................................................... 15 
1.1.1 
Stroke and silent cerebral infarction in children with SCD ........................................................ 15 
1.1.2 
Progressive Disease with a high mortality rate for adults with SCD .......................................... 17 
1.2 
Rapid disease progression in adults with SCD .............................................................................. 18 
1.3 
HCT is a therapeutic option for SCD ............................................................................................. 19 
1.4 
HCT for SCD – conditioning regimens ......................................................................................... 20 
1.5 
Haploidentical HCT with post-transplant cyclophosphamide ....................................................... 21 
1.6 
Haploidentical HCT for SCD – preliminary results ....................................................................... 23 
1.7 
Disease Severity in SCD and transplant eligibility ........................................................................ 27 
1.7.1 
Lack of curative treatments for adults with SCD........................................................................ 27 
2 
STUDY DESIGN .......................................................................................................................... 28 
2.1 
Study Overview ............................................................................................................................. 28 
2.1.1 
Primary Objective ....................................................................................................................... 28 
2.1.2 
Secondary Objectives ................................................................................................................. 28 
2.2 
Patient Eligibility ........................................................................................................................... 29 
2.2.1 
Inclusion Criteria ........................................................................................................................ 29 
2.2.2 
Exclusion Criteria ....................................................................................................................... 32 
2.3 
Donor Eligibility for Haploidentical-bone marrow........................................................................ 33 
2.3.1 
Donor Selection Criteria ............................................................................................................. 33 
2.3.2 
Donor Prioritization Schema ...................................................................................................... 33 
2.3.3 
Donor Exclusion Criteria ............................................................................................................ 34 
2.4 
Treatment Plan ............................................................................................................................... 34 
2.4.1 
Indwelling central venous catheter ............................................................................................. 34 
2.4.2 
Preparative regimen .................................................................................................................... 34 
2.4.3 
Bone marrow transplantation and graft information ................................................................... 37 
2.4.4 
Post-Transplantation cyclophosphamide .................................................................................... 37 
2.4.5 
GVHD prophylaxis ..................................................................................................................... 37 
2.4.6 
Encephaloduroarteriosynangiosis (EDAS) ................................................................................. 38 
2.4.7 
Additional Supportive Care ........................................................................................................ 38 
2.4.8 
Infection Prophylaxis .................................................................................................................. 39 
2.4.9 
EBV Monitoring ......................................................................................................................... 39 
2.4.10 
Transfusion Support ................................................................................................................... 39 
2.4.11 
Indwelling Central Venous Catheter .......................................................................................... 39 
2.4.12 
Prevention of post-BMT Neurological Events and Posterior Reversible Encephalopathy 
Syndrome (PRES) ....................................................................................................................... 39 
2.4.13 
Pre-infusion Medication and Hydration Regimen ...................................................................... 40 
2.4.14 
Contraception Practices .............................................................................................................. 40 
2.4.15 
Management of Slow Engraftment and Graft Failure................................................................. 40 
2.5 
Study Drug Information ................................................................................................................. 40 
2.5.1 
Fludarabine ................................................................................................................................. 40 
2.5.2 
Cyclophosphamide (Cytoxan®) ................................................................................................. 41 
2.5.3 
Mesna (sodium-2-mercapto ethane sulphonate) ......................................................................... 41 
2.5.4 
Thiotepa ...................................................................................................................................... 42 
2.5.5 
Sirolimus (rapamycin, Rapamune®) .......................................................................................... 42 

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2.5.6 
Summary of Sirolimus Toxicities ............................................................................................... 43 
2.5.7 
Mycophenolate Mofetil (Cellcept®) .......................................................................................... 44 
2.5.8 
Rabbit antithymocyte globulin (rATG) ...................................................................................... 44 
2.5.9 
Hydroxyurea ............................................................................................................................... 45 
2.5.10 
Corticosteroids ............................................................................................................................ 45 
2.5.11 
Total Body Irradiation ................................................................................................................ 45 
3 
STUDY ENDPOINTS .................................................................................................................. 47 
3.1 
Primary Endpoint ........................................................................................................................... 47 
3.2 
Secondary Endpoints ..................................................................................................................... 47 
3.2.1 
Overall Survival .......................................................................................................................... 47 
3.2.2 
Event Free Survival .................................................................................................................... 47 
3.2.3 
Engraftment and Graft Rejection ................................................................................................ 47 
3.2.4 
Lineage Specific Chimerism following HCT for SCD ............................................................... 48 
3.2.5 
Transplant-related Complications ............................................................................................... 48 
3.3 
Infection ......................................................................................................................................... 49 
3.4 
Sickle Vasculopathy ....................................................................................................................... 49 
3.5 
Disease Recurrence ........................................................................................................................ 49 
3.6 
Patient-reported HRQoL Outcomes including Pain and Fatigue Domains in the Adult Stratum .. 49 
3.7 
Pain Intensity ................................................................................................................................. 49 
3.8 
Disease-related Complications ....................................................................................................... 50 
3.8.1 
Stroke .......................................................................................................................................... 50 
3.8.2 
Occurrence of Sickle Related Events ......................................................................................... 50 
3.9 
Lung function (PFTs) ..................................................................................................................... 51 
3.10 
TRJV (Cardiac Function) ............................................................................................................... 51 
3.11 
6-minute Walk Distance (6MWD) ................................................................................................. 51 
3.12 
Hematological Outcomes ............................................................................................................... 51 
3.13 
Proportion of Participants Still on Immunosuppression 2 years after BMT .................................. 51 
4 
PATIENT ENROLLMENT AND EVALUATION .................................................................. 52 
4.1 
Screening Procedures ..................................................................................................................... 52 
4.1.1 
Participant Entry and Registration .............................................................................................. 52 
4.1.2 
Pain and Priapism Adjudication ................................................................................................. 52 
4.2 
Participant Assessments ................................................................................................................. 52 
4.2.1 
Follow-up Schedule .................................................................................................................... 52 
4.2.2 
Pre-enrollment Evaluations ........................................................................................................ 53 
4.2.3 
7KHIROORZLQJHYDOXDWLRQVDUHUHTXLUHGGD\VSULRUWRHQUROOPHQWLQWR6HJPHQW$ ............. 55 
4.2.4 
7KHIROORZLQJHYDOXDWLRQVDUHUHTXLUHGGD\VSULRUWRLQLWLDWLRQRI 56 Thymoglobulin  (Day 
-9) and are considered standard of care evaluations in transplant patients: ................................ 56 
4.2.5 
Transplant Evaluations ............................................................................................................... 56 
4.2.6 
Post-Transplant Evaluations ....................................................................................................... 56 
4.3 
Data Reporting and Study Monitoring ........................................................................................... 65 
4.3.1 
Reporting Participant Deaths ...................................................................................................... 65 
4.3.2 
Adverse Event Reporting ............................................................................................................ 65 
4.3.3 
Required Adverse Event Reporting: ........................................................................................... 66 
4.3.4 
* Elective transfer to an advanced care/ICU unit for a scheduled intervention does not ... 67 need 
to be reported via the expedited AE reporting system in AdvantageEDC. ................................ 67 
4.4 
Data Monitoring ............................................................................................................................. 68 
4.4.1 
Criteria for Forms Submission.................................................................................................... 68 

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4.4.2 
Center for International Blood and Marrow Transplant Research (CIBMTR) Data Reporting . 68 
4.4.3 
Internal Data Monitoring ............................................................................................................ 68 
4.4.4 
Data Monitoring and Auditing .................................................................................................... 68 
4.4.5 
Records ....................................................................................................................................... 68 
4.4.6 
Archiving Records ...................................................................................................................... 68 
4.4.7 
Planned Protocol Amendments................................................................................................... 69 
4.4.8 
On-study Date ............................................................................................................................. 69 
5 
STATISTICAL CONSIDERATIONS ....................................................................................... 70 
5.1 
Study Design .................................................................................................................................. 70 
5.1.1 
Accrual........................................................................................................................................ 70 
5.1.2 
Study Duration ............................................................................................................................ 70 
5.1.3 
Randomization and Blinding ...................................................................................................... 70 
5.1.4 
Primary Endpoint ........................................................................................................................ 71 
5.2 
Sample Size Considerations ........................................................................................................... 71 
5.3 
Interim Analysis and Stopping Guidelines .................................................................................... 72 
5.3.1 
Monitoring Guideline: 100-day Graft Failure Rate within a Stratum ......................................... 73 
5.3.2 
Table 5.3.1: Stopping Rule for 100-Day Graft Failure ............................................................... 74 
5.3.3 
Monitoring Guideline: Grade III-IV Acute GVHD by Day 100 Post Transplant within a 
Stratum........................................................................................................................................ 74 
5.3.4 
Monitoring Guideline: Overall Mortality by Day 180 Post Conditioning within a Stratum ...... 75 
5.3.5 
Monitoring Guideline: 18-Month Severe Chronic GVHD Within a Stratum ............................. 76 
5.4 
Demographic and Baseline Characteristics .................................................................................... 77 
5.5 
Analysis of Secondary Endpoints .................................................................................................. 77 
5.5.1 
Overall Survival .......................................................................................................................... 77 
5.5.2 
One-year Event-free Survival ..................................................................................................... 77 
5.5.3 
Primary or Secondary Graft Rejection........................................................................................ 78 
5.5.4 
Disease Recurrence ..................................................................................................................... 78 
5.5.5 
Neutrophil and Platelet Recovery ............................................................................................... 78 
5.5.6 
Lineage Specific Chimerism following HCT for SCD ............................................................... 78 
5.5.7 
Grade II-IV and Grade III-IV Acute GVHD .............................................................................. 78 
5.5.8 
Chronic GVHD ........................................................................................................................... 79 
5.5.9 
Complications and Events .......................................................................................................... 79 
5.5.10 
Quality of Life and Pain Intensity .............................................................................................. 79 
5.5.11 
Other Secondary Endpoints ........................................................................................................ 80 
5.6 
Safety Analysis .............................................................................................................................. 80 
APPENDIX A 
HUMAN SUBJECTS ................................................................................................. 82 
APPENDIX B 
INFORMED CONSENTS ......................................................................................... 83 
APPENDIX C 
IMMUNE RECONSTITUTION ANCILLARY STUDY PROCEDURES ......... 138 
APPENDIX D 
CONSENSUS CRITERIA FOR GRADING OF SEVERITY OF ACUTE  
GVHD ........................................................................................................................ 142 
APPENDIX E 
NIH CONSENSUS CRITERIA FOR DIAGNOSIS AND GRADING OF 
SEVERITY OF CHRONIC GVHD ........................................................................ 144 
APPENDIX F 
LANSKY/KARNOFSKY PERFORMANCE STATUS SCALES ....................... 153 
APPENDIX G 
QUALITY OF LIFE ASSESSMENT PROMIS PAIN & FATIGUE  .......................  
 
 
DOMAINS ................................................................................................................. 155 

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APPENDIX H 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA .......................................................................................... 157 
APPENDIX I 
GUIDELINES FOR PREVENTION AND MANAGEMENT OF PRES ............ 162 
APPENDIX J 
VENO OCCLUSIVE DISEASE CRITERIA ......................................................... 168 
APPENDIX K 
IDIOPATHIC PNEUMONIA SYNDROME (IPS) CRITERIA .......................... 170 
APPENDIX L 
HYDROXYUREA PERIOD DOSE MODIFICATION  .............................................  
 
 
RECOMMENDATIONS ......................................................................................... 172 
APPENDIX M 
REFERENCES ......................................................................................................... 175 
 

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CHAPTER 1 
1 BACKGROUND AND RATIONALE 
1.1 
Introduction 
Sickle cell disease (SCD) is caused by a single point mutation in codon 6 of the ȕ-globin chain. 
This mutation directs an amino acid substitution of valine for glutamic acid, which promotes the 
formation of long hemoglobin polymers under hypoxic conditions.3,4,5 This propensity for polymer 
formation deforms the red blood cell (RBC) and causes significant alterations in red cell integrity, 
rheologic properties, and life span.6 The presence of SCD with chronic hemolysis is directly or 
indirectly responsible for the vasculopathy that forms in virtually all body organs. SCD is a 
heritable disorder of hemoglobin. One in every 1941 newborns regardless of race7 and 1 in every 
400 African-American newborns8 in the United States have SCD. Approximately 80,000 to 
100,000 persons in the United States are affected by SCD.9 This disease burden has a considerable 
impact on individuals affected and health-care systems. In the United States alone, the medical 
cost of caring for approximately 80,000 affected individuals exceeds $1 billion.10 
The course of SCD has dramatically changed over the last 40 years. Currently children born with 
SCD are expected to live through adolescence and young adulthood with > 95% expected to reach 
their 18th birthday.11 A recent prospective cohort study in children with the most severe disease 
(based on recurrent pain or acute chest syndrome episodes or other severe manifestations) have a 
15 year estimated survival of 99% when placed on hydroxyurea therapy. In comparison, children 
from the same cohort with less severe disease that were not placed on hydroxyurea therapy had an 
overall survival of 95%. These results are similar to a Brazilian cohort demonstrating that children 
with more severe SCD that were placed hydroxyurea therapy had a higher survival rate than those 
with less severe disease that were not, (99·5% vs. 94·5%, P = 0·01), for a median of 2 years (range 
0·1-6·5) .12 Taken together, these two studies suggest that with appropriate anticipatory guidance 
for splenic sequestration, prompt management of fever, routine vaccinations, and penicillin 
prophylaxis, SCD in children is no longer life threatening.11 
1.1.1 
Stroke and silent cerebral infarction in children with SCD 
The biggest challenge in managing children with SCD is the prevention of strokes and silent 
cerebral infarcts. Once a stroke occurs, standard care for secondary prevention of overt strokes in 
children and adults with SCD includes regular blood transfusion therapy to suppress synthesis of 
hemoglobin S (HbS).13 Without transfusion therapy, approximately 67% of these children will 
have second overt strokes.14 
The SWiTCH trial was the definitive randomized trial to test the hypothesis that hydroxyurea 
therapy with phlebotomy (alternative therapy) was non-inferior to regular blood transfusion 
therapy and chelation (standard therapy) for secondary prevention of stroke recurrence. As part of 
the interim analysis, the trial was stopped prematurely based on futility assessment for decreasing 
iron stores in the alternative therapy group. However, the rate of strokes in the alternative and 
standard therapy group was 10.5% (7 of 67) and 0% (0 of 66), In one of the few prospective trials 
conducted to determine the efficacy of blood transfusion therapy to prevent both overt and silent 
cerebral infarcts (infarcts that are not coincident with a focal neurological deficit) 40 children with 

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SCD and overt strokes were enrolled at 7 academic centers and followed for a mean of 5.5 years. 
Despite the mean pre-transfusion hemoglobin S concentration of 29%, an optimal transfusion 
therapy goal, progressive cerebral infarcts occurred in 45% (18 of 40 children).15 
 
Figure 1. Survival free of new overt or silent cerebral infarcts in children 
with SCD while on transfusion therapy for secondary stroke prophylaxis. 
Participants with progressive overt and silent cerebral infarction, stratified 
for the absence (solid line) or the presence (dashed line) of progressive 
cerebral vasculopathy during chronic blood transfusion therapy. Vertical 
lines represent censored cases. Median event-free interval for new silent or 
overt infarction was 3.2 years for the group with progressive vasculopathy, 
compared with median event-free interval not reached in the group without 
progressive vasculopathy (Mantel-Cox log-rank, P = .001). 
 
A much larger, but retrospective cohort consisting of 14 centers and including 137 children with 
sickle cell disease (SCD) and strokes were followed for a median of a decade. Over the course of 
a decade, approximately 22% had a second stroke despite regular blood transfusion therapy, and 
among those with a second stroke, approximately 30% had a third stroke.16 In both the 
retrospective and prospective studies, participants had strokes when hemoglobin S levels were 1%, 
9%, 22%, 25%, and 26%. The hemoglobin S levels at the time of the stroke recurrence were all < 
30%, the maximum target percent for hemoglobin S concentration. Based on the compelling results 
from these studies and other large retrospective observational studies,17,18 blood transfusion 
therapy can only be considered palliative for secondary prevention of strokes. 
 

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Silent cerebral infarcts are the most common cause of neurological injury in children with SCD 
occurring in almost 40% before their 14th birthday.19 Recently our group completed a controlled 
randomized trial demonstrating this phenomenon in children with pre-existing silent cerebral 
infarcts. Those that received regular blood transfusion therapy for 36 months to keep their 
maximum hemoglobin S level less than 30% had a 58% relative risk reduction of infarct recurrence 
when compared to observation.20 Unfortunately, even among the children with silent cerebral 
infarcts that received regular blood transfusion therapy, recurrent infarcts (both strokes and silent 
cerebral infarcts) still occurred.21 
Thus, for children with overt strokes and silent cerebral infarcts, blood transfusion therapy to 
prevent cerebral infarct recurrence has to be continued indefinitely and is palliative. Alternative 
therapies must be pursued for this high-risk group. Haplo-identical transplant may provide an 
alternative to blood transfusion therapy for secondary prevention of cerebral infarct recurrence. 
1.1.2 
Progressive Disease with a high mortality rate for adults with SCD 
In contrast to children where advances in medical care, public health and anticipatory guidelines 
have decreased the mortality, in adults with SCD the mortality rate has remained unchanged in 
large population based studies. In the most comprehensive study of SCD conducted, the 
Cooperative Study for Sickle Cell Disease (CSSCD), from 1977 to 1998, the average life span for 
men and women with SCD was 42 and 48 years, respectively. Data from 1979 to 2005 from 
National Center for Health Statistic that included over 16,000 adults with SCD revealed that the 
median age of death was 38 and 42 years for men and women with SCD, respectively. With 
improvement in care for the adults, we know the biggest risk factors for earlier death in adults with 
SCD, however, we lack any definitive strategy to abate the progression of cardiopulmonary disease 
that leads to earlier mortality. An elevated triscuspid regurgitant jet velocity (TRJV) remains the 
biggest risk factor associated with earlier death in adults with SCD.21 In multi-institutional 
prospective cohort study, the rate of mortality for those with and without TRJV > 3 m/sec and < 
3.0 m/sec respectively is shown in Figure 2.22 Currently there is no efficacious treatment for adults 
with TRJV > 3.0 m/sec. Hydroxyurea therapy is recommended by the American Thoracic Society; 
however, no randomized trial has been conducted to demonstrate its efficacy. Sidenifil versus 
placebo was introduced as a therapy for elevated TRJV in a double blind randomized controlled 
clinical trial; however, the trial stopped prematurely because of the increased rate of vaso- 
occlusive pain events in the active treatment arm. In prospective cohort study of 430 adults with 
SCD followed for approximately 5 years, Kassim et al. demonstrated that low forced expiratory 
volume in one second % predicted (FEV1) is associated with a higher mortality rate. Again, 
understanding the risk factor for earlier death is important, however, there is no therapy for low 
FEV1% predicted in adults with SCD. Likewise, renal disease, which is common in adults with 
SCD, is also associated with higher mortality. In a prospective population study conducted by the 
CDC between 2005 and 2009, in adults with SCD and end stage renal disease that start dialysis, 
the rate of death in the first year after commencing dialysis was 26%.23 
 

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Figure 2. Kaplan Meier plot from the Walk Phast 
Cohort demonstrating the proportion alive in a 
cohort of adults with SCD that had TRJV > 3 m/sec 
(n=64) and < 2 m/sec. (n=508). 
 
In summary, adults with SCD have a significant risk of earlier death with no therapeutic option to 
prevent progression of end organ disease. 
The most debilitating complication is vaso-occlusive pain that occurs in a large proportion of 
adults with SCD. The only FDA approved treatment for prevention of vaso-occlusive pain events 
in SCD is hydroxyurea therapy; however, its effectiveness in decreasing mortality, particular in 
the subset of adults with severe pre-existing end organ disease is unclear. In a prospective cohort 
study that documented daily pain in a diary Smith et al.,24 demonstrated that majority 29.3% of 
adults with SCD reported pain almost every day in their diary days; whereas, only 14.2% reported 
pain in 5% or fewer diary days (adjusted). Most importantly when a patient reported that they had 
vaso-occlusive pain episode, referred to as crises in the manuscript, only 22% of these episodes 
resulted in health care utilization; the remaining 78% of the acute pain episodes resulted in the 
adult electing to manage the crises at home. Given the increased rate of mortality associated with 
SCD in adults coupled with the crippling effects of vaso-occlusive pain episodes, individuals with 
evidence of end-organ-disease or debilitating vaso-occlusive pain events despite medical therapy, 
should be offered an option for cure. 
1.2 
Rapid disease progression in adults with SCD 
Natural history studies show that in contrast to the improvements in outcomes in childhood, there 
is a rapid progression in organ damage, morbidity and premature mortality in adulthood. 
Progression of organ damage in adulthood is marked by pulmonary hypertension, which occurs in 

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20-40% of adult patients with a 10 fold increase in risk of premature mortality,37 renal insufficiency 
with proteinuria in 70% and progressing to renal failure in 11%, abnormal pulmonary function in 
90% and progression to irreversible organ damage in 50% of patients by 50 years of age.42 One 
third develop chronic pain syndrome and only 20% are employed.43, 25 Death in adulthood is 
frequently related to organ damage which is not preventable or easily managed with current 
medical measures.42 SCD related complications such as leg ulcers, stroke, priapism, vascular 
necrosis, anxiety, and depression further worsen the health related quality of life. The mortality 
rate of patients with SCD is 5.8-20% in the first 10 years after transition to adult care.28,43 
Premature death occurs at a median age of 38 years, a statistic that has not changed in 20 years42,26 
(Figure 3). In a long-term follow-up study of patients with symptomatic SCD who were eligible 
to participate in the multicenter study of hydroxyurea (MSH), the annual mortality rate was 4.4 
per 100 person-years among adults with SCD who satisfied eligibility criteria, which is 4.4%.  
Figure 3. Steep decline in probability of 
survival in adulthood in patients with sickle cell 
disease1 
Thus, the inexorable progression of disease and premature mortality in adulthood provides the 
strong rationale for intensifying the investigation and development of curative therapies in this 
group of patients. 
1.3 
HCT is a therapeutic option for SCD 
Supportive health care measures instituted during childhood, which include newborn screening 
and pneumococcal prophylaxis, the administration of hydroxyurea and regular red blood cell 
(RBC) transfusions, have decreased the risk of serious infections and other life-threatening 
complications, resulting in improved survival to adulthood. This has, in part, shifted the 
demographics of SCD to include a growing proportion of young adults with chronic health 
impairments. Sickle cell disease is considered a life threatening disease in adults. Multiple studies 
have demonstrated that adults with SCD, particularly those with co-morbidities have a shortened 
life span.27 Even with the most recent use of hydroxyurea therapy, the only FDA disease modifying 
therapy for SCD, the life expectancy for SCD is still in the mid-40s.28 

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As an alternative to chronic supportive care, hematopoietic cell transplantation (HCT) from a 
human leukocyte antigen (HLA)-identical sibling donor has been used sparingly in children, but 
is curative in the majority of children treated.4,10 Event-free probabilities of 90 – 95% have been 
reported after HLA-ID sibling HCT using cord blood or marrow as the source of hematopoietic 
cells, for the most part after myeloablative preparation.9,29,30,31,32,33,34 However, the application of 
BMT in children with SCD is pursued very infrequently today, despite these compelling results. 
The most important reason why so few are treated is that most patients lack a suitable donor. 
Based upon current estimates, which project that 14% will have a HLA-identical donor35 and 
recent projections published by the NMDP in which the likelihood of identifying a well-matched 
unrelated marrow donor is 18% among African-American recipients,36 it is estimated that two- 
thirds of patients will not be able to pursue transplantation. We hypothesize that HLA haplo- 
identical transplant is an alternative to blood transfusion therapy for secondary prevention of 
cerebral infarct recurrence and in abating the morbidity from the age-dependent chronic organ 
dysfunction in adult patients who lack a well-matched donor. 
1.4 
HCT for SCD – conditioning regimens 
Even when it is clear that allogeneic BMT can decrease or eliminate sickle cell disease-related 
complications30, myeloablative transplantation can cause toxicities such as GVHD, infertility and 
importantly, a fixed risk of transplantation-related mortality that has caused families and their 
providers to seek alternative safer therapies, even when the latter lack curative potential. Recently, 
progress in the development of reduced intensity conditioning regimens that facilitate the sustained 
engraftment of donor marrow with reduced toxicity has occurred. Most of these regimens 
incorporate highly immunosuppressive purine analogues, such as fludarabine, which allow the 
reduction or elimination of myeloablative agents such as busulfan or total body irradiation and still 
sustain engraftment of HLA-identical allogeneic stem cells. 
Early attempts to use a non-myeloablative conditioning regimen for HLA-identical sibling BMT 
for sickle cell disease were unsuccessful. In these trials, an initial wave of donor engraftment 
typically was observed, but the disease invariably recurred when post-grafting immunosuppression 
was withdrawn6. To investigate the cause of this failure, a group at the NIH led by John Tisdale 
studied sirolimus in a preclinical model and determined that this agent was more effective than 
standard calcineurin inhibitors at establishing bidirectional donor-host tolerance. His team tested 
this approach in humans, and Hsieh et al demonstrated stable donor engraftment in adult SCD 
patients following non-myeloablative HCT from HLA-matched sibling donors.29,30 Between 2004 
and 2013, thirty patients with severe disease who were 16 to 65 years of age were treated by a 
nonmyeloablative combination of alemtuzumab (1mg/kg in divided doses), total-body irradiation 
(300 cGy), and sirolimus followed by HLA-ID sibling filgrastim mobilized peripheral blood stem 
cell transplantation. Sirolimus alone was used for GVHD prophylaxis and 87% of recipients had 
long-term engraftment without acute or chronic GVHD. While sirolimus was discontinued in 15 
of 30 recipients, in the remaining recipients it was extended due to lymphohematopoietic 
chimerism that was judged too low to prevent a late graft rejection. The selection of sirolimus 
appeared pivotal to the very good outcome because of its inhibitory effect on effector T-cell 
proliferation and viability while preserving T-regulatory cells that are required for tolerance, and 
because sirolimus does not appear to cause posterior reversible encephalopathy syndrome (PRES) 
unlike other calcineurin inhibitors. PRES has been observed in approximately 10 - 20% of sickle 

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cell recipients who receive cyclosporine post-HCT for GVHD prevention, and is thus a leading 
contributor to adverse events after HCT for SCD.31,37 Thus, it appears that reduced intensity 
transplantation regimens that include immunoablation after treatment might be especially 
important to ensure donor engraftment after HCT for SCD. This aspect will carry even greater 
importance in the setting of HLA-mismatched donor transplantation that will be needed to tackle 
the problem of limited matched donor availability as a barrier to transplantation. Therefore, 
developing novel strategies that address the issue of expanding the donor pool while ensuring a 
low rate of graft rejection are potentially transformative to curative therapy for SCD. 
1.5 
Haploidentical HCT with post-transplant cyclophosphamide 
In the past five years, investigators at Johns Hopkins have developed a non-myeloablative 
conditioning regimen for transplantation of marrow from partially HLA-mismatched, or 
haploidentical, bone marrow from first-degree relatives. The regimen’s main goal, J9966 (RPN 
99-11-05-01), was to titrate the dose of pre- and post-transplantation cyclophosphamide (CY), a 
potent immunosuppressive drug, given in conjunction with pre-transplantation fludarabine and 
total body irradiation (TBI), to achieve a regimen that had an acceptably low risk of graft rejection 
and GVHD, the two major complications of haploidentical bone marrow transplantation (BMT). 
All patients received mycophenolate mofetil (MMF) and tacrolimus (FK), beginning on day 4 or 
5 and terminating on days 35 and 50-180, respectively, to reduce the incidence and severity of 
GVHD. The first cohort of three patients received no pre-transplantation CY and 50 mg/kg CY IV 
on day 3, and two of the patients rejected their grafts. A second cohort of 20 patients received 
14.5 mg/kg CY IV on days –6 and –5 in addition to 50 mg/kg IV on day 3. Of 18 evaluable patients, 
13 patients had donor engraftment on day 60, but accrual of patients to this dose level was stopped 
because 8/13 patients developed severe GVHD, an incidence convincingly in excess of the 
stopping criterion of 20%. To reduce the incidence of GVHD, a third cohort of patients received 
an additional dose of CY 50 mg/kg IV on day 4, and MMF dosing was increased from bid to tid, 
based upon pharmacokinetic data suggesting the need for more frequent dosing. Of seventeen 
evaluable patients so far, two patients have had non-fatal graft rejection, and only one patient 
treated according to the protocol has had severe GVHD (an additional patient developed severe 
GVHD after withdrawal of immunosuppression to treat relapse). Two patients died of causes other 
than relapse: one from GVHD, and the other from disseminated fungal infection. Of the 16 patients 
who have been followed up to 100 days for relapse, 8 have relapsed at a median of 64 days (range 
24-~100) after transplantation, and 6 patients are alive and disease free at a median of 206 days 
(range, 100-429 days [as of Feb 8, 2014]) following BMT.38 
In order to better judge the safety and efficacy of the non-myeloablative BMT protocol, the tables 
below compare the results of J9966, dose level 3, to the results of the four largest published trials 
of HLA-identical sibling peripheral blood versus bone marrow transplantation for early stage 
leukemia. 
 
 

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TABLE 1.5A: ENGRAFTMENT DATA AFTER HAPLOBMT 
Author 
N (PB/BM) 
Median age 
ANC 500/mm3† 
Plt 20K† 
Plt 50K† 
Blaise5 
48/52* 
37/36 
15/21 
13/21 
15/26 
Bensinger6 
81/91 
42/42 
16/21 
13/19 
NA 
Schmitz7 
163/166 
39/37 
12/15 
15/20 
20/26 
Couban8 
109/118 
45/44 
19/23 
16/22 
NA 
J9966 
17 
31 
16 
24 
31 
*Numbers represent: recipients of peripheral blood/recipients of bone marrow 
†Time from transplantation to designated count, sustained without transfusion 
TABLE 1.5B: OUTCOMES DATA AFTER HAPLOBMT 
Author 
aGVHD II-IV 
(%) 
aGVHD III-IV 
(%) 
cGVHD (%) TRM (%) Relapse (%) 
Blaise 
45/42* 
17/28 
55/30 
23/21† 
6/11 
Bensinger 
64/57 
15/12 
46/35 
21/30† 
14/25 
Schmitz 
52/39 
28/16 
66/50 
24/24* 
12/7 
Couban 
44/44 
26/18 
40/30 
7/16† 
15/20 
J9966 
47 
13 
NA 
13 
50 
*Numbers represent: recipients of peripheral blood/recipients of bone marrow 
†Transplant-related mortality (TRM) or relapse over entire study (median f/u ~ 2 years) 
†100 day mortality 
Compared to the patients receiving HLA-identical sibling bone marrow following myeloablative 
conditioning, patients on J9966 were younger, took longer to engraft platelets, and had a 
substantially higher rate of relapse, but were similar in the time to neutrophil recovery, the 
incidence of GVHD, and transplant-related mortality (TRM). The higher rate of relapse for patients 
on J9966 may be attributable to a benefit of myeloablative conditioning in reducing the risk of 
relapse, or that patients on J9966 had advanced, poor prognosis hematologic malignancies, which 
relapse more frequently than early leukemia after allogeneic BMT. 
Since the toxicities of non-myeloablative haploidentical BMT (haploBMT) were not known when 
the trial was written, eligibility for J9966 was restricted to patients with advanced, poor-risk 
hematologic malignancies, such as chronic myeloid leukemia in 2nd chronic phase, advanced 
myelodysplasia, acute leukemia in 2nd remission, and lymphoma in relapse after autologous BMT. 
Eligibility on the protocol has been expanded to ‘standard risk’ hematologic malignancies in trial 
J0457, which is ongoing. 
Between J9966 and J0457, 56 patients with hematologic malignancies received cyclophosphamide 
50  mg/kg  IV,  either  once  (on  day  3)  or  twice  (on  days  3  and  4)  after non-myeloablative 

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conditioning and haploidentical bone marrow transplant. Most of these patients had advanced 
disease or failed a previous autologous transplant. All were conditioned as outpatients with 
fludarabine, cyclophosphamide, and total body irradiation, transplanted with non-T cell-depleted 
marrow, and treated with tacrolimus and mycophenolate mofetil beginning the day after the last 
dose of cyclophosphamide. The most interesting finding was that compared to patients receiving 
a single dose of post-transplant cyclophosphamide, those receiving two doses had significantly 
less grade II-IV aGVHD (43% vs. 78%; p=.01) and grade III-IV aGVHD (20% vs. 53%; p=.006) 
by day 200 after transplant. Death from GVHD occurred in 5/13 assessable patients receiving one 
dose versus 2/28 assessable patients receiving 2 doses of cyclophosphamide. 
Since the data to date suggest that this treatment regimen may be as safe as HLA-identical sibling 
BMT after myeloablative conditioning, non-myeloablative haploidentical BMT may be considered 
a reasonable treatment option for patients who have severe SCD. Also, the novel use of post- 
transplant cyclophosphamide with a reduced intensity conditioning emerges as an interesting 
option of immunotherapy to prevent graft rejection. Moreover, as cancer relapse is not a concern 
in the setting of SCD, engraftment with non-myeloablative hematopoietic stem cell transplantation 
should be curative. In clinical transplantation, antithymocyte globulin (ATG) has been used 
extensively in conventional myeloablative and non-myeloablative conditioning regimens to 
facilitate engraftment in patients with sickle cell disease.9 This effect is largely mediated by in 
vivo T-cell depletion produced by the ATG, similar to the effect of monoclonal T-cell antibodies 
in the murine model. 
These preliminary data have relied upon the administration of donor marrow in lieu of umbilical 
cord blood or mobilized peripheral blood progenitor cells, which is an important consideration in 
this non-malignant condition. The use of mobilized peripheral blood progenitor cells for malignant 
and non-malignant diseases is associated with higher risk of chronic GVHD compared to bone 
marrow. It is well recognized that chronic GVHD adds to the burden of morbidity and mortality. 
In particular, for non-malignant diseases where there is not a need for graft versus tumor effect, 
there are no advantages to transplantation of peripheral blood. In patients with severe aplastic 
anemia, the most common non-malignant indication for transplantation, chronic GVHD risks are 
higher after transplantation of peripheral blood compared to bone marrow and mortality risks are 
higher after transplantation of peripheral blood from HLA-matched sibling and HLA-matched 
unrelated donors.39 In addition, graft failure rates are high after unrelated UCB transplantation for 
SCD. Data from CIBMTR/Eurocord reported an event-free survival was 50% for children with 
sickle cell disease (the predominant cause of failure was graft rejection).40 The cord blood arm of 
the recently completely BMT CTN 0601 (unrelated donor transplantation for children and 
adolescents with sickle cell disease) was closed early for excess graft failure.41 Together, the 
preliminary data presented below with the published evidence about the use of cord blood and 
mobilized peripheral blood progenitor cells in sickle cell disease strongly support the use of 
marrow in this study. 
1.6 
Haploidentical HCT for SCD – preliminary results 
The single center experience from Johns Hopkins includes 38 patients with SCD who were 
screened and 36 (95%) who proceeded to transplantation. The overall median age of transplanted 
patients was 23 years. With a median follow-up of 35 (range, 1-93) months, 97% of patients are 

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alive; one patient died from complications of graft-versus-host disease 7 months after transplant 
and one patient developed AML requiring a second BMT (now alive and in remission). Of the 36 
patients transplanted, 5 had matched sibling donors and 31 had HLA haploidentical donors. All 
five patients who received matched sibling donor transplants are alive and engrafted (4 mixed 
chimerism and 1 with full donor chimerism). In patients who received transplants from an HLA 
haploidentical donor 22/31 had stable engraftment of donor cells (71%). All patients with 
secondary graft failure recovered host hematopoiesis and survive with autologous reconstitution 
of SCD. The overall incidence of cGVHD is 5.8%. The last 5 consecutive patients who were 
transplanted (patients 32-36) received TBI increased from 200cGy to 400cGy. All 5 of these 
patients survive beyond day 60 with 100% donor chimerism. 
While these results are very good with regard to transplant-related toxicity, there is a clear need 
for improvement with regard to mitigating disease recurrence. Experimental data using high dose 
cyclophosphamide has clearly shown that in order to increase engraftment efficiency there are 
strategies that might be followed: increase the intensity of the conditioning (such as increasing the 
dose of TBI or adding additional agents to the pre-transplant regimen) or increase the cell dose of 
the graft.42,43 In this study, the former was adopted in the form of adding thiotepa to the 
conditioning regimen in order to abrogate the host-versus-graft rejection and to generate partial 
marrow ablation to promote the engraftment of donor cells. We did not find that G-CSF 
mobilization as a method to increase the cell dose improved donor engraftment; thus, it was 
discontinued. We recently increased the TBI dose in our conditioning regimen from 200 to 400 
cGy with early results as noted above. 
There is evidence that thiotepa is an active agent in the conditioning regimen for hemoglobin 
disorders that addresses the difficulty of donor engraftment after allogeneic transplantation. In a 
report by La Nasa et al, an investigation demonstrated that a combination of Bu/TT/CY 
conditioning in the initial series of 32 patients that received URD transplantation had a Transplant 
Related Mortality (TRM) of 19% and a disease-free survival probability of 69%. The Bu/TT/CY 
regimen later was replaced with Bu/Flu/TT in the subsequent series, in 17 patients who received a 
combination of Bu/Flu with thiotepa, the TRM was 0% and thalassemia free survival was 77% 
after HCT. Bernardo et al substituted busulfan with its dihyroxy derivative treosulfan and 
demonstrated updated data in 60 patients (40 URD and 20 matched related donor (MRD) recipients 
indicating an overall survival of 93% and thalassemia free survival of 84%.44) Finally, a recent 
UHSRUW RI  FRQVHFXWLYH SDUHQWDO KDSORLGHQWLFDO WUDQVSODQWV  ZLWK 6&' DQG RQH ZLWK ȕ
thalassemia major) from St. Mary’s Hospital, London was reported at the 2015 EBMT meeting. 
Eleven of the 12 patients survive with partial or full donor chimerism after receiving a preparative 
regimen of fludarabine 150 mg/m2, thiotepa 10 mg/kg, cyclophosphamide 29 mg/kg, TBI 2 Gy 
and ATG (Thymoglobulin) 4.5 mg/kg with HU, hyper-transfusion and azathioprine administered 
2 months before commencing the conditioning regimen. Patients received cyclophosphamide 50 
mg/kg on days +3 and +4, MMF and sirolimus for post-grafting immunosuppression (Delafuente 
et al EBMT 2015). Taken together, these data demonstrate steady improvement in donor 
engraftment was associated with thiotepa, and that the safety profile has been acceptable. Thus, 
we propose to add this drug to the conditioning regimen to address the problem of graft 
rejection/disease recurrence after haploBMT. 

