Clinical trial NCT01247701
Conditions: Myeloid Hematological Malignancies
Keywords: UCB Umbilical Cord Blood Transplant Umbilical Cord Blood Transplant Cord Blood Stem Cell Transplantation Pediatric Myeloid Hematological Malignancies Busulfan Cytoxan Cyclophosphamide Fludarabine
Sponsor: Baylor College of Medicine
Start date: 2010-11-01; Completion date: 2019-10-01
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this study, the investigators will use busulfan and cyclophosphamide (BuCy) backbone with the addition of fludarabine as the preparative Stem Cell Transplant (SCT) regimen. As an attempt to improve engraftment rate and reduce infections, the investigators are going to incorporate fludarabine in the conditioning regimen. The use of a BuCy backbone has been widely used and comparable to total body irradiation and cyclophosphamide (Cy/TBI) regimen.

Encouraging data on adding fludarabine to the SCT 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 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.

In an attempt to decrease the rate of viral infection and reactivation, the investigators will avoid ATG (Thymoglobulin) / Campath (anti-CD52), and instead administer Mycophenolate Mofetil (MMF). The addition of fludarabine should compensate any increase risk of graft failure with the removal of the ATG/Campath. The investigators anticipate that the removal of ATG/Campath will facilitate immune reconstitution more efficiently after receiving a UCBT.

Detailed description:
The following will be given as the conditioning regimen for the transplant:

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. Anticonvulsants will be given in accordance with standard Blood and Marrow Transplant Program recommendations.

CYCLOPHOSPHAMIDE: Cyclophosphamide (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 1 hour. 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.

FLUDARABINE: Fludarabine will be given IV daily over 1 hour for 3 days. Dosing will be as follows: for patients ≤ 10 kg: 1.3 mg/kg; for patients \> 10 kg: 40 mg/m2. Preparation, administration and monitoring will be according to standard practice procedure

POST-TRANSPLANT IMMUNOSUPPRESSION:

* CSA will begin on Day -3. For children \< 40 kg, the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. Dose adjustments will be made to maintain levels above 200 ng/mL. Levels will be done on Day 0 and then as clinical indicated. CSA will be tapered per institutional SOP. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CSA will be converted to an oral form.
* 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.

CNS Disease: Patients with CNS relapse or primary CNS disease that is symptomatic or associated to radiological changes will receive additional irradiation to the craniospinal axis.

SUPPORTIVE CARE:

* Supportive care will be provided as per standard practice of the 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 provide optimum care for that particular patient.
* IVIG: Intravenous immunoglobulin (500 mg/kg per dose) will be given monthly until discontinuation of GVHD therapy and documentation of antibody production.
* CB-CTLs: Patients enrolled in this protocol may also be eligible for infusion of CB-derived multivirus-specific CTL to provide virus-specific immune reconstitution and treatment of viral infections after CBT.

EVALUATIONS DURING THE STUDY:

Screening Procedures; Pre-HCT:

* Physical examination
* Pregnancy test
* Complete blood count and chemistries
* Electrocardiogram
* Echocardiograph
* PT/PTT/Fibrinogen/Anti-Thrombin III/von Willebrand Factor
* Viral tests
* Bone marrow aspirate and biopsy/Lumbar puncture
* Renal Function (GFR)
* Lumbar puncture will be performed
* Pulmonary Function test

EVALUATIONS BETWEEN DAY 0 AND DAY 100:

* Physical examination
* Complete blood count and chemistries
* Lytes/BUN/Cr
* Peripheral blood for STRs or FISH analysis for molecular diagnostics
* Lymphocyte phenotype testing and lymphoproliferative responses
* Bone marrow aspirate and biopsy for assessment of leukemia status and UCB engraftment
* Lumbar puncture
* Immunoglobulins

EVALUATIONS AFTER DAY 100:

* Physical examination
* Complete blood count and chemistries
* Lytes/BUN/Cr
* Serum chemistries
* Peripheral blood with assessment of engraftment by STRs or FISH analysis and enzyme levels
* Echocardiograph with LVEF
* Bone marrow aspirate and biopsy assessment of leukemia status and UCB engraftment
* Lymphocyte phenotype testing (CD3, CD4, CD8, CD19 and CD56) and lymphoproliferative responses
* Immunoglobulins

FOLLOW-UP INTERVAL:

Patients will be seen in the hospital everyday until discharge. After discharge from the hospital, the patient will be following on the BMT clinics on a regular basis as recommended by the primary physician.

Arms: arm 1: Busulfan,Cyclophosphamide, Fludarabine, Cord Blood Stem Cell Infusion
Interventions: intervention 1: Busulfan intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: Cord Blood Stem Cell Infusion
Intervention descriptions: intervention 1: Busulfan 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. It will be given on Days -9, -8, -7 and -6. intervention 2: Cyclophosphamide (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 1 hour. The total dose to be given over 4 days is 200 mg/kg. intervention 3: Fludarabine will be given IV daily over 1 hour for 3 days. Dosing will be as follows: for patients ≤ 10 kg: 1.3 mg/kg; for patients \> 10 kg: 40 mg/m\^2. intervention 4: The cord blood stem cells will be infused on Day 0.

Protocol documents:
Prot_SAP_001.pdf: 
 
1
Version 1.0 – 03/04/2010 
 
 
 
 
           Version 7.0 – 09/12/2014 
Version 2.0 – 07/27/2010 
 
 
 
 
           Version 8.0 – 08/12/2015 
Version 3.0 – 02/16/2011 
Version 9.0 – 12/19/2016 
Version 4.0 – 12/07/2011                                                                           Version 9.1 – 11/01/2018 
Version 5.0 – 08/16/2012                                                                           Version 10.0 – 5/11/2021 
Version 6.0 – 06/14/2013                                                                           Version 10.1 – 6/29/2021 
 
 
 
Umbilical Cord Blood Transplant for Children with Myeloid 
Hematological Malignancies (UCAML) 
 
 
PRINCIPAL INVESTIGATORS 
 
Caridad A. Martinez, MD 
Robert A. Krance, MD 
 
 
 
CO-INVESTIGATORS 
 
 
Helen E. Heslop, MD 
Cliona Rooney, PhD 
George Carrum, MD 
Nabil Ahmed, MD 
 
Tao Wang, PhD 
Bambi Grilley, RPh, CCRA, CCRC, CIP 
 
 
 
