Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children With Severe Sickle Cell Disease (BMT CTN #0601)
Phase: PHASE2
Conditions: Sickle Cell Disease
Sponsor: Medical College of Wisconsin

 

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Core Study Participants: 
City of Hope National Medical Center 
DFCI, Children’s Hospital of Boston 
Duke University Medical Center 
Ohio State Consortia 
- 
University of North Carolina Hospital at Chapel Hill 
Pediatric Blood and Marrow Transplant Consortium/  
Sickle Cell Disease Clinical Research Network 
All Children’s Hospital 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
Children’s Hospital of New Orleans 
Children’s Hospital of Philadelphia 
Children’s Hospital of Pittsburgh 
Children’s Hospital at Oakland CA 
Children’s Medical Center of Dallas, University of Texas Southwestern 
Children’s Mercy Hospital 
Children’s National Medical Center 
Cohen Children's Medical Center of New York 
Columbia University Medical Center, Morgan Stanley Children’s Hospital of New 
York-Presbyterian 
Cook Children’s Medical Center 
Hackensack University Medical Center 
Indiana University Medical Center, Riley Hospital 
Mattel Children’s Hospital at UCLA 
Medical University of South Carolina 
Medical College of Wisconsin 
Oregon Health & Science University 
Roswell Park Cancer Institute 
Texas Transplant Institute 
University Hospitals of Cleveland/Case Western 
University of Alabama, Lowder BMT 
University of California, San Francisco 
University of Miami, Jackson Memorial Hospital 
University of Mississippi 
University of Oklahoma Medical Center 
University of Pittsburgh Cancer Institute 
Virginia Commonwealth University 
Washington University, St. Louis Children’s Hospital 
University of Michigan 
University of Texas, MD Anderson Cancer Center 
 
 
 

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PROTOCOL SYNOPSIS – BMT CTN PROTOCOL 0601 
 
Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children  
with Severe Sickle Cell Disease  
 
Study Chairpersons: 
Shalini Shenoy, M.D., Naynesh Kamani, M.D. 
Primary Objective: 
The primary objective is to determine event-free survival (EFS) at 1 
year after unrelated donor (URD) hematopoietic stem cell 
transplantation (HCT) using bone marrow (BM) in patients with 
sickle cell disease (SCD).  Death, disease recurrence or graft 
rejection by 1 year will be considered events for this endpoint. 
Secondary Objectives: 
Secondary objectives include determining the effect of HCT on 
clinical and laboratory manifestations of severe sickle cell disease 
including stroke and determining the incidence of other transplant-
related outcomes.  The latter include: overall survival; neutrophil, 
and platelet recovery; grades II-IV and grade III-IV acute graft-
versus-host disease (GVHD); chronic GVHD; hepatic veno-
occlusive disease (VOD); idiopathic pneumonia syndrome (IPS); 
central nervous system (CNS) toxicity (reversible posterior 
leukoencephalopathy syndrome [RPLS], hemorrhage, and seizures); 
neurocognitive dysfunction; cytomegalovirus (CMV) infection; 
adenovirus infection; Epstein Barr virus infection; invasive fungal 
infection; immune reconstitution; and health-related quality of life 
(QOL).  
Study Design: 
The study is a Phase II, single arm, multi-center trial.  It is designed 
to estimate the efficacy and toxicity of unrelated donor HCT using a 
reduced-intensity conditioning regimen in patients with SCD and 
high risk features who are between 3.0 and 19.75 years of age.  
Accrual Objective: 
The target sample size is 30 BM recipients. 
Accrual Period: 
The estimated accrual period is 4 years. 
Eligibility Criteria: 
Patients 3.0-19.75 years old with symptomatic SCD AND one or 
more of the following complications: (a)-(i) a clinically significant 
neurologic event (stroke) or any neurologic defect lasting > 24 hours 
and accompanied by an infarct on cerebral magnetic resonance 
imaging (MRI); OR, (a)-(ii) patients who have a TCD velocity that 
exceeds 200 cm/sec by the non-imaging technique (or TCD 
measurement of >185 cm/sec by the imaging technique) measured at 
a minimum of 2 separate occasions one month or more apart; OR, 
(b) Minimum of two episodes of acute chest syndrome within the 
preceding 2-year period defined as new pulmonary alveolar 
consolidation involving at least one complete lung segment 
(associated with acute symptoms including fever, chest pain, 

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ii 
tachypnea, wheezing, rales, or cough that is not attributed to asthma 
or bronchiolitis) despite adequate supportive care measures; OR, (c) 
History of 3 or more severe pain events (defined as new onset of 
pain that lasts for at least 2 hours for which there is no other 
explanation) per year in the 2 years prior to enrollment despite 
adequate supportive care measures (if patients are receiving 
hydroxyurea and compliant with therapy, being symptomatic is an 
indication for transplantation; however, if patients decline 
hydroxyurea or non-compliant with this therapy, they would still 
remain eligible for study if pain criteria as described above are met).  
Lansky/Karnofsky performance score must be ≥ 40.  Hb S must be  
≤ 45%.  Patients must have an unrelated adult bone marrow donor 
who is HLA-matched at 8 of 8 HLA-A, -B, -C and -DRB1 at high 
resolution using DNA-based typing.  Patients with bridging fibrosis 
or cirrhosis of the liver, with uncontrolled bacterial, viral, or fungal 
infection in the past month, or seropositivity for HIV are excluded.  
Patients with HLA-matched family donors, or who have received 
prior HCT, and females who are pregnant or breast feeding are 
excluded. 
Treatment Description: 
The HCT preparative regimen will consist of the following: 
- Alemtuzumab: Children weighing 10 kg or more will receive  
10 mg, 15 mg, 20 mg intravenously (IV) on Days -21, -20, and  
-19, respectively  
- Fludarabine: 30 mg/m2/day IV on Days –8 through –4  
- Melphalan: 140 mg/m2 IV on Day –3  
- Rest on Day -2, -1  
- Day 0 is the day of transplant 
- GVHD prophylaxis: Tacrolimus or cyclosporine beginning Day  
–3, methotrexate (7.5 mg/m2/day) Day 1, 3, and 6 and 
methylprednisolone/ predisone on Day +7 to +28 followed by a 
taper if there is no GVHD 
Study Duration: 
Patients will be followed for two years post-transplant for 
evaluation. 
 
 

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TREATMENT SCHEMA 
(see Section 4.0 for enrollment procedures) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Treatment1 
24 hours prior 
to 1st dose of 
Alemtuzumab 
Alemtuzumab test dose  
3 mg IV once 
-22 
-21 
-20 
-19 
-18 
Alemtuzumab 10 mg IV1 
Alemtuzumab 15 mg IV1 
Alemtuzumab 20 mg IV1 
-8 
Fludarabine 30mg/m2 IV 
-7 
Fludarabine 30mg/m2 IV 
-6 
Fludarabine 30mg/m2 IV 
-5 
Fludarabine 30mg/m2 IV 
-4 
Fludarabine 30mg/m2 IV 
-3 
Melphalan 140 mg/m2 IV 
-2 
Rest 
-1 
Rest 
0 
Stem cell infusion 
+7 
G-CSF 5 μg/kg/day continue until neutrophil engraftment 
1 Alemtuzumab doses may be administered between Days -22 and -18 but are required to be on 3 consecutive days.
SUITABLE PATIENT/DONOR IDENTIFICATION 
ELIGIBILITY – reviewed by Eligibility Review Panel; 
HLA typing reviewed by Protocol Chairs and Protocol Officer 
DONOR ACTIVATED 
PATIENT CONSENT/ASSENT
PRE-TRANSPLANT WORK-UP 
PATIENT SCREENING CHECKLIST 

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TREATMENT SCHEMA (cont’d) 
 
GVHD Prophylaxis Regimens 
Day 
Regimen  
-3 
Tacrolimus or cyclosporine dosed to 
maintain appropriate levels. Given 
though Day 100 then taper to Day 180 
0 
Stem cell infusion 
+1 
Methotrexate 7.5 mg/m2 IV 
+3 
Methotrexate 7.5 mg/m2 IV 
+6 
Methotrexate 7.5 mg/m2 IV 
+7 
Methylprednisolone 1.0 mg/kg/day IV 
or 
Prednisone 1.2 mg/kg/day PO in 
divided doses 
Continued through Day +28, then taper 
 
 
 
 
 
 
 
 
TWO-YEAR FOLLOW-UP 

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TABLE OF CONTENTS 
 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Role of Hematopoietic Cell Transplantation ............................................................... 1-2 
1.2. 
Toxicities of Myeloablative Conditioning Regimen .................................................... 1-2 
1.3. 
Bone Marrow as a Source of Hematopoietic Stem Cells ............................................ 1-3 
1.4. 
HCT for Severe Sickle Cell Disease .............................................................................. 1-3 
1.5. 
Non-myeloablative or Reduced-intensity Conditioning Regimens: Rationale and 
Clinical Experience ................................................................................................... 1-4 
1.6. 
Objectives and Experience with the Conditioning Regimen Proposed ..................... 1-5 
1.7. 
Immune Reconstitution ................................................................................................. 1-7 
1.8. 
Alemtuzumab Pharmacokinetics .................................................................................. 1-8 
1.9. 
Risk of HCT Related Complications ............................................................................ 1-9 
1.10. Health-related Quality of Life ....................................................................................... 1-9 
1.11. Neurocognitive Testing .................................................................................................. 1-9 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Hypothesis and Study Objectives ................................................................................. 2-1 
2.2.1. 
Primary Hypothesis ..................................................................................................... 2-1 
2.2.2. 
Secondary Hypotheses ................................................................................................ 2-1 
2.2.3. 
Primary Objective ....................................................................................................... 2-1 
2.2.4. 
Secondary Objectives .................................................................................................. 2-1 
2.3. 
Patient Eligibility ........................................................................................................... 2-2 
2.3.1. 
Inclusion Criteria ......................................................................................................... 2-2 
2.3.2. 
Exclusion Criteria........................................................................................................ 2-3 
2.3.3. 
Donor Selection Criteria ............................................................................................. 2-4 
2.4. 
Treatment Plan............................................................................................................... 2-4 
2.4.1. 
Hb S Level Prior to Initiation of Alemtuzumab .......................................................... 2-5 
2.4.2. 
Patients Receiving Iron Chelation Therapy Prior to HCT .......................................... 2-5 
2.4.3. 
Patients Receiving Hydroxyurea Prior to HCT ........................................................... 2-5 
2.4.4. 
Alemtuzumab (Campath-1H) ...................................................................................... 2-5 
2.4.5. 
Fludarabine .................................................................................................................. 2-6 
2.4.6. 
Melphalan .................................................................................................................... 2-6 
2.4.7. 
Infusion of Hematopoietic Stem Cells ........................................................................ 2-7 
2.5. 
GVHD Prophylaxis ........................................................................................................ 2-7 
2.5.1. 
GVHD Prophylaxis Regimen ...................................................................................... 2-7 
2.6. 
Supportive Care ............................................................................................................. 2-9 
2.6.1. 
Engraftment Syndrome ............................................................................................... 2-9 
2.6.2. 
Venous Access ............................................................................................................ 2-9 
2.6.3. 
Seizure Prophylaxis ..................................................................................................... 2-9 
2.6.4. 
Blood Pressure Monitoring and Control ..................................................................... 2-9 
2.6.5. 
Growth Factor ........................................................................................................... 2-10 
2.6.6. 
Blood Products .......................................................................................................... 2-10 
2.6.7. 
Treatment of Fever/Infections ................................................................................... 2-10 

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2.6.8. 
Infection Surveillance and Prophylaxis .................................................................... 2-11 
2.6.9. 
Intravenous Immune Globulin .................................................................................. 2-12 
2.6.10. 
Guidelines for Infusing a Second Stem Cell Product or Donor Cellular Infusion .... 2-12 
2.6.11. 
Supportive Care Guidelines for CNS Toxicities ....................................................... 2-12 
2.7. 
Toxicities ....................................................................................................................... 2-13 
2.7.1. 
Pancytopenia ............................................................................................................. 2-13 
2.7.2. 
Alemtuzumab ............................................................................................................ 2-13 
2.7.3. 
Fludarabine ................................................................................................................ 2-13 
2.7.4. 
Melphalan .................................................................................................................. 2-13 
2.7.5. 
Hematopoietic Cell Infusion ..................................................................................... 2-14 
2.7.6. 
Growth Factor or G-CSF (Filgrastim, Neupogen) .................................................... 2-14 
2.7.7. 
Tacrolimus................................................................................................................. 2-14 
2.7.8. 
Cyclosporine ............................................................................................................. 2-14 
2.7.9. 
Methylprednisolone and Prednisone ......................................................................... 2-14 
2.7.10. 
Methotrexate ............................................................................................................. 2-14 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoint .......................................................................................................... 3-1 
3.1.1. 
Event-free Survival ..................................................................................................... 3-1 
3.1.2. 
Graft Rejection ............................................................................................................ 3-1 
3.1.3. 
Disease Recurrence ..................................................................................................... 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. 
Overall Survival .......................................................................................................... 3-1 
3.2.2. 
Cumulative Incidence of Neutrophil and Platelet Engraftment .................................. 3-2 
3.2.3. 
Grade II-IV and Grade III-IV Acute GVHD............................................................... 3-2 
3.2.4. 
Chronic GVHD ........................................................................................................... 3-2 
3.2.5. 
Frequency of Transplant-related Complications ......................................................... 3-2 
3.2.6. 
Frequency of Disease-related Complications.............................................................. 3-3 
3.2.7. 
Health-related Quality of Life (QOL) ......................................................................... 3-3 
3.2.8. 
Immune Reconstitution ............................................................................................... 3-3 
3.2.9. 
Neurocognitive Testing ............................................................................................... 3-4 
4. 
PATIENT REGISTRATION, ENROLLMENT AND EVALUATIONS ................. 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.1.1 
Screening and Eligibility Procedures .......................................................................... 4-1 
4.2. 
Patient Assessments ....................................................................................................... 4-1 
4.2.1. 
Pre-transplant Evaluations .......................................................................................... 4-1 
4.2.2. 
Post-transplant Evaluations ......................................................................................... 4-3 
4.2.3. 
Summary of Patient Clinical Assessments .................................................................. 4-4 
4.3. 
Study Monitoring ........................................................................................................... 4-7 
4.3.1. 
Follow-up Schedule .................................................................................................... 4-7 
4.3.2. 
Adverse Event Reporting ............................................................................................ 4-8 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Study Design ................................................................................................................... 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Study Duration ............................................................................................................ 5-1 

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5.1.3. 
Randomization ............................................................................................................ 5-1 
5.1.4. 
Primary Endpoint ........................................................................................................ 5-1 
5.2. 
Sample Size and Power Considerations ....................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.3.1. 
Overall Mortality ......................................................................................................... 5-3 
5.3.2. 
Graft Rejection ............................................................................................................ 5-4 
5.3.3. 
Grade III-IV Acute GVHD ......................................................................................... 5-5 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-5 
5.5. 
Analysis of Primary Endpoint ...................................................................................... 5-5 
5.6. 
Analysis of Secondary Endpoints ................................................................................. 5-6 
5.7. 
Safety Analysis ............................................................................................................... 5-7 
 
 
LIST OF APPENDICES 
APPENDIX A 
HUMAN SUBJECTS 
APPENDIX B 
CONSENT FORM 
APPENDIX C 
LABORATORY PROCEDURES 
APPENDIX D 
LANSKY/KARNOFSKY PERFORMANCE STATUS SCALE 
APPENDIX E 
ELIGIBILITY REVIEW PANEL 
APPENDIX F 
HEALTH-RELATED QUALITY OF LIFE (QOL) 
PROCEDURE 
APPENDIX G 
NEUROCOGNITIVE TESTING 
APPENDIX H 
CRANIAL MAGNETIC RESONANCE IMAGING (MRI) 
PROTOCOL 
APPENDIX I 
REFERENCES

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1-1 
CHAPTER 1 
 
 
1. BACKGROUND AND RATIONALE 
 
Sickle cell disease (SCD) is a recessive genetic disorder caused by a point mutation that results 
in the substitution of valine for glutamic acid at the sixth position in the ß-chain of hemoglobin.  
The homozygous gene disorder affects approximately 1 in every 400 African American 
newborns and an estimated 70,000 persons in the United States.  A major cause of morbidity and 
mortality in severe SCD is vaso-occlusion, often causing irreversible damage in target organs 
such as the central nervous system (CNS), lung, bone, and joints.  Sequelae of this genetic defect 
can occur in any organ.  The most devastating result is cerebral infarction.1  Other serious 
complications of SCD include restrictive pulmonary disease secondary to recurrent acute chest 
syndrome (ACS), pulmonary hypertension, and severe vaso-occlusive painful crises.  These 
complications predict for early mortality, recurrent sickle-related complications such as ACS, 
and poor quality of life.2, 3, 4, 5  The average life expectancy for male patients with SCD is 42 
years, and 48 years for females.6  Among patients with Hb SS and S-ß thalassemia, the overall 
rates of death and stroke were 0.59 and 0.85/100 patient-years.  The cumulative overall and 
stroke-free survival decreases to 85.6% and 88.5% by 18 years of age.7   
 
Children with SCD may have impaired motor and/or cognitive function because of cerebral 
infarction manifesting as overt or silent strokes.  Overt strokes occur in approximately 9% of 
patients with sickle cell disease before their 14th birthday.8  Silent cerebral infarctions, defined by 
abnormal and increased signal intensity in T2 weighted images but with no history or physical 
findings of focal neurologic deficits lasting longer than 24 hours, are another common form of 
neurologic injury in children with SCD.  By 14 years of age, 18% of children with sickle cell 
anemia (Hb SS) have silent cerebral infarcts.9  Silent cerebral infarcts are associated with an 
increased risk of overt stroke, lower IQ, and poor academic achievement.10, 11, 12, 13 
 
Regular blood transfusion is less than optimal for prevention of recurrent strokes.  Scothorn et al. 
identified 137 children with a stroke that were followed for a mean and median of 10 years.14  
Participants were included if they had continuous blood transfusion therapy throughout the 
observation period with a maximum transfusion interval of less than six weeks.  Despite regular 
blood transfusion therapy, approximately 20% (1 in 5) developed a second stroke, and of that 
group, 30% (1 in 3) had a third stroke.  In the subgroup group of patients that had second or third 
strokes, the hemoglobin S levels were documented to be less than 30%.  Given the high rate of 
second and third strokes, even with optimal transfusion therapy, stem cell transplant for this 
high-risk population is a therapeutic option that may provide benefit over transfusions.  
Improved cerebrovascular patency following HCT has been previously described in SCD.15 
 
Other complications of sickle cell disease associated with increased morbidity and/or mortality 
and/or poor quality of life include severe, persistent, and recurrent painful episodes, recurrent 
pulmonary vaso-occlusion resulting in progressive pulmonary changes, and the development of 
pulmonary hypertension.  For these co-morbid conditions, the natural history is not well defined 
but there is a significant risk of progression and early mortality, especially if they remain 

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unresponsive to hydroxyurea therapy and supportive care measures such as therapy for asthma.16  
This is another subset of patients that could benefit from successful HCT. 
 
The majority of patients with severe disease manifestations and organ damage have Hb SS or Hb 
S-βº thalassemia.  However, clinical severity of the disease is dependent on several factors such 
as leukocyte and platelet counts, non-globin gene modifiers, Hb S polymer fractions, and the 
level of reduction of beta chain synthesis.17, 18, 19, 20  This results in a severe disease phenotype in 
some patients with sickle cell disease variants such as Hb S-β+ thalassemia, Hb SC, etc.  Since 
the pathology and progression of disease in these patients is comparable with those with severe 
Hb SS disease, it is logical to consider the curative option of stem cell transplantation in all 
patients with Hb S variant disease that manifest a severe phenotype.   
 
1.1. 
Role of Hematopoietic Cell Transplantation 
 
Hematopoietic Cell Transplantation (HCT) is the only curative treatment currently available for 
patients with SCD and can benefit patients who are likely to have significant morbidity and early 
mortality from the disease.21, 22  Limitations of HCT include the lack of HLA-identical family 
donors for most patients, the risk of mortality or treatment related toxicities especially in the 
unrelated donor setting, and increased complications and mortality following HCT in young 
adult SCD recipients.23, 24, 25  Another problem is the absence of a reliable method of defining 
high-risk patients, for whom the benefits of HCT outweigh the risks associated with the 
procedure before they develop serious irreversible SCD complications.  This is important 
because in patients on chronic therapy and supportive care for SCD manifestations, the success 
of HCT is compromised by organ damage and exposure to multiple transfusions.26 , 27, 28  A 
study of alternative donor HCT in patients with SCD should hence involve careful patient 
selection and a safe transplant conditioning regimen leading to reliable donor cell engraftment 
while minimizing treatment-related toxicity and mortality.  In addition, avoiding late effects of 
HCT, such as infertility, needs to be considered when proposing HCT for disorders that may not 
be immediately life-threatening.  
 
1.2. 
Toxicities of Myeloablative Conditioning Regimen 
 
Myeloablative therapy facilitates durable engraftment of donor cells after HCT but is limited by 
toxicities of conditioning drugs and transplant-related complications.  These include early and 
late organ toxicities of individual agents and depend on the age of the recipient and the 
combination of chemotherapy and/or radiotherapy applied.29  Since graft failure is a major 
barrier especially in immunocompetent and extensively transfused recipients, transplantation in 
this setting has relied upon myeloablative conditioning to achieve donor cell engraftment. 
 
