Clinical trial NCT00950846
Conditions: Congenital Pediatric Disorders
Keywords: Congenital Pediatric Disorders Umbilical Cord Blood Transplant Congenital Abnormalities Cord Blood Stem Cell Transplantation Busulfan Cytoxan Cyclophosphamide Fludarabine
Sponsor: Baylor College of Medicine
Start date: 2009-09-01; Completion date: 2021-02-04
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the safety and effectiveness of Umbilical Cord Blood Transplant (UCBT) to treat the patient's disease, and to see if this treatment can decrease the incidence of GVHD.

This study is for patients that were born with a disease that affects their body's metabolism or immune system. The doctor plans to treat the patient for this illness with a stem cell transplant.

While improved medical care has allowed many people with these diseases to live longer, the only way to truly cure the diseases is by means of a stem cell transplant from a donor who does not have the disease. A stem cell transplant will replace sick cells with new healthy donor cells. Stem cells grow into different types of blood cells that people need, including red blood cells, white blood cells, and platelets. In a stem cell transplant, the patients own stem cells would be killed by chemotherapy drug and then replaced by stem cells from the donor. Stem cells can be collected from the bone marrow, peripheral blood or umbilical cords. In this study, umbilical cords will be the source of the stem cells.

Currently, large inventories of umbilical cord blood units are available in public banks for transplantation in those lacking bone marrow donors. 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 (as compared to recipients of unrelated donor marrow and peripheral blood cells).

The two main causes of death after umbilical cord blood transplantation for disorders for these kinds of patients, are graft failure and infection.

In this study we are trying to address these two problems by using different drugs to prepare patients for the transplant.

To help improve engraftment (cells begin to grow), we will include the drug Fludarabine to the usually used Busulfan and Cytoxan that the study patients will receive before their transplant.

We will try to decrease the chance of developing graft-versus-host disease (GvHD) by using Cyclosporin A (CSA) and Mycophenolate Mofetil (MMF), instead of Anti-Thymocyte Globulin (ATG) which is normally used.

Detailed description:
Patients will be examined to make sure that they meet the requirements of this study. There will be tests of the heart and of the lungs. X-rays will be taken of the lungs and other organs, depending on the disease. An MRI and consultations with different specialists will also be conducted.

Patients also must have a negative pregnancy test before entering this study if they are a woman of childbearing potential. The blood will be tested for viruses and to look at the functioning of the liver and kidneys. The examination also includes HIV testing. If the patient has HIV, they will not be able to be treated on this protocol.

After we have determined that the patient is eligible for treatment on this study and a suitable UCB stem donor has been found, they will have a central line placed.

After placement of the central line, the following chemotherapy will be given to after admission to the hospital:

* 9 days before the infusion through 6 days before the infusion: Busulfan every 6 hours for 16 total doses.
* 5 days before the infusion through 2 days before the infusion: Cytoxan given daily for 4 days over 2 hours. (It can be given over 1 to 4 hours if needed as decided by the physician). Mesna will be given per standards.
* 4 days before the infusion through 1 day before the infusion: Fludarabine given daily for 4 days over 1 hour.

Stem cell transplant (infusion of the UCB stem cells) - defined as Day 0 of the treatment. All other "numbered" days relate to this infusion date. For example, Day 1 is the first day after the stem cell transplant.

Standard Therapy: Phenytoin will be given according to the standards of the TCH formulary.

Cyclosporin A (CSA) will be given starting 2 days prior to the stem cell infusion. It will be given daily over 2 hours every 12 hours, and then tapered if no GvHD is present.

Administration of Mycophenolate Mofetil (MMF) will start on the day the stem cell infusion is completed, and will continue daily for 45 days unless the patient develops GvHD.

Intravenous Immunoglobulins (IVIG) will be given as per CAGT SOP for infections prophylaxis.

Granulocyte Colony-Stimulating Factor (GCSF) will be given daily starting at Day +7 until ANC is greater than 2,500 for three consecutive days.

Study Evaluation: Patients will have various study evaluations, including blood samples, before and after the transplant.

