Umbilical Cord Blood Transplant for Congenital Pediatric Disorders
Phase: NA
Conditions: Congenital Pediatric Disorders
Sponsor: Baylor College of Medicine

 
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UCB Version 1.0  05/07/2009  
 
 
 
 
       UCB Version 8.0  04/09/14 
UCB Version 2.0  04/26/2010  
 
 
 
 
       UCB Version 9.0  06/06/14 
UCB Version 3.0  02/16/2011  
 
 
 
 
     UCB Version 10.0  01/06/15 
UCB Version 4.0  08/02/2011  
 
 
 
 
     UCB Version 11.0  04/13/15 
UCB Version 5.0  12/07/2011 
 UCB Version 12.0  08/30/2017 
UCB Version 6.0  08/16/2012                                                                      UCB Version 13.0  11/01/2018 
UCB Version 7.0  06/14/2013                                                                       UCB Version 14.0 03/02/2020 
UCB Version 15.0 06/01/2021 
 
 
 
 
Umbilical Cord Blood Transplant for Congenital Pediatric Disorders (UCB) 
 
 
PRINCIPAL INVESTIGATORS 
 
Caridad A. Martinez, MD 
Robert A. Krance, MD 
 
 
 
CO-INVESTIGATORS 
 
Helen E. Heslop, MD, FRACP, FRCPA 
Cliona M. Rooney, PhD 
Nabil M. Ahmed, MD 
Ghadir Sasa, MD 
Bambi J. Grilley, RPh, RAC, CIP, CCRA, CCRC 
Tao Wang, PhD 
 
 
 
 
 
 
 
 
Center for Cell and Gene Therapy (CAGT) 
 
Texas Children’s Hospital 
6621 Fannin Street 
Houston, TX  77030-2399 
 
 
Dan L. Duncan Comprehensive Cancer Center (DLDCCC) 
Baylor College of Medicine 

 
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TABLE OF CONTENTS 
 
 
 
CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY INFORMATION ................ 3 
 
1.0  OBJECTIVES .......................................................................................................................... 4 
 
2.0  BACKGROUND AND RATIONALE .................................................................................... 4 
 
3.0  ELIGIBILITY .......................................................................................................................... 8 
 
4.0  PREPARATIVE THERAPY/IMMUNOSUPRESSIVE THERAPY ...................................... 9 
 
5.0  EVALUATIONS DURING THE STUDY ............................................................................ 11 
 
6.0  STUDY ENDPOINTS ........................................................................................................... 15 
 
7.0  STUDY DRUGS .................................................................................................................... 16 
 
8.0  EVALUATION OF TOXICITIES ........................................................................................ 19 
 
9.0  RISKS .................................................................................................................................... 19 
 
10.0  STATISTICAL CONSIDERATIONS................................................................................. 20 
 
11.0  RECORDS TO BE KEPT .................................................................................................... 21 
 
12.0  REPORTING REQUIREMENTS ....................................................................................... 21 
 
13.0  INFORMED CONSENT ..................................................................................................... 21 
 
14.0  DATA MONITORING PLAN ............................................................................................ 22 
 
15.0  REFERENCE LIST ............................................................................................................. 23 
 
APPENDIX I ................................................................................................................................ 26 
 
 
 
 
 
 
 
 
 
 

 
3
CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY INFORMATION 
(Patient Eligibility Checklist) 
 
Patient ID ________________________    Patient Name __________________________ 
 
YES         NO         VALUE/DATE 
Any “NO” answers will make a patient ineligible for study participation: 
 
____        ____        ______    Patients less than 18 years of age. 
 
____        ____        ______    Patients with a congenital or acquired immunologic, metabolic or  
 
 
 
 
hematological pediatric disease (including SCID) in which stem  
 
 
 
 
cell transplantation has been beneficial. 
 
____        ____        ______    Related or unrelated UCB units identified as the HSC source with  
0-1 antigen mismatch (must be HLA matched at 5-6 HLA- A and 
B (at low to intermediate resolution) and DRB1 (at high 
resolution). 
 
____        ____        ______    Total cryopreserved HSC graft cell dose must be ≥ 5 x 107  
nucleated cells per kilogram recipient body weight. 
 
____        ____        ______    Lansky/Karnofsky scores ≥ 60. 
 
____        ____        ______    Patient has DLCO > 50% predicted or FEV1 > 50% predicted, if  
applicable. 
 
____        ____        ______    Patient/Guardian able to give informed consent. 
 
Any “YES” answers will make a patient ineligible for study participation: 
 
____        ____        ______    Severe intercurrent infection. 
  
____        ____        ______    Severe renal disease (Creatinine > 3X normal for age). 
 
____        ____        ______    Severe hepatic disease (direct bilirubin > 3mg/dl, or SGOT  > 500). 
 
____        ____        ______    Patients with symptomatic cardiac failure unrelieved by medical  
therapy or evidence of significant cardiac dysfunction by  
echocardiogram (shortening fraction  < 20%). 
 
____        ____        ______    HIV positive. 
 
Signature of MD ____________________    Date ________________________________ 
To check eligibility of a patient, call Dr. Martinez at 832-824-4692. 

 
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1.0  OBJECTIVES 
1.1  To determine the safety and overall survival at 100 days, 1 year, and 3 years  
        after umbilical cord blood transplant in pediatric patients with congenital diseases. 
1.2  To evaluate donor engraftment at 100 days, 6 months, and 12 months after transplant. 
1.3  To determine neutrophil and platelet recovery at Day 42. 
1.4  To estimate the risk of severe Grade III-IV acute GvHD at Day 100. 
1.5  To estimate the risk of chronic GvHD at 1 year. 
 
2.0  BACKGROUND AND RATIONALE 
2.1  Introduction 
Umbilical cord blood (UCB) is a readily available alternative source of HSCs that is capable of 
reconstituting hematopoiesis after myeloablative therapy.  A recent survey by the Institute of 
Medicine found that more than 180,000 UCB units have been banked and more than 6,000 
unrelated donor UCB transplantations have been performed1-8.  In recent years, use of umbilical 
cord blood as an alternative source of transplantable hemopoietic stem cells has increased 
substantially, extending the availability of this treatment, especially for children. 
 
2.2  Background of Congenital Diseases 
Many children with rare congenital diseases such as immunodeficiencies, familial histiocytic 
disorders, bone marrow failure syndromes, lysosomal and peroxisomal inborn errors of 
metabolism characteristically present in the first decade of life with complications that prove 
debilitating and life threatening. 
 
