Clinical trial NCT00357565
Conditions: Leukemia Myelodysplastic Syndromes Childhood Acute Myeloid Leukemia in Remission Recurrent Childhood Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Childhood Acute Lymphoblastic Leukemia in Remission Previously Treated Myelodysplastic Syndrome Secondary Myelodysplastic Syndrome Refractory Anemia With Excess Blasts in Transformation Refractory Anemia With Excess Blasts Refractory Anemia De Novo Myelodysplastic Syndrome Childhood Myelodysplastic Syndrome
Keywords: MDS AML
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2005-11-01; Completion date: 2025-03-11
Enrollment: 34 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Giving chemotherapy, such as busulfan, fludarabine, and melphalan, before a donor umbilical cord blood stem cell transplant helps stop the growth of abnormal or cancer cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil may stop this from happening.

PURPOSE: This phase II trial is studying how well combination chemotherapy followed by a donor umbilical cord blood transplant works in treating infants with high-risk acute leukemia or myelodysplastic syndromes.

Detailed description:
OBJECTIVES:

Primary

* Determine the incidence of engraftment, defined as achieving donor-derived neutrophil count \> 500/mm³ by day 42, in infants with high-risk acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes treated with a non-irradiation containing myeloablative conditioning regimen comprising busulfan, fludarabine, and melphalan followed by double umbilical cord blood transplantation (UCBT) with two partially HLA-matched units.

Secondary Objectives

* Determine the incidence of transplant-related mortality (TRM) at 6 months after UCBT
* Evaluate pattern of chimerism after double UCBT
* Determine the incidence of platelet engraftment at 1 year after UCBT
* Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day 100 after UCBT
* Evaluate the developmental outcome after UCBT

Transplant Related Objectives

* Determine the incidence of chronic GVHD at 1 year after UCBT
* Determine the survival and disease free survival at 1 and 2 years after UCBT
* Determine the incidence relapse at 1 and 2 years after UCBT

Arms: arm 1: Patients that receive 2 units of umbilical cord blood transplantation (UCBT). arm 2: Patients that receive one unit of umbilical cord blood transplantation (only if 2 adequate size and matched units are not available).
Interventions: intervention 1: filgrastim intervention 2: busulfan intervention 3: cyclosporine intervention 4: fludarabine phosphate intervention 5: melphalan intervention 6: mycophenolate mofetil intervention 7: umbilical cord blood transplantation
Intervention descriptions: intervention 1: All patients will receive G-CSF 5 mcg/kg/day intravenous (IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10\^9/L for three consecutive days and then discontinued. If the ANC decreases to \<1.0 x 10\^9/L, G-CSF will be reinstituted. intervention 2: Administered 1.1 mg/kg if \<12 kg intravenous (IV) every 6 hours (0.8 mg/kg if \>12 kg IV every 6 hours on Days -8 through -5. intervention 3: Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of \>200 ng/mL. For children \< 40 kg the initial dose will be 2.5 mg/kg intravenous (IV) over 2 hours every 8 hours. intervention 4: Administered 25 mg/m\^2 intravenous (IV) over 60 minutes on Days -4 through -2. intervention 5: Administered 60 mg/m\^2 intravenous (IV) over 30 minutes on Days -4 through -2. intervention 6: All patients will begin mycophenolate mofetil (MMF) on day -3. Patients \<45 kilograms will receive MMF at the dose of 15 mg/kg/dose every 8 hours (max dose 1gm/dose) orally or intravenously (PO or IV). intervention 7: The product is infused via IV drip directly into the central line without a needle, pump or filter on Day 0.

Protocol documents:
Prot_SAP_000.pdf: 
UNIVERSITY OF MINNESOTA BLOOD & MARROW TRANSPLANTATION PROGRAM 
 
 
 
 
 
Hematopoietic Stem Cell Transplantation in the Treatment of Infant Leukemia and Myelodysplastic 
Syndrome 
MT2005-25  
CPRC #2005LS075 
 
 
 
BMT Study Committee 
Christen Ebens, M.D., Principal Investigator 
Claudio G. Brunstein, M.D., Ph.D. 
Brenda Weigel, M.D. 
Margaret MacMillan, M.D., M.Sc. 
Bruce R. Blazar, M.D. 
John E. Wagner, M.D. (co-Principal Investigator) 
Kristina Nelson, PharmD 
Susie Long, PharmD 
 
Biostatistician 
Todd DeFor, M.S. 
 
 
Version Date: 
August 25, 2021 
 
 
 
 
This document contains confidential information that is the property of the Blood and Marrow Transplant 
Program. Do not copy, disclose, or circulate without written authorization from 
the University of Minnesota-Fairview Blood and Marrow Transplant Services Medical Director. 


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Revision History 
 
Version 
Date 
Amendment 
# 
Details of changes 
Consent 
change? 
10/11/05 
original 
 
 
2/1/2006 
 
Minor clarifications required for CPRC approval 
 
4/27/2006 
1 
Eligibility clarification: deleted section 4.1.1. Patients 
with a matched sibling donor will no longer be excluded from this 
study 
 
6/4/2007 
2 
Modified eligibility to allow for subjects with minimal 
residual disease (section4.2.5) 
 
09/14/2011 
3 
Clinical changes: section 4 change LFT eligibility from 2 x the 
upper limit of normal to 5 x ULN as on checklist; section 6 - 
change seizure prophylaxis from Dilantin to Keppra; correct 
exclusion criteria on page 4 to reflect previous protocol 
amendment (4/27/2006) 
 
Generalized protocol update to current template and language; 
Make study title consistent throughout – add CPRC #; section 1 – 
separate out secondary objectives to clinical, transplant and 
research related; section 4 – minor edits to match eligibility 
checklist; section 5 – update registration procedures; section 6 –; 
remove references to and appendices for outdated clinical policies 
and replace with “per current institutional guidelines” or similar 
language for UCB infusion, supportive care and slow engraftment; 
section 7 – split table of tests and procedures into two tables – 
SOC and research; section 8 – replace previous with current 
adverse event reporting language; section 8 – replace previous 
with current data and safety monitoring plan, expand section with 
other data related language; section 11 – add conduct of study 
section; renumber and update appendices, move expected 
toxicities from protocol body to an appendix. 
Remove Drs. Kumar and Baker from study document (previously 
done with the IRB). 
Reforma
tted and 
updated 
03/16/2015 
4 
Restrict graft source to one partially HLA matched unit 
Update background 
Revise upper age limit from 2 years of age to 3 
Expand enrollment to other high risk leukemic subtypes where 
transplant may be indicated 
Update patient registration procedures 
Update preparative regimen dosing to current practices 
Remove fludarabine and MMF PK’s from protocol deleting 
appendices IV and V 
Add ursodiol for VOD prophylaxis  
Change toxicity assessment to weekly through day 42, then at day 
60 and 100, make LP as clinically indicated 
Remove research related sample collection, delete correlative 
endpoints 
 
yes 


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2005LS075 
Version 
Date 
Amendment 
# 
Details of changes 
Consent 
change? 
 
 
Update AE documentation and reporting requirements to current 
requirements 
Increase enrollment goal for single cord units and update the 
statistical section to reflect increase 
Other edits throughout 
 
05/18/2015 
5 
Schema, sections 1,1, 3, 4.1.1, and 10.2, and eligibility checklist: 
Permit matched sibling donors 
– exclusion was originally removed from the 
protocol with amendment 1, but was lost in subsequent revisions 
Yes 
11/30/16 
5A 
Update PI to Christen Ebens 
Updated Cancer Center DSMP location 
Updated eligibility checklist to current template 
No 
04/12/2017 
6 
Added donor-specific antibody testing guidelines under section 4.1 
Graft criteria, section 7, and eligibility checklist; removed post 
transplant lansky assessment under section 7; removed Melisa 
Stricherz from trial 
No 
07/26/2017 
6A 
Updated enrollment goals 
 
03/02/2020 
7 
Updates to align with institutional practices for: 
Umbilical cord blood selection criteria 
Busulfan dosing 
Graft-versus-host disease prophylaxis 
-remove eligibility checklist from protocol (checklists are being 
kept in Oncore) 
 
Yes 
11/16/2020 
7A 
Updated Melphalan administration timing per current pharmacy 
standard of care; removed year 5 neuropsychological exam; 
updated G-CSF discontinuation parameters; incorporated updated 
busulfan units. 
No 
08/25/2021 
8 
Updated study committee 
Removed section 2.3.3 (Background on double UCBT) as study is 
no longer using double UCBT 
Section 2.4 Updated reference; removed double cord blood 
Per pharmacy review: Updated Section 6.2 busulfan AUC goal 
units, per new local standard clinical care 
Removed text of Appendix #II – as no longer standard of care  
References  Added reference 27 
Minor edits throughout for wording and error correction 
Yes 
 