Commonly used myeloablative conditioning regimens contain high doses of total body 
irradiation (TBI) or busulfan and another alkylating agent.  In addition to prolonged 
myelosuppression, acute toxicities include gastrointestinal (mucositis, diarrhea, nausea, 
vomiting, anorexia), genitourinary (renal, hemorrhagic cystitis), cardiac, cutaneous (erythema, 
desquamation, hyperpigmentation), CNS (seizures, hemorrhage, encephalopathy), pulmonary, 
and hepatic (VOD) manifestations.30  Organ toxicities are more likely and more severe in 

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patients who have impaired organ function before HCT.  Late toxicities include chronic 
pulmonary dysfunction, endocrine insufficiency, gonadal failure and sterility, learning disorders, 
neurocognitive deficits, and chronic alopecia.31, 32, 33, 34, 35 
 
Patients receiving non-transplant therapy for SCD are at risk for disease- or therapy-related 
organ complications such as hepatotoxicity or cardiotoxicity from transfusional iron overload 
and inadequate chelation, pulmonary fibrosis or pulmonary hypertension, renal damage, and 
neurotoxicity/hypertension/seizure disorder as a consequence of sickle neurovascular disease.  
These toxicities render many patients who might benefit from HCT ineligible or more 
susceptible to transplant related toxicities.  The risk of conditioning regimen-related toxicity in 
these patients must be balanced with the risk of graft rejection due to inadequate host 
immunosuppression when transplant conditioning options are considered.36  
 
1.3. 
Bone Marrow as a Source of Hematopoietic Stem Cells 
 
Only 14% of patients with SCD are likely to have a HLA-identical sibling donor.24  Use of HLA 
compatible unrelated donors is necessary to pursue HCT as a therapeutic option in most patients 
with SCD.  Donors who are matched at 6 (HLA-A, B and DRB1 loci) to 10 HLA-antigens 
(including HLA-C and DQB1 loci) can be identified via the National Marrow Donor Program in 
approximately 80% of Caucasian recipients; however, the likelihood of identifying a similarly 
HLA-matched URD is less likely in other ethnic groups due to under-representation of these 
groups in the volunteer donor pool and greater genetic diversity of some groups, particularly 
African-Americans.37  Identifying a suitable donor is a difficult problem in HCT for SCD and 
can limit the application of HCT for those who might benefit.38 
 
Treatment related mortality (TRM) and the incidence and severity of acute and chronic GVHD 
depend on the level of HLA matching especially in the unrelated donor setting.  The incidence of 
grade II-IV acute GVHD (within the initial 100 days after HCT) ranges from 10-50% after HLA-
identical sibling bone marrow transplantation.39  The incidence of chronic GVHD ranges 
between 60-80% in long-term survivors of unrelated HCT.  As expected, GVHD rates are higher 
after unrelated donor HCT, dependent on the degree of HLA mismatch.40, 41  GVHD rates also 
vary with age, conditioning therapy, stem cell source, prior transfusions, GVHD prophylaxis, 
infections, etc.  Since HCT outcomes appear to be optimal when bone marrow donors are HLA-
matched (at the allele level) at 8 loci (A, B, C and DRB1), this level of matching will be adopted 
for this study.42  The recent Health Resources and Services Administration (HRSA) report from 
2006 suggests that 36.1% of African American patients will be able to locate a donor matched 
for 8/8 HLA alleles in the unrelated donor registry (personal communication – D. Confer).  
 
1.4. 
HCT for Severe Sickle Cell Disease 
 
Allogeneic HCT for SCD following myeloablative conditioning ensures donor cell engraftment 
and can ameliorate SCD symptoms, improve quality of life, and stabilize vasculopathy.  In a 
multicenter trial of BM transplantation from HLA-identical sibling donors, 59 children with 
symptomatic SCD received a myeloablative preparative regimen of busulfan, cyclophosphamide, 
and ATG or Campath-1G before transplantation.43  Ninety-two percent of children had stable 

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engraftment.  Thirteen of these had stable mixed chimerism (11-90% donor cells); all had a 
normal hemoglobin levels (11.2 to 14.2 g/dl).  Hb S levels ranged from 0-7% when donor 
chimerism ranged between 11-74% (normal donors) and 36-37% when donor chimerism ranged 
between 25-60% in donors with SS trait.  Stable donor engraftment (whether associated with 
complete or mixed chimerism) resulted in resolution of symptoms of vaso-occlusive crisis 
(VOC), stroke and acute chest syndrome.  Thus, though 1 in 5 patients developed stable mixed 
donor-host hematopoietic chimerism, the majority of these patients continue to survive free of 
SCD symptomatology.  The overall survival was 94% and the event-free survival was 85%.  A 
similar study by a French group demonstrated the need for immune ablation to achieve 
successful donor cell engraftment.44, 45  Graft failure rates were significantly lower after the 
addition of rabbit anti-thymocyte globulin (rATG) to a myeloablative combination of busulfan 
and cyclophosphamide.  TRM was 10% and DFS was 85%.  Thus, HLA identical sibling HCT 
has acceptable results and ameliorates disease symptoms, especially in children.  Of significance, 
5 of 7 female recipients in the first study developed ovarian failure after exposure to 
myeloablative BU dosing.46  Sterility and other late effects of myeloablative conditioning 
regimen remain of concern in transplants for children with non-malignant disorders where the 
preparative regimen is used solely to achieve stable donor engraftment. 
 
Related donor UCB transplantation for hemoglobinopathies has also been successful.  Locatelli 
et al reported outcomes in 44 children with sickle cell disease (N=11) or thalassemia major 
(N=33) who received myeloablative doses of busulfan, cytoxan +/- ATG, or busulfan, 
cytoxan/fludarabine and thiotepa.47  The median number of TNC infused was 4.0 x 107/kg (range 
1.2-10 x 107/kg).  No patient died of transplant-related complications.  Thirty-six of 44 recipients 
remained disease-free after HCT, with a median follow-up of 2 years.  Eight patients had graft 
failure, mainly in the thalassemia cohort and 3 successfully underwent a second HCT.  The two-
year EFS rates were 79% for thalassemia and 90% for SCD.  Graft failure rates were lower after 
intensifying the conditioning regimen with the addition of thiotepa and eliminating methotrexate 
from the GVHD prophylaxis. 
 
Although sibling donor HCT for SCD and thalassemia major has demonstrated the effectiveness 
of this treatment, the approach is only feasible if a suitable donor is available.  Consequently, 
unrelated donor transplant strategies must be designed to explore methods of safely treating 
patients with hemoglobinopathies by HCT utilizing alternative donors/graft types with 
acceptable rates of early and late toxicities. 
 
1.5. 
Non-myeloablative or Reduced-intensity Conditioning Regimens: Rationale and 
Clinical Experience 
 
Myeloablative conditioning ensures engraftment of donor cells in most HCT recipients.  
However, reduced intensity conditioning is attractive due to its potential for reduced toxicity.  
Since stable mixed chimerism is sufficient to ameliorate symptoms of the underlying disease in 
disorders such as SCD and thalassemia, it is possible that reduced intensity conditioning might 
be effective even if it results in stable chimerism.  
 

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Murine and canine transplantation models demonstrate that myeloablation is not necessary to 
achieve donor engraftment; suppression of host lymphocytes is adequate to permit this process.  
This approach could have the following potential advantages: 1) lower regimen-related toxicity, 
both early and late; 2) a shorter period of neutropenia; 3) shorter hospitalizations; and 4) 
consideration of transplantation in some recipients with pre-existing disease-related end organ 
dysfunction.48 
 
The experience of HCT utilizing ‘minimally ablative’ conditioning regimens is largely limited to 
malignant disorders, especially in elderly or high-risk patients, and has been successful in 
achieving stable engraftment of donor cells in that setting.49  Several groups have observed graft 
rejection in most hemoglobinopathy patients after administration of a minimal toxicity regimen 
of fludarabine, low dose busulfan or TBI, and ATG before HCT, presumably due to applying this 
approach in immunocompetent, transfusion-sensitized recipients.50, 51  In one study, 6 of 7 
recipients experienced graft rejection when post-grafting immunosuppression was discontinued 
after a preparative regimen of 200 cGy TBI and fludarabine, and none of the 7 had stable 
engraftment of donor cells.52  Exposure to minor histocompatibility antigens after RBC 
transfusions has also been implicated as a cause of graft failure.28  Further, two patients in 
another report died of GVHD and infection.  A successful cord blood transplant has been 
reported recently with an intensely immunosuppressive approach.53  Reduced intensity 
transplants with busulfan or melphalan with fludarabine have also demonstrated a high incidence 
of GVHD similar to that predicted in myeloabative regimens.54, 55, 56 
 
Reduced intensity regimens vary substantially in the levels of myeloablation and immune 
suppression achieved.  It is clear that if a reduced intensity regimen is to be successful, a high 
level of immunoablation is necessary for successful donor engraftment following transplantation 
for non-malignant disorders such as hemoglobinopathies.  Further, GVHD offers no benefit in 
this group (in contrast to patients with malignancies where GVHD-associated anti-cancer effects 
mitigate the recurrence risk), and strategies to minimize the incidence of GVHD while ensuring 
engraftment would optimize outcomes after HCT. 
 
1.6. 
Objectives and Experience with the Conditioning Regimen Proposed 
 
A reduced intensity conditioning regimen consisting of alemtuzumab, fludarabine, and 
melphalan was developed in 2001 as a multi-institutional study for non-malignant disorders.  The 
primary goal of this study was to determine if intensive host immunosuppression was sufficient 
for donor cell engraftment while minimizing conditioning-related toxicities and TRM in 
pediatric non-malignant disorders.  Reducing GVHD was a secondary end point of the study.  
Hematopoietic stem cell sources included marrow, peripheral blood, and UCB.   
 
There is previous experience with the use of fludarabine and melphalan combinations in reduced 
intensity transplant regimens.55, 57  Alemtuzumab, a humanized monoclonal antibody against 
CD52, targets an antigen expressed predominantly on the surface of lymphocytes and 
macrophages.58  The purpose of alemtuzumab administration in the trial was to deplete recipient 
lymphocytes that cause graft rejection.  In addition, macrophage depletion by alemtuzumab 
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regimen was based in part on the observations of Chakraverty, et al where the combination of 
alemtuzumab (following a contracted time course of administration nearer the stem cell infusion) 
with fludarabine and melphalan was administered in 44 patients with malignant disorders 
immediately before HCT and resulted in a low rate (2 of 44 patients) of graft failure and a very 
low frequency of acute (3/44) and chronic GVHD (0/44).59  Alemtuzumab was commenced 4-8 
days before HCT in that study.  Because it has a serum half-life of 42-57 hours, its presence in 
the recipients’ serum early post-transplant was probably available to bind donor cells and reduce 
the GVHD risk.  In this group, early TRM was 14.9%, and graft failure was 4.5%. 
 
There are two disadvantages to the approach described above.  Elimination of donor T cells by 
exposure to high levels of alemtuzumab potentially favors graft failure in an immunocompetent 
host.  Pharmacokinetic studies show that a concentration of up to 0.5µg/mL of alemtuzumab can 
be detected by indirect immunofluorescence through 56 days after HCT when 100 mg 
alemtuzumab is given between Days –8 and –4.60  Persistence of the antibody, with 
accompanying donor immunodepletion, also results in delayed immune reconstitution and 
increased risk of late infections and infection-related mortality.61, 62, 63  Hence, we modified the 
alemtuzumab dosing and administration schedule, moving it to Days –21, –20, and –19, well 
before infusion of donor cells, to reduce the level and duration of exposure of the infused donor 
cells to the antibody.  
 
Initial experience with this modified conditioning regimen has been published.64 65  To date, 60 
pediatric patients between the ages of 2 months and 20 years were treated by HCT with this 
regimen.  Four recipients received second allografts after experiencing a graft rejection following 
an initial myeloablative or reduced intensity regimen.  The children were treated by unrelated 
donor (33 bone marrow; 12 cord) and HLA-identical sibling donor HCT (15).  One unrelated 
donor was matched at 9/10 HLA alleles but mismatched for a single class I antigen; another was 
matched at 8/10 HLA-alleles but mismatched for 2 class I antigens.  Cord blood donors (all 
unrelated) were mismatched at 1-2 HLA antigens.  The median period of follow-up is 15 months 
(range 1-52 months).  The regimen caused little toxicity with the exception of reactions during 
alemtuzumab infusion.  Most had only urticaria and fever that responded to pre-medication.  One 
patient developed superficial blisters on the trunk and extremities and the last dose of 
alemtuzumab could not be administered.  Another patient did not receive the final 5 mg because 
of generalized urticaria.  Myeloid (ANC > 0.5x109/L) and platelet (> 50x109/L) engraftment 
occurred at a median of 13 (10-36) and 26 (12-82) days, respectively.  Among 52 patients with 
follow-up the overall survival was 87% and event free survival was 77%. 
 
Graft failure (defined as less than 20% donor cells in lymphoid, myeloid, or bone marrow 
compartments) occurred in 5% of the patients.  All graft failures occurred within 9 months of 
transplantation.  Withdrawal of immunosuppression tended to stabilize or increase donor 
chimerism in recipients with mixed chimerism in contrast to observations of graft rejection that 
occurred in patients with mixed donor chimerism treated by reduced intensity conditioning 
regimens.  No late graft failure has occurred to date.  Two patients with graft rejection had SCD 
and received a de-escalated dose of melphalan at 70 mg/m2 as part of an effort to reduce the 
intensity of conditioning.  Consequently, dose de-escalation of melphalan was discontinued.  A 

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third patient had Hurler syndrome, received 140 mg/m2 of melphalan, and rejected peripheral 
blood stem cells from a HLA-identical sibling donor.   
 
TRM at 100 days post-HCT was 10%.  Causes of TRM were: CMV disease (N=1); 
Pseudomonas sepsis (N=1); GVHD and multi-organ failure (N=1); interstitial pneumonitis 
(N=1); and intracranial hemorrhage (N=1).  The following changes to the protocol were 
instituted after consideration of these events: 1) exclusion of patients with invasive infections 
within a month prior to commencing treatment; 2) weekly monitoring and therapy for CMV 
infection; 3) maintaining higher platelet count after HCT; and 4) the addition of methotrexate to 
the GVHD prophylaxis for UCB transplants.  Acute GVHD (grades II-IV) developed in 15% and 
chronic GVHD in 11% of patients.  The onset of chronic GVHD was 6-9 months post-transplant.  
Post-transplant complications were predominantly bacterial and viral infections, most frequent in 
the first 3 months following HCT.  No major infections were observed beyond 6 months post-
transplant unlike other alemtuzumab-based transplant protocols; this is perhaps due to early 
immune reconstitution following early administration of alemtuzumab.66, 67 
 
Ten patients with hemoglobinopathies (3 with thalassemia and 7 with SCD) were treated by HCT 
with this regimen.  There was no significant regimen-related toxicity and no treatment related 
mortality.  Indications for HCT among SCD patients were stroke and severe VOC, and all 
patients were receiving chronic RBC transfusions prior to HCT.  Two of the 10 patients received 
a reduced dose of melphalan (70 mg/m2) and experienced graft failure as noted above.  The 
remaining 8 patients received a melphalan dose 140 mg/m2.  Five received bone marrow from 
HLA-identical sibling donors, and 2 received URD BM grafts.  One URD marrow donor was 
matched at 8/8 HLA loci, and the other was matched at 6 of 8 HLA loci.  The remaining patient 
received an unrelated UCBT that was matched at 5/6 HLA loci.  With median follow-up of 9.5 
months (range 1.5 to 44 months), all 8 who received full-dose melphalan have engraftment of 
donor cells.  No patient developed acute GVHD; one patient developed chronic extensive GVHD 
of the skin.  
 
Based upon the preliminary experience of HCT for hemoglobinopathies in this study, it appears 
that the conditioning regimen is safe in most patients, and there were no deaths related to 
transplantation in this small series.  Several additional patients who were treated with this 
regimen also had received chronic transfusion therapy (for Evan syndrome, congenital 
dyserythropoietic anemia type I, and aplastic anemia) before HCT and all had stable engraftment 
of donor cells.  Of interest, an adolescent female had an uneventful pregnancy 9 months after 
HCT, and delivered healthy twins, which suggests that it is possible to preserve fertility after 
transplantation with this reduced intensity regimen.  Together, these preliminary data support the 
development of a larger investigation to determine the risks and benefits of unrelated donor HCT 
for sickle cell disease, adapting this approach in selected subjects with severe disease. 
 
1.7. 
Immune Reconstitution 
 
Lymphocyte and NK cellular recovery was monitored after HCT.  NK cells recovered 3 months 
after HCT, temporally followed by CD8+ T cells, B cells, and finally CD4+ T cells between 9 

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and 12 months.  Lymphocyte proliferation, immunoglobulin levels, and tetanus toxoid antibody 
titers mirrored lymphocyte recovery.64  Immunizations were resumed at 1 year.  
 
TABLE 1.7:  IMMUNE RECONSTITUTION KINETICS POST-TRANSPLANT 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.8. 
Alemtuzumab Pharmacokinetics 
 
In 10 patients, serum alemtuzumab levels were measured serially by an ELISA test that is 
currently the most sensitive method of analyzing serum levels (BioAnaLab, UK).  Peak levels 
were determined on the last day of administration of alemtuzumab (Day –19), and repeated on 
Days 0, 30, 100, and 120.  Peak levels ranged between 89.68 and 698.95 ng/mL on Day –19.  
The weights of the patients ranged from 9 kg to 34.5 kg.  It should be noted that alemtuzumab 
levels were undetectable on Day 0 irrespective of weight in 8 patients who had received no 
previous immunosuppressive therapy.  One patient with IPEX syndrome, who was receiving 
extensive immune suppressive therapy before HCT, had levels of 206 and 220ng/mL on Day 0 
and 30 respectively.  Levels were undetectable (< 31.25 ng/mL) on Day 100.  Another patient 
with Wiskott-Aldrich syndrome had levels of 623.54 and 226.40 ng/mL on Days 0 and 30 
respectively.  Levels were undetectable on Day 100.  Both these recipients have stable mixed 
donor chimerism (50 and 51%) and completed immunosuppressive therapy > 6 months ago.  
Thus, despite dosing alemtuzumab similarly for all patients (with a different dosing regimen for 
those less than and ≥ 10 kg), the drug was eliminated by Day 30 in the absence of previous 
immune suppression or immune deficiency.  This is due to uniform binding of the drug to 
CD52+ cells irrespective of age and weight and subsequent elimination.  In view of these 
findings, we propose to use a similar alemtuzumab dosing regimen in this study. 
 
N CD4
N CD8
B and NK cells
0
200
400
600
800
1000
1200
1400
1
3
6
9
12
18
24
months post transplant
cell count 10
3 /mcL
CD 19
CD 16+56
N CD 19
N CD 16+56
Lymphocyte proliferation
0
50
100
150
200
250
300
350
1
3
6
9
12
18
24
months post transplant
% of normal control
PHA
PWM

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1.9. 
Risk of HCT Related Complications 
 
Treatment-related mortality after HCT is influenced by the conditioning regimen, the 
hematopoietic cell source, development of post-transplant infections, and development of 
GVHD.  The risk of TRM is minimized after HLA-identical sibling HCT, especially in non-
malignant hematologic disorders.  Delayed engraftment after unrelated and HLA-mismatched 
UCB transplantation is associated with higher TRM within the first 100 days (34-36%).45  TRM 
following unrelated HCT with HLA-matched BM as the stem cell source is comparable to that 
after HLA-matched or 1-HLA antigen mismatched UCBT.  In an attempt to minimize the risk of 
TRM, the proposed study incorporates a plan for optimal donor selection, careful post-HCT 
safety monitoring, prophylaxis against infections, early therapy for infectious complications, and 
SCD-specific supportive care.  Nevertheless, there will be a period of profound immune 
suppression until engraftment and immune reconstitution occurs, during which time the risk of 
opportunistic infections will be increased.  Stopping rules are in place to suspend the trial and 
evaluate results in the event that there is an unacceptable rate of graft rejection, severe acute 
GVHD, and treatment-related mortality. 
 
The conditioning regimen is designed to minimize the risk of organ toxicity.  If successful, this 
approach will provide a much needed curative option for patients with SCD who currently 
receive lifelong supportive care and transfusion therapy, and have a risk of recurrent 
complications (stroke, acute chest syndrome, and pain crisis), poor quality of life, and a 
shortened life span.  This conditioning approach may also preserve fertility. 
 
1.10. Health-related Quality of Life 
 
Health-related quality of life (QOL) is a measure of a patient’s well being from a physical, 
emotional, and social perspective.  It is a valid patient reported outcome that measures the impact 
of disease, morbidity from disease, and treatment of disease on the well being and functioning of 
the patient and family.  Health-related QOL is traditionally measured at multiple intervals to 
track impact of treatment and the natural history of the disease.  It will be used in this setting to 
determine the impact of HCT on the well being of the child. 
The Child Health Questionnaire (CHQ) is a widely used instrument to measure health-related 
QOL that has been validated in children with sickle cell disease and in children with other 
chronic diseases.68  More importantly, it has also been shown to be sensitive to change in disease 
status over time.69  It is designed to be self-completed by both parents and children 10 years of 
age and older.  See Appendix F for details on QOL measurement. 
 
1.11. Neurocognitive Testing 
 
Neurocognitive testing measures higher neurologic functions such as those listed below.  Patients 
with sickle cell disease can have damage to brain blood vessels that can result in brain 
parenchymal damage in the form of an overt or silent stroke, and that this damage is 
progressive.70  A major manifestation of silent stroke is deterioration of neurocognitive function, 
and there is evidence too that the decline in neurocognitive function is also progressive over 
time.71  Reduced intensity conditioning as is proposed in this study is designed to minimize 

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further neurologic toxicity from high dose chemotherapy.  The aim of HCT is to stabilize disease 
related neurologic toxicity after donor cell engraftment, and assess for stabilization and even 
improvement in neurocognitive function over time.  We propose to do this by testing 
neurocognitive function before and two years after transplantation.  
 
Basic measures of neurocognitive testing are proposed to monitor performance before and after 
transplant.  The simple battery of tests described provide screening of neurocognitive abilities 
before and after transplant and are appropriate for administration to children and adolescents 
with SCD, reflecting the recipient population on this study.  The age range for testing is 2.5 to 
young adults, with test batteries divided between 3 groups (2.5 to 3 years, 4-5 years, and 6 years 
and over).  The testing instruments are listed below and address specific domains that are 
impaired in patients with SCD.  Similar testing is previously reported and also underway in an 
international trial of chronic transfusion therapy for SCD and silent stroke and correlate with 
MRI changes.13, 72 
1. WPPSI and Wechsler Abbreviated Scale of Intelligence (WASI): Intelligence scale.  
2. BRIEF (completed by parent): Executive function. 
3. VMI: Visual Motor skills. 
4. CPT: Attention. 
5. Children’s Memory Scale (CMS): Learning, Memory (verbal/visual, recall/recognition/ 
working, short-delay/long-delay). 
6. California Verbal Learning Test (CVLTC): Verbal learning.  
 