Primary cellular immunodeficiencies are a group of inherited disorders characterized by severe 
impairment of the innate or adaptive immune systems, which generally leads to early death from 
infectious complications.  These disorders can be further categorized depending on the primary 
cell lineage affected, into two major groups:  SCID (Severe Combined Immunodeficiency 
syndrome) with absent T and/or B lymphocyte function and non-SCID (defective T, B 
lymphocyte, or granulocytes).  The most common non-SCID diseases include: Wiskott-Aldrich 
syndrome (WAS), T cell deficiencies (Omenn syndrome, HLA-class II deficiency, CD40 ligand 
deficiency), Phagocytic-cell disorders (agranulocytosis, Chronic granulomatous disorders, 
Leukocyte 
adhesion 
deficiency), 
and 
Hemophagocytic 
syndromes 
(Familial 
Lymphohistiocytosis, Chediak-Higashi syndrome, Griscelli syndrome).  While improved 
supportive care has extended the life span of patients affected by these diseases and recent 
advances in gene therapy hold significant promise, definitive cure is generally only achieved by 
allogeneic hematopoietic stem cell transplant (HSCT). 
 
The storage diseases represent a diverse group of lysosomal and peroxisomal disorders.  Single 
gene defects involving a lysosomal hydrolytic enzyme or vital peroxisomal function lead to these 
devastating diseases and their systemic abnormalities affect multiple organs including the brain.  
Progressive loss of neurodevelopmental milestones and/or neurologic function is common.  
Shortened life-expectancy is often due to cardiopulmonary disease.  Treatment options depend 
upon the stage of disease and rate of progression, and include HSCT, enzyme replacement 
(ERT), substrate depletion and gene therapy.  The clinical response to ERT is variable, 
depending upon the disease, the organ or tissue involved the dose of enzyme, and the schedule of 

 
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administration.  Of particular importance is the observation that there is limited-to-no penetration 
of exogenous, intravenous enzyme into the nervous system.  These limitations make HSCT an 
attractive alternative to ameliorate/cure the disease, with best results obtained if the procedure is 
performed in the early stages of the disease. 
 
2.3  Clinical Experience with Stem Cell Transplant for Congenital Diseases 
The first successful allogeneic human HCT was performed in an infant with SCID who remains 
well more than 3 decades following an HLA-matched sibling transplant.  Transplantation of 
unmodified BM from an HLA-identical sibling remains the treatment of choice for infants with 
SCID in whom overall survival now exceeds 90% if the transplant is performed early.  Despite a 
later median age of transplant due to the time needed to perform a search, some groups report 
good outcomes (OS 63-67%) with  unrelated donor transplants.  Grunebaun et al.23 reported that 
recipients of matched unrelated donor stem cells had superior 2 year overall survival (81%) 
compared to recipients of mismatched related donor grafts (53%).  Antoine et al.24 reported 3-
year survival, with evidence of sustained engraftment and improvement of the immunodeficiency 
disorder, which was significantly better for HLA-identical than for HLA-mismatched 
transplantation (77% vs 54%; p=0.002).  The main causes of death were infections; graft vs host 
disease, toxic effects of the conditioning regimen and rejection24. 
 
In selected lysosomal and peroxisomal inborn errors of metabolism (IEM) such as Hurlers 
syndrome (MPS I), Maroteaux-Lamy syndrome (MPS IV), α-mannosidosis, childhood onset 
cerebral X-linked adrenoleukodystrophy (COCALD), metachromatic leukodystrophy (MLD) and 
globoid-cell leukodystrophy (GLD), timely HSCT positively modifies the natural history of the 
disease by providing cells of hematopoietic origin capable of providing the missing gene 
product.  Some benefit has also been described from engraftment of donor-derived glial cells in the 
brain.  Stem cell transplant is currently the only method of providing a self-replenishing source of 
enzyme to these patients.  Transplantation of marrow stem cell from a non-deficient donor will 
provide cells of the monocyte /macrophage system which are of donor origin and therefore 
competent to produce the target enzyme.  These donor derived cells replace the host fixed tissue 
macrophages in the liver, bone, lung, lymph nodes, and skin.  At least for some of the lysosomal 
and peroxisomal storage diseases, enzyme produced in the fixed tissue macrophage system is 
capable of uptake into recipient cells, where it is targeted to lysosomes.  By this process, 
accumulated storage material can be hydrolyzed, reducing  organomegaly and stabilizing or 
improving organ function.  Since the marrow continuously replenishes the body with donor fixed 
tissue macrophages, the effects can be expected to be permanent. Over 200 marrow transplant 
have been performed in the past decade in patients with various lysosomal and peroxisomal 
storage diseases.  Most of this experience is with matched related bone marrow transplantation.  
The rates of engraftment and 2 yr OS ranged between 60-65% and 50%, respectively. 
 
In most of these congenital diseases, the outcomes of HSCT is affected mainly by (1) age at 
transplantation, (2) stem cell source, with best results using HLA-identical sibling donors, (3) 
timing of HSCT, in which delay can substantially compromise effectiveness of HSCT, (4) type 
of preparative regimen, and (5) cell dose. 
 
2.4  Justification for Umbilical Cord Blood Transplantation 
The major limiting step to HSCT in these hereditary disorders is the availability of a suitable  

 
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matched stem cell source.  It is well known that delaying a HSCT in patients with congenital 
diseases increases the risk of infections, organ damage and progression of the disease.  Recent 
reports demonstrate the successful use of unrelated cord blood transplantation for the treatment 
of malignant and non-malignant diseases. Currently, large inventories of UCB units are available in 
public banks for transplantation in those lacking bone marrow donors.  In some experienced centers, 
unrelated umbilical cord blood (UCB) has become an acceptable and sometimes a preferred stem 
cell source because of its availability and lower incidence of graft-vs-host-disease (GvHD).  
Recent studies showed that patients transplanted at a very young age (2-3 yrs/old) before the 
onset of clinical symptoms can develop neurologically at a normal rate 3-5 yrs after transplant.  
The first umbilical cord transplantation (UCBT) was performed in 1988, in a child with Fanconi 
Anemia.  Since then, several thousand UCBT has been performed for malignant and non-
malignant disorders. 
 
In a recent report by Prasad, Kutzberg et al.19, 159 patients with inherited metabolic diseases 
were review after unrelated cord blood transplant.  A total of 97% achieved high (> 90%) donor 
chimerism with normalization of serum enzyme levels.  In a multivariate analysis, patient age of 
2 years or younger at transplantation, more than 2.1 x 105/kg of infused CD34, and more than 5.7 
x 104/kg of infused CFUs were favorable factors for neutrophil engraftment. Grade III-IV acute 
GvHD occurred in 10.3% of patients.  Extensive cGvHD occurred in 10.8% of patients by 1 
year.  Overall survival at 1 and 5 years was 71.8% and 58% in all patients.  8 patients had graft 
failure for an incidence of 12.9%.19  These findings were comparable and better than those with 
marrow products. 
 