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To date, the aforementioned single center experience from St. Mary’s London now includes a total 
of 23 pediatric patients (18 SCD, 5 thalassemia, ages 3 to 18 years). With a median follow up of 
10.7 (range, .7 to 23) months, 20 patients are alive and disease free. Of the 3 (13.0%) patients who 
died, one patient died from secondary graft failure and complications of IPS at Day +90, a second 
patient died at D +36 of septic shock and meningitis and the third died at Day + 148 due to IPS. 
cGVHD was observed in 5 patients (29.4%) beyond Day+ 100, however no cGVHD was reported 
beyond 12 months. Additional data regarding count recovery and GVHD incidence is presented in 
Table 1.6a below; while details regarding this group’s percent donor chimerism is broken down at 
specific intervals as seen in Table 1.6b. 
TABLE 1.6A: ST. MARY’S LONDON EXPERIENCE: OUTCOMES 
Stem Cell Source 
BM (G-CSF primed) 
TNC x 108/kg 
Median: 9.66 
Range: 2.35 - 20.53 
CD34 x 106/kg 
Median: 3.46 
Range: 1.12 - 9.21 
Survival Months 
Median: 10.7 
Range: 0.7 - 23.0 
Neutrophil engraftment 
Median: 17 
Range: 15 – 29 
Plt >20 
Median: 35.5 
Range: 20 – 64 
Plt>50 
Median: 35.5 
Range: 20 - 64 
Chimerism 
See Table 2 for chimerism summary 
Graft Failure/Relapse 
2 (8.7%) 
x One secondary graft failure day +60. 
x One primary graft failure day +28. 
aGvHD grade I 
7 (30.4%) 
D*Y+'JUDGH 
2 (8.7%): 
x Day +35 skin stage 3, treated with MSC 
x Day +16 gut stage 3, treated with MSC 
cGvHD >day +100 Limited 
2 (8.7%) 
x Day +320 skin 
x Day +259 liver, treated with steroids 
cGvHD >day +100 Extensive 3 (13.0%) 
x Day +187 lung, day +308 skin, day +320 muscoskeletal. 
x Day +257 skin and liver 
x Day +180 gut, treated with MSC. 
cGvHD >day +100 Total 
5 (21.7%) 
cGvHD >18 months 
None 

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Stem Cell Source 
BM (G-CSF primed) 
Deaths 
3 (13.0%) 
x Day +90. CoD: Secondary Graft Failure/Infection/IPS 
x Day +148. CoD: Idiopathic Pneumonia Syndrome 
x Day +36. CoD: Septic shock and meningitis. 
VOD 
1 (4.3%) Day +78 post-haplo but day +4 post-auto rescue. 
Days to 
Cessation of 
immunosuppress
ion: 
Median: 145.5 
Range: 108 - 432 
 
One patient prolonged course of immunosuppression due to low 
donor T cell fraction: 432days. 
Disease Free Survival 
87.0% 
Overall Survival 
87.0% 
TABLE 1.6B: ST. MARY’S LONDON EXPERIENCE: CHIMERISM ANALYSIS 
Haplo 
of the total evaluable patients at each time point 
Time point 
(days post- 
BMT) 
Day +28 
Day +90 
Day +180 
GD\ 
Evaluable 
patients (n) 
22 
22 
13 
13 
14 
14 
9 
9 
% Donor 
Chimerism 
WB 
T cell 
WB 
T cell 
WB 
T cell 
WB 
T cell 
 
91.0 
72.7 
76.9 
69.2 
85.8 
78.6 
77.8 
88.9 
90-94 
4.5 
9.1 
0 
23.1 
7.1 
14.3 
11.1 
0 
50-89 
4.5 
9.1 
23.1 
0 
7.1 
0 
11.1 
0 
<50 
0 
9.1 
0 
7.7 
0 
7.1 
0 
11.1 
The administration of HU in advance of the conditioning regimen and the donor hematopoietic 
cell administration has been studied in the setting of HCT for hemoglobin disorders as a strategy 
to mitigate the risk of graft rejection. It was incorporated into protocol 26 in treating children with 
thalassemia major who had class III risk-group features and it was associated with a lower 
incidence of graft rejection compared to historical observations.45 In another contemporary series 
of 50 children with SCD treated in Belgium between 1988 and 2013, the DFS after HLA-ID sibling 
HCT was 85.6% and 94.1% of recipients survived.46 Of interest, all children treated since 1995 
had hydroxyurea administered well before HCT, which comprised a group of 38 recipients, as first 

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reported in 2004.47 Thirty-seven of these individuals survive free of SCD with an 8-year estimate 
of DFS that is 97.1%, and which is significantly higher compared to the DFS in those who did not 
receive HU before HCT (P<0.001). Together, these data strongly suggest that HU might be safely 
administered in advance of transplantation to exert its immunosuppressive and myelosuppressive 
effects to promote engraftment of donor cells. 
1.7 
Disease Severity in SCD and transplant eligibility 
The application of experimental HCT therapy in SCD must strike a balance between the underlying 
disease severity and the possibility of a direct benefit of the treatment, particularly in pediatric 
populations. Thus, the SCD subjects targeted for enrollment are patients at risk for early mortality 
and progressive global organ damage, as occurs in adults, and also children at risk for progressive 
brain injury following an initial cerebral infarction, for whom the possibility of a curative outcome 
will have the greatest impact. In these two groups, there are compelling reasons to consider an 
investigational transplant option. 
1.7.1 Lack of curative treatments for adults with SCD 
The prevailing framework of clinical research in SCD shifts in the transition from childhood to 
adulthood. Among pediatric hematologists, the dominant view is that survival to adulthood is 
excellent, and that children, on average, have a very good quality of life as a result of supportive 
care measures such as antibiotics, family education, and the judicious use of transfusions. In 
addition, a great deal of effort has focused on identifying children who have high-risk features, so 
that the risk of any specific intervention might be balanced by the severity of disease in that 
individual. Thus, clinical research studies in children with SCD have focused primarily on safety 
and efficacy, often in the setting of a high-risk population, such as children at risk for a stroke. 
While HCT has curative potential, its routine application remains quite limited in children with 
SCD, due in part to its toxicities which include a risk of dying from the procedure itself. As a 
result, clinical studies of transplantation in children with SCD have suffered from poor accrual and 
despite excellent disease-free survival, HCT is not routinely considered in children with SCD. 
In contrast, the prevailing view among clinicians who care for adults is that SCD is, on average, a 
severe disease with a significant risk of sudden death and the development of chronic medical 
problems and that supportive care options for young adult patients are not adequate to address the 
overwhelming nature of this disease. Thus, clinical studies in adults with SCD have focused on 
interventions that prolong survival and improve the quality of life. Unlike children, adults with 
SCD are much more likely to have a debilitating complication. As a result, the risk/benefit ratio of 
HCT is very favorable in adults, particularly if an approach to HCT that defines an acceptable level 
of toxicity can be established. If successful, such an approach could significantly improve the 
outlook of many adults with SCD and broaden the therapeutic choices. 
 
 
 

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CHAPTER 2 
2 STUDY DESIGN 
2.1 
Study Overview 
This study is a phase II, single arm, multi-center study designed to estimate the efficacy and 
toxicity of haploidentical BMT in patients with SCD who are in two groups: (1) children between 
5.00-14.99 years with SCD with strokes; and (2) adults between 15.00-45.99 years with severe 
SCD. 
2.1.1 Primary Objective 
The primary objective is to estimate event-free survival (EFS) at 2 years after a reduced intensity 
conditioning regimen and human leukocyte antigen (HLA)-haploidentical bone marrow 
transplantation (haploBMT) in children with SCD and adults with severe SCD. 
2.1.2 Secondary Objectives 
Within each stratum: 
1. 
Estimate overall survival at one year and two years after enrollment and after 
haploBMT. 
2. 
Estimate EFS at one year after haploBMT. 
3. 
Estimate incidence of primary and secondary graft rejection at one and two 
years after haploBMT. 
4. 
Estimate incidence and severity of acute GVHD until Day 100 then chronic 
GVHD at six months, one year, 18 months, and two years post-transplant. 
5. 
Characterize donor hematopoietic chimerism in peripheral blood at days 28, 42, 
100, and 180 and at 1 and 2 years after haploBMT. 
6. 
Characterize hematologic and non-hematologic toxicities of haploBMT, 
including the incidence and severity of acute and chronic graft-versus-host 
disease; time to and probability of red blood cell, neutrophil, and platelet 
recovery; hepatic veno-occlusive disease (VOD); idiopathic pneumonia 
syndrome (IPS); central nervous system (CNS) toxicity (reversible posterior 
leukoencephalopathy 
syndrome 
[RPLS], 
hemorrhage, 
and 
seizures); 
cytomegalovirus (CMV) infection; adenovirus infection; Epstein Barr virus post- 
transplant lymphoproliferative disease (EBV PTLD); invasive fungal infection. 
7. 
Evaluate if sickle vasculopathy is halted by successful transplantation as determined by 
comparing brain MRI pre- and 2 years post-haploBMT. Cerebral MRI/MRA is required 
for only pediatric patients enrolled under a neurologic indication to assess status of CNS 
disease. For adults where the indication for the transplant is a stroke, cerebral MRI/MRA 
is required after transplant to assess progression of CNS disease. 
8. 
Estimate disease recurrence at one and two years after haplo BMT. 

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9. 
Evaluate sickle-related events and end organ function in all recipients after haploBMT to 
determine if severe and debilitating vaso-occlusive pain and cerebral infarction are 
stabilized after transplantation. 
10. Evaluate patient-reported quality of life (pain and fatigue domains) pre- and 1 and 2 years 
post-haploBMT in the adult stratum for English and Spanish-speaking patients 
11. Lung function pre- and 2 years post-haploBMT 
12. TRJV pre- and 1 and 2 years post-haploBMT 
13. 6 min walk distance pre- and 1 and 2 years post-haploBMT 
14. Pain intensity assessed by an electronic pain diary at baseline, 1 and 2 years post- 
haploBMT for English-VSHDNLQJSDWLHQWV\HDUVRIDJHDWWLPHRI enrollment 
15. Hematological outcomes at 2 years (hgb, retic, %HbS, LDH, bili, last date of red blood 
cell transfusion) 
16. Viral mold infections/bacterial or fungal sepsis at any time up to 2 years post-transplant 
17. Proportion on immunosuppression at 2 years post-haploBMT 
2.2 
Patient Eligibility 
2.2.1 Inclusion Criteria 
Some inclusion criteria differ by age. 
2.2.1.1 
Inclusion Criteria for Both Strata (Stratum 1 and Stratum 2) 
Participants in both strata must have adequate physical function as measured by all of 
the following: 
1. $.DUQRIVN\/DQVN\SHUIRUPDQFHVFRUHRI 60. 
2. Cardiac function: Left ventricular ejection fraction (LVEF) > 40%; or LV 
shortening fraction > 26% by cardiac echocardiogram or by MUGA scan. 
3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of t 85% and 
DLCO > 40% (corrected for hemoglobin). 
a. Patients unable to perform DLCO due to young age or other inability are not 
required to have a specified threshold but must have no evidence of dyspnea 
at rest and O2 saturation level must be greater than 88% in room air at 
baseline. 
4. Renal function: Serum FUHDWLQLQH[XSSHUOLPLWRIQRUPDOIRUDJHand 
HVWLPDWHGRUPHDVXUHGFUHDWLQLQHFOHDUDQFHP/PLQ m2. 
5. Hepatic function: 
a. 6HUXPFRQMXJDWHGGLUHFWELOLUXELQ[XSSHUOLPLWRIQRUPDOIRUDJHDVSHU
local laboratory. Participants are not excluded if the serum conjugated 
(direct) bilirubin is >2x the upper limit of normal for age as per local 
laboratory and: 

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i. There is evidence of a hyperhemolytic reaction after a recent RBC 
transfusion, OR 
ii. There is evidence of moderate direct hyperbilirubinemia defined as direct 
serum bilirubin < 5 times ULN and not caused by underlying hepatic 
disease. 
b. ALT and AST < 5x upper limit of normal as per local laboratory. 
6. Liver MRI using a validated methodology per institutional preference (T2* or 
R2* or by ferriscan [R2 MRI]) for estimation of hepatic iron content is required 
IRUSDUWLFLSDQWVZKRDUHFXUUHQWO\UHFHLYLQJSDFNHGUHGEORRGFHOOWUDQVIXVLRQV
SHU\HDUIRU\HDURUKDYHUHFHLYHGSDFNHGUHGEORRGFHOOWUDQVIXVLRQV
(lifetime cumulatLYH3DUWLFLSDQWVZKRKDYHKHSDWLFLURQFRQWHQWPJ)HJ
liver dry weight by liver MRI must have a gastroenterology/hepatology 
consultation with liver biopsy and histological examination including 
documentation of the absence of cirrhosis, bridging fibrosis[1], and active 
hepatitis. 
7. Lack of clinical evidence of overt stroke or transient ischemic attack (TIA) within 
180 days prior to enrollment in Segment A. Participants with clinical evidence of 
an overt stroke or TIA within 180 days prior to enrollment in Segment A will 
require a cerebral MRI/MRA confirming stabilization of the neurologic event 
prior to proceeding to enrollment. 
8. Participants must be HLA typed at high resolution using DNA based typing at 
HLA-A, - B, -C, DRB1, and have available: 
a. An HLA haploidentical first degree relative donor (parents, siblings or half 
siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is 
willing and able to donate bone marrow. A unidirectional mismatch in either 
the graft versus host or host versus graft direction is considered a mismatch. 
The donor and recipient must be HLA identical for at least one antigen (using 
high resolution DNA based typing) at the following genetic loci: HLA-A, 
HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be 
considered sufficient evidence that the donor and recipient share one HLA 
haplotype and typing of additional family members is not required. 
Confirmatory donor HLA typing must be completed < 100 days prior to 
Segment A enrollment 
9. Umbilical cord blood or peripheral blood stem cell donors will not be accepted. 
2.2.1.2 
Inclusion Criteria for Stratum 1: Children Ages 5.00 - 14.99 at enrollment 
1. Age 5.00 – 14.99 years at Segment A enrollment 
2. Participants with sickle cell anemia (Hb SS or Sß° Thalassemia) who have one or 
more of the following: 
a. $QHXURORJLFDOHYHQWUHVXOWLQJLQIRFDOQHXURORJLFGHILFLWVWKDWODVWHG
hours (classical clinical definition of stroke, not requiring imaging studies of 
the brain) OR a focal neurological event resulting in abnormalities on T2-

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weighted or FLAIR images using a MRI scan, indicative of an acute infarct, 
with no other reasonable medical explanation (definition of a stroke supported 
with MRI imaging scans of the brain), OR both. 
b. Abnormal transcranial Doppler (TCD) measurement with a timed average 
maximum mean velocity of at least 200 cm/sec in the terminal portion of the 
internal carotid or proximal portion of middle cerebral artery or if the imaging 
TCD method is used > 185 cm/sec plus evidence of intracranial vasculopathy. 
c. Silent Cerebral Infarct defined as an infarct-like lesion based on an MRI 
signal abnormality at least 3 mm in one dimension and visible in two planes 
on FLAIR or T2-weighted images (or similar image with 3D imaging) and 
documented neurological examination performed by a neurologist 
demonstrating the participant has a normal neurologic examination or an 
abnormality on examination that could not be explained by the location of the 
brain lesion(s). 
d. Acute severe vaso-occlusive pain episodes requiring hospitalization and 
recalcitrant to maximum medical therapy. Episodes of pain to be adjudicated 
by selected committee. 
e. At least one acute chest syndrome episode resulting in intensive care 
admission requiring non-mechanical ventilatory support: simple nasal 
cannula, face mask that requires oxygen content (venti mask, non-rebreather), 
simple nasal cannula, face mask 
f. 
O2 (e.g. ventimask, non-rebreather), CPAP, SiPAP, BiPAP, high flow nasal 
cannula (HFNC) or invasive mechanical ventilatory support (delivered by 
ETT or trach). 
g. Right heart catherization confirmed pulmonary artery pressure >25 
mmHg or mean pulmonary vascular resistance 206(57-421) 
dyn·s·cmí. 
h. Essential hypertension on antihypertensive medications >95% 
upper limit of normal for age (as defined according to the American 
Academy of Pediatrics). 
i. 
Recurrent priapism (episodes lasting at least 4 hours at least twice 
in the last 12 months or 3 times in the last 24 months) recalcitrant 
to medical treatment or unable to use hydroxyurea due to SCD 
phenotype, with the approval of the adjudication committee. 
 
 
[1]The absence of bridging fibrosis will be determined using the histological grading and staging scale as 
described by Ishak and colleagues (1995)1,2,3. 
 
2.2.1.3 
Inclusion Criteria for Stratum 2: Adults Ages 15.00 - 45.99 at enrollment 
1. Age 15.00-45.99 years at Segment A enrollment 
2. Participants with sickle cell anemia (any clinically significant sickle 

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genotype, for H[DPSOH +E 66 6& 6' 6ȕ 7KDODVVHPLD 6ȕ+ 
Thalassemia, S-OArab) who have one or more of the following: 
a. A neurological event resulting in focal neurologic deficits that 
ODVWHG   KRXUV FODVVLFDO clinical definition of stroke, not 
requiring imaging studies of the brain) OR a focal neurological 
event resulting in abnormalities on T2-weighted or FLAIR images 
using a MRI scan, indicative of an acute infarct, with no other 
reasonable medical explanation (definition of a stroke supported 
with MRI imaging scans of the brain), OR both. 
b. History of two or more episodes of acute chest syndrome (ACS) in 
the 2-year period preceding enrollment despite the institution of 
supportive care measures (i.e. asthma therapy and/or hydroxyurea); 
c. History of three or more severe vaso-occlusive pain crises per year 
in the 2-year period preceding enrollment despite the institution of 
supportive care measures (i.e. a pain management plan and/or 
treatment with hydroxyurea); painful episodes related to priapism, 
osteonecrosis or any sickle-related complication are acceptable;  
d. Administration of regular red blood cell (RBC) transfusion therapy, 
defined as 8 or more transfusion events per year (in the 12 months 
before enrollment) to prevent vaso- occlusive clinical complications 
(i.e. pain, stroke, or acute chest syndrome); 
e. An echocardiographic finding of tricuspid valve regurgitant jet 
YHORFLW\75-9PVHF 
2.2.2 Exclusion Criteria 
Participants fulfilling any of the following criteria are ineligible for participation on this protocol: 
1. Participants who have an HLA-matched sibling who is able and willing 
to donate bone marrow. Patients with an HLA-matched unrelated donor 
are not excluded. 
2. Uncontrolled bacterial, viral or fungal infection in the 6 weeks before 
enrollment (currently taking medication with evidence of progression 
of clinical symptoms or radiologic findings). 
3. Evidence of HIV infection or known HIV positive serology. 
4. Participants who have received a previous HCT. 
5. Participants who have had an Encephaloduroarteriosynangiosis 
(EDAS) procedure in the 6 months prior to enrollment. 
6. Participants who have received a prior solid organ transplant. 
7. Participants who have participated in another clinical trial in which the 
patient received an investigational or off-label use of a drug or device 
within 3 months of enrollment. 

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8. Females who are pregnant or breastfeeding. 
9. Participants with clinically significant, uncontrolled autoimmune disease, 
requiring active medical management (immunosuppressive therapy or 
chemotherapy), which, in the judgment of the local Principal Investigator, 
indicates that the patient could not tolerate transplantation. 
10. Females of child bearing potential (to include all female participants > 10 years 
of age, unless postmenopausal for a minimum of 1 year before the time of consent 
or surgically sterilized), who do not agree to practice two (2) effective methods 
of contraception at the same time, or do not agree to practice true abstinence when 
this is in line with the preferred and usual lifestyle of the subject, from the time of 
signing of informed consent through 12 months post-transplant. 
11. Males (even if surgical sterilized) who do not agree to practice effective barrier 
contraception, or who do not agree to practice true abstinence from the time of 
signing informed consent through 12 months post-transplant. 
12. Presence of anti-donor specific HLA antibodies. HLA antibody presence and 
specificity will be determined by solid phase immunoassays. An anti-donor 
specific HLA antibody will be considered positive when the mean fluorescence 
intensity (MFI) is higher than the cut-off defined by each institution. 
Recommended cut-off values are MFI >1000 for donor specific antibody to HLA-
A, -B, and DRB1 and MFI >2000 for HLA-C, DQB1 and DPB1. This must be 
measured before the final donor selection, and < 100 days before enrollment in 
Segment A (preferably < 30 days before Segment A enrollment). If MFI >1000 for 
donor specific antibody to HLA-A, -B, DRB1 and/or MFI >2000 for HLA-C, 
DQB1 and DPB1, documentation must be submitted to the DCC coordinator for 
review and approval by a Protocol Chair and/or Protocol Officer prior to 
enrollment. 
2.3 
Donor Eligibility for Haploidentical-bone marrow 
2.3.1 Donor Selection Criteria 
Donors must be: 
1. HLA-haploidentical  first-degree  relatives  of  the  patient.(Section 
2.2.1.1 describes acceptable HLA typing and relationship to the 
patient) 
2. The donors must be willing to donate bone marrow 
3. Donor must meet institutional criteria for donation. 
2.3.2 Donor Prioritization Schema 
In the event that two or more haploidentical donors are identified (section 2.3.1), the following 
order of priority is recommended: 
1. Donor age <40 years 

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2. Avoid female donors for male recipients 
3. Avoid major/minor ABO mismatched transplants 
4. Avoid CMV mismatched donor-recipient transplants 
2.3.3 Donor Exclusion Criteria 
Donors fulfilling the following criteria are ineligible for registration onto this study: 
1. All donors will be screened by hemoglobin electrophoresis; donors 
with a clinically significant hemoglobinopathy are ineligible. Sickle 
trait is acceptable. 
2.4 
Treatment Plan 
2.4.1 Indwelling central venous catheter 
Placement of a double lumen central venous catheter will be required for administration of IV 
medications and transfusion of blood products. 
2.4.2 Preparative regimen 
The preparative regimen described below and in Table 2.4.2 will be used for all patients enrolled 
and transplanted on the study. Any modifications to the preparative regimen must be reported to 
the BMT CTN DCC protocol coordinator for review and receive written approval by the Protocol 
Chairs/Officer prior to initiation of the preparative regimen. 
Any deviation from the protocol-specified regimen must be reported to the BMT CTN DCC 
protocol coordinator. 
 
 

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TABLE 2.4.2: PREPARATIVE AND TREATMENT REGIMEN 
Days –70 o –10 
Hydroxyurea 30 mg/kg po daily 
 
Hgb S fraction < 35% prior to administration of Thymoglobulin. If Hbg S > 
35%, automated exchange transfusion (RBC apheresis) is the preferred 
strategy to lower Hgb S with a goal of 20% and the maximum Hgb S fraction 
not to exceed 35%. 
Day –9*** 
Thymoglobulin 0.5 mg/kg IV with pre-meds 
Day –8*** 
Thymoglobulin 2 mg/kg IV qd with pre-meds 
Day –7*** 
Thymoglobulin 2 mg/kg IV qd with pre-meds 
Thiotepa 5 mg/kg IV q 12 h (10 mg/kg total) 
Days –6, –5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then Cyclophosphamide (CY) 
14.5 mg/kg IV over 1-2 hours* 
Days –4 o –2 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Day –1 
TBI 200 cGy with gonadal shielding** 
Day 0 
Non-T-cell depleted bone marrow 
Days +3, +4 
Cyclophosphamide 50 mg/kg IV 
Mesna 40 mg/kg IV* 
Day +5 
Begin sirolimus (section 2.4.5.1)**, mycophenolate mofetil (MMF) 15 mg/kg 
pot id with maximum daily dose 3 gm/d 
Day +35 
Discontinue MMF 
*Uroprophylaxis may be altered per institutional preference (see below) 
     **See Section 2.4.2.10 and section 4.4.6 regarding planned protocol change in TBI dose if safety monitoring guideline for 100-day 
graft failure is passed in the first 12 evaluable participants per stratum. 
***If using corticosteroids as premedication, discontinue before Day -1. 
The following are suggested dose adjustment formulas: 
2.4.2.1 
Recommended Ideal Body Weight Calculation for Children Age 5-17 Years: 
IBW = (Height (cm)2 x 1.65)/1000 
2.4.2.2 
Recommended Ideal Body Weight Calculation for Adults Age > 18 Years: 
IBW (females) = (Height (cm) ÷ 
2.54 – 60) x 2.3 kg + 45.5 kg IBW 
(males) = (Height (cm) ÷ 2.54 – 
60) x 2.3 kg + 50 kg 
2.4.2.3 
Adjusted Ideal Body Weight (AIBW) (all ages): AIBW = adjusted ideal body weight  
 
is estimated as follows: AIBW = IBW + [(0.25) x (ABW - IBW)] 
(ABW = actual body weight) 

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2.4.2.4 
Patients Receiving Iron Chelation Therapy before BMT 
Iron chelation therapy will be discontinued before commencing hydroxyurea on Day -70. Iron 
chelation therapy or a program of phlebotomy may be resumed after neutrophil and red cell 
recovery at the discretion of the transplant center. 
2.4.2.5 
Hydroxyurea 
Hydroxyurea (30 mg/kg/day) will be commenced as a single daily oral dose on Day -70 and 
continued through Day -10. Hydroxyurea will be adjusted to the ideal body weight (IBW) in 
children and adults weighing > 125% IBW. A CBC will be obtained weekly and the dose will be 
reduced if the ANC<1500 or platelet <100,000. HU will be discontinued on Day -10. 
2.4.2.6 
Thymoglobulin 
Thymoglobulin (rATG) will be infused through a 0.22 micron filter with pre-medications to 
include: Oral or intravenous (IV) acetaminophen and diphenhydramine. An anaphylaxis kit will 
be kept at bedside during Thymoglobulin administration. The dose will be 0.5 mg/kg IV on Day -
9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours. Solumedrol should be administered 
per institutional standard to prevent infusional toxicity. An intradermal skin test prior to dose of 
Thymoglobulin may be performed per institutional practice. 
2.4.2.7 
Thiotepa 
Thiotepa 5 mg/kg will be administered IV every 12 hours over 2 hours or per institutional 
guidelines on Day -7 (administer 2 doses to total 10 mg/kg). Thiotepa will be adjusted to the ideal 
body weight (IBW) in children weighing > 125% IBW. 
2.4.2.8 
Fludarabine 
Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days 
–6 through –2 for a total dose of 150 mg/m2. Fludarabine will be dosed according to the recipient’s 
actual body weight. Patients who have an estimated or measured creatinine clearance < 70 
mL/min/1.73 m2 are excluded from enrollment, thus there will be no adjustment in the fludarabine 
dose for renal insufficiency. 
2.4.2.9 
Pre-transplantation Cyclophosphamide 
Hydration prior to cyclophosphamide may be given according to institutional standards. A 
recommended approach is as follows: Patients are instructed to increase fluids overnight before 
cyclophosphamide administration. Hydration with normal saline at 3 mL/kg/hr IV will be started 
2 hours prior to cyclophosphamide, then the rate will be reduced to 2 mL/kg/hr for 1 hour pre- 
cyclophosphamide and continued at 2 mL/kg/hr for 8 hours post-cyclophosphamide. 
Mesna may be administered per institutional standards. Mesna dose will be based on the 
cyclophosphamide dose being given. The total daily dose of mesna must be equal to 80% of the 
total daily dose of Cy. A suggested approach is as follows: divided doses IV 30 min pre-Cy and at 
3, 6, and 8 hours post-Cy. 
Cyclophosphamide 14.5 mg/kg/day will be administered as a 1-2 hour intravenous infusion on 

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Days –6 and –5. Cyclophosphamide will be dosed according to the recipient’s ideal body weight 
(IBW), unless the patient weighs more than 125% of IBW, in which case the drug will be dosed 
according to the adjusted IBW (AIBW; see Section 2.4.2.3 for formulas). Uroprotection can be 
administered according to institutional guidelines. Mesna is recommended to accompany pre- 
transplantation Cy but is not required. 
Cyclophosphamide will be dosed according to the recipient’s ideal body weight (IBW), unless 
actual body weight is less than IBW, in which case use actual body weight. If the patient weighs 
greater than125% of IBW, cyclophosphamide will be dosed according to the adjusted IBW 
(AIBW). 
2.4.2.10 
Total Body Irradiation 
200 cGy TBI will be administered in a single fraction on Day –1. Radiation sources and dose rates 
will be defined by the institution. TBI may be delivered from either linear accelerator or Cobalt 
sources. Graft may be infused on the same day as TBI administration as long as there is 4-6 hours 
between administration of TBI and infusion of bone marrow. 
If graft failure rate exceeds that specified in the 100-day safety monitoring guideline for graft 
rejection and notice is provided to all centers by the DCC, then future participants will be 
administered 400 cGy TBI in a single fraction on Day -1. 
For either the 200cGy TBI or 400cGy TBI, gonadal shielding will be used in all male patients. 
Gonadal shielding will not be used in females. 
2.4.3 Bone marrow transplantation and graft information 
On Day 0, patients will receive unprocessed bone marrow unless there is a major ABO 
incompatibility, in which case red blood cells will be depleted from the donor marrow using 
institutional practices. Institutional practices will determine if there will be processing for minor 
ABO incompatibilities. Donor bone marrow will be harvested to minimum yield of 2.5 x 108 with 
a target yield of 4 x 108 nucleated cells per kilogram of recipient’s IBW or actual BW (ABW), 
whichever BW is lower. We recommend taking no more than 10 mL per aspirate. In addition to 
calculating the total nucleated cell dose /kg, flow cytometry will need to be done on the sample to 
determine the content of CD34+cells. The use of cryopreserved marrow is not permitted. 
2.4.4 Post-Transplantation cyclophosphamide 
Cyclophosphamide 50mg/kg will be given as an IV infusion over 1-2 hours (depending on volume) 
on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post- 
transplant (24 hours after Day 3 cyclophosphamide). 
Corticosteroids may not be used as anti-emetic agent and should not be administered until 24 hours 
after the completion of post-transplant cyclophosphamide unless used for adrenal support or during 
a medical emergency (e.g., treatment of anaphylaxis). 
 
2.4.5 GVHD prophylaxis 
On Day 5, patients will begin prophylaxis with Sirolimus and Mycophenolate Mofetil (MMF). 

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2.4.5.1 Sirolimus 
Sirolimus for participants 18.00 years old: A one-time sirolimus loading dose, 6 mg PO, is 
given on Day 5, at least 24 hours after Cyclophosphamide completion. Sirolimus is then continued 
at a maintenance dose (start 2 mg PO QD), with dose adjustments to maintain a trough of 5 – 15 
ng/mL as measured by HPLC or immunoassay. There is no planned taper. Sirolimus prophylaxis 
is discontinued after the last dose on Day 365 or may be continued if there is GVHD. Sirolimus 
troughs should be measured weekly at a minimum. 
Sirolimus for participants < 18.00 years old: Sirolimus dosing is based on actual body weight; 
however, an adjusted body weight may be used if the actual weight is > 50% greater than IBW. A 
one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day 
5, at least 24 hours after Cyclophosphamide completion. Sirolimus is then continued at a 
maintenance dose (start 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to 
maintain a trough of 3 – 12 ng/mL as measured by HPLC or immunoassay. There is no planned 
taper. Sirolimus prophylaxis is discontinued after the last dose on Day 365 or may be continued if 
there is GVHD. 
2.4.5.2 Mycophenolate Mofetil 
MMF will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) with the 
maximum total daily dose not to exceed 3 grams (1 g PO TID). MMF prophylaxis will begin on 
Day 5 post-transplant and will be discontinued after the last dose on Day 35 or may be continued 
if active GVHD is present. 
2.4.6 Encephaloduroarteriosynangiosis (EDAS) 
If the local team elects Encephaloduroarteriosynangiosis (EDAS) to be performed prior to 
transplant as adjunctive therapy for secondary stroke prevention, then it is strongly recommended 
to delay the initiation of pre-transplant hydroxyurea treatment at least 6 months due to the 
minimum time expected for the revascularization to benefit from the engrafted vessel. Since 
hydroxyurea is a myelosuppressive agent, treatment with hydroxyurea may impede healing of the 
new engrafted vessels after the revascularization procedure. 
2.4.7 Additional Supportive Care 
Ursodiol should begin at time of hydroxyurea conditioning (Day -70) in all patients. Supportive 
care for VOD will follow institutional practice. There is a significant risk of intracranial 
hemorrhage after HCT in patients with SCD and stroke. For this reason and because of inconsistent 
efficacy, heparin and low molecular weight heparin (LMWH) are not permitted for VOD/SOS 
prophylaxis. 48,49 
 

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2.4.8 Infection Prophylaxis 
Participants will receive infection prophylaxis and nutritional support according to institutional 
guidelines. Infection prophylaxis should include, but is not limited to, agents or strategies (e.g., 
PCR screening and preemptive therapy) to reduce the risk of bacterial, herpes simplex, CMV, 
HHV-6, EBV, Pneumocystis jiroveci, and fungal infections. Penicillin prophylaxis or its 
equivalent should be administered per institutional standard due to asplenism that occurs in sickle 
cell disease. 
2.4.9 EBV Monitoring 
It is recommended that patients will have EBV DNA quantitative PCR testing on peripheral blood 
every two weeks from Day 14 to Day 100. In the event of persistent EBV virema or 
signs/symptoms consistent with EBV-related post-transplant lymphoproliferative disease (PTLD, 
adenopathy, fever, etc.) therapy with rituximab is recommended per local institutional standard. 
2.4.10 Transfusion Support 
The hemoglobin level must be maintained between 9.0 and 11.0 g/dL and platelet count 
50,000/mm3 after transplantation until transfusion independent to minimize the risk of 
neurological adverse events. Irradiated blood products should be administered universally, and 
Cytomegalovirus (CMV) negative or leuko-filtered blood products are recommended for CMV 
sero-negative recipients. 
2.4.11 Indwelling Central Venous Catheter 
Placement of a double or triple lumen central venous catheter will be required for the 
transplantation procedure and administration of IV medications and transfusion of blood products. 
This catheter may be removed and replaced as clinically indicated. However, the graft MUST be 
infused through a central line. 
2.4.12 Prevention of post-BMT Neurological Events and Posterior Reversible Encephalopathy 
Syndrome (PRES) 
Prophylaxis against seizures is mandatory in all recipients and should be commenced at the start 
of thymoglobulin conditioning. Suitable drugs for prophylaxis should be administered according 
to institution guidelines. Seizure prophylaxis should be continued for 365 days after transplant or 
until sirolimus is discontinued, whichever is later. Serum magnesium level should be maintained 
> 1.5 mg/dL during the period of treatment to reduce the risk of seizures. 
Hypertension should be strictly controlled to prevent central nervous system (CNS) toxicity. Blood 
pressure should be monitored closely and both systolic and diastolic hypertension should be treated 
promptly to maintain blood pressure at the patient’s pre-transplant baseline. Explicit orders must 
be written to intervene if systolic or diastolic blood pressure exceeds 10% over baseline. Detailed 
guidelines for management of Posterior Reversible Encephalopathy Syndrome (PRES) are 
included in Appendix I. 
 

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2.4.13 
Pre-infusion Medication and Hydration Regimen 
The pre-medication and hydration regimen prior to blood products transfusion and transplantation 
will be given following institutional guidelines. 
2.4.14 
Contraception Practices 
Females of child bearing potential (to include all female participants > 10 years of age, unless 
postmenopausal for a minimum of 1 year before the screening visit or surgically sterilized), must 
agree to practice two (2) effective methods of contraception at the same time, or agree to practice 
true abstinence when this is in line with the preferred and usual lifestyle of the subject, from the 
time of signing of informed consent through 12 months post-transplant. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
Male subjects (even if surgically sterilized) must agree to one of the following: practice effective 
barrier contraception, or practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject, from the time of signing of informed consent through 12 months post- 
transplant. Periodic abstinence and withdrawal are not acceptable methods of contraception. 
2.4.15 
Management of Slow Engraftment and Graft Failure 
Slow engraftment or graft failure shall be managed according to institutional practices and may 
include the administration of colony stimulating factors and prophylactic antibiotics. 
Graft failure following BMT in patients with sickle cell disease is usually associated with 
autologous reconstitution of the bone marrow with host hematopoiesis. It is associated with a 
steady decline in donor chimerism, increasing representation of hemoglobin S (in the absence of 
ongoing RBC transfusion therapy) and clinical manifestations of sickle cell disease. A second 
transplant or donor cellular infusion should not be considered unless the patient has < 5% donor 
chimerism. 
2.5 
Study Drug Information 
2.5.1 Fludarabine 
Fludarabine phosphate is commercially available. 
Fludarabine phosphate is purine antimetabolite that, after administration, undergoes rapid 
conversion in plasma to the nucleoside 2-fluoro ara-A (F-araA). F-araA subsequently enters cells 
where it is phosphorylated to F-araATP and the monophosphate F-araAMP. Once activated, F-
araATP inhibits DNA polymerase and ribonucleotide reductase. The monophosphate F-araAMP, 
once incorporated into DNA, is an effective DNA chain terminator. 
Fludarabine monophosphate, 50 mg/vial, is reconstituted with 2 ml of sterile water, resulting in a 
25mg/ml solution. The desired dose is further diluted to concentrations of 0.04-1 mg/ml in normal 
saline or 5% dextrose (50-100ml) for injection and will be administered by IV infusion over 30 
minutes or longer. 