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 
 
 
TABLE OF CONTENTS ............................................................................................................. 2 
1.0 OBJECTIVES ......................................................................................................................... 4 
2.0 BACKGROUND AND RATIONALE ....................................................................................... 4 
3.0 ELIGIBILITY ......................................................................................................................... 7 
4.0 
Preparative Therapy / Immunosuppressive Therapy ................................................................ 8 
5.0 
EVALUATIONS DURING THE STUDY .......................................................................... 10 
6.0 
STUDY ENDPOINTS ...................................................................................................... 14 
7.0 
STUDY DRUGS.............................................................................................................. 14 
8.0 
EVALUATION OF TOXICITIES...................................................................................... 18 
9.0 
RISKS ............................................................................................................................ 18 
10.0 
STATISTICAL CONSIDERATIONS ................................................................................ 18 
11.0 
RECORDS TO BE KEPT ................................................................................................. 20 
12.0 
REPORTING REQUIREMENTS ...................................................................................... 21 
13.0  
INFORMED CONSENT ............................................................................................... 21 
14.0 
DATA MONITORING PLAN ........................................................................................... 21 
15.0 
OFF STUDY CRITERIA .................................................................................................. 21 
16.0 
REFERENCE LIST .......................................................................................................... 22 
 


 
3
Umbilical Cord Blood Transplant for Children with Myeloid Hematological Malignancies (UCAML) 
 
CHECKLIST FOR PATIENT ELIGIBILITY AND NECESSARY INFORMATION  
 
Patient ID ________________________  
Patient Name_______________________________ 
 
YES         NO      VALUE/DATE 
Any “NO” answers will make a patient ineligible for study participation: 
 
 
 
 
 
____        ____      ______     
Patients with a myeloid hematologic malignancy (acute 
myelogenous leukemias, secondary myelogenous leukemia or 
myelodysplastic syndrome) unlikely to be cure by standard 
chemotherapy.  This includes patients who have relapsed after 
standard chemotherapy treatments and patients in first remission 
with unfavorable prognostics features.   
 
____        ____      _____ 
UCB units identified as the HSC source 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  
 
 
 
 
 
≥4 x 107 nucleated cells per kilogram recipient  
 
 
 
 
 
body weight. 
 
____        ____      ______     
 
Lansky/Karnofsky scores > 60 
 
____        ____      ______     
 
Written informed consent and/or signed assent line from  
patient, parent or guardian. 
 
____        ____      ______     
 
Negative Pregnancy Test, if applicable 
 
Any “YES” answers will make a patient ineligible for study participation: 
 
_____        ____      ______      
 
Severe intercurrent infection (see Section 3.2.1) 
  
             _____      _____        ______                        
 Severe renal disease (Creatinine > 3X  
 
 
 
 
normal for age) 
 
____       _____        ______              
Severe hepatic disease (direct bilirubin > 3mg/dl, or SGOT > 500) 
 
_____       _____      ______ 
 
Patient has DLCO < 50% predicted or FEV1 < 50%  
of predicted, if applicable 
 
_____       _____    _____  
 
Patients with symptomatic cardiac failure unrelieved   
 
 
 
 
 
by medical therapy or evidence of significant cardiac  
 
 
 
 
 
dysfunction by echocardiogram (shortening fraction 
 
 
 
 
 
<20%). 
 
____        ____      ______     
 
HIV Positive 
 
Patient/Guardian able to give informed consent:  ______________________________ 
Signature of MD: ____________________Date:________________________________ 
To check eligibility of a patient, call Dr. Martinez 832-824-4692.


 
4
 
1.0 OBJECTIVES 
1.1 Primary Objective 
1.1.1 To determine the safety and overall survival at 100 days, 1 year, and 3 years 
after umbilical cord blood transplant in pediatric patients with myeloid 
hematological malignancies. 
1.2 Secondary Objectives 
1.2.1 To evaluate donor engraftment at 100 days, 6, 9, 12, 24 and 36 months after 
transplant. 
1.2.2 To determine neutrophil recovery at Day 42 and platelet recovery at Day 180.  
1.2.3 To estimate the risk of severe grade III-IV acute GvHD at Day 100. 
1.2.4 To estimate the risk of chronic GvHD at 1 year. 
1.2.5 To assess leukemia free survival at 1 and 3 years. 
1.2.6 To assess relapse rate at 1 and 3 years after transplant. 
1.3 Exploratory Objective 
1.3.1 To evaluate T/B/NK cell recovery and function at day 100, 6, 9, 12, 24 and 36 
months after transplant. 
 
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 performed [1-8]. 
In recent years, use of umbilical cord blood as an alternative source of transplantable 
haemopoietic stem cells has increased substantially, extending the availability of this 
treatment, especially for children. 
 
2.2 Background of Hematological Malignancies and Cord Blood Transplantation 
Despite major advances in curing children with leukemias over the last 30 years, 
approximately 20% of patients relapse and are candidates for transplantation [1]. Many 
of these patients will not be able to identify a matched related or unrelated bone marrow 
donor in a timely fashion. Transplantation of bone marrow from an unrelated adult 
volunteer donor however is limited by HLA-matching requirements, high risk of graft-
versus-host disease (GvHD), opportunistic infections, and donor availability. In recent 
years, use of umbilical cord blood as an alternative source of transplantable 
haemopoietic stem cells has increased substantially, extending the availability of this 
treatment, especially for children. Although time to engraftment is slower, most reports 
show a lower risk of severe GvHD after transplantation of unrelated-donor umbilical 
cord blood than of unrelated-donor bone marrow, despite the frequent use of HLA-
mismatched graft for transplantation of umbilical cord blood [9-19]. 
 
Recent results of COBLT, a multi-institutional, prospective NIH-sponsored trial of 
unrelated donor UCB transplantation, have further advanced the field of UCB 
transplantation. In this Phase II study, 191 pediatric patients diagnosed with a 


 
5
hematologic malignancy [(median age = 7.7 years) (range: 1-18)]; [(median weight = 
25.9 kg) (range: 7.5 – 118.4 kg)] were transplanted with one UCB unit. All patients 
received total body irradiation (TBI), cyclophosphamide and antithymocyte globulin 
(ATG) for pre-transplant conditioning, and post-transplant cyclosporine and 
methylprednisone for GvHD prophylaxis. The median cell dose delivered as 
measured by the pre-cryopreservation cell count was 5.2 x 107 cells/kg and 1.5 x 105 
CD34 cells/kg. Donor selection was based on low resolution DNA-based HLA typing 
at Class IA and B, and high resolution DNA-based typing at Class II DRB1. The 
cumulative incidence of neutrophil engraftment, defined as achieving an ANC of 
500/mcL by Day +42 with > 90% donor chimerism, was 75% (95% confidence interval 
[CI] 69-81%). The cumulative incidence of platelet engraftment, defined as maintaining 
a platelet count of > 50 x 109/L without transfusion support by Day 180 was 50% (95% 
CI 42-59%). The cumulative incidence of acute grades III/IV GvHD at Day +100 was 
19% (95% CI 12-24%). The incidence of chronic GvHD at 1 year was 20% (95% CI 
15- 26%) with 70% of the chronic GvHD classified as limited disease. In multivariate 
analysis, HLA matching was associated with the incidence of GvHD (P = 0.007). Most 
of the children enrolled on this study had high risk (CR1 with high risk features, CR2-3, 
active disease) hematologic malignancies. Their cumulative incidence of relapse at one 
year was 19% (95% CI 14-25%). Overall 95/191 patients died on study, with 41% of 
deaths from relapse, 19% from graft failure, and 18% from GvHD (50% of those dying 
from GvHD had infection as a secondary cause of death) [20]. 
 