Follow-Up: After year 1, the patients will be asked to return to the clinic once a year for consultations. These consultations with specialists will be similar to the ones the patients had before their transplant.

Arms: arm 1: Busulfan, Cytoxan, Fludarabine, Cord Blood Stem Cell Infusion
Interventions: intervention 1: Busulfan intervention 2: Cytoxan intervention 3: Fludarabine intervention 4: Cord Blood Stem Cell Infusion
Intervention descriptions: intervention 1: Day -9, -8, -7 and -6

Patients less than or equal to 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. intervention 2: (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 2 hours (can be given over 1 to 4 hours as determined by the treating physician). The total dose to be given over 4 days is 200 mg/kg. intervention 3: 40 mg/m2/day IV over 1 hour for patients greater than 10 kg, or 1.3 mg/kg/day for patients less than or equal to 10 kg. intervention 4: The cord blood stem cells will be infused on Day 0.

Protocol documents:
Prot_SAP_001.pdf: 
 
1
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 


 
2
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. 


 
4
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 


 
5
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  


 
6
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% 


 
7
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). 


 
9
 
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  


 
11
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 
 
 

ICF_000.pdf: 
CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
Background
When reading this form, please note that the words “you” and “your” refer to the person in the study, 
rather than to a parent or guardian, or legal representative who might sign this form on behalf of the 
person in the study.
You were born with a disease that affects your body's metabolism (the system that helps eliminate 
toxins from your cells) or immune system (which is responsible for helping you fight infections). Your 
doctor plans to treat you for this illness with a stem cell transplant. While improved medical care has 
allowed many people with these diseases to live longer, the only way to truly cure these diseases is by 
means of a stem cell transplant from a donor who does not have the disease. A stem cell transplant will 
replace sick cells with new healthy donor cells. Stem cells grow into different types of blood cells that 
you need, including red blood cells, white blood cells, and platelets. In a stem cell transplant, your own 
stem cells will be killed by a chemotherapy drug, and then replaced by stem cells from the donor. Stem 
cells can be collected from the bone marrow, peripheral blood or umbilical cords. In this study, umbilical 
cords will be the source of the stem cells.
Currently, large inventories of umbilical cord blood units are available in public banks for transplantation 
in those lacking bone marrow donors. UCB transplants (UCBT) 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 graft-versus-host disease (GVHD), as compared to recipients of unrelated donor 
marrow and peripheral blood cells. GVHD will be discussed in more detail later in this consent.
The two main causes of death after umbilical cord blood transplantation for disorders like yours are 
graft failure (this is when the donor cells do not replace your cells permanently), and infection. In this 
study, we are trying to address these two problems by using different drugs to prepare you for the 
transplant.
To help improve engraftment (when the transplanted cells begin to grow), we will add the drug 
fludarabine to the usually used busulfan and cytoxan that you will receive before your transplant. We will 
try to decrease the chance for infections by using mycophenolate mofetil (MMF) instead of 
anti-thymocyte globulin (ATG), which is normally used. 
Please read the information in this consent form carefully to decide whether you want to participate. 
Your participation in this study will last for about 3 years.
This research study is sponsored by Baylor College of Medicine.
Purpose
To determine the safety and effectiveness of umbilical cord blood transplant (UCBT) to treat your 
disease, and to see whether this treatment can decrease the incidence of GVHD.
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 1 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
Procedures
The research will be conducted at the following location(s):  
Baylor College of Medicine and TCH: Texas Children's Hospital.
Up to 60 patients will take part in this study. 
You will be examined to make sure that you meet the requirements of this study. There will be tests of 
your heart (echocardiogram, an ultrasound of the heart) and of your lungs (pulmonary function studies to 
see how well your lungs are functioning). X-rays will be taken of your lungs and other organs, depending 
on your disease. An MRI and consultations with different specialists (such as genetics, vision, hearing, 
liver, lung, brain, and heart) will also be conducted.