 
PI Contact Information: 
Christen Ebens, MD, MPH  
Hematology/Oncology and Transplantation Department of Pediatrics 
MMC 484 
420 Delaware Street SE Minneapolis, MN 55455 
612-626-8094 (phone) 
612-626-2815 (fax) 
ebens012@umn.edu(email) 


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Table of Contents 
PROTOCOL SYNOPSIS ......................................................................................................................................... 5 
TREATMENT PLAN .............................................................................................................................................. 5 
1 
OBJECTIVES ................................................................................................................................................... 6 
2 
BACKGROUND ............................................................................................................................................... 6 
3 
STUDY DESIGN ............................................................................................................................................ 10 
4 
PATIENT SELECTION ................................................................................................................................ 11 
5 
PATIENT REGISTRATION ........................................................................................................................ 12 
6 
TREATMENT PLAN .................................................................................................................................... 13 
7 
STUDY PARAMETERS ............................................................................................................................... 17 
8 
ADVERSE EVENT MONITORING AND REPORTING ......................................................................... 18 
9 
DATA COLLECTION AND MONITORING PLAN .................................................................................. 19 
10 
STATISTICAL CONSIDERATIONS ...................................................................................................... 20 
11 
REFERENCES ............................................................................................................................................ 23 
APPENDIX I - LANSKY PLAY SCORE ............................................................................................................. 25 
APPENDIX II – BUSULFAN DOSE SELECTION, AUC MONITORING AND ALGORITHM FOR DOSE 
MODIFICATION USING ONCE DAILY IV DOSING ...................................................................................... 26 
APPENDIX III – EXPECTED TOXICITIES OF STANDARD THERAPIES ................................................ 27 


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PROTOCOL SYNOPSIS 
 
MT 2005-25 
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE TREATMENT OF INFANT 
LEUKEMIA AND MYELODYSPLASTIC SYNDROME 
 
Study 
design: 
Open label, single institution, non-randomized phase II trial 
Primary 
objective: 
Determine incidence of donor derived neutrophil recovery at day 42 
Secondary 
objectives: 
• Determine the incidence of transplant-related mortality (TRM) at 6 
months after UCBT 
• Determine the incidence of platelet engraftment at 1 year after UCBT 
• Determine the incidence of acute graft-versus-host disease (GVHD) grade 
II-IV and grade III-IV at day 100 after UCBT 
• Evaluate the developmental outcome after UCBT at 1, 2, and 5 years after 
UCBT 
Eligibility 
criteria: 
Subjects must be ≤ 3 years old at diagnosis of infant leukemia or 
myelodysplastic syndrome; adequate organ function; Lansky play score 
≥50. Matched sibling donor, if available, or an unrelated partially HLA 
matched UCB graft 
Eligible 
diseases: 
Acute leukemia in complete remission (high risk CR1 or subsequent CR); 
myelodysplastic syndrome or other leukemic sub-types where transplant is 
indicated and 2 members of the protocol team concur with this decision. 
Exclusion 
criteria: 
History of HIV infection or known HIV positive serology; current active 
serious infection; patients with acute lymphocytic leukemia in relapse or 
>15% acute myelocytic leukemia blasts. 
Accrual 
objective: 
3 to 4 patients per year 
 
TREATMENT PLAN 
 
Day 
Drug 
Dose 
-8 
Busulfan 
Once daily over 3 hrs with initial dose determined by model-based 
dosing* 
-7, -6, -5 
Busulfan 
Once daily over 3 hrs with dose adjusted based on PK results 
-4, -3, -2 
Fludarabine 
Melphalan 
25 mg/ m2/day (0.83 mg/kg/day if < 10 kg) IV over 60 min& 
50 mg/m2/day (1.7 mg/kg/day if < 10 kg) IV over 15 min 
-1 
Rest 
0 
BM or UBC infusion 
*Initial dose will be determined by model-based dosing utilizing Bayesian pharmacokinetic software  
&Initial dose may be based on Bayesian pharmacokinetic software if available 
Refer to section 6.2 for preparative regimen dosing specifics 
Begin GVHD prophylaxis (Tacrolimus and MMF) on day -3 per section 6.3 


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1 OBJECTIVES 
1.1 Primary Objective 
The primary objective of this study is to determine the incidence of engraftment (defined as 
achieving donor derived neutrophil count >500/uL by day 42) in young children with leukemia 
or myelodysplastic syndrome undergoing a matched sibling or a partially matched unrelated 
single unit umbilical cord blood transplant (UCBT) after a myeloablative preparative regimen 
consisting of busulfan, melphalan and fludarabine. 
 
1.2 Secondary Objectives 
• 
Determine the incidence of transplant-related mortality (TRM) at 6 months after UCBT 
• 
Determine the incidence of platelet engraftment at 1 year after UCBT 
• 
Determine the incidence of leukemia relapse at 2 years after UCBT 
• 
Determine the incidence of acute graft-versus-host disease (GVHD) grade II- IV and 
grade III-IV at day 100 after UCBT 
• 
Evaluate the developmental outcome after UCBT at 1, 2 and 5 years 
 
1.3 Transplant Related Objectives 
• 
Determine the incidence of chronic GVHD at 1 year after UCBT 
• 
Determine the survival and disease free survival at 1 and 2 years after UCBT 
• 
Determine the incidence relapse at 1 and 2 years after UCBT 
 
2 BACKGROUND 
2.1 Infant Acute Leukemia 
Infantile leukemia is a unique entity in pediatric hematology commonly presenting with 
hyperleukocytosis, organomegaly, extramedullary disease and CNS leukemia. Infantile 
leukemia is a relatively rarely occurring entity with ~200 cases/year in the 
U.S. (reviewed in 1). Flow cytometry demonstrates a unique immunophenotype (i.e., CD10-) 
with either lymphocytic (T or B cell) or myeloid features. Cytogenetic analysis frequently shows 
abnormalities in chromosomal band 11q23, indicative of rearrangements in the mixed lineage 
leukemia (MLL) gene. Microarray data demonstrate that leukemia with MLL gene 
rearrangements have a distinct gene expression profile when compared to conventional acute 
lymphocytic or myeloid leukemia, supporting the concept that infant leukemia is a separate 
clinical entity 2. Despite aggressive chemotherapy, the majority of infants with leukemia will 
suffer early relapse and death. Overall survival on modern chemotherapy protocols range from 
20-40% 1,3,4. Children with high WBC counts (>100,000/ml), or the 4;11 translocation appear to 
be ultrahigh risk with an event free survival (EFS) of ~5% (reviewed in 1). Given the 
unsatisfactory results using standard chemotherapy, some groups have resorted to allogeneic 
hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1) for such high-
risk leukemia patients. The role for this approach has not been fully established. For instance, 
Pui and coworkers retrospectively examined the outcome of infants with 11q23 chromosomal 
rearrangements and found that those receiving chemotherapy (n=173) had better overall and 
disease free survival (OS and DFS) compared to those that undergoing a variety of different 
types of hematopoietic cell transplantation (autologous, matched and mismatched related and 
unrelated donors) (n=55) 3. The difference between the chemotherapy and transplant groups was 


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attributable to both relapse and toxicity. 
 
While the above study casts doubt on the role of transplantation in infant ALL, other studies 
show that allo-HCT, in fact, improves outcomes. Balduzzi and coworkers recently published the 
results from a European cooperative group study (both BFM and EBMT) on infant leukemia 4.  
This study used aggressive induction chemotherapy followed by a “genetic” randomization to 
transplantation. Thus, if infants had an HLA-matched sibling donor, transplantation was to be 
performed within 2-5 months of achieving CR1. Of the 357 children enrolled, 77 underwent 
matched sibling donor transplantation with a conditioning regimen of total body irradiation 
(TBI), etopiside, busulfan and cyclophosphamide. Children that received transplantation had a 
better 5 yr DFS rate compared to those receiving chemotherapy (56.7% vs. 40.6%, p=0.02). 
Likewise, a recent publication from the Japan Infant Leukemia Study Group showed favorable 
results with transplantation using either sibling or unrelated donors 5. The 3-year OS and EFS 
for patients undergoing transplantation in this study was 58.2% and 43.6%, comparing favorably 
to nearly all chemotherapy protocols. Interestingly, infants transplanted in CR1 had significantly 
better outcome than those transplanted in CR2 (64.4% vs. 22.2%, p=0.0044). A recent single 
center study (Seattle) showed a similar improvement in DFS for patients transplanted early in 
the disease course 6. Comparing the DFS for patients transplanted in CR1 vs. CR2/3 vs. relapse 
showed an advantage for early transplantation (76% vs. 45% vs. 8%, p<0.001). Like the above 
protocols, the Seattle study used a TBI-based regimen. Of the 15 patients who had 
developmental testing, ~2/3rds of patients showed some degree of either motor or language 
delay—most delays were assessed as mild. 
 