The total nucleated cell dose and CD34 cell dose are extremely important in the setting of 
umbilical cord blood transplant.  In a report by Gluckman et al.14, a graft nucleated cell dose > 
3.7 x 107/kg was associated with shorter time to neutrophil recovery (25 days vs 35 days). 
Similarly, Rubinstein et al.7,16 demonstrated that a step-wise increase in graft nucleated cell dose 
was associated with progressively shortened time to neutrophil recovery.  Rubinstein et al.16 
suggested that the threshold was a cryopreserved nucleated cell dose > 2.5 x 107/kg; while the 
Minnesota group observed a threshold for the infused CD34+ cell dose of > 1.7 x 105/kg5.  Other 
prognostic factors have also been reported but these have not been consistently observed.  As one 
example, Rubinstein et al.7,16 observed a relationship between HLA match and neutrophil 
recovery (23 days for HLA matched vs 28 days for HLA mismatched grafts, p = 0.0027); this 
association was not observed by Gluckman et al.14 and Wagner et al.5 
 
In larger series the neutrophil engraftment has been reported as high as 92%.5  The incidence of 
acute GvHD reported in larger series ranges from 33-44% to 11-22% for grades II-IV and III-IV 
acute GvHD, respectively9-12.  The incidence of chronic GvHD ranges from 0-25%.9-12  These 
results are particularly notable since most UCB donor-recipient pairs are 1-2 HLA antigen 
mismatched. 
 
There is little information regarding outcome of UCST for Primary Immunodeficiency Diseases 
(PID).  Although PIDs, make up a small proportion of disorders amenable to treatment by HSCT, 
cord blood is an ideal source for many of these patients, who are often small, so that the limited 
stem cell dose in a cord blood unit is often adequate.  Diaz de Heredia et al.21 reported an 
engraftment rate of 100% in 15 patients with SCIDs after UCBT.  Of these patients, 33% 

 
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developed Grade III-IV aGvHD and 9% developed cGvHD.  The overall survival reported at 5 
years was 73% with a follow-up post transplant of 64 months.  The most common causes of 
death included grade IV aGvHD and interstitial viral pneumonitis.  Nine of the fifteen patients 
received horse antithymocyte globulin (ATG).  One of those patients died of aGvHD after 
receiving a 4/6 HLA match cord unit.  Only one patient of 11 patients receiving a unit matched at 
5-6 antigens developed aGvHD III-IV.21 
 
Bhattacharya et al.22 reported a very low incidence of GvHD after a 6/6 HLA antigen matched 
UCBT for PIDs in fourteen patients transplanted (2/14).  They reported a median time of 
neutrophil engraftment of 22 days and a median time of 51 days to platelet independence.  
Patients with high risk diagnosis and increase risk of graft failure (MHC class II, Reticular 
dysgenesis, Omen syndrome) were successfully transplanted with 100% chimerism in all cell 
lineages after the use of a conditioning regimen.  There was an increase mixed chimerism in 
patients transplanted without a conditioning regimen.  The reported overall survival was 86%.22 
 
Hence, UCB transplants offer several advantages over adult bone marrow or peripheral blood 
stem cell transplants, including: 1) rapid availability, 2) absence of donor risk, 3) low risk of 
transmissible infectious diseases, 4) low risk of acute GvHD in the setting of HLA mismatch (as 
compared to recipients of unrelated donor marrow and peripheral blood).  UCB is particularly 
beneficial for patients of ethnic and racial minority descent for whom adult marrow and blood 
donors often cannot be identified. 
 
2.5  Major Problems after Umbilical Cord Blood Transplant 
The disadvantages of UCSCT include non-availability of the donor for  booster stem cell 
infusion, lack of viral specific cytotoxic T cells, slower engraftment and small stem cell dose.  
Infection related treatment related mortality is still of concern after UCBT; rates of hemopoietic 
recovery are slower after UCBT; therefore infectious complications including viral infections or 
reactivations occur frequently.  The two major causes of death after umbilical cord blood 
transplantation for congenital disorders reported in the literature are graft failure (20%) and 
infection (15%). 
 
2.6  Protocol Proposal 
In this study, we aim to address engraftment, incidence of acute and chronic Graft vs Host 
Disease, incidence of infections, immune reconstitution and overall survival in congenital 
childhood disorders after Umbilical Cord Stem Cell Transplant.  With this study we are 
proposing an alternative conditioning regimen that will address the two major causes of death 
after UCBT for congenital diseases.  To improve engraftment rate and reduce infections we will 
incorporate fludarabine in the conditioning regimen.  Purine-analogs like fludarabine, have 
emerged as powerful immunosuppressive agents with minimal systemic toxicities. Fludarabine-
based, preparative regimens have been shown to allow alloengraftment in the related and 
unrelated donor setting with acceptable systemic toxicity in patients with a variety of 
hematologic malignancies.13-15 
 
Encouraging data on the fludarabine-cytoxan regimen have been reported.  A fludarabine-based, 
conditioning regimen, with adequate immunosuppressive activity could conceivably allow 
engraftment of stem cells from alternative donors in hematologic malignancies patients with 

 
8
acceptable engraftment rates and low transplant-related mortality. Regimen-related toxicity is 
believed to be a major contributing factor to GVHD. Therefore this approach may also lead to 
reduced GVHD, as some investigators have suggested.16, 17 
 
We will attempt to decrease the rate of viral infection and reactivation by removing ATG 
(thymoglobulin) from our conditioning regimen and substituting mycophenolate mofetil (MMF). 
We anticipate that the removal of ATG will facilitate immune reconstitution after UCBT.  The 
addition of fludarabine should compensate for any increased risk of graft failure due to removal 
of the ATG. 
 
3.0  ELIGIBILITY 
3.1  Inclusion Criteria 
3.1.1 Patients less than 18 years of age. 
 
3.1.2   Patients with a congenital or acquired immunologic, hematological or metabolic 
pediatric diseases (including SCID) in which stem cell transplantation has been 
beneficial. 
 
3.1.3 Related or Unrelated Umbilical Cord Blood Unit with 0-1 antigen  mismatch (5-6  
            HLA- A and B (at low to intermediate resolution) and DRB1 (at high resolution). 
 
3.1.4 Total cryopreserved HSC graft cell dose must be ≥ 5x107 nucleated cells per 
kilogram recipient body weight. 
 
3.1.5 Lansky/Karnofsky scores ≥ 60. 
 
3.1.6 Patient has DLCO > 50% predicted or FEV1 > 50%, if applicable. 
 
3.1.7 Written informed consent and/or signed assent line from patient, parent or 
guardian. 
 
3.2  Exclusion Criteria 
3.2.1  Patients with uncontrolled infections as assessed by the principal investigator only. 
          For bacterial infections, patients must be receiving definitive therapy and have no  
          signs of progressing infection for 72 hours prior to starting conditioning.  For  
          fungal infections patients must be receiving definitive systemic antifungal therapy  
          and have no signs of progressing infection for 1 week prior to enrollment.   
          Progressing infection is defined as hemodynamic instability attributable to sepsis or  
          new symptoms, worsening physical signs or radiographic findings attributable to  
          infection.  Persisting fever without other signs or symptoms will not be interpreted  
          as progressing infection. 
 
 
3.2.2  Severe renal disease (creatinine > 3X normal for age). 
 
3.2.3 Severe hepatic disease (direct bilirubin > 3 mg/dL or SGOT > 500). 

 
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3.2.4 Patients with symptomatic cardiac failure unrelieved by medical therapy or 
evidence of significant cardiac dysfunction by echocardiogram (shortening 
fraction < 20%). 
 