2.3 Justification for Umbilical Cord Blood Transplantation 
The major limiting step to HSCT in hematologic diseases is the availability of a 
suitable matched stem cell source. It is well known that delaying a HSCT in patients 
with malignacies 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. Umbilical 
cord blood transplantation has extended the availabitliy of allogeneic hematopoietic 
SCT to patients who would otherwise not be eligible for this curative approach. 
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). In 2003, Michel et al. [29], on behalf of Eurocord, analyzed 95 
children (16 years old or less) who underwent unrelated CBT for AML (1994-2002). In 
all, 20 were transplanted in CR1, 47 in CR2, 5 in CR3 and 23 were not in remission. 
Poor prognosis cytogenetic abnormalities were identified in 29 of 81 available cases 
(36%). TBI was given in 44 children and BU ot 47. CSA and steroid were used to 
prevent GvHD in 63 cases. The number of HLA disparities range from 0-3/6. The 
median number of infused nucleated cells was 4.4 x 107/kg. Cumulative incidence of 
neutrophil recovery at Day 60 was 78%, 100 day acute GvHD incidence was 35% and 
100 day TRM was 20%. The 2 year cumulative incidence for relapse was 29%. This 
study confirmed that UCB is an adequate alternative of a stem cell source in patients 
with AML. 
 
2.4 Major Problems after Umbilical Cord Blood Transplant 


 
6
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 haemopoietic 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%) [11-21]. 
 
2.5 Protocol Proposal 
In our study, we will use busulfan and cyclophosphamide (BuCy) backbone with the 
addition of fludarabine as the preparative SCT regimen. As an attempt to improve 
engraftment rate and reduce infections, two major causese of death reported on the 
COBLT study, we are going to incorporate fludarabine in the conditioning regimen.  
Purine-analogs, in particular 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. 
 
The use of a BuCy backbone has been widely used and comparable to total body 
irradiation and cyclophosphamide (Cy/TBI) regimen. Although Cy/TBI was found to 
be significantly better in a randomized French study of adult patients, these results were 
not confirmed in a similar French pediatric study comparing Bu/Cy to Cy/TBI [24, 25].   
Children with AML treated with Bu/Cy had EFS of 80%, compared to 42% following 
TBI. Finally, a comparison of the two regimens in patients with AML from the Acute 
Leukemia Working Party of the European Group for Blood and Marrow 
Transplantation (EBMT) could find no difference in leukemia-free survival in 237 
patients treated with Bu/Cy versus 237 patients treated with Cy/TBI [26]. Avoiding 
irradiation in pediatric patients is desirable to minimize growth retardation and 
intellectual deficits. An initial study by Wingard et al. showed that growth impairment 
may be similar with the two cytoreductive regimens [27]. Two subsequent more 
comprehensive analyses demonstrated that non-TBI containing regimens do not cause 
growth failure following SCT [28]. A review of the relevant literature reveals that 
Bu/Cy regimens are as effective as TBI regimens, with fewer late effects, and will 
therefore be used as the standard backbone cytoreductive regimen for SCT patients in 
this protocol. 
 
Encouraging data on adding fludarabine to the SCT 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 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 [22, 23]. 
 
In our study, as an attempt to decrease the rate of viral infection and reactivation, we 
will avoid ATG (Thymoglobulin) / Campath (anti-CD52), and instead administer 


 
7
MMF. The addition fludarabine should compensate any increase risk of graft failure 
with the removal of the ATG/Campath. We anticipate that the removal of 
ATG/Campath will facilitate immune reconstitution more efficiently after receiving a 
UCBT. 
 
3.0 ELIGIBILITY 
3.1 Inclusion Criteria 
3.1.1 Patients with a myeloid hematologic malignancy (acute myelogenous 
leukemia, secondary myelogenous leukemia or myelodysplastic syndrome) 
unlikely to be cure by standard chemotherapy. This includes patients who 
have relapsed after standard chemotherapy treatments, and patients in first 
remission with unfavorable prognostics features. 
3.1.2 Related or unrelated umbilical cord blood unit with 0-1 antigen mismatch at 
HLA-A and B (at low resolution) and DRB1 (at high resolution) with a total 
nucleated cell dose of ≥ 4 x 107/kg. 
3.1.3 Lansky/Karnofsky scores ≥ 60. 
3.1.4 Written informed consent and/or signed assent line from patient, parent or 
guardian. 
3.1.5 Negative pregnancy test, if applicable. 
 
3.2 Exclusion Criteria 
3.2.1 Patients with uncontrolled infections. For bacterial infections, patients must 
be receiving definitive therapy and have no signs of progressing infection 
for 72 hours prior to enrollment. 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) 
3.2.4 Patient has DLCO < 50% predicted or FEV1 < 50% of predicted, if 
applicable. 
3.2.5 Patients with symptomatic cardiac failure unrelieved by medical therapy or 
evidence of significant cardiac dysfunction by echocardiogram (shortening 
fraction < 20%). 
3.2.6 HIV positive. 


 
8
 
4.0 Preparative Therapy / Immunosuppressive Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-9 
-8 
  -7 
  -6 
    -5 
    -4 
    -3 
    -2 
    -1 
   0 
Busulfan 
Cytoxan 
CSA 
MMF 
Fludarabine 
Cytoxan 
Busulfan 
Fludarabine 


 
9
 
Day 
Agent 
 
-9 
Busulfan 
 
-8 
Busulfan 
 
-7 
Busulfan 
 
-6 
Busulfan 
 
-5 
Cyclophosphamide 
 
 
50 mg/kg/day IV over 1 hour (MESNA; 
continuous infusion or 5 times daily) 
 
-4 
Cyclophosphamide 
50 mg/kg/day IV over 1 hour (MESNA; 
continuous infusion or 5 times daily) 
 
 
 
-3 
Cyclophosphamide 
 
 
Fludarabine 
50 mg/kg/day IV over 1 hour (MESNA; 
continuous infusion or 5 times daily) 
 
40 mg/m2/day IV over 1 hour 
-2 
Cyclophosphamide 
 
Fludarabine 
50 mg/kg/day IV over 1 hour (MESNA; 
continuous infusion or 5 times daily) 
 
40 mg/m2/day IV over 1 hour 
-1 
Fludarabine 
40 mg/m2/day IV over 1 hour 
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. Anticonvulsants will be 
given in accordance with standard Blood and Marrow Transplant Program 
recommendations. 
4.2 Cyclophosphamide: Cyclophosphamide (50 mg/kg/dose) will be given IV on 
Days -5, - 4, -3 and -2 over 1 hour. 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 3 days. Dosing 
will be as follows: for patients ≤ 10 kg: 1.3 mg/kg; for patients > 10 kg: 40 mg/m2. 