Collectively the above studies demonstrate that infant leukemia is aggressive and outcome with 
standard chemotherapy is poor. Some recent large studies show a benefit for early 
transplantation (i.e., CR1) using TBI containing regimens. In addition, the Seattle study showed 
that such patients have some degree of developmental delay, but whether this is secondary to 
TBI or other factors (i.e., their chronic illness) is difficult to determine. 
2.2 Allogeneic Hematopoietic Cell Transplantation And Umbilical Cord Blood 
Transplantation (UBCT) 
Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard treatment option for an 
increasing number of malignant disorders. To reconstitute hematopoiesis after an intensive 
myeloablative therapy, the transplantation of pluripotent hematopoietic stem cells (HSCs) is 
required. Such HSCs are typically recovered from the bone marrow of related or unrelated 
donors or the bone marrow or apheresed peripheral blood of the patients themselves 7. 
Unfortunately, suitable marrow is frequently not available 8. Either the patient's own marrow is 
contaminated with tumor cells or potential allogeneic marrow donors are unsuitable most often 
on the basis of HLA mismatch. Human umbilical cord blood (UCB) is an alternative source of 
HSCs that is capable of reconstituting hematopoiesis after intensive myeloablative therapy 9-16. 
 
As a result of the early successes with umbilical cord blood transplantation (UCBT) from sibling 
donors, pilot programs for the banking of unrelated donor UCB were initiated in many countries 
around the world. Known benefits of banked UCB include: 1) rapid availability, 2) absence of 
donor risk, 3) absence of donor attrition, and 4) very low risk of transmissible infectious 
diseases, such as CMV and EBV, and 5) low risk of acute GVHD despite HLA mismatch. UCB 
is particularly beneficial for patients of ethnic and racial minority descent for whom adult 
marrow and blood donors often cannot be identified. 


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2.3 UCBT Experience at the University Of Minnesota 
 
2.3.1 Single Unit UCBT 17. 
Between 1994 and 2001, 102 consecutive patients (median age 7.4 years) received a single, 
unrelated UCB unit after a myeloablative conditioning for malignant (n = 65; 68% high-risk) 
and non-malignant diseases (n = 37). Median infused cell dose of UCB was 3.1 x 107 NC/kg 
(range 0.7-57.9), and 2.8 x 105 CD34+ cells/kg (range 0.4-39.1). Fourteen percent had an 
HLA matched unit and 86% had a 1-3 HLA-match. Neutrophil recovery occurred at a 
median of 23 days (range 9-54) after UCBT with cumulative incidence of engraftment of 
88% (95% CI: 81-95) by day 42. Speed and likelihood of neutrophil recovery were strongly 
associated with cell dose, with markedly inferior engraftment (72% at a median of 34 days) 
in patients receiving a CD34+ cell dose <1.7 x 105 cells/kg. 
 
The incidences of grade II-IV and III-IV acute GVHD were 39% (95% CI: 29-49) and 11% 
(95% CI: 5-17), respectively, at day 100, with 10% (95% CI: 4-14) of patients having chronic 
GVHD at 1 year. One year transplant-related mortality (TRM) was 30% (95% CI: 21-39) 
which was strongly associated with CD34+ cell dose. The probabilities of 1 and 2-year 
survival were 58% (95% CI: 49-70) and 47% (95% CI: 36-57), respectively. Importantly, 
with a graft cell dose >1.7 x 105 
CD34+ cells/kg, survival was 70% (95% CI: 49-90) at 1 year. 
The principal conclusions of this study were: 1) an adequate cell dose (>1.7 x 105 CD34+ 
cells/kg or >2.5 x 107 nucleated cells/kg) consistently leads to engraftment; 2) GVHD is low 
despite HLA mismatch; 3) survival and risk of relapse are comparable to that observed after 
BMT, and; 4) cell dose significantly limits the applicability of UCB, particularly in adult 
size recipients. 
 
2.3.2 UCBT in Young Children with Leukemia (COBLT Study) 18 
Between January 1999 and May 2002, the University of Minnesota participated in a multi-
institutional trial evaluating the efficacy of a conditioning regimen containing busulfan and 
melphalan in the treatment of 32 young children with infant leukemia or myelodysplastic 
syndrome. Infant leukemia was defined as all children diagnosed with leukemia prior to 6 
months of age, or diagnosed prior to 12 months of age with cytogenetic rearrangements 
carrying the MLL gene. 
 
Median age of the patients at transplant was 1.6 years (range 0.5, 3.9 years); 56% were 
Caucasian and 59% were female. The primary diagnosis was ALL (44%), AML (41%), 
JMML (6%), MDS (6%) and undifferentiated leukemia (3%). The median cryopreserved 
cell doses were 10.7 × 107 total nucleated cells (TNC)/kg (range, 4.6-29.2), 2.6 × 105 
CD34+ cells/kg (range, 0.7-8.3) and 1.6 × 107 CD3+ 
cells/kg (range 0.6, 3.3). 
 
The incidence of neutrophil recovery at day 42 was 0.59 (95% CI, 0.44, 0.78). No factor, 
including age, weight, gender, ethnicity, primary disease, HLA disparity, recipient CMV 
status, graft nucleated cell dose, CD34+ dose and CD3+ dose, was associated with incidence 
of neutrophil engraftment. Also, there was no difference in the occurrence of primary graft 
failure between patients receiving IV versus oral busulfan. The median time to engraftment 


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was 31 days (range, 11-55). 
Maximum Bearman toxicity across all organ systems was reported for the period up to day 
42 after UCBT. Five patients exhibited severe toxicity with 59% having a maximum toxicity 
of grade 1-2. Notably, no patient had severe grade 4 mucositis. However, three patients were 
reported to have grade 4 cardiac toxicity. 
 
The incidence of grade II-IV and III-IV acute GVHD at day 100 was 0.41 (95% CI, 0.25, 
0.56) and 0.25 (95% CI: 0.09, 0.41), respectively. Six patients out of 23 surviving at least 
100 days developed chronic GVHD for an incidence of 0.26 (95% CI, 0.09, 0.44). 
 
Ten patients relapsed. The incidence of leukemia relapse at two years was 0.31 (95% CI, 
0.16, 0.47) at a median of 200 days (range, 41-464). No difference in the incidence of relapse 
was observed by disease (ALL versus AML) or disease status at the time of transplant (CR1 
versus >CR2). The probability of relapse-free survival at 2 years was 0.28 (95% CI, 0.13, 
0.44). Relapse was hematologic (n=9), or extramedullary (n=1); no patient had CNS relapse 
after CBT. The overall probability of survival was 0.56 (95% CI, 0.39, 0.73) and 0.47 (95% 
CI, 0.30, 0.64) at day 180 and 1 year, respectively.  Age, weight, gender, ethnicity, primary 
disease, recipient CMV status, TNC dose, CD34+ dose, CD3+ dose and transplant center 
did not significantly influence survival. Donor/recipient gender match (p<0.01) and high 
resolution HLA match (p<0.01) were the only two factors that were associated with 
improved survival. Twenty-two of the 32 patients died. The most common causes of death 
were relapse (n=8), graft failure (n=4), acute GVHD (n=5) and chronic GVHD (n=3). One 
death was attributed to each of viral infection and interstitial pneumonia. 
 
 
2.3.3 Outcomes of Mismatched Cord Blood Transplantation-UMN Experience 
Recently, we have reviewed the outcomes of 342 adult patients undergoing UCB 
transplantation at the University of Minnesota (Brunstein, manuscript submitted). 
Approximately one third of patients underwent myeloablative conditioning and the 
remainder received reduced intensity conditioning. All patients were transplanted with two 
UCB units. Following double UCB transplantation, the majority of patients have 
engraftment from a single unit within the first 100 days. To examine transplant outcomes 
patients were assigned to 3 different groups based on the HLA match of the engrafting unit. 
The groups consisted of HLA 2- 5/10 (n=108), 6-8/10 (n=202) and 9-10/10 (n=32) based on 
matching at HLA-A, - B, -C and –DRB1. These groups did not differ with respect to the 
incidence of neutrophil or platelet recovery (p=0.33 and p0.22). Similarly, the incidence of 
non-relapse mortality or grade II-IV aGVHD was not different between the groups (p=0.87 
and p=0.71). Somewhat paradoxically, after adjusting for the conditioning regimen, there 
was a 1.8-fold higher (p=.08) risk of relapse for patients receiving a 9-10/10 HLA-matched 
graft, as compared to a 2-5/10 HLA- matched graft. Similarly, when patients engrafted with 
a poorly matched unit (2- 5/10) vs. a well matched unit (9-10/10) they were 2.4-fold less 
likely to relapse (p=0.02). Collectively, these results in adult patients suggest that for patients 
at high risk for relapse, it may be beneficial to receive purposely mismatched UCB units. 
Similar results (high relapse rates) in well matched units 20 or lower rates of for poorly 
mismatched units 19,21 have been reported by some, but not others 22. 
Given that relapse is a major barrier to success for infants with leukemia (section 
2.1 and 2.2), we will test the hypothesis that poorly matched units are safe and result in lower 
rates of leukemia relapse in this patient population. 