You must have a negative pregnancy test before entering this study if you are a woman of childbearing 
potential. Your blood will be tested for viruses, and to look at the functioning of your liver and kidneys. 
The examination also includes HIV testing. HIV is the virus that causes Acquired Immune Deficiency 
Syndrome (AIDS). If you have HIV, you will not be able to be treated on this protocol.
After we have determined that you are eligible for treatment on this study, and a suitable UCB stem 
donor has been found, you will have a central line placed. A central line involves the placement of a large 
tube (called a double lumen catheter) into a large vein in your body. The large vein will be either in the 
groin or in the chest. The catheter will be placed by a surgeon. The risks of having a central line placed 
are primarily related to this surgical procedure. They will be discussed further in the RISKS section of 
this consent form. The risks of having a central line placed will also be
discussed with you separately, and you will sign a separate consent form for the placement procedure.
RESEARCH THERAPY:
After placement of the central line, the following chemotherapy will be given to you after admission to the 
hospital:
- 9 days before the infusion through 6 days before the infusion: busulfan every 6 hours for 16 total doses.
- 5 days before the infusion through 2 days before the infusion: cytoxan given daily for 4 days over 2 
hours (can be given over 1 to 4 hours as decided by the physician). MESNA will be given per standards.
- 4 days before the infusion through 1 day before the infusion: fludarabine given daily for 4 days over 1 
hour.
Stem cell transplant (infusion of the UCB stem cells) is defined as Day 0 of the treatment. All other 
"numbered" days relate to this infusion date. For example, Day 1 is the first day after the stem cell 
transplant.
STANDARD THERAPY:
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 2 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
Phenytoin will be given according to institutional standards.
Cyclosporin A (CSA) will be given starting 2 days prior to the stem cell infusion. It will be given daily over 
2 hours every 12 hours, and then tapered if no GVHD is present.
Administration of mycophenolate mofetil (MMF) will start on the day the stem cell infusion is completed, 
and will continue daily for 45 days, unless you develop GVHD.
Intravenous immunoglobulin (IVIG) and Granulocyte-Colony Stimulating Factor (G-CSF) will be given as 
per institutional standard.
STUDY EVALUATIONS:
The following evaluations will be collected before transplant:
- Pregnancy test
- Chest X-ray
- ECG/ECHO
- Pulmonary Function Tests, as applicable
- DXA Scan, as applicable
- BRAIN MRI
- Low dose ACTH
- Endocrine testing
- Urinalysis
- Immunoglobulin Levels
- Genetic counseling
- Audiology consultation*
- Ophthalmology consultation*
- Endocrinology evaluation*
- Cardiology consultation*
- Pulmonary consultation*
- Neurology evaluation*
- Neuropsychometric testing will occur at Months 12, 24, 36 and 60.
*Multidisciplinary team evaluation also performed at Day 180 and Month 12, 24, 36 and 60 if 
applicable.
The following evaluations will be collected before transplant; at Days 0, 21, 42, 60, and 100; and at 
Months 6, 9, 12, 24, 36 and 60:
- Physical exam, weight, height, vital signs, performance status.
- CBC with differential and platelets
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 3 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
- Electrolytes, BUN, Creatinine
- AST, ALT, Bilirubin, Albumin and LDH
- ECHO*
* Months 12, 24,36 and 60 only.
Enzyme analysis will be collected as clinically indicated.
PB STRs / FISH will be collected on Days 21, 60, and 100; and as clinically necessary.
Lymphocytes subset / PHA assay will be collected between Days 21-42; Days 60-100; and at Months 6, 
9, 12, 24, 36 and 60. Immunoglobulin levels will be collected pre-study, at Day 100, and at 6, 9, 12, 24, 
36 and 60 months.
BLOOD SAMPLES:
To study how these cells are working in your system, blood samples will be taken on Days 21, 42, 60, 
and 100; at Months 6, 9 and 12; and at Year 2 and Year 3 following transplant. Approximately 6-8 
teaspoons of blood will be collected each time. The total blood drawn for this study over three years 
should not exceed 1 and 3/4 cups. This amount is considered safe in adults. The amount of blood 
collected will be decreased in children and/or in patients where this amount of blood collection would 
not be appropriate.
If you have a central line, the blood will be taken from it, so that extra needlesticks should not be needed. 
If you do not have a central line, you will need to have one placed. This will be a separate procedure for 
which you will sign a separate consent form. You will need to come to the clinic on the days of blood 
drawing and to be seen at Texas Children's Hospital. This blood is not for research purposes, but rather 
for treatment response monitoring.
FOLLOW-UP:
After year 1, you will be asked to return to the clinic once a year for consultations. These consultations 