3.2.5 HIV-positive. 
 
4.0  PREPARATIVE THERAPY/IMMUNOSUPPRESSIVE THERAPY 
 
 
 
 
 
 
 
 
 
 
 
Day 
Agent 
 
-9 
Busulfan 
 
-8 
Busulfan 
 
-7 
Busulfan 
 
-6 
Busulfan 
 
-5 
Cytoxan 
 
50 mg/kg/day IV over 2  hours. Can be 
given over 1 to 4 hours if needed (MESNA; 
continuous infusion or 5 times daily) 
 
-4 
Cytoxan 
 
Fludarabine 
50 mg/kg/day IV over 2 hours. Can be 
given over 1 to 4 hours if needed (MESNA; 
continuous infusion or 5 times daily) 
 
40 mg/m2/day IV over 1 hour for patients > 
10 kg, or 1.3 mg/kg/day for patients ≤ 10 kg 
-9 
-8 
  -7 
  -6 
    -5 
    -4 
    -3 
    -2 
    -1 
   0 
Busulfan
Cytoxan 
CSA 
MMF 
Cytoxan 
Busulfan
Fludarabine 

 
10
-3 
Cytoxan 
 
Fludarabine 
50 mg/kg/day IV over 2  hours. Can be 
given over 1 to 4 hours if needed (MESNA; 
continuous infusion or 5 times daily) 
 
40 mg/m2/day IV over 1 hour for patients > 
10 kg, or 1.3 mg/kg/day for patients ≤ 10 kg 
-2 
Cytoxan 
 
Fludarabine 
50 mg/kg/day IV over 2  hours. Can be 
given over 1 to 4 hours if needed (MESNA; 
continuous infusion or 5 times daily) 
 
40 mg/m2/day IV over 1 hour for patients > 
10 kg, or 1.3 mg/kg/day for patients ≤ 10 kg 
-1 
Fludarabine 
40 mg/m2/day IV over 1 hour for patients > 
10 kg, or 1.3 mg/kg/day for patients ≤ 10 kg 
0 
 
Stem Cell Infusion 
4.1  Busulfan:  Busulfan (intravenous BUSULFEX) dosing will be as follows: 
Patients  12 kg: 1.1 mg/kg/dose IV every 6 hours for 16 doses total; patients > 12 kg: 
0.8 mg/kg/dose IV every 6 hours for 16 doses.  Administration and pharmacokinetic monitoring 
will be performed as per standard practice.  Phenytoin/fosphenytoin will be given in accordance 
with standard TCH Formulary guidelines. 
 
4.2  Cytoxan:  Cytoxan (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 2 
hours. It can be given over 1 to 4 hours as needed and as determined by the treating physician. 
The total dose to be given over 4 days is 200 mg/kg.  Mesna will be given in accordance with 
standard Blood and Marrow Transplant program recommendations. 
4.3  Fludarabine:  Fludarabine will be given IV daily over 1 hour for 4 days.  Preparation, 
administration and monitoring will be according to standard practice procedure. 
4.4  Post-Transplant Immunosuppression: 
4.4.1  Cyclosporin A (CSA) will begin on Day -2. The initial dose will be 2.5 mg/kg IV 
over 2 hours every 12 hours. Dose adjustments will be made on the basis of toxicity and 
low CSA levels with a trough level of < 200 mg/L.  Once the patient can tolerate oral 
medications and has a normal gastrointestinal transit time, CSA will be converted to an 
oral form. 
4.4.2  MMF will begin on Day 0 at a dose of 15 mg/kg IV or orally TID and will be 
discontinued on Day +45 unless GvHD is present. 
4.5  Supportive Care: 
4.5.1  Supportive care will be provided as per standard operating procedures of the  

 
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Blood and Marrow Stem Cell Transplant program at the Texas Children's Hospital, 
including all prophylactic and therapeutic clinical care issues.  These practices may be 
modified if necessary for any individual patient in order to optimize care. 
4.5.2  IVIG (intravenous immunoglobulin 500 mg/kg per dose – pharmacy to round dose 
to nearest vial size) will be given as per CAGT SOP for infection prophylaxis. 
 
4.5.3  G-CSF (Granulocyte-Colony Stimulating Factor: 10 mcg/kg IV/SC) to be given 
daily starting at Day +7 until ANC > 2500 for three consecutive days. 
 
 
5.0  EVALUATIONS DURING THE STUDY 
 
5.1  Screening Procedures; Pre-HCT: 
 
5.1.1  Physical examination by Pediatric Bone Marrow Transplant physician. 
 
5.1.2 Evaluation by pediatric neurologist as applicable. 
 
5.1.3    Pulmonary consultation for MPS I (Hurler), Niemann-Pick B and others as 
applicable. 
 
5.1.4    Pediatric Cardiology consultation for MPS I, MPS VI, MPS VII, and 
mannosidosis as applicable. 
 
5.1.5 Evaluation with Pediatric Endocrinology as applicable. 
 
5.1.6 Pediatric Ophthalmology consultation as applicable. 
 
5.1.7 Audiology consultation with BAER/BVER as applicable. 
 
5.1.8 Genetic Counseling unless previously done here or at another institution as 
applicable. 
 
5.1.9 Cerebral MRI with high field strength volumetric acquisition and multiplanar 
diffusion tensor imaging unless performed at our institution within 1 month as applicable. 
 
5.1.10 Chest radiograph. 
 
5.1.11 Electrocardiogram. 
 
5.1.12 Echocardiography. 
 
5.1.13 Pulmonary Function Tests: DLCO and FEV1 as applicable. 
 
5.1.14 Dual energy E-ray Absorptiometry (DXA) scan with bone age is to  be performed 
on all patients greater than 5 years old as applicable. 
 
5.1.15 Confirmation of diagnosis, if not clearly established. This may include 
enzyme/substrate quantization, genetic studies, or VLCFA  determination for ALD. 
 
5.1.16 CBC with differential, INR/PTT for all patients. 
 
5.1.17 Serum chemistries, including liver function testing. 
 
5.1.18 Endocrine testing including TSH, free thyroxine (FT4), vitamin D 25, vitamin 
D1,25, intact PTH, IGF-1 and IGF-BP3 for growth hormone deficiency screening as 
applicable. 
 
5.1.19 For patients with ALD, a low-dose ACTH stimulation test along with renin 
activity will be performed as applicable. 
 
5.1.20 Urinalysis. 
 
5.1.21 Pregnancy test (serum) as applicable. 
 
5.1.22  HIV testing. 
 
5.1.23 IgG, IgA, and IgM levels. 

 
12
 
5.2 
Evaluations Between Day 0 and Day 100: 
 
5.2.1 Peripheral blood for STRs or FISH analysis for molecular diagnostics on Days 21, 
60, and 100.5.2.2 
For patients with measurable enzymes (including the lysosomal 
disorders), perform enzyme analysis at Day 42 and Day 100. 
5.2.3 Lymphocyte phenotype testing (CD3, CD4, CD8, CD14, CD19 and CD56), other 
general viral immune reconstitution studies (ex. ELISPOT, spectrotyping, B cell panel) 
will be performed at Days 21-42, and Days 60-100. 
5.2.4 IgG, IgA, and IgM levels at Day 100. 
5.2.5  PHA stimulation assay to evaluate T cell function at Days 21-42, and Days 60-
100. 
5.2.6 History, physical exam, vital signs, and weight at Days 0, 21, 42, 60, and 100. 
5.2.7 Performance Status on Day 100. 
5.2.8 CBC with differential and platelets at Days 0, 21, 42, 60, and 100. 
5.2.9 Electrolytes, BUN, Creatinine, AST, ALT, Bilirubin, Albumin and LDH at Days 
0, 21, 42, 60, and 100. 
 