 
10
Preparation, administration and monitoring will be according to standard practice 
procedure. 
 
4.4 Post-Transplant Immunosuppression 
4.4.1 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 to maintain levels 
above 200 ng/mL. Levels will be done on Day 0 and then as clinically 
indicated.  =CSA will be tapered per institutional SOP. 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 CNS Disease 
Patients with CNS relapse or primary CNS disease that is symptomatic or 
associated to radiological changes will receive additional irradiation to the 
craniospinal axis. See Appendix. 
 
4.6 Supportive Care 
4.6.1 Supportive care will be provided as per standard practice of the 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 
provide optimum care for that particular patient. 
4.6.2 IVIG: Intravenous immunoglobulin (500 mg/kg per dose) will be given 
monthly until discontinuation of GvHD therapy and documentation of 
antibody production. 
4.6.3 CB-CTLs: Patients enrolled in this protocol may also be eligible for infusion 
of CB-derived multivirus-specific CTL to provide virus-specific immune 
reconstitution and treatment of viral infections after CBT. 
 
5.0 EVALUATIONS DURING THE STUDY 
 
5.1 Screening Procedures; Pre-HCT 
5.1.1 Physical examination by Pediatric Bone Marrow Transplant physician 
(includes History, Physical Examination, Weight, Vital Signs, Pulse Ox and 
Performance Status). 
5.1.2 Pregnancy test 
5.1.3 Complete blood count with leukocyte differential, C-reactive protein 
5.1.4 Lytes/BUN/Cr 
5.1.5 Serum chemistries (AST/ALT/Bili/Alb/LDH) 
5.1.6 Electrocardiogram 
5.1.7 Echocardiograph 
5.1.8 PT/PTT/Fibrinogen/Anti-Thrombin III/von Willebrand Factor 
5.1.9 Viral tests (HSV, CMV, EBV, HIV, HBsAg, HBcAb, HC, HTLV1/2) 
5.1.10 Bone marrow aspirate and biopsy/lumbar puncture within 2-3 weeks of 
starting conditioning, as clinically indicated. 


 
11
5.1.11 Renal function (GFR) 
5.1.12 Lumbar puncture will be performed to evaluate any evidence of disease 
recurrence (if previously positive), as clinically indicated. 
5.1.13 Pulmonary function test, if applicable. 
 
5.2 Evaluations Between Day 0 and Day 100 
5.2.1 Physical examination by Pediatric Bone Marrow Transplant physician on 
Days 0, 21, 42, 60, 100 (includes History, Physical Examination, Weight, 
Vital Signs, Pulse Ox [on Day 0 only] and Performance Status) 
5.2.2 Complete blood count with leukocyte differential, C-reactive protein on 
Days 0, 21, 42, 60, 100 
5.2.3 Lytes/BUN/Cr on Days 0, 21, 42, 60, 100 
5.2.4 Serum chemistries (AST/ALT/Bili/Alb/LDH) on Days 0, 21, 42, 60, 100 
5.2.5 Peripheral blood for STRs or FISH analysis for molecular diagnostics 
around Days 21, 60 and 100 
5.2.6 Lymphocyte phenotype testing (CD3, CD4, CD8, CD19 and CD56), other 
general viral immune reconstitution studies (ex. ELISPOT, spectrotyping), 
and lymphoproliferative responses will be performed between Day 21-42 
and 60-100 
5.2.7 Bone marrow aspirate and biopsy for assessment of leukemia status and 
UCB engraftment between Day 21-42 and will be repeated between Day 90-
100 as clinically indicated. Bone marrow DNA specimen submitted to 
Molecular Diagnostic Laboratory. 
5.2.8 Lumbar puncture will be performed on Day 21-42 and Day 90-100 to 
evaluate any evidence of disease recurrence (if previously positive), as 
clinically indicated. 
5.2.9 Immunoglobulins (IgG, IgA, IgM) will be taken prior to administration of 
IVIG from Day 60-100. 
 
5.3 Evaluations after Day 100 
5.3.1 Physical examination by Pediatric Bone Marrow Transplant physician 
(includes History, Physical Examination, Weight, Vital Signs, and 
Performance Status) around 6, 9, 12, 24 and 36 months. 
5.3.2 Complete blood count with leukocyte differential, C-reactive protein around 
6, 9, 12, 24 and 36 months. 
5.3.3 Lytes/BUN/Cr around 6, 9, 12, 24, and 36 months. 
5.3.4 Serum chemistries (AST/ALT/Bili/Alb/LDH) around 6, 9, 12, 24 and 36 
months. 
5.3.5 Peripheral blood with assessment of engraftment by STRs or FISH analysis 
and enzyme levels (as appropriate) around 6, 12, and 24 or more frequently 
as clinically indicated. 
5.3.6 Echocardiograph with LVEF at 1 year. 
5.3.7 Bone marrow aspirate and biopsy assessment of leukemia status and UCB 
engraftment around 6, 9, 12 and 24 months, as clinically indicated. Bone 
marrow DNA specimen submitted to Molecular Diagnostic Laboratory. 
5.3.8 Lymphocyte phenotype testing (CD3, CD4, CD8, CD19 and CD56), other 
general viral immune reconstitution studies (ex. ELISPOT, spectrotyping), 


 
12
and lymphoproliferative responses will be performed around 6, 9, 12 and 24 
months after transplant. 
5.3.9 Immunoglobulins (IgG, IgA, IgM) will be taken at 6, 9, 12 and 24 months. 
 
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 clinics on a regular basis as 
recommended by the primary physician. 
 