with specialists will be similar to the ones you had before your transplant.
Authorization to Use or Disclose (Release) Health Information that Identifies You for a Research Study
If you sign this document, you give permission to people who give medical care and ensure quality from 
Baylor College of Medicine and TCH: Texas Children's Hospital  to use or disclose (release) your health 
information that identifies you for the research study described in this document.
The health information that we may use or disclose (release) for this research includes:
Research related health information
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 4 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
     •  Information from health records such as diagnoses, progress notes, medications, lab or radiology 
findings, etc.
     •  Specific information concerning HIV
     •  Demographic information (name, D.O.B., age, gender, race, etc.)
     •  Billing or financial records
     •  Photographs, videotapes, and/or audiotapes of you
The health information listed above may be used by and or disclosed (released) to researchers, their 
staff and their collaborators on this research project, the Institutional Review Board, Baylor College of 
Medicine, and TCH: Texas Children's Hospital. 
Agents of the U.S. Food and Drug Administration may inspect the research records including your 
health information. Agents of regulatory agencies such as the U.S. Department of Health and Human 
Services will be permitted to inspect the research records including your health information.
A Data and Safety Monitoring Board will have access to the research records including your health 
information.
Use or Disclosure Required by Law
Your health information will be used or disclosed when required by law.
Your health information may be shared with a public health authority that is authorized by law to collect or 
receive such information for the purpose of preventing or controlling disease, injury, or disability and 
conducting public health surveillance, investigations or interventions.
Baylor College of Medicine and TCH: Texas Children's Hospital are required by law to protect your 
health information. By signing this document, you authorize Baylor College of Medicine and TCH: Texas 
Children's Hospital to use and/or disclose (release) your health information for this research. Those 
persons who receive your health information may not be required by Federal privacy laws (such as the 
Privacy rule) to protect it and may share your information with others without your permission, if 
permitted by laws governing them.
Please note that the research involves treatment.  You do not have to sign this Authorization, but if you 
do not, you may not receive research-related treatment.  To maintain the integrity of this research study, 
you generally will not have access to your personal health information related to this research until the 
study is complete. However, your health information that is necessary to your care will be provided to 
you or your physician. At the conclusion of the research and at your request, you generally will have 
access to your health information that Baylor College of Medicine and TCH: Texas Children's Hospital 
maintain in a designated record set, which means a set of data that includes medical information or 
billing records used in whole or in part by your doctors or other health care providers at Baylor College 
of Medicine and TCH: Texas Children's Hospital to make decisions about individuals. Access to your 
health information in a designated record set is described in the Notice of Privacy Practices provided to 
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 5 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
you by representatives of the specific institution where you are being enrolled into this research study 
which are: Baylor College of Medicine and TCH: Texas Children's Hospital.
Please note that you may change your mind and revoke (take back) this Authorization at any time. Even 
if you revoke this Authorization, researchers, their staff and their collaborators on this research project, 
the Institutional Review Board, regulatory agencies such as the U.S. Department of Health and Human 
Services, FDA, Baylor College of Medicine, Data and Safety Monitoring Board, and TCH: Texas 
Children's Hospital may still use or disclose health information they already have obtained about you as 
necessary to maintain the integrity or reliability of the current research.  If you revoke this Authorization, 
you may no longer be allowed to participate in the research described in this Authorization .
To revoke this Authorization, you must write to: Dr. Caridad Martinez, MD
BCM Center for Cell and Gene Therapy, Suite 1640
Feigin Center, 1102 Bates Avenue
Houston, TX 77030
This authorization does not have an expiration date. If all information that does or can identify you is 
removed from your health information, the remaining information will no longer be subject to this 