5.3 
Evaluations After Day 100: 
5.3.1 Peripheral blood with assessment of engraftment by STRs or FISH analysis and 
enzyme levels will be done as  applicable. 
5.3.2 Lymphocyte phenotype testing (CD3, CD4, CD8, CD14, CD19 and CD56), other 
general viral immune reconstitution studies (ex. ELISPOT, spectrotyping, B cell panel) 
will be performed at 6, 9, 12,  and 24 months and 3 years. 
5.3.3 IgG, IgA, and IgM levels at 6, 9, 12, and 24 months and 3 years. 
5.3.4  PHA stimulation assay to evaluate T cell function at 6, 9, 12, and 24 months and 3 
years. 
5.3.5 Neuropsychometric testing at 1 year, and yearly for three years. 
 
5.3.6 Echocardiography with LVEF at 1 year, 2 years, and 3 years. 
5.3.7 History, physical exam, vital signs, weight, performance status at months 6 and 9, 
and at 1 year, 2 years, and 3 years. 
5.3.8 CBC with differential and platelets at months 6 and 9, and at 1 year, 2 years, 3 
years and 5 years. INR/PTT at 2 years, and 3 years. 
5.3.9 Electrolytes, BUN, Creatinine, AST, ALT, Bilirubin, Albumin and LDH at 
months 6 and 9, and at 1 year, 2 years, and 3 years. 
5.3.10  Pulmonary Function Tests: DLCO and FEV1 as applicable at 1 year, 2 years and 
3 years. 
5.3.11 For patients that can return at Day 180 for evaluation, evaluations by the 
multidisciplinary team if applicable. 
5.3.12 Yearly visits for evaluation by the multidisciplinary team (neurology, 
neuropsychology, endocrinology, ophthalmology, and others (cardiology, pulmonary, 
orthopedics, etc.) for three years. 
 
5.4 
Follow-Up Interval: 
Patients will be seen in the hospital everyday until discharge.  After discharge from the  
hospital, the patient will be followed in the BMT clinic on a regular basis as 
recommended by the primary physician. 

 
13
5.5  Calendar of Study Evaluations: 
 
 
Pre-
HCT Day   
0 
Day 
21 
Day 
42 
Day 
60 
Day 
100 
M6 
M9 
M12 
 
M24 
 
M36 
Infusion of cells 
 
X 
 
 
 
 
 
 
 
 
 
Hx 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
Chest x-ray 
X 
 
 
 
 
 
 
 
 
 
 
ECHO  
X 
 
 
 
 
 
 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
Pulmonary 
Function Tests 
X 
 
 
 
 
 
 
 
 
X 
X 
DXA Scan2 
X 
 
 
 
 
 
 
 
 
 
 
Cerebral MRI 1 
X 
 
 
 
 
 
 
 
 
 
 
Genetic 
Counseling1 
X 
 
 
 
 
 
 
 
 
 
 
Audiology 
Consultation1 
X 
 
 
 
 
 
 
 
X 
X 
X 
Ophthalmology 
Consultation1 
X 
 
 
 
 
 
 
 
X 
X 
X 
Endocrinology 
Evaluation1 
X 
 
 
 
 
 
 
 
X 
X 
X 
Cardiology 
Consulation1 
X 
 
 
 
 
 
 
 
X 
X 
X 
Pulmonary 
Consultation1 
X 
 
 
 
 
 
 
 
X 
X 
X 
Neurology 
X 
 
 
 
 
 
 
 
X 
X 
X 

 
14
 
Pre-
HCT Day   
0 
Day 
21 
Day 
42 
Day 
60 
Day 
100 
M6 
M9 
M12 
 
M24 
 
M36 
Evaluation1 
Neuropsychometric 
Testing 
 
 
 
 
 
 
 
 
X 
X 
X 
CBC d/p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR/PTT 
X 
 
 
 
 
 
 
 
 
X 
X 
Anti-Xa and 
heparin cofactor II-
thrombin complex 
X 
 
 
 
 
 
 
 
 
 
 
Lytes/BUN/Cr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AST/ALT/Bili/Alb/
LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Low-dose ACTH 
per 5.1.19, if 
applicable 
X 
 
 
 
 
 
 
 
 
 
 
Endocrine testing 
per 5.1.18 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
Enzyme Analysis3 
 
 
 
X 
 
X 
 
 
 
 
 
PB STRs / FISH 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
Lymphocyte 
subset/PHA assay, 
other general viral 
immune 
reconstitution 
studies (ex. 
ELISPOT, 
spectrotyping, B 
cell panel ) 
 
 
X4 
 
X4 
 
X 
X 
X 
 
 
 
 
X 
X 
Immunoglobulin 
levels 
X 
 
 
 
 
X 
X 
X 
X 
 
X 
X 

 
15
  1  As applicable; these evaluations are also performed on Day 180 as applicable. 
  2  On all patients greater than 5. 
  3  For patients with measurable enzymes. 
  4  To be performed between Days 21 and 42, and between Days 60 and 100.

 
16
6.0  STUDY ENDPOINTS 
6.1  Engraftment 
 
6.2  Overall survival and organ function: 
100 days, 1, and 3years after UCBT. 
 
6.3  Acute and Chronic GvHD: 
Assess severity based on standard criteria. 
 
6.4  Systemic Infections: 
Classified as infections documented microbiologically occurring within 6 months.  Viral 
load will be monitored for CMV, EBV and AdV as per institutional protocols.  If there is 
any evidence of infection with these viruses, the patient will be started on medical or 
cellular therapy. 
 
6.5  Enzyme levels (when applicable): 
Determine the replaced enzyme levels at Day 100, 6,12, 24, and 36months after 
transplant. 
 
7.0  STUDY DRUGS 
7.1  Busulfan 
7.1.1  Therapeutic Classification:  Bifunctional alkylating agent. 
 
7.1.2  Pharmaceutical Data:  Busulfan (Busulfex Injection® Orphan Medical) is 
supplied as a sterile solution in single-use ampules containing 60 mg at a concentration of 
6 mg/mL.  It is provided as a mixture of demethylacetamide (DMA) and polyethylene 
glycol 400 (PEG400). 
 