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2.3.4 Consequences of TBI in Young Children 
In probably the largest study to date, Willard and coworkers studied the outcomes of 183 
children undergoing allogeneic transplantation 23. Patients were assessed using age 
appropriate neuropsychological testing, sequentially before and after transplantation (pre-
transplant and at 1, 3, and 5 years after transplantation). 
 
Approximately half of the patients received TBI, while the others did not. Using a variety of 
age-appropriate functional assessments (intelligence quotient (IQ), etc.) they demonstrate 
that all patients, regardless of conditioning, have a decrement in IQ score in the first year 
after transplantation. However, non-TBI treated patients recover to their pre-transplant 
baseline by 3 years (and maintain their performance at 5 years). In striking contrast, TBI 
treated patients were less likely to recover to baseline between 1 to 3 years post-transplant. 
More importantly, from years 3 to 5 after transplant these TBI-treated patients had further 
decrement in IQ function, suggesting that the effects of TBI are not completely appreciated 
for up to 5 years after transplant. This is a time when most transplant physicians are no longer 
involved in the care of the patient, perhaps leading to the bias, by some transplant physicians, 
that TBI does not significantly impact infants. These findings we age dependent since 
patients who were <3 years at the time of TBI had the most significant impairment (p=0.05). 
Thus, these findings strongly support the exploration of a non-TBI containing regimens in 
young children. 
 
2.4 Summary 
Poor engraftment and relapse are the two principal reasons for treatment failure in young patients 
with leukemia/myelodysplastic syndrome treated with busulfan and melphalan followed by 
UCBT. While effective, TBI results in long-term, irreversible cognitive dysfunction. Methods 
to prevent non-engraftment, relapse and long term neurocognitive complications are needed. 
There have been two recent changes in the field of allogeneic transplantation that have positively 
impacted outcomes. First, the introduction of fludarabine into the conditioning regimen has 
enhanced engraftment across histocompatibility barriers and has spawned an era of “non-
myeloablative” transplantation due to its potent immune suppressive effects. While the 
transplantation regimen proposed here is not a non-myeloablative regimen, this drug has also 
had a positive impact on myeloablative transplants. For instance, Fanconi anemia patients who 
have received a regimen of cyclophosphamide/TBI had an engraftment rate of 60%, but the 
addition of fludarabine to this regimen (i.e., flu/ cyclophosphamide/TBI) resulted in 100% 
engraftment27. Thus, we hypothesize that incorporation of fludarabine into a regimen of 
busulfan/melphalan will, likewise, enhance engraftment in a cohort of infants. The second recent 
change in UCB transplant is the observation that in UCBT, engraftment with a more mismatched 
unit results in lower relapse and equivalent leukemia free survival (our unpublished data and 
19,21). Thus, our overall hypothesis is that the addition of fludarabine and the use of a partially 
matched UCB unit will improve the rate of hematopoietic recovery (engraftment) and overall 
survival in infants with leukemia. 
 
3 STUDY DESIGN 
This is a single institution, phase II study to determine the incidence of engraftment in patients with 
hematological malignancy undergoing a match sibling donor or an unrelated, partially matched 


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single unit umbilical cord blood transplant (UCBT) after a myeloablative preparative regimen 
consisting of busulfan, melphalan and fludarabine. 
 
4 PATIENT SELECTION 
4.1 Graft Criteria 
4.1.1 
Matched sibling donor (HLA 8/8) cord blood or marrow, if available, or an unrelated 
partially HLA matched single umbilical cord blood (UCB) unit  
4.1.2 
UCB unit selection: Considering only units containing ≥2 x 107 total nucleated 
cells/kg and ≥1 x 105 CD34+ cells/kg: 
• 1st priority: HLA-mismatch (HLA-A, -B, -DRB1): 4/6 preferred over 5/6, 5/6 
preferred over 6/6 
• 2nd priority: Anti-HLA antibody testing will be completed per institutional 
guidelines with preference to UCB units for which the patient does not have 
donor specific antibodies. However, the presence of donor specific antibodies 
does not preclude the use of the UCB unit as long as the risks and potential 
benefits are discussed with the parent or legal guardian and documented. 
Antibody debulking should be considered. 
• 3rd priority: If above priorities are fulfilled and equal, select the unit with the 
largest CD34+/kg cell dose  
• Additional considerations: If all above priorities fulfilled and equal, consider 
matching on ABO and race (latter when data available) 
 
 
 
4.2 Age and Disease Criteria 
4.2.1 
Age ≤ 3 years at diagnosis (not age of transplant) 
 
4.2.2 
Meeting of one of the following disease criteria: 
Acute myeloid leukemia: high risk CR1 as evidenced by: 
High risk cytogenetics 
t(4;11) or other MLL rearrangements chromosome 5, 7, or 19 abnormalities 
complex karyotype (>5 distinct changes) 
≥ 2 cycles to obtain CR; CR2 or higher Preceding MDS 
All patients must be in CR or early relapse (i.e., <15% blasts in BM). 
 
Acute lymphocytic leukemia: high risk CR1 as evidenced by: High-risk 
cytogenetics: 
t(4;11) or other MLL rearrangements hypodiploid 
t(9;22) 
>1 cycle to obtain CR CR2 or higher 
All patients must be in CR as defined by hematological recovery, AND 
<5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. 
 
Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory 
anemia with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by 
a representative bone marrow aspirate morphology. 


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Persistent or rising minimal residual disease (MRD) after standard chemotherapy 
regimens: Patients with evidence of minimal residual disease at the completion of 
therapy or evidence of rising MRD while on therapy. MRD will be defined by either 
flow cytometry (>0.1% residual cells in the blast gate with immune phenotype of 
original leukemic clone), by molecular techniques (PCR or FISH) or conventional 
cytogenetics (g- banding). 
 
New Leukemia Subtypes: A major effort in the field of pediatric hematology is to 
identify patients who are of high risk for treatment failure so that patients can be 
appropriately stratified to either more (or less) intensive therapy. This effort is 
continually ongoing and retrospective studies identify new disease features or 
characteristics that are associated with treatment outcomes. Therefore, if new high 
risk features are identified after the writing of this protocol, patients can be enrolled 
with the approval of two members of the study committee. 
 
4.3 Organ Function and Performance Status Criteria 
4.3.1 
Lansky play score ≥ 50 (appendix I) 
4.3.2 
Acceptable organ function defined as: 
o Renal: glomerular filtration rate > 60ml/min/1.73m2 
o Hepatic: bilirubin, AST/ALT, and ALP < 5 x upper limit of normal 
o Pulmonary function: oxygen saturation >92% 
4.3.3 
Cardiac: left ventricular ejection fraction ≥ 45% 
4.3.4 
Voluntary written informed consent before performance of any study- related 
procedures not part of normal medical care. 
 
 
4.4 Exclusion Criteria 
4.4.1 Active uncontrolled infection at time of transplantation (including active infection 
with Aspergillus or other mold within 30 days) 
4.4.3 
History of HIV infection or known positive serology 
4.4.4 
Myeloablative transplant within the last 6 months 
4.4.5 
Evidence of active extramedullary disease (including CNS leukemia) 
5 PATIENT REGISTRATION 
To be eligible for registration to this study, the patient must meet each criteria listed on the eligibility 
checklist (kept in Oncore) based on the eligibility assessment documented in the patient’s medical 
record. 
 
Participants will be registered in the Masonic Cancer Center’s clinical database, OnCore by a BMT 
CDA. 
 
Any patient receiving unlicensed unrelated umbilical cord blood (UCB) will be co- enrolled in the 
University of Minnesota protocol MT2011-13R “Infusion of Cell Populations from Unlicensed 
Umbilical Cord Blood Units” (IND 14797 C. Brunstein S/I). 
 


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6 TREATMENT PLAN 
In order to provide optimal patient care and to account for individual medical conditions, 
investigator discretion may be used in the prescribing of all supportive care drug therapy (i.e. 
acetaminophen, diphenhydramine, methylprednisolone, G-CSF, etc). 
 