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Following IV administration, the drug is metabolized to 2-F-araA and widely distributed in tissues. 
2-F-araA is excreted primarily in urine and has a terminal elimination half-life of 7 to 12 hours. 
Clinical toxicities of fludarabine monophosphate include myelosuppression, primarily 
lymphopenia and granulocytopenia, alopecia, rash, dermatitis, nausea, vomiting, anorexia, 
stomatitis, diarrhea, somnolence, fatigue, peripheral neuropathy, mental status changes, cortical 
blindness, hepatocellular toxicity with elevation in serum transaminase, and interstitial 
pneumonitis. These effects are reversible when the drug is discontinued. 
Fludarabine may cause dose-related CNS toxicity, including the posterior reversible 
encephalopathy syndrome (PRES), acute toxic leukoencephalopathy (ATL) and other 
leukoencephalopathy conditions (OLE). PRES is usually reversible with supportive care. Typical 
clinical features include seizures, persistent headache, and vision changes, accompanied by 
variable mental status alterations. Patients with ATL can present with cognitive dysfunction, 
decreased levels of consciousness, and vision changes. Other leukoencephalopathy (OLE) includes 
patients who behave similar to the ATL group, but with less prominent deep white matter changes 
on MRI. Both ATL and OLE are less likely to be reversible50. 
Fludarabine will be administered by IV infusion over 30 minutes in a dose of 30 mg/m2/day on 
Days -6 to -2. 
2.5.2 Cyclophosphamide (Cytoxan®) 
Cyclophosphamide is commercially available. 
Cyclophosphamide is an alkylating agent which prevents cell division primarily by cross-linking 
DNA strands. Cyclophosphamide is cell cycle non-specific. 
Cyclophosphamide for injection is available in 2000 mg vials which are reconstituted with 100 ml 
sterile water for injection. The concentration of the reconstituted product is 20 mg/ml. The 
calculated dose will be diluted further in 250-500 ml of Dextrose 5% in water. Each dose will be 
infused over 1-2 hr (depending on the total volume). 
Clinical toxicities of cyclophosphamide include alopecia, nausea and vomiting, headache and 
dizziness, 
hemorrhagic 
cystitis, 
cardiotoxicity, 
immunosuppression, 
myelosuppression, 
pulmonary fibrosis, increased hepatic enzymes and syndrome of inappropriate anti-diuretic 
hormone (SIADH). 
2.5.3 Mesna (sodium-2-mercapto ethane sulphonate) 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the 
oxasophosphorines (cyclophosphamide and ifosphamide). 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. 
Mesna is available in 200 mg, 400 mg and 1000 mg vials containing a 100 mg/ml solution. Each 
dose of mesna will be diluted further in 50 ml of normal saline to be infused over 15 minutes (or 

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as per institutional standards). Mesna dose will be based on the cyclophosphamide dose being 
given. The total daily dose of mesna is equal to 80% of the total daily dose of cyclophosphamide. 
At the doses used for uroprotection mesna is virtually non-toxic. However, adverse effects which 
may be attributable to mesna include nausea and vomiting, diarrhea, abdominal pain, altered taste, 
rash, urticaria, headache, joint or limb pain, hypotension and fatigue. 
2.5.4 Thiotepa 
Antineoplastic and alkylating agent, that reacts with DNA phosphate groups to produce cross- 
linking of DNA strands leading to inhibition of DNA, RNA, and protein synthesis; mechanism of 
action has not been explored as thoroughly as the other alkylating agents, it is presumed that the 
aziridine rings open and react as nitrogen mustard; reactivity is enhanced at a lower pH. No dosage 
adjustment provided in manufacturer’s labeling. For renal or hepatic impairment, caution and dose 
adjustment may be required. Extensively hepatic; major metabolite (active): TEPA. Half-life 
elimination: Terminal (dose-dependent clearance): ~2 hours; excretion: Urine (as metabolites and 
unchanged drug) 
Solution Reconstituted, Injection: Generic: 15 mg (1 ea); I.V.: Administer as a rapid injection. 
Infusion times may be longer for high-dose (unlabeled use) treatment. 
The most common adverse reactions include: Fertility effects: May be mutagenic and teratogenic; 
Myelosuppression, secondary malignancies: Potentially carcinogenic; myelodysplastic syndrome 
and acute myeloid leukemia (AML) have been reported; Use with caution in participants with 
hepatic and renal impairment; dosage reduction recommended. It can cause significant skin 
toxicity due to lipid solubility, thus bathing three times daily during its administration through 24 
hours after the last dose is strongly recommended. 
2.5.5 Sirolimus (rapamycin, Rapamune®) 
Sirolimus is an immunosuppressant that inhibits cytokine-stimulated T-cell activation and 
proliferation, and also inhibits antibody formation. The mean bioavailability of sirolimus after 
administration of the tablet is ~27% higher than the oral solution. Sirolimus oral tablets are not 
bioequivalent to the oral solution. Clinical equivalence has been demonstrated at the 2mg dose 
level; however, it is not known if higher doses are clinically equivalent on an mg to mg basis. 
2.5.5.1 Sirolimus oral solution 
Sirolimus oral solution (1 mg/mL) should be stored protected from light and refrigerated at 2°C to 
8°C (36°F to 46°F). For dilution, the appropriate dose should be measured using an amber oral 
syringe, then added to a glass or plastic container that holds at least 60 mL. Before taking the dose, 
it should be diluted with water or orange juice then taken immediately; it should not be diluted 
with grapefruit juice. The syringe should be discarded after one use. Sirolimus oral solution 
provided in bottles may develop a slight haze when refrigerated, which does not affect product 
quality; allow the product to stand at room temperature and shake gently until the haze disappears. 
 

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2.5.5.2 Sirolimus tablets 
Sirolimus tablets are available in 1mg and 2mg tablets that cannot be crushed or broken. Sirolimus 
tablets should be stored at 20° to 25° C (68°–77°F), protected from light. The most common 
adverse reactions of sirolimus are peripheral edema, hypertriglyceridemia, hypercholesterolemia, 
hypertension, increased creatinine, constipation, abdominal pain, nausea, diarrhea, headache, 
fever, urinary tract infection, anemia, thrombocytopenia, arthralgia, pain. Adverse reactions that 
have resulted in rates of sirolimus discontinuation >5% were increased creatinine, 
hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP) / thrombotic 
microangiopathy (TMA). Sirolimus toxicities are summarized: 
2.5.6 Summary of Sirolimus Toxicities 
 
Common (>20%) 
Occasional (5-20%) 
Rare (<5%) 
Immediate (within 
1-2 days) 
Headache (L), 
hypertension (L), 
immunosuppressio
n (L), fever, 
nausea, diarrhea, 
constipation 
Chest pain, insomnia, 
dyspepsia, vomiting, dyspnea 
Hypotension, 
asthma, cough, flu-
like syndrome, 
tachycardia, 
anorexia, 
hypersensitivity 
reactions 
Prompt (within 
2-3 weeks) 
Tremor (L), renal 
dysfunction, pain 
(abdominal, back, 
arthralgias), 
hyperlipidemia c 
(hypercholesterolemi
a, 
hypertriglyceridemia
), hyperglycemia, 
edema including 
peripheral edema, 
anemia 
Elevated LFT’s (with elevated 
sirolimus levels) a, stomatitis, 
infections (including UTI, URI), 
mild thrombocytopenia, 
leukopenia, electrolyte 
disturbances (hyper/hypokalemia 
[L], hypophosphatemia, 
hypomagnesemia [L]), rash, hives, 
pruritus, delayed wound healing 
or dehiscence (L), proteinuria, 
TTP/HUS/TMA b especially with 
concurrent CNI 
Pleural and 
pericardial effusions, 
pulmonary toxicity 
(non-infectious 
pneumonitis, BOOP, 
pulmonary fibrosis), 
thrombosis, myalgias 
Delayed (any time later 
during therapy, 
excluding above 
conditions) 
Acne 
 
Kidney 
disease, 
CHF, 
ascites, 
arthrosis, 
bone 
necrosis, 
osteoporosis 
Late (any time after 
completion of 
treatment) 
 
 
Lymphoproliferati
ve disorders, skin 
malignancies 
Unknown frequency 
and timing 
Embryo/fetotoxic; unknown whether excreted in human milk 
(L): Toxicity may also occur later. 
a Significant transaminitis, generally without sequelae, may occur. Sirolimus has been associated with higher rates of 
veno-occlusive disease after myeloablative conditioning. 

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b Incidence 3% to < 20% in a trial of kidney transplantation. In allogeneic BMT, increase in TMA from 4.2% with 
tacrolimus or cyclosporine alone, versus 10.8% with tacrolimus/sirolimus combination was noted.66 
c Lipid-lowering agent may be required; consider if fasting serum triglycerides are > 2.5 x ULN and recommend 
starting if > 800 mg/dL. 
 
 
Sirolimus is associated with a high risk for VOD after myeloablative conditioning, but this risk is 
lower in patients after RIC HCT, such as the regimen that will be utilized in this study. There is a 
still a possibility of VOD/SOS after RIC conditioning, however as illustrated in a sub-group of 
patients treated by second RIC HCT after a first HCT51. 
Drug interactions: Sirolimus is known to be a substrate for both cytochrome CYP3A4 and 
P-glycoprotein. Agents that may increase sirolimus levels include tri-azole drugs (especially 
voriconazole and posaconazole*), amiodarone, calcium channel blockers, macrolide antibiotics 
(but 
not 
azithromycin), 
micafungin, 
gastrointestinal 
prokinetic 
agents 
(cisapride, 
metoclopramide), cimetidine, cyclosporine, grapefruit juice, and HIV protease inhibitors. Agents 
that may decrease sirolimus levels include anticonvulsants (carbamezepine, phenobarbital, 
phenytoin), rifamycins, St. John’s Wort. 
Dose adjustments: The sirolimus dose is adjusted to maintain a serum trough level of 5 –15 ng/mL. 
Changes in levels due to altered bioavailability should be apparent within 24-48 hours. For 
sirolimus without CNI as in this study, a 20-25% reduction of sirolimus dose is recommended for 
trough levels >15 – 18 ng/mL, and a 20-25% increase is recommended for trough levels < 5 ng/mL. 
Renal failure does not affect the excretion of sirolimus. Excretion is reduced in liver failure; 
impaired hepatic function should prompt consideration of reduction in sirolimus maintenance 
doses, but no dose adjustment of the loading dose is necessary. 
Due to extreme interactions with voriconazole and posaconazole, these drugs are relatively 
contraindicated during sirolimus therapy. Sirolimus dose is to be reduced by 90% when 
voriconazole is initiated and should also be significantly reduced with posaconazole. 
2.5.7 Mycophenolate Mofetil (Cellcept®) 
Mycophenolate Mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid 
(MPA). This active metabolite is a noncompetitive, reversible inhibitor of inosine monophosphate 
dehydrogenase (IMPDH). There are no pharmacokinetic interactions with ganciclovir, 
cotrimoxazole, oral contraceptives and cyclosporine. 
Side effect profiles include diarrhea, leukopenia, sepsis, allergic reactions, and vomiting. There is 
also an increase in certain types of infection mainly from the herpes virus family (CMV, HSV & 
VZV) and Candida. 
2.5.8 Rabbit antithymocyte globulin (rATG) 
Thymoglobulin® [Anti-thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma immune 
globulin, obtained by immunization of rabbits with human thymocytes. This immunosuppressive 
product contains cytotoxic antibodies directed against antigens expressed on human T- 
lymphocytes. This drug is commonly used to treat graft rejection in kidney transplantation. It is 
also commonly used in bone marrow transplantation as part of the conditioning regimen to avoid 

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graft failure and to prevent graft-versus-host disease. 
Thymoglobulin is a sterile, freeze-dried product for intravenous administration after reconstitution 
with Sterile Water for Injection, USP (SWFI). Each 10 mL vial contains 25 mg anti-thymocyte 
globulin (rabbit) as well as 50 mg glycine, 50 mg mannitol, and 10 mg sodium chloride. After 
reconstitution with 5 mL SWFI, each vial of reconstituted product contains approximately 5 
mg/mL of Thymoglobulin, of which >90% is rabbit gamma immune globulin (IgG). The 
reconstituted solution has a pH of 7.0 ± 0.4. Human red blood cells are used in the manufacturing 
process to deplete cross-reactive antibodies to non-T-cell antigens. The manufacturing process is 
validated to remove or inactivate potential exogenous viruses. All human red blood cells are from 
US registered or FDA licensed blood banks. A viral inactivation step (pasteurization, i.e., heat 
treatment of active ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is 
released following potency testing (lymphocytotoxicity and E-rosette inhibition assays), and cross- 
reactive antibody testing (hemagglutination, platelet agglutination, anti-human serum protein 
antibody, antiglomerular.) 
Adverse side effects include immunodeficiency, infusion related toxicities such as hypertension, 
chills, rigors, tachycardia, capillary leak syndrome, hyperglycemia, cytopenias, transient hepatitis, 
anaphylaxis, serum sickness, myalgias, sensory changes including hearing loss, headaches, renal 
toxicity, dyspnea and bronchial spasm, fevers. The drug is potentially teratogenic and is unknown 
if it can be passed to children in breastfeeding. 
rATG–rabbit must be infused through a 0.22 micro filter with premedication per institutional 
standard. If corticosteroids are used, please discontinue prior to Day -1. 
Note: Keep anaphylaxis kit at bedside during Thymoglobulin administration. 
2.5.9 Hydroxyurea 
Administration can cause anemia, neutropenia, thrombocytopenia, nausea, vomiting, mouth sores, 
rash, painful and difficult urination, kidney damage, headache, dizziness, jaundice, hallucinations, 
seizures, diarrhea, temporarily increased levels of liver enzymes, darkening of the skin, and nail 
changes. 
2.5.10 Corticosteroids 
Corticosteroids may not be used as an anti-emetic agent and should not be administered until 24 
hours after the completion of post-transplantation cyclophosphamide, unless used for adrenal 
support or during a medical emergency (e.g. treatment of anaphylaxis). Corticosteroids may be 
used as a pre-medication during Thymoglobulin infusion and discontinued immediately thereafter. 
2.5.11 Total Body Irradiation 
Total body irradiation will be administered (200 cGy). This dose is a fraction of the irradiation 
delivered in typical myeloablative conditioning regimens, thus modulated toxicity is anticipated. 
Nonetheless, irradiation can cause short-term and long-term toxicities, particularly in children. The 
long-term toxicities include a risk of malignancy secondary to the exposure and a risk of infertility. 
 

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x Testicular shielding will be administered to all male patients. 
The testis is one of the most radiosensitive tissues, and even low doses of radiation can 
cause impairment of function. In adult men, doses as low as 10 cGy can cause damage to 
spermatogonia52. At single fraction doses of 200 to 300 cGy there is overt damage to 
spermatocytes in adult men and return to pre-irradiation sperm concentrations and 
germinal cell numbers may take up to 30 months53. Fractionated doses are more toxic to 
spermatogenesis, and complete sterilization may occur if the fractionated dose exceeds 
100 – 200 cGy. However, in the pre-pubertal state, the impact of radiotherapy is 
mitigated. In one study of 12 pre-pubertal boys who received 2400 cGy testicular 
irradiation to treat ALL, it was observed that testosterone levels were normal in all 12 
and basal LH was normal in 9 and elevated in 354. Nonetheless, to preserve fertility and 
Leydig cell function in post- pubertal males, we propose to administer testicular 
shielding to all males during the single fraction of TBI. This shielding will have no 
impact on the immunosuppressive effect of the radiotherapy. 
x There will be no gonadal shielding in female patients. 
The effects of radiotherapy on ovarian function and fertility are dose- and age-
dependent. However, ovarian doses of less than 400 cGy do not result in permanent 
ovarian dysfunction and the calculated LD50 of the human oocyte dose is approximately 
400 cGy55 56 57. Thus, ovarian shielding to preserve ovarian function will not be 
necessary for the dose of TBI administered in this investigation; moreover, shielding in 
this setting could reduce the immunosuppressive effects of TBI if intra-abdominal 
lymph nodes were inadvertently shielded. 

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CHAPTER 3 
3 STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint is event-free survival (EFS) at 2 years post-transplant estimated within each 
stratum. EFS is defined as survival without a qualifying event. Primary graft rejection, secondary 
graft rejection, second infusion of hematopoietic cells or death will count as events for this 
endpoint. A secondary endpoint will assess EFS at 1 year post-transplant. 
3.2 
Secondary Endpoints 
All endpoints are stratum-specific. 
3.2.1 Overall Survival 
Overall survival will be described post-enrollment and 1 and 2 years post-HaploBMT. Death from 
any cause will be the event and patients will be censored at the date of last contact or two years 
post-HaploBMT whichever comes first. Start time will either be the date of enrollment or 
HaploBMT for the two objectives. 
3.2.2 Event Free Survival 
Event-free survival is defined as survival without a qualifying event. 
3.2.3 Engraftment and Graft Rejection 
3.2.3.1 Engraftment 
Engraftment is defined as having greater than or equal to 5% donor cells post-transplant, from any 
molecular chimerism assessment (e.g., unsorted, myeloid, or T-cell) on a peripheral blood or bone 
marrow aspirate sample. 
3.2.3.2 Primary Graft Failure 
Primary graft failure is defined as never achieving  5% donor whole blood or myeloid chimerism 
(myeloid is preferable) assessed by bone marrow or peripheral blood chimerism assays by day +42 
post-transplant. Second infusion of stem cells is also considered indicative of primary graft failure 
by day +42 post-transplant. 
3.2.3.3 Secondary Graft Failure 
Secondary graft failure is defined as < 5% donor whole blood or myeloid chimerism 
(myeloid is preferable) in peripheral blood or bone marrow beyond day +42 post-
transplant in patients with prior documentation of hematopoietic recovery with >5% 
donor cells by day +42 post-transplant. Second infusion of stem cells is also considered 
indicative of secondary graft failure. 

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3.2.3.4 Second Transplant or Infusion of Hematopoietic Cells 
Infusion of a second stem cell product will be considered graft rejection, and counted 
toward primary or, depending on timing of the second infusion, secondary graft 
rejection. 
3.2.4 Lineage Specific Chimerism following HCT for SCD 
Current methods for measuring hematopoietic chimerism are based on DNA polymorphisms that 
distinguish recipient from donor. Pyrosequencing of lineage-specific mRNA directly measures 
functional reconstitution of donor cells and provides valuable information that can affect clinical 
decisions in patients with nonmalignant diseases following allogeneic transplant. Peripheral blood 
samples on post-transplant days 28, 42, 100 and 180 days, 365 and 730 will be assayed into 
CD3+CD56- (T-lymphocytes) and CD15+, CD33+ or CD45+ (granulocytes) per institutional 
standard. Genomic DNA extracted from peripheral blood will be analyzed for variable number of 
tandem repeats (VNTR) to detect donor engraftment in mononuclear cells and CD3+ lymphocytes. 
Percent donor chimerism will be analyzed per institutional standard. 
3.2.5 Transplant-related Complications 
3.2.5.1 Grade II-IV and Grade III-IV Acute GVHD 
Incidence of grade II-IV and III-IV acute GVHD will be graded according to the NIH consensus 
criteria (refer to Appendix D). 
3.2.5.2 Chronic GVHD 
Incidence and severity of chronic GVHD will be scored according to the NIH consensus criteria. 
(refer to Appendix E). 
3.2.5.3 Neutrophil Recovery 
Time to neutrophil recovery is defined as the first of 3 measurements on different days when the 
SDWLHQWKDVDQDEVROXWHQHXWURSKLOFRXQWRIȝ/DIWHUFRQGLWLRQLQJ 
3.2.5.4 Platelet Recovery 
Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different 
days that WKHSDWLHQWKDVDFKLHYHGDSODWHOHWFRXQW!ȝ/$1'GLGQRWUHFHLYHDSODWHOHW
transfusion in the previous 7 days. The exception is the case in which a subject is given a platelet 
transfusion specifically to achieve a platelet threshold to allow an elective invasive procedure, such 
as a central catheter removal. 
3.2.5.5 Veno-occlusive Disease 
Veno-occlusive disease (VOD) will be diagnosed and defined in accordance with either the 
modified Seattle or Baltimore criteria as outlined in Appendix J. 
 

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3.2.5.6 Idiopathic Pneumonia Syndrome (IPS) 
IPS will be defined evidence of widespread alveolar injury and in which infectious etiologies and 
cardiac dysfunction, acute renal failure, or iatrogenic fluid overload have been excluded.58 Refer 
to Appendix K for complete IPS criteria. Diagnosis via bronchoscopy is strongly encouraged. 
3.2.5.7 CNS Toxicity 
CNS toxicity will be defined as seizures, CNS hemorrhage, or Posterior reversible 
leukoencephalopathy syndrome (PRES or RPLS). PRES is defined as an increased diffusion 
coefficient in areas of T2 hyperintensities on diffusion-weighted imaging in the context of clinical 
symptoms or physical findings including headache, seizures, visual disturbances, and altered level 
of consciousness. Please refer to Appendix I for additional details and recommended guidelines 
regarding PRES prophylaxis and management 
3.3 
Infection 
Significant infections will be recorded including but not limited to bacterial or fungal sepsis, CMV 
reactivation with/without clinical disease, adenovirus infection, EBV PTLD, or other significant 
viral reactivations or community-acquired viral mold infections and invasive fungal infections. 
3.4 
Sickle Vasculopathy 
Evaluate if sickle vasculopathy is halted by successful transplantation as determined by comparing 
brain MRI pre- and 2 years post-haploBMT. Cerebral MRI is required for all pediatric patients to 
assess progression of CNS disease. For adults with where the indication for the transplant is a 
stroke, cerebral MRI is required after transplant to assess progression of CNS disease. 
3.5 
Disease Recurrence 
Disease recurrence is defined as the return of sickle erythropoiesis (in the absence of RBC 
transfusion, Hb S level > 70%), or primary or secondary graft rejection, as defined above, or second 
infusion of hematopoietic cells. 
3.6 
Patient-reported HRQoL Outcomes including Pain and Fatigue Domains in the Adult  
 
Stratum 
Using Patient Reported Outcome Measurement Information System (PROMIS) modules as the 
standardized assessment tool, patient reported outcomes in two specific quality of life domains, 
pain and fatigue, will be obtained from patients in the adult stratum at baseline (prior to the 
initiation of hydroxyurea), 1 year and 2 years post-transplant. Only English- and Spanish-speaking 
adult stratum patients are eligible to participate in the HRQoL component of this trial. 
3.7 
Pain Intensity 
Change in pain intensity between the baseline (prior to the initiation of hydroxyurea), one-year, 
and two-year assessments for English-speaking patients  15.00 years of age at time of enrollment. 

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Based on estimates of daily pain in adults with SCD59, we anticipate that patients will report pain 
in pain diaries with a mean pain intensity of 3.9 on a scale of 10 at baseline. We anticipate that 
adult patients will demonstrate a clinically significant decline in mean pain intensity to a level of 
1.3 units on a scale of 10 two years later. While our endpoint is the change between the baseline 
and two-year assessments, we will also examine pain at one year, in order to better understand the 
trajectory of changes during the two year follow up period. 
3.8 
Disease-related Complications 
3.8.1 Stroke 
An overt stroke is defined as a focal neurologic event and neurologic deficit lasting more than 24 
hours with neuroimaging changes. Patients with new MRI lesions and ongoing neurologic injury 
to the brain that does not result in focal motor impairment are referred to as having silent cerebral 
infarcts. These lesions are defined as a MRI signal abnormality measuring at least 3 mm visible 
on two views on T-2 weighted images. Both forms of neurologic injury that develop as a new event 
post-transplant will be considered a disease related complication. 
3.8.2 Occurrence of Sickle Related Events 
In addition to stroke as outlined above, participants will be followed for the entire 2 year duration 
of their time on study for the recurrence of SCD related complications. These SCD related 
complications are henceforth referred to as SCD events of special interest (SCD-EOSI). For all 
participants, the following specific, SCD related events are expected events of special interest 
(SCD-EOSI): 
x pulmonary hypertension 
x significant cerebrovascular events, including: 
o stroke 
o transient ischemic attack 
o seizure 
x renal function compromise, including: 
o proteinuria 
o LQFUHDVHGFUHDWLQLQHJUDGHVSHU&7&$(YHUVLRQ 4.0 
x avascular necrosis of the hip or shoulder 
x leg ulcers 
x acute chest syndrome (ACS) requiring hospitalization 
x painful vaso-occlusive crises (VOC) requiring hospitalization or parenteral 
opioid drugs in the outpatient setting (self-reported events without clinical 
documentation should not be included) 
While these events do not require expedited reporting via completion of the Adverse Events forms, 
each occurrence of any SCD event of special interest (SCD-EOSI) must be reported on the SCD- 

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EOSI Form at each regularly scheduled follow up interval. A single event occurrence is defined as 
a new onset of any of the above listed SCD-EOSIs after screening evaluations are completed. A 
single occurrence resolves once the SCD-EOSI returns to the participant’s baseline. Therefore, 
multiple occurrences of the same or several SCD-EOSIs may be reported in one reporting interval. 
The completion of the SCD-EOSI Form is required and further detailed in the Data Management 
Handbook. 
3.9 
Lung function (PFTs) 
A growing body of evidence indicates the pulmonary toxicities associated with SCD are 
progressive in nature. A complete set of pulmonary function tests (PFTs) will be obtained at 
baseline (prior to the initiation of hydroxyurea), 1 year and 2 years post-transplant. In addition to 
assessing changes in FEV1 at 1 and 2 years post BMT as compared with baseline, we will also 
assess the proportion of participants in whom evidence of restrictive lung disease is found. For the 
purposes of this protocol, restrictive lung disease is defined as TLC below the 5th percentile 
adjusted for age, gender, race and height. In the interest of good clinical practice, PFTs should be 
obtained more frequently if clinically indicated, in the setting of cGVHD and/or in accordance 
with institutional standard of care mandates. A 6 minute walk test should accompany any 
significant decrease (>15% drop in predicted value of FEV1 or FEV1/FVC to determine if 
alternation in PFTs is associated with significant DOE). 
3.10 
TRJV (Cardiac Function) 
Tricuspid regurgitant jet velocity (TRJV) is a marker for the severity and progression of SCD. 
Changes in TRJV from baseline (prior to the initiation of hydroxyurea) to 1 year and 2 years post- 
transplant will be measured. 
3.11 
6-minute Walk Distance (6MWD) 
The 6MWD, a common assessment tool utilized in this disease population, will be administered at 
baseline (prior to the initiation of hydroxyurea), 1 year and 2 years post-transplant, with all testing 
to be administered under standardized procedures and in the same clinical setting. This endpoint 
will measure absolute change from baseline, with increased distance identified as positive change. 
3.12 
Hematological Outcomes 
Hematological outcomes including Hgb, reticulocyte count, %HbS, LDH, bilirubin, and last date 
of red blood cell transfusion will be measured pre-transplant and on post-transplant days 28, 100 
and 180 days, 365 and 730. 
3.13 
Proportion of Participants Still on Immunosuppression 2 years after BMT 
Proportion of participants still receiving immunosuppressive therapy because of GVHD or concern 
about graft rejection will be determined. 

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CHAPTER 4 
4 PATIENT ENROLLMENT AND EVALUATION 
4.1 
Screening Procedures 
Prospective participants at participating institutions will be identified and recruited by the site 
investigator or their designee. The investigator or designee at the enrolling site will conduct a 
donor evaluation for prospective enrollees. If a suitable haploidentical donor is identified, written 
informed consent and assent for study enrollment review will be obtained and eligibility 
determined. 
The participating center will register the participant using the BMT CTN Advantage Electronic 
Data Capture (AdvantageEDC) System. An authorized user at the center will complete the initial 
screening by entering patient demographics, the Segment 0 registration (date of informed consent), 
and the HLA form. 
4.1.1 Participant Entry and Registration 
If the participant is determined to be eligible for enrollment, an authorized user at the center will 
complete the Segment A enrollment form (inclusion/exclusion criteria). The Segment A form must 
be completed no more than 30 days prior to initiation of the hydroxyurea conditioning regimen. 
The date of completion of the Segment A enrollment form is the date of study enrollment. The 
Segment A enrollment successful screen must be obtained prior to initiating the protocol-specified 
dose of hydroxyurea. 
4.1.2 Pain and Priapism Adjudication 
For only the pediatric stratum, the protocol chairs will review a completed questionnaire for 
potential participants referred for multiple pain episodes or multiple priapism episodes. In 
addition to the responses to the questionnaire, children meeting either of the two criteria (pain or 
priapism) will be considered eligible; 1) acute severe vaso-occlusive pain episodes requiring 
hospitalization and recalcitrant to maximum medical therapy and 2) recurrent priapism (episodes 
lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months) 
recalcitrant to medical treatment or unable to use hydroxyurea due to SCD phenotype. 
After the protocol chairs review the questionnaire responses and the two eligibility criteria, 
participants will be designated as eligible, not eligible, or not evaluable based on the available 
information. 
4.2 
Participant Assessments 
4.2.1 Follow-up Schedule 
The Follow-up Schedule for scheduled study visits is outlined in Table 4.2.1. A detailed 
description of each of the forms and the procedures required for forms completion and submission 
can be found in the Data Management Handbook and User’s Guide. 

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TABLE 4.2.1: FOLLOW-UP SCHEDULE 
 
Study Visit 
Target Day 
Pre-Enrollment 
Pre-Enrollment 
GD\VSULRUWR6HJPHQW$(QUROOPHQW$1'25GD\VSULRUWR
Segment A Enrollment as specified in section 4.2.2 
Pre-transplant 
Pre-HU 
Within 30 days Post Segment A Enrollment, 
Prior to start of Hydroxyurea 
Pre- 
Thymoglobulin 
GD\VSULRUWRstart of Thymoglobulin 
Post-transplant 
1 week 
7 r 3 days 
2 week 
14 r 3 days 
3 week 
21 r 3 days 
4 week 
28 r 3 days 
5 week 
35 r 3 days 
6 week 
42 r 3 days 
7 week 
49 r 3 days 
8 week 
56 r 3 days 
9 week 
63 r 3 days 
10 week 
70 r 3 days 
11 week 
77 r 3 days 
12 week 
84 r 3 days 
13 week 
91 r 3 days 
100 day 
100 r 3 days 
6 month 
180 r 28 days 
One year 
365 r 28 days 
Day 540 
540 ± 28 days 
Two years 
730 r 28 days 
4.2.2 Pre-enrollment Evaluations 
The following observations are required within the following time frames prior to transplant. 
4.2.2.1 Evaluations Required Prior to Enrollment 
The following evaluations are required  180 days prior to enrollment into Segment A unless 
otherwise noted below (considered standard of care evaluations for transplant patients). 
Observations prior to enrollment will be done according to institutional guidelines: 

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1. CBC with differential, reticulocyte count, serum creatinine, creatinine clearance, 
direct/conjugated bilirubin, alkaline phosphatase, ALT, and AST, serum ferritin, 
magnesium. 
2. Solid Phase Immunoassay for HLA antibody specificity testing to confirm absence of anti- 
donor HLA antibodies (see Section 2.2.2 for definition of a positive anti-donor HLA 
antibody; preferably  30 days before Segment A enrollment and must be < 100 days before 
Segment A enrollment). 
3. Baseline EKG. 
4. A 6-minute walk distance test. 
5. Baseline 2-D transthoracic echocardiography and/or MUGA for left ventricular ejection 
fraction (LVEF), left ventricular shortening fraction, and presence or absence of tricuspid 
regurgitation (TRJV). 
a. If tricuspid regurgitation present, measure TRJV as a risk factor for early mortality 
and pulmonary hypertension. 
6. Liver MRI for estimation of hepatic iron content is required for participants who are 
FXUUHQWO\UHFHLYLQJSDFNHGUHGEORRGFHOOWUDQVIXVLRQVSHU\HDUIRU\HDURUKDYH
UHFHLYHGSDFNHGUHGEORRGFHOOWUDQVIXVLRQVOLIHWLPHFXPXODWLYH/LYHU05,PXVW be 
performed using a validated methodology per institutional preference (T2* or R2* or by 
ferriscan [R2 MRI]). 
a. ,IKHSDWLFLURQFRQWHQWPJ)HJOLYHr dry weight, a Gastroenterology/hepatology 
consultation with a liver biopsy is required to document the absence of cirrhosis, 
bridging fibrosis1[1], and active hepatitis.[2] 
7. A cardiac (T2*) MRI imaging when clinically indicated. Given the uncommon event of 
asymptomatic cardiac hemosiderosis in SCD, patients should be considered for evaluation 
with cardiac MRI on a case-by-case basis and per institutional preference if liver iron 
concentration (LIC) is > 22 mg of iron per gram of dried tissue.60,61 
8. Pulmonary function testing: Spirometry and lung volumes, including FEV1, FVC, and 
DLCO. Record oxygen saturation by pulse oximetry. 
a. Patients unable to perform DLCO due to young age or other inability must record 
absence or presence of dyspnea at rest and O2 saturation level. 
9. HLA typing by allele-level methodology at HLA -A, -B, -C, and DRB1 loci, ABO and Rh 
typing. Confirmatory donor typing must be completed < 100 days prior to enrollment in 
Segment A. 
 
[1]The absence of bridging fibrosis will be determined using the histological grading and 
staging scale as described by Ishak and colleagues (1995)1,2,3. 
[2] ,IDOLYHUELRSV\LVSHUIRUPHGSULRUWRHQUROOPHQWLQ6HJPHQW$D/LYHU05,LVQRW
required to be repeated prior to enrollment. 

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4.2.3 7KHIROORZLQJHYDOXDWLRQVDUHUHTXLUHGGD\VSULRUWRHQUROOPHQWLQWR6HJPHQW$ 
(considered standard of care evaluations for transplant patients). Observations prior to 
enrollment will be done according to institutional guidelines: 
1. History, physical examination, height, and weight. 
2. Lansky / Karnofsky performance status (Appendix F). 
3. ȕ-HCG serum pregnancy test for females of childbearing potential; to include all 
female participants > 10 years of age unless post-menopausal for a minimum of 1 year 
before the screening visit or surgically sterilized. 
4. CMV antibody test, hepatitis panel (HepA Ab, HepB sAb, HepB sAg, HepB Core Ab, 
HepC Ab), herpes simplex, syphilis, HIV and HTLV1 I/II antibody, varicella zoster 
virus antibody, and EBV serostatus. 
5. Hemoglobin evaluation by HPLC, electrophoresis, IEF, or gene test for quantification 
of: Hb F, Hb S, Hb A levels per institutional standards. In chronically transfused 
patients or those transfused within the last 3 months prior to enrollment, SCD genotype 
must be confirmed by one of the following: 
a. 
Prior laboratory determination of SCD genotype by referring providers, OR 
b. 
Confirmation test by HPLC or Hb electrophoresis after positive 
newborn screening, OR 
c. 
DNA based test from peripheral blood for globin chain analysis 
4.2.3.1 Evaluations Required Post-Segment A Enrollment but Pre-Transplant: 
The following evaluations are required post-Segment A enrollment, but prior to initiation of 
Hydroxyurea (Day -70)1: 
1. Baseline health-related quality of life (HRQoL) assessments (PROMIS pain and fatigue 
domains) (Appendix G) for English- and Spanish-speaking patients in the adult 
VWUDWXP3520,6PRGXOHVVKRXOGEHDGPLQLVWHUHGRQDVLQJOHGD\GD\VDQG
days from initiating the 28 day electronic pain diary. 
2. 28-day pain diary for English-VSHDNLQJ SDWLHQWV   \HDUV RI DJH at time of 
enrollment (twice daily for 28 days prior to starting HU). For patients who were on HU 
pre-enrollment, patients may complete pain diary while on protocol dose of HU. 
3. Review and documentation of SCD Events of Special Interest (SCD-EOSI) at baseline 
(see Section 3.8.2) 
 
1 Refer to Section 2.4.6 for recommendations regarding Encephaloduroarteriosynangiosis 
(EDAS) performed prior to transplant as adjunctive therapy for secondary stroke prevention. 

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4.2.4 The following evaluDWLRQVDUHUHTXLUHGGD\VSULRUWRLQLWLDWLRQRI 
Thymoglobulin  (Day -9) and are considered standard of care evaluations in 
transplant patients: 
1. Lansky / Karnofsky performance status (Appendix F). 
2. CBC with differential, reticulocyte count, serum creatinine, direct/conjugated bilirubin, 
alkaline phosphatase, ALT, and AST, serum ferritin, magnesium. A CBC will be 
obtained weekly during hydroxyurea (Day -70 until Day -10) and the dose will be 
reduced if the ANC<1500 or platelet <100,000. 
3. Radionuclide Glomerular Filtration Rate (GFR) or creatinine clearance (CrCl) 
(although GFR or CrCl is permissible, GFR is preferred) 
4. Chest x-ray or chest CT scan (contrast not required for CT chest) 
5. ȕ-HCG serum pregnancy test for females of childbearing potential; to include all 
female participants > 10 years of age unless post-menopausal for a minimum of 1 year 
before the screening visit or surgically sterilized. 
6. MRI/MRA of the brain to assess for radiologic evidence of cerebral vasculopathy. 
a. Cerebral MRI/MRA is required for all pediatric patients enrolled under any of the 
neurological criteria prior to transplant to assess status of CNS disease. For children 
ages 5.00 to 14.99 years of age with overt stroke ischemia, if there is clinical or 
radiologic evidence of a recent cerebral infarct, participants will be deferred for at 
least 6 months with repeat cerebral MRI/MRA to ensure stabilization of the 
neurologic event prior to proceeding to transplantation. Cerebral MRI images will 
be uploaded for central MRI review. Additional information is located on Sharepoint in 
the 1507 subweb Transplant Center Materials >> Cerebral MRI_MRA subfolder . 
b. For adults where the indication for the transplant is a stroke, cerebral MRI/MRA is 
required prior to transplant to assess progression of CNS disease. 
7. Optional Immune Reconstitution Research Samples as described in Appendix C: 
a. Children < 15: 24-40 mL into three-four 10 mL Vacutainer tubes, containing 
sodium heparin anticoagulant collected prior to initiating conditioning 
(Thymoglobulin). 
b. Adults >15: 40 mL into four 10 mL Vacutainer tubes, containing sodium heparin 
anticoagulant collected prior to initiating conditioning (Thymoglobulin). 
c. Donors: 20 mL into two 10 mL Vacutainer tubes, containing sodium heparin 
anticoagulant collected prior to donation. 
4.2.5 Transplant Evaluations 
Total nucleated cell and CD34+ cell content of the infused marrow product on Day 0. 
4.2.6 Post-Transplant Evaluations 
The following assessments should be conducted at the specified time points post-transplant: 
1. History, physical exam, height, and weight weekly until Day 28, then at Day 
100, six months, one year and two years post-transplant. 