7.1.3  Solution Preparation:  Busulfan solution for injection must be diluted with  0.9% 
Sodium Chloride Injection (NS).  The diluent quantity must be 10 times the volume of 
busulfan, ensuring that the final concentration is 0.5 mg/mL.  Sample calculation for a 50 
kg patient: (50 kg) x (0.8 mg/kg of busulfan) = 40 mg = 6.7 mL.  6.7 mL of busulfan + 67 
mL of NS = 74 mL total volume.  Final concentration: 0.54 mg/mL. 
 
7.1.4  Stability and Storage Requirements:  After dilution with NS or D5W, busulfan is 
stable at room temperature (25 degrees Celsius) for 8 hours.  The infusion must be 
completed within that time.  Prior to mixing: store under refrigeration (2 to 8 degrees 
Celsius).  Busulfan for injection is stable at 4C for at least 12 months. 
 
7.1.5  Route of Administration:  Busulfan should be administered intravenously via a 
central venous catheter as a two-hour infusion. 
 
7.1.6  Usual Dosage Range:  0.8-1.1 mg/kg/dose given every 6 hours for a total of 16 
doses.  For patients  12 kg a dose of 1.1 mg/kg/dose will be used, and for patients > 12 

 
17
kg the starting dose will be 0.8 mg/kg/dose.  Doses are based on actual body weight, 
unless the patient’s weight is greater than 30% of ideal body weight, then dosing will be 
based on adjusted weight of ideal plus 25%.  Busulfan pharmacokinetics will be 
performed on all patients with dose adjustment as appropriate. 
 
7.1.7  Pharmacokinetics:  Doses will be adjusted to achieve the desired plasma area 
under the curve (AUC) of 800 – 1200 µmol/min/L.  Doses will be adjusted as necessary 
pending the results of the first dose pharmacokinetics.  For patients whose AUC values 
are greater than 5% outside the acceptable AUC range, the dose will be adjusted to 
achieve a target AUC of 1125 µmol/min/L (midpoint of acceptable range) not to exceed a 
maximum dose of 1.6 mg/kg per dose of busulfan. 
 
7.1.8  Side-Effects:  Myelosuppression, neurotoxicity (manifesting as seizures), mild to 
moderate nausea and vomiting, mild to moderate tachycardia, skin hyperpigmentation, 
sterility, and rarely hepatotoxicity (hepatic veno-occlusive disease) and pulmonary 
toxicity (interstitial fibrosis). 
 
7.1.9  Special Precautions:  Increased toxicity in obese patients unless dose is adjusted 
appropriately. Generalized seizures have been reported after use of high dose busulfan.  
Phenytoin/fosphenytoin will be given in accordance with TCH Formulary guidelines. 
 
7.1.10  Mechanism of Action:  Busulfan is a bifunctional alkylating agent in which two 
labile methanesulfonate groups are attached to opposite ends of a four-carbon alkyl chain.  
In aqueous media, busulfan hydrolyzes to release the methanesulfonate groups.  This 
produces reactive carbonium ions that can alkylate DNA.  DNA damage is thought to be 
responsible for much of the cytotoxicity of busulfan. 
 
7.1.11  Human Pharmacology:  Busulfan can be administered orally or intravenously.  
Busulfan achieves levels in cerebrospinal fluid similar to plasma levels.  Busulfan is 
predominantly metabolized by conjugation with glutathione, both spontaneously and by 
glutathione S-transferase (GST) catalysis.  This conjugate undergoes further extensive 
oxidative metabolism in the liver.  Approximately 30% of busulfan and metabolites can 
be recovered in the urine within 48 hours after administration. 
 
7.2  CYTOXAN (CTX, Cyclophosphamide) - Commercially Available 
7.2.1  Formulation:  Oral drug is supplied as 25 mg and 50 mg tablets. Injectable form is 
available as lyophilized cakes containing 100 mg, 200 mg, or 500 mg of active drug, and 
75 mg of mannitol per 100 mg of active drug in single-use vials. 
 
7.2.2  Storage:  Cytoxan is to be kept dry and at room temperature until reconstitution 
and use. 
 
7.2.3  Stability:  All preparations are stable at room temperature (not to exceed 30 
degrees Celsius). Discard reconstituted solutions after 24 hours at room temperature; 
stable up to 6 days if refrigerated (2-8 degrees Celsius). Since there is no preservative, 
precautions should be taken to insure sterility, or solution should be discarded within 8 

 
18
hours. The parenteral form of cytoxan prepared as a liquid oral preparation diluted to < 2 
mg/mL can be refrigerated (2-8 degrees Celsius) for up to 14 days. 
 
7.2.4  Administration:  50 mg/kg will be given IV over 2 hours daily for a total of 4 
doses. It can be given over 1 to 4 hours (as needed and as determined by the treating 
physician). Cyclophosphamide may be diluted in D5NS 200 mL/m2. 
 
7.2.5  Toxicities: 
 
Known Toxicities: 
 
Common (21-100% 
Frequency) 
Occasional 
(5-20% Frequency) 
 
Rare 
(<5% Frequency) 
 
Immediate: 
Anorexia (L), nausea 
(L), vomiting (L) 
Metallic taste (L), 
Inappropriate ADH 
secretion1 
 
Transient blurred 
vision1, cardiac 
toxicity with 
arrythmias1, 
myocardial 
necrosis2(L) 
 
Prompt: 
Myelosuppression 
(L), alopecia (L) 
 
Hemorrhagic 
cystitis (L) 
 
 
Delayed: 
Immunosuppression, 
gonadal 
dysfunction/sterility 
 
 
Pulmonary fibrosis 3 
(L) 
 
Late: 
 
 
Secondary 
malignancy, 
bladder fibrosis 
 
Unknown 
Timing 
and Frequency 
 
Fetal and teratogenic toxicities 4,5 
 
  
(L) Toxicity may also occur later. 
 
1 Less common with lower doses. 
 
2 Only with very high doses. 
 
3 Risk increased with chest radiation. 
 
4 Fetal toxicities and teratogenic effects of cytoxan (alone or in combination with other anti-neoplastic agents) have been 
noted in humans. Toxicities include: chromosome abnormalities, multiple anomalies, pancytopenia, and low birth weight. 
 
5 Cytoxan is excreted into breast milk. Neutropenia has been reported in breast-fed infants. 
 
Cytoxan is considered to be contraindicated during breast feeding because of the reported cases of neutropenia and because 
of the potential adverse effects relating to immune suppression, growth, and carcinogenesis. 
 
7.3  FLUDARABINE 
 
7.3.1  Therapeutic Classification:  Purine antimetabolite. 
 
7.3.2  Pharmaceutical Data:  In vials of 50 mg. 
 

 
19
7.3.3  Solution Preparation:  Reconstituted with 2 mL of sterile water for injection.  The 
resulting solution will contain 25 mg/mL.  For infusion (maximum concentration of 10 
mg/mL) intravenously in 60 mL/m2 of D5W over 1 hour. 
 
7.3.4  Stability and Storage Requirements:  Prior to mixing: store under refrigeration at 
2 to 8 degrees Celsius. After mixing: stable for 16 days at room temperature, but needs to 
be used in 8 hours because of the lack of antibacterial preservatives. 
 