 
6.1 Treatment Plan 
Begin Keppra on day -9 and continuing until day – 3 or as medically indicated. 
Day 
Drug 
Dose 
-8 
Busulfan 
Once daily over 3 hrs with initial dose determined by model-
based dosing*  
-7 
Busulfan 
Once daily over 3 hrs with dose adjusted based on  therapeutic drug 
monitoring 
-6 
Busulfan 
Once daily over 3 hrs with dose adjusted based on therapeutic drug 
monitoring 
-5 
Busulfan 
Once daily over 3 hrs with dose adjusted based on therapeutic drug 
monitoring 
-4 
Fludarabine 
Melphalan 
25 mg/ m2 (0.83 mg/kg if <10 kg) IV over 60 min& 
50 mg/m2 (1.7 mg/kg if <10 kg) IV over 15 min 
-3 
Fludarabine  
Melphalan 
25 mg/ m2 (0.83 mg/kg if <10 kg) IV over 60 min& 
50 mg/m2 (1.7 mg/kg if <10 kg) IV over 15 min 
-2 
Fludarabine  
Melphalan 
25 mg/ m2 (0.83 mg/kg if <10 kg) IV over 60 min& 
50 mg/m2 (1.7 mg/kg if <10 kg) IV over 15 min 
-1 
Rest 
0 
UCB or BM infusion 
*Initial dose will be determined by model-based dosing utilizing Bayesian pharmacokinetic software if available 
&Initial dose may be based on Bayesian pharmacokinetic software if available 
 
 
 
6.2 Conditioning Regimen 
6.2.1 Busulfan 
BUSULFAN DOSING AND ADMINISTRATION:  
Busulfan compounding, administration and monitoring should be performed per institutional 
guidelines. 
 
The first busulfan dose will be determined by model-based dosing utilizing Bayesian 
pharmacokinetic software with a cumulative area under the curve (cAUC) target of 62 
mg*hr/L.  
An IP pediatric BMT pharmacist will be consulted for assistance in first (and subsequent) 
busulfan dose determinations.  
 
Busulfan will be given every 24 hours (i.e., on a daily basis). Busulfan will be administered 
over 3 hours per the University of Minnesota Blood and Marrow Transplant Program 
busulfan SOC guidelines on days -8, -7, -6, and -5.  
• 
Levetiracetam 
(Keppra) 
will 
be 
administered 
in 
accordance 
with Busulfan SOC guidelines as seizure prophylaxis during busulfan therapy.    


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• 
Concomitant administration of interacting medications such as azole anti-fungal 
agents (except fluconazole) should be avoided. 
• 
It is recommended that acetaminophen administration, particularly on 72 hours prior 
to or after busulfan administration, be limited to necessary indications (such as pre-
medication for the prevention of ATG reactions). When acetaminophen use is deemed 
necessary on or near the days of busulfan administration, conservative dosing of 10 
mg/kg/dose (max 500 mg/dose) is recommended.  
 
BUSULFAN THERAPEUTIC DRUG MONITORING (TDM):  
Area under the curve (AUC) analyses will be calculated in-house per University of 
Minnesota BMT SOC guidelines for all BMT patients. The AUC will be calculated for each 
dose using serum busulfan concentrations analyzed by the Special Chemistry/Drug Analysis 
Lab.    
Busulfan therapeutic drug monitoring (TDM) will be used to target a cumulative (or overall) 
exposure 
for 
the 
entire 
course cAUC = 
58-67 
mg*h/L 
(Target cAUC = 
62 
mg*h/L). Results of TDM performed with the first dose will inform subsequent busulfan 
dosing (doses #2, #3 and #4).   
An IP pediatric BMT pharmacist will be consulted for TDM. Subsequent busulfan doses will 
be determined by busulfan AUC calculations. Refer to Busulfan SOC Guideline for blood 
sample collection process, busulfan results reporting, and therapeutic drug monitoring 
procedures.  
 
 
6.2.2 Fludarabine 
Fludarabine will be administered at a dose of 25 mg/m2/day x 3 days, total dose 75 mg/m2 
(days –4 to –2). For children < 10 kg, fludarabine dosing will be 0.83 mg/kg/day x 3 days, 
total dose 2.49 mg/kg (days -4 to -2). If available, dosing may be calculated using Bayesian 
pharmacokinetic software. Dosing is based on actual body weight. The fludarabine dose will 
be administered IV over one hour at a constant rate. If the normalized GFR is <70 ml/min, 
a 20% dose-reduction of fludarabine may be considered after discussion between the 
protocol PI, patient’s primary BMT physician and pediatric BMT pharmacist. 
 
6.2.3 
Melphalan 
Melphalan will be administered at a dose of 50 mg/m2/day x 3 days, total dose150 mg/m2 
(days -4 to - 2). For children <10 kg, melphalan dosing will be 1.7 mg/kg/day IV x 3 days, 
total dose 5.1mg/kg (days -4 to -2). Melphalan is to be administered 12 hours after 
fludarabine, infused over 15 minutes, with maintenance hydration (>1500ml/m2/day) during 
administration and for 24 hours following infusion. 
6.3 
Immunosuppressive Therapies 
All patients will receive GVHD prophylaxis with Tacrolimus and Mycophenolate mofetil 
(MMF) as per institutional guidelines: 
 
6.3.1 Tacrolimus 
Tacrolimus will start day -3 and will be administered as a continuous IV infusion at a starting 
dose of 0.03 mg/kg/day. Goal trough levels will be 10-15 ng/mL for the first 14 days post-
transplant and then decreased to a goal of 5-10 ng/ml thereafter. Dose adjustments will be 


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made on the basis of toxicity and/or tacrolimus levels outside of goal range. Conversion from 
IV to oral tacrolimus will be done as the patient tolerates and prior to discharge. Potential 
toxicities are detailed in Appendix III. 
Patients will receive tacrolimus until day +100. If no GVHD, the dose will be tapered 10% 
per week beginning on day 101, to discontinue at approximately day +180. 
 
In the presence of severe tacrolimus toxicities, other alternative agents may be used after 
review and approval by the co-PIs. 
 
6.3.2 Mycophenolate mofetil (MMF) 
MMF will start on day -3 at a dose of 15 mg/kg/dose IV every 8 hours (max dose 1 gm/dose).  
 
Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute GVHD. 
Definition of engraftment is 1st day of 3 consecutive days of absolute neutrophil count 
[ANC] > 0.5 x 109/L. If the patient has acute GVHD requiring systemic therapy, MMF 
should continue for at least 7 days after initiation of systemic therapy for acute GVHD. 
Afterward, use of MMF is at the discretion of the treating physician. 
 
6.4 Umbilical Cord Blood Transplantation (UCBT) 
The unit will be infused on day 0 according to the current institutional guidelines for a single 
cord UCB transplant. 
 
6.4.1 
Pre Infusion Treatment Plan 
All patients will receive intravenous hydration plus pre-medication with acetaminophen and 
diphenhydramine hydrochloride (or similar alternatives) with doses adjusted for the patient’s 
age and weight approximately 30 minutes prior to the infusion of the UCB product. 
 
Emergency drugs such as epinephrine, hydrocortisone, diphenhydramine and atropine in 
appropriate dosages and dilutions should be available and administered according to 
institutional guidelines. Oxygen should be available in the patient’s room. 
 
6.4.2 
Infusion of Minimally Manipulated UCB Unit 
After positive identification and crosschecking according to institutional SOPs, the UCB 
unit will be infused through a central line according to institutional guidelines. The UCB 
infusion rate is not to exceed 10 mL/min regardless or recipient age or size. However for 
patients <20 kg, the final volume is adjusted upon washing such that the unit is re-suspended 
in a maximum volume 100 mL (range 60-100 mL). 
 
6.4.3 
Monitoring of Vital Signs 
Based on existing Transplant Unit SOPs, vital signs are obtained prior to and every 15 
minutes during the infusion and at the completion of infusion. This monitoring may be 
intensified or prolonged if clinically indicated 
 
6.4.4 
Management of Infusion Reactions 
In case of a life threatening infusion related reaction, such as severe allergic reaction or 
cardiac arrhythmia, the infusion will be stopped and the patient will be evaluated and treated 


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2005LS075 
by the medical team. Once the patient has improved and is medically stable, the team will 
determine whether or not the UCB infusion should be completed. 
 
In case of a non-life-threatening/serious reaction (e.g. hypertension), the infusion may be 
slowed or stopped and the patient treated, as deemed appropriate by the medical team. Once 
the patient has improved and is medically stable, the infusion may be restarted at a slower 
rate. 
 
6.5 Growth Factor 
All patients will receive G-CSF 5 mcg/kg/day IV based on the actual body weight IV beginning 
on day +1 after UCB infusion. G-CSF will be administered daily until the ANC exceeds 1.5 x 
109/L for three consecutive days, or if ANC exceeds 3 x 109/L on a single day, then discontinue. 
If the ANC decreases to <1.0 x 109/L, G-CSF will be provided as needed. 
6.6 Treatment Related Toxicities 
Refer to appendix III for expected treatment related toxicities. 
 
6.7 Supportive Care Guidelines 
Patients will receive transfusions, infection prophylaxis, and nutritional support according to the 
current University of Minnesota supportive care guidelines. 
 
For veno-occlusive disease (VOD) prophylaxis, patients should receive ursodiol 10 mg/kg 
enterally TID upon admission until day +30 or hospital discharge, whichever occurs earlier. 
 
 


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7 STUDY PARAMETERS 
Scheduled evaluations prior to engraftment (day 30) may be performed +/-3 days from the targeted 
date; assessments to be performed between engraftment and day 100 may be done +/-7 days of the 
targeted date; assessments after day 100 may be performed +/-30 days of the targeted date. In 
addition, targeted days may be altered as clinically appropriate. 
 