Each of the tests will be applied in an age dependent manner.  Testing will occur prior to HCT 
(and before initiation of conditioning therapy) and at 2 years after HCT.  This is intended to 
provide data on the natural history of neurocognitive function following HCT.  Additional details 
are provided in Appendix G.  
 
Rationale for Choosing Neuropsychologic Tests:  The selected measures were chosen to 
provide optimal screening of neurocognitive abilities that may be impaired in children with SCD, 
especially those who have had prior stroke.  Measures assessing specific cognitive domains were 
selected for the following characteristics: 1) appropriate for administration to children and young 
adults in the age ranges to be studied; 2) widely used in clinical practice; and 3) having good 
psychometric properties.  For example, the WASI was selected because it can be administered to 
individuals from 6 years of age to adults, which permits assessment across school-age children of 
all ages without compromising study design due to changes in measures as children age.  The 
WASI also is widely used for the assessment of intelligence, and the reliability and validity of 
the scale is well documented.  Other tests were selected for similar reasons. 
 

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CHAPTER 2 
 
 
2. STUDY DESIGN 
 
2.1. 
Study Overview 
 
The primary goal of this Phase II study is to determine whether a reduced intensity conditioning 
regimen in the setting of unrelated donor (URD) HCT is successful in achieving donor 
engraftment, inhibiting sickle erythropoiesis, and limiting disease-related organ toxicity in 
patients at high risk for morbidity and mortality associated with SCD.  The donor of choice is an 
unrelated adult bone marrow (BM) donor who is HLA-matched at 8 of 8 at HLA-A, -B -C and  
-DRB1 at high resolution using DNA-based typing.  The transplant conditioning regimen will 
include alemtuzumab, fludarabine, and melphalan.  GVHD prophylaxis will consist of tacrolimus 
or cyclosporine in combination with short course methotrexate (MTX) and methylprednisolone/ 
prednisone.  Post-transplant supportive care will include infection surveillance and prophylaxis, 
and disease-specific supportive care. 
 
2.2. 
Hypothesis and Study Objectives 
 
2.2.1. Primary Hypothesis 
 
A preparative regimen that provides intense host immunosuppression without myeloablation will 
promote stable engraftment of unrelated donor hematopoietic cells, inhibit sickle erythropoiesis, 
and result in an event free survival of ≥ 75% of children with SCD. 
 
2.2.2. Secondary Hypotheses 
 
SCD patients who undergo URD HCT following the reduced intensity conditioning regimen 
described in this study will have stable donor-derived hematopoiesis and immune reconstitution 
with acceptable rates of acute and chronic GVHD and TRM.  QOL following URD HCT will be 
superior to QOL prior to HCT.  Neurocognitive function will not be adversely affected by HCT 
 
2.2.3. Primary Objective 
 
To determine event-free survival at 1 year after URD HCT using BM grafts and a pre-transplant 
conditioning regimen of alemtuzumab, fludarabine, and melphalan in patients with SCD who are 
3.0-19.75 years of age at time of enrollment.  
 
2.2.4. Secondary Objectives 
 
Secondary objectives are to determine the effects of HCT on clinical and laboratory 
manifestations of SCD and to determine the incidence of HCT complications.  Secondary 
outcome variables include: 

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1. Overall survival 
2. Neutrophil and platelet engraftment 
3. Graft failure 
4. Grade II-IV and III-IV acute GVHD 
5. Chronic GVHD 
6. Transplant related complications – hepatic veno-occlusive disease (VOD), idiopathic 
pneumonia syndrome (IPS), and CNS toxicity (reversible posterior leukoencephalopathy 
syndrome [RPLS], hemorrhage, and seizures) 
7. Reactivation of CMV, adenovirus, invasive fungal infection, and EBV  
8. SCD related complication of recurrent stroke 
9. QOL measurements 
10. Immune reconstitution – lymphocyte subpopulations (absolute number of CD3, CD4, 
CD8, CD 16+56, and CD19 cells), immunoglobulin levels (Ig G, A, and M) and splenic 
function 
11. Neurocognitive function and neuroimaging 
 
2.3. 
Patient Eligibility 
 
2.3.1. Inclusion Criteria 
1. Patient is 3.0-19.75 years of age at time of enrollment. 
2. Patients must have symptomatic SCD AND have 1 or more of the following clinical 
complications. 
a. (i) Clinically significant neurologic event (stroke) or any neurologic deficit lasting  
> 24 hours that is accompanied by an infarct on cerebral MRI; OR (ii) patients who 
have a TCD velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD 
measurement of > 185 cm/sec by the imaging technique) measured at a minimum of 2 
separate occasions one month or more apart; OR, 
b. Minimum of two episodes of acute chest syndrome in the preceding two-year period 
prior to enrollment (defined as new pulmonary alveolar consolidation involving at 
least one complete lung segment associated with acute symptoms including fever  
≥ 38.5°C, chest pain, tachypnea per age adjusted normal, intercostal retractions/nasal 
flaring/use of accessory muscles of respiration, wheezing, rales, or cough that is not 
attributed to asthma or bronchiolitis) despite adequate supportive care measures (i.e. 
despite the use of supportive care and interventions including asthma therapy and/or 
hydroxyurea; patients who decline hydroxyurea or non-compliant with this therapy 
are eligible if they meet the other pulmonary criteria defined above for inclusion);73, 
74 OR, 
c. History of 3 or more severe pain events (defined as new onset of pain that lasts for at 
least 2 hours for which there is no other explanation) per year in the 2 years prior to 

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enrollment despite adequate supportive care measures (if patients are receiving 
hydroxyurea and compliant with therapy, being symptomatic is an indication for 
transplantation; however, if patients decline hydroxyurea or are non-compliant with 
this therapy, they would be considered eligible for study if pain criteria are otherwise 
met).  Pain may occur in typical sites associated with vaso-occlusive painful events 
and cannot be explained by causes other than vaso-occlusion mediated by sickle cell 
disease. 
3. A Lansky/Karnofsky performance status scale of ≥ 40. 
4. Patients must have an unrelated adult bone marrow donor who is HLA-matched at 8 of 8 
HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based typing. 
5. Patients with adequate physical function as measured by 
a. Cardiac: Left ventricular ejection fraction (LVEF) > 40%; or LV shortening fraction 
> 26%. 
b. Pulmonary: Pulse oxymetry with a baseline O2 saturation of ≥ 85% is required for all 
patients, DLCO > 40% (corrected for hemoglobin) for patients in whom pulmonary 
function testing can be performed. 
c. Renal: Serum creatinine ≤ 1.5 x upper limit of normal for age and GFR  
> 100 mL/min/1.73 m.  For patients ≥16 years of age, GFR should be > 70 
mL/min/1.73 m2. 
d. Hepatic: Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per 
local laboratory; ALT and AST < 5 times upper limit of normal as per local 
laboratory. 
6. If the patient has been receiving chronic transfusion therapy for ≥ 1 year AND has 
clinical evidence of iron overload (serum ferritin level of > 1000 ng/ml), a liver biopsy 
shall be obtained within 90 days of starting conditioning therapy (alemtuzumab).  Histologic 
exam of the liver must document absence of bridging fibrosis or cirrhosis of the liver.  In 
other cases, a liver biopsy is optional. 
7. Hb S should be ≤ 45% 7 days prior to initiation of alemtuzumab. 
8. Signed informed consent. 
 
2.3.2. Exclusion Criteria 
 
1. Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking 
medication and progression of clinical symptoms) within 1 month prior to starting the 
conditioning regimen.  Patients with fever or suspected minor infection should await 
resolution of symptoms before starting the conditioning regimen. 
2. Pregnant (βHCG +) or breastfeeding. 
3. Patients with 8/8 HLA-matched related family donors able to donate. 
4. Seropositive for the human immunodeficiency virus (HIV). 

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5. Prior allogeneic marrow or stem cell transplantation. 
6. Iron chelation must be discontinued ≥ 48 hours before initiating the conditioning 
regimen. 
7. Hydroxyurea (if receiving this therapy) must be discontinued ≥ 48 hours before initiating 
the conditioning regimen. 
 
2.3.3. Donor Selection Criteria 
 
Donors will be identified through the National Marrow Donor Program (NMDP) and must fulfill 
all of the NMDP’s criteria for donation.  Donors will sign an informed consent acknowledging 
that their donation will be used by a patient participating on this study; consent document 
available upon request.  The target total nucleated cell count (TNC) is 3.0-8.0 x 108/kg of 
recipient weight.   
 
2.4. 
Treatment Plan 
 
All patients will receive the treatment regimen as shown in Table 2.4  
 
TABLE 2.4:  SCHEMA OF CONDITIONING REGIMEN TRANSPLANTS 
 
Day 
Treatment  
24 hours prior 
to 1st dose of 
Alemtuzumab 
Alemtuzumab test dose 
3 mg IV once 
–22 
 
Alemtuzumab 10 mg IV1 
Alemtuzumab 15 mg IV1 
Alemtuzumab 20 mg IV1 
–21 
–20 
–19 
–18 
–8 
Fludarabine 30mg/m2 IV 
–7 
Fludarabine 30mg/m2 IV 
–6 
Fludarabine 30mg/m2 IV 
–5 
Fludarabine 30mg/m2 IV 
–4 
Fludarabine 30mg/m2 IV 
–3 
Melphalan 140 mg/m2 IV 
–2 
Rest  
–1 
Rest 
0 
Stem cell infusion 
+7 
G-CSF 5 μg/kg/day continue until 
neutrophil engraftment 
1Alemtuzumab doses may be administered between Days  
–22 and –18 but are required to be on three consecutive 
days. 
 

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The cytoreductive medications fludarabine and melphalan will be adjusted to the ideal body 
weight (IBW) in children weighing > 125% IBW. 
 
The following are dose adjustment formulas: 
 
Ideal Body Weight Formulas for patients 1 to 18 years of age: (ht = in, IBW = lb) 
 
Less than 60 inches:  
IBW = (ht2 x 1.65)/1000  
More than 60 inches:  Males IBW = 39.0 + [2.27 x (ht - 60)]  
Females IBW = 42.2 + [2.27 x (ht - 60)]  
Adjusted Ideal Body Weight Formula: AIBW = IBW + [(0.25) x (ABW - IBW)] 
(ABW = actual body weight) 
 
2.4.1. Hb S Level Prior to Initiation of Alemtuzumab 
 
Hb S level must be ≤ 45% within 7 days prior to the initiation of alemtuzumab.  
 
2.4.2. Patients Receiving Iron Chelation Therapy Prior to HCT 
 
Iron chelation therapy will be discontinued no later than 48 hours prior to commencement of 
alemtuzumab.  Iron chelation therapy or a program of phlebotomy may be resumed after 
neutrophil and red cell engraftment at the discretion of the transplant center.  
 
2.4.3. Patients Receiving Hydroxyurea Prior to HCT 
 
Hydroxyurea will be discontinued no later than 48 hours prior to administration of alemtuzumab. 
 
2.4.4. Alemtuzumab (Campath-1H) 
 
Patients that receive > 75% of dose (e.g., 36 mg) will be evaluated for outcome.  If a patient 
cannot receive the complete dose, the choice of conditioning regimen will be left to the 
institution; however, the patient must be followed per protocol. 
 
2.4.4.1. 
Pre-medication 
 
Pre-medication should be commenced 30 minutes prior to each infusion of alemtuzumab and 
including the test dose and should be continued for at least 48 hours after the last dose of 
alemtuzumab.  
 
Recommended pre-medication include the following combination of medications:  
Diphenhydramine: 1 mg/kg IV or PO q 8 hours (maximum 50 mg/dose) 
Acetaminophen: 10-15mg/kg PO q 6 hours (maximum 4 grams qd) 
Hydrocortisone: 1-2 mg/kg IV q 6 hours  
Meperidine: 0.5 mg/kg IV q 4-6 hours may be used as needed for rigors  

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2.4.4.2. 
Test dose and administration 
 
Alemtuzumab doses may be administered between Days –22 and –18 but are required to be on 
three consecutive days.  Alemtuzumab will be administered in-patient and the patient may be 
discharged the day after completion of Alemtuzumab infusions.  The test dose of alemtuzumab 
(3 mg IV) must be administered over 2 hours and not less than 24 hours prior to administration 
of the first dose.  It is recommended that the test dose be administered Monday through 
Thursday, in the morning, to allow for time for notification of the Study Chair in the case of a 
severe adverse reaction.  
 
If the test dose is not tolerated: 
If the patient has a severe or life threatening adverse reaction to alemtuzumab (e.g., severe 
hypotension, severe bronchospasm) the adverse event meets expedited reporting requirements 
(within 24 hours) through the expedited AE reporting system via AdvantageEDCSM (see Section 
4.3.2).  The study chair(s) may also be consulted regarding further doses at the discretion of 
treating physician. 
 
If the test dose is tolerated:  
Alemtuzumab will be diluted in 100cc of 0.9% normal saline (NS) and infused intravenously 
over a minimum of 6 hours each day for three consecutive days beginning between Days –22 and 
–18. 
Patients ≥ 10 kg: 10-15-20 mg over 3 days.  
 
Since serious infusion reactions are not uncommon during alemtuzumab infusion, it is strongly 
recommended that vital signs should be recorded q 15-30 minutes during each infusion of 
alemtuzumab. 
 
2.4.5. Fludarabine 
 
Fludarabine will be administered IV, on Day –8 to Day –4 (for a total of 5 days) given over a 
minimum of 30 minutes daily.  The infusion can take longer per institutional guidelines.  
Patients ≥ 10 kg: 30 mg/m2/day 
 
Preparation, administration, and monitoring will be according to institutional standard practice. 
 
Fludarabine will be adjusted to the ideal body weight (IBW) in children weighing > 125% IBW.   
 
2.4.6. Melphalan  
 
Melphalan will be given IV on Day –3 given over a minimum of 30 minutes.  The infusion can 
take longer per institutional guidelines.  
Patients ≥ 10 kg dose: 140 mg/m2  
 

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Melphalan will be adjusted to the ideal body weight (IBW) in children weighing > 125% IBW.   
 
2.4.7. Infusion of Hematopoietic Stem Cells 
 
Under no circumstances is the stem cell product to be irradiated.  Vital signs should be 
monitored before beginning the infusion and periodically during administration.  Pre-
medications and hydration prior to stem cell infusion will be administered per institutional 
procedure.  Diphenhydramine, epinephrine, and hydrocortisone should be available at the 
bedside for emergency use if infusion reactions occur.  Oxygen with nasal prongs for standby use 
should be present in the room.   
 
2.5. 
GVHD Prophylaxis 
 
Patients will receive the regimen as described in Table 2.5.   
 
TABLE 2.5 GVHD PROPHYLAXIS REGIMENS 
Day 
Regimen  
-3 
Tacrolimus or cyclosporine dosed to 
maintain appropriate levels.  Given 
though Day 100 then taper to Day 180 
0 
Stem cell infusion 
+1 
Methotrexate 7.5 mg/m2 IV 
+3 
Methotrexate 7.5 mg/m2 IV 
+6 
Methotrexate 7.5 mg/m2 IV 
+7 
Methylprednisolone 1.0 mg/kg/day IV 
or 
Prednisone 1.2 mg/kg/day PO in 
divided doses 
Continued through Day +28, then taper 
 
2.5.1. GVHD Prophylaxis Regimen  
 
2.5.1.1. 
Tacrolimus (FK 506) or cyclosporine (CSA) 
 
Tacrolimus administration will commence on Day –3, and doses will be adjusted to maintain a 
level of 8-12 ng/mL by the IMx immunoassay technique (Abbott Diagnostics) or a level of  
5-8 ng/mL if measured by a LC-tandem mass-spectrometric assay.  If using another method to 
measure levels then dose should be adjusted to maintain appropriate levels.  Tacrolimus can be 
administered by intermittent infusion over 6 hours twice daily (BID) or by continuous infusion to 
maintain therapeutic levels per institutional guidelines. 
 

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Dose adjustments will be made on the basis of toxicity and tacrolimus levels.  Once the patient 
can tolerate oral medications and has a normal gastro-intestinal transit time, tacrolimus will be 
converted to an oral form.  Tacrolimus dosing will be monitored and altered as clinically 
appropriate. 
 
From Day 100 to 180, tacrolimus will be gradually tapered in patients without significant acute 
or chronic GVHD (taper approximately 5-10% per week). 
 
Alternately, cyclosporine (CSA) may be administered beginning on Day –3 and doses will be 
adjusted to maintain a level of 250-500 ng/mL by TDX method (or 100-250 ng/mL by Tandem 
MS or equivalent level for other CSA testing methods).  CSA can be administered by continuous 
or intermittent infusion per institutional guidelines. 
 
Dose adjustments will be made on the basis of toxicity and CSA levels.  Once the patient can 
tolerate oral medications and has a normal gastro-intestinal transit time, CSA will be converted 
to an oral form, preferably microemulsion, at 2-3x the current IV dose.  CSA dosing will be 
monitored and altered as clinically appropriate.   
 
Patients will receive CSA until Day +100 and tapered between Days 100 to 180.  If there is no 
GVHD, the dose will be tapered 10% per week beginning on Day 100.  
 
Centers will declare their preferences of tacrolimus or cyclosporine.  However, in the event of 
toxicity, centers may change calcineurin inhibitors. 
 
2.5.1.2. 
Methylprednisolone/prednisone 
 
Starting on Day 7, methylprednisolone 1.0 mg/kg/day intravenous (IV) or prednisone  
1.2 mg/kg/day (orally [PO]) will be administered in two divided doses daily and continued until 
Day 28.  In the absence of GVHD, prednisone will be tapered 20% per week. 
 
2.5.1.3. 
Methotrexate 
 
Methotrexate will be given at a dosage of 7.5 mg/m2 IV on Days 1, 3, and 6.  The Day 1 dose of 
methotrexate should not be administered until 24 hours following completion of the marrow 
infusion.  Leucovorin rescue may be used per institutional practice guidelines.  
 
Methotrexate dose will be adjusted as follows:  
 
 
MTX dose 
 
Full 
50% 
Hold dose 
Direct bilirubin 
< 2.0 mg/dL 
2.0-4.0 mg/dL 
> 4.0 mg/dL 
AST or ALT 
< 399 U/L 
400-600 U/L 
> 600 U/L 
Serum creatinine 
- 
- 
> 2.5 mg/dL 
 

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2.6. 
Supportive Care 
 
Institutional standard care practice guidelines will be followed after transplantation for 
nutritional support, treatment of infections, and blood product support.  Supportive care 
guidelines are detailed below.  
 
2.6.1. Engraftment Syndrome  
 
Engraftment syndrome is a clinical diagnosis.  The most frequently reported manifestations are 
transient fever, rash, and respiratory symptoms not attributable to infection or GVHD.  The 
pathophysiology is multifactorial mediated by cellular, complement, and cytokine components.  
Diagnostic criteria include fever (temperature >38.5° C) without an identifiable infectious cause 
within 4 days of the start of neutrophil recovery + an erythematous rash not attributable to 
GVHD or medications or capillary leak (weight gain, edema, ascites, effusions) or respiratory 
symptoms not attributable to IPS.  Mild symptoms may not require therapy due to the self-
limiting nature of this syndrome.  For progressive symptoms, methylprednisolone at 2 mg/kg/day 
is recommended for 5 days.  If recurrent or prolonged, investigation for GVHD is recommended. 
 
2.6.2. Venous Access 
 
Recipients will have appropriate long-term central venous access placed, per institutional 
standard practice, prior to beginning the conditioning regimen.  The placement of a double lumen 
tunneled catheter is recommended. 
 
2.6.3. Seizure Prophylaxis  
 
Prophylaxis against seizures is mandatory in all recipients and should be commenced at the start 
of conditioning with alemtuzumab.  Suitable drugs for prophylaxis include gabapentin or 
levetiracetam, and should be administered according to institution guidelines.  Seizure 
prophylaxis should be continued for 180 days after transplant or until tacrolimus is discontinued, 
whichever is later. 
 
Serum magnesium level should be maintained > 1.5 mg/dL during the period of treatment with 
calcineurin inhibitors cyclosporine or tacrolimus to reduce the risk of seizures. 
 
2.6.4. Blood Pressure Monitoring and Control 
 
Blood pressure should be strictly controlled to prevent CNS toxicity.  Blood pressure should be 
monitored closely (every four hours) and both systolic and diastolic hypertension should be 
treated promptly to maintain blood pressure within 10% above the baseline age-related median 
systolic and diastolic pressure as described in children with SCD in Pegelow et al Am J Med 
1997; 102: 171-77.  Table I provides age-related medians of blood pressure in patients with 
sickle cell disease as published in the manuscript.  In addition, close attention should be paid to 

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fluid balance since fluid overload (patient weight is > 10% of base weight in euvolemic state at 
the time of admission to the BMT unit) may contribute to elevations in blood pressures. 
 
 
 
2.6.5. Growth Factor 
 
G-CSF (5 µg/kg/day) will be given subcutaneously or IV starting Day 7, after completion of 
methotrexate doses.  G-CSF will be continued until the absolute neutrophil count (ANC) is  
> 1500/μL for 3 measurements taken on different days after the nadir. 
 
2.6.6. Blood Products 
 
The hemoglobin level must be maintained between 9.0 and 11.0 g/dL for at least 100 days post-
transplant and platelet count > 50,000/µL post-transplant and post-alemtuzumab administration 
until recovered to avoid neurological adverse events, as described previously.25  Irradiated blood 
products should be administered universally, and CMV negative blood products are 
recommended for CMV sero-negative recipients. 
 
2.6.7. Treatment of Fever/Infections 
 
Patients should be monitored closely for clinical manifestations of infection and treated per 
institution guidelines with broad spectrum antibacterial, antiviral and antifungal agents.  Early 
and severe immunosuppression of the patient necessitates prompt and adequate treatment of 
infections to prevent systemic spread.  Since patients receive alemtuzumab, they are especially 
susceptible to bacterial and viral infections in the early post-transplant period. 
 

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2.6.8. Infection Surveillance and Prophylaxis 
 
2.6.8.1. 
HSV prophylaxis 
 
Acyclovir prophylaxis is recommended for 6 months for patients who are sero-positive for HSV 
or VZV.  If unable to tolerate PO medications, IV therapy will be necessary.  
 