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2. Lansky / Karnofsky performance status (Appendix E) weekly until Day 28, then at 
Day 100, six months, one year and two years post-transplant. 
3. History and physical exam to assess GVHD and other morbidity weekly until Day 100 
post-transplant, then at six months, one year, 18 months, and two years post-transplant. 
GVHD evaluation and grading as outlined in the BMT CTN MOP. 
4. Quality of life assessment (at 1 year and two years post-transplant) for English- and 
Spanish-speaking patients in the adult stratum using the PROMIS pain and fatigue 
domains (Appendix G). PROMIS modules should be administered on a VLQJOHGD\
GD\VDQGGD\VIURPLQLWLDWLQJWKH-day electronic pain diary. 
5. Pain diary twice daily over a 28-day period for English-VSHDNLQJSDWLHQWV\HDUV 
of age at time of enrollment (Year 1: day 337 to 365; Year 2: day 702 to 730). 
6. CBC three times a week from Day 0 until neutrophil recovery. Platelet count three 
times a week from Day 0 until platelet recovery. Thereafter, CBC and platelet count 
twice weekly until Day 28, then weekly until 12 weeks, then six months, one year and 
two years post- transplant. 
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on two different days, then at six months, one year and two years post-transplant. 
8. Quantitative hemoglobin evaluation (Hb F, Hb A, Hb A2, and Hb S) and last date of 
red blood cell transfusion on Day 28, 100, 6 months, one year, and two years post-
transplant. 
9. Creatinine, bilirubin, alkaline phosphatase, ALT, AST, magnesium twice weekly until 
Day 28, then weekly until 12 weeks, and then at Day 100, six months, one year and 
two years post-transplant. 
10. Serum ferritin at 1 year and two years post-transplant. 
11. Radionuclide Glomerular Filtration Rate (GFR) or creatinine clearance (CrCl) 
(although either GFR or CrCl is permissible, GFR is preferred); urine protein (or 
microalbumin) to creatinine ratio at 1 year and 2 years post-transplant. 
 
12. Heparinized peripheral blood sample for post-transplant chimerism assay by 
molecular methods collected at Day 28, Day 421, and at Day 100, 6 months and 1 and 
2 years. All patients must have chimerism assay between day 21 and day 42. For 
patients with primary graft failure (i.e. anytime within day 42 reporting period) a 
separate measurement is not required. For patients with mixed chimerism (tested 
between day 21 – 42), follow up chimerism assays per local institutional standard is 
recommended to document sustained engraftment or graft failure. Secondary graft 
rejection is based on two separate measurements obtained a minimum of 1 week and 
a maximum of 2 weeks apart. 
 
[1]The absence of bridging fibrosis will be determined using the histological grading and staging scale as 
described by Ishak and colleagues (1995)1,2,3. 
 
 

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13. Fractionated chimerism examining the myeloid and lymphoid fractions at Day 28, Day 
421, and at Day 100, 6 months and 1 and 2 years (bone marrow aspirate preferred, 
particularly at Day 100). If a center is unable to perform the bone marrow aspiration 
procedure as standard of care, peripheral blood is acceptable. Secondary graft rejection 
is based on two separate measurements obtained a minimum of 1 week and a 
maximum of 2 weeks apart. 
14. Pulmonary function testing with FEV1, FVC, DLCO, and oxygen saturation by pulse 
oximetry at 1 and 2 years post-transplant. 
a. Patients unable to perform DLCO, lung volumes or spirometry due to young age 
or other inability must record absence or presence of dyspnea at rest and O2 
saturation level. 
15. For adults where the indication for the transplant is echocardiographic finding of 
tricuspid valve regurgitant jet velocity 75-9PVHFDWDPLQLPXPVXUYHLOODQFH
with 2-D transthoracic echocardiography for assessment of LVEF, left ventricular 
shortening fraction, presence or absence of tricuspid regurgitation at one and two years 
post-transplant is recommended. As some institutional standards may not require 
surveillance for left ventricular function or assessment of TRJV if the last velocity is 
< 2.7 m/sec, echocardiogram assessments post-transplant may be performed per 
institutional standards. 
16. A 6-minute walk distance test at one and two years post-transplant. 
17. MRI/MRA of the brain to assess for radiologic evidence of cerebral vasculopathy will 
be obtained at 1 and 2 years post-transplant. Cerebral MRI is required for all pediatric 
patients 1 and 2 years post-transplant to assess status of CNS disease. For adults where 
the indication for the transplant is a stroke, cerebral MRI is required 1 and 2 years 
post- transplant to assess status of CNS disease. Cerebral MRI images will be uploaded 
for central MRI review. Refer to the BMT CTN 1507 MOP for details. 
18. Liver MRI is recommended when clinically indicated and per institutional preference. 
Patients with transfusional iron overload (defined as liver iron concentration  10 mg 
Fe/g liver dry weight) should be evaluated by a validated methodology (T2* or R2* 
or by ferriscan [R2 MRI]) for hepatic iron concentration per institutional preference 
at one year and two years post-transplant. 
19. A cardiac (T2*) MRI imaging when clinically indicated. Given the uncommon event 
of asymptomatic cardiac hemosiderosis in SCD, patients should be considered for 
evaluation with cardiac MRI on a case-by-case basis and per institutional preference 
if liver iron concentration (LIC) is > 22 mg of iron per gram of dried tissue (1 and 2 
years post- transplant). 
20. Review and documentation of SCD Events of Special Interest (SCD-EOSI) at 6 
months, 1 year, Day 540, and 2 years post-transplant (refer to Section 3.8.2) 
21. HbS percent beginning at Day 100, 1 and 2 years post-transplant for patients who are 
transfusion independent. 
22. Optional Immune Reconstitution Research Samples at Days 28, 60, 100, 180, and 1 
year post-transplant as described in Appendix C: 

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a. Children < 15: 24-40 mL into three-four 10 mL Vacutainer tubes, containing 
sodium heparin anticoagulant. 
b. Adults >15: 40 mL into four 10 mL Vacutainer tubes, containing sodium 
heparin anticoagulant. 
 
 
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blood or myeloid chimerism (myeloid is preferable) in peripheral blood or bone marrow, the day 42 
chimerism does not need to be completed 
 
 
 

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TABLE 4.2.2A: SCHEDULE OF EVALUATIONS PRIOR TO TRANSPLANT1 
 
 
Pre-Enrollment 
Pre-Transplant 
Assessments 
GD\VSULRUWR
Enrollment 
GD\VSULRUWR
Enrollment 
Pre-HU 
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7K\PRJOREXOLQ 
CBC with differential and blood chemistries4 
X 
 
 
X8 
Renal Function Assessments5 
X 
 
 
X 
Anti-donor HLA Antibody Testing 
X 
 
 
 
EKG 
X 
 
 
 
6-minute walk distance test 
X 
 
 
 
Echocardiogram or MUGA6 
X 
 
 
 
Liver MRI 
X 
 
 
 
Liver biopsy7 
X 
 
 
 
Cardiac MRI imaging 
X 
 
 
 
Pulmonary Function Assessments (per section 4.2.2.1) 
X 
 
 
 
Confirmatory HLA typing (per section 4.2.2.1) 
X 
 
 
 
History, physical exam, height, weight 
 
X 
 
 
Karnofsky/Lansky Performance Score 
 
X 
 
X 
Pregnancy Test 
 
X 
 
X 
Infectious disease titers (per section 4.2.2.1) 
 
X 
 
 
Hemoglobin evaluation and date of last RBC transfusion  
X 
 
 
QOL assessment (PROMIS) 
 
 
X 
 
28-Day Pain Diary9 
 
 
X 
 
Evaluation of Sickle Cell Disease Events of Special 
Interest 
 
 
X 
 
Chest X-ray or chest CT scan 
 
 
 
X 
Cerebral MRI/MRA (Per section 4.2.2.2) 
 
 
 
X 
Optional blood samples10 
 
 
 
X 
1Assessments summarized in this table should be performed per section 4.2.2.1 and 4.2.2.2 of the protocol as applicable. 
2 Baseline assessments (pre-HU) should be performed < 30-day after enrollment in Segment A, and prior to initiation of hydroxyurea, unless otherwise noted. 
3 Pre-transplant conditioning assessments should be performed < 30-day prior to initiation of Thymoglobulin (these assessments can be completed 
during administration of hydroxyurea). 

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4 Blood Chemistries performed per sections 4.2.2.1 and 4.2.2.2 include reticulocyte count, direct/conjugated bilirubin, alkaline phosphatase, ALT, 
AST, serum ferritin, and magnesium. 
5 Serum Creatinine and Creatinine Clearance required <180 days prior to enrollment. Radionuclide Glomerular Filtration Rate (GFR) or creatinine 
clearance (CrCl) required prior to initiation of thymoglobulin (although GFR or CrCl is permissible, GFR is preferred). Refer to protocol sections 
4.2.2.1 and 4.2.2.2. 

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6 Refer to section 4.2.2.1 for 2-D transthoracic echocardiography requirements. 
7 ,IKHSDWLFLURQFRQWHQWPJ)HJDJDVWURHQWHURORJ\KHSDWRORJ\FRQVXOWDWLRQZLWKOLYHUELRSV\LVUHTXLUHGWRGRFXPHQWDEsence of cirrhosis, 
bridging fibrosis, and active hepatitis. 
8 A CBC will be obtained weekly during hydroxyurea (Day -70 until Day -10) and the dose will be reduced if the ANC <1500 or platelet <100,000. CBC 
9 Pain diary at baseline is completed twice daily over 28 days prior to starting hydroxyurea. For patients who were on HU pre-enrollment, patients 
may complete pain diary while on protocol dose of HU. 
10 Only required for patients and donors that consent to provide option research samples. 

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TABLE 4.2.2B: SCHEDULE OF EVALUATIONS FOLLOWING TRANSPLANT1 
 
'D\V3RVW-HCT 
Assessments 
 
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Total nucleated cell and CD34+ cell content of the infused marrow 
product 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History, physical exam, height, weight 
 
X 
X 
X 
X  
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Karnofsky/Lansky Performance Score 
 
X 
X 
X 
X  
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
GVHD and morbidity assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QOL assessment (PROMIS)2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
28-Day Pain Diary3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
CBC with differential4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
X 
X 
 
X 
Reticulocyte (per section 4.2.4) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Hemoglobin evaluation and date of last RBC transfusion 
 
 
 
 
X  
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Blood Chemistries5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
 
X 
Serum ferritin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Renal Function Assessments6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Chimerism (per section 4.2.4) 
 
 
 
 
X  
X  
 
 
 
 
 
 
X 
X 
X 
 
X 
Pulmonary Function Assessment (per section 4.2.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Echocardiogram or MUGA (per section 4.2.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
6-minute walk distance test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Cerebral MRI/MRA (Per section 4.2.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Liver MRI7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Evaluation of Sickle Cell Disease Events of Special Interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Optional blood samples8 
 
 
 
 
X  
 
 
 
X  
 
 
 
X 
X 
X 
 
 
1 Assessments summarized in this table should be performed per section 4.2.4 of the protocol. 
2 Should be administered to English- and Spanish-speaking patients in the adult stratum on a single day  7 days and  28 days from initiating the 28-
day electronic pain diary. 
3 Pain diary over a 28-day period for English-VSHDNLQJSDWLHQWVIURP'D\WRDQG'D\WR 
4 CBC three times a week from Day 0 until neutrophil recovery. Platelet count three times a week from Day 0 until platelet recovery. Thereafter, 
CBC and platelet count twice weekly until Day 28, then weekly until 12 weeks, then six months, 1 year and 2 years post-transplant. 
5 Blood Chemistries include serum creatinine, bilirubin, alkaline phosphatase, ALT, AST, magnesium twice weekly until Day 28, then weekly until 
12 weeks, and then at six months, one year and two years post-transplant. 

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6 Measured Radionuclide Glomerular Filtration Rate (GFR) or eGFR with creatinine clearance (CrCl) is permissible. However, measured GFR is preferred. 
Report urine albumin-to-creatinine ratio. 
7 May be performed per institutional preference and as clinically indicated. 
8 Only required for patients and donors that consent to provide option research samples. 

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4.3 
Data Reporting and Study Monitoring 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, 17, January 27, 1981, part 56) and 
the Office for Protection from Research Risks Reports: Protection of Human Subjects (Code of 
Federal Regulations 45 CFR 46. 
4.3.1 Reporting Participant Deaths 
Death information must be entered into AdvantageEDCSM within 24 hours of knowledge of the 
participant’s death. If the cause of death is unknown at that time, it need not be recorded at that 
time. However, once the cause of death is determined, the form must be updated in 
AdvantageEDCSM. In addition, death must be reported via the expedited reporting requirements in 
AvantageEDCSM (see 4.2.3 below). 
4.3.2 Adverse Event Reporting 
Adverse Event: An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study treatment or 
any procedure specified in the protocol, even if the event is not considered to be related to the 
study. 
Expectedness: An adverse event can be Expected or Unexpected 
x 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, or 
is included in the informed consent document as a potential risk. 
x 
Unexpected adverse events are those that vary in nature, intensity or frequency from 
information in the current adverse event list, the Investigator’s Brochure, or when it is not 
included in the informed consent document as a potential risk. 
Serious Adverse Event: A serious adverse event (SAE), as defined by per 21 CFR 312.32, is any 
adverse event that results in one of the following outcomes, regardless of causality and 
expectedness: 
x Results in death. 
x Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
x Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24- 
hour 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). 

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x 
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
x 
Is a congenital anomaly or birth defect; or 
x 
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether expected reporting is 
also appropriate in situations other than those listed above. For example, important medical events 
may not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject 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 a Serious 
Adverse Event). Any event is considered a Serious Adverse Event if it is associated with clinical 
signs or symptoms judged by the investigator to have a significant clinical impact. 
4.3.3 Required Adverse Event Reporting: 
Adverse event reporting will be consistent with BMT CTN procedures (BMT CTN Administrative 
Manual of Procedures, Chapter 6). It is BMT CTN policy that AEs must be reported even if the 
investigator is unsure whether a relationship exists between the adverse event and the use of study 
treatment. Unexpected serious adverse events will be reported through the expedited AE reporting 
system in AdvantageEDC. Unexpected, Grade 4-5 SAEs must be reported within 24 hours of 
knowledge of the event. All other unexpected SAEs must be reported within three business days 
of knowledge of the event. Events entered in AdvantageEDC will be reported using NCI’s 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Expected AEs will be 
reported using NCI’s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at 
regular intervals as defined on the Form Submission Schedule (e.g. Re-Admission/Hospitalization, 
Infection, GVHD, and Toxicity Forms). Any expected life-threatening SAE not collected on 
another study form must be reported through the expedited AE reporting system via 
AdvantageEDC. 
The NHLBI Data and Safety Monitoring Board will receive summary reports of all adverse 
experiences at least twice yearly. 
In addition to the standard BMT CTN SAE reporting, all deaths, central nervous system (CNS) 
events, diagnosis of posterior reversible encephalopathy syndrome (PRES)/reversible posterior 
leukoencephalopathy syndrome (RPLS), and/or events requiring advanced care interventions or 
admission/transfer to an intensive care unit (ICU) are required to be reported via the expedited AE 
reporting system in AdvantageEDC for this study. All event reporting is to be expedited. Grade 4- 
5 events should be reported within 24 hours of knowledge of the event. All other events should be 
reported within three business days of the event. 

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For the purposes of this protocol, examples of “ICU” or “advanced care intervention” requiring 
expedited AE reporting are one or more of the following: 
x The patient is transferred to an advanced care unit or the ICU* (see footnote below) 
x Continuous Renal Replacement Therapy (CRRT) by dialysis (CAVHD) or 
filtration (CAVH) 
x Non-invasive positive pressure ventilation: continuous positive airway pressure 
(CPAP), bi-level positive airway pressure (BIPAP), intermittent positive pressure 
ventilation (IPPV) 
x Endotracheal intubation with mechanical ventilation 
x Pressor support 
x Organ failure – acute renal failure, acute liver failure, acute respiratory distress 
syndrome, respiratory failure, or multi-organ failure 
4.3.4 * Elective transfer to an advanced care/ICU unit for a scheduled intervention does not  
need to be reported via the expedited AE reporting system in AdvantageEDC. 
4.3.4.1 Sickle Cell Disease Related Events of Special Interest Reporting: 
The following sickle cell disease related events of special interest (SCD-EOSI) are expected events 
for all participants: 
x pulmonary hypertension 
x significant cerebrovascular events, including: 
o stroke 
o transient ischemic attack 
o seizure 
x renal function compromise, including: 
o proteinuria (absent or present, and if present, date of onset) 
o LQFUHDVHGFUHDWLQLQHJUDGHVSHU&7&$(YHUVLRQ 4.0 
x avascular necrosis of the hip or shoulder 
x leg ulcers 
x acute chest syndrome (ACS) requiring hospitalization 
x painful vaso-occlusive crises (VOC) requiring hospitalization or parenteral opioid 
drugs in the outpatient setting (self-reported events without clinical documentation 
should not be included.) 
While these events may not require expedited reporting via completion of the Adverse Events 
forms, each occurrence of any SCD-EOSI must be reported on the SCD Events of Special Interest 
Form at each regularly scheduled follow up interval. A single event occurrence is defined as a new 
onset of any of the above listed SCD-EOSIs after screening evaluations are completed. A single 
occurrence resolves once the SCD-EOSI returns to the participant’s baseline. Therefore, multiple 
occurrences of the same or several SCD-EOSIs may be reported in one reporting interval. 

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4.4 
Data Monitoring 
4.4.1 Criteria for Forms Submission 
Forms that are not entered into AdvantageEDCSM within the specified time will be considered 
delinquent. A missing form will continue to be requested either until the form is entered into the 
AdvantageEDCSM and integrated into the Data and Coordinating Center’s (DCC) master database, 
or until an exception is granted and entered into the Missing Form Exception File. 
4.4.2 Center for International Blood and Marrow Transplant Research (CIBMTR) Data  
Reporting 
Centers participating in BMT CTN trials must register pre- and post-transplant outcomes on all 
consecutive hematopoietic stem cell transplants done at their institution during their time of 
participation to the Center for International Blood and Marrow Transplant Research (CIBMTR). 
Registration is done using procedures and forms of the Stem Cell Transplant Outcomes Database 
(SCTOD). (Note: Federal legislation requires submission of these forms for all US allotransplant 
recipients.) Enrollment on BMT CTN #1507 must be indicated on the SCTOD pre-transplant 
registration form. Additionally, CIBMTR pre- and post-transplant Report Forms must also be 
submitted for all patients enrolled on this trial. CIBMTR forms will be submitted directly to the 
CIBMTR at the times specified on the Form Submission Schedule. 
4.4.3 Internal Data Monitoring 
It is the responsibility of the site PI to ensure the validity of all participant data as well as the safety 
of all participants. 
4.4.4 Data Monitoring and Auditing 
The Data Safety and Monitoring Board (DSMB) for the BMT CTN will convene as per standard 
procedure to review serious toxicities and adverse events for the purpose of determining whether 
the trial should be modified or stopped. Triggers for referral to the DSMB are described in the 
Stopping Rules Criteria of section 5.3. 
4.4.5 Records 
Any publication or presentation will refer to patients by a unique patient number and not by name 
to assure patient confidentiality. 
4.4.6 Archiving Records 
Archival of participant study charts/records should be conducted in accordance with the guidelines 
provided in the Data Management Handbook. 

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4.4.7 Planned Protocol Amendments 
If the monitoring of the safety endpoints described in Section 5.3 results in a trigger for 
consultation with the DSMB, the DSMB may make recommendations about whether or not to 
continue accrual. 
In addition, if the rate of 100-day graft failure passes the stopping guideline in the 12 evaluable 
participants in a stratum (see section 5.3.1), the conditioning regimen will change from TBI 
200cGy to TBI 400cGy in the affected stratum. Accrual to the strata under the original TBI dose 
of 200cGy will be stopped. The goal will be to enroll 40 more participants for the stratum that 
implements the changed regimen. Safety monitoring for all safety endpoints in that stratum will 
be restarted only using participants enrolled after the new conditioning regimen is implemented. 
4.4.8 
On-study Date 
Participants will be in the screening phase from date of consent to date of enrollment onto Segment 
0 or notice of non-eligibility. Participants will be on-study from the date of enrollment onto 
Segment A. All patients enrolled in Segment A will be followed for 2 years post-transplant 
regardless of the treatment received. 

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CHAPTER 5 
5 STATISTICAL CONSIDERATIONS 
5.1 
Study Design 
This study is designed as a Phase II multi-center trial to determine the feasibility of achieving a 
high rate of event-free survival at 2 years post-transplant using pre-conditioning HU with a 
conditioning regimen that consists of a combination of rATG/CY/Flu/TT with post-grafting high- 
dose cyclophosphamide in patients with severe SCD who have HLA-haploidentical donors. EFS 
is defined as survival without a qualifying event (see Section 3.1). This is a single arm study in 
which participants will be enrolled into one of two strata. The first stratum will be restricted to 
children who have stroke and 40 children will be transplanted in this stratum. The second stratum 
will consist of adult patients with severe sickle cell disease and 40 participants will be transplanted 
in this stratum. 
Safety monitoring will occur on a monthly basis for several safety endpoints. If the safety criterion 
for graft rejection is met in either stratum, and if the DSMB and sponsor agree that accrual to a 
stratum should stop, then accrual to that stratum will be halted. For that stratum, participants 
already accrued will continue to be followed per protocol. Further, with DSMB and sponsor 
approval, an additional 40 participants will be transplanted in the strata but will use a different 
conditioning regimen. Safety monitoring for all safety endpoints will be reset for the stratum that 
changes conditioning regimen (see Section 5.3 for further details). 
All analyses are within-stratum, and each stratum will follow it is own timeline of completion for 
the primary analysis for the stratum If a new conditioning regimen is implemented for any strata, 
then for that stratum, descriptive statistics or listings will be provided using data from participants 
enrolled under the original dose of TBI; the stratum-specific analyses will be limited to the 
participants enrolled under the new conditioning regimen. 
5.1.1 
Accrual 
It is estimated that it will require four years to complete the accrual with 10 patients transplanted 
in each stratum per year. If accrual to any arm is restarted based on the planned change in 
conditioning regimen, then it is estimated accrual in that strata will take four years from the time 
when the change in conditioning regimen is implemented. 
5.1.2 Study Duration 
Participants will be followed for the 28-day baseline pain diary period, 70 day conditioning period 
and for two years post-transplant for primary and secondary endpoints. 
5.1.3 Randomization and Blinding 
This is a single arm trial with no randomization and no blinding. 

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5.1.4 Primary Endpoint 
The primary objective of this clinical trial is to estimate two-year post-transplant event-free 
survival in each age stratum. EFS is defined as survival without a qualifying event. Events 
contributing to this endpoint are as below: 
i. 
Primary graft rejection 3ULPDU\JUDIWIDLOXUHLVGHILQHGDVQHYHUDFKLHYLQJGRQRU
whole blood or myeloid chimerism (myeloid is preferable) assessed by bone marrow 
or peripheral blood chimerism assays by day +42 post-transplant. Second infusion of 
stem cells is also considered indicative of primary graft failure by day +42 post-
transplant).  
ii. Secondary graft rejection (Secondary graft failure is defined as < 5% donor whole 
blood or myeloid chimerism (myeloid is preferable) in peripheral blood or bone 
marrow beyond day +42 post-transplant in patients with prior documentation of 
hematopoietic recovery with >5% donor cells by day +42 post-transplant. Second 
infusion of stem cells is also considered indicative of secondary graft failure).  
iii. Second infusion of hematopoietic cells (Infusion of a second stem cell product will be 
considered graft rejection, and counted toward primary or, depending on timing of the 
second infusion, secondary graft rejection). 
iv. Death (from any cause by 2 years post-transplant)  
The EFS probability estimates will be based on the Kaplan-Meier product limit estimator using 
Greenwood’s formula as the variance estimate. For the primary analysis, time to event will be 
calculated as the minimum of the time from study start of HU conditioning to the first event, loss 
to follow-up, or two years post- transplant. Reasons for not getting a transplant or not starting 
conditioning will be described. 
A secondary endpoint will assess EFS at 1 year post-transplant. Further analyses include EFS from 
time of transplant and will restrict analyses to those receiving a transplant. 
5.2 
Sample Size Considerations 
The sample size is 40 transplanted participants per each of the two stratum in this trial. Ninety- 
five percent confidence intervals were calculated for varying probabilities based on the sample 
size. The primary endpoint, event-free survival (EFS), is considered for sample size determination. 
Table 5.2 provides confidence intervals for a variety of observed proportions based on the binomial 
proportion. Of particular interest is where the EFS probability is 80%. If the observed EFS 
probability is 80%, the width of the confidence interval is 24.8. The tabulated percentages and 
confidence intervals for observed probabilities above and below 80% are meant to represent other 
plausible EFS percentages. 
 

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TABLE 5.2A: CONFIDENCE INTERVAL LENGTHS AND POSSIBLE CONFIDENCE 
INTERVALS 
FOR 
VARIOUS 
OBSERVED 
EVENT-FREE 
SURVIVAL 
PROBABILITIES 
40 participants enrolled and transplanted 
N (per 
stratum) 
Event-free 
survival % 
Length of 95% 
Confidence Interval 
Possible 
Confidence Intervals 
40 
90 
18.6 
80.7 
99.3 
40 
85 
22.1 
73.9 
96.1 
40 
80 
24.8 
67.6 
92.4 
40 
75 
26.8 
61.6 
88.4 
The EFS probability estimate will be based on the Kaplan-Meier product limit estimator using 
Greenwood’s formula as the variance estimate. In the absence of censoring, the Kaplan-Meier 
estimate reduces to the simple binomial proportion. If the linear confidence intervals extend 
beyond 0 or 100, log-log confidence intervals may be used. 
It is estimated that there may be more than 40 participants enrolled to reach 40 transplanted 
participants. For example, there may be 53 participants enrolled with 15% censored. The 
following table shows how the binomial confidence intervals would change based on 45 
participants who were not censored for the primary endpoint. 
TABLE 5.2B: CONFIDENCE INTERVAL LENGTHS AND POSSIBLE CONFIDENCE 
INTERVALS 
FOR 
VARIOUS 
OBSERVED 
EVENT-FREE 
SURVIVAL 
PROBABILITIES 
45 participants not censored for primary endpoint 
N (per 
stratum) 
Event-free 
survival % 
Length of 95% 
Confidence Interval 
Possible 
Confidence Intervals 
45 
88.9 
18.4 
79.7 
98.1 
45 
84.4 
21.1 
73.9 
95.0 
45 
80.0 
23.4 
68.3 
91.7 
45 
75.6 
25.1 
63.0 
88.1 
5.3 
Interim Analysis and Stopping Guidelines 
There will be no formal interim analyses for this trial. 
Monitoring of key safety endpoints will be conducted monthly, and if rates significantly 
exceed pre-set thresholds, the NHLBI will be notified in order that the DSMB can be 
advised. Policies and composition of the DSMB are described in the BMT CTN's Manual 
of Procedures. The stopping guidelines serve as a trigger for consultation with the DSMB 
for additional review. 

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The key safety endpoint of 100-day graft failure will be monitored, with a planned protocol 
modification of the conditioning regimen planned if rates exceed 15% in the first 12 
evaluable participants in a stratum. After the first 12 evaluable participants, if the stopping 
boundary has not been crossed, then the graft failure rate will continue to be monitored as a 
safety guideline for consultation with the DSMB but it is unlikely the conditioning regimen 
will change and accrual be restarted. 
Within each stratum, the additional key safety endpoints to be monitored are the following rates: 
x Acute, grade III-IV GVHD by 100 days post-transplant 
x Overall mortality by 180 days post initiation of hydroxyurea 
x Severe chronic GVHD by 18 months post-transplant 
A truncated version of the sequential probability ratio test (SPRT) will be used for monitoring, as 
described in greater detail below and in Appendix H. This sequential testing procedure conserves 
type I error across all of the planned examinations for a treatment arm for a given stopping rule 
and stratum. Two versions of the SPRT will be used. For graft failure, a binomial SPRT will be 
used, and a plot will display the number of evaluable patients versus the number of observed 
events. Other safety endpoints will be monitored using an extension to the SPRT for censored 
exponential data. This extension will plot the observed time on study versus the number of 
observed events (see Appendix H). The continuation region for both versions of the SPRT is 
defined by two parallel lines. Only the upper boundary will be used for monitoring to protect 
against excessive rates. If the graph crosses the upper boundary, the SPRT rejects the null 
hypothesis, and concludes that there are more events than predicted. Otherwise, the SPRT 
continues until the monitoring period is complete. 
The usual measures of performance of an SPRT are the error probabilities D and E of rejecting H0 
when T = T0 and of accepting H1 when T = T1, respectively, and the expected sample size E(N|Ti). 
5.3.1 Monitoring Guideline: 100-day Graft Failure Rate within a Stratum 
The monitoring of graft failure is a key safety endpoint for which a protocol modification for a 
change in the dose level of TBI is pre-planned in the event the boundary is crossed within the first 
12 evaluable participants. 
This monitoring procedure assumes a binary distribution for graft failure during the first 100 days 
post-transplant. If the participant has been transplanted but has had primary or secondary graft 
rejection by day 100, the participant is assumed to be a graft failure at day 100. Chimerism from 
samples collected within the D100 visit window will be used for evaluation of graft failure at Day 
100. This monitoring guideline uses an SPRT contrasting a null hypothesis of 15% versus an 
alternative of 35% 100-day graft failure which results in decision boundaries with a common slope 
of 0.240 and an upper intercept of 2.59, with nominal type I and type II errors of 5% and 10%, 
respectively. Table 5.3.1 summarizes the stopping rule. 
 

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5.3.2 Table 5.3.1: Stopping Rule for 100-Day Graft Failure 
1XPEHURIHYDOXDEOH
SDUWLFLSDQWV 
6WRSLIJUDIWIDLOXUHRFFXUVLQ 
4-5 
4 
6-10 
5 
11-14 
6 
15-18 
7 
19-22 
8 
23-26 
9 
27-30 
10 
31-34 
11 
35-39 
12 
5.3.2.1 Modified Conditioning Regimen 
While participants are enrolled under the 200 cGy dose of TBI, if the stopping boundary is crossed 
before the end of the first 12 evaluable participants, then a planned protocol modification may be 
discussed by the DSMB. If a decision is made to stop accrual under the initial conditioning regimen, 
then sites will be notified to stop accrual in that stratum. If the DSMB and sponsor choose to 
implement the modified conditioning regimen, accrual will be restarted using the modified 
conditioning regimen (TBI 400 cGy). An additional 40 patients will be enrolled with the new 
conditioning regimen and the first 12 patients receiving the modified regimen will be monitored for 
incidence of 100-day graft failure. Safety monitoring for all endpoints for participants in that 
stratum will be restarted. 
If the safety boundary has not been triggered in the first 12 evaluable participants in each stratum 
and the DSMB recommends continuing accrual, then safety monitoring for 100-day graft failure 
will continue using the SPRT. Alternatively, if the stopping boundary is crossed after the first 12 
evaluable participants, then DSMB will be consulted but it is anticipated the recommendation will 
be to terminate accrual in that stratum and not restart with the new regimen, given the logistical 
difficulty of completing enrollment of an additional 40 participants in a timely manner. 
5.3.3 Monitoring Guideline: Grade III-IV Acute GVHD by Day 100 Post Transplant within a  
Stratum 
The incidence of acute grade III-IV GVHD is approximately 15-17% after HLA-identical sibling 
BMT.62, 63, 64, 65 Each month, the null hypothesis that the 100-day acute GVHD rate is 20% is tested. 
This monitoring procedure assumes a censored exponential distribution for the time until acute 
grade III-IV GVHD during the 100 days post-transplant, and censors follow-up time after 100 
days. Only events that occur after transplant and on or before the participant has been followed for 
100 days post-transplant are counted. Total time on study is computed as time from transplant to 
acute grade III-IV GVHD, or to 100 days, whichever comes first, summed for all transplanted 
participants on study. This monitoring guideline uses an SPRT contrasting a null hypothesis of 
20% versus an alternative of 40% 100-day acute grade III-IV GVHD which results in decision 

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boundaries with a common slope of 1.27 and an upper intercept of 2.94, with nominal type I and 
type II errors of 7% and 20%, respectively. 
The actual operating characteristics of this truncated test, shown in Table 5.3.2, were determined 
in a simulation study that assumed uniform accrual and transplant of 40 individuals per strata over 
a 4-year time period with monitoring occurring monthly after the first transplant for 52 months. 
TABLE 5.3.2: OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR 100-DAY ACUTE GVHD FROM A SIMULATION STUDY WITH 
100,000 REPLICATIONS 
Acute GVHD at 100 Days Post-Transplant 
 
True 100-Day Post-Transplant Rate 20% 
25% 
30% 
35% 
40% 
Probability Reject Null 
0.05 
0.17 
0.37 
0.62 
0.82 
Mean Month Stopped Post-Transplant 
50.5 
47.5 
42.1 
35.0 
27.9 
Mean # Endpoints in 100 days 
7.8 
9.2 
9.8 
9.6 
8.8 
Mean # Participants Transplanted 
39.0 
36.8 
33.1 
28.2 
22.9 
5.3.4 Monitoring Guideline: Overall Mortality by Day 180 Post Conditioning within a Stratum 
Overall mortality (OM) is defined as death with or without disease recurrence. The monitoring 
procedure assumes a censored exponential distribution for the time until death during the first 180 
days, and censors follow-up time after 180 days. Deaths that occur on or before the participant has 
been followed for 180 days are counted as events. Total time on study is computed as time from 
start of hydroxyurea (HU) at day -70 pre-BMT to death, loss to follow-up, or to 180 days, 
whichever comes first, summed for all participants on study. This monitoring guideline uses an 
SPRT contrasting a null hypothesis of 10% versus an alternative of 30% 180-day mortality, which 
results in decision boundaries with a common slope of 0.42 and an upper intercept of 2.05, with 
nominal type I and type II errors of 7% and 15%, respectively. 
The actual operating characteristics of this truncated test, shown in Table 5.3.3, were determined 
in a simulation study that assumed uniform accrual of 40 individuals per stratum over a 4-year 
time period with monitoring occurring monthly for 54 months. 
TABLE 5.3.3A: OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR DAY 180 POST CONDITIONING OM FROM A SIMULATION 
STUDY WITH 100,000 REPLICATIONS 
Overall Mortality at Day 180 post HU Conditioning, N=40 
 
True Rate at Day 180 post HU initiation 
10% 
15% 
20% 
25% 
30% 
Probability Reject Null 
0.05 
0.20 
0.47 
0.73 
0.90 
Mean Month post HU Conditioning Stopped 
52.5 
47.9 
40.1 
31.4 
24.0 

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True Rate at Day 180 post HU initiation 
10% 
15% 
20% 
25% 
30% 
Mean # Endpoints 
3.9 
5.3 
6.0 
5.9 
5.4 
Mean # Participants Enrolled 
39.0 
36.0 
30.9 
25.0 
19.7 
The following table shows the simulated results for 53 people accrued per stratum over a 4-year 
time period with monitoring occurring monthly for 54 months. 
TABLE 5.3.3B: OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR DAY 180 POST CONDITIONING OM FROM A SIMULATION 
STUDY WITH 100,000 REPLICATIONS 
Overall Mortality at Day 180 post HU Conditioning, N=53 
 
True Rate at Day 180 post HU initiation 
10% 
15% 
20% 
25% 
30% 
Probability Reject Null 
0.05 
0.23 
0.54 
0.81 
0.95 
Mean Month post HU Conditioning Stopped 52.3 
46.7 
37.2 
27.3 
19.9 
Mean # Endpoints 
5.1 
6.9 
7.3 
6.7 
5.7 
Mean # Participants Enrolled 
51.5 
46.5 
38.1 
29.1 
21.9 
5.3.5 Monitoring Guideline: 18-Month Severe Chronic GVHD Within a Stratum 
The incidence of severe chronic GVHD (defined as NIH severe chronic GVHD) is approximately 
5-20% after HLA-identical sibling BMT.62,66,67 The working hypothesis is that the overall toxicity 
of mini-haploBMT is not significantly greater than HLA-identical sibling BMT after 
myeloablative conditioning. 
This monitoring procedure assumes a censored exponential distribution for the time until severe 
cGVHD during the eighteen months post-transplant, and censors follow-up time after eighteen 
months. Only events that occur after transplant and on or before the participant has been followed 
for 18 months post-transplant are counted. Total time on study is computed as time from transplant 
to severe cGVHD, or to eighteen months, whichever comes first, summed for all transplanted 
participants on study. This monitoring guideline uses an SPRT contrasting a null hypothesis 20% 
versus an alternative hypothesis of 40% 18-month severe cGVHD which results in decision 
boundaries with a common slope of 0.23 and an upper intercept of 2.87, with nominal type I and 
type II errors of 8% and 14%, respectively. 
The actual operating characteristics of this truncated test, shown in Table 5.3.4, were determined 
in a simulation study that assumed uniform accrual and transplant of 40 individuals per strata over 
a 4-year time period with monitoring occurring monthly after the first transplant for 66 months. 
 