authorization and may be used or disclosed for other purposes.
No publication or public presentation about the research described above will reveal your identity 
without another authorization from you.
RISK OF CENTRAL LINE PLACEMENT:
The risks of central line placement include the risk of the surgical procedures to insert the catheter. 
These risks include a pneumothorax (air inside the chest), bleeding, infection, and the risk of 
anesthesia. These risks will be explained in greater detail by your surgeon prior to placement of the 
central line. After placement, the central line may become infected, necessitating hospitalization, 
treatment with intravenous antibiotics, and possibly removal of the line and placement of a new line. In 
addition, a blood clot may develop in the line. If the clot cannot be dissolved, the line will need to be 
replaced and a new line inserted.
RISKS OF BUSULFAN:
The side-effects of this agent include the suppression of bone marrow activity, resulting in reduction in 
the number of platelets, red cells, and white cells found in the circulation. It can also cause nerve 
damage, which could result in seizures. Other side-effects include rapid heart rate, darkening of the 
skin, and sterility. Rarely, it can cause serious liver and lung problems.
RISKS OF CYTOXAN:
Common side-effects may include upset stomach and vomiting, mouth sores and stomach ulcers, fluid 
retention with seizures, diarrhea, bladder problems that cause pain when urinating or cause blood in the 
urine (this may be prevented by giving extra amounts of fluids by vein or by a drug called MESNA), hair 
loss, skin rashes, low blood counts with higher risk for infection, bleeding and/or anemia, and sterility 
Potential Risks and Discomforts
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 6 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
(inability to have children). Rare side-effects may include heart damage, second cancers (very rare), 
lung damage, and blurred vision.
RISKS OF FLUDARABINE:
Likely (may happen in more than 20% of patients):
Low number of red blood cells (anemia); Low number of white blood cells; Low number of blood 
platelets; Feeling tired; Nausea (feeling sick to your stomach); Throwing up (vomiting); Weak immune 
system; Pneumonia; Infection; Bleeding; Pain; Electrolyte imbalance.
Less likely (may happen in fewer than 20% of patients):
Diarrhea; Mouth sores; Skin rash; Fever; Swelling of hands and feet; Numbness and tingling in hands 
and/or feet; Loss of appetite.
Rare but serious (may happen in fewer than 2% of patients):
Changes in vision; Feeling nervous or anxious; Confusion; Cough; Difficulty breathing; Feeling weak; 
Severe brain injury which can lead to death; Kidney damage that could require dialysis; Coma; New 
(secondary) cancers. 
RISKS OF MESNA (SODIUM 2-MERCAPTOETHANE SULFONATE MESNEX):
May cause nausea and vomiting, and a bitter taste in your mouth during IV administration. Rare 
side-effects have included abdominal discomfort, headache, limb and joint pain, tiredness, and 
diarrhea.
RISKS OF MYCOPHENOLATE MOFETIL (MMF):
Risks may include upset stomach, including diarrhea and vomiting; risk of serious infections; bleeding 
and easy bruising; risk of certain cancers with long-term treatment; risks to an unborn baby during 
pregnancy.
These drugs are standard in the treatment of your disease:
CYCLOSPORIN A (CSA): Risks may include acne; dizziness; headache; increased hair growth; 
nausea; runny nose; sleeplessness; stomach discomfort; vomiting.
PHENYTOIN: Risks may include constipation; dizziness; headache; mild nervousness; nausea; trouble 
sleeping; vomiting.
IVIG: Risks include headache, myalgia, fever, chills, backache, chest pain, nausea and/or vomiting.
G-CSF: Risks may include aching or pain in the bones; local irritation at the site of the Injection; 
headache; higher than normal levels of liver enzymes in the blood which may indicate liver irritation or 
damage; increase of uric acid in the blood; a low number of platelets in the blood which may cause you 
to bruise and bleed more easily; low fever; enlargement of the spleen (an organ in the abdomen/belly 
which stores blood cells) which may cause pain in the abdomen or left shoulder; rash or worsening of 
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 7 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
skin rashes; inflammation of blood vessels in theskin leading to a raised purple rash and bruising that 
has been seen mainly in patients who are treated for a long time; higher than normal white blood coun; 
skin condition marked by fever and painful skin lesions that appear mainly on the face, neck, back and 
arms. 
Rarely it may cause:
- Allergic reactions which can be life threatening with shortness of breath, low blood pressure, rapid 
heart rate, hives and facial swelling. This reaction is very rare and has been associated mainly with 
intravenous administration If you are known to have sickle cell disease, filgrastim may cause a sickle 
cell crisis; 