2.6.8.2. 
PCP prophylaxis 
 
Trimethoprim-sulfamethoxazole or an equivalent drug should be administered beginning after 
neutrophil recovery and continued post-transplant for 1 year.  
 
2.6.8.3. 
Fungal prophylaxis 
 
Due to the level of immune suppression, anti-fungal prophylaxis against Aspergillus sp. is 
recommended with agents such as itraconazole, voriconazole, or posaconazole until Day 180.  
Frequent monitoring of tacrolimus or CSA levels will be necessary during azole therapy to avoid 
toxic drug levels.  
 
2.6.8.4. 
Bacterial prophylaxis 
 
Prophylaxis against bacterial infections is recommended with a broad spectrum antibiotic such as 
ciprofloxacin after alemtuzumab administration to Day 180.  
 
2.6.8.5. 
CMV surveillance 
 
All recipients must be tested weekly using the PCR method beginning a week after commencing 
alemtuzumab until Day 100.  From Day 100 to Day 180 all patients should be tested at least 
twice monthly.  Antiviral therapy for CMV reactivation should commence pre-emptively if 
CMV testing reveals a high or rising viral load.  If CMV reactivation occurs at or before 
engraftment, foscarnet may be considered to prevent marrow suppression. 
 
2.6.8.6. 
Adenovirus and EBV intervention guidelines 
 
Adenovirus:  
Testing for adenovirus infection in the blood by PCR method is recommended in the event of 
symptoms suspicious for infection such as diarrhea, hepatic dysfunction, or respiratory 
symptoms.  If an active systemic infection is diagnosed, therapy should be instituted with 
cidofovir or other active agents per institution guidelines. 
 
EBV:  
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 viremia or signs/symptoms consistent 
with EBV-related PTLD (adenopathy, fever, etc.) therapy with rituximab is recommended. 
 

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2.6.9. Intravenous Immune Globulin 
 
Intravenous immune globulin may be administered according to institutional practice guidelines. 
 
2.6.10. Guidelines for Infusing a Second Stem Cell Product or Donor Cellular Infusion 
 
A second transplant or donor cellular infusion (DCI) should not be considered unless the patient 
has < 20% donor chimerism.  If donor chimerism declines to less than 20% then the patient may 
be treated per institutional guidelines. 
 
2.6.11. Supportive Care Guidelines for CNS Toxicities 
 
Patients with sickle cell disease and cerebral vasculopathy have a high incidence of new CNS 
toxicities (seizures, labile hypertension, RPLS, PRES, intracranial hemorrhage, stroke, etc.) 
during the entire transplant process, beginning with the conditioning regimen and lasting through 
the time that immunosuppression is eventually discontinued.  In order to minimize or avoid these 
risks, adherence to the following guidelines is necessary for all BMT CTN #0601 patients: 
1. The baseline blood pressure in patients with sickle cell disease is often less than “normal” 
for age.  Elevations in blood pressure can ensue following fluid infusions, or with the use 
of medications such as corticosteroids and calcineurin inhibitors, even after short term 
use.  Blood pressure (both systolic and diastolic) should be monitored closely (at least 
every 4 hours) and strictly maintained within 10% above the median baseline blood 
pressure documented for that age in Pegelow et al Am J Med 1997; 102: 171-77 (see 
section 2.6.4 for table).  Aggressive (and often parenteral) use of anti-hypertensive drugs 
will be required to control elevations in blood pressure.  In addition, close attention 
should be paid to fluid balance since fluid overload (patient weight is > 10% of base 
weight in euvolemic state at the time of admission to the BMT unit) may contribute to 
elevations in blood pressure. 
2. Seizure prophylaxis should be commenced with conditioning therapy i.e., from the date 
of the first alemtuzumab infusion (the test dose) and continued at least until 
immunosuppression is withdrawn.  If neurontin is used as the prophylactic antiseizure 
medication, it is recommended that it be started several days before the test dose of 
alemtuzumab so that the patient can be on the full dose by the day of administration of 
the test dose. 
3. Platelet counts should be monitored frequently after starting the conditioning therapy 
(including alemtuzumab) and platelet transfusions should be administered as needed to 
keep levels > 50,000/µL. 
 

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2.7. 
Toxicities 
 
2.7.1. Pancytopenia 
 
The administration of fludarabine and melphalan is expected to produce pancytopenia with ANC 
< 500/μL, hemoglobin < 7-8 gram/dL and platelet < 50,000/μL for at least a week in many 
patients.  Most patients will require transfusions of red blood cells and platelets during this 
period.  In addition, many patients will develop fever and approximately 30% will develop a 
documented infection during the period of neutropenia.  Complications related to pancytopenia 
may be life-threatening or fatal. 
 
2.7.2. Alemtuzumab 
 
Administration can cause fevers, rigors, nausea, vomiting, hypotension, fatigue, rash, urticaria, 
dyspnea, headache, cough, pruritis, diarrhea, pain, anorexia, increased sweating, sepsis, myalgia, 
asthenia, hypertension, pharyngitis, abdominal pain, back pain, dizziness, anemia, infections, 
neutropenia, and thrombocytopenia. 
• Fever and chills:  These are regularly observed, particularly during initial infusions of 
alemtuzumab.  They probably result from a breakdown of cells binding the antibody. 
• Skin rash and itching:  A complication that is probably due to minor allergic reactions to 
the antibody.  These symptoms will usually be prevented by or controlled with anti-
histamines as well as with concomitant administration of corticosteroids.  
• Anaphylaxis:  A rare but severe allergic reaction which may cause a life threatening drop 
in blood pressure, wheezing and difficulty breathing, and severe hives or skin exfoliation.  
This complication can be treated with anti-histamines and steroids. 
• Platelet and white cell count depression:  These are frequently observed and are probably 
caused by the binding of the antibody to human blood elements.  Platelet transfusions 
will be administered to reduce the chance of bleeding or life threatening hemorrhage. 
 
2.7.3. Fludarabine 
 
Administration can cause hemolytic anemia, neutropenia or thrombocytopenia, low blood counts 
secondary to bone marrow suppression, nausea, vomiting, diarrhea, stomatitis, skin rash, 
pneumonitis, edema, fever, chills, fatigue, blurred vision, peripheral neuropathy, confusion, 
coma, decreased immunity, and rarely encephalopathy (in very high doses). 
 
2.7.4. Melphalan 
 
Administration can cause decreased blood counts, nausea, vomiting, diarrhea, oral ulcers, 
decreased immunity, sterility, interstitial pneumonitis, lung fibrosis, allergic reactions, and rarely 
seizures (with very high doses).  
 

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2.7.5. Hematopoietic Cell Infusion 
 
Infusion of allogeneic BM cells can result in shortness of breath, fever, hemolysis with renal 
dysfunction and back pain or anaphylaxis.  To reduce the risk of reactions to product infusion, 
patients will be hydrated before and after administration of allogeneic BM, and will be 
monitored closely before, during, and after infusion. 
 
2.7.6. Growth Factor or G-CSF (Filgrastim, Neupogen) 
 
G-CSF may cause: bone pain, insomnia, headaches, dyspnea, body aches, rash, fever, 
splenomegaly allergic reaction, fatigue, edema, and nausea/vomiting. 
 
2.7.7. Tacrolimus 
 
Tacrolimus can cause predisposition to infection, renal insufficiency, hypertension, cholestatic 
hepatic toxicity, gingival hyperplasia, thrombotic microangiopathy, seizures, tremors, hirsutism, 
anorexia, nausea, and possibly later B-cell lymphomas.  To reduce the risk of toxicity, blood 
pressure, tacrolimus levels, renal function, and liver enzymes will be monitored closely and vital 
signs aggressively maintained at baseline. 
 
2.7.8. Cyclosporine 
 
Cyclosporine may cause: nephrotoxicity, seizures, hypertension, hirsutism, thrombotic 
microangiopathy, electrolyte imbalances, paresthesias/neuropathy, gingival hyperplasia, 
transient-blindness, and hepatic dysfunction. 
 
2.7.9. Methylprednisolone and Prednisone 
 
Methylprednisolone and prednisone can cause predisposition to infection, electrolyte 
disturbances, gastritis with GI bleeding, insomnia and mental status changes, fluid retention, 
edema, fat accumulation causing a change in facial appearance, and aseptic necrosis.  To reduce 
the risk of steroid toxicity, the medication will be tapered early per protocol in the absence of 
GVHD.   
 
2.7.10. Methotrexate 
 
The most methotrexate sensitive organs are the bone marrow and the gastrointestinal mucosa, so 
that myelosuppression and stomatitis are the most common dose-limiting side effects.  At the 
dosage used in this study, no other significant side effects are anticipated. 
 

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CHAPTER 3 
 
 
3. STUDY ENDPOINTS 
 
3.1. 
Primary Endpoint 
 
The primary endpoint will be event-free survival at 1 year post-transplant.  
 
3.1.1. Event-free Survival 
 
Event-free survival is defined as the time interval to an event.  Primary or late graft rejection, 
disease recurrence, or death will count as events for this endpoint.  
 
3.1.2. Graft Rejection 
 
Primary Graft Rejection  
Primary graft rejection is defined as the presence of < 20% donor cells assessed by bone marrow 
or peripheral blood chimerism assays on Day 42.  Infusion of a second stem cell product on or 
prior to Day 42 will be considered primary graft rejection. 
 
Late Graft Rejection 
The presence of < 20% donor derived hematopoietic cells in peripheral blood or bone marrow 
after Day 42 in a patient with prior evidence of > 20% donor cells will be considered late graft 
rejection.   
 
Infusion of a second stem cell product beyond Day 42 will be considered late graft rejection.  
The Study Chair(s) should be contacted prior to any decisions regarding infusion of additional 
donor cells/second transplant.  
 
3.1.3. Disease Recurrence 
 
Disease recurrence is defined as the return of sickle erythropoiesis (Hb S level > 70%) with or 
without recurrence of clinical complications of sickle cell disease such as stroke, acute chest 
syndrome, and veno-occlusive crisis (VOC). 
 
3.2. 
Secondary Endpoints 
 
Secondary endpoints are evaluations of the effects of HCT on clinical and laboratory 
manifestations of SCD at 2 years and evaluation of other transplant-related outcomes.  These will 
include the following. 
 
3.2.1. Overall Survival 
 
Overall survival is defined as time from transplant to death or last follow-up. 

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3.2.2. Cumulative Incidence of Neutrophil and Platelet Engraftment 
 
Neutrophil Engraftment  
Time to ANC engraftment is defined as the first of three measurements on different days that the 
patient has an absolute neutrophil count of ≥ 500/µL following conditioning regimen induced 
nadir. 
 
Platelet Engraftment  
Platelet engraftment will be defined as the first day of a minimum of three measurements on 
different days that the patient has achieved a platelet count > 50,000/µL AND is platelet 
transfusion independent for a minimum of seven days following conditioning regimen induced 
nadir. 
 
Subjects must not have had platelet transfusions during the preceding 7 days after the day of 
engraftment, unless the platelet transfusion is being given specifically to achieve a platelet 
threshold to allow an elective invasive procedure, such as a central catheter removal. 
 
3.2.3.  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 BMT CTN 
Manual of Procedures (MOP). 
 
3.2.4.  Chronic GVHD 
 
Incidence and severity of chronic GVHD will be scored according to the BMT CTN MOP. 
 
3.2.5. Frequency of Transplant-related Complications 
 
3.2.5.1. 
Idiopathic pneumonia syndrome (IPS) 
1. Evidence of widespread alveolar injury  
a. 
Radiographic evidence of bilateral, multi-lobar infiltrates (by chest X-ray or CT 
scan), AND 
b. 
Evidence for abnormal respiratory physiology, based upon a room air oxygen 
saturation (SpO2) < 93%, or the need for supplemental oxygen to maintain an 
oxygen saturation ≥ 93% 
2. Absence of active lower respiratory tract infection 
 
3.2.5.2. 
Veno-occlusive disease 
 
Veno-occlusive disease (VOD) is diagnosed by the presence of two or more of the following 
with no other identifiable cause for liver disease: 75 
1. Jaundice (direct bilirubin >  2 mg/dL or > 34 μmol/L) 

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2. Hepatomegaly with right upper quadrant pain 
3. Ascites and/or weight gain (> 5% over baseline) 
 
3.2.5.3. 
CNS toxicity 
 
CNS toxicity will be defined as patient experiencing seizures, CNS hemorrhage, or RPLS.   
 
Reversible posterior leukoencephalopathy syndrome (RPLS).76, 77 or Posterior Reversible 
Encephalopathy Syndrome (PRES) 
 
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. 
 
3.2.5.4. 
Infection 
 
Infection is defined as CMV reactivation with/without clinical disease, adenovirus infection, 
EBV, and invasive fungal infections. 
 
3.2.6. Frequency of Disease-related Complications 
 
3.2.6.1. 
Stroke 
 
An overt stroke is defined as a focal neurologic event and neurologic deficit lasting more than 24 
hours with neuroimaging changes.  Children 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.   
 
3.2.7. Health-related Quality of Life (QOL) 
 
Health-related QOL will be assessed using the Child Health Questionnaire (CHQ).  The CHQ 
Parent Form 50 (PF50) and the CHQ Child Form 87 (CF87) will be used.  It will only be 
assessed in English speaking patients and patients with English speaking parents.  Additional 
details are described in Appendix F. 
 
3.2.8. Immune Reconstitution 
 
Lymphocyte subpopulations (absolute number of CD3, CD4, CD8, CD 16+56, and CD19 cells) 
will be measure by flow cytometry.  Immunoglobulin levels (IgG, A, and M) will also be 
quantified.  Splenic function will be measured by quantifying the pitted red cell count. 
 

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3.2.9. Neurocognitive Testing 
 
Age-appropriate standard neurocognitive tests for recipients aged between 3.0 years and 19.75 
years are administered prior to transplant and at 2 years.  These tests are validated for children 
with sickle cell disease and are in application in clinical trials involving chronic transfusion 
therapy for sickle cell disease.  Additional details are provided in Appendix G.  
 
 
 

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CHAPTER 4 
 
 
4. PATIENT REGISTRATION, ENROLLMENT AND EVALUATIONS 
 
4.1. 
Enrollment Procedures 
 
4.1.1 Screening and Eligibility Procedures 
 
Patients will be identified at the participating institutions.  Eligibility will be reviewed and 
confirmed by a majority of an expert panel prior to enrollment.  See Appendix E for details 
regarding the eligibility review panel. 
1. Before a patient can be enrolled in this study, the patient must be evaluated for eligibility 
by the eligibility review panel, which is an external expert panel familiar with the natural 
history of sickle cell disease and unconnected with this study.  The eligibility screening 
(Segment 0) includes a question confirming that the patient (or legal guardian) signed the 
informed consent.  Transplant centers will enter screening information using the BMT 
CTN AdvantageEDCSM Electronic Data Capture System.  At least two weeks prior to the 
initiation of the conditioning therapy, an authorized user at the transplant center enters the 
patient demographics and Segment 0 of the Enrollment Form.  In addition, the transplant 
center will provide the patient’s and donor’s HLA typing results (HLA-A, -B, -C, and  
-DRB1 at high resolution using DNA-based typing) to the DCC. 
2. The DCC distributes this screening information to the eligibility review panel.  The 
review panel has one week to determine the patient’s eligibility.  The DCC will distribute 
the HLA typing results to the Protocol Chairs and Protocol Officer to determine that the 
patient and donor are appropriately HLA-matched. 
3. If the patient is eligible the DCC contacts the transplant center coordinator and requests 
that they complete the Segment A and Segment B enrollment forms.  The Segment B 
enrollment form must be completed prior to initiation of conditioning regimen.  
4. A visit schedule based on transplant date is displayed for printing and is referred to as 
‘Segment B Follow-up.’ 
 
4.2. 
Patient Assessments 
 
4.2.1. Pre-transplant Evaluations 
 
The following observations are required within the following time frames. 
 
4.2.1.1. 
Required ≤ 90 days prior to initiation of alemtuzumab 
 
A liver biopsy should be done if the patient has been transfused for greater than one year PLUS 
their serum ferritin is > 1000 ng/mL.  If the patient does not meet this criterion, then the biopsy 
will be optional. 

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4.2.1.2. 
Required ≤ 60 days prior to initiation of alemtuzumab 
1. Neurocognitive testing (see Appendix G). 
2. Pitted red cell count (see Appendix C). 
3. Baseline quality of life (QOL) assessments (CHQ PF50-parent form and CF87).  The 
CF87 is completed by patients > 10 years of age.  If ≤ 10 years of age, the PF50 is 
completed by a parent (for English speaking patients and families only).  This must be 
administered prior to alemtuzumab and may be administered up to 60 days prior to 
initiation of conditioning therapy.  
 
4.2.1.3. 
Pre-transplant evaluations required ≤ 30 days prior to initiation of alemtuzumab 
1. History, physical examination, height, and weight. 
2. Lansky/Karnofsky performance status. 
3. Hb-electrophoresis: Hb F, Hb S, Hb A2. 
4. CBC with differential and platelet count, serum creatinine, bilirubin, alkaline 
phosphatase, ALT, and AST, serum ferritin, magnesium. 
5. Radionuclide GFR is strongly recommended as the test of choice.  Measurement of 24-
hour urine creatinine clearance is acceptable if the former is not available.  
6. 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, and varicella zoster 
virus antibody. 
7. HLA typing at HLA -A, -B, -C, and -DRB1 at high resolution using DNA-based typing, 
ABO and Rh typing, if not already performed.   
8. Baseline peripheral blood samples for chimerism analysis by molecular methods 
(STR/VNTR). 
9. Baseline EKG. 
10. Baseline echocardiography for left ventricular ejection fraction (LVEF), left ventricular 
shortening fraction and presence or absence of tricuspid regurgitation.  If present, 
measure jet velocity as a measure of pulmonary hypertension.  It is strongly 
recommended that these tests be performed ≤ 30 days prior to initiation of the 
conditioning regimen.  However, they can be done Day –60 to Day –30 prior to initiation 
of the conditioning regimen, provided the patient has been asymptomatic since the time 
of the tests. 
11. Pulmonary function testing: FEV1, FVC, and DLCO.  Record oxygen saturation by pulse 
oxymetry.  It is strongly recommended that these tests be performed ≤ 30 days prior to 
the initiation of the conditioning regimen.  However they can be done Day –60 to Day  
–30 prior to the initiation of the conditioning regimen, provided the patient has been 
asymptomatic since the time of the tests. 
12. β-HCG serum pregnancy test for females of childbearing potential. 

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13. Chest X-ray or CT scan.  It is strongly recommended that the X-ray or scan be performed 
≤ 30 days prior to the initiation of the conditioning regimen.  However, it can be done 
Day –60 to Day –30 prior to the initiation of the conditioning regimen, provided the 
patient has been asymptomatic since the time of the X-ray or scan. 
14. MRA/MRI of the brain to assess for radiologic disease.  Images will be sent for central 
review.  
15. Total nucleated cell count and CD34+ count of the infused product on Day 0. 
 
4.2.2. Post-transplant Evaluations 
 
The following evaluations are considered standard evaluations for transplant patients:   
1. History and physical exam to assess GVHD and other morbidity weekly until Day 100 
post-transplant, then at six months, one year, and then two years post-transplant.  GVHD 
evaluation and grading to be in keeping with BMT CTN MOP. 
2. CBC at least three times a week from Day 0 until neutrophil engraftment.  Platelet count 
at least three times a week from Day 0 until platelet engraftment.  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. 
3. Quantitative hemoglobin electrophoresis (Hb F, Hb A, Hb A2, and Hb S) on Day 100, 6 
months, one year, and 2 years post-transplant.  
4. Creatinine, bilirubin, alkaline phosphatase, ALT, AST, twice a week until Day 28, then 
weekly until 12 weeks, and then at six months, one year, and two years post-transplant. 
Serum ferritin at 1 and 2 years post-transplant. 
5. Peripheral blood sample for post-transplant chimerism assay by molecular methods 
collected between Day 28-42, Day 100, 6 months, 1 and 2 years.  Fractionated chimerism 
examining the myeloid and lymphoid fractions is preferred but total chimerism is 
acceptable. 
6. Oxygen saturation by pulse oxymetry 1 and 2 years post-transplant, pulmonary function 
testing with FEV1, FVC, DLCO in whom pulmonary function testing can be performed. 
7. Echocardiography for left ventricular shortening fraction and presence or absence of 
tricuspid regurgitation.  If present, measure jet velocity as a measure of pulmonary 
hypertension at 1 and 2 years post-transplant. 
8. Immune reconstitution, (absolute lymphocyte numbers) by flow cytometry for 
lymphocyte subpopulations (CD3, CD4, CD8, CD19, and CD16+56 cell subsets), 
immunoglobulin levels (G, A, and M) at 6 months, 12 months (and 24 months if 12 
month result is abnormal or GVHD developed in the past year).  Pitted red cell count – 
Blood samples will be sent at 2 years post-transplant for analysis of pitted red cell counts 
as a measure of splenic function (see Appendix C for details of procedure). 
9. MRA/MRI of the brain at 2 years post-HCT to assess for radiologic disease or transplant 
induced CNS toxicity.  Images will be sent for central review.  

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10. Neurocognitive follow-up testing (same battery used pre-transplant) 2 years post-
transplant (see Appendix G).  Pre- and post-transplant test results will be collated for all 
patients for central review. 
11. Health-related quality of life (QOL) measures (CHQ PF50 and CF87) will be completed 
by the parent and/or child during scheduled clinic visits at Day 100, 6 months, 1 year, and 
2 years post-transplant.  Please see Appendix F for additional details. 
 
4.2.3. Summary of Patient Clinical Assessments 
 
Table 4.2.3. Summarizes patient clinical assessments over the course of the study. 

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TABLE 4.2.3:  SUMMARY OF PATIENT CLINICAL ASSESSMENTS 
Table notes on the next page. 
 