7.3.5  Routes of Administration:  IV infusion. 
 
7.3.6  Usual Dosage Range:  For patients  10 kg: 1.3 mg/kg/day; for patients > 10 kg: 
40 mg/m2/day given IV over 1 hour for a total of 4 doses. 
 
7.3.7  Side-Effects:  Myelosuppression, exacerbation of hemolytic anemia, prolonged 
immunosuppression, opportunistic infection, and rare neurotoxicity. 
 
7.3.8  Special Precautions:  Increased myelosuppression in patients with creatinine 
clearances of less than 50 mL/min. 
 
7.3.9  Mechanism of Action:  A purine antimetabolite modified with fluorine and 
monophosphate to resist deamination by adenosine deaminase and to increased solubility.  
Dephosphorylation followed by cellular incorporation and conversion to active 
triphospahte, which is a competitive inhibitor of DNA synthesis. 
 
7.3.10  Antitumor Data:  The drug has greater activity to T cells than B cells, but 
clinical activity is observed in B cell malignancies. 
 
7.3.11  Human Pharmacology:  Fludarabine can only be given via intravenous route.  
Renal excretion accounts for 23%.  Half-life is 10 hours. 
 
8.0  EVALUATION OF TOXICITIES 
The criteria listed in the NCI Common Toxicity Criteria Scale will be used in grading toxicity. 
(Version 4.0 located at http://ctep.cancer.gov).  GVHD will be graded by the method of 
Przepiorka et al. (see Appendix I). 
 
9.0  RISKS 
9.1  Non-Engraftment 
One major risk of patients undergoing stem cell transplant for non-malignant diseases is non-
engraftment.  We are anticipating lower incidence of graft failure or autologous recovery with 
the use of fludarabine in our protocol. 
 
9.2  GvHD 
Acute GvHD produces a skin rash, liver dysfunction, and enteritis.  GvHD prophylaxis in most 
types of patients reduces the incidence of grade II-IV GvHD to about 35% with commonly used 
regimens of today.  Recent reports showed an incidence of aGvHD grade III-IV of 10% (Prasad 

 
20
et al., Blood 2008).  Chronic GvHD is a multiorgan autoimmune disease usually requiring 
therapy with steroids and other immunosuppressives.  It is seen in about 30% of adults 
undergoing transplant and lower percentage of children.  The risk of cGvHD after UCBT for 
congenital pediatric diseases has been reported to be as low as 8% (unpublished data of the 
University of Minnesota; Martinez, C., Orchard, P. and Tolar, J.). 
 
9.3  Additional Risks 
The degree of immune suppression of marrow transplant patients leads to an increased risk of 
opportunistic infections, especially those due to CMV, HSV, EBV, Pneumocystis, and other 
viruses and fungi.  Prophylaxis is given where possible (Acyclovir, Bactrim, Antifungal, and 
antibacterial mouth rinses, etc.), and treatment for suspected agents is initiated very promptly, 
usually before the infection is confirmed. 
 
Partial or incomplete T cell function sometimes leads to immune dysregulation and has been 
associated with autoimmune phenomena in patients with primary immune deficiency.  These 
phenomena include but are not limited to autoimmune hemolytic anemia, neutropenia and 
thrombocytopenia.  These complications may occur as a result of the underlying immune 
deficiency or from incomplete reconstitution following allogeneic SCT. 
 
Patients with SCID or PID may be at risk for malignancy, in particular lymphoreticular 
malignancies often associated with primary or reactivated EBV infection.  The risk for these 
cancers remains high in patients until immune recovery has been attained. 
 
Other complications of an unexpected nature may be seen. In fact, most every patient presents 
with some new or very rare complication during transplant.  There is a chance the patient could 
die from this treatment or from side effects of the treatment such as bleeding or infection. 
Patients are made aware of this possibility. 
 
10.0  STATISTICAL CONSIDERATIONS 
10.1  Sample Size Considerations 
 
The protocol is designed to demonstrate that pediatric patients with congenital diseases received 
umbilical cord blood transplant will have a 1-year overall survival rate of at least 60%. Accrual 
of pediatric patients with congenital diseases who are eligible to receive umbilical cord blood 
transplant is about 3 subjects per year. If we suppose that a true 1-year overall survival rate of 
40% would not be unacceptable, then we would need to accrue 22 patients to have 80% power to 
detect the deficiency in overall survival (with alpha level 0.05 and one-sided testing). The 
accrual period is 6 year with follow-up of at least 3 years or till death for each patient. 
 
10.2  Monitoring Overall Survival 
The primary outcome of overall survival will be compared to a fixed null hypothesis 1-year 
survival rate of 40% by a one-sided. Survival data and toxicity data will be summarized and 
monitored every year by the TXCH Data Review and Monitoring Committee. 
 
10.3  Statistical Analysis 

 
21
In addition to routine summary statistics for the outcome data, we will compute Kaplan-Meier 
estimates and confidence intervals for time to overall survival, disease-free survival, graft failure 
and length of remission.  Additionally, we will also calculate incidence rates and 95% confidence 
intervals for engraftment, acute GvHD, neutrophil and platelet recovery at Day 42. As requested 
by TXCH-DRC, these short-term secondary endpoints will also be analyzed according to the two 
cohorts defined by the timing of G-CSF (G-CSF starting at Day +7 vs. G-CSF starting after Day 
+7).  It should be noted that these analyses are exploratory, because the timing of G-CSF is not 
the goal of the study, hence not powered. 
 
11.0  RECORDS TO BE KEPT 
 
The CAGT data manager will maintain a database documenting the clinical parameters as well as 
the chemistries and hematologic parameters.  The clinical status and occurrence of any adverse 
events and subsequent interventions are to be kept on all patients. 
 
 Imaging reports 
 Surgical summaries 
 Autopsy summaries, where appropriate 
 Informed consent documents 
 
All required clinical evaluation records will be the responsibility of Dr. Martinez, who will also 
be responsible for analysis of the clinical outcome and toxicity. 
 
The laboratory evaluation of immunological efficacy will be the responsibility of Dr. Martinez. 
 
12.0  REPORTING REQUIREMENTS 
12.1     Register all patients with Cell and Gene Therapy Research Nurse. 
 
12.2     Enter all patients by calling Drs. Martinez/Krance.  The following forms should 
 
be completed: 
 Eligibility Checklist 
 Adverse Events Record 
 Follow-Up Forms 
 Off-Study Forms 
 
12.3    Drug Toxicity and/or Adverse Reactions 
Adverse events will be collected per SOP J 02.05.XX, J 02.06.XX and J 02.78.XX. 
 
13.0  INFORMED CONSENT 
All patients and/or their legal guardian must sign a document of informed consent consistent 
with local institutional and Federal guidelines stating that they are aware of the investigational 
nature of this protocol and of the possible side effects of treatment.  Further, patients must be 
informed that no efficacy of this therapy is guaranteed, and that unforeseen toxicities may occur. 
Patients have the right to withdraw from this protocol at any time.  No patient will be accepted 

 
22
for treatment without such a document signed by him or his legal guardian.  Full confidentiality 
of patients and patient records will be provided according to institutional guidelines. 
 