- Severe damage to the spleen (an organ in the abdomen/belly which stores blood cells) which could 
lead to pain and loss of blood into the abdomen (belly) and maybe life threatening; 
- Difficulty breathing and lung damage that may be due to the white blood cells that are stimulated by 
filgrastim traveling to the lungs when they are inflamed or infected; 
- A blood disorder or leukemia that has only been seen in patients with certain immune disorders who 
are treated for a very long time.
RISK OF GRAFT FAILURE:
Graft failure occurs when the stem cells from the donor do not begin to grow and produce healthy blood 
cells. This means that you would have low blood counts for a long time. This increases your chances of 
bleeding or getting an infection, which can be fatal. If no further treatment is received, or despite 
treatment, it is still possible that you may die from your disease or from complications caused by having 
too few stem cells.
RISK OF GRAFT VERSUS HOST DISEASE (GVHD):
Another significant risk of this research study is that GVHD may develop. GVHD occurs when the new 
stem cells (known as the graft) recognize that the body tissues of the patient (host) are different from 
those of the donor. When that happens, the graft attacks host and can cause significant health 
problems, specifically in the lungs, eyes, mouth, liver, skin, joints, and muscles. The risks of GVHD are 
higher with unrelated donor transplants. Signs of GVHD include diarrhea, skin rashes and blisters, and 
liver problems. Severe GVHD disease can be life-threatening and requires drug treatment. 
Occasionally, it may be fatal despite the best available treatment.
RISKS OF BLOOD DRAWS:
The risks of having blood drawn include pain during the procedure, and a rare chance of bleeding 
and/or infection at the site of the needlestick, as well as a bruised feeling following the procedure. The 
amount of blood taken will not exceed the amount that is considered safe by institutional guidelines.
ADDITIONAL RISKS:
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 8 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
The degree of immune suppression in stem cell transplant patients leads to an increased risk of 
infections, especially those due to cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr 
virus (EBV), pneumonia, and other viruses. Preventative medicines are given when possible (Acyclovir, 
Bactrim, antifungal and antibacterial mouth rinses, etc.), and treatment is started very promptly, usually 
before the infection is confirmed. The hematologic malignancy may recur. The administration of blood 
products carries the risk of blood born infections such as hepatitis,
CMV, and HIV. Blood products are carefully screened for these agents.
Other complications of an unexpected nature may occur. In fact, almost every patient develops some 
new or very rare complication during his/her transplant. In addition, there is a chance that you could die 
from this treatment or from side-effects of the treatment, such as bleeding or infection.
Study staff will update you in a timely way on any new information that may affect your decision to stay in 
the study.  There is a small risk for the loss of confidentiality. However, the study personnel will make 
every effort to minimize these risks.
Potential Benefits
The benefits of participating in this study may be: improved potential for cure or improved survival. 
Improved survival means you may live longer before the disease comes back (in remission) than you 
would do without the transplant. You may also experience decreased risk of toxicities from the UCB 
stem cell transplant.  However, you may receive no benefit from participating.
Alternatives
The following alternative procedures or treatments are available if you choose not to participate in this 
study: other chemotherapy, other drugs being studied, the standard preparative regimen for an 
allogeneic stem cell transplant, or no treatment at all.
Subject Withdrawal from a Study
Withdrawing from this protocol during the conditioning regimen (and before infusion of the stem cells) 
may lead to serious consequences, including death. Please contact your study doctor if you decide to 
withdraw from the study. She will help you stop safely.
Subject Costs and Payments
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 9 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
All medical expenses related to this treatment protocol will be the responsibility of the patient. You will 
have an opportunity to discuss the expenses or costs associated with participation in this study. All 
costs related to your medical care will be charged to you or your insurance carrier.
You or your insurance company will be responsible for all treatments, medicines (including Busulfan, 
Cytoxan, Fludarabine, Mesna, MMF, Cyclosporin A, IVIG and Phenytoin), and/or procedures in this 
study.
You will not be charged for studies or procedures that are performed solely for research purposes , such 
as the blood collected to learn more about the way the new cells are growing (mentioned above in the 