Baseline1 
Days Post-transplant 
 
 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
100 
6 
months 
1 
year 
2 
years 
History, physical exam, weight, height, and 
Lansky/Karnofsky performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Health-related Quality of Life Assessment 
(Child Health Questionnaire Parent Form 50 
& Child Form 87) 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Cerebral MRA/MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurocognitive assessmentA 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pitted red cell count 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hb-electrophoresis Hb F, Hb S, Hb A2, Hb 
A 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CBC3, differential, platelet count, and blood 
chemistries4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Serum ferritin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Radionuclide GFR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease titers5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood Sample for Chimerism7 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Function by 2D echocardiography 
LVEF or shortening fraction, tricuspid 
regurgitation, and jet velocity(if present)B 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
FEV1, FVC, DLCO, O2 saturation B 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
ß-HCG serum pregnancy test  
females of childbearing 
potential only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or CT scan B 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver biopsy 
A liver biopsy is required 
within 90 days of starting 
conditioning regimen 
(alemtuzumab) in patients 
on chronic transfusion 
therapy ≥ 1 year + clinical 
evidence of iron overload 
(serum ferritin level of > 
1000 ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nucleated cell CD34+ cell counts 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune reconstitution assays8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
GVHD and other morbidity assessments9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessments 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Serious adverse events 
 
From initiation of alemtuzumab test dose until 2 years post-transplant 

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Notes for Table 4.2.3: 
1 Baseline assessments should be made within a 30 day window prior to initiation of the conditioning regimen, unless otherwise noted. 
2 These assessments should be made within a 60 day window prior to initiation of the conditioning regimen.  
3 CBC performed at least three times a week from Day 0 until neutrophil engraftment.  Platelet counts performed at least three times a week from Day 0 until platelet engraftment.  Thereafter, CBC 
and platelet count performed twice weekly until Day 28.  CBC and platelet count performed weekly after Day 0 and neutrophil engraftment. 
4 Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST, and ALT, and magnesium (where standard of care should be according to institutional guidelines).  Blood 
chemistries performed twice weekly until Day 28.  Blood chemistries performed weekly after Day 28 until 12 weeks post-transplant, 6 months, 1 and 2 years post-transplant. 
5 Infectious disease titers include: CMV, Hepatitis panel (HepA, Ab, HepB sAb, HepB sAg, HepB Core Ab, HepC Ab), herpes simplex virus, syphilis, HIV and HTLV I/II antibody, and varicella 
zoster. 
6 HLA typing at -A,-B, -C, and -DRB1 at high resolution using DNA-based typing and patient must also have ABO and Rh typing performed, if not already performed.   
7 Chimerism will be measured by molecular methods.  Fractionated chimerism for the lymphoid and myeloid fractions is preferred but total chimerism is acceptable. 
8  The 24 month tests are only required if 12 month test result is abnormal or if GVHD developed in the past year. 
9 GVHD and other morbidity assessments performed weekly until Day 100 post-transplant, and then at 6 months, 1 year and 2 years. 
A The same battery must be used for pre-transplant and 2-year follow-up testing.  If a patient has crossed age groups between two testing periods, the tests will still be administered in the 
age-appropriate manner. 
B It is strongly recommended that these tests be performed ≤ 30 days prior to the initiation of conditioning regimen.  However, provided the patient has been asymptomatic since the time of 
the tests, they can be done up to Day -60 prior to the initiation of conditioning regimen. 
.

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4.3. 
Study Monitoring 
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook.  Forms that are not entered into the web-based data 
entry system within the specified time will be considered delinquent.  A missing form will 
continue to be requested either until the form is entered into the web based data entry system and 
integrated into the DCC's master database, or until an exception is granted and entered into the 
Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Reporting Patient Deaths: Recipient Death Information must be entered into the web-based 
data entry system on both the Death and Unexpected Grade 3-5 Adverse Event (AE) Forms 
within 24 hours of knowledge of the patient’s death.  If the cause of death is unknown at that 
time, it need not be recorded at that time.  However, once the cause of death is determined, the 
form must be updated in the web-based data entry system. 
 
4.3.1. Follow-up Schedule 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.3.1.  A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide. 
 
TABLE 4.3.1:  FOLLOW-UP SCHEDULE 
 
Study Visit Target Day Post-transplant 
1 week 
7 ± 3 days 
2 week 
14 ± 3 days 
3 week 
21 ± 3 days 
4 week 
28 ± 3 days 
5 week 
35 ± 3 days 
6 week 
42 ± 3 days 
7 week 
49 ± 3 days 
8 week 
56 ± 3 days 
60 days 
60 ± 3 days 
9 week 
63 ± 3 days 
10 week 
70 ± 3 days 
11 week 
77 ± 3 days 
12 week 
84 ± 3 days 
13 week 
91 ± 3 days 
14 week 
98 ± 3 days 
100 day 
100 ± 3 days 
6 month 
180 ± 28 days 
12 month 
365 ± 28 days 
24 month 
730 ± 28 days 

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Laboratory samples are due ± one month from the target date.  Samples should still be collected 
even if outside target window. 
 
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 #0601 must be indicated on the SCTOD pre-
transplant registration form, if applicable.  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. 
 
Weekly GVHD Monitoring:  GVHD should be monitored in accordance with BMT CTN 
guidelines as specified in the Manual of Procedures.  Patients should be assessed weekly until 
Day 100 post-transplant for GVHD.  After Day 100 patients will be assessed at each follow-up 
visit (Day 180, 365, and 730) for the presence of GVHD.   
 
4.3.2. Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of 
knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business days 
of knowledge of the event. 
 
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. 
 
Serious Adverse Events will be consistent with BMT CTN procedures (BMT CTN 
Administrative Manual of Procedures, Chapter 6) and reported through an expedited Adverse 
Event (AE) reporting system.  Serious and unexpected Grades 3-5 adverse events should be 
reported within three working days.  Deaths are to be reported within 24 hours.  Other SAEs will 
be tracked periodically as defined in the Form Submission Schedule, and staged according to 
CTCAE, Version 4.0. 
 
In addition to the standard BMT CTN Unexpected Grade 3-5 Adverse Event reporting, all 
central nervous system (CNS) events, or events requiring intensive care (ICU) or advanced care 
interventions are required to be reported via the Unexpected Grade 3-5 Adverse Event forms 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.  Grade 3 events should be reported within 
three business days of the event. 
 
For the purposes of this protocol, examples of “ICU” or “advanced care treatment” are one or 
more of the following: 
o The patient is transferred to an advanced care unit or the ICU* (see footnote below) 

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o Continuous Renal Replacement Therapy (CRRT) by dialysis (CAVHD) or filtration 
(CAVH) 
o Non-invasive positive pressure ventilation: continuous positive airway pressure (CPAP), 
bi-level positive airway pressure (BIPAP), intermittent positive pressure ventilation 
(IPPV) 
o Endotracheal intubation with mechanical ventilation 
o Invasive blood pressure monitoring   
o Pressor support 
o Continuous cardiac monitoring 
o Organ failure – acute renal failure, acute liver failure, acute respiratory distress 
syndrome, respiratory failure, or multi-organ failure 
 
* Elective transfer to an advanced care/ICU unit for a scheduled intervention does not need 
to be reported via the Unexpected Grade 3-5 Adverse Event forms in AdvantageEDC. 
 
 
 

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CHAPTER 5 
 
 
5. STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Design 
 
The study is a Phase II, single arm, multi-center trial.  It is designed to estimate the efficacy and 
toxicity of a HCT procedure for SCD patients using unrelated BM grafts.  The study population 
is children with SCD.  The sample size is 30 BM recipients for this trial. 
 
5.1.1. Accrual 
 
It is estimated that four years of accrual will be necessary to enroll the targeted sample size.  
Accrual will be reported by gender and age. 
 
5.1.2. Study Duration 
 
Patients will be followed for a minimum of two years post-transplant. 
 
5.1.3. Randomization 
 
There is no randomization aspect to this trial. 
 
5.1.4. Primary Endpoint 
 
The primary objective is to assess event-free survival (EFS) probability 1 year post-transplant.  
Death, primary or late graft rejection, or recurrence of disease will be considered events for this 
endpoint.  
 
5.2. 
Sample Size and Power Considerations 
 
The sample size is 30 patients for this trial.  Ninety-five percent confidence intervals were 
calculated for varying probabilities based on the sample size.  Table 5.2 provides confidence 
intervals for a variety of observed proportions.  Of particular interest is where the EFS 
probability is 75%, which is the anticipated 1 year EFS probability based on the available data 
showing that EFS for HLA-matched sibling donor transplants for SCD is 85%.  
 
For this setting, the confidence interval length is 31%.  The percentages above and below 75% 
are meant to represent other plausible EFS percentages.   
 

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TABLE 5.2:  CONFIDENCE INTERVAL LENGTHS AND POSSIBLE CONFIDENCE 
INTERVALS FOR VARIOUS UNDERLYING EVENT-FREE SURVIVAL 
PROBABILITIES 
 
N (BM) 
Event-free 
Survival % 
Length of 95% 
Confidence Interval 
Possible  
Confidence Intervals 
30 
 
90 
20.7 
79.3 
100.0 
85 
25.6 
72.2 
97.8 
80 
28.6 
65.7 
94.3 
75 
31.0 
59.5 
90.5 
70 
32.8 
53.6 
86.4 
60 
35.0 
42.5 
77.5 
 
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. 
 
5.3. 
Interim Analysis and Stopping Guidelines 
 
Monitoring of key safety endpoints (overall mortality, graft rejection, and GVHD) will be 
conducted.  The stopping guidelines serve as a trigger for consultation with the DSMB for 
additional review. 
 
A truncated Sequential Probability Ratio Test (SPRT) for a binomial outcome will be used to 
monitor each type of toxicity as described below.  This sequential testing procedure conserves 
type I error across all of the monitoring looks for each toxicity, but not across the three toxicity 
outcomes.  Thus for a single toxicity the type I error is approximately 10%, and across all the 
toxicities, the study-wide type I error is < 30%.  A type I error rate of 10% per toxicity was 
selected to be more conservative with regard to the safety of a new treatment in a less well 
studied disease indication. 
 
The rationale for not conserving type I error across multiple toxicities is twofold.  First, adjusting 
the size of the test for multiple comparisons would reduce statistical power to detect adverse 
outcomes, which seems imprudent.  Secondly, the procedure is a guideline for requiring 
additional review by the Data and Safety Monitoring Board, and is not a formal “stopping rule” 
that would mandate automatic closure of study enrollment.   
 
The SPRT can be represented graphically.  At each interim analysis, the total number of patients 
enrolled is plotted against the total number of patients who have experienced toxicity.  The 
continuation region of the SPRT is defined by two parallel lines.  Only the upper boundary will 
be used for monitoring the study to protect against high incidences of toxicity.  If the graph falls 
above the upper boundary, the SPRT rejects the null hypothesis and concludes that the toxicity 
rate is higher than predicted by the observed number of patients enrolled on study.  Otherwise, 
the SPRT continues until enrollment reaches the target goal.   

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The usual measures of performance of an SPRT are the error probabilities α and β of rejecting 
H0 when θ = θ0 and of accepting H1 when θ = θ1, respectively, and the expected sample size 
E(N|θI).  Note that since the test uses only the upper boundary, and is truncated by a finite 
sample size, the size of the test will be slightly lower than the nominal level given %.  The tests 
to be used in this protocol were developed from SPRT’s described in more detail in the following 
subsections.   
 
5.3.1. Overall Mortality 
 
Overall mortality in this trial is projected to be ≤ 15% at 100 days.  The stopping rule for overall 
mortality will be triggered if there is significant evidence that the 100 day overall mortality rate 
exceeds 15% based on the truncated SPRT.  This truncated SPRT is based on contrasting 15% 
versus 30% 100 day mortality, with nominal type I and II errors of 14% and 10%, respectively.  
The common slope of the parallel lines is 0.219 and the intercept for the upper boundary is 
2.097.  The stopping rule is summarized in the following table. 
 
TABLE 5.3.1a:  STOPPING RULE FOR OVERALL MORTALITY BY DAY 100 
(ALSO APPLIES TO GRADE III-IV aGVHD BY DAY 100) 
 
Number of Evaluable 
Patients Enrolled1 
Number of Deaths 
3-4 
3 
5-8 
4 
9-13 
5 
14-17 
6 
18-22 
7 
23-26 
8 
27-30 
9 
1 Evaluable patients are defined as those who proceed to transplant. 
 
The actual operating characteristics of this stopping rule, shown in the table below, were 
determined in a simulation study that assumed uniform accrual of 30 individuals over a four-year 
time period.   
 

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TABLE 5.3.1b:  OPERATING CHARACTERISTICS OF STOPPING RULE FOR 
OVERALL MORTALITY FROM A SIMULATION STUDY WITH  
10,000 REPLICATIONS 
 
True 100-Day Rate 
15% 
25% 
30% 
35% 
Probability Reject Null 
0.08 
0.48 
0.70 
0.85 
Mean Month Stopped 
46.0 
37.2 
30.7 
25.2 
Mean # Endpoints in 100 Days 
4.5 
5.9 
5.9 
5.6 
Mean # Patients Enrolled 
29 
23 
19 
16 
 
The testing procedure for overall mortality rejects the null hypothesis in favor of the alternative 
8% of the time when the true 100 day overall mortality rate is 15%, and 85% of the time when 
the rate is 35%.  This corresponds to a type I error rate of α = 0.08 and a type II error rate of β = 
0.15.  When the true 100 day mortality rate is 35%, on average, the stopping rule will be 
triggered 25 months after opening, when 6 events have been observed in 16 patients. 
 
5.3.2. Graft Rejection  
 
Failure to engraft donor cells (defined as < 20% donor chimerism) by Day 100 should occur in  
< 20% of patients with this approach.  The stopping rule will be triggered if there is significant 
evidence that the Day 100 graft rejection rate exceeds 20% based on the truncated SPRT.  This 
truncated SPRT is based on contrasting 20% versus 35% Day 100 graft rejection, with nominal 
type I and II errors of 12% and 20%, respectively.  The common slope of the parallel lines is 
0.271 and the intercept for the upper boundary is 2.473.  The stopping rule is summarized in the 
following table. 
 
TABLE 5.3.2a:  STOPPING RULE FOR GRAFT REJECTION BY DAY 100 
 
Number of Evaluable 
Patients Enrolled1 
Stop if Graft Rejection  
Occurs in 
3-5 
4 
6-9 
5 
10-13 
6 
14-16 
7 
17-20 
8 
21-24 
9 
25-27 
10 
28-30 
11 
1 Evaluable Patients are defined as those who proceed to transplant. 
 

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Operating characteristics of the stopping rule for graft failure were determined in a simulation 
study that assumed uniform accrual of 30 individuals receiving unrelated donor BM over a four-
year time period.   
 
TABLE 5.3.2b:  OPERATING CHARACTERISTICS OF STOPPING RULE FOR 
GRAFT FAILURE (GF) FROM A SIMULATION STUDY WITH 10,000 
REPLICATIONS 
 
True 100-Day Rate 
20% 
30% 
35% 
40% 
Probability Reject Null 
0.08 
0.41 
0.64 
0.82 
Mean Month Stopped 
46.3 
39.2 
33.6 
28.0 
Mean # Endpoints in 100 Days 
5.9 
7.5 
7.5 
7.1 
Mean # Patients Enrolled 
29 
25 
21 
17 
 
The testing procedure for graft failure rejects the null hypothesis in favor of the alternative 8% of 
the time when the true Day 100 graft failure rate is 20%, and 82% of the time when the rate is 
40%.  This corresponds to a type I error rate of α = 0.08 and a type II error rate of β = 0.18.  
When the true Day 100 graft failure rate is 40%, on average, the stopping rule will be triggered 
28 months after opening, when 7 non-engraftment events have been observed in 17 patients. 
 
Secondary graft rejection will be monitored and reported to the DSMB. 
 
5.3.3. Grade III-IV Acute GVHD 
 
Grade III-IV acute GVHD should occur in ≤ 15% of patients by Day 100 with this approach.  
The grade III-IV acute GVHD rates are not expected to differ substantially by stem cell source, 
so that the monitoring rule will include both stem cell sources together.  The stopping rule will 
be triggered if there is significant evidence that the rate of acute GVHD on Day 100 is more than 
15% based on the truncated SPRT.  The stopping rule and operating characteristics are identical 
to that for overall mortality and are not reproduced here. 
 
5.4. 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, stem cell source, performance status, HLA match, disease 
symptoms, serum bilirubin level, serum creatinine level, pulmonary function tests, cardiac 
function, donor age, donor gender, donor ethnicity, splenic function, hemoglobin electrophoresis, 
cerebral MRI, serum ferritin, QOL, neurocognitive function. 
 
5.5. 
Analysis of Primary Endpoint 
 
The primary analysis will consist of estimating 1 year EFS probability based on the Kaplan-
Meier product limit estimator.  The 1 year EFS probability and confidence interval will be 

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calculated.  All transplanted patients will be considered for this analysis.  In addition, the 
frequencies of each component of the composite endpoint (primary graft failure, secondary graft 
failure, and disease recurrence) will be described.  
 
5.6. 
Analysis of Secondary Endpoints 
 
Overall survival:  The survival distribution will be estimated by the Kaplan-Meier curve.  All 
patients will be followed for a minimum of two years post-transplant for mortality. 
 
Incidence of neutrophil and platelet engraftment:  To assess the incidence of each type of 
engraftment from day of transplant, a cumulative incidence curve will be computed along with a 
95% confidence interval at 100 days post-transplant.  Death prior to each type of engraftment 
will be considered as a competing risk.  
 
Time to acute GVHD:  To assess the incidence of grades II-IV or grades III-IV acute GVHD 
from day of transplant, the first day of acute GVHD onset at either grades II-IV or grades III-IV 
will be used to calculate a cumulative incidence curve for that acute GVHD grade.  A 95% 
confidence interval at 100 days post-transplant will be computed.  Death prior to development of 
acute GVHD will be considered as a competing risk.  
 
Time to first clinical onset of chronic GVHD: To assess the incidence and severity of chronic 
GVHD from day of transplant, a cumulative incidence curve will be computed along with a 95% 
confidence interval at two years post-transplant.  Death prior to occurrence of chronic GVHD 
will be considered as a competing risk. 
 
Transplant-related complications:  The frequency of transplant-related complications, both 
overall and by type of complication, will be described using proportions (along with 95% 
confidence intervals). 
 
Disease-related complications:  The frequency of disease-related complications (stroke) will be 
described using proportions (along with 95% confidence intervals). 
 
Immune reconstitution:  Descriptive statistics will be computed for all the immune 
reconstitution assays. 
 
Health-related QOL:  Mean QOL scores and confidence intervals will be computed at each 
time point.  For both parent and child reported health-related QOL mean scores, a paired student 
T test will be used to look for differences in mean scores between baseline and 2 years after the 
HCT.  To determine the magnitude of differences, standardized effect sizes (or z-scores) will be 
calculated.  This will be done by taking the difference between the mean domain scores of the 
baseline score and the follow-up scores and dividing by the standard deviation of the baseline.  
Domain scores will also be compared between baseline and 2 years post-transplant with a 
Bonferroni correction for multiple testing.  In addition, mixed models for repeated measures data 
will be used to assess whether QOL is changing significantly over each time point among 
survivors. 

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Pearson correlation coefficients will be used to determine the association between child and 
parent health-related QOL scores.  Fisher’s z-transformation will be used to test whether this 
correlation is significantly different from 0 and to construct confidence intervals for the 
correlation coefficient.  A paired t-test will be used to test the difference between the mean CHQ 
scores of the child and parent at each time point.  
 
Neurocognitive evaluation:  All patients will be assessed with a cognitive battery at study entry 
and 2-year follow-up.  The major indicator of cognitive loss will be decline in general 
intellectual abilities (IQ) as assessed by the Wechsler Abbreviated Scale of Intelligence (WASI) 
or Wechsler Preschool and Primary Scale of Intelligence (WIPPSI-III).   
 
Other secondary outcomes, including the Behavior Rating Inventory of Executive Function 
(BRIEF) Continuous Performance Test Second Edition (CPT-II), VMI, Children’s Memory 
Scale (CMS), and California Verbal Learning Test (CVLTC) will be compared in the same 
manner by comparing the composite t-score for each age-appropriate cognitive domain test over 
time. 
 
A paired t-test will be used to assess the change from baseline in WASI IQ and change from 
baseline in BRIEF and other age-appropriate tests T-Scores over time.  In addition to using 
statistical techniques to evaluate changes in IQ, clinical significance will also be evaluated.  
 
Functional scores and confidence intervals will be computed at each time point in age-
appropriate fashion.  Mixed models for repeated measures data will be used to assess whether 
functional scores change significantly after transplant over time.  
 
Secondary analysis of the secondary outcome will be performed.  This secondary analysis will be 
an adjustment of the secondary study outcome for potential confounding factors (e.g., adjust the 
secondary study outcome for confounding factors such as gender, age, medical history,  
co-morbidities, etc.).  Since the secondary study outcome is a continuous measure, we will be 
able to make these adjustments with the use of generalized linear models (e.g., analysis of 
covariance).  Generalized linear models can help to determine whether the apparent effect of one 
variable (e.g., treatment) on the outcome of interest (e.g., the mean change from baseline of IQ 
after 2-years of follow-up) is accounted for by differences in other patient characteristics (e.g., 
treatment compliance, gender, age, medical history, co-morbidities, etc.). 
 
5.7. 
Safety Analysis 
 
The DSMB will review the study for safety endpoints at least twice per year or more often if 
stopping guidelines are reached.  Accrual will not stop during this evaluation.  The reporting of 
serious adverse events will be consistent with standard BMT CTN procedures.  The type and 
severity of adverse events will be analyzed. 
 
 
 

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APPENDIX A 
 
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 physician will conduct the conference.  All potential risks associated with the 
use of conditioning regimen and GVHD prophylaxis medications should be discussed as 
objectively as possible.   
 
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 Institutional Review Board of the institution 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 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. 
 
4. 
Ethical Considerations 
 
Patients are referred to the Transplant Center for consideration of hematopoietic cell 
transplantation.  While there will be every effort to seek out and include females and minority 
patients, the patient population is dependent upon the referral pattern and the ability to identify 
suitable donors.  Female and minority patients are eligible for all aspects of the study and their 
participation will be actively encouraged.  
 