 

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TABLE 5.3.4: OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR 18-MONTH POST TRANSPLANT SEVERE CGVHD FROM A 
SIMULATION STUDY WITH 100,000 REPLICATIONS 
 
True 18-Month Post-Transplant Rate 20% 
25% 
30% 
35% 
40% 
Probability Reject Null 
0.05 
0.17 
0.38 
0.63 
0.83 
True 18-Month Post-Transplant Rate 20% 
25% 
30% 
35% 
40% 
Mean Month Post-Transplant Stopped 
64.0 
59.9 
52.8 
43.7 
35.1 
Mean # Endpoints in 18 Months 
7.8 
9.1 
9.8 
9.5 
8.7 
Mean # Participants Transplanted 
39.1 
37.5 
34.7 
30.8 
26.6 
5.4 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all participants. Characteristics 
to be examined may include: age, gender, race/ethnicity, Karnofsky/Lansky performance status, 
number and duration of prior transfusions, TRJV, disease risk characteristics, disease symptoms, 
donor characteristics, HLA match, serum bilirubin level, serum creatinine level, pulmonary 
function tests, cardiac function, splenic function, hemoglobin electrophoresis, cerebral MRI, 
serum ferritin, QOL, and other baseline characteristics. 
5.5 
Analysis of Secondary Endpoints 
All secondary endpoints will be reported within each stratum. The primary analysis of the 
secondary endpoints will be limited to the participants enrolled under the TBI conditioning 
regimens in effect at the close of the study. The data from participants enrolled under the initial 
conditioning regimens that were subsequently modified as part of the planned protocol amendment 
will be provided using descriptive statistics or lists only. If the endpoint definitions indicate the 
endpoint is only for adults, the analysis will be restricted to those participants. 
5.5.1 Overall Survival 
Overall survival will be estimated using the Kaplan-Meier estimator. Death from any cause 
will be the event and patients will be censored at the date of last contact or two years from 
the analysis start day, whichever comes first. Start day will either be the date of enrollment 
or date of HaploBMT for the two objectives. A point estimate and confidence interval will 
be provided for the rate of OS at one year and two years for both analyses. 
5.5.2 One-year Event-free Survival 
For those who start HU conditioning, EFS from start of HU conditioning will be estimated 
using the Kaplan-Meier estimator. A point estimate and confidence interval will be provided 
for the rate of EFS at one year since the start of HU conditioning. 
For those with a transplant, EFS from day of transplant will be estimated using the Kaplan-

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Meier estimator. A point estimate and confidence interval will be provided for the rate of 
EFS at one and two years post-transplant. 
5.5.3 Primary or Secondary Graft Rejection 
Primary graft failure will be summarized by the frequency and proportion of participants 
experiencing primary graft failure at Day 42 post-transplant. 
Secondary graft rejection will be estimated using the cumulative incidence function, treating 
death as a competing risk. A point estimate and confidence interval will be provided for the 
cumulative incidence at one year and two years post-transplant for secondary graft rejection. 
5.5.4 Disease Recurrence 
To assess the incidence of disease recurrence from enrollment, a cumulative incidence curve will 
be estimated, treating death as a competing risk. A point estimate and confidence interval will be 
provided for the cumulative incidence at one year and two years post conditioning, and post-
transplant, respectively. 
5.5.5 Neutrophil and Platelet Recovery 
The incidence of neutrophil recovery from transplant will be estimated using the cumulative 
incidence function, treating death or second transplant as a competing risk. A point estimate and 
confidence interval will be provided for the cumulative incidences at Day 42 post-transplant. 
The incidence of platelet recovery from transplant will be estimated using the cumulative incidence 
function, treating death or second transplant as a competing risk. A point estimate and confidence 
interval will be provided for the cumulative incidence at Day 100 post-transplant. 
5.5.6 Lineage Specific Chimerism following HCT for SCD 
Lineage specific chimerism taking into account the genotype of the donor will be described. A 
point estimate and confidence interval will be provided for the mean percent donor chimerism at 
the time points specified in the Schedule of Evaluations Table. The proportions with mixed (5-
95%), full (>95%), or low (<5%) will be tabulated and described. 
5.5.7 Grade II-IV and Grade III-IV Acute GVHD 
Rates of acute GVHD will be tabulated. Cumulative incidence of acute grade II-IV GVHD will be 
estimated using the cumulative incidence function, treating death and second transplant prior to 
acute GVHD as a competing risk. A point estimate and confidence interval will be provided for 
the cumulative incidence at day 100 post-transplant. Time to GVHD will be calculated from 
transplant date. 
Cumulative incidence of acute grade III-IV GVHD will be estimated using the cumulative 
incidence function, treating death and second transplant prior to acute GVHD as a competing risk. 
A point estimate and confidence interval will be provided for the cumulative incidence at day 100 

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post-transplant. 
5.5.8 Chronic GVHD 
Rates of chronic GVHD will be tabulated by severity. Cumulative incidence of chronic GVHD 
will be estimated using the cumulative incidence function, treating death and second transplant 
prior to chronic GVHD as a competing risk. A point estimate and confidence interval will be 
provided for the cumulative incidence at 6 months, one year, and two years post-transplant. 
Analysis of severe, chronic GVHD will be similar. Time to GVHD will be calculated from 
transplant date. 
5.5.9 Complications and Events 
The frequency of the following complications and events will be tabulated, and the proportion of 
participants experiencing each at baseline and by 1 year and 2 years will be estimated, with 
confidence intervals provided for each estimate: 
x Idiopathic pneumonia syndrome (IPS) 
x Veno-occlusive disease 
x Various CNS toxicities 
x Stroke 
x Infection – bacterial/fungal sepsis, CMV reactivation with/without clinical disease, 
adenovirus, EBV PTLD, adenovirus, invasive fungal infection, CMV specified, viral 
mold infections and invasive fungal infections 
x Proportion of participants still on immunosuppression for GVHD 
The number of significant infections and number of participants experiencing infections will be 
tabulated by type of infection, severity, and time period post-transplant. 
In addition, the proportion of participants still on immunosuppression at 2 years after transplant 
will be estimated and a confidence interval will be provided. 
5.5.10 Quality of Life and Pain Intensity 
Quality of life will be described using the PROMIS pain and fatigue domains. Descriptive 
statistics and confidence intervals for the change from baseline will be reported for each 
domain for English- and Spanish-speaking patients in the adult stratum. Exploratory models 
may be used to investigate the change over time adjusted for participant covariates. 
The electronic pain diary is administered twice daily for 28 consecutive days for English-
VSHDNLQJSDWLHQWV\HDUVRIDJHDWWKHWLPHRIHQUROOPHQW$QDYHUDJHvalue will be 
computed for each day on which the diary shows two entries. If the diary reflects only a 
single entry for a day, then the single value will be used, and if a patient did not enter a 
value on a given day, that non- adherence will be tallied separately. The mean pain intensity 
from the diary will be the sum of the reported daily pain intensities averaged over the 

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number of days on which at least one pain intensity was reported. Descriptive statistics and 
confidence intervals for the change from baseline will be reported. Exploratory models may 
be used to investigate the change over time adjusted for participant covariates. 
5.5.11 Other Secondary Endpoints 
The following outcomes will be analyzed for transplanted participants: 
x Hematological outcomes 
x Renal function 
x Sickle vasculopathy as measured by brain MRI 
x Lung function (PFT), including FEV1 and restrictive lung disease 
x Cardiac Function (TRJV) 
x 6 minute walk distance 
x Other SCD-EOSI (defined in Section 3.8.2) 
For binary outcomes, proportions and confidence intervals will be provided at each time point. For 
continuous outcomes, results will be summarized with descriptive statistics and confidence 
intervals will be provided where appropriate. 
5.6 
Safety Analysis 
AEs and toxicities will be reported and summarized, and descriptive statistics will be provided. 
Infections will be reported as described in section 5.5.9. 
Hospitalizations will be tabulated and summarized. 

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APPENDIX A  
HUMAN SUBJECTS 

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HUMAN SUBJECTS
1. SUBJECT CONSENT
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease. The Principal Investigator or 
another designated qualified staff member will conduct the conference. All potential risks 
associated with the use of conditioning regimen, GVHD prophylaxis medications, and all study 
treatments and interventions should be discussed as objectively as possible.
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 their 
Institutional Review Board (IRB) of record. The DCC will verify the adequacy of the consent 
forms prior to submission to the IRB. Each center must provide evidence of IRB approval.
The consent document should be reviewed with the patient and family prior to proceeding to 
transplantation. Informed consent from the patient and the patient’s parent/guardian will be 
obtained using a form approved by the Institution’s IRB of record prior to enrolling the patient.
2. CONFIDENTIALITY
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code. The code linking the patient’s identity with the ID code will be kept separately at 
the center. The ID code will be transmitted to the BMT CTN Data and Coordinating Center upon
enrollment.
3. PARTICIPATION OF WOMEN AND MINORITIES AND OTHER POPULATIONS
Women and ethnic minorities and other populations will be included in this study. Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities expected 
from data reported to the CIBMTR. Centers will be notified if their rates differ significantly from 
those expected and asked to develop appropriate recruitment strategies.
It is expected that the number of minority patients on this study will be large given the disease 
being studied.

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INFORMED CONSENTS

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INFORMED CONSENT TO PARTICIPATE IN RESEARCH 
 
 
YOUR NAME:  
  
 
 
 
 
 
 
 
 
Study Title: 
Reduced Intensity Conditioning for Haploidentical Bone 
Marrow Transplantation in Patients with Symptomatic 
Sickle Cell Disease 
 
Protocol: 
BMT CTN # 1507 
 
Principal Investigator: 
[Insert site PI] 
 
Co-Investigators: 
[Insert site co-I] 
 
Study Coordinators: 
[Insert site study coordinator/s] 
 
[Insert site department/facility name, address, and phone number] 
 
National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health 
(the NIH), Bethesda, Maryland 
 
 
CONSENT FOR AN ADULT OR CHILD TO BE A SUBJECT IN CLINICAL RESEARCH 
AND AUTHORIZATION TO PERMIT THE USE AND DISCLOSURE OF 
IDENTIFIABLE 
MEDICAL 
INFORMATION 
(PROTECTED 
HEALTH 
INFORMATION) FOR RESEARCH PURPOSES. 
 
 
 
 
[Insert site logo and/or address] 

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1. INTRODUCTION 
We invite you to join this clinical trial. A clinical trial is a research study. You’re being asked to 
join this study because: 
 You have Severe Sickle Cell Disease (SCD) 
 You’re between 5 - 45 years old 
 An allogeneic transplant is a treatment option for you 
 You have a donor (parent, brother, sister, or other family member) who is a half match 
SCD is sometimes treated with an allogeneic transplant (also known as a bone marrow 
transplant). An allogeneic transplant may use a matched or mismatched donor. 
We’re doing this study to learn if a new type of allogeneic transplant called a haploidentical 
transplant is safe and effective to treat SCD. This study will use a parent, brother, sister or other 
family member who is a mismatched donor that has a half match with you. 
If you agree to be in the study it will be for 2 years. The study will include 80 people (40 
children and 40 young adults) at 30 – 40 transplant centers. 
Definitions of bolded terms are in the next section. 
This Consent Form will tell you about the purpose of the study, possible risks and benefits, other 
options available to you, and your rights as a participant in the study. Please take your time to 
make your decision. 
Everyone who takes part in research at [insert facility name] should know that: 
 Being in any research study is voluntary. 
 You may or may not benefit from being in the study. Knowledge we gain from 
this study may benefit others. 
 If you join the study, you can quit the study at any time. 
 If you decide to quit the study, it will not affect your care at [insert name of 
facility or institution]. 
 Please ask the study staff questions about anything that you do not understand, 
or if you would like to have more information. 
 You can ask questions now or any time during the study. 
 Please take the time you need to talk about the study with your doctor, study 
staff, and your family and friends. It’s your decision to be in the study. If you 
decide to join, please sign and date the end of this Consent Form. 
 

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You and your doctor will discuss other treatment choices if you don’t want to participate 
in this study. 
2. STUDY BACKGROUND 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN), are providing staff support and money for this 
research study. The BMT CTN and the NIH will make decisions about how to manage 
the study. 
SEVERE SICKLE CELL DISEASE AND ALLOGENEIC TRANSPLANT 
Severe Sickle Cell Disease (SCD) is a blood disorder you’re born with. Red blood cells carry 
oxygen to different parts of your body. SCD is caused by a change in hemoglobin, the protein 
that helps red blood cells carry oxygen in the body. The change blocks the blood flow in small 
vessels which can cause severe (serious) pain. It can also damage your lungs, brain, kidneys, and 
other organs. A person with SCD lives about 30 years shorter than a person without SCD. 
An allogeneic transplant, or bone marrow transplant, uses healthy blood-making cells from a 
donor to replace unhealthy ones. It requires donors and patients to have matched human 
leukocyte antigens (HLA). HLA is a protein marker found on most cells in your body. HLA 
markers are inherited (given to you from your mother or father). You get half of your HLA 
markers from your mother and half from your father. 
A haploidentical transplant is an allogeneic transplant where the donor matches exactly half of 
your HLA. Parents are always a half-match for their biological children and children are always 
a half-match for their biological parents. Biological siblings (brothers or sisters) have a 50% (1 
out of 2) chance of being a half-match for each other. 
In this study, we want to learn if a haploidentical transplant is effective and safe to treat SCD. 
This study will use a parent or other half-matched family member donor. This treatment may 
stop the disease and many of its health problems. But there is also a chance that it may not work, 
and the disease can come back. 
ALLOGENEIC TRANSPLANT – REDUCED INTENSITY TRANSPLANT 
There are 2 main steps with allogeneic transplant. First, to prepare your body, we use 
chemotherapy and radiation to destroy the abnormal blood cells. This step is called the 
conditioning regimen. Then, when the conditioning regimen is done, you’re given the donor 
cells for your transplant. 
In this study, your doctor will use lower doses of chemotherapy and radiation than are normally 
used for allogeneic transplant. This is called a reduced intensity transplant. 

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3. STUDY PURPOSE 
We’re doing this study to learn if a haploidentical transplant is safe and effective to treat SCD. 
A haploidentical transplant uses a half or partially matched donor. (“Haplo” means half.) This 
study will use a parent or other family member who is a half tissue match. 
You’re being asked to join this study because you: 
 Are between 5 – 14 years old and had one or more of the following: 
o Prior or silent stroke 
• 
Overt stroke –a permanent injury to the brain associated with physical 
manifestations that is associated with future overt strokes or silent strokes  
• 
Silent stroke –a permanent injury to the brain associated with decreased 
thinking abilities that might be as severe as an overt stroke and is 
associated with future silent stroke or overt strokes.  
o Serious pain episodes requiring hospitalization not fully managed by medical 
therapy. 
o One episode of life-threatening acute chest syndrome episode resulting in intensive 
care admission. 
o Increased blood pressure in the arteries of your lungs (pulmonary hypertension) or 
in the rest of your body (systemic hypertension) that can make it difficult to breathe. 
o Recurrent priapism (prolonged penile erection for at least 4 hours) occurring twice 
in 12 months or 3 times in 24 months while on hydroxyurea if indicated.   
 Are between 15 – 45 years old and had 1 or more of the following: 
o Stroke 
o 2 or more episodes of acute chest syndrome in the last 2 years while 
getting other treatment such as hydroxyurea 
o 3 or more episodes of serious pain crises in the last 2 years while 
getting other treatment such as hydroxyurea 
o Regular red blood cell (RBC) transfusions (8 or more transfusion events 
during the last year to prevent sickle-related health problems) 
o Fast blood flow in your heart and in the wrong direction. This may mean 
you may have a higher risk of dying. 
 Have a donor (parent, brother, sister, or other family member) who is a 
half match You can’t be in this study if you have one or more of the 
following: 
o A brother or sister who closely matches more than half of your HLA 
o Liver cirrhosis (damage to the liver which can lead to scarring and liver failure) 
o A very serious bacterial, fungal, or viral infection in the past 6 weeks 

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o HIV infection 
o Already had a bone marrow transplant 
o Joined a study where you took a study drug or used a medical device. 
 
o A serious autoimmune disorder (where your own immune system attacks 
your body) like lupus or scleroderma 
o Are currently pregnant or breast feeding 
o Do not agree to use contraception or sexual abstinence for 12 months 
after the bone marrow transplant 
4. RIGHT TO ASK QUESTIONS AND/OR WITHDRAW 
You have the right to ask questions about the study at any time. If you have questions about your 
rights as a participant or you want to leave the study, please contact: 
[Insert contact info] 
Being in this study is voluntary. You can choose to not be in this study or leave this study at any 
time. 
If you choose not to take part or to leave this study, it will not affect your regular medical care in 
any way. 
Your study doctor and study staff will be available to answer any questions that you may have 
about taking part or leaving this study. 
5. STUDY TREATMENTS AND TESTS 
If you join this study, we’ll check your health before, during, and for 2 years after your 
treatment. 
A. BEFORE YOUR TREATMENT 
You’ll have several check-ups and tests before your transplant. Some of these tests are given 
to all patients who get a transplant. Others are for this study only. 
Some of the tests will be done up to 6 months before you enroll and some of the tests will be 
done later, about a month before enrolling on the study and then again before starting the 
drug called hydroxyurea, or before starting the drug called ATG (Thymoglobulin). The tests 
that are given to all transplant patients (not just patients in this study) and include: 
 
Medical history, including past and present use of medications. Note: Incomplete 
information could have a serious effect on your health and safety. 

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 
Physical exam, height and weight 
 
Performance score to see how well you can do certain activities like going to work 
and caring for yourself 
 
Urine test to check for proteins and infections 
 
Radiology test or a 24-hour urine collection to learn how well your kidneys work 
 
1 tablespoon of blood to check for: 
o 
Blood counts including the number of platelets 
o 
Number of elements and minerals in your blood 
o 
Different kinds of hemoglobin proteins in your red blood cells 
o 
Infections with hepatitis, herpes simplex, syphilis, HIV, Human T-
Lymphotropic Virus (HTL), chicken pox, and shingles that are active now or 
happened in the past 
 
1 teaspoon of blood for: 
 
Pregnancy test, if you’re female and able to get pregnant 
The total amount of blood needed for these tests will be a little over 3 teaspoons. 
 
Optional research samples 
o 
If you agree, we will also collect about 4-8 teaspoons of blood for research. 
Other tests for this study include: 
 
Pain diary: Your doctor and/or research team will provide the instructions you will 
need to complete the pain dairy. If you speak English and are 15 or older, self-
documentation of pain will occur twice daily for 28 days via an electronic application. 
 
Questions about your health and quality of life if you speak English or Spanish and 
are 15 years or older (to find out how healthy you feel you are and how well you can 
do your everyday activities): a survey to measure health outcomes from the patient 
perspective. Your doctor and/or the research team will provide the instructions and 
materials you will need to complete the survey at each time point it is due. 
 
Electrocardiogram (ECG and EKG) to take pictures of your heart and see how well 
it’s working 
 
Chest X-ray 
 
Lung function tests to see how well your lungs work (including a test to see how far 
you can walk in 6 minutes) 
 
Brain scan (MRA or MRI) to show a picture of your brain and its blood vessels 
 
MRI of your liver if you’ve had a lot of red blood cell transfusions 
 
Liver biopsy if needed (we’ll take a small sample of your liver if your liver MRI 
shows high iron) to see if there is damage from iron 
 
Cardiac scan (MRI) if needed 

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 
HLA typing and blood test for rejecting the donor bone marrow 
 
Data regarding your clinical situation, including follow-up 2 years after your 
transplant, may be obtained from the CIBMTR, which captures information on all 
US transplants. 
B. DURING YOUR TREATMENT 
Getting Your Catheter: 
A surgeon will place a central venous catheter in your body, most likely in your chest. A 
catheter is a thin, hollow tube that allows medicines, blood transfusions, and blood draws to 
be done painlessly and to avoid repeated needle sticks. It’s also called the “central line”. 
The catheter will need to be cleaned every day to avoid blood clots and infection. You and 
your caregiver will be given instructions on how to take care of the catheter. 
The surgeon will talk with you before the surgery about the risks related to having a 
catheter.  
Preparing for Transplant: 
To prepare your body for transplant, we use chemotherapy and radiation to destroy or stop 
the abnormal blood cells from being made. This step is called the “conditioning regimen”. 
The chemotherapy (chemo) drugs also help the donor cells engraft. “Engraft” means that 
the cells start to grow and make new cells and show up in your blood. 
See Table 1: Schedule of Treatments Before and After Transplant for a list of the 
chemo drugs you’ll get and how often you’ll take them. The chemo drugs and radiation 
before transplant include: 
1. 
Hydroxyurea: This treatment will start in the hospital (or clinic) and continue at 
home. 
2. 
Rabbit anti-thymoglobulin (rATG) 
3. 
Thiotepa 
4. 
Fludarabine 
5. 
Cyclophosphamide 
6. 
Total body irradiation (TBI): A single dose will be given while you are put 
in front of a machine. 
Transplant Day: 
On transplant day (Day 0), you’ll get your donor cells through your catheter. 
Your blood pressure, heart and respiration rates, and temperature will be 

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taken before and during the transplant. 
The study doctor may also give you medicines before the transplant to help with any 
side effects or discomfort. Some of these side effects and discomforts include: 
 
Complications with catheter like blood clots and infection 
 
Slow recovery of blood counts 
 
New stem cells aren’t growing at all (graft failure) which means you continue 
to have your disease 
 
Graft-Versus-Host Disease (GVHD) (described below) 
 
Damage to the vital organs in your body 
 
Serious infections 
 
Disease comes back (this happens when your body rejects the new stem cells) 
 
Death 
 
Reproductive risks (ability to have or father children after the transplant) 
See Section 6: Risks and Discomforts for more information. 
C. AFTER YOUR TRANSPLANT 
Graft Versus Host Disease (GVHD) Prevention Drugs: 
Graft Versus Host Disease (GVHD) happens when the donor cells see your body 
as foreign (or different) and attack it. It can be a very serious side effect of 
transplant. 
We’ll give you 3 drugs to help prevent GVHD after your transplant. See Table 1: 
Schedule of Treatments Before and After Transplant for a list of the GVHD 
prevention drugs you’ll get and how often you’ll take them: 
1. 
Cyclophosphamide: You’ll get cyclophosphamide to prevent GVHD and 
also to help the donor cells engraft. “Engraft” means that the cells start to 
grow and make new cells and show up in your blood. 
2. 
MESNA: Because there is a risk of irritation and damage to the bladder, 
MESNA will be given before and after cyclophosphamide to help protect 
the bladder. 
3. 
Mycophenolate mofetil (MMF): Your doctor may keep giving MMF to you 
after 35 days, if you have GVHD. 
4. 
Sirolimus: The study doctor may change the dose based on how your body 
reacts to the drug. Also, your doctor may keep giving it to you after 1 year, 
if you have GVHD. 

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TABLE 1: SCHEDULE OF TREATMENTS BEFORE AND AFTER TRANSPLANT 
 
 
Treatments 
Days 
-70 to -10 
Days 
-9, -8 
Da y 
-7 
Days 
-6, -5 
Days 
-4 to -2 
Da y 
-1 
Day 0 
(Transplant 
day) 
Days 
+3, +4 
Days 
+5 to 
+35 
Days 
+5 to +365 / 
1 year 
Hydroxyurea, by mouth 
X 
 
 
 
 
 
 
 
 
 
Rabbit anti-thymocyte globulin (rATG), 
by IV 
 
X 
X 
 
 
 
 
 
 
 
Thiotepa, by IV 2 times in one day 
 
 
X 
 
 
 
 
 
 
 
Cyclophosphamide, by IV 2 times 
daily 
 
 
 
X 
 
 
 
 
 
 
Fludarabine, by IV 
 
 
 
X 
X 
 
 
 
 
 
Total body irradiation (TBI), 1 dose 
standing in front of machine 
 
 
 
 
 
X 
 
 
 
 
Transplant day (donor marrow) 
 
 
 
 
 
 
X 
 
 
 
Cyclophosphamide, by IV 
 
 
 
 
 
 
 
X 
 
 
Mesna, by IV before and after 
cyclophosphamide 
 
 
 
 
 
 
 
X 
 
 
Mycophenolate mofetil (MMF), by 
mouth or injection 3 times daily 
 
 
 
 
 
 
 
 
X 
 
Sirolimus, by mouth 
 
 
 
 
 
 
 
 
 
X 

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After-Transplant Tests: 
1 to 100 days after your transplant (Day 1 – 100) 
 
Weekly GVHD tests 
 
Weekly Medical history, physical exam, height and weight (until Day 28) 
 
Weekly Performance score to see how well you can do certain activities like 
going to work and caring for yourself (until Day 28) 
 
1 Tablespoon of blood to check for: 
o 
Blood counts including the number of platelets (two times per week until 
Day 28, weekly until Day 84) 
o 
Number of elements and minerals in your blood (beginning on Day 28 until 
Day 100) 28 days after your transplant (Day 28) 
 
Blood or bone marrow sample to find the amount of donor cells in your body 
(chimerism test) done at Day 28 and Day 42 (if needed) 
 
Weekly Medical history, physical exam, height and weight 
 
Optional blood samples 
60 days after your transplant (Day 60) 
 
Optional blood samples 
100 days after your transplant (Day 100) 
 
Medical history, physical exam, height and weight 
 
Hemoglobin (blood) test to measure how much sickle hemoglobin is in your blood 
 
Performance score to see how well you can do certain activities like going to 
work and caring for yourself 
 
Blood or bone marrow sample to find the amount of donor cells in your body 
(chimerism test) 
 
Optional blood samples 
6 months after your transplant (Day 180) 
 
Performance score to see how well you can do certain activities like going to 
work and caring for yourself 
 
Hemoglobin (blood) test to measure how much sickle hemoglobin is in your blood 
 
GVHD tests 

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 
Blood sample to find the amount of donor cells in your body (chimerism test) 
 
Blood counts including the number of platelets 
 
Weekly Medical history, physical exam, height and weight 
 
Optional blood samples 
18 months after your transplant (Day 540) 
 GVHD tests 
1 and 2 year(s) after your transplant (Day 365 and Day 730) 
 
Medical history and physical exam, including height and weight 
 
GVHD tests 
 
Immune system test to see how well your immune system is working 
 
Hemoglobin (blood) test to measure how much sickle hemoglobin is in your blood 
 
Blood counts including the number of platelets 
 
24-hour urine collection to learn how well your kidneys work 
 
Lung function test and oxygen level 
 
6 minute walk distance test 
 
Echocardiogram (echo) to take pictures of your heart and see how well it’s 
working if your doctor determines this is needed 
 
Cardiac MRI if needed 
 
Liver MRI for those with iron overload 
 
Brain scan to show a picture of your brain and its blood vessels 
 
Questions about your health and quality of life if you speak English or Spanish and 
are 15 or older 
 
Blood sample to find the amount of donor cells in your body (chimerism test) 
 
Twice daily pain diaries if you are 15 or older (Days 337-365 and Days 702-730) 
 
Optional blood samples (at Day 365) 
Most of these tests will be done as part of your regular medical care after transplant. The 
tests for this study include lung function test, echocardiogram (if needed), questions 
about your health and quality of life, brain scan, and optional blood samples. 

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Table 2: Timeline of Tests after Your Transplant lists the tests you’ll have after your bone marrow transplant. 
 
TABLE 2: TIMELINE OF TESTS AFTER YOUR TRANSPLANT 
 
Tests 
Days After Transplant 
Day 1- 100 
(weekly) 
+42 
+60 
+100 
+180 
+365 
+540 
+730 
Tests for GVHD 
 
 
 
 
 
 
 
 
Test required by the hospital, 
including blood and urine tests 
 
 
 
 
 
 
 
 
Hemoglobin (blood) test 
 
 
 
 
 
 
 
 
Tests to see how much of the 
donor cells are in your body 
(chimerism) 
 
(Day 28) 
 
(if needed) 
 
 
 
 
 
 
Quality of life surveys if you speak 
English or Spanish and are 15 or older 
 
 
 
 
 
 
 
 
Performance score to see how well 
you can do certain activities like going 
to work and caring for yourself 
 
(weekly until 
Day 28) 
 
 
 
 
 
 
 
Immune system test 
 
 
 
 
 
 
 
 

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Tests 
Days After 
Transplant 
Day 1- 100 
(weekly) 
+42 
+60 
+100 
+180 
+365 
+540 
+730 
Lung function test (including a 
test to see how far you can walk 
in 6 minutes) 
 
 
 
 
 
 
 
 
Echocardiography test to take 
pictures of your heart and see 
how well it’s working (if 
needed) 
 
 
 
 
 
 
 
 
Brain scan 
 
 
 
 
 
 
 
 
Pain diaries over 28 days if you 
speak English and are 15 or 
older 
 
 
 
 
 
 
 
 
Cardiac MRI (if needed) 
 
 
 
 
 
 
 
 
Liver MRI (for those with 
iron overload 
 
 
 
 
 
 
 
 
Optional blood samples 
 
(Day 28) 
 
 
 
 
 
 
 

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6. RISKS AND DISCOMFORTS 
You may have side effects while on the study. Side effects can range from mild to serious. Your 
health care team may give you medicines to help with certain side effects like nausea (feeling 
sick to your stomach). In some cases, side effects can last a long time or may never go away. 
A. RISKS OF MEDICINES 
Table 3: Risks and Side Effects shows how side effects are grouped together. The 3 groups are 
based on how often patients get each side effect. 
 
TABLE 3: RISKS AND SIDE EFFECTS 
 
Likely 
What it means: This type of side effect is expected in more than 20% 
of patients. This means that 21 or more patients out of 100 might get 
this side effect. 
Less Likely 
What it means: This type of side effect is expected in 20% of patients 
or fewer. This means that 20 patients or fewer out of 100 might get 
this side effect. 
Rare, but Serious 
What it means: This type of side effect is expected in fewer than 2% 
of patients. This means that 1 or 2 patients (or fewer) out of 100 
might get this side effect. It doesn’t happen very often but is serious 
when it does. 
 
Risks of Conditioning Regimen Medicines 
 
The risks of the chemotherapy drugs you get as part of the conditioning regimen are listed below. 

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HYDROXYUREA – CHEMOTHERAPY DRUG 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% 
of patients) 
x Nausea (feeling sick to 
your stomach) 
x Throwing up 
x Diarrhea 
x Loss of appetite 
x Low number of red blood 
cells (anemia) 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Mouth sores 
x Throat inflammation (sore, 
red, swollen throat), going 
down to the stomach 
x Bleeding 
x Infection 
x Dizziness 
x Headaches 
x Changes in behavior 
x Confusion 
x Seeing or hearing things 
that are not really there 
x Feeling drowsy 
x Abnormal liver tests 
x Yellow tint to skin or eyes 
(jaundice) 
x Darkening skin 
x Pain and difficulty with 
urination 
x Kidney damage 
x Seizures 
x Finger and toe nail changes 
x Hives 
x Skin rash 
x Sudden high fever 

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FLUDARABINE (FLUDARA®) – CHEMOTHERAPY DRUG 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% 
of patients) 
x Low number of red 
blood cells (anemia) 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Feeling tired 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Weak immune system 
x Pneumonia 
x Infection 
x Bleeding 
x Pain 
x Electrolyte imbalance 
x Diarrhea 
x Mouth sores 
x Skin rash 
x Fever 
x Swelling of hands and feet 
x Numbness and tingling in 
hands and/or feet 
x Loss of appetite 
x Changes in vision 
x Feeling nervous or anxious 
x Confusion 
x Cough 
x Difficulty breathing 
x Feeling weak 
x Severe brain injury which 
can lead to death 
x Kidney damage that could 
require dialysis 
x Coma 
x New (secondary) cancers 

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RABBIT ANTI-THYMOCYTE GLOBULIN (R-ATG, 
THYMOGLOBULIN®) – CHEMOTHERAPY DRUG 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 
2% of patients) 
x Fever 
x Chills 
x Low number of red 
blood cells (anemia) 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Weak immune system 
x Bleeding 
x Infection 
x Skin rash 
x Joint ache and pain 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Diarrhea 
x Headache 
x Sweating 
x Back pain 
x Severe itching 
x Feeling tired 
x Loss of appetite 
Serum sickness with: 
x Severe skin rash 
x Mouth sores 
x Vaginal sores, if female 
x Pain and swelling in 
joints 
x Kidney damage 
x Stomach (belly) pain 
x Feeling dizzy 
x High blood pressure 
x Blisters 
x Muscle pain 
x Herpes simplex infection 
x Throat inflammation (sore, 
red, swollen throat) 
x Kidney failure 
Severe allergic reaction which 
may cause: 
x Life-threatening drop in 
blood pressure 
x Wheezing 
x Difficulty breathing 
x Severe hives 

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THIOTEPA – CHEMOTHERAPY DRUG 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% 
of patients) 
x Low number of red blood 
cells (anemia) 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Bleeding 
x Infection 
x Diarrhea 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Mouth and throat sores 
x Liver damage 
x Temporary hair loss 
x Loss of appetite 
x Infertility (inability to 
have children) 
x Change in vision 
x Swelling in lower legs 
and feet 
x Abnormal liver tests 
x Skin rash 
x Skin darkening 
x Red face 
x Painful and difficult 
urination 
x Kidney damage 
x Yellow tint to skin and eyes 
(jaundice) 
x Headache 
x Feeling dizzy 
x Seeing or hearing things 
that are not really there 
x Confusion 
x Disorientation 
x Seizures 
x Temporarily increased 
levels of liver enzymes 
x Finger or toenail changes 
x New (secondary) cancers 

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TOTAL BODY IRRADIATION (TBI) – RADIATION THERAPY 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% 
of patients) 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Diarrhea 
x Stomach (belly) pain 
x Feeling tired 
x Low number of red blood 
cells (anemia) 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Bleeding 
x Infection 
x Temporary hair loss 
x Cataracts 
x Slow growth in children 
x Infertility (inability to 
have children) 
x Thyroid problems or 
diabetes 
x Mouth sores 
x Lung inflammation and 
pneumonia 
x Red skin color 
x Abnormal liver tests 
x Pain and swelling under the 
chin 
x Difficulty swallowing 
x Back pain 
x New (secondary) cancers 
x Lung damage 
x Kidney damage 

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Risks of Drugs Used to Prevent GVHD 
 
You will get medicines to help prevent GVHD after your transplant. The side 
effects of the GVHD drugs are listed below. These side effects usually stop when 
you’re done taking the medicines. 
 
CYCLOPHOSPHAMIDE (CYTOXAN®) – GVHD PREVENTION DRUG 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% of 
patients) 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Bleeding 
x Infection 
x Blood in urine 
x Weak immune system 
x Temporary hair loss 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Headache 
x Dizziness 
x Loss of appetite 
x Sores in mouth or on lips 
x Diarrhea 
x Menstrual periods stop in 
females 
x Low sperm count in males 
x Low number of red blood 
cells (anemia) 
x Temporary darkening of 
finger and toenail beds 
x Acne 
x Feeling tired 
x Damage to unborn baby or 
miscarriage 
x Birth defects 
x Lung scars, with cough and 
shortness of breath 
x Severe heart muscle injury and 
death 
x New (secondary) cancers 

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MESNA – BLADDER DAMAGE PREVENTION DRUG 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% 
of patients) 
x Nausea (feeling sick to 
your stomach) 
x Low blood pressure 
x Feeling dizzy or faint 
 
x Throwing up (vomiting) 
 
x Diarrhea 
 
x Stomach (belly) pain 
 
x Feeling tired 
 
x Headache 
 
x Pain in joints 
 
x Pain in arms and hands, 
legs and feet 
 
x Change in the way things 
taste 
 
x Skin rash 
 
x Hives 
 

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SIROLIMUS – GVHD PREVENTION DRUG 
Likely 
 
(May happen in more 
than 20% of patients) 
Less Likely 
 
(May happen in fewer 
than 20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 
2% of patients) 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Diarrhea and/or 
constipation 
x High blood pressure 
x Tremor (shaking) 
x Infection 
x Fever 
x Feeling weak 
x Feeling tired 
x Abnormal kidney tests 
x Low number of red 
blood cells (anemia) 
x Headache and/or back 
pain 
x Joint or muscle pain 
x Stomach or belly pain 
x High levels of sugar in 
the blood 
x High cholesterol 
x Swelling in feet and 
lower legs 
x Weight gain 
x Acne 
x Chest pain 
x Insomnia (unable to 
sleep) 
x Low level of magnesium, 
potassium and/or 
phosphate 
x Abnormal liver tests 
x Skin rash or hives 
x Upset stomach 
(heartburn) 
x Throat inflammation 
(red, sore, swollen 
throat), going down to 
stomach 
x Shortness of breath 
x Low number of white 
blood cells 
x Low number of blood 
platelets 
x Bleeding 
x Infections 
x Slow wound healing 
x Unwanted hair growth 
x Low blood pressure 
x Lung problems, including 
asthma 
x Loss of appetite 
x Serious infections 
x Fast heartbeat 
x Heart damage 
x Blood clots 
x Kidney failure 
x Bone thinning 
(osteoporosis) or loss 
(necrosis) which may 
cause broken bones 
x New (secondary) skin 
cancers 

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MYCOPHENOLATE MOFETIL (MMF, CELLCEPT®) – GVHD 
PREVENTION DRUG 
 
Likely 
 
(May happen in more than 
20% of patients) 
Less Likely 
 
(May happen in fewer than 
20% of patients) 
Rare, but Serious 
 
(May happen in fewer than 2% 
of patients) 
x Birth control pills may not 
work 
x Birth defects 
x Damage to unborn baby or 
miscarriage 
x Nausea (feeling sick to 
your stomach) 
x Throwing up (vomiting) 
x Diarrhea 
x Stomach (belly) pain 
x Headache 
x Low number of white blood 
cells 
x Infection 
x Swelling of hands, feet, or 
lower legs 
x Low number of red blood 
cells (anemia) 
x Skin rash 
x Insomnia (unable to sleep) 
x Feeling dizzy 
x Hand shaking (tremors) 
x Difficulty breathing 
x Abnormal bruising 
x Fast heartbeat 
x Feeling very tired 
x Feeling weak 
x Blood in stool 
x Blood in vomit 
x New (secondary) cancers 
x Progressive multifocal 
leukoencephalopathy (a 
disease that damages the brain 
and may lead to death) 
 
Risks and Toxicities Related to Transplant 
 
The following problems may happen because of your transplant. These risks may happen with all 
allogeneic transplants, whether they are part of a study or not. The risks include: 
 
Complications with Central Venous Catheter: 
The most common problems with central venous catheters are: 1) blood clots in the catheter and 
2) 
infection. Your doctor will inject medicines into the catheter to dissolve a clot or treat an 
infection. If the medicines don’t work, the catheter might be replaced with a new one. 