 
13
5.5 Calendar of Study Evaluations 
 
 
Pre- 
UCBT 
Day 0 
Day 21 
Day 42 
Day 60 
Day 100 
M6 
M9 
M12 
M24 
M36 
Infusion of cells 
 
X 
 
 
 
 
 
 
 
 
 
History  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
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 
Pulse Ox 
X 
X 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
PT/PTT/Fibrinogen/ 
Anti-thrombin III/CRP//von 
Willebrand Factor 
X 
 
 
 
 
 
 
 
 
 
 
Viral tests (HSV, CMV, EBV, 
HIV, HBsAg, HBcAb, HC, 
HTLV1/2, ) 
X 
 
 
 
 
 
 
 
 
 
 
Complete blood count with 
leukocyte differential, 
C-reactive protein 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lytes/BUN/Cr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries - 
AST/ALT/Bili/Alb/ LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood with 
Assessment of engraftment by 
STRs or FISH analysis and 
enzyme levels (as appropriate) 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Echocardiograph 
X 
 
 
 
 
 
 
 
X 
 
 
Renal Function (GFR) 
X 
 
 
 
 
 
 
 
 
 
 
Lymphocyte phenotype testing 
(CD3, CD4, CD8, CD19 and 
CD56), other general viral immu
reconstitution studies 
(ex. ELISPOT, spectrotyping), 
and lymphoproliferative 
responses 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunoglobulins 
(IgG, IgM, IgA) 
 
 
 
 
X* 
X* 
X 
X 
X 
X 
 
Bone marrow aspirate and 
biopsy assessment of leukemia 
status and UCB engraftment. 
Bone marrow DNA specimen 
submitted to Molecular 
Diagnostic Laboratory for 
chimerism studies 
X 
 
X** 
X** 
 
X** 
X 
X 
X 
X 
 
Pulmonary Function Test, if 
applicable 
X 
 
 
 
 
 
 
 
 
 
 
Lumbar Puncture - if previous 
positive 
X 
 
X** 
X** 
 
X** 
 
 
 
 
 
* Immunoglobulin levels (IgG, IgA, IgM) will be taken as scheduled prior to receiving the monthly IVIG. 
** Bone marrow aspirate and lumbar puncture will be performed once during these days: 21-42 and 90-100. 


 
14
6.0 STUDY ENDPOINTS 
6.1 Engraftment: Neutrophil and platelet recovery will be analysed separately. 
Achievement of absolute neutrophil count > 0.5 x 109/L and of untransfused 
platelet count > 20 x 109/L on three consecutive days are considered events. 
Presence of > 95% donor cells will be considered full chimerism by molecular 
studies (STRs or FISH). 
6.2 Overall survival and organ function: 100 days, 1 year and 3 years after UCBT. 
6.3 Acute and Chronic GvHD (assessment of severity based on standard criteria). 
6.4 Systemic Infections: All microbiology documented infections occurring within 6 
months. Viral load will be monitored for CMV, EBV and AdV as institutional 
protocols. If there is any evidence of infection with these viruses, the patient will 
be started on medical or cellular therapy. 
6.5 Disease-Free Survival: Evaluate the incidence and disease-free survival at 1 and 3 
years. 
 
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) prior to administration. 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° 
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 kg the  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%. 


 
15
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. All patients will be treated with anticonvulsant therapy 
while receiving Busulfan. The clinical pharmacist must review orders for 
anticonvulsants. Blood anticonlvulsant levels should dictate dosing. 
 
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 Cyclophosphamide (CTX, Cytoxan) - Commercially Available 
7.2.1 Formulation: 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: Cyclophosphamide 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 C). Discard reconstituted solutions after 24 hours at room 


 
16
temperature; stable up to 6 days if refrigerated (2-8 degrees C). Since there 
is no preservative, precautions should be taken to insure sterility, or solution 
should be discarded within 8 hours. The parenteral form of 
cyclophosphamide prepared as a liquid oral preparation diluted to < 2 
mg/mL can be refrigerated (2-8 degrees C) for up to 14 days. 
 
7.2.4 Administration: 50 mg/kg will be given over 1 hour daily for a total of 4 
doses. 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 fibrosis3 (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 cyclophosphamide (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 Cyclophosphamide is excreted into breast milk. Neutropenia has been reported in 
breast-fed infants. Cyclophosphamide 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. 
 


 
17
7.3 FLUDARABINE 
7.3.1 Therapeutic Classification: Purine antimetabolite. 
 
7.3.2 Pharmaceutical Data: In vials of 50 mg. 
 
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 100 mL of 
standard intravenous piggy back fluid (dextrose 5%, or normal saline) over  
1 hour. 
 
7.3.4 Stability and Storage Requirements: Prior to mixing: Store under 
refrigeration 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; for patients > 10 kg: 
40 mg/m² IV over 1 hour daily for a total of 3 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. 
 
7.4 MYCOPHENOLATE MOFETIL (MMF): Risks may include upset stomach, 
including diarrhea and vomiting; risk of serious infections; bleeding and easy 
bruising; risk of some cancers with long term treatment; risk to baby in pregnancy. 
It will also cause decrease function on your lymphocytes (immunosuppression). 
 


 
18
7.5 CYCLOSPORIN A (CSA): Risks may include acne, dizziness, headache, 
increased hair growth, nausea, runny nose, sleeplessness, stomach discomfort, 
vomiting and seizures. It will also cause decreased function on your lymphocytes 
(immunosuppression). 
 
7.6 IVIG: Risks include headache, myalgia, fever, chills, backache, chest pain, nausea 
and/or vomiting. 
 
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 Leukemia relapse. 
9.2 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. 
9.3 GvHD: Acute GvHD leads to 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, V. 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 
pediatric diseases have been reported to be as low as 8% (Unpublished data of the 
University of Minnesota. Martinez, C, Orchard, P., and Tolar, J.). 
9.4 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. Other complications of 
an unexpected nature may be seen. There is a chance that 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 myeloid 
hematological malignancies received umbilical cord blood transplant will have a 
1-year overall survival rate of at least 60%. Accrual of pediatric patients with 


 
19
lymphoid hematological malignancies who are eligible to receive umbilical cord 
blood transplant is about 2 subjects per year. The accrual period is 10 years with 
follow-up of at least 2 years or till death for each patient. If we suppose that a true 
1-year overall survival rate of 40% would not be unacceptable, then we would 
need to accrue 20 patients to have 83% power to confirm the clinically 
meaningful 1-year overall survival rate of 60%. The type-I error is 0.05 with one-
sided testing, and the sample size determination was based on the assumptions of 
uniform accrual, no loss to follow-up and exponentially distributed survival time 
(30). 
 
10.2 Monitoring Overall Survival and Engraftment 
We will monitor grade III-IV GvHD continuously. Accrual to the trial will be 
halted if the rate of GvHD is estimated to be significantly higher than 10% using a 
one-sided 2.5% significance level. The choice of 10% aGvHD rate is consistent 
with the literature as summarized in Section 9.3. Patients will be monitored 
sequentially. Sequential monitoring will be implemented by a Pocock-type 
stopping boundary: The rule states that when the second patient finishes toxicity 
follow-up, if patient 2 had grade III-IV GvHD, then the trial will be halted; for 3rd 
to 6th enrolled patients who have finished follow-up, the trial will be halted if 
there are 3 or more grade III-IV GvHD; for 7th to 12th enrolled patients who have 
finished follow-up, the trial will be halted if there are 4 or more grade III-IV 
GvHD; for 13th to 17th enrolled patients who have finished follow-up, the trial will 
be halted if there are 5 or more grade III-IV GvHD; for 18th to 20th enrolled 
patients who have finished follow-up, the trial will be halted if there are 6 or more 
grade III-IV GvHD. 
 