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APPENDIX B 
 
CONSENT AND ASSENT FORMS 
 
 
 

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Informed Consent to Participate in Research 
 
Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children  
with Severe Sickle Cell Disease  
 
 
This is a clinical trial, which is a research study to answer specific medical questions.   
The information from this study may also help future patients.  The Study doctor (the 
person in charge of the research) will explain the study to you and your child.  This 
research study will include only people who choose to take part.  Please take your time to 
make your decision about allowing your child to take part.  You may discuss your decision 
with family and friends.  You and your child should also discuss this with your child’s 
health care team.  If you, or your child, have any questions, you and your child can ask the 
Study doctor for more explanation. 
 
 
This is a consent for a research study.  Your child is being invited to participate in this study 
because your child has severe sickle cell disease that may be treated with a bone marrow 
transplant.  This form is intended to give you and your child information to help you decide if 
you and your child want to participate in this study.  You should read this form and ask any 
questions you or your child may have before agreeing to be in the study.   
 
Children with sickle cell disease are born with a defect in hemoglobin. Hemoglobin is a protein 
in red blood cells that carries oxygen to vital organs such as the brain, heart, lungs and kidneys.  
Defective hemoglobin damages red blood cells and makes them sticky.  This causes them to look 
like a sickle.  The damaged or sickled red blood cells can block blood flow in blood vessels and 
block oxygen and nutrients from reaching organs.  As a result almost all the organs in the body 
can be damaged but it is especially bad when vital organs are involved.  When the flow of blood 
is blocked in a blood vessel in the brain, a stroke occurs.  When blood flow is blocked in a bone 
or muscle, this causes severe pain.  If it occurs in the lung, this complication is called acute chest 
syndrome and causes chest pain and a low oxygen level.  Sickle cell disease can also cause 
anemia.  
 
It is possible to replace the defective red blood cells with normal blood cells in children with 
severe sickle cell disease by performing a bone marrow transplant.  We know this from recent 
studies where bone marrow from a brother or sister has replaced the defective sickled red cells 
after transplantation.  Blood vessels are no longer blocked, and the anemia goes away.   
 
However, a bone marrow transplant is an intensive medical procedure and there are serious risks 
involved.  Therefore, it is usually offered only to children who have had severe complications of 
sickle cell disease such as stroke, frequent painful crises, or repeated episodes of acute chest 
syndrome.  In most cases, it is offered only to children who have a healthy brother or sister who 

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is HLA-identical, which means that the donor has the same ‘tissue’ type as the person receiving 
the transplant.   
 
Most children with severe sickle cell disease do not receive a transplant because they do not have 
the same tissue type as their healthy brothers or sisters.  These children are often treated with 
medicines and regular red blood cell transfusions for many years to try to control symptoms and 
organ damage.  However, in children with sickle cell disease who have had a stroke, 20% (1 in 
5) will develop a second stroke and, of that group, 30% (1 in 3) children will develop a third 
stroke even if they are receiving regular blood transfusions.   
 
Cells in the bone marrow that make healthy red cells are called blood stem cells.  
 
This study is a clinical trial for children with severe sickle cell disease that do not have a brother 
or sister with the same tissue type who can serve as their donor.  Although previous studies have 
shown that a bone marrow transplant is possible for patients with a healthy related bone marrow 
donor, this study will determine if this is a good treatment option for patients transplanted with 
cells from an unrelated donor.  Patients who participate in this study will also receive lower 
intensity treatment (conditioning) before transplant with bone marrow donated by a healthy adult 
donor. 
 
This lowered intensity conditioning treatment (reduced intensity conditioning regimen – RIC) is 
being used to decrease the side effects or toxicities of the conditioning treatment.  It is not known 
whether this RIC will be successful in allowing donor cells to settle in the patient and grow 
successfully.  This is the research question that is being asked in this study. 
 
Before you decide whether or not to have your child join the study, please read all the 
information in this consent form.  Feel free to ask questions to understand your child’s rights and 
protections.  The choice to take part in this study is completely voluntary. 
 
Sponsor and source of funding: 
This study is sponsored by the National Institutes of Health (NIH) and the National Marrow 
Donor Program® who is the primary source of funding.  Additional NIH sponsors include the 
Sickle Cell Disease Clinical Research Network (SCD-CRN) and the National Center on Minority 
Health and Health Disparities.  The NIH is a government program that funds the Blood and 
Marrow Transplant Clinical Trials Network (BMT CTN), a group of transplant programs 
conducting research in transplantation for several diseases including severe sickle cell disease.  
 

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If you decide to allow your child to take part in this research study: 
• You or your child’s insurance company will be responsible for all medical bills from your 
child’s transplant. 
• You or your child will not pay for any extra tests that are being done for the study (these 
are lab tests, scans and other special tests that are not part of regular, routine care).  The 
extra research tests that are being done for this study are a blood test to measure function 
of the spleen, a special scan of the brain called an MRA/MRI (magnetic resonance 
angiography and imaging after injection of contrast), measurement of brain function 
using performance tests that are age-dependent, and question sheets that measure quality 
of life.  The tests that measure learning and brain function will be done before transplant 
and again 2 years after transplant.  Quality of Life question/answer sheets will be 
completed before transplant and at 3, 6, 12 and 24 months after transplant. 
• You or your child will not be paid to take part in this study. 
 
If you decide not to allow your child to participate in this study, your child’s study doctor 
will discuss other treatment options with you. 
 
What other choices does your child have if your child does not take part in the study? 
Your child’s other choices may include: 
• Treatment with drugs such as hydroxyurea that may lessen complications of severe sickle 
cell disease. 
• Experimental treatments with new drugs for severe sickle cell disease. 
• A transplant using bone marrow without being part of this study where the choice of 
medicines before and after transplant, and other guidelines may be different. 
• Other treatments such as regular RBC transfusions to try to control symptoms related to 
your child’s severe sickle cell disease. However, RBC transfusion therapy may not 
prevent further strokes in all children who have had an initial stroke.  
 
It is important that you talk to your child’s study doctor about your child’s treatment choices 
before you decide to have your child participate in this study. 
 
Why is this study being done? 
This study is being done to determine if blood cell transplants, with bone marrow from unrelated 
donors, are effective in children with severe sickle cell disease and if this treatment approach has 
acceptable risks and side effects.  The study will also look into the risk of death associated with 
this treatment approach and if it is acceptable considering the potential benefit of avoiding the 
long-term consequences of severe sickle cell disease.  Transplant studies for sickle cell disease 
have previously used high dose chemotherapy to prepare patients for transplant (myeloblative 
conditioning).  This has been successful mostly in patients who had tissue-matched family 
members such as brothers or sisters, as donors.  In this study, the success of transplant for sickle 
cell disease is being measured after using reduced intensity conditioning treatment to reduce 
toxicities of treatment using tissue-matched unrelated donor cells.  This is being done to try to 
avoid the toxicities of more intense conditioning treatment. 
 

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This research study is being done to answer the following questions: 
• Is it safe to transplant children who have severe sickle cell disease with bone marrow 
from a healthy, unrelated donor? 
• Are the drugs given to patients in this study (reduced intensity conditioning) effective in 
destroying sickle cells and allowing blood cells from a healthy donor to grow in the 
recipient? 
• After transplant, will children with sickle cell disease make healthy red blood cells and 
avoid the health problems caused by sickle cell disease? 
• After transplant, will children with sickle cell disease experience any side effects that 
shorten their life or worsen their quality of life?   
 
How many children will take part in the study? 
Thirty (30) children in the U.S. will take part in this study.  To be part of the study your child 
must: 
• Be between the ages of 3 and 19 years  
• Have severe sickle cell disease with one or more of the following sickle cell 
complications: 
o Stroke or other severe sickle cell disease complication affecting the brain 
o Repeated acute chest syndrome episodes, despite treatment 
o Repeated severe pain episodes despite treatment 
• Not have a healthy brother or sister who has the same tissue type who is able and willing 
to donate 
• Have an acceptable unrelated marrow donor available 
• Provide a signed consent for participation in the study (your child signs an assent form if 
they are old enough to understand the risks and benefits) 
 
What will happen if your child takes part in this research study?   
 
Before the transplant: 
The first step in considering your child for an unrelated blood or marrow transplant is to have an 
eligibility review panel (a group of 5 sickle cell disease experts and blood and marrow transplant 
physicians unconnected with this trial) review your child’s medical history.  Once they have 
confirmed that your child is eligible for this trial we will proceed with the pre-transplant work-up 
and research tests listed below.  In the unlikely event that they determine that your child is not 
eligible for this trial, your doctor will discuss other transplant and treatment options with you. 
 
The following research tests will be performed: 
• Question/answer sheets to measure quality of life before transplant. 
• Pitted red cell count before transplant to measure spleen function which is decreased by 
sickle cell disease. 
• Special tests of learning and brain function called ‘Neurocognitive testing’.  These tests are 
done to learn about any effects of sickle cell disease on brain function before the transplant, 
and compare 2 years after transplant to see if there is a change. 
• MRA and MRI tests before transplant will be performed as part of the research for this 
study. 

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These tests will be done as an outpatient before the transplant over the course of several days.    
 
To help with the administration of medicines, blood transfusions and obtaining blood for lab 
tests, a central venous catheter (also known as a ‘Hickman’ or ‘Broviac’ catheter) will be placed 
before the transplant.  This is a hollow tube that is inserted by a surgeon or radiologist usually in 
the operating room.  The doctor performing the procedure will explain it in more detail before 
the procedure.  Your child’s anesthesiologist will describe the risks of a general anesthetic.  The 
tube is placed in the chest and allows medicines, transfusions, etc. to be given painlessly into the 
vein without the need for repeated sticking of needles in your child’s arms.  Once the central 
venous catheter is placed, it will need daily care at home with cleaning and injection of 
medications to prevent catheter-related blood clots.   
 
Transplant/conditioning: 
Conditioning is the chemotherapy and other medicines given to prepare your child to receive 
donor cells.  It prevents your child’s immune system from rejecting donor cells.  Conditioning 
will start 22 days before transplant. 
 
The medicines used are alemtuzumab, fludarabine, and melphalan.  Alemtuzumab will be given 
intravenously (through your child’s central venous catheter) once a day for 3 days (after a small 
test dose) beginning 3 weeks before the transplant.  The test dose is given to make sure that your 
child will not have a bad reaction to the full dose.  If your child has a bad reaction, your doctor 
will discuss the best way to proceed.  Your child will be admitted during alemtuzumab infusions 
and may be discharged if well the day after the infusions are completed. 
 
Next, your child will return to the hospital for admission to the bone marrow transplant unit to 
receive fludarabine and melphalan starting 8 days before the transplant.  Fludarabine will be 
given intravenously once a day for 5 days.  Finally, melphalan will be given intravenously 3 days 
before the transplant.  This will be followed by 2 “rest days” when your child will not receive 
any chemotherapy. 
  

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Day 
Treatment 
24 hours before 1st dose of 
Alemtuzumab 
Alemtuzumab test dose 
 
 
Alemtuzumab  
Alemtuzumab  
Alemtuzumab  
21 days before transplant 
20 days before transplant 
19 days before transplant 
 
8 days before transplant 
Fludarabine  
7 days before transplant 
Fludarabine  
6 days before transplant 
Fludarabine  
5 days before transplant 
Fludarabine  
4 days before transplant 
Fludarabine  
3 days before transplant 
Melphalan  
2 days before transplant 
Rest 
1 day before transplant 
Rest 
Transplant day 
Bone marrow infusion 
 
Bone marrow transplant: 
Your child will be given the marrow transplant on Day 0.  The donated marrow will come from a 
suitably tissue-matched unrelated person.  The donor cells will be given through the central 
venous catheter, in a manner similar to a blood transfusion. 
 
Immunosuppression to prevent graft-versus-host disease (GVHD): 
Three days before the transplant, your child will begin to receive medicines to hold back the 
immune system and these medicines will continue after the transplant.  This may make your 
child develop more infections than usual.  However, these drugs are important to allow donor 
cells to accept their new role and to lower the chance of their injuring your child’s organs by 
causing graft-versus-host disease (GVHD).  GVHD is an attack by the donor cells against your 
child’s body.  GVHD is discussed in greater detail below.  Your child will receive one or more 
standard drugs to prevent GVHD and these will be given for at least 6 months after the 
transplant.  These drugs include tacrolimus (also called FK 506 or Prograf®), 
methylprednisolone or prednisone, methotrexate, and cyclosporine (also called Gengraf® or 
Neoral®) and may be used in different combinations.   Choice of drugs may depend on the 
preference of the transplant team at your hospital. 
 
Post-transplant follow-up and care:  
The conditioning regimen will destroy your child’s blood and marrow cells.  This will cause low 
counts of white blood cells, red blood cells, and platelets.  Blood stem cells from the donor will 
produce new blood cells to replace the destroyed recipient cells.  To speed this process along 
after the transplant, your child will receive granulocyte-colony-stimulating factor (also called G-
CSF or Neupogen).  G-CSF is a natural protein made in the body that increases the white blood 
cell count and that is used to help protect against infections.  Your child will start receiving G-
CSF one week after the transplant.  It is given either by injection under the skin or intravenously.  
Your child will receive it daily until the white blood cell count has recovered. 

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Your child will stay in the hospital after the transplant until the doctor feels it is safe for your 
child to go home.  During that time, your child will be carefully watched for signs of infection 
and other problems.  A physical exam and blood tests will be done daily.  Additional blood tests, 
medications, and procedures may be required if problems arise. 
 
After leaving the hospital, your child will need to visit the transplant clinic at least once a week 
for check-ups, blood counts, and chemistries to make sure that he/she is doing well medically.  
Eventually the visits will be less frequent.  Your child will be examined at 100 days, 6 months, 1 
year and 2 years after transplant to check your child’s progress and treat any problems.  The 
following tests will be performed during these visits:  
 
CLINICAL TESTS 
Test 
Purpose 
When Performed 
Blood Tests (1-3 tablespoons or 
10-30 ml) 
Check number of donor 
cells in your child, 
hemoglobin level, and 
recovery of immunity 
28 days, 42 days, 100 days, 180 
days, one year, and two years 
after transplant 
Lung and Heart Function 
Check the health of heart 
and lungs 
One year and two years after 
transplant 
 
 
TESTS FOR RESEARCH  
Test 
Purpose 
When Performed 
MRA/MRI Scan 
Check structure and flow of 
blood vessels in the brain 
2 years after transplant 
Neurocognitive Testing  
Detect any changes in 
memory and learning 
abilities 
2 years after transplant 
Quality of Life Questionnaire  
Check child’s quality of life 
compared to before 
transplant  
Before transplant, and 100 
days, six months, one year and 
two years after transplant 
 
You may decide to take your child out of any research test at any time. 
 
In addition to these, your doctor will decide if other tests and treatments that are not part of this 
research study are necessary for good medical care. 
 
How long will your child be in the study?  
Your child will be in the study for 2 years.  Please notify your child’s transplant doctor if you 
move or change your child’s primary care doctor so that we will be able to obtain all the 
necessary information about your child’s health.  
 

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Can your child stop being in the study?  
You can decide to stop your child’s participation at any time.  Tell your child’s doctor if you or 
your child are thinking about stopping or decide to stop.  The doctor will tell you and your child 
how to stop safely.  It is important to note that once your child receives the medicines for the 
conditioning regimen, he/she must receive the unrelated donor marrow in order for the blood 
counts to recover in a timely fashion.   
 
If you decide to withdraw your child, or your child’s doctor withdraws your child from the study, 
we will ask your permission to use all the information about your child that has already been 
collected as part of the study.  We will also ask your permission to continue to allow your child’s 
doctor to tell us about his/her progress until at least two years post-transplant.  You can choose to 
give or not to give this permission. 
 
Can the doctor who is the Principal Investigator withdraw your child from this study?   
Your child can be taken off the study (with or without your consent) for any of the following 
reasons: 
• Your child needs a medical treatment not allowed in this study 
• The investigator decides that continuing in the study would be harmful to your child 
• Your child becomes pregnant and the study treatment could be harmful to the fetus 
• The study is cancelled by the Food and Drug Administration (FDA) or the National 
Institutes of Health (NIH) 
 
What are the risks of being in this study?  
 
Catheter placement: Pain at insertion site, minor bleeding and infection may happen.  Rare side 
effects associated with this procedure include lung puncture and severe bleeding.  A chest X-ray 
or CT scan will be obtained to confirm the catheter location before it is used for the first time.   
 
POTENTIAL SIDE EFFECTS OF STUDY DRUGS  
 
The most common side effects of the treatments to be used in this study are listed below.  There 
is also the risk of very uncommon or previously unknown side effects.   
 

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Alemtuzumab 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• Fever 
• Chills 
• Anemia due to decreased 
number of red cells 
• Infection due to 
decreased number of 
white blood cells  
• Bleeding due to 
decreased numbers of 
platelets 
• Weakened immune 
system 
 
• 
Nausea 
• 
Vomiting 
• 
Diarrhea 
• 
Rash 
• 
Headache 
• 
Sweating 
• 
Back pain 
• 
Severe itching 
• 
Allergic reaction of skin 
and blood vessels 
• 
Tiredness 
• 
Loss of appetite 
• Abdominal pain 
• Dizziness 
• High blood pressure 
• Blisters 
• Pain in the muscles 
• Herpes simplex infection 
• Inflammation of the throat 
 
 
Fludarabine 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• 
Anemia due to 
decreased number of 
red cells 
• 
Infection due to 
decreased number of 
white blood cells  
• 
Bleeding due to 
decreased numbers of 
platelets  
• 
Tiredness  
• 
Nausea  
• 
Vomiting 
• 
Weakened immune 
system 
  
• Pneumonia  
• Diarrhea 
• Mouth sores 
• Skin rash 
• Fever 
• 
Swelling of hands and 
feet  
 
• 
Numbness and tingling in 
hands and/or feet related 
to irritation of nerves of 
the hand and/or feet 
• 
Changes in vision  
• 
Agitation/nervousness  
• 
Confusion  
• 
Cough  
• 
Difficulty breathing  
• 
Weakness 
• 
Severe brain injury and 
death  
 
 

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Melphalan 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• 
Loss of appetite 
• 
Nausea 
• 
Vomiting 
• 
Skin breakdown if 
drug leaks from vein 
• 
Anemia due to 
decreased number of 
red cells 
• 
Infection due to 
decreased number of 
white blood cells  
• 
Bleeding due to 
decreased numbers of 
platelets  
• 
Mouth sores 
• 
Temporary hair loss 
 
• 
Diarrhea 
• 
Inflammation of the 
lung 
• 
Weakness 
• 
Weight loss 
 
 
• 
Low blood pressure 
• 
Excessive perspiration 
• 
Allergic reaction 
• 
Damage/ scarring of lung 
tissue 
• 
Sterility 
• 
Seizure 
 
 
 
 
G-CSF (Filgastim) 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
 
• Local irritation (skin) at 
injection site 
• Ache or pain inside the 
bones.  Increased levels 
of liver enzymes and uric 
acid in the blood 
• Bleeding due to 
decreased numbers of 
platelets 
 
• Allergic reaction, low fever 
• Enlargement or rupture of 
the spleen  
• Worsening of pre-existing 
skin rashes 
• Temporary hair loss  
• Inflammation of a blood 
vessel in the skin 
 
 
 

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Potential Risk of RPLS/PRES  
The Data Safety and Monitoring Board (DSMB) of the Blood and Marrow Transplant Clinical 
Trials Network is a group of transplant, sickle cell disease and other experts that ensure the 
safety of patients treated on this and other trials.  This group carefully monitors the experience of 
patients to make sure that the side effects that they experience are not unusual or more frequent 
or more severe than would be expected.  
 
The DSMB has noted that children transplanted on the clinical trial BMT CTN 0601 have a 
higher than expected occurrence of a usually uncommon (< 5%) complication called reversible 
posterior leukoencephalopathy syndrome (RPLS) also known as posterior reversible 
encephalopathy syndrome (PRES).  Patients with RPLS/PRES have confusion and other changes 
in their ability to think.  Sometimes, they experience seizures, sleepiness or, rarely, loss of 
consciousness.  RPLS is diagnosed with an MRI of the brain.  It is a disorder that is sometimes 
seen in patients with sickle cell disease even if they do not have a transplant.  In transplant 
patients, it is usually caused by some of the drugs used to prevent or treat graft versus host 
disease.  It can often, but not always, be prevented by very careful control of blood pressure.  It 
is treated by changing graft versus host disease drugs, controlling blood pressure and/or giving 
anti-seizure medicines.  About a quarter of the patients on BMT CTN 0601 have developed 
RPLS/PRES; all were successfully treated for this complication.  Thus far, no RPLS/PRES has 
been observed in any patient more than 6 months from their date of transplant.  We believe that 
children who are on prednisone or other corticosteroids, or immunosuppressive drugs such as 
cyclosporine or tacrolimus or have high blood pressure are more likely to develop RPLS/PRES. 
 
If your child experiences any of these side effects or changes in mental status, you should 
contact your child’s transplant physician right away, since early treatment is important.  It 
is also important that any blood pressure medication be taken as prescribed to decrease the 
risk of RPLS/PRES.   
 
RISKS AND TOXICITIES RELATED TO STANDARD TRANSPLANT PROCEDURES 
 
Graft-versus-Host Disease (GVHD):  This condition results from white cells called T cells in 
the donor’s bone marrow cells recognizing your child’s body as foreign and attacking it.  Your 
child is more likely to get GVHD if the donor’s tissue type does not match your child’s tissue 
type well.   
 
There are two forms of GVHD: acute GVHD (usually occurs in the first 3 months after 
transplant) and chronic GVHD (usually occurs later and lasts longer).  Acute GVHD may 
produce skin rash, nausea, vomiting, diarrhea, abdominal pain, abnormalities of liver function 
and an increased risk of infection.  Chronic GVHD may produce skin rashes, hair loss, thickened 
skin, joint stiffness, 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 child may be asked 
to have a skin biopsy (i.e., taking a small sample of skin tissue to look at under the microscope) 
and possibly an intestinal biopsy and rarely a liver biopsy. 
 

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There is a 10-20% chance that your child will develop GVHD after the transplant.  Your child 
will be watched closely for this complication and given treatment to treat it further if it occurs 
despite the medicines given to prevent it.  In most cases, GVHD can be successfully treated.  If 
GVHD does not respond to the medicines listed above, treatment can involve combinations of 
many other medicines with different side effects.  Treatment may be necessary for many years as 
GVHD symptoms can last for many months or years.  Prolonged treatment for chronic GVHD 
can result in a weak immune system and infections and may need frequent medical care and 
hospitalization.  Sometimes GVHD is severe or difficult to treat and may lead to death.  
 