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Slow Recovery of Blood Counts: 
The red blood cells, white blood cells, and platelets can be slow to recover after a transplant. Until 
your blood counts recover, you’ll be at risk for bleeding and infection, and you’ll need blood and 
platelet transfusions. 
 
Graft Failure: 
We’ll check your blood often to see how well the stem cells (the “graft”) are growing inside your 
body. If the graft isn’t growing well or at all (graft failure), we’ll give you medicines to help the 
stem cells grow. You may also need a second transplant. 
 
Past experience suggests that there can be a 10 - 15% chance of graft failure. If your graft fails, 
you’ll stop being in this study and receive the standard care for SCD. 
 
Graft-Versus-Host Disease (GVHD): 
GVHD happens when the donor cells see your body as foreign and attack it. In most cases, 
GVHD can be successfully treated. Sometimes GVHD is serious or difficult to treat and may 
lead to death. You’ll be watched closely for GVHD and given drugs to help prevent and treat it. 
 
Acute GVHD, which can happen 0 – 3 months after transplant, may cause skin rash, nausea, 
vomiting, diarrhea, abdominal pain, problems with your liver, and an increased risk of infection. 
 
Chronic GVHD, which can happen 3 months or later after transplant, may produce skin rashes, 
hair loss, thickened dry skin, dry eyes, dry mouth, liver disease, weight loss, diarrhea, and an 
increased risk of infection. 
 
To confirm the diagnosis of acute or chronic GVHD, your doctor may do a biopsy of your skin, 
gut, or liver. A biopsy is a small sample of your tissue to look at under the microscope. 
 
Damage to the Vital Organs in Your Body: 
The transplant may cause problems with your organs such as the heart, lungs, liver, gut, kidneys, 
bladder, or brain. The kidneys and liver are most likely to be damaged. 
 
Some patients will experience serious lung problems from an infection, from chronic GVHD or 
from the chemotherapy and radiation. 
 
Serious Infections: 
Full and complete recovery of your immune system may take several months. During this time, 
there is an increased risk of infection. We’ll give you drugs to reduce the chance of infection, but 
these treatments don’t always work. If you get an infection, you may have to stay in the hospital 
longer or be re-hospitalized. Most infections can be treated, but some result in death. 

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Recurrence of Disease and Graft Rejection: 
There is a risk that the new marrow will fail to “take” and won’t grow after your transplant. This 
is called graft rejection. If this happens, your own marrow will recover, and sickle cell disease 
will come back. Pain crises or other complications might also return. Very rarely, other 
complications from graft rejection can happen including serious infection and the need for a 
blood transfusion. 
 
Damage to Central Nervous System (CNS): 
The transplant may affect your central nervous system (CNS). Your CNS includes your brain 
and spine. We’ll watch you closely after your transplant for any side effects to your brain or 
spine. 
 
Risk of Death: 
Side effects of an allogeneic transplant can be very serious and possibly lead to death. Death can 
occur either as a result of the medications you receive to prepare your body for transplant or 
from a complication of transplant. We’ll do everything we can to make the transplant as safe as 
possible for you. 
 
Reproductive Risks: 
The drugs used in this research study may damage your reproductive organs and affect your ability 
to have children. We don’t know the exact risk of sterility (inability to have children) caused by 
taking the study drugs. 
 
You should talk to a specialist about your options for fertility preservation. Your options may 
include storing your sperm or eggs, or tissue from your ovary or testes. We’ll refer you to a 
fertility preservation center before your transplant. 
 
The treatments in this study have not been proven to be safe at any stage of pregnancy, including 
when the sperm enters the egg (conception). 
 
If you’re female: 
o Your menstrual cycle might become irregular or permanently stop if you’ve gone 
through puberty. 
o You must use 2 effective methods of birth control if you’re sexually active (having 
sexual intercourse with a male partner) during your transplant. You must continue to use 
2 effective birth control methods or refrain from all acts of vaginal sex (abstinence) until 
you’re finished with your GVHD prevention medicines or GVHD treatment or 12 
months after your transplant (whichever comes last). 
 

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Examples of effective birth control include: 
 
1. Consistent use of birth control pills 
2. Injectable birth control methods (Depo-Provera, Norplant) 
3. Tubal sterilization or male partner who has undergone a vasectomy 
4. Placement of an IUD (intrauterine device) 
5. Use a diaphragm with contraceptive jelly every time you have sex and/or 
6. Use condoms with contraceptive foam every time you have sex. 
Tell your doctor right away if you become pregnant during the study. 
 
 If you’re male: 
o If you’re sexually active (having sexual intercourse with a female partner), you or your 
partner must use 2 effective methods of birth control during your transplant. You or your 
partner must continue to use 2 effective birth control methods or refrain from all acts of 
vaginal sex (abstinence) until you are finished with your GVHD prevention medicines or 
GVHD treatment or 12 months after your transplant (whichever comes last). 
 
Examples of effective birth control include: 
 
1. Consistent use of birth control pills 
2. Injectable birth control methods (Depo-Provera, Norplant) 
3. Tubal sterilization or male partner who has undergone a vasectomy 
4. Placement of an IUD (intrauterine device) 
5. Use a diaphragm with contraceptive jelly every time you have sex and/or 
6. Use condoms with contraceptive foam every time you have sex. 
Tell your doctor right away if your partner becomes pregnant during the study. 
 
Check with your doctor to understand more about these risks. 

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OTHER RISKS 
 
Quality of Life Surveys: 
There are a few risks from completing the quality of life surveys. Some of the questions or topics 
may upset you. You may feel emotional or that your privacy is lost. Talk to your doctor about 
your privacy concerns. We can put you in touch with a counselor or trained support specialist, if 
needed. 
 
Risks of Blood Draws: 
There are no major risks with blood draws. Having your blood drawn can be uncomfortable and 
may cause a bruise. In rare cases, a blood draw can cause fainting. Only trained people will draw 
your blood. 
 
Unforeseen Risks: 
Other new risks might appear at any time during the study. These risks might be different from 
what is listed in this Consent Form. There may be some unknown or unanticipated discomforts or 
risks associated with this treatment in addition to those specified above, but every precaution will 
be taken to assure your personal safety and to minimize discomforts. 
 
Other Treatments or Medicines: 
Some medicines react with each other, so it’s important to tell the study doctor or staff about any 
other drugs, treatments, or medicines you’re taking. This includes non-prescription or over-the- 
counter medicines, vitamins, and herbal treatments. 
 
It’s also important that you tell the study staff about any changes to your medicines while you’re 
in the study. 
 
For more information about risks and side effects, ask your study doctor. 
 
7. OTHER TREATMENTS 
 
It’s optional to join this study. If you choose not to join, you may still receive an allogeneic 
transplant to treat your disease. The treatment you’d receive could be very similar to what you’d 
receive in this study. 
 
Your study doctor will talk with you about your options. Your other choices may include: 
 
 Other types of transplant that use different doses of medicines (check with your doctor) 
 Other clinical trials that use mismatched related (parent, brother, sister or 
other family member) donors, unrelated donors or other stem cell sources 
(check with your doctor) 

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 Standard care for SCD (such as hydroxyurea or blood transfusions) 
 Another experimental treatment that is not a transplant 
 
Every treatment option has risks and benefits. Your study doctor will discuss 
the options, including the risks and benefits, with you. 
 
If you decide not to join this study, your medical care will not be affected in any way. 
 
8. POSSIBLE BENEFITS 
 
We don’t know if the treatments in this study will make your SCD better. If the transplant works 
well, you may not have any more symptoms of SCD such as serious pain. 
 
The study results will help doctors know what works best to treat SCD. This knowledge could 
help SCD patients in the future. 
 
9. NEW INFORMATION AVAILABLE DURING THE STUDY 
 
The study doctors could learn new information about the risks and benefits of allogeneic 
transplant and the study medicines while the study is going on. If this happens, they’ll tell you 
about it. Your doctor may decide to stop your participation. You may decide that you don’t want 
to continue in the study. 
 
If you decide to stop being in the study, your doctor will discuss other treatment options with 
you. 
 
10. 
PRIVACY, CONFIDENTIALITY AND USE OF INFORMATION 
 
Your privacy is very important to us. The study doctors will make every effort to protect it. The 
study doctors have a privacy permit to help protect your records if there is a court case. However, 
some of your medical information may be given out if required by law. If this should happen, the 
study doctors will do their best to make sure that any information that goes out to others will not 
identify who you are. 
 
If information from this study is published or presented at scientific meetings, your name and other 
personal information will not be used. Your study number is not related to your name, social 
security number or medical record number at [insert facility name]. 
 
Information about your transplant from your original medical records may be seen or sent to 
national and international transplant registries, including: 
 The Center for International Blood and Marrow Transplant Research (CIBMTR) 

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 The National Marrow Donor Program (NMDP) 
 
 The Food and Drug Administration (FDA) 
 
 The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
 
 Data and Coordinating Center of the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN) 
 
 Data Warehouse Consultants (DWC) which is an agent of Emory University that will 
manage the pain diary. DWC will have access to your phone number, email address, IP 
Address and data that is entered in the pain dairy application. 
 
 Researchers and staff members at Vanderbilt University for central review of brain 
MRI/MRA images. 
 
 Dr. Allistair Abraham and laboratory staff at Children’s National Medical Center 
 
 Other authorized study organizations 
 
We’ll not identify you by name in any publications or reports that come from these 
organizations or groups. 
11. 
ENDING YOUR PARTICIPATION 
 
The study doctor or the study sponsor may stop the study at any time. We may ask you to leave 
the study if you don’t follow directions or if you suffer from side-effects of the treatment. If you 
are asked to leave the study, the reasons will be discussed with you. 
 
Possible reasons to end your participation in this study include: 
 
 You don’t meet the study requirements. 
 You need a medical treatment not allowed in this study. 
 The study doctor decides that it would be harmful to you to stay in the study. 
 You’re having serious side-effects. 
 You become pregnant. 
 You can’t keep appointments or take study drugs as directed. 
 The study is stopped for any reason. 
 
12. 
PHYSICAL INJURY AS A RESULT OF PARTICIPATION 

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It’s important that you tell your study doctor or study staff if you feel that you’ve been hurt or 
injured because of taking part in this study. 
 
You’ll get medical treatment if you’re injured as a result of taking part in this study. You and/or 
your health plan will be charged for this treatment. This study will not pay for this medical 
treatment. 
 
In case of injury resulting from this study, you don’t lose any of your legal rights to seek payment 
by signing this form. 
 
13. 
COMPENSATION OR PAYMENT 
 
If you speak English and are 15 years or older, you will be asked to complete a pain diary when 
first enrolled and then 1 and 2 years later. If you complete the pain diary twice daily, you will 
receive a $50 gift card. This compensation will be the same for all three of the 28-day reporting 
periods. The potential compensation for completing the pain diary at all of these time points is 
$150 ($50 for each 28-day reporting period). 
 
14. 
COSTS & REIMBURSEMENTS 
 
Most of the visits for this study are standard care for SCD patients who have an allogeneic 
transplant and will be billed to your insurance company. 
 
You and/or your health insurance company will need to pay for some or all of the costs of standard 
treatment in this study. 
 
You will not be charged for the collection of optional samples. 
 
15. 
ETHICAL REVIEW 
 
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 
16. 
FOR MORE INFORMATION 
 
If you‘d like more information about this study, or if you have any problems while you’re 
participating in this study, you can contact the study doctor or staff. 
 
They may be contacted at the telephone numbers listed here: 
 
[Insert name and contact details] 
 
A description of this clinical trial will also be available on http://www.ClinicalTrials.gov, as 

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required by U.S. Law. This web site will not include information that can identify you. At most, the 
web site will include a summary of the results. You can search this web site at any time. 
 
17. 
INDEPENDENT CONTACT 
 
If you wish to speak to someone not directly involved in the study, or have any complaints or 
questions about your rights as a research participant, you may contact: 
 
[Insert appropriate contact details] 
 
18. 
OPTIONAL BLOOD SAMPLES FOR TRIAL-RELATED RESEARCH STUDIES 
This section of the Consent Form is about providing optional blood samples for use in 
additional research. 
You can choose to give blood samples for optional trial-specific studies if you want to. You can 
still be a part of the main study even if you say “no” to giving optional blood samples for these 
studies. Please mark your choice at the end of this section. 
Researchers are trying to learn more about how the human body recovers in SCD patients after 
transplant. This research is meant to gain knowledge that may help people in the future and make 
transplants even more successful. 
If you agree to provide optional blood samples, here is what will happen: 
 We’ll take the sample from your catheter or by a vein in your arm. We will collect 40mL (about 
8 teaspoons) if you are 15 years or older, or 24-40 mL (about 4-8 teaspoons) if you are 5 - 14 
years old. We’ll collect this sample when you have your check-up before treatment starts and 
28, 60, 100, 180, and 365 days after your transplant. 
o These blood samples will be shipped on the day of collection to Children’s Research 
Institute laboratory for an important study related to this trial. All research samples will be 
given a bar code that cannot be linked to you by researchers testing your samples. Your 
research samples will be sent to Children’s Research Institute laboratory to be used for this 
research. 
o Your name and other information that could directly identify you (such as address or social 
security number) will not be used. Researchers have a duty to protect your privacy and to 
keep your information confidential. 
 

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Benefits 
The research that may be done with your blood samples is not designed specifically to help you. 
The benefits of research using blood samples include learning more about how the immune system 
recovers in SCD patients after transplant. 
Risks 
There is a small risk of an infection or fainting from the blood draw. 
A possible risk is the loss of confidentiality about your medical information. We will do our best 
to make sure that your personal information is kept private. The chance that this information will 
be given to someone else is very small. 
Some general things to think about when letting us collect your blood samples for research are: 
 The choice to let us collect your blood samples is up to you. No matter what you decide to 
do, it will not affect your care. 
 If you decide now that your blood samples can be collected for research, you can change your 
mind at any time. Just contact your study doctor in writing and let him or her know that you 
do not want us to collect anymore of your blood samples for research. His/her mailing address 
is on the first page of this form. Then any further optional blood samples needed for this 
research will not be collected. However, samples that have already been collected cannot be 
taken back or destroyed. 
 People who do research on these blood samples may need to know more about your health. 
While the study doctor or others involved in running this study may give the researchers reports 
about your health, they will not give them your name, address, phone number, or any other 
information that will let the researchers know who you are. 
 Your blood will be used only for research and will not be sold. The research done with your 
blood may help to develop new products in the future. You will not get paid for any samples 
or for any products that may be developed from current or future research. 
 Reports about research done with your blood will not be given to you or your doctor. These 
reports will not be put in your health record. The research will not have an effect on your care. 
Making Your Choice 
Please read each sentence below and think about your choice. After reading each sentence, please 
indicate your choice below. If you have any questions, please talk to your doctor or nurse, or call 
our research review board at [telephone number]. 
No matter what you decide to do, it will not affect your care. 
You can change your mind at any time about allowing us to use your samples for research. 
However, samples that have already been collected cannot be taken back or destroyed. 
 

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5HVHDUFK6WXGLHV 
The purpose of collecting optional blood samples, the procedures involved, and the risks and 
benefits have been explained to me. I have asked all the questions I have at this time and I have 
been told whom to contact if I have more questions. I have been told that I will be given a signed 
copy of this consent form to keep. I understand that I do not have to allow the collection and 
storage of my blood samples for study-specific research. If I decide to not let you collect research 
samples now or in the future, it will not affect my medical care in any way. 
 
I voluntarily agree that optional blood samples may be collected and that my blood samples can 
be sent to the Children’s Research Institute Laboratory for research to learn about immune system 
recovery in sickle cell disease patients after transplant. 
 
 I do agree to give blood samples for study-specific research. 
 
 I do not agree to give blood samples for study-specific research. 
 
 
 
 
Signature 
Date 

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HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT 1 (HIPAA1) 
AUTHORIZATION TO USE AND DISCLOSE INDIVIDUAL HEALTH 
INFORMATION FOR RESEARCH PURPOSES 
 
A. Purpose 
As a research participant, I authorize the Principal Investigators and the 
researcher’s staff to use and disclose my individual health information for the 
purpose of conducting the research study: 
(List PI and research staff names) 
B. Individual Health Information to be Used or Disclosed 
My individual health information that may be used or disclosed to do this research includes: 
 Demographic information (for example: date of birth, sex, weight). 
 Medical history (for example: diagnosis, complications with prior treatment). 
 Findings from physical exams. 
 Laboratory test results obtained at the time of work up and after treatment (for 
example: blood tests, biopsy results). 
 
C. Parties Who May Disclose My Individual Health Information 
The researcher and the researcher’s staff may collect my individual health information 
from: 
 
(List hospitals, clinics or providers from which health care information can be requested). 
 
D. Parties Who May Receive or Use My Individual Health Information 
The individual health information disclosed by parties listed in item c and information 
disclosed by me during the course of the research may be received and used by the 
following parties: 
 
 Principal Investigator and the 
researcher’s staff (List names) 
 
 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 

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 Study Sponsors 
National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH); Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN) 
 U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research 
Protections (OHRP) 
 U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state and local health 
departments. 
 Data Warehouse Consultants (DWC) which is an agent of Emory University that 
will manage the pain diary. DWC will have access to your phone number, email 
address, IP Address and data that is entered in the pain dairy application. 
 Dr. Allistair Abraham and laboratory staff at Children’s National Medical Center 
E. Right to Refuse to Sign this Authorization 
I do not have to sign this authorization. If I decide not to sign the authorization, I will not 
be allowed to participate in this study or receive any treatment related to research that is 
provided through the study. 
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits. 
 
F. Right to Revoke 
I can change my mind and withdraw this authorization at any time by sending a written 
notice to the Principal Investigator to inform the researcher of my decision. 
If I withdraw this authorization, the researcher may only use and disclose the protected health 
information already collected for this research study. No further health information about me 
will be collected by or disclosed to the researcher for this study. 
G. Potential for Re-disclosure 
My individual health information disclosed under this authorization may be subject to re- 
disclosure outside the research study and no longer protected. 
Examples include potential disclosures for law enforcement purposes, mandated reporting or 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 

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H. This authorization does not have an expiration date. 
 
Principal Investigator(s) 
 
 
 
Email: 
 
 I’ve read and understood this Consent Form. The nature and purpose of the research 
study has been explained to me. 
 I’ve had the chance to ask questions and understand the answers I’ve been given. I 
understand that I may ask questions at any time during the study. 
 I freely agree to be a participant in the study. 
 I understand that I may not directly benefit from taking part in the study. 
 I understand that, while information gained during the study may be published, I won’t 
be identified, and my personal results will stay confidential. 
 I’ve had the chance to discuss my participation in this research study with a family 
member or friend. 
 I understand that I can leave this study at any time and doing so will not affect my 
current care or prevent me from receiving future treatment. 
 I understand that I’ll be given a copy of this signed consent form. 
 
 
Participant or Parent/Guardian Name 
Date 
 
 
Participant or Parent/Guardian Signature 
Date 
 
 
Parent/Guardian Signature 
Date 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks. I believe the participant has understood the information provided. 
 
 
Counseling Physician 
Date 
 
 
Signature of Counseling Physician 
Date 
Name: 
Phone: 
Address: 
Fax: 

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ASSENT TO PARTICIPATE IN RESEARCH 
 
 
Study Title: Reduced Intensity Conditioning for Haploidentical Bone Marrow 
Transplantation in Patients with Symptomatic Sickle Cell 
Disease 
 
Protocol: 
BMT CTN 1507 
 
 
A. 
Why am I here? 
 
We are inviting you to join our study because you have severe Sickle Cell Disease 
(SCD) or because you’ve had a stroke from the disease. You are now getting blood 
transfusions, hydroxyurea or other medicines. There is another treatment for sickle cell 
disease called bone marrow transplant (BMT). 
 
SCD is a blood disease. In SCD, the red blood cells, which are normally shaped like a 
donut, become sickle shaped. When this happens, they can get stuck in your blood 
vessels. This can cause pain and damage in different body parts. 
 
BMT uses blood making cells from another person to replace your cells that are not 
healthy. Donor is the name for a person who gives some of their cells for a transplant. 
In order for them to give you their cells, their DNA has to match yours. 
B. 
WHY ARE YOU DOING THIS STUDY? 
 
We know that a transplant can cure SCD but we don’t know if it works when the donor 
is not a perfect match. We are doing this study to see if a transplant with a donor who is 
related to you, but is not a perfect match, is safe and if it makes you better. 
C. 
WHAT WILL HAPPEN TO ME? 
 
If you say you want to be in the study, we will ask you to: 
 
 Have check-ups with the study doctors 
 Give some blood (about 3 teaspoons) 
 
 
Reduced Intensity Conditioning for Haploidentical Bone Marrow 
Transplantation in Patients with Symptomatic Sickle Cell Disease 

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 If you agree, we will collect extra blood (about 4 teaspoons) at 5 different times. 
Your blood samples will be used for research about transplant in patients with 
sickle cell disease. Your samples will be sent to a lab for an important study. All 
research samples will be tied to a number and researchers testing your samples 
will not be able to identify you. 
 
We will watch you carefully for fevers, any sign of infection or other problems. The study 
will be done over 2 years. 
Before your transplant, you will get a small bendable tube put in your chest in the 
operating room (you will be asleep for this). The small tube makes it easier for you to get 
your medicines. It will also make it easier for drawing blood for tests because you will 
not be poked. 
 
We will give you medicines that will help make the cells from your donor grow in your 
body. These medicines might make you feel sick. You might throw up, lose your hair, or 
get sores in your mouth. 
 
You will get cells from your donor. This is your transplant. Your new cells will come 
from your donor's bone marrow. The cells may make new and healthy cells in your body. 
Because your donor is not a perfect match, you will also get medicines after the transplant 
to stop the donor cells from attacking your body. This is a problem called graft-versus-
host disease (GVHD). 
 
GVHD happens when the donor cells attack your body. It can give you diarrhea, a skin 
rash, make you feel sick and throw up, or make you not feel hungry. Your doctors will 
give you medicines to try to make sure you don’t get GVHD. 
 
You will stay in the hospital for several days before your transplant and for about 4 weeks 
after your transplant. After you go home, you will need to go back to see your doctor 
often. 
 
It is possible that your disease will come back. If this happens, your doctor will find 
another way to treat you. 
D. 
WILL IT HURT? 
 
For your transplant, we will put a small tube in your chest. It might hurt a little and you 
might bleed a little. Your doctor and nurses will make sure you feel as little pain as 
possible. If you get mouth sores or if you get graft-versus-host disease, this can also hurt, 
but your doctor will give medicine to help with the pain. These problems usually will get 
better after a while. 

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When you have your blood taken with a needle, it may feel like a pinch. It will hurt for a 
minute and sometimes the place where the needle went might be red and sore. You might 
get a little bruise from the needle, but it goes away in a few days. 
The medicines you get might also make you sick. You might feel sick to your stomach 
or throw up. You might feel tired and your body might hurt. But your doctor will give 
you other medicine to help you feel better. Also, you might lose your hair. But it will 
grow back after you are done taking the medicines. 
 
E. 
WILL THE STUDY HELP ME? 
 
We don’t know if the study will help you or not. What we learn from it might help other 
people in the future. 
 
F. 
WHAT IF I HAVE QUESTIONS? 
 
You can ask any questions that you have about the study. If you forget to ask a question 
and think of it later, you can call me [insert office number]. You can also ask your 
question the next time you see me. 
 
You can call the study office at any time to ask questions about the study. 
 
G. 
DO I HAVE TO BE IN THIS STUDY? 
 
If you don’t want to be in the study, you need to tell us and your parent or guardian. 
Your doctor will not be angry or upset if you don’t want to join. 
 
Whether you are in the study or not, you will still need to have treatment for SCD. There 
might be other studies for sickle cell disease you can join, or a different kind of 
transplant 
 
You can say yes now and change your mind at any time. Your doctor will not be angry 
if you change your mind. 
 
Please talk this over with your parent or guardian before you decide if you want to be in 
the study. We will also ask your parents or guardian to give their permission for you to 
join this study. 
 
Writing your name on this page means that you agree to be in the study and know what 
will happen to you. If you decide to quit the study, all you have to do is tell the person in 
charge. 

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You and your parent or guardian will get a copy of this form after you sign it. 
 
 
 
Signature of Participant 
Date 
 
 
 
Printed Name of Participant 
 
 
Signature of Researcher 
Date 
 
 
 
Printed Name of Researcher 

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Donor Informed Consent to Participate in Research
Your Name:
Study Title:
Reduced Intensity Conditioning for Haploidentical Bone 
Marrow Transplantation in Patients with Symptomatic Sickle 
Cell Disease
Protocol:
BMT CTN #1507
Co-Investigator: Allistair Abraham, M.D.
Children’s National Medical Center Assistant Professor Pediatrics
111 Michigan Ave NW Washington, DC 20010
(O) 202-476-5772
aabraham@childrensnational.org
Principal
Investigator:
[Insert local PI information]
Sponsor:
The National Institutes of Health (NIH) is sponsoring this study by 
providing financial support through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN).
1. INTRODUCTION
We invite you to provide blood samples for research. You’re being asked to join because 
you’re a bone marrow donor for a family member who is going to receive a haploidentical 
(half-matched) transplant in the main study, BMT CTN 1507.
This consent form is about a research study to learn how patients’ immune system recovers 
after they get cells from a donor (transplant). In order to do this study, we will need extra blood
samples from you.
It’s your choice to give blood samples. Even if you say 'no' to giving samples for this research 
study, your family member can still receive a transplant from you as part of the main study.
If you agree to give blood samples, we will collect them at the time of your bone marrow
donation.
Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation 
in Patients with Symptomatic Sickle Cell Disease

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This Consent Form will tell you about the purpose of the samples for research, the possible 
risks and benefits, other options available to you, and your rights as a research participant. 
Everyone who takes part in research at [insert facility name] should know that: 
 Being in any research study is voluntary. 
 You will not directly benefit from being in the study. Knowledge we gain from this 
study may benefit others. 
 If you give blood samples for research, you can change your mind at any time. 
 If you decide to quit the study, it will not affect your care or the care of your family 
member at [insert name of facility or institution]. 
 Please ask the study staff questions about anything that you do not understand, 
or if you would like to have more information. 
 You can ask questions now or any time during the study. 
 Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends. It is your decision to provide blood samples for research. If you 
decide to join, please sign and date the end of the Consent Form. 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), are giving staff support and money for this research study. 
The BMT CTN will lead the research study and, along with the NIH, will make decisions 
about how to manage the study. 
 
2. STUDY PURPOSE 
We are collecting extra blood samples because we want to learn more about how the 
immune system recovers in SCD patients that have received a haploidentical donor bone 
marrow transplant 
 
3. RIGHT TO ASK QUESTIONS AND/OR WITHDRAW 
You have the right to ask questions about the study at any time. If you have questions about 
your rights as a study participant or you want to leave the study, please contact: 
 
[insert contact info] 
Giving blood samples for research is voluntary. You can choose not to give 
samples or change your mind at any time. 

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If you choose not to take part or change your mind, it will not affect your donation process 
or the treatment of your family member in the main study in any way. 
If you change your mind, any unused blood samples will be destroyed. However, samples and 
information that have already been used for research cannot be taken back or destroyed. 
Your study doctor and study staff will be available to answer any questions that you may 
have. 
 
4. STUDY TREATMENTS AND TESTS 
If you agree to give blood samples, here is what will happen: 
a.) We will collect an extra blood sample at the time of your bone marrow donation. The 
amount of blood collected from you will be 20 mL (about 4 teaspoons). 
b.) The blood samples will be sent to the Children’s Research Institute laboratory for 
processing. All samples will be given a unique bar code that cannot be linked to you 
by the researchers testing your samples. 
 
5. RISKS AND DISCOMFORTS 
There are no major risks to having your blood drawn. It can be uncomfortable to have your 
blood taken and it can sometimes leave a bruise. You might faint, but this is unlikely to 
happen. Only trained people will take your blood. 
 
6. POSSIBLE BENEFITS 
You will not directly benefit from taking part in this study. The information from this study 
will help doctors learn more about how well transplant recipients do with a haploidentical 
(half- matched) donor. 
This information could help other people with SCD who may need a transplant in the future. 
 
7. PRIVACY, CONFIDENTIALITY AND USE OF INFORMATION 
Your privacy is very important to us. The study doctors will make every effort to protect it. 
The study doctors have a privacy permit to help protect your records if there is a court case. 
However, some of your medical information may be given out if required by law. If this 
should happen, the study doctors will do their best to make sure that any information that goes 
out to others will not identify who you are. 

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[Name of Transplant Center] and the organizations listed below will not disclose your 
participation by any means of communication to any person or organization, except by your 
written request, or permission, or unless required by federal, state or local laws, or regulatory 
agencies. 
 The National Institutes of Health (NIH), which include the National Heart, Lung, 
and Blood Institute (NHLBI) and the National Cancer Institute (NCI) 
 U.S. government agencies that are responsible for overseeing research such as The 
Food and Drug Administration (FDA) and the Office of Human Research Protection 
(OHRP) 
 U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state, and local health 
departments 
 The Data and Safety Monitoring Board (DSMB), not part of [Institution] 
 Institutional Review Boards (IRBs) responsible for this study 
 Blood and Marrow Transplant Clinical Trials Network Data and Coordinating 
Center (BMT CTN DCC), including: 
 The Center for International Blood and Marrow Transplant Research 
(CIBMTR) 
 The National Marrow Donor Program (NMDP) 
 Emmes, who is coordinating the studies of the BMT CTN 
 Dr. Allistair Abraham and laboratory staff at Children’s National Medical Center 
 Study investigators 
Individuals authorized by the organizations above will have access to your research and 
medical information. They may use this information for inspections or audits to study the 
outcomes of your treatment. In agreeing to participate, you consent to these inspections. You 
also consent to allow authorized individuals to copy parts of your records, if required by these 
organizations. 
We may give out your personal information if required by law. If information from this study 
is published or presented at scientific meetings, your name and other personal information 
will not be used. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time. 
For questions about access to your medical records, please contact [name] at [number]. 

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8. ENDING YOUR PARTICIPATION 
The study doctor or the study sponsor may stop the study at any time, and we may ask you to leave 
the study. We may ask you to leave the study if you do not follow directions or if you suffer from 
side effects of the blood draw. The study sponsor may decide to end the study at any time. If we 
ask you to leave the study, the reasons will be discussed with you. 
Possible reasons to end your participation in this study include: 
 You do not meet the study requirements. 
 You become unable to donate bone marrow to your family member. 
 The study is stopped for any reason. 
 
9. PHYSICAL INJURY AS A RESULT OF PARTICIPATION 
It’s important that you tell your doctor, [investigator's name(s)], or study staff if you feel that you 
have been injured because you provided blood samples for research. You can tell the doctor in 
person or call him/her at [telephone number]. 
You will get all available medical treatment if you are injured as a result of providing blood 
samples for research. 
You, your health plan, or your family member’s health plan will be charged for this treatment for 
injury. The study will not pay for medical treatment. 
In case of injury resulting from providing blood samples for this study, you do not lose any of your 
legal rights to seek payment by signing this form. 
 
10. PAYMENT AND STUDY COSTS 
You will not be paid for your participation in the research study or for providing blood samples for 
research. 
You will not be compensated or reimbursed for any extra costs (for example, travel and meals) from 
taking part in this study. 
The visit at which this sample will be collected are standard for bone marrow donors and will be billed 
to your family member’s insurance company. 
You will not be charged for the collection of these optional samples or for the research tests done with 
these samples. The costs of shipping your blood samples will be paid by the BMT CTN. 
For questions about your costs, financial responsibilities, and/or medical insurance coverage for 
your transplant and this study, please contact /Center/ Financial Counselor at /Number. 
 
 
 
 

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11. 
FOR MORE STUDY INFORMATION 
If you need more information about providing blood samples for research, or if you have problems 
while you are participating in this study, you can contact the study doctor or his/her staff. They can 
be reached at the telephone numbers listed here: 
[Insert name and contact details]. 
 
12. 
CONTACT SOMEONE ABOUT YOUR RIGHTS 
If you wish to speak to someone not directly involved in the study, if you have any complaints about 
the study, or would like more information about your rights as a research participant, you may contact: 
[Insert appropriate contact details]. 
The ethical aspects of this research study have been reviewed and approved by 
For more information about your rights when providing blood samples for research, call the [name 
of center] Institutional Review Board (a group of people who review the research to protect your 
rights) at [telephone number]. 
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT (HIPAA)1 
AUTHORIZATION TO USE AND DISCLOSE RESEARCH PURPOSES: 
A. 
PURPOSE: 
As a research participant, I authorize the Principal Investigators and the researcher’s staff to 
use and disclose my individual health information for the purpose of conducting the research 
study, Reduced Intensity Conditioning for Haploidentical Bone Marrow Transplantation in 
Patients with Symptomatic Sickle Cell Disease. 
 
B. 
INDIVIDUAL HEALTH INFORMATION TO BE USED OR DISCLOSED: 
My individual health information that may be used or disclosed to do this research includes: 
 Demographic information (for example: date of birth, sex, weight) 
 Medical history 
 Findings from physical exams 
 Laboratory test results obtained at the time of work up 
 
C. 
PARTIES WHO MAY DISCLOSE MY INDIVIDUAL HEALTH INFORMATION: 
The researcher and the researcher’s staff may collect my individual health 
information from: [List hospitals, clinics or providers from which health 
care information can be requested] 
[name of IRB]. 

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D. 
PARTIES WHO MAY RECEIVE OR USE MY INDIVIDUAL HEALTH 
INFORMATION: 
The individual health information disclosed by parties listed in item c and information 
disclosed by me during the course of the research may be received and used by the following 
parties: 
 Principal Investigators and the researcher’s staff: 
o Dr. Robert Brodsky, Co-Principal Investigator 
o Dr. Michael DeBaun, Co-Principal Investigator 
o Dr. Adetola Kassim, Co-Principal Investigator 
o Dr. Mark Walters, Co-Principal Investigator 
 Dr. Allistair Abraham and laboratory staff at Children’s National Medical Center 
 Study Sponsors: 
o National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer 
Institute (NCI), both of the National Institutes of Health (NIH), 
o Blood and Marrow Transplant Clinical Trials Network (BMT CTN), data 
coordinating center 
 U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research 
Protections (OHRP) 
 U.S. government agencies that are responsible for overseeing public health concerns 
such as the Centers for Disease Control (CDC) and federal, state, and local health 
departments. 
 The Data and Safety Monitoring Board (DSMB), not part of [Institution] 
 Institutional Review Boards (IRBs) responsible for this study 
E. 
RIGHT TO REFUSE TO SIGN THIS AUTHORIZATION: 
I do not have to sign this Authorization. If I decide not to sign the Authorization, I will not 
be allowed to participate in this study or receive any treatment related to research that is 
provided through the study. 
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits. 
F. 
RIGHT TO REVOKE: 
I can change my mind and withdraw this authorization at any time by sending a written notice 
to the Principal Investigator to inform the researcher of my decision. 

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If I withdraw this authorization, the researcher may only use and disclose the protected health 
information already collected for this research study. No further health information about me 
will be collected by or disclosed to the researcher for this study. 
 
G. 
POTENTIAL FOR RE-DISCLOSURE: 
My individual health information disclosed under this authorization may be subject to re- 
disclosure outside the research study and no longer protected. 
Examples include potential disclosures for law enforcement purposes, mandated reporting 
for abuse or neglect, judicial proceedings, health oversight activities and public health 
measures. 
 
H. 
THIS AUTHORIZATION DOES NOT HAVE AN EXPIRATION DATE. 
TITLE: BMT CTN 1507: Reduced Intensity Conditioning for Haploidentical Bone 
Marrow Transplantation in Patients with Symptomatic Sickle Cell Disease 
Principal Investigator: 
 
 
 
For donors under 18, consent must be provided by the Legally Authorized 
Representative and Donor Assent is required (see Assent Section on the next 
page). 
 I have had the chance to ask questions and understand the answers I have been given. I 
understand that I may ask questions at any time during the study. 
 I freely agree to be a participant in the study. 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information. 
 
 I understand that I will not directly benefit from taking part in the study. 
 I understand that, while information gained during the study may be published, I will 
not be identified, and my personal results will stay confidential. 
 I have had the chance to discuss my participation in this research study with a family 
member or friend. 
 I understand that I can leave this study at any time and doing so will not affect my 
family member’s current care or prevent my family member from receiving future 
treatment. 
Address 1: 
Fax: 
Address 2: 
Email: 
Name: 
Phone: 

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 I understand that I will be given a copy of this signed consent form. 
 
 
Participant Name 
Date 
 
 
Participant’s Signature (if 18 years or older) 
Date 

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

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PEDIATRIC DONOR ASSENT TO PARTICIPATE IN RESEARCH 
Study Title: Reduced Intensity Conditioning for Haploidentical Bone Marrow  
Transplantation in Patients with Symptomatic Sickle Cell Disease 
 
Protocol: 
BMT CTN 1507 
 
A. Why am I here? 
 
If you give us your permission, we would like to have an extra sample of your blood. We 
would collect the extra sample at the same time you donate your bone marrow. 
 
B. Why are you doing this study? 
 
We are collecting blood samples from donors, like you, to learn more about SCD 
patients do after their transplants. Your name will not be on the samples. 
 
C. What will happen to me if I join the study? 
 
If you say you want to be in the study, we will ask you for: 
 
 1 extra blood sample: We’ll collect about 4 teaspoons of blood 1 time. 
 
We will use a small needle to collect the blood from a vein in your arm. 
 
D. Will the blood draw hurt? 
 
When we collect your blood from a vein in your arm, it may feel like a pinch. It will hurt 
for a minute and the place where the needle went might be red and sore. You might get a 
little bruise from the needle but it goes away in a few days. We will collect the extra 
sample at the same time as you have other blood tests done. 
 
E. What if I have questions? 
You can ask any questions that you have about this study. If you forget to ask a question 
and think of it later, you can call me at: [insert office number]. 
 
You can also ask your question the next time you see me. You can call the study office 
at any time to ask questions about the study. 
F. How will you use my health information and blood samples? 

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Your blood samples will be used for a study about transplant in patients with sickle cell 
disease. 
 
G. Where will my blood samples be sent? 
 
Your blood samples will be sent to a laboratory at Children’s Research Institute. 
 
All research samples will be tied to a number. This number will not be linked to your 
name or other identifying information. 
 