Additionally, we will monitor engraftment failures (failure to reach an ANC of 
500/µL by Day 42) by employing the group sequential method. Specifically, we 
will exam the number of engraftment failures 5 times in a group of 4 patients 
each. The table, below, lists the number of engraftment failures necessary to 
trigger a suspension of accrual until a thorough reevaluation of the protocol has 
been completed. Those numbers are determined by the O’Brien-Fleming method 
to reduce the chance to erroneously suspend the trial early when in fact it is the 
true rate of engraftment failure is the acceptable 10%. They also increase the 
chance to suspend the trial early when the true rate of engraftment failure is 
greater than 10%. The probabilities of trial suspension under three possible rates 
of engraftment failure (p=0.1, 0.2, 0.3) are also listed in the table below calculated 
by the exact method using binomial distribution. 
 
Engraftment Failure Safety Monitoring Guidelines (p: true rate of engraftment failure) 
 
# Patients 
Entered  
# Engraftment 
Failures  
For Trial 
Suspension 
Prob. To Suspend 
if p=0.1 
Prob. To Suspend 
if p=0.2 
Prob. To Suspend 
if p=0.3 
4 
1 
0.34 
0.59 
0.76 
8  
2 
0.19 
0.50 
0.74 


 
20
12  
2 
0.10 
0.17 
0.16 
16 
2 
0.17 
0.21 
0.13 
20 
2 
0.19 
0.14 
0.05  
 
10.3 Statistical Analysis 
The primary outcome of overall survival after transplantation will be compared to 
a fixed null hypothesis 1-year survival rate of 40% by a one-sided test. In addition 
to the 1-year overall survival, the secondary endpoints included engraftment 
(neutrophil and platelet), acute and chronic GvHD, disease-free survival, long-
term survival, relapse, and regimen-related toxicities. Neutrophil engraftment is 
defined as the first of 3 consecutive days of achieving an ANC of 500/µL with 
more than 90% donor cell chimerism. Platelet engraftment is defined as achieving 
a platelet count of 50,000/µL without transfusion support for 7 days. Primary 
graft failure is defined as failure to reach an ANC of 500/µL by Day 42. 
Secondary graft failure is defined as either severe persistent neutropenia 
unresponsive to growth factor therapy or loss of donor chimerism after initial 
engraftment. Relapse is defined as more than 25% blasts in the blood or bone 
marrow or more than 5% blasts in the bone marrow with reappearance of the 
original cytogenetic abnormality associated with patient's malignancy or more 
than 5% blasts in the bone marrow on multiple occasions or any extramedullary 
relapse. 
 
We will calculate Kaplan-Meier estimates and confidence intervals for time to 
overall survival, disease-free survival and primary graft failure. We will use 
cumulative incidence curves for engraftment and GvHD endpoints with death as a 
competing risk. The impact of HLA match, cell dose, race or ethnicity, disease 
status, age, performance status, risk status, and patient CMV seropositivity will be 
assessed. We will use the log-rank test for differences in survival between groups 
in the univariate survival analysis. The Cox proportional hazards model will be 
used for multivariate analysis of covariates on the main survival endpoints. 
 
We will summarize incidence rates and 95% confidence intervals for engraftment 
failure, acute GvHD, neutrophil recovery at Day 42 and platelet recovery at Day 
180. 
 
11.0 RECORDS TO BE KEPT 
The CAGT research nurse/coordinator will maintain a database documenting the dates 
and doses of therapy as well as clinical 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 
 


 
21
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 
On study form 
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 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 Data Safety Monitoring 
Board Plan for investigator-initiated Phase I and II studies in the Dan L. Duncan Cancer 
Center at Baylor College of Medicine. 
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. 
 
15.0 OFF STUDY CRITERIA 
• Refusal of further study follow up by patient or legal guardian 
• Relapse 
• Primary Engraftment Failure 
• Acute Graft Rejection 
• Lost to follow up 
• Completion of Study Procedures and Follow-up 
• Death 


 
22
16.0 REFERENCE LIST 
 
1) Pui CH,, Schrappe M, Ribeiro RC, Niemeyer CM. Childhood and adolescent lymphoid 
and myelid leukemia.  Hematology Am Soc Hematol Educ Program. 2004; 118-145 
 
2) Eapen M, Rubistein P, Zhang M-J, Stevens C, Kurtzberg J. et al Lancet; 369:1947-1954 
 
3)  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 
 
4) ] Rubinstein P, Taylor PE, Scaradavou, et al. Unrelated placental blood for bone marrow 
reconstitution: Organization of the placental blood program. Blood Cells 1994; 20: 587-600 
 
5) Broxmeyer HE. The past, present, and future of cord blood transplantation. In: Broxmeyer 
HE, ed. Cellular characteristics of cord blood and cord blood transplantation. Bethesda: 
AABB Press; 1998:1-9 
 
6) Ballen K, Broxmeyer HE, McCullough J et al. Current status of cord blood banking and 
transplantation in the United States and Europe. Biol Blood Marrow Transplant. 2001; 7: 
635- 645 
 
7) 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 
 
8) Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell 
transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233-4244. 
 
9) Rubinstein P, Carrier C, Scaradavou A et al. Outcomes among 562 recipients of 
placentalblood transplants from unrelated donors. New England Journal of Medicine. 1998; 
339: 1565 - 1577 
 
10) Laughlin MJ, Barker J, Bambach B et al. Hematopoietic engraftment and survival in 
adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001;344: 
1815 - 1822 
 
11) Rocha V, Arcese W, Sanz G, et al. Prognostic factors of outcome after unrelated cord 
blood transplantation *UCBT) in adults with haematological malignancies. Blood 2000; 96: 
567a 
 
12) Goldberg SL, Chedid S, Jennis AA, Preti RA. Unrelated cord blood transplantation in 
adults: a single institution experience. Blood 2000; 96: 208a 
 


 
23
13) Barker JN, Wagner JE. Umbilical-cord blood transplantation for the treatment of cancer. 
Nature Reviews Cancer. 2003; 3: 526-532 
 
14) 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 J Med 1996; 335: 157-166 
 
15) Wagner JE, Rosenthal J, Sweetman R, Shu XO, Davies SM, Ramsay NK, 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: 795-802 
 
16) 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 
 
17) Locatelli F, Rocha 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 
 
18) Rocha V, Cornish J, Sievers EL et al. Comparison of outcomes of unrelated bone marrow 
and umbilical cord blood transplants in children with acute leukemia. Blood 2001; 97: 2962-
2971 
 
19) Rubinstein P, Stevens CE. Placental blood for bone marrow replacement: the New York 
Blood Center's program and clinical results. Baillieres Best Pract Res Clin Haematol 2000; 
13: 565- 584 
 
20) Kurtzberg J, Prasad V, Carter S, Wager J, Baxter-Lowe L, Wall D, et al. Results of the 
Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical 
cord blood transplantation in pediatric patients with hematologic malignancies. Blood 2008; 
112: 4318-4327   
 