SIDE EFFECTS OF MEDICINES USED TO PREVENT GVHD 
 
The side effects listed below are usually reversible once the medicines are discontinued. 
 
Cyclosporine: This drug may be used for all patients. 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• 
High blood pressure 
• 
Kidney problems 
• 
Headaches 
• 
Nausea 
• 
Vomiting 
• 
Stomach pain or 
indigestion 
• 
Swelling of the hands 
or feet 
 
• 
Tremors 
• 
Increased hair growth 
 
• 
Muscle cramps 
• 
Numbness and tingling of 
the hands or feet 
• 
Seizure 
 
 

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Tacrolimus: This drug may be used for all patients. 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• 
Anemia 
• 
Loss of appetite 
• 
Diarrhea 
• 
High potassium levels 
• 
High blood pressure 
• 
Nausea 
• 
Fever 
• 
Headache 
• 
High blood sugar 
 
• 
Hair loss 
• 
Vomiting 
• 
Tingling sensation in 
the extremities 
• 
Itching 
• 
Rash 
• 
Abdominal pain 
 
 
• 
Confusion 
• 
Painful joints 
• 
Increased sensitivity to 
light 
• 
Blurred vision 
• 
Insomnia 
• 
Infection 
• 
Jaundice 
• 
Kidney injury 
• 
Seizures 
 
 

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Methotrexate: This drug will be used as part of GVHD prophylaxis Regimen 1 for bone marrow 
recipients. 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• 
High levels of liver 
enzymes 
 
• 
Nausea 
• 
Vomiting 
• 
Loss of appetite 
• 
Diarrhea 
• 
Mouth sores 
• 
Sensitivity to sunlight 
• 
Increased risk of 
sunburn 
• 
Decreased number of 
red and white blood 
cells and platelets 
 
• 
Hair loss 
• 
Dizziness 
• 
Redness, tenderness, 
darkening, and peeling of 
skin 
• 
Blurred vision 
• 
Allergic reaction 
• 
Damage to nerve tissue 
• 
Kidney damage 
• 
Seizures 
• 
Decreased lung function 
• 
Decreased liver function - 
temporary 
• 
Bone and tissue damage 
• 
Loss of memory, 
concentration, balance, 
and walking 
• 
Poor nervous system 
function 
 
 

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Methylprednisolone: This drug will be used as part of GVHD prophylaxis Regimen 1 for bone 
marrow recipients. 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
• 
Water retention 
• 
Overeating 
• 
Weakened immune 
system 
• 
Temporary personality 
changes 
• 
Abnormal hormone 
production 
• 
High blood sugar 
• 
Slowed growth 
• 
Decreased bone density 
• 
Headaches  
• 
Poor wound healing 
• 
Stomach swelling or 
pain 
• 
Tissue swelling 
• 
High blood pressure 
• 
Stomach ulcer 
• 
Muscle weakness 
• 
Cataracts 
 
• 
Difficulty in falling asleep 
• 
Worsening of diabetes 
• 
Inflammation of pancreas 
• 
Personality disturbances 
• 
Bleeding in the stomach 
and intestines 
• 
Increased pressure within 
the eye 
• 
Disturbance of bone 
calcium which can lead to 
possible fractures or 
permanent bone damage 
 
 
 
Damage to the vital organs in your body.  The conditioning or GVHD treatment could result in 
problems in the heart, lungs, liver, intestine, kidneys and bladder, brain etc.  Lung problems can 
be the result of infections or chemotherapy.  Some patients can have veno-occlusive disease of 
the liver (VOD).  This complication usually results from high doses of chemotherapy.  Patients 
with VOD become jaundiced (yellowish skin), have liver function abnormalities, fluid retention, 
abdominal swelling, and abdominal pain.  If organ damage symptoms are severe, your child may 
have to stay in the hospital longer or be re-hospitalized after transplant.  Although many patients 
recover completely, these complications may cause permanent damage or even death. 
 
Serious infections.  Full and complete recovery of your child’s immune system may take many 
months following the initial recovery of your child’s cell counts.  During this time, there is an 
increased risk of infections.  Your child will be prescribed certain medications to reduce the 
chance of those infections.  However, preventive treatments are not always effective.  If your 
child has an infection, he/she may have to stay in the hospital longer or be re-hospitalized after 
transplant.  Although most infections can be successfully treated, some infections are fatal. 
 
Recurrence of disease and graft rejection.  Since the study uses a conditioning treatment 
regimen of reduced intensity, it may not allow donor cells to grow and your child may partially 
or fully reject the donor’s bone marrow.  If this happens, your child’s blood cells will grow back 
again and the severe sickle cell disease may persist or come back even if the transplant is initially 
successful. 
 

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Central venous catheter complications.  The most common complications associated with 
central venous catheters are blood clots in the catheter and infection.  If clots form, a medicine will 
be injected to dissolve the clot.  If it cannot dissolve, the catheter may need to be replaced.  
Infections will be treated with medicines; sometimes, removal of the infected catheter is required 
and a new catheter will need to be placed.   
 
Impact on reproductive hormone function and sexuality.  High doses of chemotherapy can 
cause sterility (inability to have children) and decreased hormone levels.  Some patients with 
chronic GVHD have reported impaired sexual function due to decreased sexual desire and vaginal 
dryness.  Since the chemotherapy doses used in the preparative regimen for this study are lower, 
the risk of sterility may be lower.  Some patients treated with this preparative regimen have had 
children after their transplant.  However, it is difficult to know the exact risk of sterility after 
transplant with the use of this conditioning regimen.  
 
Risk of death.  Some of the side effects of an unrelated donor transplant may be very severe and 
may cause death of the recipient despite using all supportive care.  Though all precautions will be 
taken to make the transplant as safe as possible for your child, there is still a 10% chance of the 
patient’s death following unrelated donor transplantation. 
 
Quality of life surveys.  Completion of the quality of life surveys will not cause you or your 
child any physical discomfort, although it is possible that you or your child will find some of the 
questions or topics upsetting.  You or your child may experience emotional distress or feel a loss 
of privacy.  If you do, there will be someone available to speak with you and your child.  They 
will be able to refer you to appropriate counselors or other support people.   
 
Are there benefits to taking part in the study?  
Your child may or may not benefit from taking part in this study.  If the transplant is successful, 
your child may benefit by not having further symptoms and complications of severe sickle cell 
disease.  The information obtained from your child’s participation in this study will help doctors 
treat future patients with severe sickle cell disease who require a transplant using unrelated donor 
bone marrow.  
 
What are the costs of taking part in this study?   
Most of the care given in this study is standard care; it will be billed to you or your child’s 
insurer in the usual way.  Standard costs include those of your child’s hospitalization, doctor's 
visits, standard laboratory tests, medications, and the cost of the donor’s bone marrow.  There 
will be no charge for research tests.   
 
What happens if your child is injured because of participation in this study?   
In the event that this research activity results in an injury, treatment will be available, including 
first-aid, emergency treatment and follow-up care as needed.  Care for such injuries will be billed 
in the ordinary manner, to your child’s insurance company.  If you or your child thinks that your 
child has suffered a research-related injury, let the study doctors know right away.  It is 
important that you tell your child’s doctor, __________________ [investigator's name], if you 
or your child feel that your child has been injured because of taking part in this study.  You can 

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tell the doctor in person or call him/her at __________________ [telephone number].  Your 
child will receive medical treatment if injured as a result of taking part in this study.  You or your 
child’s insurance will be charged for this treatment.   
 
What are your child’s rights if your child takes part in this study?  
You may choose to allow your child to either take part or to not take part in the study.  If you 
decide to allow your child to take part in this study, your child may leave the study at any time.  
No matter what decision is made, there will be no penalty and your child will not lose any of his 
or her regular benefits.  If your child leaves the study, he/she can still get medical care from your 
child’s doctor and transplant center.  We will tell you and your child about new information or 
changes in the study that may affect your child’s health or your willingness to continue in the 
study.  In the case of injury resulting from this study, your child does not lose any legal rights to 
seek payment by signing this form.  
 
Who can answer your and your child’s questions about the study?   
You and your child can talk to your child’s doctor about any questions or concerns about this 
study.  Contact your child’s doctor __________________ [name(s)] at ______________ 
[telephone number]. 
 
For questions about your child’s rights while taking part in this study, call the __________[name 
of center] Institutional Review Board (a group of people who review the research to protect your 
child’s rights) at __________________ (telephone number).  
 
Will your child’s medical information be kept private?   
We will do our best to make sure that the personal information in your child’s medical record be 
kept private.  However, we cannot guarantee total privacy.  Your child’s personal information 
may be given out if required by law.  If information from this study is published or presented at 
scientific meetings, your child’s 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 your child.  At most, 
the Web site will include a summary of the results.  You can search this Web site at any time. 
 
Organizations that may look at and/or copy your child’s medical records and protected health 
information for research, quality assurance, and data analysis include: 
• 
Members of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), 
which is conducting this study 
• 
The EMMES Corporation, a research organization that is helping to coordinate this study 
• 
The National Marrow Donor Program (NMDP) and the Center for International Blood 
and Marrow Transplant Research (CIBMTR), organizations involved in research on 
blood and marrow transplantation and in the coordination of this study 
• 
The National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute 
(NCI) and other government agencies, like the Food and Drug Administration (FDA), 
involved in keeping research safe for people 

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• 
The Sickle Cell Disease Clinical Research Network (SCD CRN) 
• 
Researchers and staff members at Washington University for central review of MRI 
images 
 
Expiration date for retention of records: 
The study results will stay in your child’s research record at (insert Institution) for at least six years 
or until after the study is completed, whichever is longer.  At that time either the research 
information not already in your child’s medical record will be destroyed or your child’s name and 
other identifying information will be removed from such study results.  Research information in 
your child’s medical record will be kept indefinitely. 
 
How will the researcher(s) benefit from your child being in this study? 
In general, presenting research results helps the career of a scientist.  Therefore, the Principal 
Investigator may benefit if the results of this study are presented at scientific meetings or in the 
scientific press.  In addition, the sponsor (the NIH) is paying the Principal Investigator to conduct 
this study.  The investigators have no financial interest in the drugs used in the study. 
 
HIPAA1 authorization to use and disclose individual health information for research 
purposes: 
 
a. Purpose:  As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my child’s individual health information for the 
purpose of conducting the research study entitled Unrelated Donor Hematopoietic Cell 
Transplantation for Children with Severe Sickle Cell Disease Using a Reduced Intensity 
Conditioning Regimen. 
 
b. Individual Health Information to be Used or Disclosed: My child’s individual health 
information that may be used or disclosed to conduct this research includes: demographic 
information (e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, 
complications with prior treatment), physical examination findings, and laboratory test 
results obtained at the time of work up and after transplantation (e.g., blood tests, biopsy 
results).  The identities of individuals such as names and addresses will not be shared or 
de-identified to make sure information cannot be linked to you. 
 
c. Parties Who May Disclose My Child’s Individual Health Information: The researcher and 
the researcher’s staff may obtain my child’s (my) individual health information from: 
(list: hospitals, clinics or providers from which health care information can be requested) 
 
 
 
 
 
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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d. Parties Who May Receive or Use My Child’s Individual Health Information: The 
individual health information disclosed by parties listed in item c and information 
disclosed by my child during the course of the research may be received and used by the 
following parties: 
• Members of the BMT CTN Data and Coordinating Center and BMT CTN #0601 
Protocol Team 
• National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH), study sponsors  
• The National Marrow Donor Program and the Center for International Blood and 
Marrow Transplant Research 
• 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 Sickle Cell Disease Clinical Research Network (SCD CRN) 
 
 
 
 
e. Right to Refuse to Sign this Authorization: I do not have to sign this Authorization.  If I 
decide not to sign the Authorization, my child will not be allowed to participate in this 
study or receive any research-related treatment that is provided through the study.  
However, 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 the 
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 my child (me) will be collected by or disclosed to the researcher for 
this study. 
g. Potential for Re-disclosure: My child’s individual health information disclosed under this 
authorization may be subject to re-disclosure outside the research study and no longer 
protected.  Examples include potential disclosures for law enforcement purposes, 
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities 
and public health measures. 
h. This authorization does not have an expiration date.  However, you can elect at any time 
to withdraw your authorization to participate in the study. 
 

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You will receive a copy of this form.  If you (or your child) need more information about this 
study, ask the study doctor. 
 

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************************************************* 
SIGNATURE 
 
I have read the information in this consent form and have had the study explained to me.  
My questions have been answered to my satisfaction.  I agree to allow my child to 
participate in the study. 
 
 
_________________________________________________  
_______________ 
Signature of Subject’s Mother/Guardian 
  
Date 
 
 
_________________________________________________  
 
Printed Name of Subject’s Mother/Guardian 
 
 
_________________________________________________  
_______________ 
Signature of Subject’s Father/Guardian 
  
Date 
 
 
_________________________________________________  
 
Printed Name of Subject’s Father/Guardian 
 
 
_________________________________________________ 
Signature of Patient/Study Subject (if greater than or equal to 18 years of age) 
 
 
_________________________________________________ 
Printed Name of Patient/Study Subject (if greater than or equal to 18 years of age) 
 
I certify that the nature and purpose, the potential benefits, and possible risks associated 
with participation in this research study have been explained to the above individual(s) and 
that any questions about this information have been answered. 
 
_________________________________________________ 
_______________ 
Signature of Physician Obtaining Consent 
  
Date 
 
 
_________________________________________________ 
Printed Name of Physician Obtaining Consent  

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Assent to Participate in Research (Ages 7 to 11 years old) 
 
Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children  
with Severe Sickle Cell Disease  
 
You are being invited to be in a research project.  This research project is about seeing if 
transplants can help children who have severe sickle cell disease.  People with sickle cell disease 
do not make healthy red blood cells.  In this research project, doctors will see if a bone marrow 
transplant can help children with sickle cell disease make healthy red blood cells.  You should 
talk to your parents about this research project.  If you have questions, ask your parents or your 
doctor. 
 
Before the transplant, your doctors will give you medicines so that your body will let the new 
cells grow.  These medicines are not as strong as the ones that have been used before and are 
called reduced intensity medicines.  The medicines may make you throw up, lose your hair or 
have mouth sores.   
 
After the medicines, you will get a transplant of new cells from an unrelated donor.  An 
unrelated donor is a person you do not know.  The cells will come from the donor's bone 
marrow. The cells should make new and healthy red blood cells in your body.  Sometimes the 
donor’s cells can cause a problem called GHVD.  GVHD can give you diarrhea, a skin rash, or 
make you not feel hungry.  Your doctors will give you medicines to try to make sure that you 
don’t get GVHD.  Sometimes the donor cells may not establish themselves and grow in your 
body.  If donor cells are rejected from your body, your own blood cells will grow again and your 
sickle cell disease problems will come back. 
 
You will stay in the hospital for several days before your transplant and for about four weeks 
after your transplant.  After you go home, you will need to go back to see your doctors often.   
 
You don't have to be in this research project.  Your doctors and nurses will not be mad at you if 
you don't want to be in the research project.  If you decide you don't want to be in this research 
project, you should talk to your doctor and parents about other things to do for your disease.  
 
Sign your name on the line below if you want to be in this research project.  You can keep a copy 
of this form at home. 
 
______________________________________________  ______________________________ 
Minor’s Signature 
Date 
 
______________________________________________  ______________________________ 
Print Name of Minor 
Age of Minor 
 
Certification of Counseling Healthcare Professional: I certify that the nature and purpose, the 
potential benefits, and possible risks associated with participation in this study have been 

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explained to the above individual and that any questions about this information have been 
answered. 
 
______________________________________________  ______________________________ 
Counseling Healthcare Professional 
Date 

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Assent to Participate in Research (Ages 12 to 17 years old) 
 
Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children  
with Severe Sickle Cell Disease  
 
Patients with sickle cell disease have a defect in hemoglobin.  Hemoglobin is a protein in red 
blood cells (RBCs) that carries oxygen to vital organs such as the brain, heart, lungs and kidneys.  
When hemoglobin is damaged the RBCs are sticky and look like a sickle.  The damaged RBCs 
cannot flow well through blood vessels, and block oxygen and nutrients from reaching organs.  
This can damage almost all the organs in the body.  It is especially bad when vital organs are 
involved.   
 
Recent studies have shown that a bone marrow transplant from a brother or sister can replace the 
damaged RBCs with healthy red blood cells.  Because of the risks of a bone marrow transplant, 
transplants are usually only given to patients with severe complications.  Usually a bone marrow 
transplant is only done if the patient has a brother or sister as a donor who has the same ‘tissue’ 
type.  Before a transplant, patients receive high doses of chemotherapy called conditioning to 
allow donor cells to grow in the patient.  Since most patients with severe sickle cell disease do 
not have a brother or sister with the same tissue type, they do not receive a transplant.  These 
patients often receive medicines and red cell transfusions to try to control symptoms and organ 
damage.  These treatments may be given for many years.  
 
This is a research study of unrelated donor transplantation in patients with severe sickle cell 
disease.  There will be as many as 30 patients with sickle cell disease participating in this 
research study.  It is being done to learn if the intensity of the conditioning can be reduced to 
reduce the side effects or toxicities and if bone marrow transplants from unrelated donors can 
help patients with sickle cell disease make healthy red blood cells.  In this study, patients who do 
not have a brother or sister with the same tissue type can receive a transplant from an unrelated 
donor.  The cells for the transplant can come from bone marrow.  Bone marrow cells are donated 
by volunteers who agree to donate some of the cells made in their bone marrow.   
 
You are being invited to join this research study because you have severe sickle cell disease. 
Because your red blood cells cannot flow well through your blood vessels, this has caused 
problems with your brain, lungs, or other parts of your body.  That is the reason that you have 
pain, breathing difficulties or weakness.  Your doctors think that a transplant may be an option 
for you.  
 
This form gives you information to help you decide if you want to be in this study.  You should 
read this form and ask any questions you have before agreeing to be in the study.  It is up to you 
to decide if you want to be in the study.   
 

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What other choices do I have if I do not take part in the study? 
If you decide not to participate in this study, your doctor will discuss other treatment options 
with you and your parents.  Other choices may include: 
• Treatment with drugs such as hydroxyurea that can lessen complications of severe sickle 
cell disease 
• Experimental treatments with new drugs for severe sickle cell disease 
• A transplant using bone marrow without being part of this study  
• Other treatments such as regular RBC transfusions to try to control symptoms related to 
your severe sickle cell disease  
 
Why is this study being done?   
This research study is being done to answer the following questions: 
1. Is it safe to do a transplant in patients who have severe sickle cell disease using bone 
marrow from healthy unrelated donors?   
2. Is a “reduced intensity” transplant effective and safe in performing unrelated donor 
transplants?  This “reduced intensity” approach will use a new combination of drugs at 
reduced doses compared to those previously used for traditional transplants.  
3. After the transplant, will the patients with severe sickle cell disease make healthy red 
blood cells and be protected from health problems of severe sickle cell disease?   
 
What will happen if I take part in this research study?   
 
Before enrolling on study: 
Your doctor will check to see if you have a type matched bone marrow donor available for your 
transplant.   
 
Before the transplant: 
You will have several tests done to check your organ function.  These tests will check your heart, 
lungs, and brain. Most of these tests are X-rays or scans, questions, or blood tests.  The doctors 
will look at the results of all these tests to make sure that it is okay for you to have a transplant.   
 
A central line will be placed in your chest in the operating room (you will be asleep for this).  A 
central line makes it easier for you to receive drugs and for drawing blood for tests (you will not 
be poked for blood tests or receive shots).   
 
Preparation for the transplant: 
Before the transplant, you will need to receive medicines so that your body can accept the new 
bone marrow cells.  This is called a ‘preparative regimen.’  Before the transplant, you will be 
given 3 drugs.  You will get the first drug called alemtuzumab for 4 days about 3 weeks before 
your transplant.  You will go home and return to the hospital to stay 8 days before your 
transplant.  At that time you will get two more drugs called fludarabine and melphalan.  All these 
drugs are given through your central line.  
 
Three days before the transplant, you will also get medicines to suppress your immune system.  

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These medicines are given to allow the donor cells to grow.  There are many drugs that can be 
used to suppress your immune system.  The names of these medicines are tacrolimus, 
methylprednisolone/prednisone, methotrexate, and cyclosporine.  
 
Bone marrow - infusion of cells: 
Bone marrow from an unrelated donor will be used for the transplant.  These cells will be given 
through the central venous catheter, just like a blood transfusion.  On the day of your transplant, 
the new bone marrow cells will be given through your central line.  
 
Post-transplant follow-up and care:  
After the transplant you will continue to get medicines to help the donor cells grow.  These drugs 
will also help lower the chance of getting graft versus host disease (GVHD).  GVHD is a 
complication that happens when the donor’s cells attack your body. You will receive one or more 
medicines to prevent GVHD.  You will continue to receive these drugs for at least 6 months after 
the transplant.  
 
You will be in the hospital for about four weeks after your transplant.  You will be allowed to go 
home from the hospital when your doctor feels it is safe.  After you go home you will need to 
return to visit your doctors so they can check your recovery.  Your doctors will need to check 
your blood and bone marrow after the transplant to make sure the new blood cells are growing in 
your body.  Your doctors will also do blood tests and other tests to make sure your organs are 
working well. When blood is needed for these tests it will be drawn through the central line. 
 
Can the doctor who is the Principal Investigator withdraw me from this study?   
You can be taken off the study (with or without your consent) for any of the following reasons: 
• You need a medical treatment not allowed in this study 
• The investigator decides that continuing in the study would be harmful to you 
• You become pregnant and the study participation could be harmful to the fetus 
• The study is cancelled by the Food and Drug Administration (FDA) or the National 
Institutes of Health (NIH) 
 
What are the risks of being in this study?  
The drugs may cause a skin rash, hair loss, nausea and vomiting, diarrhea and infections. Your 
blood counts will fall and you may get fevers, infections or start bleeding.  You may also get 
mouth sores.  These are temporary and you will feel better as your new bone marrow grows.   
 