H. Will the study help me? 
 
This study will not help you or your family member, but it may help other SCD patients 
who have a transplant in the future. 
 
I. Will I be paid to be in the study? 
 
No, you will not be paid to be in the study. It will not cost you anything to be in the 
study. 
 
J. Do I have to be in this study? 
 
If you don’t want to be in this study, you need to tell us and your parent or guardian. 
 
Your doctor will not be angry or upset if you do not want to join. You can still give bone 
marrow to your family member who needs it. They will still get the exact same care. 
 
You can say yes now and change your mind at any time. 
 
Please talk this over with your parents before you decide if you want to give an extra 
blood sample for research. We will also ask your parents to give their permission for you 
to give an extra sample for research. 

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TITLE: BMT CTN 1507: Reduced Intensity Conditioning for Haploidentical Bone Marrow 
Transplantation in Patients with Symptomatic Sickle Cell Disease 
 
Principal Investigator: 
 
 
 
 
 
 
Writing your name on this page means that you agree to give an extra blood sample 
and know what will happen. 
 
If you want to quit the study, all you have to do is tell the person in 
charge. You and your parent or guardian will get a copy of this 
form after you sign it. 
 
 
 
Signature of Child 
Date 
 
 
 
 
Signature of Person Conducting Assent 
Date 
Name: 
Phone: 
Address 1: 
Fax: 
Address 2: 
Email: 

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APPENDIX C 
IMMUNE RECONSTITION ANCILLARY STUDY 
PROCEDURES 

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IMMUNE RECONSTITUTION ANCILLARY STUDY PROCEDURES
Study patients and associated haploidentical bone marrow donors will be provided the 
opportunity to participate in an optional correlative laboratory study associated with the 
BMT CTN 1507 trial. The overall objective of the protocol-defined correlative laboratory 
study is to examine in greater detail how the immune system recovers in SCD patients that 
have received a haploidentical donor bone marrow transplant.
1. Background:
Recent data presented at the 2016 BMT Tandem Meeting showed that in 8 sickle cell 
patients receiving ex-vivo T-cell deplete transplant that sustained engraftment was seen
and the average Day +30 donor NK chimerism was 90%68. Early predominant donor NK
chimerism may thus be an important part of engraftment and may serve as an early marker 
of success. However, the role of NK cell chimerism in a post-transplant cyclophosphamide
based T-cell depletion approach for sickle cell disease, as proposed for the BMT CTN 1507 
trial, is unknown; this correlative laboratory study hopes to address this gap in knowledge.
As T cell depletion in an important part of GVHD prevention in a mismatched setting such 
as haploidentical transplantation it is important to confirm that viral T cell immunity is not 
negatively impacted. Performing T cell depletion of donor lymphocytes ex-vivo often
leads to delayed viral-specific immunity (up to one year) leaving the patient susceptible to
life threating viral infection. CMV, EBV and Adenovirus infections/reactivations are 
particularly problematic, with adenovirus alone affecting > 80% of pediatric patients after 
T cell depleted haploidentical transplant and is associated with significant morbidity and 
a high mortality rate if the patient develops viral disease69. However, in a previously 
published study from the Johns Hopkins group after haploidentical transplant for sickle 
cell disease, 3 of 14 (21%) of patients had CMV reactivation but no patient developed 
CMV disease, and one of these patients had EBV reactivation treated effectively with a 
single dose Rituximab70. In the preliminary experience of reduced intensity haploidentical 
transplantation for SCD for the BMT CTN 1507 trial, 7 of 12 patients had viral reactivation 
(CMV, EBV, VZV, HHV6) but no disease. We hypothesize that with a post-transplant
cyclophosphamide approach that viral-specific T cells transferred with the allograft remain 
relatively intact given that alloreactive T cells rather than viral-specific T cells are most 
active at the day
+3 and +4 time-points of cyclophosphamide infusion and are preferentially depleted and 
accounts for the absence of viral disease. We plan to test this hypothesis by evaluating 
patients post-transplant for the presence of viral-specific T cells in their peripheral blood.
2. Immune Reconstitution Study Aims:
a. To determine if predominantly donor Day 28, NK cell chimerism (>90%) is more 
predictive of sustained engraftment than Day 28 T cell chimerism following 
haploidentical donor BMT for sickle cell disease

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b. To determine at what time-point viral specific T cells are detectable after 
haploidentical BMT using a post-transplant cyclophosphamide approach for 
sickle cell disease. 
3. Study Procedures 
Study patients will be presented the option to participate in this important correlative 
laboratory study at the time of informed consent. For those patients agreeing to provide 
the optional research blood samples, their haploidentical bone marrow donor will also be 
asked to participate in this research study. 
 
Peripheral blood samples will be collected from consenting patients within 30 days prior 
to transplant conditioning and on Days 28, 60, 100, 180 and 365 post-transplant. A single, 
pre-bone marrow donation peripheral blood sample will be collected from associated 
haploidentical donors consenting to provide an optional research sample only if the patient 
agrees to participate in this research study. 
 
x 
Adult Patients: 40 mL peripheral blood collected in four 10 mL sodium heparin 
tubes. 
x 
Pediatric Patients (5.00 – 14.99 years old): 24-40 mL peripheral blood collected 
in 3-4, 10 mL sodium heparin tubes based on a 3 mL/kg sample collection 
guidance. 
x 
Haploidentical Bone Marrow Donors: 20 mL peripheral blood collected in two 
10 mL sodium heparin tubes. 
 
Table 1: Requirements for Immune Reconstitution Correlative Study samples based 
on Donor and Patient consent 
Scenario 
Sample Requirement 
Patient AND Donor consent to provide 
optional immune reconstitution samples 
Patient and Donor samples should be provided at 
specified timepoints 
Patient consents to provide optional immune 
reconstitution samples and Donor does NOT 
consent to provide optional immune 
reconstitution samples 
Patient samples should be provided at specified 
timepoints; Donor samples should NOT be provided 
at specified timepoints 
Patient does NOT consent to provide 
optional immune reconstitution samples 
and Donor does 
NOT consent to provide optional 
immune reconstitution samples 
 
No Patient or Donor samples should be provided at 
specified timepoints 
 
Patient does NOT consent to provide optional 
immune reconstitution samples and Donor 
consents to provide optional immune 
reconstitution samples 
No Patient or Donor samples should be provided at 
specified timepoints. 
 
Note: if patient does not consent to provide samples, it is 
not 
required to approach the Donor with the optional 
research sample consent form. 
 
 

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The blood tubes will be shipped on the day of collection to the Children’s Research Institute project 
laboratory by Priority Overnight FedEx courier. Please see the protocol-specific Research Sample 
Information Guide for detailed sample labeling, GlobalTrace, and same-day sample shipping 
procedures 
 
Table 2: Optional – Immune Reconstitution Correlative Study Research Samples 
Subjects 
Sample 
Type 
Sample 
Collection Time 
Points 
Sample Collection 
Summary 
Shipping 
Specifications 
Shipping 
and 
TestingLo
cation 
Patients 
Peripheral 
Blood 
(sodium 
heparin) 
 
40 mL 
(adults) 
 
24-40 mL 
(pediatric 
age 5-14) 
Pre-HSCT 
Conditioning 
Within 30 days 
prior to 
transplant 
conditioning 
(Thymoglobulin
) 
 
Post-transplant 
Day 28, 60, 100, 
180, 365 
Collect the peripheral 
blood sample and place 
into four (3-4 for 
children) 10 mL 
Vacutainer tubes, 
containing sodium 
heparin anticoagulant. 
Gently mix sample by 
inversion 8-10 times to 
mix sample well with 
anticoagulant. 
Blood sample tubes 
will be shipped at 
ambient 
temperature, on the 
day of collection, to 
project laboratory 
by priority 
overnight FedEx® 
delivery. 
Children’s 
Research 
Institute 
Laboratory 
Haploidentical 
Donors 
Peripheral 
Blood 
(sodium 
heparin) 
 
20 mL 
Prior to Bone 
Marrow Collection 
Collect the peripheral 
blood sample and place 
into two 10 mL 
Vacutainer tubes, 
containing sodium 
heparin anticoagulant. 
Gently mix sample by 
inversion 8-10 times to 
mix sample well with 
anticoagulant. 
Blood sample tubes 
will be shipped at 
ambient 
temperature, on the 
day of collection, to 
project laboratory 
by priority 
overnight FedEx® 
delivery. 
Children’s 
Research 
Institute 
Laboratory 

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APPENDIX D 
CONSENSUS CRITERIA FOR GRADING OF 
SEVERITY OF ACUTE GVHD 

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CONSENSUS CRITERIA FOR GRADING OF SEVERITY OF ACUTE GVHD
TABLE 1: ACUTE GVHD GRADING CRITERIA
Stage
Skin
Liver 
(Bilirubin)
GI Tract (Stool Output/d)
0
No GVHD rash
<2 mg/dL Adult: <500 mL/d 
Child: <10 mL kg/d
1
Maculopapular rash
<25% BSA
2–3 mg/dL
Adult: 500–999 mL/d
Child: 10–19.9 mL/kg/d or persistent nausea, vomiting, 
or anorexia, with a positive upper GI biopsy
2
Maculopapular rash 
25%–50% BSA
3.1–6 mg/dL Adult: 1000–1500 mL/d
Child: 20–30 mL/kg/d
3
Maculopapular rash
>50% BSA
6.1–15 mg/dL Adult: >1500 mL/d
Child: >30 mL/kg/d
4
Generalized
erythroderma with 
bullous formation
>15 mg/dL Severe abdominal pain with or without ileus
Overall clinical grade: grade 0, no stage 1–4 
of any organ; 1, stage 1–2 skin rash and no 
liver or GI involvement;
2, stage 3 skin rash, or stage 1 liver involvement, or stage 1 GI involvement;
3, stage 0–3 skin rash, with stage 2–3 liver involvement, or stage 2–3 
GI involvement; 4, stage 4 skin rash, liver, or GI involvement.
o
Grade 0 indicates no clinical evidence of disease.
o
Grade I indicates rash on less than 50% of skin and has no gut or liver
involvement.
o
Grade II indicates rash covering more than 50% of skin, bilirubin 
level of 2-3 mg/dL, diarrhea of 10-15 mL/kg/d, or persistent
nausea.
o
Grade III or IV indicates generalized erythroderma with bullous 
formation, bilirubin level of more than 3 mg/dL, or diarrhea of 
more than 16 mL/kg/d.

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APPENDIX E 
 
NIH CONSENSUS CRITERIA FOR DIAGNOSIS AND 
GRADING OF SEVERITY OF CHRONIC GVHD 

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NIH CONSENSUS CRITERIA FOR DIAGNOSIS AND GRADING OF 
SEVERITY OF CHRONIC GVHD
TABLE 1: 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 of Chronic 
GVHD)
Other features
Common (Seen 
with Both Acute 
and Chronic 
GVHD)
Skin
Poikiloderma
Depigmentation
Sweat impairment
Erythema
Lichen planus-like 
features
Ichthyosis
Maculopapular 
rash
Sclerotic features
Keratosis pilaris
Pruritus
Morphea-like 
features
Hypopigmentation
Lichen sclerosus-
like features
Hyperpigmentation
Nails
Dystrophy
Longitudinal ridging, 
splitting, or brittle 
features
Onycholysis
Pterygium unguis
Nail loss (usually 
symmetric; affects
most nails)†
Scalp and 
body hair
New onset of scarring 
or nonscarring scalp 
alopecia (after 
recovery from 
chemoradiotherapy)
Scaling, 
papulosquamous
lesions
Thinning scalp hair, 
typically patchy, 
coarse, or dull (not 
explained by 
endocrine or other 
causes)
Premature gray hair
Mouth
Lichen-type 
features
Xerostomia
Gingivitis

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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 of Chronic 
GVHD) 
 
 
Other features 
 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
 
Hyperkeratotic 
plaques 
Mucocele 
 
Mucositis 
 
Restriction of 
mouth opening 
from sclerosis 
Mucosal atrophy 
Pseudomembranes † 
Ulcers † 
 
Erythema 
Pain 
Eyes 
 
New onset dry, gritty, 
or painful eyes‡ 
Photophobia 
 
 
 
Cicatricial 
conjunctivitis 
Keratoconjunctivitis 
sicca ‡ 
Confluent areas of 
punctate keratopathy 
 
 
Periorbital 
hyperpigmentation 
 
 
 
 
Blepharitis (erythema 
of the eyelids with 
edema) 
 
Genitalia 
Lichen planus-like 
features 
Erosions† 
 
 
 
Vaginal scarring or 
stenosis 
Fissures† 
 
 
 
 
Ulcers† 
 
 
 
 
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 
(infants and 
children) 
 
 
Liver 
 
 
 
Total bilirubin, 
alkaline 
phosphatase >2 × 
upper limit of 
normal† 

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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 of Chronic 
GVHD) 
 
 
Other features 
 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
 
 
 
 
ALT or AST >2 
× upper limit of 
normal 
 
Lung 
Bronchiolitis 
obliterans 
diagnosed with 
lung biopsy 
Bronchiolitis 
obliterans diagnosed 
with PFTs and 
radiology‡ 
 
 
BOOP 
 
Muscles, 
fascia, joints 
Fasciitis 
Joint stiffness or 
contractures 
secondary to 
sclerosis 
 
Myositis or 
Polymositis 
 
Edema 
Muscle cramps 
Arthralgia or arthritis 
 
Hematopoieti 
c and immune 
 
 
Thrombocytopenia 
 
 
 
 
Eosinophilia 
 
 
 
 
Lymphopenia 
 
 
 
 
Hypo- or 
hypergammaglobulin 
emia 
 
 
 
 
Autoantibodies 
(AIHA and ITP) 
 
Other 
 
 
Pericardial or pleural 
effusions 
 
 
 
 
Ascites 
 
 
 
 
Peripheral neuropathy  
 
 
 
Nephrotic syndrome 
 
 
 
 
Myasthenia gravis 
 
 
 
 
Cardiac conduction 
abnormality or 
cardiomyopathy 
 
Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed 
† In all cases, infection, drug effects, malignancy, or other causes must be excluded 
‡ Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 

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The Working Group recommends that the diagnosis of chronic GVHD require at least 1 diagnostic 
manifestation of chronic GVHD or at least 1 distinctive manifestation, with the diagnosis 
confirmed by pertinent biopsy, laboratory tests, or radiology in the same or another organ. As in 
acute GVHD, infection and other causes may confound or complicate the differential diagnosis of 
chronic GVHD (e.g., nail dystrophies associated with onychomycosis, herpes simplex, or Candida 
albicans infections of the oral cavity; drug toxicity) and must be excluded. Diagnostic and 
distinctive manifestations of chronic GVHD can be found in the skin and appendages, mouth, eyes, 
female genitalia, esophagus, lungs, and connective tissues. Biopsy or other testing is always 
encouraged and often valuable to confirm the presence of chronic GVHD, but it is not always 
feasible and is not mandatory if the patient has at least 1 of the diagnostic findings of chronic 
GVHD (Table 1). Please note that an in-depth discussion of recommended terminology for 
histopathologic interpretation may be found in a forthcoming histopathology working group 
report. A biopsy read as “consistent with” or “unequivocal” chronic GVHD will be considered 
sufficient to establish the diagnosis of chronic GVHD if accompanied by at least 1 distinctive 
clinical manifestation. 
 
Characteristics that establish the diagnosis of chronic GVHD might not serve as the most 
appropriate parameters for assessing the severity of chronic GVHD. Valid and reliable diagnostic 
criteria might not be sufficiently sensitive to change to be useful as treatment- response criteria. 
Conversely, a sensitive measure of chronic GVHD response might not necessarily serve as an 
appropriate diagnostic and scoring tool. 
 
A. Organ-specific manifestations of chronic GVHD 
 
In all cases, drug reaction, infection, recurrent or new malignancy, and other causes must be 
excluded. Diagnostic clinical or laboratory features sufficient for the diagnosis of chronic GVHD 
are italicized in the sections below. 
 
B. Skin 
 
Diagnostic manifestations include poikiloderma (e.g., atrophic and pigmentary changes), lichen 
planus-like eruption (e.g., erythematous/violaceous flat-topped papules or plaques with or without 
surface reticulations or a silvery or shiny appearance on direct light), deep sclerotic features (e.g., 
smooth, waxy, indurated skin—“thickened or tight skin,” caused by deep and diffuse sclerosis over 
a wide area), morphea-like superficial sclerotic features (e.g., localized patchy areas of moveable 
smooth or shiny skin with a leathery-like consistency, often with dyspigmentation), or lichen 
sclerosus-like lesions (e.g., discrete to coalescent gray to white moveable papules or plaques, often 
with follicular plugs, with a shiny appearance and leathery consistency). Severe sclerotic features 
characterized by thickened, tight, and fragile skin are often associated with poor wound healing, 
inadequate lymphatic drainage, and skin ulcers from minor trauma. 
 
A distinctive feature for chronic GVHD (not seen in acute GVHD, but not sufficiently unique to 
be considered diagnostic of chronic GVHD) is depigmentation. However, depigmentation would 
contribute to the diagnosis of chronic GVHD in combination with 

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biopsy or laboratory confirmation of GVHD in skin or another organ. Sweat impairment and 
intolerance to temperature change from loss of sweat glands are seen in chronic GVHD. Other 
common, nondistinctive skin manifestations found with both acute and chronic GVHD include 
erythema, maculopapular rash, and pruritus. 
 
C. Nails 
 
Dystrophy consisting of longitudinal ridging, nail splitting or brittleness, onycholysis, pterygium 
unguis, and nail loss (usually symmetric and affecting most nails) are distinctive signs of chronic 
GVHD but are not sufficient for diagnosis. 
 
D. Hair 
 
Distinctive features of chronic GVHD include new scarring and nonscarring scalp alopecia (after 
recovery from chemotherapy or radiotherapy) and loss of body hair. Other characteristics seen 
with chronic GVHD include premature graying, thinning, or brittleness, but these findings are not 
diagnostic. 
 
E. Mouth 
 
Diagnostic features of oral chronic GVHD include lichen planus-like changes (white lines and 
lacy-appearing lesions of the buccal mucosa, tongue, palate, or lips), hyperkeratotic plaques 
(leukoplakia), or decreased oral range of motion in patients with sclerotic features of skin GVHD. 
Distinctive features of chronic GVHD include xerostomia (dryness), mucoceles, mucosal atrophy, 
pseudomembranes, and ulcers (infectious pathogens such as yeast or herpesvirus; secondary 
malignancy must be excluded). Manifestations common to both acute and chronic GVHD include 
gingivitis, mucositis, erythema, and pain. 
 
F. Eyes 
 
Distinctive manifestations of chronic GVHD include new onset of dry, gritty, or painful eyes; 
cicatricial conjunctivitis; keratoconjunctivitis sicca; and confluent areas of punctate keratopathy. 
Other features include photophobia, periorbital hyperpigmentation, difficulty in opening the eyes 
in the morning because of mucoid secretions, and blepharitis (erythema of the eye lids with edema). 
1HZRFXODUVLFFDGRFXPHQWHGE\ORZ6FKLUPHUWHVWYDOXHVZLWKDPHDQYDOXHRIERWKH\HVPP
at 5 minutes or a new onset of keratoconjunctivitis sicca by slit-lamp examination with mean values 
of 6 to 10 mm on the Schirmer test is sufficient for the diagnosis of chronic GVHD if accompanied 
by distinctive manifestations in at least 1 other organ. 
 
G. Genitalia 
 
Diagnostic features for the genitalia include lichen planus-like features and vaginal scarring or 
stenosis (often associated with oral GVHD). 

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H. Gastrointestinal Tract 
 
Diagnostic features for the gastrointestinal (GI) tract include esophageal web, stricture, or 
concentric rings documented by endoscopy or barium contrast radiograph. Chronic GVHD may be 
associated with pancreatic exocrine insufficiency, which often improves with enzyme 
supplementation. Manifestations common to both acute and chronic GVHD (as well as other 
causes, such as drug side effects, motility disorders, infections, or malabsorption) include anorexia, 
nausea, vomiting, diarrhea, weight loss, and failure to thrive. Wasting syndrome may be a 
manifestation of chronic GVHD but is often multifactorial (e.g., decreased caloric intake, poor 
absorption, increased resting energy expenditures, and hypercatabolism). Endoscopic findings of 
mucosal edema and erythema or focal erosions with histologic changes of apoptotic epithelial cells 
and crypt cell dropout may be seen but are not considered diagnostic of chronic GVHD unless the 
patient also has distinctive features in a non-GI system. Patients with unresolved acute GVHD may 
have more severe intestinal mucosal lesions, including ulcers and mucosal sloughing. 
 
I. Liver 
 
Hepatic acute and chronic GVHD typically presents as cholestasis, with increased bilirubin or 
alkaline phosphatase, but it may also present as acute hepatitis. Because of many possible 
alternative diagnoses, liver biopsy is required to confirm GVHD involvement of the liver. Note 
that because of the histologic similarity between acute and chronic liver GVHD, the diagnosis of 
chronic GVHD cannot be made on the basis of liver biopsy alone but requires a distinctive 
manifestation in at least 1 other organ system. 
 
J. Lungs 
 
The only diagnostic manifestation of chronic GVHD is biopsy-proven BO. BO diagnosed via 
pulmonary function and radiologic testing requires at least 1 other distinctive manifestation in a 
separate organ system to establish the diagnosis of chronic GVHD. BO is characterized by the new 
onset of an obstructive lung defect. Clinical manifestations may include dyspnea on exertion, 
cough, or wheezing. Some patients may be asymptomatic early in the disease process. 
Pneumothorax, pneumomediastinum, and subcutaneous emphysema are rare and often represent 
advanced disease. Restrictive pulmonary function abnormalities secondary to advanced sclerosis 
of the chest wall are attributable to skin GVHD. BO is clinically diagnosed when all of the 
following criteria are met: 
1. 
Forced expiratory volume in 1 second/forced vital capacity ratio <0.7 and forced 
expiratory volume in 1 second <75% of predicted. 
2. 
Evidence of air trapping or small airway thickening or bronchiectasis on high- resolution 
chest computed tomography (with inspiratory and expiratory cuts), residual volume 
>120%, or pathologic confirmation of constrictive bronchiolitis. 
3. 
Absence of infection in the respiratory tract, documented with investigations directed by 
clinical symptoms, such as radiologic studies (radiographs or computed tomographic 
scans) or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, 
sputum culture, or bronchoalveolar lavage). 

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4. 
BO-organizing pneumonia not due to infections may represent a manifestation of either 
acute or chronic GVHD and is considered a common feature. 
 
K. Musculoskeletal System 
 
Diagnostic features include fascial involvement often affecting the forearms or legs and often 
associated with sclerosis of the overlying skin and subcutaneous tissue. Fascial involvement may 
develop without overlying sclerotic changes of the skin and can result in joint stiffness or 
contractures when present near joints. Fasciitis is detected on examination by stiffness, a restricted 
range of motion (e.g., often decreased dorsal wrist flexion or inability to assume a Buddha prayer 
posture), edema of the extremities with or without erythema (early sign), peau d’orange (edematous 
skin with prominent pores resembling the surface of an orange), or joint contractures (late 
complications). Clinical myositis with tender muscles and increased muscle enzymes is a 
distinctive but nondiagnostic manifestation of chronic GVHD. Myositis may present as proximal 
myopathy, but this complication is rare and does not explain the frequent complaints of severe 
cramps. Evaluation of myositis involves electromyography and measurement of creatine 
phosphokinase or aldolase. Arthralgia and arthritis are uncommon and are occasionally associated 
with the presence of autoantibodies. 
 
L. Hematopoietic and Immune Systems 
 
Abnormalities are common in chronic GVHD but cannot be used to establish the diagnosis of 
chronic GVHD. Cytopenias may result from stromal damage or autoimmune processes. 
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hypergammaglobulinemia may be present. Autoantibodies may develop with autoimmune 
hemolytic anemia and idiopathic thrombocytopenic purpura. ThrRPERF\WRSHQLDȝ/ at 
the time of chronic GVHD diagnosis has been associated with a poor prognosis. 
 
M. Other Findings 
 
Serositis (pericardial or pleural effusions or ascites), peripheral neuropathy, myasthenia gravis, 
nephrotic syndrome, and cardiac involvement have been attributed to chronic GVHD, but these 
manifestations are rare. For these manifestations, chronic GVHD is often a diagnosis of exclusion. 
 
Differential diagnosis between acute and chronic GVHD 
 
The Working Group recognized 2 main categories of GVHD, each with 2 subcategories (Table 2). 
The broad category of acute GVHD includes (1) classic acute GVHD (maculopapular rash, nausea, 
vomiting, anorexia, profuse diarrhea, ileus, or cholestatic hepatitis) occurring within 100 days after 
transplantation or DLI (without diagnostic or distinctive signs of chronic GVHD) and (2) 
persistent, recurrent, or late acute GVHD: features of classic acute GVHD without diagnostic or 
distinctive manifestations of chronic GVHD occurring beyond 100 days of transplantation or DLI 
(often seen after withdrawal of immune suppression). The broad category of chronic GVHD 
includes (1) classic chronic GVHD without features characteristic of acute GVHD and (2) an 
overlap syndrome in which features of chronic and acute GVHD appear together. In the absence 

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of histologic or clinical signs or symptoms of chronic GVHD, the persistence, recurrence, or new 
onset of characteristic skin, GI tract, or liver abnormalities should be classified as acute GVHD 
regardless of the time after transplantation. With appropriate stratification, patients with persistent, 
recurrent, or late acute GVHD or overlap syndrome can be included in clinical trials with patients 
who have chronic GVHD. 
 
TABLE 2: CATEGORIES OF ACUTE AND CHRONIC GVHD 
 
Category 
Time of Symptoms 
after HCT or DLI 
Presence of Acute 
GVHD Features 
Presence of Chronic 
GVHD Features 
Acute GVHD 
 
 
 
Classic acute GVHD 
G 
Yes 
No 
Persistent, recurrent, or 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 
GVHD indicates graft-versus-host disease; HCT, hematopoietic cell transplantation; DLI, Donor lymphocyte 
infusion 

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APPENDIX F  
LANSKY/KARNOFSKY PERFORMANCE STATUS SCALES 

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LANSKY/KARNOFSKY PERFORMANCE STATUS SCALES
LANSKY SCALE FOR PARTICIPANTS < 15.00 YEARS
Percentage
100
Fully Active
90
Minor restriction in physically strenuous play
80
Restricted in strenuous play, tires more easily, otherwise active
70
Both greater restrictions of, and less time spent in, active play
60
Ambulatory up to 50% of time, limited active play with assistance/supervision
50
Considerable assistance required for any active play; fully able to engage in quiet 
play
40
Able to initiate quiet activities
30
Needs considerable assistance for quiet activity
20
Limited to very passive activity initiated by others (e.g., TV)
10
Completely disabled, not even passive play
0
Dead
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Percentage
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled, hospitalization indicated. Death not imminent
20
Very sick, hospitalization necessary, active supportive treatment necessary
10
Moribund, fatal processes, progressing rapidly
0
Dead

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APPENDIX G 
 
QUALITY OF LIFE ASSESSMENT PROMIS PAIN & FATIGUE DOMAINS AND 
ELECTRONIC PAIN DIARY 

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QUALITY OF LIFE ASSESSMENT PROMIS PAIN & FATIGUE 
DOMAINS
Using PROMIS modules regarding pain and fatigue as the standardized assessment tool, QoL 
measures will be administered to English- and Spanish-speaking patients in the adult stratum 
prior to the initiation of hydroxyurea, at 1 year post-transplant, and 2 years post-transplant to 
participants in each stratum. All QoL assessments will be completed during the routine clinic 
visit associated with the corresponding study time point. PROMIS modules should be 
DGPLQLVWHUHGRQDVLQJOHGD\GD\VDQGGD\VIURm initiating the 28 day electronic pain 
diary.
A. ELECTRONIC PAIN DIARY
Subjects who speak English and are 15 years or older will be asked to use a web-based diary to 
report pain. The questions are generally related to description of pain and the impact it has on 
different aspects of life. The pain diary will be completed twice a day for a period of 4 weeks prior 
to the transplant, at 1 year, and 2 years after the transplant. The pain diary can be accessed viathe 
internet using your personal computer, tablet or smart phone. Subjects will receive automated 
reminders to report pain at least twice a day, which will be set based on their stated preference 
after joining the study. Additionally, study staff may follow up with the subject after multiple days 
of missed pain diary entries. The study will not provide any smartphones or electronic devices or 
provide any compensation for phone and internet plans/bills as part of this study. If patients are 
admitted to the hospital during one of these 4-week periods, information about pain and related 
information from the medical record. The electronic diary is NOT a means of communicating with 
healthcare providers or for seeking healthcare attention. It is ONLY a reporting tool for this study. 
If subjects have any concerns, they MUST contact their healthcare provider or go to the 
Emergency Room. They must not wait for study staff to contact them.

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APPENDIX H 
DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR 
CENSORED EXPONENTIAL DATA 

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DERIVATION OF A SEQUENTIAL TEST STATISTIC FOR CENSORED 
EXPONENTIAL DATA
Background – The Sequential Probability Ratio Test
Let f (.,T) be the density function for random variable X. According to Neyman and Pearson, the
most powerful test of H0 :T  To versus H1 :T  T1 decides in favor of H 1 or H 0 if Ln ! cD or
n
Ln  cD , respectively, where
Ln   f (xi ;T1 ) / f (xi ;T 0 ) is the likelihood ratio, and
i
cD is
determined to have the size D . When the sample size is not fixed in advance, further improvement 
is possible by using Wald’s Sequential Probability Ratio Test (SPRT). The SPRT continues to
sample as long as B Ln  A for some constant B  1  A , stops sampling and decides in favor of
H1 as soon as Ln ! A, and stops sampling and decides in favor of H 0 as soonas Ln  B .
The usual measures of performance of such a procedure are the error probabilities
and E of
rejecting H 0when T  T 0 , and of accepting H 0when T  T1 , respectively, and the expected
sample size E(N | T j ) { E j (N) . Wald and Wolfowitz showed that among all tests, sequential or
not,forwhich Pr0(rejectH0)dD andPr1(rejectH0)dE ,andforwhich E j (N ) are finite, j=0,1,
the SPRT with error probabilities
and E minimizes E0(N) and E1 (N) . If, in addition, the
x1, x2,... are independent and identically distributed (i.i.d.) with density function
f (x,T) , with
monotone likelihood ratio in 
decreasing power function.
W (x) , then any SPRT for testing T0against T1(!T0) has non-

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0
1
For the SPRT witherror probabilities
and E, the SPRT boundaries are given 
approximately by
A  (1 E ) /
D
and
B  E /(1  D ).
The operating characteristics of the SPRT are given by
O(T,D, E,T ,T )  (Ah(T ) 1)/(Ah(T )  Bh(T)
)
³( f (x;T1) / f (x,T 2 ))h(T ) f (x;T )dx  1 .
where h(T ) is the non-trivial solution to the equation
The formula E(N;T )  [[(1 O(T)]log A  O(T)log B]/ E(z;T )provides the average sample number
for an arbitrary T . The sample size distribution is very highly skewed, Var(N)|[E(N)]2 . Thus
we will consider a truncated test with maximum sample size of 
operating characteristics of the test.
N 0 and simulate to obtain the

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n
Derivation of the SPRT for Censored Exponential Survival Times
Suppose that we wish to construct a sequential test for the composite null hypothesis that the rate 
of overall mortality at an early time point t is less than or equal to p0 versus the alternative 
hypothesis that it is greater than or equal to p0. Let us assume that the survival times, T1,T2,...,Tn,
are i.i.d. with exponential density function f (T ,T)  TeTT . Although an exponential model may
not fit well for overall mortality, it usually provides a reasonable model over a short time frame 
for modeling toxicity, so in all discussion below we assume that exponential survival times are 
censored at time point t. In the exponential parameterization, a t-day survival rate of p0 translates 
into a mean survival of μ0=-t/ln(1-p0) (rate parameter T0  -ln(1-p0)/t).
The SPRT is derived with reference to a simple null and alternative hypothesis for the rate
parameter, in this case, H0:T  To versus H1 :T  T1 . The log-likelihood ratio for the exponential
in
the
presence
of
censoring
is
log f (xi;T1)log f(xi,T0) d(log(T1)log(T0))(T1T0)¦Ti , where d is the number of
i
i
i
events. The SPRT can be represented graphically when plotting the number of deaths (d) on the
n
y axis against the total time on study ¦Ti
i
bounded by two parallel lines given by
on the x axis. The continuation region in terms of d is
ª log(B)
º 
ª
(T1 T0 
)
º¦
n T   d  ª log(A)
º 
ª
(T1 T0 
)
º¦
n  
T
«(logT   logT )» «(log
T
 logT )»
i
«(logT   logT )» «(log
T
 logT )»
i
¬
1
0  ¼
¬
1
0 ¼ i
¬
1
0  ¼
¬
1
0 ¼ i
with
common
slope
(T1T0)/(logT1logT0),
and
intercepts
logA/(lnT1lnT0)
and
logB/(lnT1lnT0), fortheupper and lower bounds, respectively. For
monitoring purposes, at an interim analysis calendar time point s, suppose that
d(s) events have occurred and that the total
time on study is ¦Ti(s).The cumulative number of events d(s) is plotted on the y axis
against the
i
total time on study, ¦Ti (s) .  When this graph crosses the upper boundary, the null 
n
n
n
n

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hypothesis is 
i 
rejected. In practice, monitoring will be scheduled monthly after the start of 
enrollment to the study. 
 
A truncated version of the SPRT can be obtained by specifying a maximum sample 
size. We truncate the SPRT by declaring that if the test has failed to terminate after 
the maximum sample size, that the null hypothesis will be accepted. Since the 
probability that the untruncated SPRT would reject the null at the maximum 
sample size is negligible, it makes little difference how the final boundary value is 
selected, and this rule is chosen for simplicity. The operating characteristics of this 
proposed truncated SPRT for censored exponential data can be estimated by 
simulation. 

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APPENDIX I  
PRES GUIDELINES 

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GUIDELINES FOR PREVENTION AND MANAGEMENT OF PRES
Mission Statement
To describe the pathophysiology, clinical diagnosis, prevention and management of Posterior 
reversible encephalopathy syndrome (PRES). PRES is a disorder of reversible subcortical 
vasogenic brain edema with a constellation of acute neurological symptoms and brain imaging 
findings of vasogenic edema predominantly involving the bilateral parieto-occipital regions. 
Patients with sickle cell disease are particularly susceptible to PRES.71,72
Pathophysiology
PRES results from endothelial injury related to abrupt blood pressure changes or direct effects of 
cytokines on the endothelium, which leads to the breakdown of the blood–brain barrier and 
subsequent brain edema. With early diagnosis and appropriate management, PRES is reversible, 
both radiographically and clinically, and generally has a favorable prognosis.
Clinical Presentation
Clinical presentation of PRES include73,74,75,76,77,78 seizure (60–75%), encephalopathy (50–80%), 
headache (50%), visual disturbances (33%), focal neurological deficit (10–15%), and Status 
epilepticus (5–15%). Symptoms typically occur in the setting of renal failure, blood pressure 
fluctuations, cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia.76
Calcineurin inhibitor (CNI)-induced PRES may occur with elevated blood pressure within days to 
weeks of CNI initiation and typically occurs without elevated medication levels.79 Clinical and 
radiographic recovery occur in 75–90% of patients with a mean time to full clinical recovery range 
of 2–8 days, although some patients can take several weeks to achieve full recovery.79,80,81,82
Concomitant GVHD with the use of steroids is an important risk factor for PRES.83
Imaging
Brain imaging is useful to confirm the diagnosis of PRES and to exclude alternative 
diagnoses.76,77,82,84 Although vasogenic edema can be visualized using non-contrast CT in some 
patients, brain MRI (particularly T2-weighted sequences such as fluid-attenuated inversion 
recovery [FLAIR]) is much more sensitive.82,84 Brain imaging usually reveals vasogenic edema in 
the parieto-occipital regions of both cerebral hemispheres. The subcortical white matter is always
affected, and the cortex is also often involved. The edema is usually asymmetric, but almost always 
bilateral. Three primary descriptive variations exist in approximately 70% of patients: a dominant 
parieto-occipital pattern, holo-hemispheric watershed pattern, and superior frontal sulcus pattern. 
Neither the pattern nor the severity of brain edema, is associated with the type or severity of clinical
presentation.76,82
Differential Diagnosis

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The symptoms and signs are non-specific, thus necessitating brain imaging with the primary intent 
to exclude alternative diagnoses. However, the diagnosis of PRES is not solely radiological; the 
clinical context and the judgment of the clinician are crucial to making the correct diagnosis.
Differential diagnoses to be considered include infectious encephalitis, vasculitis, post-transplant 
lymphoproliferative disorder and progressive multifocal leucoencephalopathy.
Risk factors in HCT predisposing to PRES
Incidence of PRES in allo-HCT is 7-9% with greater risks with myeloablative than with non-
myeloablative regimens (16% vs 3%). PRES commonly occurs in the first month following HCT 
and is associated with increased HLA mismatch and with acute GVHD. Low –levelneurotoxicity 
such as tremors, anxiety, and psychiatric dysfunction has been observed in 10%-40% of patients 
receive CNIs. Cyclosporine can induce endothelial injury/dysfunction leading to enhanced 
vasoconstrictive effects, increased sympathetic activation, and coagulation effects. Blood levels of 
Cyclosporine do not appear to correlate with severe neurotoxicity or PRES. Immune challenge 
from the transplant such as rejection and GVHD, effects of chemotherapy, and sepsis may all 
contribute to the risk of PRES. Discontinuation or switch of CNIs usually results in clinical 
improvement.
Unique Risk for PRES in patients with SCD undergoing HCT
Patients with SCD have impaired dynamic cerebrovascular autoregulation with decreased ability 
to buffer the transfer of blood pressure surges to cerebral tissue85 as well as reduced 
cerebrovascular reserve capacity or vasodilatory capacity.86 This may place them at unique risk 
for developing PRES. PRES has been reported in patients with SCD following severe acute chest 
syndrome, blood transfusion, hyper-transfusion with rapid increase in hemoglobin, recent use
ofcorticosteroids, hypomagnesaemia, and in the absence of any precipitating factors.87,88,89,90,91
3HJHORZ&HWDO$P-0HGS-

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The prevalence of seizures in children with SCD is 10 times that of the general population.92,93,94 
The observation of neurological complications in 30% of patients including intracranial 
hemorrhages in  38%  of  those  with  a  previous  history of  stroke   in  an  early series  of  patients  
with SCD undergoing HCT led to the universal adoption of measures for the prevention of PRES.71 
Measures for prevention of PRES include extended duration of anticonvulsant prophylaxis, 
intensified antihypertensive management and aggressive platelet support.71 
 
Prevention of PRES in HCT for SCD 
Prevention of PRES requires careful attention to the following measures (Table 2): 
a. Control of Blood pressure. Blood pressure in patients with SCD has been reported 
to be lower than published standards for age, sex, and race-matched controls.95,96,97 Decreased 
survival has been observed for patients with SCD whose systolic or diastolic pressures were 
above the 90th percentile for HbSS subjects.97 Pressures above the 90th percentile for HbSS 
may overlap levels considered normal in non-SCD patients. Blood pressures may be elevated 
with fluid infusions or use of medications such as corticosteroids or CNIs. Supportive care 
orders must indicate the importance of keeping BP within 10% above the median for age for 
HbSS patients as described by Pegelow et al (Table I) or the baseline BP for the patient, 
whichever is lower. Mean arterial pressure (MAP) should be maintained at <70mmHg. Close 
monitoring and aggressive management with anti-hypertensive agents will be required to 
prevent PRES. 
b. Maintenance of adequate platelet count. Thrombocytopenia and coagulopathy may be 
associated with increased risk of PRES-related ICH.71,98 It is therefore recommended to keep 
platelet count> 50, ȝ/71 
c. Maintenance of euvolemic state. 
Large fluid shifts should be avoided.98 Close attention must be paid to fluid balance since fluid 
overload with weight gain associated with increased blood pressure and consequently, increased 
risk of PRES. 
 