Screen 
Day 1 to engraftment2 
Days 31-100 
Follow-up 
daily 
weekly 
Day 
+21 
Day 
+28 
weekly 
Day 
+60 
Day 
+100 
6 months, 
1 & 2 yrs 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
X 
 
 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
X 
Lansky play score 
X 
 
 
 
 
 
 
 
 
Height/Weight 
X 
 
 
 
 
 
 
 
X 
GVHD evaluation 
 
 
X 
 
 
Per institutional guidelines 
CMV Surveillance 
 
 
 
 
 
Per institutional guidelines 
Toxicity assessment 
 
 
X 
 
 
X thru 
day +42 
X 
X 
 
Laboratory 
CBC, diff 
X 
X2 
 
 
 
X 
 
 
X 
Platelet 
X 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
AST ALT, alk phos, bili (T/D) 
X 
 
 
 
 
 
 
 
 
Creatinine, Na, K, HCO3 
X 
prn 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
prn 
 
 
 
 
 
 
GFR 
X 
 
 
 
 
 
 
 
 
Bone marrow bx/asp 
w/chimerism 
X 
 
 
X 
X3 
 
 
X 
X 
Lumbar puncture4 
X 
 
 
 
 
 
X 
X 
X 
Chimerism – PB 
X 
 
 
X 
X 
 
X 
X 
X 
PRA: Initial5 
X 
 
 
 
 
 
 
 
 
PRA: Confirmatory w/in 21 days 
of treatment5 
X 
 
 
 
 
 
 
 
 
Procedures 
EKG 
X 
 
prn 
 
 
prn 
 
 
prn 
MUGA or echocardiogram 
X 
 
prn 
 
 
prn 
 
 
1 yr then 
prn 
Chest x-ray or CT 
X1 
 
prn 
 
 
prn 
 
 
prn 
Oxygen saturation (or PFTs if old 
enough) 
X 
 
prn 
 
 
prn 
 
 
prn 
 Additional disease evaluations4 
X 
 
X 
 
 
 
 
X 
X 
Neuropsych Eval 
X 
 
 
 
 
 
 
 
X (1 & 2  
years) 
1 – CT without contrast to exclude occult infection for patients with a history of the following: 
• 
MDS 
• 
2 or more consecutive leukemia inductions 
• 
prolonged neutropenia, as defined as ≥ 4 weeks of neutropenia within the 2 months prior to BMT  
2 – Complete blood count with leukocyte differential daily until the absolute neutrophil count (ANC) > 0.5 x 109/L for 
3 consecutive measurements  
3 – Day 28 Bone marrow biopsy if slow engraftment and proceed per U of MN guidelines  
4 – as clinically indicated 
5 – UCBT recipients only 


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8 ADVERSE EVENT MONITORING AND REPORTING 
8.1 Definitions 
An adverse event (AE) is any symptom, sign, illness or experience, regardless of causality, that 
develops or worsens in severity during the course of the study. The occurrence of an adverse 
event will be based on changes in the patient’s physical examination, laboratory results, and/or 
signs and symptoms. Intercurrent illnesses or injuries should be regarded as adverse events if at 
least possibly related (i.e. temporal relationship to the study treatment, known toxicity of the 
treatment, etc.). 
 
Attribution: 
• Unrelated - The AE is clearly NOT related to the intervention 
• Unlikely - The AE is doubtfully related to the intervention 
• Possible - The AE may be related to the intervention 
• Probable - The AE is likely related to the intervention 
• Definite - The AE is clearly related to the intervention 
 
Unanticipated (unexpected) problems/events are those that are not already described as 
potential risks in the consent form, not listed in the Investigator’s Brochure or not part of an 
underlying disease. 
 
Anticipated (expected) problems are those that are already described as potential risks in the 
consent form, listed in the Investigator’s Brochure or part of an underlying disease. 
 
8.2 Monitoring and Documentation of Toxicity 
Toxicity assessments will be done once weekly for the start of any study therapy through day 
42 and at each milestone visit through day 100. 
 
Refer to appendix III for a list of expected toxicities. 
 
Adverse event documentation requirements will be determined based on grade, expectedness 
and relationship to study therapy as follows: 
 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 and 5 
Expected or 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not 
required 
Not required 
Not 
required 
Not required 
Required 
Possible 
Probable 
Definite 
Not required 
Not 
required 
Not required 
Not 
required 
Required (Non-
hematologic only) 
Required 
Stopping rule events: The following events count toward a study stopping rule per section 10.4 
and must be reported to the MCC SAE Coordinator using the Study Stopping Rule Report Form: 
• Graft failure by day 42 (defined as failing to achieve an ANC > 500/uL of donor origin 
by day 42) 


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• Treatment related mortality by day 100 
 
Events that count toward an early stopping rule do not necessarily constitute a an adverse event 
requiring expedited reporting and should be reported as such only if they meet the criteria for 
expedited reporting to the IRB as defined in section 8.3. 
 
8.3 Required Reporting to University Of Minnesota IRB and Masonic Cancer Center 
The reporting period for this study is from initiation of any study treatment through day +100; 
however after day +100, the investigator must report upon knowledge any study treatment 
related event meeting the expedited reporting criteria below. 
 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
Copy AE to: 
U of MN 
IRB 
Events requiring prompt reporting 
including, but not limited to unanticipated 
death of a locally enrolled subject(s); new 
or increased risk; any adverse event that 
require a change to the protocol or 
consent form or any protocol deviation 
that resulting in harm. For a complete list 
and the Report Form refer to 
http://www.research.umn.edu/irb/guidanc
e/ae.html# definition 
Within 5 
business 
days of 
event 
discovery 
IRB’s 
Report 
Form 
irb@umn.edu 
SAE 
Coordinator 
mcc- 
saes@umn.ed
u 
All problems/events that do not meet the 
IRB’s requirements for prompt reporting 
Report to the IRB in summary form at 
the time of continuing review. 
Not 
applicable 
Masonic 
Cancer 
Center SAE 
Coordinator 
Events that meet the criteria for early 
study stopping rule 
At time of 
reporting 
OnCore 
Form 
SAE 
Coordinator 
mcc- 
saes@umn.ed
u 
Not 
applicable 
 
The SAE Coordinator, if applicable, will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on the individual 
SAE (as reported or in a summary format). 
 
9 DATA COLLECTION AND MONITORING PLAN 
9.1 Data Management 
Patients will be registered in The Online Enterprise Research Management Environment 
(OnCoreTM), a web based Oracle® database. Specific transplant related endpoints will be 
recorded in the University Of Minnesota Blood and Bone Marrow Database as part of the 
historical database maintained by the department. 
9.2 Data and Safety Monitoring Plan 
The study’s Data and Safety Monitoring Plan will be in compliance with the University of 
Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP), which can be 
accessed at http://z.umn.edu/dmsp . 
 
For the purposes of data and safety monitoring, this study is classified as moderate risk. 


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Therefore the following requirements will be fulfilled: 
• The PI will complete and submit a twice yearly Trial Progress Report to the Masonic 
Cancer Center Data and Safety Monitoring Council (DSMC) with the understanding the 
Cancer Protocol Review Committee (CPRC) may require more frequent reporting. 
• The PI will comply with at least yearly monitoring of the project by the Masonic Cancer 
Center monitoring services. 
• The PI will oversee the submission of all reportable adverse events per the definition of 
reportable in section 8.3 to the Masonic Cancer Center’s SAE Coordinator and the 
University of Minnesota IRB. 
 
In addition, at the time of the continuing review with the University of Minnesota IRB, a copy 
of the report with any attachments will be submitted to the Cancer Protocol Review Committee 
(CPRC). 
 
9.3 Record Retention 
The investigator will retain study records, including source data, copies of CRF’s and all study 
correspondence in a secure facility for at least 6 years after the study file is closed with the IRB. 
In addition, the Clinical Trials Office will keep a master log of all patients participating in the 
study with sufficient information to allow retrieval of the medical records. 
 
9.4 Monitoring 
The investigator will permit study-related monitoring, audits, and inspections by the University 
of Minnesota compliance groups and government regulatory bodies. The investigator will make 
available all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data, etc.). The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.) will 
be available for trial related monitoring, audits, or regulatory inspections. 
 
10 STATISTICAL CONSIDERATIONS 
10.1 Objectives 
10.1.1 Primary objective 
The principal aim of this study is to estimate the incidence of neutrophil recovery by day 
+42 after UCBT after a myeloablative preparative regimen. 
 