14.0  DATA MONITORING PLAN 
This protocol will be monitored in accordance with current TXCH Data Safety Monitoring 
Board Plan for investigator-initiated Phase I and II studies. The conduct of this clinical trial will 
be evaluated in accordance with the Texas Children’s Cancer Center and the Center for Cell and 
Gene Therapy Quality Assurance Policy and Procedure Plan. 

 
23
15.0  REFERENCE LIST 
 
1) 
Wagner, J.E., N.A. Kernan, M. Steinbuch, et al., Allogeneic sibling umbilical-cord-blood 
transplantation in children with malignant and non-malignant disease. Lancet, 1995.346(8969): 
214-9. 
 
2) 
Wagner, J.E., J. Rosenthal, R. Sweetman, et al., Successful transplantation of HLA-
matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of 
engraftment and acute graft-versus-host disease. Blood, 1996. 88(3): 795-802. 
 
3) 
Kurtzberg, J., M. Laughlin, M.L. Graham, et al., Placental blood as a source of 
hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med, 1996. 
335(3): 157-66. 
 
4) 
Gluckman, E., V. Rocha, A. Boyer-Chammard, et al., Outcome of cord-blood 
transplantation from related and unrelated donors. Eurocord Transplant Group and the European 
Blood and Marrow Transplantation Group. N Engl J Med, 1997. 337(6): 373-81. 
 
5) 
Rubinstein, P., C. Carrier, A. Scaradavou, et al., Outcomes among 562 recipients of 
placental blood transplants from unrelated donors. N Engl J Med, 1998. 339(22): 1565-77. 
 
6) 
Laughlin, M.J., J. Barker, B. Bambach, et al., Hematopoietic engraftment and survival in 
adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med, 2001. 
344(24):1815-22. 
 
7) 
Laughlin, M.J., M. Eapen, P. Rubinstein, et al., Outcomes after transplantation of cord 
blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med, 
2004.351(22): 2265-75. 
 
8) 
Rocha, V., M. Labopin, G. Sanz, et al., Transplants of umbilical-cord blood or bone 
marrow from unrelated donors in adults with acute leukemia. N Engl J Med, 2004. 351(22): 
2276-85. 
 
9) 
Gluckman E, Broxmeyer HA, Auerbach AD et al. Hematopoietic reconstitution in a 
patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. 
N Engl J Med. 1989; 321: 1174-1178. 
 
10) 
Kurtzberg J, Graham M, Casey J et al. The use of umbilical cord blood in a mismatched 
related and unrelated hematopoietic stem cell transplantation. Blood Cells 1994;20: 275-84. 
 
11) 
Wagner JE, Barker JN, Defor TE, Baker KS, Blazar BR, Eide C, Goldman A, Kersey J, 
Krivit W, MacMillan M, Orchard P, Peters C, Weisdorf DJ, Ramsay NKC, Davies SM.  
Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and 
nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related 
mortality and survival. Blood. 2002;100:1611-1618. 
 

 
24
12) 
Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell 
transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233-4244. 
 
13) 
Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, et al. 
Outcomes of cord-blood transplantation from related and unrelated donors. Eurocord Transplant 
Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337: 
373-381. 
 
14) 
Broxymeyer HE, Hangoc G. Cooper S et al.  Growth and expansion of human umbilical 
cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci USA 
1992:89:4109-4113. 
 
15) 
Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC, et al. Placental 
blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N 
Engl Med 1996; 335: 157-166. 
 
16) 
Locatelli F, Rocah V, Chastang C et al.  Factors associated with outcome after cord blood 
transplantation in children with acute leukemia.  Eurocord-Cord Blood Transplant Group. Blood. 
1999; 93:3662-3671. 
 
17) 
Mielcarek M, Martin PJ, Leisenring W et al. Graft-versus-host disease after 
nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood. 2003;102: 
756-762. 
 
18) 
Couriel DR, Saliba RM, Giralt S et al. Acute and chronic graft-versus-host disease after 
ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Bl 
Marrow Tr 2004;10:178-185.  
 
19) 
Prasad V, Mendizabal A, Parikh S, Szabolcs P, Kurtzberg J et al.  Unrelated donor 
umbilical cord blood transplantation for inherited metabolic disorders in 159 pediatric patients 
from a single center: influence of cellular composition of the graft on transplantation outcomes. 
Blood. 2008;112: 2979-2989. 
 
20) 
Thomas’s Hematopoietic Cell Tranplantation, 3rd edition. 
 
21) 
Diaz de Heredia C, Ortega J, Diaz MA, Sanchez de Toledo J et al.  Unrelated  
Cord blood transplantation for severe combined immunodeficiency and other primary 
immunodeficiencies.  Bone Marrow Transplanation. 2008;41: 627-633. 
 
22) 
Bhattacharya A, Slatter MA, Chapman CE, Gennery AR et al.  Single center experience 
of umbilical cord stem cell transplantation for primary immunodeficiency.  2005;36:295-299.  
 
23) 
Roifman CM, Somech R, Grunebaum E.  Matched unrelated bone marrow transplant for 
T + combined immunodeficiency.  Bone Marrow Transplanation.2008; 41: 627-633. 
 

 
25
24) 
Antoine C, Muller S, Cant A et al. Long term survival and transplantation of 
haemopoietic stem cell for immunodeficiencies: Report of the European experience 1968-99.  
Lancet. 2003; 361: 553-60. 
 
25) 
Pai SY, Logan B, Griffith L, et al. Transplantation Outcomse for Severe Combined 
Immunodeficiency, 2000-2009. N Engl J Med 2014; 371;5: 434-446. 
 
 

 
26
APPENDIX I 
 
 
GVHD STAGES AND GRADES 
 
For skin: 
Stage  
Skin Involvement 
0 
 
0 
1 
 
greater than 0, less than 25% 
2 
 
greater than or equal to 25%, less than or equal to 50% 
3 
 
greater than 50% 
4 
 
greater than 50% with blisters 
 
For gut: 
Stage  
Stool Volume 
0 
 
less than 7 cc/kg 
1 
 
greater than or equal to 7 cc/kg, less than 14 cc/kg 
2 
 
greater than or equal to 14 cc/kg, less than 21 cc/kg 
3 
 
greater than or equal to 21 cc/kg, less than 28 cc/kg 
4 
 
greater than or equal to 28 cc/kg 
 
For liver: 
Stage  
Bilirubin (mg/dL) 
0 
 
less than 2 
1 
 
greater than or equal to 2, less than 3 
2 
 
greater than or equal to 3, less than 6 
3 
 
greater than or equal to 6, less than 15 
4 
 
greater than or equal to 15 
 
Overall: 
Grade  
Organ Stage 
0 
 
0 
1 
 
skin = 1 or 2 
2 
 
skin = 3, or skin less than or equal to 3 and gut or liver equal to 1 
3 
 
skin greater than or equal to 3 and gut or liver equal to 2 or 3 
4 
             skin, gut or liver equal to 4