Table 2. Measures for Prevention of PRES 
Measure 
Action 
Control of Blood pressure 
Physician to be notified and PRN anti- hypertensives 
to be administered if systolic or diastolic BP exceeds 
10% above median for age in HbSS patients or > 10% 
baseline for patient, whichever is lower. 
Maintenance of adequate platelet count. 
7UDQVIXVHWRNHHS3ODWHOHWV!ȝ/ 
Maintenance of euvolemic state 
Avoid rapid fluid shifts. Maintain weight as close to 
baseline as possible. 
Maintenance of adequate magnesium level 
0DLQWDLQ VHUXP PDJQHVLXP OHYHO  PJG/ 
0.75mmol/L) when lab normal range (1.7–2.4 mg/dL 
or 0.7–1 mmol/L) 
Prevention of seizures 
Institute anticonvulsant therapy before Busulfan and 
continue through the duration of administration of any 
calcineurin inhibitor. 
 

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c. Maintenance of adequate level of serum Magnesium. Severe hypomagnesemia can present 
with clinical and radiological features similar to PRES.99,100 Magnesium sulphate is considered 
the drug of choice in the treatment of PRES associated with Eclampsia.101 It is therefore 
recommended that patients receive magnesium supplementation in order maintain patient 
Maintain serum magnesium level  1.5mg/dL (0.75mmol/L) or  1.8 mg/dLwhen lab normal 
range (1.7– 
2.4 mg/dL or 0.7–1 mmol/L). Maintenance of mild hypermagnesemia with serum 
Magnesium 2- 3mg/dL may be advisable, but maybe difficult to achieve because of side effects 
of P.O Magnesium. Bioavailability of magnesium in the aspartate, citrate, lactate, diglycinate 
and chloride forms is higher than magnesium oxide or sulfate.102,103,104,105,106,107 
 
e. Treatment and management of PRES 
The management of PRES consists of eliminating the precipitating cause, control of blood 
pressure and the institution of comprehensive supportive measures (Table 3). If PRES is 
caused by a specific medication, this medication should be discontinued. Failure to do so can 
perpetuate the syndrome. Alternative immunosuppression might be considered, but 
corticosteroids should be avoided. If steroids are added, careful consideration must be given 
to aggressive management of blood pressure. While it is important to treat the hypertension, 
the initial goal in treating patients with severe hypertension is to reduce blood pressure by 
25% within the first few hours.3 Pronounced fluctuations of blood pressure should be 
avoided, and continuous infusions of intravenous drugs might be required. Excessive or rapid 
blood pressure reduction could provoke cerebral ischemia. Seizures are treated with 
antiepileptic medications. Other underlying disorders, such as sepsis, and flare-ups of 
autoimmune disorders, should be treated. 
 
Table 3. Measures for Treatment and Management of PRES 
Measure 
Action 
Supportive care 
Immediately admit to ICU and initiate management as below 
while evaluating cause for neurological manifestations. High 
index of suspicion and early diagnosis are key. Obtain MRI 
with FLAIR. Monitor neurological status closely. 
Removal 
of 
drug 
precipitating 
PRES 
Caution is advised in adding steroids because of the risk of 
hypertension and progression of PRES. 
Control of Blood pressure 
Institute intravenous medications to control Blood pressure. 
Labetalol is drug of choice. Decrease BP by 25% over 6 
hours. Gradual reduction of BP thereafter. 
Maintenance of adequate platelet count. 
7UDQVIXVHWRNHHS3ODWHOHWV!ȝ/ 
Maintenance of euvolemic state 
Avoid rapid fluid shifts. Maintain weight as close to 
baseline as possible. Close attention to intake and 
output. Avoid hypertransfusion. Keep Hb<12gm/dL. 
Maintenance 
magnesium level 
of 
adequate 
Correct hypomagnesemia. Maintain serum magnesium 
OHYHOPJG/PPRO/ZKHQODEQRUPDOUDQJH
(1.7–2.4 mg/dL or 0.7–1 mmol/L) 

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Table 3. Measures for Treatment and Management of PRES 
Measure 
Action 
Treatment of seizures 
Institute 
immediately. 
anticonvulsant 
therapy 
Management of concurrent illness 
Treat sepsis, or fluid overload. 
Rehabilitation 
Consider early introduction of physical and 
occupational therapy as appropriate 
 
f. Prognosis 
Despite its name, PRES is not always fully reversible. Early diagnosis and prompt management 
is crucial since the most severe forms of the PRES result in death, or chronic neurological 
sequelae.108 Severe neurological injury and death can be attributed to intracranial hemorrhage, 
posterior fossa edema with brainstem compression, acute hydrocephalus109, or marked diffuse 
cerebral edema and increased global intracranial pressure. Persistent neurological sequelae are 
reported in 10–20% of patients with PRES.72,73,74,75,76,77,78 

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APPENDIX J 
VENO-OCCLUSIVE DISEASE CRITERIA 

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VENO OCCLUSIVE DISEASE CRITERIA
Veno occlusive disease will be defined using either the Baltimore or modified 
Seattle criteria as detailed in table I.1 below. This table is adapted from Dignan 
FL et al. Br J Haematol.110
TABLE I1. MODIFIED SEATTLE CRITERIA AND BALTIMORE CRITERIA
Modified Seattle Criteria
Two of the following symptoms must be present within 20 days of transplant:
x
Bilirubin > 34.2 μmol/L (2 mg/dL)
x
Hepatomegaly or right upper quadrant pain
x
Weight gain (>2% from pre-transplant weight)
Baltimore Criteria
Bilirubin > 34.2 μmol/L (2 mg/dL) within 21 days of transplant and 2 of the following 
symptoms:
x
Hepatomegaly
x
Ascites
x
Weight gain (>5% from pre-transplant weight)

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APPENDIX K  
IPS CRITERIA 

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IDIOPATHIC PNEUMONIA SYNDROME (IPS) CRITERIA
IDIOPATHIC PNEUMONIA SYNDROME
I: Evidence of widespread alveolar injury:
a. Multilobar infiltrates on routine chest radiographs or computed tomography
b. Symptoms and signs of pneumonia (cough, dyspnea, tachypnea, rales)
c. Evidence of abnormal pulmonary physiology
1. Increased alveolar to arterial oxygen difference
2. New or increased restrictive pulmonary function 
test abnormality II: Absence of active lower respiratory 
tract infection based upon:
a.Bronchoalveolar lavage negative for significant bacterial pathogens 
including acid-fast bacilli, Nocardia, and Legionella species
b. Bronchoalveolar lavage negative for pathogenic nonbacterial microorganisms:
1. Routine culture for viruses and fungi
2. Shell vial culture for CMV and respiratory RSV
3. Cytology for CMV inclusions, fungi, and Pneumocystis jiroveci (carinii)
4.Direct fluorescence staining with antibodies against CMV, RSV, HSV, 
VZV, influenza virus, parainfluenza virus, adenovirus, and other
organisms
c. Other organisms/tests to also consider:
1.Polymerase chain reaction for human metapneumovirus, rhinovirus, 
coronavirus, and HHV6
2. Polymerase chain reaction for Chlamydia, Mycoplasma, and Aspergillus species
3. Serum galactomannan ELISA for Aspergillus species
d. Transbronchial biopsy if condition of the patient permits
III: Absence of cardiac dysfunction, acute renal failure, or iatrogenic fluid overload as
etiology for pulmonary dysfunction

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APPENDIX L 
 
HYDROXYUREA PERIOD DOSE MODIFICATIONS 
RECOMMENDATIONS 

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HYDROXYUREA PERIOD DOSE MODIFICATION 
RECOMMENDATIONS
Hydroxyurea (30 mg/kg/day) will be commenced as a single daily oral dose on Day -70 and 
continued through Day -10. Hydroxyurea will be adjusted to the ideal body weight (IBW) in 
children and adults weighing > 125% IBW. A CBC will be obtained weekly and the dose will be 
reduced if the ANC<1500 or platelet <100,000. HU will be discontinued on Day -10.
1. Patients with side effects to hydroxyurea such as headache, mild gastrointestinal symptoms, 
including abdominal discomfort or nausea, dermatologic changes, including skin 
hyperpigmentation or darkening of the nails (melanonychia), are sporadic and not dose-
dependent.
Recommendations: Patients with nausea or gastrointestinal complaints should be
advised to take hydroxyurea at bedtime and using single dosing. If symptoms persist,
suggest dose reduction by 2.5 -5 mg/kg/day decrements.
2. If a patient on protocol dose of hydroxyurea therapy is admitted or treated for an acute pain 
episode, hydroxyurea should not be held unless there is evidence of hematological toxicity. 
Table 1 list suggested hydroxyurea dose modifications based on published studies.
Table 1. Hematological toxicity thresholds requiring hydroxyurea dose modifications
Lab parameter
Value
Action1
Neutrophils
absolute neutrophil count (ANC) < 1.5 
×109/L (1000/μL
Hold hydroxyurea
Hemoglobin 
(Hb)
Decline in Hb >20% from the baseline, or 
Hb <5.0 g/dL, with low reticulocytes
Hold hydroxyurea
Reticulocytes
<80×109/L 
(80,000/μL) 
unless 
the 
hemoglobin concentration is >8.0 gm/dL
Hold hydroxyurea
Platelets
<100×109/L (100,000/μL)
Hold hydroxyurea
Non- hematologic 
toxicity
Increase in serum creatinine by
Non- hematologic 
toxicity
1 If toxicity is identified, hydroxyurea will be held, and when the laboratory abnormality resolved, hydroxyurea will 
be resumed at the previous dose. If toxicity lasted for more than 2 weeks or reoccurred after the medication was 
resumed, the dose was permanently decreased by 2.5 mg/kg/day.

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a. In patients who develop unexpected serious medical complications or complicated vaso- 
occlusive pain episode (i.e., sickle cell pain episode complicated by acute chest 
syndrome, stroke, pneumonia, acute kidney injury, bacteremia/sepsis or splenic 
sequestration), hydroxyurea will be held and resumed at treating physician’s discretion. 
b. For adults prescribed hydroxyurea in 500 mg capsules, the hydroxyurea dose will be 
rounded up if dose calculation is between doses of 500 mg. If not tolerated, then the dose 
may be titrated down as indicated above7. 
c. Any modifications to the preparative regimen or drug stoppage should be reported to the 
BMT CTN DCC protocol coordinator for review and approval by the Protocol 
Chairs/Officer prior to continuation of the protocol. 

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APPENDIX M  
REFERENCES

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REFERENCES
1 Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke 
by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler 
ultrasonography. N Engl J Med. 1998 Jul 2; 339(1):5-11).
2 DeBaun MR, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. 
N Engl J Med. 2014 Aug 21;371(8):699-710).
3 Walters MC, Patience M, Leisenring W et al. Bone marrow transplantation for sickle cell disease. 
New England Journal of Medicine. 1996;335:369-376.
4 Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haemopoietic stem-cell 
transplantation for treatment of non-malignant diseases in children. Lancet. 2004;364:156-162.
5 Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell 
transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-
dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. Bone Marrow 
Transplantation. 2005;35:171-177.
6 Iannone R, Casella JF, Fuchs EJ et al. Results of minimally toxic nonmyeloablative transplantation 
in patients with sickle cell anemia and beta-thalassemia. Biology of Blood and Marrow 
Transplantation. 2003;9:519-528.
7 Therrell BL Jr, Lloyd-Puryear MA, Eckman JR, Mann MY. Newborn screening for sickle cell 
diseases in the United States: A review of data spanning 2 decades. Semin Perinatol. 2015 
Apr;39(3):238-51.
8 Lorey FW, Arnopp J, Cunningham GC. Distribution of hemoglobinopathy variants by ethnicity in 
a multiethnic state. Genet Epidemiol. 1996;13(5):501-12.
9 Bernaudin F, Socie G, Kuentz M et al. Long-term results of related myeloablative stem-cell 
transplantation to cure sickle cell disease. Blood. 2007; 110(7):2749-2756.
10 Steiner CA, Miller JL. Sickle Cell Disease Patients in US Hospitals, 2004. Healthcare Cost and 
Utilization Project Statistical Brief #21. 2004 Dec. Agency for Healthcare Research and Quality, 
Rockville, Md. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb21.pdf.
11 Lê PQ, Gulbis B, Dedeken L, et al. Survival among children and adults with sickle cell disease in 
Belgium: Benefit from hydroxyurea treatment. Pediatric Blood and Cancer. 2015 
Nov;62(11):1956-61.
12 Lobo CL, Pinto JF, Nascimento EM, Moura PG, Cardoso GP, Hankins JS. The effect of 
hydroxcarbamide therapy on survival of children with sickle cell disease. British Journal of 
Haematology. 2013 Jun;161(6):852-60.
13 Kassim AA, Galadanci NA, Pruthi S, DeBaun MR. How I treat and manage strokes in sickle 
cell disease. Blood. 2015 May 28;125(22):3401-10.
14 Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The natural history of stroke in sickle cell 
disease. American Journal of Medicine. 1978 Sep;65(3):461-71.
15 Hulbert ML, McKinstry RC, Lacey JL, et al. Silent cerebral infarcts occur despite regular blood 
transfusion therapy after first strokes in children with sickle cell disease. Blood. 2011
Jan20;117(3):772-9.
16 Scothorn DJ, Price C, Schwartz D. Risk of recurrent stroke in children with sickle cell disease 
receiving blood transfusion therapy for at least five years after initial stroke. Journal of 
Pediatrics. 2002 Mar;140(3):348-54.

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17 Scothorn, Douglas J. et al. Risk of recurrent stroke in children with sickle cell disease receiving 
blood transfusion therapy for at least five years after initial stroke. The Journal of Pediatrics , 
Volume 140 , Issue 3 , 348 - 354 
18 Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell 
disease treated with erythrocyte transfusions. Journal of Pediatrics. 1995 Jun;126(6):896-9. 
19 Bernaudin F, Verlhac S, Arnaud C, et al. Impact of early transcranial Doppler screening and 
intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. 
Blood. 2011 Jan 27;117(4):1130-40. 
20 DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral 
infarcts in sickle cell anemia. New England Journal of Medicine. 2014 Aug 21;371(8):699- 710. 
21 Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in 
patients with sickle cell disease. New England Journal of Medicine. 2004 Feb 26;350(9):886– 
95. 
22 Gladwin MT, Barst RJ, Gibbs JS, et al. Risk factors for death in 632 patients with sickle cell 
disease in the United States and United Kingdom. PLoS One. 2014 Jul 2;9(7). 
23 McClellan AC, Luthi JC, Lynch JR, et al. High one year mortality in adults with sickle cell 
disease and end-stage renal disease. British Journal of Haematology. 2012 Nov;159(3):360-7. 
24 Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with sickle 
cell disease. Annals of Internal Medicine. 2008 Jan 15;148(2):94-101 
25 Slavin S, Nagler A, Naparstek E et al. Allogeneic nonmyeloablative stem cell transplantation 
(NST) as an emerging new modality for immunotherapy of hematologic malignancies and non- 
malignant disorders [abstract]. Blood. 1998;92:519a. 
26 Greenberg P, Cox C, LeBeau MM et al. International Scoring System for Evaluating Prognosis 
in Myelodysplastic Syndromes. Blood. 1997;89:2079-2088. 
27 Gladwin MT, Barst RJ, Gibbs JS, et al. Risk factors for death in 632 patients with sickle cell 
disease in the United States and United Kingdom. PLoS One. 2014; 9(7): e99489. 
28 Lanzkron S, Carroll C, Haywood C Jr. Mortality rates and age at death from sickle cell disease: 
U.S., 1979-2005. Public Health Reports. 2013 Mar-Apr;128(2):110-6. 
29 Walters MC, Hardy K, Edwards S, et al. Pulmonary, gonadal, and central nervous system status 
after bone marrow transplantation for sickle cell disease. Biology of Blood and Marrow 
Transplantation. 2010 Feb;16(2):263-72. 
30 Dedeken L, Le PQ, Azzi N, et al. Haematopoietic stem cell transplantation for severe sickle cell 
disease in childhood: a single centre experience of 50 patients. British Journal of Haematology. 
2014 May;165(3):402-8. 
31 Bhatia M, Jin Z, Baker C, et al. Reduced toxicity, myeloablative conditioning with BU, 
fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell 
disease.Bone Marrow Transplantation. 2014 Jul;49(7):913-20. 
32 McPherson ME, Hutcherson D, Olson E, Haight AE, Horan J, Chiang KY. Safety and efficacy 
of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT 
for sickle cell disease. Bone Marrow Transplantation. 2011 Jan;46(1):27-33. 
33 King AA, Kamani N, Bunin N, et al. Successful Matched Sibling Donor Marrow Transplantation 
Following Reduced Intensity Conditioning in Children with Hemoglobinopathies. American 
Journal of Hematology. 2015 Dec;90(12):1093-8. 
34 Locatelli F, Kabbara N, Ruggeri A, et al. Outcome of patients with hemoglobinopathies given 
either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood. 2013 

Blood and Marrow Transplant Clinical Trials Network    
Haplo Sickle Cell – Protocol 1507
 
 
Version 5.0 dated May 19, 2021 
 
 CONFIDENTIAL  
                   177 
Aug 8;122(6):1072-8. 
35 Mentzer WC, Heller S, Pearle PR, Hackney E, Vichinsky E. Availability of related donors for 
bone marrow transplantation in sickle cell anemia. American Journal of Pediatric 
Hematology/Oncology. 1994 Feb;16(1):27-9. 
36 Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell 
grafts in the U.S. registry. New England Journal of Medicine. 2014 Jul 24;371(4):339-48. 
37 Couban S, Simpson DR, Barnett MJ et al. A randomized multicenter comparison of bone marrow 
and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid 
malignancies. Blood. 2002;100:1525-1531. 
38 Bolaños-Meade J., Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. 
HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide 
expands the donor pool for patients with sickle cell disease. Blood. 2012 Nov 22, 120(22):4285-
4291. 
39 Anderlini, P, Wu, J, et al. Cyclophosphamide conditioning in patients with severe aplastic 
anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Blood. 
2007 110 (4): 1397-1400. Blood. 2011 118:2618-2621. 
40 Ruggeri A, Eapen M, Scaravadou A et al. Umbilical cord blood transplantation for children with 
thalassemia and sickle cell disease. Biol Blood Marrow Transplant. 2011; 17:1375-82. 
41 Kamani NR, Walters MC, Carter S et al. 2012 Unrelated donor cord blood transplantation for 
children with severe sickle cell disease: results of one cohort from the phase II study from the 
Blood Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow 
Transplant. 2015:18(8):1265-72. 
42 Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplantation. 1995;15:825-828. 
43 Giralt S, Estey E, Albitar M et al. Engraftment of allogeneic hematopoietic progenitor cells with 
purine analog-containing chemotherapy: harnessing graft-versus- leukemia without 
myeloablative therapy. Blood. 1997;89:4531-4536. 
44 Bernardo ME, Piras E, Vacca A et al. Allogeneic hematopoietic stem cell transplantation in 
thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of 
treosulfan. Blood 2012 May 18;120:473-76. 
45 Gaziev J, Isgro A, Sodani P et al. Optimal Outcomes in Young Class 3 Patients With 
Thalassemia Undergoing HLA-Identical Sibling Bone Marrow Transplantation. 
Transplantation. 2015 Oct 9. [Epub ahead of print]. 
46 Dedeken L, Le PQ, Azzi N et al. Haematopoietic stem cell transplantation for severe sickle cell 
disease in childhood: a single centre experience of 50 patients. British Journal of Haematology. 
2014 Jan 16; 165(3):402-8. 
47 Brachet C, Azzi N, Demulder A, et al. Hydroxyurea treatment for sickle cell disease: impact on 
haematopoietic stem cell transplantation's outcome. Bone Marrow Transplant. 2004 Apr; 
(8):799-803. 
48 Dignan F, Wynn RF, Hadzic N, et al. BCSH/BSBMT guideline: diagnosis and management of 
veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell 
transplantation. British Journal of Haematology. 2013 Sep 17; 163(4):444-47. 
49 Walters MC, Sullivan KM, Bernaudin F, et al. Neurologic complications after allogeneic 
marrow transplantation for sickle cell anemia. Blood. 1995 Feb 15; 85(4):879-84. 
50 Beitinjaneh A, McKinney AM, Cao Q, Weisdorf DJ. Toxic leukoencephalopathy following 

Blood and Marrow Transplant Clinical Trials Network    
Haplo Sickle Cell – Protocol 1507
 
 
Version 5.0 dated May 19, 2021 
 
 CONFIDENTIAL  
                   178 
fludarabine-associated hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011 
Mar;17(3):300-8 
51 Ramasamy K, Lim ZY, Pagliuca A, et al. Incidence and management of hepatic venoocclusive 
disease in 237 patients undergoing reduced-intensity conditioning (RIC) haematopietic stem 
cell transplantation (HSCT). Bone Marrow Transplant. 2006 Dec:38(12):823-4. 
52 Shalet SM. Effect of irradiation treatment on gonadal function in men treated for germ cell 
cancer. Eur Urol 1993:23:148-51 discussion 152. 
53 Howell S, Shalet S. Gonadal damage from chemotherapy and radiotherapy. Endocrinology and 
Metabolism Clinics of North Amereica. 1998:27:927-43. 
54 Thorner MO, Rogol AD, Blizzard RM et al. Acceleration of growth rate in growth hormone- 
deficient children treated with human growth hormone-releasing hormone. Hormone Research. 
1988:30:111-4. 
55 Van Dorp W, van der Geest I, Laven JSE, van den Heuvel-Eibrink M. Gonadal function recovery 
in very long-term male survivors of childhood cancer. International Journal of Radiation 
Oncology, Biology, Physics 1990; 19:873-80 
56 Faddy MJ, Gosden RG, Gougeon A et al. Accelerated disappearance of ovarian follicles in mid-
life: implications for forecasting menopause. Human Reproduction 1992; 7:1342-6. 
57 LaRiviere PD. The quality of high-energy X-ray beams. British Journal of Radiology 1989; 
62:995-8 
58 Panoskaltsis-Mortari A, Griese M, Madtes DK, et al. An Official American Thoracic Society 
Research Statement: Noninfectious Lung Injury after Hematopoietic Stem Cell Transplantation: 
Idiopathic Pneumonia Syndrome. American Journal of Respiratory and Critical Care Medicine. 
2011 May 1;183(9):1262-79. 
59 Smith WR, Bovbjerg VE, Penberthy LT, et al. Understanding pain and improving management 
of sickle cell disease: the PiSCES study. Journal National Medical Association. 
2005;97(2):183-193. 
60 Meloni A, Puliyel M, Pepe A, Berdoukas V, Coates TD, Wood JC. Cardiac iron overload in 
sickle-cell disease. American Journal of Hematology. 2014 Jul;89(7):678-83 
61 Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the 
early diagnosis of myocardial iron overload. European Heart Journal. 2001 Dec;22(23):2171-
9. 
62 Lucarelli G, Isgro A, Sodani P, et al. Hematopoietic SCT for the Black African and non-Black 
African variants of sickle cell anemia. Bone Marrow Transplantation. 2014 Nov;49(11):1376- 
81. 
63 Soni S, Gross TG, Rangarajan H, Baker KS, Sturm M, Rhodes M. Outcomes of matched sibling 
donor hematopoietic stem cell transplantation for severe sickle cell disease with myeloablative 
conditioning and intermediate-dose of rabbit anti-thymocyte globulin. Pediatric Blood and 
Cancer. 2014 Sep;61(9):1685-9. 
64 Hsieh M.M., Fitzhugh C.D., Weitzel R., et al: Nonmyeloablative HLA-matched sibling 
allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014 
Jul 2;312(1):48-56. 
65 Walters M.C., Patience M., Leisenring W., et al: Stable mixed hematopoietic chimerism after 
bone marrow transplantation for sickle cell anemia. Biology of Blood Marrow Transplantation. 
2001;7(12):665-73. 
 

Blood and Marrow Transplant Clinical Trials Network    
Haplo Sickle Cell – Protocol 1507
 
 
Version 5.0 dated May 19, 2021 
 
 CONFIDENTIAL  
                   179 
66 Locatelli F., Kabbara N., Ruggeri A., et al: Outcome of patients with hemoglobinopathies given 
either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood. 2013 
Aug 8;122(6):1072-8. 
67 Panepinto J.A., Walters M.C., Carreras J., et al: Matched-related donor transplantation for sickle 
cell disease: report from the Center for International Blood and Transplant Research. British 
Journal of Haematology. 2007 Jun;137(5):479-85. 
68 Hamill D, Shenoy S, Morris E, Fabricatore S, Brand P, Ayello J, et al. Robust Donor Chimerism 
and Engraftment Following Familial Haploidentical (FHI) (CD34 Enriched and T- Cell 
Addback) Allogeneic Stem Cell Transplantation in Patients with High Risk Sickle Cell Disease 
(SCD). 
Biology 
of 
Blood 
and 
Marrow 
Transplant. 
2016;22(3). 
doi: 
10.1016/j.bbmt.2015.11.396. 
69 Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ, et al. Cytotoxic T lymphocyte 
therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after 
haploidentical and matched unrelated stem cell transplantation. Blood. 2009;114(19):4283-92. 
Epub 2009/08/25. doi: 10.1182/blood-2009-07-232454. PubMed PMID: 19700662; PubMed 
Central PMCID: PMCPmc2774556. 
70 Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, et al. HLA- 
haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the 
donor pool for patients with sickle cell disease. Blood. 2012;120(22):4285-91. Epub 
2012/09/08. doi: 10.1182/blood-2012-07-438408. PubMed PMID: 22955919; PubMed Central 
PMCID: PMCPmc3507140. 
71 Walters MC, Bernaudin F, Johnson FL, et al. Neurologic Complications After Allogeneic Bone-
Marrow Transplantation for Sickle-Cell-Anemia. Blood. 1995 Feb 15;85(4):879-84. 
72 Noe A, Cappelli B, Biffi A, et al. High incidence of severe cyclosporine neurotoxicity in children 
affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell 
transplantation: early diagnosis and prompt intervention ameliorates neurological outcome. 
Italian Journal of Pediatrics. 2010 Feb 6;36:14. 
73 Liman TG, Bohner G, Heuschmann PU, Endres M, Siebert E. The clinical and radiological 
spectrum of posterior reversible encephalopathy syndrome: the retrospective Berlin PRES 
study. Journal of Neurology. Jan 2012;259(1):155-164. 
74 Li Y, Jenny D, Castaldo J. Posterior reversible encephalopathy syndrome: clinicoradiological 
spectrum and therapeutic strategies. Hospital Practice. Feb 2012;40(1):202-13. 
75 Brewer J, Owens MY, Wallace K, et al. Posterior reversible encephalopathy syndrome in 46 
of 
47 patients with eclampsia. American Journal of Obstetrics and Gynecology. Jun 
2013;208(6):468 e461-466. 
76 Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and 
radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurology. 
Sep 2015;14(9):914-25. 
77 Fugate JE, Claassen DO, Cloft HJ, Kallmes DF, Kozak OS, Rabinstein AA. Posterior reversible 
encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clinic 
Proceedings. May 2010;85(5):427-32. 
78 Legriel S, Schraub O, Azoulay E, et al. Determinants of recovery from severe posterior 
reversible encephalopathy syndrome. PLoS One. 2012;7(9):e44534. 
 

Blood and Marrow Transplant Clinical Trials Network    
Haplo Sickle Cell – Protocol 1507
 
 
Version 5.0 dated May 19, 2021 
 
 CONFIDENTIAL  
                   180 
79 Burnett MM, Hess CP, Roberts JP, Bass NM, Douglas VC, Josephson SA. Presentation of 
reversible posterior leukoencephalopathy syndrome in patients on calcineurin inhibitors. 
Clinical Neurology and Neurosurgery. Dec 2010;112(10):886-891. 
80 Moon SN, Jeon SJ, Choi SS, et al. Can clinical and MRI findings predict the prognosis of variant 
and classical type of posterior reversible encephalopathy syndrome (PRES)? Acta Radiologica. 
Dec 2013;54(10):1182-1190. 
81 Liman TG, Bohner G, Endres M, Siebert E. Discharge status and in-hospital mortality in 
posterior reversible encephalopathy syndrome. Acta Neurologica Scandinavica. Jul 
2014;130(1):34-39. 
82 Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and 
clinical features. American Journal of Neuroradiology. Jun 2008;29(6):1036-1042. 
83 Erer B, Polchi P, Lucarelli G, et al. CsA-associated neurotoxicity and ineffective prophylaxis 
with clonazepam in patients transplanted for thalassemia major: analysis of risk factors. Bone 
Barrow Transplantation. Jul 1996;18(1):157-162. 
84 Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior 
reversible encephalopathy syndrome. American Journal of Neuroradiology. Aug 
2007;28(7):1320-1327. 
85 Kim YS, Nur E, van Beers EJ, et al. Dynamic cerebral autoregulation in homozygous Sickle 
cell disease. Stroke; A Journal of Cerebral Circulation. Mar 2009;40(3):808-814. 
86 Nur E, Kim YS, Truijen J, et al. Cerebrovascular reserve capacity is impaired in patients with 
sickle cell disease. Blood. Oct 15 2009;114(16):3473-3478. 
87 Raj S, Killinger J, Overby P. Blood transfusion in sickle cell disease leading to posterior 
reversible encephalopathy syndrome (PRES). Journal of Child Neurology. Oct 
2013;28(10):1284-1286. 
88 Nair A, Testai FD. Recurrent posterior reversible encephalopathy syndrome in a sickle cell 
patient. Journal of the National Medical Association. Feb 2011;103(2):170-172. 
89 Parameswaran BK, Krishnan PR, Al Dossary J. Recurrent posterior reversible encephalopathy 
syndrome in a patient with sickle cell disease. Annals of Saudi Medicine. May-Jun 
2007;27(3):206-211. 
90 Niyadurupola N, Burnett CA, Allen LE. Reversible posterior leucoencephalopathy syndrome: a 
cause of temporary cortical blindness. The British journal of Ophthalmology. Jul 
2005;89(7):924-925. 
91 Henderson JN, Noetzel MJ, McKinstry RC, White DA, Armstrong M, DeBaun MR. Reversible 
posterior leukoencephalopathy syndrome and silent cerebral infarcts are associated with severe 
acute chest syndrome in children with sickle cell disease. Blood. Jan 15 2003;101(2):415-419. 
92 Kassim AA, Galadanci NA, Pruthi S, DeBaun MR. How I treat and manage strokes in sickle 
cell disease. Blood. May 28 2015;125(22):3401-3410. 
93 Liu JE, Gzesh DJ, Ballas SK. The Spectrum of Epilepsy in Sickle-Cell-Anemia. Journal of the 
Neurological Sciences. May 1994;123(1-2):6-10. 
94 Prengler M, Pavlakis SG, Boyd S, et al. Sickle cell disease: ischemia and seizures. Annals of 
Neurology. Aug 2005;58(2):290-302. 
95 Rodgers GP, Walker EC, Podgor MJ. Is "relative" hypertension a risk factor for vaso-occlusive 
complications in sickle cell disease? The American Journal of the Medical Sciences. Mar 
1993;305(3):150-156. 
 

Blood and Marrow Transplant Clinical Trials Network    
Haplo Sickle Cell – Protocol 1507
 
 
Version 5.0 dated May 19, 2021 
 
 CONFIDENTIAL  
                   181 
96 Dejong PE, Landman H, Vaneps LWS. Blood-Pressure in Sickle-Cell Disease. Archives of 
Internal Medicine. 1982;142(6):1239-1240. 
97 Pegelow CH, Phillips G, Wright E. Blood-Pressure (Bp) in Sickle-Cell Disease (Scd). Blood. 
Nov 15 1993;82(10):A473-A473. 
98 Aranas RM, Prabhakaran S, Lee VH. Posterior reversible encephalopathy syndrome associated 
with hemorrhage. Neurocritical Care. 2009;10(3):306-312. 
99 Boulos MI, Shoamanesh A, Aviv RI, Gladstone DJ, Swartz RH. Severe hypomagnesemia 
associated with reversible subacute ataxia and cerebellar hyperintensities on MRI. The 
neurologist. Jul 2012;18(4):223-225. 
100 Te Riele MG, Verrips A. Severe hypomagnesaemia causing reversible cerebellopathy. 
Cerebellum. Oct 2014;13(5):659-662. 
101 Kutlesic MS, Kutlesic RM, Koratevic GP. Posterior reversible encephalopathy syndrome in 
eclamptic patients: neuroradiological manifestation, pathogenesis and management. Medicinski 
pregled. Jan-Feb 2015;68(1-2):53-58. 
102 Siener R, Jahnen A, Hesse A. Bioavailability of magnesium from different pharmaceutical 
formulations. Urological Research. Apr 2011;39(2):123-127. 
103 Ranade VV, Somberg JC. Bioavailability and pharmacokinetics of magnesium after 
administration of magnesium salts to humans. American Journal of Therapeutics. Sep-Oct 
2001;8(5):345-357. 
104 Firoz M, Graber M. Bioavailability of US commercial magnesium preparations. Magnesium 
Research. Dec 2001;14(4):257-262. 
105 Walker AF, Marakis G, Christie S, Byng M. Mg citrate found more bioavailable than other Mg 
preparations in a randomised, double-blind study. Magnesium Research. Sep 2003;16(3):183-
191. 
106 Lindberg JS, Zobitz MM, Poindexter JR, Pak CY. Magnesium bioavailability from magnesium 
citrate and magnesium oxide. Journal of American College Nutrition. Feb 1990;9(1):48-55. 
107 Schuette SA, Lashner BA, Janghorbani M. Bioavailability of magnesium diglycinate vs 
magnesium oxide in patients with ileal resection. Journal of Parenteral and Enteral Nutrition. 
Sep-Oct 1994;18(5):430-435. 
108 Striano P, Striano S, Tortora F, et al. Clinical spectrum and critical care management of 
Posterior Reversible Encephalopathy Syndrome (PRES). Medical Science Monitor: 
International 
Medical 
Journal 
of 
Experimental 
and 
Clinical 
Research. 
Nov 
2005;11(11):CR549-553. 
109 Grossbach AJ, Abel TJ, Hodis B, Wassef SN, Greenlee JD. Hypertensive posterior reversible 
encephalopathy syndrome causing posterior fossa edema and hydrocephalus. Journal of 
Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia. Feb 
2014;21(2):207-211. 
110 Dignan FL, Wynn RF, Hadzic N, et al. BCSH/BSBMT guideline: diagnosis and management 
of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem 
cell transplantation. British Journal of Haematology. 2013;163(4):444-457. 
109 Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, et al. Long-term outcome 
and evaluation of organ function in pediatric patients undergoing haploidentical and matched 
related hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 
2013;19(5):820-30. Epub 2013/02/19. doi: 10.1016/j.bbmt.2013.02.010. PubMed PMID: 
23416852. 

Blood and Marrow Transplant Clinical Trials Network    
Haplo Sickle Cell – Protocol 1507
 
 
Version 5.0 dated May 19, 2021 
 
 CONFIDENTIAL  
                   182 
110 Flahault A, Cadilhac M, Thomas G. Sample size calculation should be performed for design 
accuracy in diagnostic test studies. J Clin Epidemiol. 2005;58(8):859-62. Epub 2005/07/16. doi: 
10.1016/j.jclinepi.2004.12.009. PubMed PMID: 16018921. 
111Kinney TR, Helms RW, O'Branski EE, Ohene-Frempong K, Wang W, Daeschner C, Vichinsky 
E, Redding-Lallinger R, Gee B, Platt OS, Ware RE. Safety of hydroxyurea in children with 
sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea 
Group. Blood. 1999 Sep 1;94(5):1550-4. 
112Wang WC, Wynn LW, Rogers ZR, Scott JP, Lane PA, Ware RE. A two-year pilot trial of 
hydroxyurea in very young children with sickle-cell anemia. J Pediatr. 2001 Dec;139(6):790- 
6. 
113Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, Ware RE. 
Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in 
children with sickle cell disease. Blood. 2004 Mar 15;103(6):2039-45. 
114Russell E. Ware. How I use hydroxyurea to treat young patients with sickle cell anemia. 
Blood. 
2010;115(26):5300-5311 
115Strouse JJ, Heeney MM. Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, 
toxicity, and management in children. Pediatr Blood Cancer. 2012 Aug;59(2):365-71.