procedures section). The cost of this treatment and your insurance coverage will be discussed with the 
patient's insurance carrier, or other agencies as needed. Financial counseling is available upon request 
to discuss the cost of this treatment and your insurance coverage, or coverage as provided by other 
agencies.
You will not be paid for taking part in this study.
This institution does not plan to pay royalties to you if a commercial product is developed from blood or 
tissue obtained from you during this study.
Research Related Injury
If you are injured as part of your participation in this study, there are no plans to pay you. Please contact 
your study doctor, Dr. Caridad Martinez, if you feel you have been injured as a result of taking part in this 
study.
Research personnel will try to reduce, control, and treat any complications from this research. If you are 
injured because of this study, you will receive medical care that you or your insurance will have to pay for 
just like any other medical care.
Women of Childbearing Potential
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 10 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
It is possible that the medicines used in this study could injure a fetus if you or your partner becomes 
pregnant while taking them. Because of the potential risks involved, you or your partner should not 
become pregnant while you are participating in this study.
If you are sexually active or become sexually active and can get pregnant or can get your partner 
pregnant, you must agree to use one of the following forms of birth control every time you have sex and 
for (3) months afterwards:
* oral contraceptives ("the pill"),
* intrauterine devices (IUDs),
* contraceptive implants under the skin, or contraceptive injections,
* condoms with foam.
Should you become pregnant while on this study, you must immediately notify the study personnel.
The investigator will assist you in finding appropriate medical care. The investigator also may ask to be 
allowed to continue getting information about your pregnancy. You can choose not to provide this 
information.
Subject's Rights
Your signature on this consent form means that you have received the information about this study and 
that you agree to volunteer for this research study.
You will be given a copy of this signed form to keep.  You are not giving up any of your rights by signing 
this form.  Even after you have signed this form, you may change your mind at any time. Please contact 
the study staff if you decide to stop taking part in this study.
If you choose not to take part in the research or if you decide to stop taking part later, your benefits and 
services will stay the same as before this study was discussed with you.  You will not lose these 
benefits, services, or rights.
The investigator, CARIDAD A. MARTINEZ, and/or someone he/she appoints in his/her place will try to 
answer all of your questions. If you have questions or concerns at any time, or if you need  to report an 
injury related to the research, you may speak with a member of the study staff: DR. CARIDAD 
MARTINEZ at 832-824-4692 during the day, and 832-826-0860 after hours.
Members of the Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals (IRB) 
can also answer your questions and concerns about your rights as a research subject. The IRB office 
number is (713) 798-6970. Call the IRB office if you would like to speak to a person independent of the 
investigator and research staff for complaints about the research, if you cannot reach the research staff, 
or if you wish to talk to someone other than the research staff.
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 11 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
If your child is the one invited to take part in this study you are signing to give your permission. Each 
child may agree to take part in a study at his or her own level of understanding. When you sign this you 
also note that your child understands and agrees to take part in this study according to his or her 
understanding.
Please print your child's name here __________________________
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 12 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018


CONSENT FORM 
TREATMENT CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-25064-  UMBILICAL CORD BLOOD TRANSPLANT FOR CONGENITAL PEDIATRIC 
DISORDERS (UCB)
Signing this consent form indicates that you have read this consent form (or have had it read to you), 
that your questions have been answered to your satisfaction, and that you voluntarily agree to 
participate in this research study.  You will receive a copy of this signed consent form.
Subject
Date
Legally Authorized Representative
Parent or Guardian
Date
Investigator or Designee Obtaining Consent
Date
Witness (if applicable)
Translator (if applicable)
Date
Date
Approved  from September 04, 2018  to September 03, 2019        Chair Initials: G. H.
Page 13 of 13
UCB Protocol Version 12.0, Dated 8/30/2017
Last Amendment:
3/22/2018