10.1.2 Secondary Endpoints 
• 
Determine the incidence of transplant-related mortality (TRM) at 6 months after 
UCBT 
• 
Evaluate pattern of chimerism after double UCBT days 21, 100, 6 months, 1 year and 
2 years 
• 
Determine the incidence of platelet recovery at 1 year after UCBT 
• 
Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and 
grade III-IV at day 100 after UCBT 
• 
Evaluate the developmental outcome after UCBT 
 
 


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10.1.3 Transplant Related Endpoints 
• 
Determine the incidence of chronic GVHD at 1 year after UCBT 
• 
Determine the survival and disease free survival at 1 and 2 years after UCBT 
• 
Determine the incidence relapse at 1 and 2 years after UCBT 
10.2 Statistical Analysis 
Survival and disease-free survival will be estimated by the Kaplan-Meier method. Non-relapse 
mortality, relapse, neutrophil and platelet engraftment, acute and chronic GVHD will be 
estimated by cumulative incidence treating non-event deaths as competing risks. Chimerism will 
be evaluated both by simple proportions and median (range) values among assessable patients. 
Ninety-five percent confidence intervals will be used to make inferences. Comparisons of time-
to-event endpoints by various factors will be completed by the Log-rank or Gray’s test. 
Comparison of simple proportions will be evaluated by the Chi-square test and the general 
Wilcoxon test will be used to evaluate differences between continuous factors. Simple 
descriptive statistics and plots will be given for the neuropsychiatric parameters. 
 
Addendum (03/02/2020): Since we are changing the UCB selection, Busulfan dosing and 
GvHD prophylaxis, endpoints will be estimated separately for patients enrolled before and after 
this addendum. Methods will stay the same.  
 
10.3 Rationale for Sample Size 
We expect to enroll 3 to 4 patients per year. Based on prior experience with fludarabine and 
double UCB, we hope to get better than 75% engraftment and estimate that we will achieve 90% 
engraftment by day 42 post-transplant. If 95% of patients have access to two UCB donors, this 
will give a lower 95% confidence bandwidth of at least 0.15. This is assuming that there are no 
patients with early death prior to an evaluable graft assessment. Enrollment on the double unit 
and single unit arms of the study is expected to be a minimum of 14 and 1 patients respectively. 
No more than 20 patients will be enrolled on this protocol before evaluation of the primary 
endpoint. Transplantation at the University of Minnesota of patients that fit the eligibility criteria 
in this study averaged 3 patients per year in recent years. 
 
addendum (03/16/2015 and 5/19/15): We have reached the maximum sample size of 20 
patients and therefore the protocol will be redesigned. To permit continued access to transplant 
until that time, 7 additional patients will be enrolled using a single UCBT or a matched sibling 
donor. Among the currently enrolled 14 patients in the double UCBT cohort, engraftment is 
100%. However, the observation that in both single and double UCBT, engraftment with a more 
mismatched unit results in lower relapse and equivalent leukemia free survival (our unpublished 
data and 19,21), single mismatched UCB transplants will now be performed instead of double 
UCBT in this protocol. There is currently 1 graft failure among 6 SUCBT patients. The 
cumulative incidence of engraftment is 83% (95% CL, 48-99%). To improve precision, 7 
patients will be added for a total of 13 single UCB transplants. With 13 patients and an expected 
engraftment of 93%, the lower 95% confidence band will be 65% and the upper limit will be 
100%. Due to a very limited number of matched sibling donor transplants expected, results from 
these patients will be listed descriptively. 
 
Addendum (07/26/2017): After reaching the revised accrual goal, we will enroll an additional 
10-15 subjects in order to give patients access to transplant until a replacement study is 


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2005LS075 
approved. The replacement protocol is currently being written and should be submitted to the 
IRB/CPRC within 3 months. The current regimen continues to be safe with no additional graft 
failures. Although allowing time for a newly developed protocol is the primary reason for 
revising the accrual goal, the additional patients will also help to improve precision of our 
primary endpoint of neutrophil engraftment. With potentially 28 patients and an expected 
engraftment of 93%, the lower 95% confidence band will be 77% and the upper limit will be 
99%. 
 
Addendum (03/02/2020): We are updating the protocol to be more in line with institutional 
practices for UCB selection, Busulfan dosing and GvHD prophylaxis. We will enroll an 
additional 10-15 subjects in order to give patients access to transplant until a replacement study 
is approved.  
 
10.4 Toxicity Monitoring and Stopping Rules 
Monitoring guidelines will be set up for graft failure by day +42 and treatment related mortality 
by day +100 post-transplant. Monitoring guidelines are for the single UCBT cohort only using 
a continuous monitoring strategy based on an adaptation of Pocock stopping boundaries26. In 
the event that a stopping rule is triggered, enrollment will be halted and reviewed by the full 
study committee and if appropriate by the IRB, prior to initiation of re-enrollment. 
 
Addendum (07/26/2017): Since the regimen has not changed, the stopping rules will include 
prior events from the single UCBT cohort 
 
10.4.1 Graft Failure by day +42 
The goal is to construct a boundary based on graft failure (defined as failing to achieve an 
ANC >500/uL of donor origin by day +42) such that the probability of early stopping is at 
most 10% if the true graft failure rate is equal to 7% and our sample size is 28. Given these 
parameters, the upper stopping boundary for graft failure is 2/5 or 3/11, 4/19 or 5 patients 
fail to engraft. 
 
10.4.2 Treatment Related Mortality by 100 days 
Stopping rules were developed for excessive non-event mortality (TRM) by day +100 post-
transplant. The goal is to construct a boundary based on TRM such that the probability of 
early stopping is at most 10% if the true rate is equal to 30% and our sample size is 28. Given 
these parameters, the upper stopping boundary for TRM is 3 deaths out of 3 patients, 4/5, 
5/7, 6/9, or 7 /11, 8/13, 9/16, 10/18, 11/21, 12/24, 13/26 or 14 patients with TRM by 100 
days. 
 
Addendum (03/02/2020): Since the regimen is changing, the stopping rules will start over after 
this addendum among the single UCB cohort. We do not expect more than 15 additional patients. 
 
10.4.1 Graft Failure by day +42 
The goal is to construct a boundary based on graft failure (defined as failing to achieve an 
ANC >500/uL of donor origin by day 42) such that the probability of early stopping is at 
most 10% if the true graft failure rate is equal to 7% and our sample size is 28. Given these 
parameters, the upper stopping boundary for graft failure is 2/5 or 3/11, 4/19 or 5 patients 
fail to engraft. 


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10.4.2 Treatment Related Mortality by 100 days 
Stopping rules were developed for excessive non-event mortality (TRM) by day +100 post-
transplant. The goal is to construct a boundary based on TRM such that the probability of 
early stopping is at most 10% if the true rate is equal to 30% and our sample size is 28. Given 
these parameters, the upper stopping boundary for TRM is 3 deaths out of 3 patients, 4/5, 
5/7, 6/10, or 7 /12, 8/14 or 9 patients with TRM by 100 days. 
 
Due to the addition of stopping rules, it is understood that the overall power may be slightly 
decreased in this study. 
 
10.5 Gender and Ethnicities Statement 
This study is open to both males and females and to all racial/ethnic groups. The patient 
enrollment pattern is expected to be similar to that of other hematological malignancy studies. 
It is not anticipated that the outcome will be affected by either race or gender. The study will 
not have separate accrual targets for different subgroups. 
 