Since you will not be able to fight infections while your new bone marrow is growing back, you 
may need to get antibiotics.  You may also need to get blood transfusions since your new bone 
marrow will not be making new blood cells right away.   
 
Even with medicines to prevent it, you may get GVHD.  This can cause skin rash, vomiting, 
diarrhea, stomach pain, lung and liver problems, swelling of the hands and feet, dry eyes, stiff 
joints, and tiredness.  These problems are usually mild but can become very serious and 
prolonged. Medicines are given to prevent GVHD during and after transplant.  If GVHD occurs 
even after taking these medicines, other medicines will need to be started and hospital stays may 

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be necessary. The medicines used to treat GVHD also have side effects.  They can cause 
tiredness, depression, sleep problems and mood swings.  They can also make you get severe 
infections very easily.  Your doctors will do their best to make you feel better and keep you safe.  
Often this may require many hospital stays.  However, it is important to understand that there is a 
small risk (about a 1 in 10 chance) that you may die as a result of one or more of the 
complications of unrelated donor transplantation.   
 
It is possible that instead of new bone marrow, your old red blood cells will grow back.  If it 
does, you will continue to have severe sickle cell disease and its problems.  
 
Are there benefits to taking part in the study?  
You may or may not benefit from taking part in this study.  If the transplant is successful, you 
may benefit by not having further symptoms and complications of severe sickle cell disease.  The 
knowledge gained from this study may help other patients with severe sickle cell disease.  
 
What are your rights if you decide to take part in this study?  
It is up to you if you want to participate in this research study.  If you leave the study you can 
still get medical care from your doctor and transplant center.  You will be told about new 
information or changes in the study that may affect your health or your willingness to continue in 
the study.   
 
Will your medical information be kept private?   
We will do our best to make sure that the personal information in your medical record be kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given 
out 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.  
 
You will receive a copy of this form.  If you need more information about this study, ask the 
study doctor. 
 

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************************************************* 
Minor’s Assent 
 
I have read the information in this consent form and have had the study explained to me.  My 
questions have been answered to my satisfaction.  I agree to participate in the study. 
 
______________________________________________ 
_____________ 
Signature of Minor 
 
 
 
 
 
 
Date 
 
___________________________________________ 
_____________ 
Print Name of Minor 
Age of Minor 
 
 
Certification of Counseling Healthcare Professional 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
participation in this study have been explained to the above individual and that any questions 
about this information have been answered. 
 
______________________________________________ 
_____________ 
Counseling Healthcare Professional  
 
 
             Date 
 

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APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
Red Blood Cell Pit Score Studies 
 
Pitted red cell count: Blood samples will be drawn from recipients within 60 days of 
conditioning, fixed in formalin, and sent to Children’s Hospital of Oakland for central analysis. 
Testing will be repeated 2 years post-transplant in similar fashion to assess splenic function, and 
samples will be processed as described below: 
 
SAMPLE COLLECTION AND SHIPPING INSTRUCTIONS 
 
Children’s Hospital Oakland will provide the collection tubes.   
Please keep tubes refrigerated until use. 
 
To collect sample: 
• Immediately after blood draw, add one small drop (about 30 µl) of whole EDTA blood to 
collection tube.  Please DO NOT add more than one (1) small drop.  Make sure blue cap 
is on securely.   
• MIX GENTLY BUT THOROUGHLY.  If this is not done, cells will clump together and 
sample will be unreadable.   
• Store at 4°C.   
 
To ship sample: 
Ship overnight Monday through Thursday (for receipt Tuesday through Friday) in Styrofoam 
box with WET ice to:  
Attn:  Mahin Azimi, MT 
Hemoglobinopathy Lab – Rm 202 
Children’s Hospital Oakland 
747  52nd Street 
Oakland, CA 94609 
(510) 450-7688 
 
• Be sure and mark outside of box: DO NOT FREEZE. 
• Please notify Mahin Azimi, MT prior to sending samples. 
 
 
 

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APPENDIX D 
 
LANSKY/KARNOFSKY PERFORMANCE STATUS SCALES 
 
 
 
LANSKY SCALE < 16 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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KARNOFSKY SCALE ≥ 16 YEARS 
 
 
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 E 
 
ELIGIBILITY REVIEW PANEL 
 
 
Patients will be screened for protocol eligibility by a five-member review panel composed of 
experts in hemoglobinopathies and transplantation.  Approval for transplant is based on data 
contained in the patient registration and pre-transplant forms, as well as in supporting 
documentation.  If the majority of panel review members and the Principal Investigators agree 
that a patient meets eligibility criteria, the Protocol Coordinator will contact the Transplant 
Center Coordinator and confirm that the patient can be enrolled.   
 
The Review Panel will include: hemoglobinopathy experts, Dr. George Buchanan (Dallas), Dr. 
Jim Eckman (Emory, Atlanta), Dr. Alexis Thompson (Northwestern Chicago); and, transplant 
physicians Dr. John DiPersio (St. Louis) and Dr. Catherine Wu (Boston).  Review materials will 
be sent to the panel at least two weeks prior to enrollment to confirm eligibility.  A panel 
member will recuse him/herself if a patient from his/her center is being discussed. 
 
HLA typing will be reviewed by the Protocol Chairs and Protocol Officer to determine that the 
patient and donor are appropriately HLA-matched. 
 

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APPENDIX F 
 
HEALTH-RELATED QUALITY OF LIFE ASSESSMENT 
 
 
The CHQ Parent Form 50 and Child Form 87 health-related QOL measures will be administered 
pre-transplant, at Day 100, 6 months, 1 year, and 2 years post-transplant to all parents of 
children 5 years of age or greater and to children greater than 10 years of age78, 79.  The forms 
will be self completed by the parent and/or child during the routine clinic visit.  It is expected 
that it will take approximately 20 minutes for the parents to complete the form and 30 minutes 
for the child. 
 
Child Health Questionnaire Parent Form 50: To be administered to all parents with children who 
are 5 to 18 years of age at the time of the QOL assessment.   
 
Child Health Questionnaire Child Form 87: To be administered to all children who are 10 to 18 
years of age at the time of the QOL assessment.  The form is intended to be self completed by 
the child without help from the parent.  If the child needs help completing the survey, this should 
be done with the aid of a research assistant who can read the questions and responses to the 
child.  
 
The information below from the User’s Manual of the CHQ should aid in administering the 
questionnaires.  
 
ADMINISTERING THE CHILD HEALTH QUESTIONNAIRE 
(From Landgraf, Abetz, and Ware, Child Health Questionnaire (CHQ): A User’s Manual, 1999) 
 
The Child Health Questionnaire (CHQ) is intended to be completed by the individual without the 
help of an administrator.  The administrator should present the importance of the questionnaire 
and why their responses to the questions will be helpful in understanding the quality of life of 
children with silent stroke.  The administrator should also ensure the questionnaires are 
completed and done correctly. 
 
The CHQ is designed to be able to be read and understood by all those with a 3rd grade reading 
level.  If the person completing the questionnaire is not able to read at this level, the form should 
be read to them using the interview script designed for the questionnaire (please see Interview 
Script section). 
 
Each questionnaire should contain a unique identifier (this should be the subject’s study ID 
number) that will be used to keep the information confidential yet linked to each study subject.  
 

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INTRODUCING THE CHQ 
 
Spouses, or other family members, or visitors, should not assist parents in completing the CHQ. 
 
The CHQ was designed to provide reliable information about the everyday functioning and well-being of 
children in ways that matter most to them and their families.  The CHQ asks questions about your child’s 
physical wellness, his/her feelings, behavior, and activities at school and with family and friends.  The 
parent-completed CHQ also asks a few questions about you. 
 
The CHQ is simple to complete. Be sure to read the instructions [point to them].  The CHQ contains 
questions that ask how you feel.  Remember, there are no right or wrong answers.  This is not a test.  
Choose the response that best represents the way you feel. Please do not share or compare responses 
with your child or other family members. 
 
Please fill out the questionnaire now.  I will be nearby in case you want to ask me any questions.  Return 
your completed questionnaire to me. 
 
 
ADMINISTERING AND COMPLETING THE HEALTH QUESTIONNAIRE 
 
Provide a firm writing surface such as a clipboard or tabletop.  Provide a number 2 pencil. 
 
When the parent returns the CHQ, check the questionnaire for completeness.  Note whether the 
questionnaire is complete by simply scanning the pages of the questionnaire.  If it is not complete, bring 
the missing section or questions to the respondent's attention.  If they chose not to answer a series of 
questions, gently encourage them to do so.  If there are more than half of the items missing for a scale the 
data will be discarded and it will not be possible to calculate their responses.  If the parent/child has an 
objection or difficulty completing any items or sections, simply record their reason(s) for non-completion.  
Never force someone to answer if they do not feel comfortable doing so on their own 
 
Closing 
 
Be sure to put the completed questionnaires in a safe and secure place to ensure confidentiality. 
 
Finally, thank the parent using the following exit script (or a variation appropriately reworded to sound 
more like your style of speech): 
 
Thank you for taking the time to complete this questionnaire.  You will complete this questionnaire again 
at the end of the study. 
 
 
ADDRESSING PROBLEMS AND QUESTIONS 
 
What to do if the CHQ parent doesn’t want to complete the CHQ? 
If the parent is able to self-administer the CHQ but declines to participate, tell the parent that its 
completion is voluntary.  They are being asked to complete the CHQ because it will provide helpful 
information for clinicians, school nurses, teachers, and others.  The goal is to better understand the 
physical, mental, and social health problems of children 
 

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Emphasize that this information is as important as any of the other medical information.  Responses are 
essential so that a complete picture of the child's health and its effect on the parent and family may be 
obtained.  Emphasize that the CHQ is simple to complete.  Suggest that it is possible that this 
questionnaire is different from others they have filled out in the past, and that they may even enjoy 
completing it.  If parent still declines, retrieve the CHQ, record the reason for the decline, and thank the 
parent 
 
What to do if the CHQ parent starts to complete the CHQ, but doesn’t want to finish? 
If non-completion is a result of the parent having trouble understanding particular items, ask the 
parent/child to explain the difficulty.  Reread the question for them verbatim, but do not rephrase the 
question.  If the parent is still unable to complete the CHQ, accept it as incomplete, and indicate on the 
CHQ itself that the parent was unable to complete the questionnaire due to difficulty understanding 
questions. 
 
If the parent is unable to self-administer the questionnaire, document the reason.  If the reason is health 
related, indicate the specific physical problem/condition. 
 
What to do if the CHQ parent is concerned that someone will look at their answers? 
Emphasize that all parents' responses to the CHQ are to be kept confidential.  You are not allowed to read 
the responses other than to check that all responses are answered.  Point out that their names do not 
appear anywhere on the questionnaire, so that their results will be linked with an ID number and not their 
name.  If this is for a clinical study, tell parents that their answers to the questionnaire will be pooled with 
other parents' answers and that they will be analyzed as a group rather than as individuals 
 
What to do if the CHQ parent asks the meaning of an item? 
While completing the questionnaire, some parents might ask the meaning of specific items so that they 
can better understand and respond, if this happens, you can assist the parent/child by rereading the 
question for them verbatim.  If the parent/child asks you to interpret the meaning of an item, do not try to 
explain it, but suggest that he/she use his/her own interpretation of the question.  All parents should 
answer the questions based on what they think the questions mean. 
 
Sometimes parents may have trouble with the response choices.  They may say "I don't know" or 
something different than what is stated on the questionnaire.  In these circumstances, it is important to 
gently guide the parent to respond in one of the pre-set categories by saying something like: 
 
“I know that it may be hard for you to think this way, but which of these categories most 
closely expresses what you are thinking or feeling?" 
 
If the parent does not like a question, or thinks it is unnecessary or inappropriate, emphasize that all 
questions in the CHQ are very important and included for different reasons.  They should try to answer all 
of the questions. 
 
Rewording items, paraphrasing or interpreting items for the parent can bias results.  Thus, it is important 
that differences in answers due to rewording of items be minimized.  If the parent has difficulty 
completing the CHQ and you feel you cannot address their concerns adequately with the instructions and 
guidance provided, thank them, retrieve the CHQ, and record the difficulty 
 

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What to do if the CHQ parent wants to know the meaning of their answers? 
If a parent asks you to interpret responses or asks for a "score" on the CHQ, tell him/her that you are not 
trained in interpreting or scoring the information. Emphasize that their responses are to be kept 
confidential. You are not allowed to read the responses other than to check that all responses are 
answered. If this is for a clinical study, tell parents that their answers to the questionnaire will be pooled 
with other parents' answers and that they will be analyzed as a group rather than as individuals. 
 
What to do if the CHQ parent asks why they must fill out the CHQ additional times? 
Optional - only appropriate in situations or studies with multiple administration of the CHQ. 
 
Explain to the parent that the reason they are being asked to complete the CHQ more than once is 
to determine if the child's health or well-being has changed over time.  Monitoring changes 
provides a more complete and appropriate representation of the child's health and its impact on 
their everyday functioning and well-being and that of their family 
 

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CHQ ADMINISTRATION DO'S AND DO NOT'S 
 
DO’s 
DO NOT’s 
Do check to make sure that all items, response 
choices, and scales on your questionnaire are the 
verbatim replicas of the CHQ before fielding 
your questionnaire 
Do not reorder items, response choices, or scales 
in the CHQ 
Do have the parent answer, the CHQ before 
they fill out any health data forms and they see 
their physicians (if appropriate)  
Do not discuss the child's health, or emotions 
with the child or parent before they complete the 
CHQ 
Do be warm, friendly, and helpful 
Do not minimize the importance of the CHQ 
Do request and encourage the parent to 
complete the CHQ 
Do not force or command the parent to complete 
the CHQ 
Do read and repeat a question verbatim for the 
parent/child 
Do not interpret or explain a question 
Do tell the parent to answer a question 
based on what they think the question 
means 
Do not accept an incomplete questionnaire 
without first encouraging the parent to fill out 
unanswered questions 
Do have the parent fill out the CHQ by 
themselves 
Do not allow spouses or family members to help 
the parent fill out the CHQ 
Do encourage the parent to complete all 
questions 
Do not force or command the parent to complete 
a particular question 
Do thank the parent for completing the CHQ 
 
Optional: Do inform parent that they will be 
asked to complete the CHQ more than once-at 
the beginning and end of the study 
 
 
 
 
 

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APPENDIX G 
 
NEUROCOGNITIVE TESTING 
 
 
Neurocognitive assessment: Age-appropriate neurocognitive evaluation will be performed in all 
patients prior to, and 2 years after transplant to document effects of transplant on cognitive 
function.  If a patient has crossed age groups between two testing periods, the child will be 
administered the same battery of tests completed at pre-screening but at the age-appropriate 
level.  Please see the CRFs for the sub tests of each tool. 
 
Time scheduled for each assessment: 2 hours 
 
For children ≥ 6 years: Wechsler Abbreviated Scale of Intelligence (WASI) (Block Design, 
Similarities, Matrix Reasoning, Vocabulary), Continuous Performance Test-Second Edition 
(CPT-II), Berry-Buktenica Developmental Test of Visual-Motor Integration (VMI), Children’s 
Memory Scale (CMS), California Verbal Learning Test (CVLTC), Adaptive Behavior system-
Second Edition (ABAS-II), and BRIEF.  
 
Age 4 and 5 years: Wechsler Preschool and Primary Scale of Intelligence (WIPPSI-III) (Block 
Design, Information, Matrix Reasoning, Vocabulary, Picture Concepts, Word Reasoning), 
ABAS-II, VMI, and BRIEF-P (parent to complete).  
 
Age 3 years: Wechsler Preschool and Primary Scale of Intelligence (WIPPSI-III) (Receptive 
Vocabulary, Block Design, Information, Object Assembly, Picture Naming, ABAS-II, VMI, and 
BRIEF-P (parent to complete). 
 

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APPENDIX H 
 
CRANIAL MAGNETIC RESONANCE IMAGING (MRI) 
PROTOCOL 
 
 
Cranial Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) will 
be performed within 30 days of commencing conditioning for transplant according to this 
protocol.  A similar scan will be repeated at 2 years post-transplant to evaluate change in 
previously existing lesions or identify and define the presence of any new onset lesions. 
 
Preparing MRI Imaging CD 
Images will be saved to CDs in Digital Imaging and Communications in Medicine (DICOM) 
format.  DICOM is a standard format for handling, storing, printing, and transmitting 
information in medical imaging.  The imaging CD will be shipped with a copy of the patient’s 
signed informed consent form to Washington University for central review at the following 
address: 
Washington University Laboratory: MIR 
Attn: Robin Haverman 
510 South Kingshighway, Box 8131 
St. Louis, Missouri  63110 
Phone: 314-747-1624 
 
Study Description: MRA/MRI 
 
Protocol Scan Time = 15 to 20 minutes. 
Standard Head Coil (circularly polarized or quadrature) 
 
1. Scout Localizer (3 planes) Time: 9 sec  
 
2. Fast/Turbo FLAIR T2-weighted Axial and Coronal Acquisition  (Must cover the whole 
brain) 
Time: 5:42 min approx (for TR 9000ms) 
 
Alignment AC-PC line (undersurface of the genu  
& splenium of the corpus callosum) 
TR = 10,000ms (acceptable value 9000- 10000 ms) 
TE = 125ms(acceptable range: 90ms- 130ms) 
TI  = Dependent on TR.  Set to null CSF signal  
(acceptable range 2000-3000) 
[for TR of 9 seconds, TI = 2500ms; for TR of 10 seconds, 
TI = 2308ms) 
Echo Train Length = 7 (acceptable range is 5 - 11) 
Echo Train Flip Angle: 180 degrees 
1 acquisition 
Matrix 256 (AP) x 192 (L-R) 
FOV 210mm  (acceptable range is 210 –230 mm) 
Slice Thickness = 5mm 
No intersection gap is desirable (acceptable intersection gap 
0 - 1mm) 
 
 

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3. T1-weighted Acquisition (for segmentation and volumetrics) 
 
Option 1:  
3-D T1-weighted fast gradient echo:  
(MPRAGE or IRprep-3DSPGR) 
Time: 7:07 min approx (for TR 1900) 
 
Option 2:  
T1-weighted Sagittal and Axial Acquisitions 
Time: 1:38 min approx (for TR 500ms) for Sagittal 
Time: 1:38 min approx (for TR 500ms) for Axial 
 
Orientation = Sagittal 
TR= 1900 ms  
TE= ~4ms 
 
Orientation 1 = Sagittal (Must 
cover the whole brain) 
Orientation 2 = Axial (Must 
cover the whole brain) 
TI= 1100 ms  
Slab Thickness=160mm (acceptable range = 160-
180mm) 
 
TR 500ms (acceptable range is 
400-800ms) 
Aligned to match the orientation 
of the FLAIR acquisition 
Slab Partitions = 128 (acceptable range = 120-
144) 
Slab Partition Thickness= 1.25 mm (acceptable 
range 1.25 – 1.5mm) 
 
TE 12ms (use minimum value, 
acceptable range 10-30ms) 
TR 500ms (acceptable range is 
500-800ms) 
 
 
FOV= 256 mm  
Matrix= 222 x 256 
 
1 acquisition 
Matrix 256 (AP) x 192 (L-R) 
TE 12ms (use minimum value, 
acceptable range 10-30ms) 
Resolution = 1.0 x 1.0 x 1.25mm (acceptable limit 
= 1.0 x 1.0 x 1.5) 
FOV 210mm  (acceptable range 
is 210 –230 mm) 
 
1 acquisition 
 
Slice Thickness = 5mm 
No intersection gap is desirable 
(acceptable intersection gap 0 - 
1mm) 
 
Matrix 256 (AP) x 192 (L-R) 
FOV 210mm  (acceptable range 
is 210 –230 mm) 
 
 
Slice Thickness = 5mm 
No intersection gap is desirable 
(acceptable intersection gap 0 -
 1mm) 
 
 
4. Fast/Turbo Spin Echo T2-weighted Axial Acquisition (Must cover the whole brain) 
 
Time: 1:16 min approx (for TR 4000ms) 
 
Aligned to match the orientation of the FLAIR 
acquisition 
TR = 5000ms (acceptable range: 3000-6000ms) 
TE = 100ms (acceptable range: 90ms - 110ms) 
Flip Angle = 180 degrees 
1 acquisition 
 
Echo Train Length = 7 (acceptable range is 5 - 11) 
Matrix 256 (AP) x 192 (L-R) 
FOV 210mm  (acceptable range is 210 –230 mm) 
Slice Thickness = 5mm 
No intersection gap is desirable (acceptable intersection gap 
0 - 1mm) 
 
 
Extended MRI Protocol 
Extended Protocol Scan Time = 15 to 20 minutes (As time allows for appropriate subjects) 
 

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5. Echo-Planar Axial Diffusion Acquisition (Repeated 2 times.  Do not use signal averaging.) 
 
Time: 45 sec (for TR 6000ms) x 2 = 1:30 min approx. 
 
Aligned to match the orientation of the FLAIR 
acquisition (if possible) 
TR  = 6000ms (allowable range: 3000ms – 6000ms) 
TE  = 90ms (minimum value desirable, allowable range: 
75 –140ms) 
1 acquisition 
Matrix: 128x128 
 
FOV: 230 mm  
Slice Thickness = 5mm 
No gap between slices:  (must not allow an intersection gap) 
b values: 0, 1000 s/mm2   
Gradient Orientation:  
Minimum X, Y, Z for computation 
of the trace of the tensor 
Desirable: 6 or more directions to compute the tensor 
 
 
 
6. 3D Time-of-Flight Magnetic Resonance Angiography 
 
Time: 9:12 min approx (for 192x512 matrix) 
 
Axial slab centered on the supraclinoid internal carotid 
artery. 
(MOTSA = multiple thin slab acquisition strategy is 
desirable) 
Slab partitions > 60, with resolution < 1mm. 
Number of Slabs= 3 
TE minimum (< 5ms) 
 
Flip Angle = 25 degrees, optimized for TR (TONE or variable 
RF pulse flip angle desirable). 
Matrix: 192 x 512 (acceptable range up to 512 x 512) 
FOV: minimum allowable for TE < 5ms, and for head size. 
MT pulse is acceptable to improve background suppression. 
Venous (Cephalad) presaturation pulse 
 
 
Protocol Scan Time = 30-40 minutes 
 
 
 

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APPENDIX I 
 
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