21) Klein AK, Patel DD, Gooding ME, Sempowski GD, Chen BF, Liu C, Kurtzberg J, 
Haynes BF and Chao NJ. T-Cell Recovery in Adults and Children Following Umbilical Cord 
blood Transplantation. Biol Blood Marrow Transplantation 7:454-466, 2001 
 
22) Mielcarek M, Martin PJ, Leisenring W et al.: Graft-versus-host disease after 
nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 102: 
756- 762, 2003 
 
23) 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 10: 178-185, 2004 
 


 
24
24) Blaise D, Maraninchi D, Archimbaud E, et al: Allogeneic bone marrow transplantation 
for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan 
versus Cytoxantotal body irradiation as preparative regimen: a report from the Group 
d'Etudes de la Greffe de Moelle Osseuse. Blood 79:2578-82, 1992 
 
25) Michel G, Gluckman E, Blaise D, et al: Improvement in outcome for children receiving 
allogeneic bone marrow transplantation in first remission of acute myeloid leukemia: a report 
from the Groupe d'Etude des Greffes de Moelle Osseuse. J Clin Oncol 10:1865-69, 1992 
 
26) Ringden O, Labopin M, Tura S, et al: A comparison of busulphan versus total body 
irradiation 
combined with cyclophosphamide as conditioning for autograft or allograft bone marrow 
transplantation in patients with acute leukaemia. Acute Leukaemia Working Party of the 
European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 93:637-45, 
1996 
 
27) Wingard JR, Plotnick LP, Fremmer CS, et al: Growth in children after bone marrow 
transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body 
irradiation. Blood 79:1068-73, 1992 
 
28) Giorgiani G, Bozzola M, Locatelli F, et al: Role of busulfan and total body irradiation on 
growth of prepubertal children receiving bone marrow transplantation and results of 
treatment with recombinant human growth hormone. Blood 86:825-31, 1995 
 
29) Michel G, Rocha V, Chevret S, Locatelli F, Gluckman E, et al. Unrelated cord blood 
transplantation for childhood acute myeloid leukemia: a Eurocord Group analysis. 
 
30) Lawless, J. Statistical Models and Methods for Lifetime Data, John Wiley and Sons, 
1982. 
 


 
25
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 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
26
APPENDIX 2 
 
RADIATION GUIDELINES 
 
1.0 CONTINGENCY: CNS RELAPSE OR PRIMARY CNS DISEASE 
1.1 It is anticipated that patients with combined CNS/hematologic relapse or isolated  
CNS relapse will enter the transplant preparative regimen only after clearance of CSF 
cytology with IT chemotherapy. 
1.2 Cranial irradiation will be administered before conditioning in 
 attempting to achieve CNS disease control except in patients < 2 years. 
1.2.1 High energy irradiation. 
1.2.2 Total dose: 10.8 By mid-plane cranium. 
1.2.3 Fractionation: 180 cGy once daily x 6 fractions. 
1.2.4 Treatment time: treatment will be completed within 8 calendar days. 

ICF_000.pdf: 
CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
Background
You are invited to take part in a research study. Please read this information and feel free to ask any 
questions before you agree to take part in the study.
You have a type of blood cell disorder that is very hard to cure. We are suggesting a treatment that 
might help you live longer without the disease. This treatment is known as a stem cell transplant. It uses 
much stronger doses of drugs and radiation to kill the diseased cells than could be given without the 
transplant. We also think that the healthy cells from the donor may help fight any diseased cells left after 
the transplant.
For the transplant to take place, we will administer stem cells from a ‘donor’ whose cells best ‘match’ 
yours and give them to you. Stem cells are special ‘mother’ cells that are found in the bone marrow (the 
spongy tissue inside the bones), blood, and umbilical cord blood of newborn babies. As stem cells 
grow, they give rise to white blood cells which fight infection, red blood cells which carry oxygen and 
remove waste products from the organs and tissues or platelets, which enable the blood to clot. In this 
study umbilical cords will be the source of the stem cells.
Before the transplant, two very strong drugs will be given to you (pre-conditioning). This treatment will kill 
most of your blood-forming cells in the bone marrow. We will then give you the healthy stem cells. Once 
these healthy stem cells are in your bloodstream they will move to the bone marrow (graft) and begin 
producing blood cells that will eventually mature into healthy red blood cells, white blood cells and 
platelets.
If you have CNS relapse or primary CNS disease, you will receive irradiation to the cranio-spinal axis 
before starting the conditioning, in an attempt to achieve CNS disease control. Irradiation will not be 
given for children under 2 years old.
Currently, many umbilical cord blood units are available in public banks for transplantation in patients 
lacking bone marrow donors. UCB transplants (UCBT) may 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 (graft-versus-host disease) as compared to recipients of unrelated donor 
marrow and peripheral blood cells. GvHD will be discussed in more detail later in this consent.
The three main causes of death after umbilical cord blood transplantation for disorders like yours are 
graft failure (this is when the donor cells do not grow), infection, and disease relapse.
In this study we are trying to address these three problems. To help improve engraftment (cells begin to 
grow) we will add the drug Fludarabine to Cytoxan and Busulfan. Fludarabine is a very strong medicine. 
We will try to decrease infections and reduce leukemia relapse (return of cancer cells) by using 
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 1 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
fludarabine instead of anti-thymocyte globulin (ATG).
Please read the information in this consent form carefully to decide if 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 UCBT to treat your disease, and to see if this treatment 
can decrease the incidence of leukemia relapse, GvHD, and infections.
Procedures
The research will be conducted at the following location(s):  
Baylor College of Medicine and TCH: Texas Children's Hospital.
A total of 20 subjects will be enrolled to 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 and electrocardiogram (ECG), an ultrasound of the heart), liver, and 
kidneys. You will have tests to check how well your lungs work if you are old enough.
You also 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 including HIV testing. HIV is the virus that 
causes Acquired Immune Deficiency Syndrome or 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 tube 
(called a double lumen catheter) into a large vein in your body. If the patient is too small for a central line 
in the arm, the central double lumen line will be placed in the chest. The large vein may also be in the 
groin. The catheter will be placed by a surgeon. They will be discussed further in the RISKS section of 
this consent form. The risks of a central line 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 and before the infusion of UCB stem cells:
9 days before the infusion through 6 days before the infusion: Busulfan every 6 hours as an intravenous 
infusion for a total of 16 doses.
5 days before the infusion through 2 days before the infusion: Cytoxan given daily for 4 days over 1 hour 
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 2 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
as an intravenous infusion. Mesna will be given per standards. Mesna is a drug given to decrease the 
side-effects of Cytoxan. It will be given daily while you receive Cytoxan.
3 days before the infusion through 1 day before the infusion: Fludarabine given daily for 3 days over 1 
hour as an intravenous infusion.
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.
The following medications will be given to help decrease side-effects from the chemotherapy and UCB 
infusion:
Cyclosporine 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 after the infusion, and then tapered if no GvHD is present.
Administration of 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) will be given monthly until GvHD therapy is stopped and there is 
evidence that your body is producing antibodies.
STUDY EVALUATIONS:
The following evaluations will be collected before transplant:
- Physical examination by a Pediatric Bone Marrow Transplant physician (includes History, Physical 
Examination, Weight, Vital Signs, Pulse Oximetry, and Performance Status)
- Pregnancy test
- Complete blood count with differential, C-reactive protein
- Serum chemistries
- Liver function tests
- An electrocardiogram: a test that shows the electrical activity of the heart
- An echocardiograph: picture of the heart in motion
- Tests to see how well blood clots
- Viral tests
- Bone marrow aspirate and biopsy/lumbar puncture within 2-3 weeks of starting conditioning, as 
clinically indicated
- Renal function
- Lumbar puncture will be performed to evaluate any evidence of disease recurrence (if previously 
positive and/or clinically indicated)
- Pulmonary function test, if applicable
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 3 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
The following evaluations will be collected on Days 0, 21, 42, 60, and 100:
- Infusion of cells on Day 0
- Physical examination by a Pediatric Bone Marrow Transplant physician(includes History, Physical 
Examination, Weight, Vital Signs, Pulse Oximetry (on Day 0 only), and Performance Status)
- Complete blood count with leukocyte differential, C-reactive protein
- Serum chemistries
- Liver function tests
- Evaluations of the graft between Days 21-42, 60 and 100
- White blood cell recovery will be performed between Day 21-42 and 60-100
- Bone marrow aspirate and biopsy for assessment of leukemia status and UCB engraftment between 
Days 21-42, and will be repeated between Days 90-100 as clinically indicated
- Lumbar puncture will be performed between Day 21-42 and between Day 90-100 to evaluate any 
evidence of disease recurrence (if previously positive and/or clinically indicated)
- Immunoglobulin (IgG, IgA, IgM) will be taken prior to administration of IVIG between Day 60-100
The following evaluations will be collected after Day 100 around 6, 9, 12, 24 and 36 months:
- Physical examination by a Pediatric Bone Marrow Transplant physician (includes History, Physical 
Examination, Weight, Vital Signs, and Performance Status)
- Complete blood count with differential, C-reactive protein
- Serum chemistries
- Liver function tests
- Evaluations of the graft around 6, 12, and 24 months or more frequently as clinically indicated
- Echocardiograph (how well your heart pumps out blood to the rest of your body) at month 12 
- Bone marrow aspirate and biopsy assessment of leukemia status and UCB engraftment around 6, 9, 
12 and 24 months, as clinically indicated.
- White blood cell recovery will be performed around 6, 9, 12 and 24 months after transplant
- Immunoglobulin (IgG, IgA, IgM) will be taken at month 6, 9, 12 and 24 months
BLOOD SAMPLES:
To study how these cells are working in your system, blood samples will be taken at about 1, 2, 3, 6, 9, 
12, 15, 18 and 24 months after the transplant. Approximately 3-4 teaspoons of blood will be collected 
each time. The total blood drawn for this study over three years should not exceed 3/4 cups. This 
amount is considered safe in adults. The amount of blood collected will be less for 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. You will need to come to the clinic on the days of blood drawing and to be 
seen at Texas Children's Hospital.
FOLLOW-UP:
After year 1, you will be asked to return to the clinic once a year for consultations and bone marrow 
tests. A follow-up bone marrow biopsy and aspirate will be done 1 and 2 years after transplant. 
Consultations with specialists will be similar to the ones you had before your transplant.
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 4 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
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:
     •  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
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, 
Research related health information
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 5 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
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 
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
BCM Center for Cell and Gene Therapy
Feigin Center, Suite 1630
1102 Bates Street
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.
BUSULFAN: The side-effects of this agent include low blood counts, 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, nausea, 
vomiting, and sterility. Rarely, it can cause serious liver and lung problems.
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 (inability to have children). Rare side-effects may include heart damage, second cancers 
(very rare), lung damage, and blurred vision.
Potential Risks and Discomforts
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 6 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
FLUDARABINE: The side-effects of this agent include low blood counts, resulting in reduction in the 
number of platelets, red cells, and white cells found in the circulation. It can also make certain kinds of 
anemia, a reduction of the red cells in the blood, worse. Rarely, it can cause your immune system to be 
suppressed for a long period of time, which could make you vulnerable to infections. Another rare 
side-effect is nerve damage, fever and central nervous system changes.
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 been abdominal 
discomfort, headache, limb and joint pain, tiredness, and diarrhea.
MYCOPHENOLATE MOFETIL (MMF): Risks may include upset stomach, including diarrhea and 
vomiting; risk of serious infections; bleeding and easy bruising; risk of some cancers with long term 
treatment; risk to baby in pregnancy. It will also cause decrease function on your lymphocytes 
(immunosuppression).
CYCLOSPORIN A (CSA): Risks may include acne, dizziness, headache, increased hair growth, 
nausea, runny nose, sleeplessness, stomach discomfort, vomiting and seizures. It will also cause 
decrease function on your lymphocytes (immunosuppression).
IVIG: Risks include headache, myalgia, fever, chills, backache, chest pain, nausea and/or vomiting.
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.
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) as different from those of the donor. When that happens, the graft attacks 
the 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.
BLOOD DRAWING: 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: The degree of immune suppression in stem cell transplant patients leads to an 
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 7 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
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, anti-fungal and anti-bacterial mouth rinses, etc), and treatment may be 
started before an 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. 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: The benefits of participating in this study may be: 
improve the 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.
Subject Costs and Payments
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 8 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
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 radiation, Cytoxan, 
Fludarabine, Mesna, MMF, Cyclosporine 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. 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.
You will not be paid for taking part in 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
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.
Approved  from August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 9 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
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 at 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.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.
The National Institutes of Health and the National Cancer Institute may have access to your records for 
research purposes. Coded information may be provided to the NIH/NCI such as Patient ID, Patient Zip 
code, Patient country code, and Patient Birth date (month/year). However, in the event of an audit 
NIH/NCI might have access to more information that is part of your research record.
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 August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 10 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017


CONSENT FORM 
TREATMENT CONSENT FORM
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-26558-  UMBILICAL CORD BLOOD TRANSPLANT FOR CHILDREN WITH MYELOID 
HEMATOLOGICAL MALIGNANCIES (UCAML)
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 August 17, 2018  to August 07, 2019        Chair Initials: K. A.
Page 11 of 11
Patient Name/ID #:__________________________
UCAML Protocol Version 9 0 Dated 12/19/16
Last Amendment:
9/5/2017