 
11 REFERENCES 
1. 
Gilliland DG, Jordan CT, Felix CA: The molecular basis of leukemia. Hematology 
(Am Soc Hematol Educ Program):80-97, 2004 
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Armstrong SA, Staunton JE, Silverman LB, et al: MLL translocations specify a 
distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 30:41-7, 2002 
3. 
Pui CH, Gaynon PS, Boyett JM, et al: Outcome of treatment in childhood acute 
lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 359:1909-
15, 2002 
4. 
Balduzzi A, Valsecchi MG, Uderzo C, et al: Chemotherapy versus allogeneic 
transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete 
remission: comparison by genetic randomisation in an international prospective study. Lancet 
366:635-42, 2005 
5. 
Kosaka Y, Koh K, Kinukawa N, et al: Infant acute lymphoblastic leukemia with 
MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell 
transplantation. Blood 104:3527-34, 2004 
6. 
Sanders JE, Im HJ, Hoffmeister PA, et al: Allogeneic hematopoietic cell 
transplantation for infants with acute lymphoblastic leukemia. Blood 105:3749-56, 2005 
7. 
Blume K, Forman SJ, Appelbaum FR: Thoma's Hematopoietic Cell Transplantation 
(ed 3nd). Malden, MA, Blackwell Science, Inc., 2004 
8. 
Confer DL: Unrelated marrow donor registries. Curr Opin Hematol 4:408- 12, 1997 
9. 
Wagner JE, Kernan NA, Steinbuch M, et al: Allogeneic sibling umbilical- cord-blood 
transplantation in children with malignant and non-malignant disease. Lancet 346:214-9, 1995 
10. 
Wagner JE, Rosenthal J, Sweetman R, 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 88:795-802, 1996 
11. 
Kurtzberg J, Laughlin M, Graham ML, et al: Placental blood as a source of 
hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 335:157-66, 
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12. 
Gluckman E, Rocha V, Boyer-Chammard A, et al: Outcome of cord-blood 
transplantation from related and unrelated donors. Eurocord Transplant Group and the European 
Blood and Marrow Transplantation Group. N Engl J Med 337:373-81, 1997 
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Rubinstein P, Carrier C, Scaradavou A, et al: Outcomes among 562 recipients of 
placental-blood transplants from unrelated donors. N Engl J Med 339:1565- 77, 1998 
14. 
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 344:1815-22, 2001 
15. 
Laughlin MJ, Eapen M, Rubinstein P, et al: Outcomes after transplantation of cord 
blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351:2265-75, 
2004 
16. 
Rocha V, Labopin M, Sanz G, et al: Transplants of umbilical-cord blood or bone 
marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351:2276-85, 2004 
17. 
Wagner JE, Barker JN, DeFor TE, et al: 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 100:1611-8, 2002 
18. 
Wall DA, Carter SL, Kernan NA, et al: Busulfan/melphalan/antithymocyte globulin 
followed by unrelated donor cord blood transplantation for treatment of infant leukemia and 
leukemia in young children: the Cord Blood Transplantation study (COBLT) experience. Biol Blood 
Marrow Transplant 11:637-46, 2005 
19. 
Wagner JE, Jr., Eapen M, Carter S, et al: One-unit versus two-unit cord- blood 
transplantation for hematologic cancers. N Engl J Med 371:1685-94, 2014 
20. 
Eapen M, Rubinstein P, Zhang MJ, et al: Outcomes of transplantation of unrelated 
donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. 
Lancet 369:1947-54, 2007 
21. 
Sanz J, Jaramillo FJ, Planelles D, et al: Impact On Outcomes Of Hla Matching By 
Allele-Level Typing In Adults With Acute Myeloid Leukemia Undergoing Umbilical Cord Blood 
Transplantation. Biol Blood Marrow Transplant, 2013 
22. 
Eapen M, Klein JP, Ruggeri A, et al: Impact of allele-level HLA matching on 
outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic 
malignancy. Blood 123:133-40, 2014 
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Willard VW, Leung W, Huang Q, et al: Cognitive outcome after pediatric stem-cell 
transplantation: impact of age and total-body irradiation. J Clin Oncol 32:3982- 8, 2014 
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Long-Boyle JR, Savic R, Yan S, et al: Population pharmacokinetics of busulfan in 
pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing 
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Le C: Study Designs, in Le C (ed): Introductory Biostatistics. Hoboken, NJ, John 
Wiley & Sons, 2003, pp 445-482 
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Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials 
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27. Tan P-L, et al. Pediatric Blood and Cancer 2006: 46: 630-6.


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Appendix I - Lansky Play Score 
 
 
 
Percentage 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of, and less time spent in, play activities 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play; able to participate 
in all 
quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
Unresponsive 
0 
Dead 


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Appendix II – Busulfan Dose Selection, AUC Monitoring and Algorithm 
for Dose Modification Using Once Daily IV Dosing 
 
Refer to University of Minnesota BMT Busulfan Standard of Care Guidelines for blood sample collection process, 
busulfan results reporting, and therapeutic drug monitoring procedures. 
 
 
 
 


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Appendix III – Expected Toxicities of Standard Therapies 
Conditioning Regimen: 
Busulfan 
Common 
Less Common 
Rare  
• low white blood cell count with 
increased risk of infection  
• low platelet count with increased 
risk of bleeding  
• low red blood cell count (anemia) 
which may cause tiredness, 
headache, dizziness  
• hair loss or thinning, including 
face and body hair (usually grows 
back after treatment)  
• long-term or short-term infertility 
(inability to have children) in men 
and women 
 
• tiredness (fatigue)  
• sores in mouth or on lips  
• fever  
• nausea  
• vomiting  
• rash  
• loss of appetite  
• diarrhea  
 
• abnormal blood tests results which 
suggest that the drug is affecting the liver  
• allergic reaction with hives, itching, 
headache, coughing, shortness of breath, 
or swelling of the face, tongue, or throat  
• scarring of lung tissue, with cough, 
difficulty breathing, and shortness of 
breath that may occur after prolonged use, 
or even months or years after stopping the 
drug  
• seizure 
• leukemia (several years after treatment)  
• darkened skin  
• heart problems with high-dose treatment, 
most often in people with thalassemia   
• problems with the hormone system that 
cause weakness, tiredness, poor appetite, 
weight loss, and darker skin  
• death due lung damage, bone marrow 
shutdown, or other causes  
 
 
 
 
Fludarabine 
Common 
Less Common 
Rare 
• low white blood cell 
count with increased risk 
of infection 
• low platelet count with 
increased 
risk 
of 
bleeding 
• low red blood cell count 
(anemia) with tiredness 
and weakness 
• tiredness (fatigue) 
• nausea 
• vomiting 
• fever and chills 
• infection 
• pneumonia 
• diarrhea 
• loss of appetite 
• weakness 
• pain 
• numbness and tingling in hands 
and/or feet related to irritation of 
nerves 
• changes in vision 
• agitation 
• confusion 
• clumsiness 
• seizures 
• coma 
• cough 
• trouble breathing 
• intestinal bleeding 
• weakness 
• death due to effects on the brain, 
infection, 
bleeding, 
severe 
anemia, skin blistering, or other 
causes 


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Melphalan 
Common 
Less Common 
Rare 
• nausea 
• vomiting 
• low white blood cell 
count with increased risk 
of infection 
• low platelet count with 
increased 
risk 
of 
bleeding 
• low red blood cell count 
(anemia) with tiredness 
and weakness 
• short-term 
or 
long-term 
infertility 
(inability to have 
children) 
• weakness 
• severe allergic reaction 
• loss of appetite 
• scarring 
(fibrosis) 
or 
inflammation of lungs 
• hair loss, including face and body 
hair 
• rash 
• itching 
• second type of cancer (may 
happen years after treatment) 
• death from lung damage or other 
causes 
 
Immunosuppressive Therapies for GvHD prophylaxis: 
Tacrolimus  
Mycophenolate mofetil (MMF) 
• high blood pressure 
• abnormalities in blood chemicals 
• seizures 
• headaches 
• renal dysfunction to renal failure requiring 
dialysis  
•  nausea and vomiting 
• diarrhea 
• constipation 
• lowering of blood counts 
• leg cramps 
• skin rash 
• difficulty sleeping 
• chemical 
imbalances
including 
high blood sugar 
• headaches 
• dizziness 
• high blood pressure 
 
 
 
Hematopoietic Cell Transplantation – regardless of stem cell source 
With the cell infusion 
• nausea and vomiting 
• possible allergic reaction (including itching, hives, flushing [red face], shortness of breath, 
wheezing, chest tightness, skin rash, fever, chills, stiff muscles, or trouble breathing) 
 
As result of cord blood or marrow transplant 
• Slow recovery of blood counts 
• Graft failure 
• Graft-Versus-Host Disease (GVHD) 
• Other complications including: 
o Damage to the vital organs 
o Serious infections 
o Relapse of disease or a new blood cancer 
o Risk to the unborn 
 
 


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Additional Risks associated with the use of Umbilical Cord Blood 
• 
DMSO Toxicity is a possible complication of UCB infusion and occurs due to the presence of DMSO in the 
thawed product. The risk of toxicity increases with the number of units (total volume per kg body weight) 
infused. Symptoms are due to histamine release and include: 
• 
cough 
• 
flushing 
• 
rash 
• 
chest tightness 
• 
nausea and vomiting 
• 
bradycardia and tachycardia 
• 
hypertension 
 
• 
Bacterial/Endotoxin Contamination of cellular therapy products may occur, but rarely cause acute, severe 
or life threatening effects. However, the onset of high fever (>2ºC or >3.5ºF rise in temperature), severe 
chills, hypotension, or circulatory collapse during or immediately after infusion should suggest the possibility 
of bacterial contamination and/or the presence of endotoxin in the product. 
 
• Transmission of Infectious Disease may occur because cellular therapy products are collected from human 
body and/or tissues. The donor selection criteria do not totally eliminate the risk of transmitting the agents 
currently tested such as HIV, HTLV, HBV, HCV, CMV, T. pallidum (Syphilis), West Nile Virus, and 
Trypanosome (Chagas). For some other infectious disease there are no routine tests to prevent disease 
transmission including Parvovirus spp., Plasmodium spp. (Malaria), the coronavirus associated with severe 
acute respiratory syndrome (SARS), and the agents of human transmissible spongiform encephalopathies 
(TSEs). 
 
G-CSF 
Common 
Less Common 
Rare 
• none 
• bone and muscle pain 
• abnormal blood tests which suggest 
that the drug is affecting the liver 
• fast heartbeat 
• low blood pressure 
• allergic reaction (may include shortness of 
breath, wheezing, swelling in the mouth or 
throat, hives, itching, flushing, or fever) 
 

ICF_001.pdf: