Clinical trial NCT00309842
Conditions: Acute Myeloid Leukemia Acute Lymphocytic Leukemia Chronic Myelogenous Leukemia Myelofibrosis MDS Refractory Anemia Chronic Lymphocytic Leukemia Prolymphocytic Leukemia Non-Hodgkin's Lymphoma Leukemia Lymphoma Multiple Myeloma Myelodysplastic Syndromes
Keywords: blastic phase chronic myelogenous leukemia primary myelofibrosis chronic myelomonocytic leukemia myelodysplastic syndromes juvenile myelomonocytic leukemia recurrent adult Burkitt lymphoma recurrent adult immunoblastic large cell lymphoma recurrent lymphoblastic lymphoma recurrent childhood acute myeloid leukemia recurrent childhood large cell lymphoma recurrent follicular lymphoma recurrent marginal zone lymphoma recurrent small lymphocytic lymphoma refractory chronic lymphocytic leukemia refractory multiple myeloma chronic myelogenous leukemia secondary acute myeloid leukemia secondary myelodysplastic syndromes multiple myeloma adult lymphoblastic lymphoma refractory anemia with excess blasts refractory anemia Burkitt lymphoma childhood large cell lymphoma adult Burkitt lymphoma mantle cell lymphoma childhood lymphoblastic lymphoma childhood myelodysplastic syndromes
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2005-07-28; Completion date: 2019-11-22
Enrollment: 213 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Giving chemotherapy drugs, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of 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 giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing an umbilical cord blood transplant for hematologic cancer.

Detailed description:
OBJECTIVES:

Primary

* Determine the 1-year survival of patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine, cyclophosphamide, and fractionated total-body irradiation.

Secondary

* Determine the incidence of transplant-related mortality at 6 months after UCBT.
* Evaluate the pattern of chimerism after double UCBT.
* Determine the incidence of neutrophil engraftment at day 42 after UCBT.
* Determine the incidence of platelet engraftment at 6 months after UCBT.
* Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT.
* Determine the incidence of chronic GVHD at 1 year after UCBT.
* Determine the disease-free survival at 1 and 2 years after UCBT.
* Determine the incidence of relapse at 1 year after UCBT.

OUTLINE: This is a nonrandomized, open-label, multicenter study.

* Preparative Regimen: Patients receive fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients also undergo total-body irradiation twice daily on days -4 to -1.
* Umbilical Cord Blood Transplantation (UCBT): Patients undergo 1 or 2 units of UCBT on day 0. Patients receive filgrastim (G-CSF) IV once daily beginning on day 1 and continuing until blood counts recover.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours 2 or 3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. Patients also receive mycophenolate mofetil IV or orally 2 or 3 times a day beginning on day -3 and continuing until day 30 or 7 days after engraftment in the absence of acute GVHD.

After completion of study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

Arms: arm 1: Patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine phosphate, mycophenolate mofetil, filgrastim, cyclophosphamide, cyclosporine and fractionated total-body irradiation.
Interventions: intervention 1: filgrastim intervention 2: cyclophosphamide intervention 3: cyclosporine intervention 4: fludarabine phosphate intervention 5: mycophenolate mofetil intervention 6: umbilical cord blood transplantation intervention 7: total-body irradiation
Intervention descriptions: intervention 1: All patients will receive G-CSF 5 mcg/kg/day intravenously(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. intervention 2: Cyclophosphamide to be administered with high volume fluid flush and mesna (MT(S) 9006) at 10:00am, or per institutional routine, on days-7 and -6 after fludarabine. Cyclophosphamide 60mg/kg/day intravenous (IV) x 2 days, total dose 120 mg/kg (days -7 and -6) Dosing is calculated based on Actual BodyWeight (ABW) unless ABW \> 30 kg above Ideal BodyWeight (IBW), in which case the dose should be computed using adjusted body weight. intervention 3: Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of \> 200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children \< 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. intervention 4: Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -8 to -6); intervention 5: All patients will begin mycophenolate mofetil (MMF) on day -3. Patients ≥ 40 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours).

Pediatric patient (\<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day. intervention 6: The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter. intervention 7: The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to -1).

Protocol documents:
Prot_SAP_000.pdf: 
 
   
 
 
 
MASONIC CANCER CENTER 
UNIVERSITY OF MINNESOTA  
BLOOD & MARROW TRANSPLANTATION PROGRAM 
 
 
 
MT2005-10 
 
TRANSPLANTATION OF UNRELATED UMBILICAL CORD BLOOD  
FOR PATIENTS WITH HEMATOLOGICAL DISEASES WITH 
CYCLOPHOSPHAMIDE/FLUDARABINE/TOTAL BODY IRRADIATION 
MYELOABLATIVE PREPARATIVE REGIMEN 
 
 
BMT Study Committee 
Claudio G. Brunstein, MD, PhD, Principal Investigator 
John E. Wagner, MD 
Bruce R. Blazar, MD 
Linda J. Burns, MD 
Kathryn Dusenbery, MD 
Margaret L.MacMillan, MD 
Jeffrey Miller, MD 
Philip B. McGlave, MD  
Daniel J. Weisdorf, MD 
Todd Defor, MS (biostatistician) 
Chap Le, PhD (biostatistician) 
 
 
 
Version Date:   
February 6, 2013 
 
 
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 Fairview-University 
Blood and Marrow Transplant Services Medical Director.


MT2005-10 – Myeloablative UCBT For Hematological Diseases 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Revision History 
 
 
Version 
Date 
Amendment 
Details of changes 
Consent 
change? 
7/28/05 
original 
 
 
8/5/05 
1A 
Clarified criteria for AML eligibility 
 
9/6/2005 
1B 
Added to ineligibility section “patients who have received 
Y-90 ibritumomab (Zevalin) or I-131 tostumomab 
(Bexxar), as part of their salvage therapy” 
 
10/28/2005 
2 
Modified section 6.3.2 MMF to read Patients ≥ 40 
kilograms will receive MMF at the dose of 3 grams/day 
divided into 2 or 3 doses (every 12 or 8 hours).  
Pediatric patient (<40 kilograms) will receive MMF at 
the dose of 15 mg/kg. 
 
11/22/2005 
3 
Minor clarifications to clean up typos, change study contact 
from Meadow Schroeder to Marilee Larkin, removed 
eligibility checklists and SAE form from appendices 
 
Section6.3.2 Clarified that pediatric patients will receive 
their MMF dosing is three times per day 
 
Section 7.2.16, table 7.1 clarified that pediatric pre-
transplant evaluation qualification: for children that are 
not able to cooperate to have a MUGA and/or 
pulmonary function tests, an echocardiogram should be 
attempted and pulse oxymetry with exercise tolerance 
obtained.  If not possible at all, it should clearly be 
documented in the physicians note. 
 
Minor edits to table 7.1 
 
12/21/2005 
 
Minor wording changes to clarify language and minimize 
chances of protocol deviations. 
 
4/6/2006 
 
Fixed typo in section 6.2.2.  Cyclophosphamide total dose 
should be measured as mg/kg 
 
11/1/2006 
4 
Fred Hutchinson Cancer Research Center will no longer be 
an affiliate in this study.  All references to FHCRC removed. 
 
4/24/2007 
 
Section 6.2, added noted about the study calendar for 
subjects co-enrolled on MT2005-01 
 
8/20/2010 
5 
Eligibility, section 4.3.1, modified the protocol eligibility 
to allow LFTs up to 5x ULN 
 
10/22/2010 
6 
Revised to remove Appendix IX: cord blood selection 
algorithm (U of MN Institutional Guidelines will now be a 
separate document). 
 
12/16/2011 
7 
Eligibility modified to allow plasma cell leukemia  
No 
1/17/2012 
8 
Eligibility modified to allow subjects up to 55 years, and 
revised definitions of high risk 
No 
8/30/2012 
9 
Added Myeloproliferative Syndromes to the eligibility 
No 
02/06/2013 
10 
Schema, section 11: update total enrollment to 300 patients 
over 10 years (IRB approved Jan 2012);  
No 


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CPRC #2005LS043   
Version 
Date 
Amendment 
Details of changes 
Consent 
change? 
Section 7: Remove research samples as patients are co-
enrolled on MT2009-22R (immune reconstitution), add 
standard language regarding flexibility around targeted 
procedure/treatment dates;  
Schema: change follow-up to 2 years to match objectives and 
current institutional procedures; 
Section 11:  delete stopping rules as they are no longer 
needed as sufficient patients enrollment has occurred;  
Generalized updating to current institutional template 
deleting outdated or unnecessary information and referring to 
institutional guidelines where appropriate 


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Table of Contents 
 
PROTOCOL SYNOPSIS ....................................................................................................................... 5 
TREATMENT PLAN ............................................................................................................................. 6 
1.0  OBJECTIVES .................................................................................................................................. 7 
2.0  BACKGROUND ............................................................................................................................. 7 
3.0  STUDY DESIGN ............................................................................................................................ 9 
4.0  PATIENT SELECTION .................................................................................................................. 9 
5.0  PATIENT REGISTRATION ......................................................................................................... 12 
6.0  TREATMENT PLAN .................................................................................................................... 12 
7.0   STUDY PARAMETERS .............................................................................................................. 17 
8.0 
STUDY ENDPOINTS ............................................................................................................... 18 
9.0  ADVERSE EVENT MONITORING and REPORTING .............................................................. 18 
10.0 
DATA AND SAFETY MONITORING PLAN ..................................................................... 21 
11.0  STATISTICAL CONSIDERATIONS ........................................................................................ 21 
12.0 RECORDS RETENTION .......................................................................................................... 22 
13.0 REFERENCES .......................................................................................................................... 23 
Appendix I - Diagnosis and Treatment Of Acute Graft Versus Host Disease ..................................... 24 
Appendix II - Karnofsky and Lansky Performance Status Scales ........................................................ 25 
Appendix III - Recommended TBI Guidelines ..................................................................................... 26 
 
 
 
 
 
 
PI Contact Information: 
Claudio G. Brunstein, MD, PhD  
Hematology, Oncology and Transplantation 
Department of Medicine 
14-154 PBW 
516 Delaware SE 
Minneapolis, MN  55455 
612 624-0400 (phone) 
612 625-6919 (fax) 
bruns072@umn.edu (email) 
 


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PROTOCOL SYNOPSIS 
 
MT 2005-10 
TRANSPLANTATION OF UNRELATED UMBILICAL CORD BLOOD FOR PATIENTS 
WITH HEMATOLOGICAL DISEASES WITH 
CYCLOPHOSPHAMIDE/FLUDARABINE/TOTAL BODY IRRADIATION 
MYELOABLATIVE PREPARATIVE REGIMEN 
 
 
Study design: Single arm non-randomized phase II trial 
 
Primary objective: 
Determine one year survival 
 
Secondary Objectives: Determine the incidence of 6 month transplant related mortality;  chimerism at 
multiple time points; neutrophil and platelet recovery by day 42 and 6 months, respectively; grades II-IV and 
III-IV acute GVHD at 100 days; chronic GVHD at 1 year; relapse at 1 year, and probability of progression-
free survival for each diagnosis at one and two years. 
 
Eligibility criteria:  
Subjects must be ≤ 55 years old without an HLA matched sibling donor; absence of 
recent active mold infection; adequate organ function; performance status >80% (Karnofsky - adults) or >50 
(Lansky - children). 
UCB graft may be composed of one or two partially HLA matched units.  Each unit must be matched at 4-6 
HLA loci to the recipient (and to each other if two units are utilized). 
 
Eligible diseases (refer to section 4.2 for detailed disease requirements): 
 
Acute myeloid leukemia (AML) 
Very high risk pediatric patients with AML 
Acute lymphocytic leukemia (ALL) 
Very high risk pediatric patients with ALL Chronic myelogenous leukemia excluding refractory blast 
crisis 
Plasma Cell leukemia 
Advanced myelofibrosis. Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or 
refractory anemia  
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell 
lymphoma or follicular lymphoma Lymphoplasmacytic lymphoma, mantle-cell lymphoma, 
prolymphocytic leukemia Large cell NHL > CR2/> PR2Lymphoblastic lymphoma, Burkitt’s 
lymphoma, and other high-grade NHL Multiple myeloma beyond PR2 
 
Exclusion Criteria:     Pregnancy or breastfeeding; evidence of HIV infection or known HIV positive 
serology; current active serious infection; patients CML in refractory blast crisis; large cell lymphoma and 
mantle cell lymphoma that is progressive on salvage therapy. 
 
Accrual Objective: 
300 patients over 10 years  
 
Duration of Study  
Participation: 
The patients will be followed for a minimum of 2 years post-transplant 


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TREATMENT PLAN 
 
Day 
 
-8 
Fludarabine 25 mg/m2 IV over 1 hour 
-7 
Fludarabine 25 mg/m2 IV over 1 hour 
Cyclophosphamide 60 mg/kg IV 
-6 
Fludarabine 25 mg/m2 IV over 1 hour 
Cyclophosphamide 60 mg/kg IV 
-5 
rest 
-4 
TBI 165 cGy twice daily 
-3 
TBI 165 cGy twice daily 
Begin CSA, MMF 
-2 
TBI 165 cGy twice daily 
-1 
TBI 165 cGy twice daily 
0 
Transplant 
+1 
began G-CSF 
 
 
 


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1.0  OBJECTIVES 
 
1.1  Primary objective 
 
The primary objective of this study is to determine the one year survival of patients undergoing 
umbilical cord blood transplantation (UCBT) after a myeloablative preparative regimen consisting of 
cyclophosphamide (CY), fludarabine (FLU) and fractionated total body irradiation (TBI).   
 
1.2  Secondary objectives 
 
Determine the incidence of transplant-related mortality (TRM) at 6 months after UCBT 
Evaluate pattern of chimerism after double UCBT 
Determine incidence of neutrophil engraftment at day 42 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 
Determine the incidence of chronic GVHD at 1 year after UCBT  
Determine the disease free survival at 1 and 2 years after UCBT  
Determine the incidence relapse at 1 and 2 years after UCBT  
 
 
2.0  BACKGROUND 
 
Bone marrow transplantation (BMT) is a standard treatment option for an increasing number of 
malignant and non-malignant disorders.  To reconstitute hematopoiesis after an intensive 
myeloablative therapy, the transplantation of pluripotential 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 [1].  Unfortunately, 
suitable marrow is frequently not available [2].  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 [3-10]. 
 
2.1  Umbilical Cord Blood Transplantation (UBCT) 
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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2.2  UCBT Experience at the University of Minnesota 
 
2.2.1 Single Unit UCBT [11].   
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 engraft; 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. 
 
2.2.2  Multi-Unit UCBT [12].   
Since cell dose has been clearly identified as a major limitation, often preventing the 
consideration of UCB for adult recipients, we have explored the possibility of infusing two 
partially HLA matched units to augment cell dose.  Between 2000 and 2005, we have 
increasingly utilized two UCB units rather than one, particularly in adults and adolescents 
who cannot find a suitable single UCB unit.  The underlying hypothesis of the original study 
(MT2000-15) was that the addition of the second unit would enhance the engraftment and the 
speed of hematopoietic recovery. 
 
We have analyzed of the results in the first 31 adult and adolescent patients [median age 24 
years (range: 13-53); median weight 73 kg (range: 48-120)] with high-risk hematologic 
malignancy who were transplanted with two partially HLA-matched UCB units after a 
myeloablative conditioning. Patient breakdown by diagnosis was: acute myelogenous 
leukemia (AML, n=15), acute lymphocytic leukemia (ALL, n=12), chronic myelogenous 
leukemia (CML, n=3) and non-Hodgkin Lymphoma (NHL, n=1). The median total infused 
dose 3.7 x 107 nucleated cells per kilogram (range 1.1-6.3) and 4.9 x 105 CD34 per kilogram 
(range, 0.9-14.5). 
 
In this study, 100% of evaluable patients (i.e., survived for 21 days [n=29]) engrafted at a 
median of 23 days (range 14-41).  This compares favorably with a 65-75% incidence of 
engraftment reported for adults [9, 10].  In each case, one unit predominated.  Thus far, no 


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factor (nucleated cell dose, CD34+ cell dose, HLA-match, ABO, sex, order infusion) predicts 
which unit will eventually be responsible for long term marrow recovery. The incidence of 
platelet recovery (>50,000/uL) was 73% (95% CI, 51-95) at day 180. Incidence of grades II-
IV and III-IV acute graft-versus-host disease (GVHD) was 65% (95% CI, 42-88) and 17% 
(95% CI, 2-32) at day 100.  Disease-free survival remains 72% at 1 year for patients 
transplanted in CR with no relapse in this cohort (median follow up: 1.2 years). 
 
These data indicate that: 1) double unit UCBT is safe in terms of engraftment (bi-directional 
immune rejection between the units was never observed);  2) one unit always predominates 
within the first 100 days;  3) >90% of adults will be able to identify two units that are partially 
HLA matched with the patient and each other;  4) incidence GVHD is similar to that observed 
after single UCBT; and  5) survival exceeds that of historical data with a single UCB unit.    
 
As a result of these promising early data, we plan to extend this trial in order to 1) confirm the 
initial observations and 2) establish survival outcomes and relapse risk for individual disease 
groups.   
 
3.0  STUDY DESIGN 
This is a single arm, phase II study to determine the one year survival of patients undergoing umbilical 
cord blood transplantation (UCBT) after a myeloablative preparative regimen consisting of 
cyclophosphamide , fludarabine and fractionated total body irradiation (TBI) for the treatment of 
study specific hematological malignancies. 
 
4.0  PATIENT SELECTION 
 
4.1  Graft Criteria 
 
4.1.1 The unrelated cord blood donor(s) must be 4-6/6 HLA-A, B, DRB1 matched with the 
recipient (HLA matching using molecular techniques: A and B to antigen level resolution 
and DR to allele level resolution). 
 
4.1.2 No existing HLA-identical related donor is available. 
 
4.1.3 Suitable UCB units available according to the current University of Minnesota Umbilical 
Cord Blood Graft selection algorithm.  The UCB graft may consist of one or two UCB 
units.  
 
4.2  Age and Disease Criteria 
 
4.2.1 Patients aged ≤ 55 years must have a hematological malignancy as described below: 
 
4.2.2 Acute myeloid leukemia (AML): high risk CR1 (as evidenced by preceding MDS, high 
risk cytogenetics, ≥ 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia; 


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CR2+.  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%.  
 
4.2.3 Very high risk pediatric patients with AML.  Patients <21 years, however, are eligible 
with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles 
of chemotherapy. This group of patients will be analyzed separately.  
 
4.2.4 Acute lymphocytic leukemia (ALL): high risk CR1 as defined by cytogentics (such as 
t(9;22), t (1:19), t(4;11), other MLL rearrangements, hypodiploidy, or IKZF1 
abnormalities), DNA index < 0.81, > 1 cycle to obtain CR or presence minimal residual 
disease (MRD). Patients in CR2+ are eligible.  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%. 
 
4.2.5  Very high risk pediatric patients with ALL.  patients <21 years are also considered high 
risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 
marrow at the end of induction. They are eligible once they achieved a complete 
remission 
 
 
4.2.6  Chronic myelogenous leukemia excluding refractory blast crisis. To be eligible in first 
chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate. 
 
4.2.7  Plasma Cell leukemia after initial therapy, who achieved at least a partial remission 
 
4.2.8 Advanced myelofibrosis 
 
4.2.9 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. 
 
4.2.10 Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal 
zone B-cell lymphoma or follicular lymphoma are eligible if there was disease 
progression/relapse within 12 of achieving a partial or complete remission. Patients 
who had remissions lasting > 12 months, are eligible after at least two prior therapies. 
Patients with bulky disease (nodal mass greater than 5 cm) should be considered for 
debulking chemotherapy before transplant.   
 
4.2.11 Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are 
eligible after initial therapy in CR1+ or PR1+. 
 
4.2.12 Large cell NHL > CR2/> PR2. Patients in CR2/PR2 with initial short remission (<6 
months) are eligible. 
 
4.2.13 Lymphoblastic lymphoma, Burkitt’s lymphoma, and other high-grade NHL after initial 
therapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year. 
 


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4.2.14 Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first 
response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered 
for this protocol after initial therapy. 
4.2.15 Myeloproliferative syndromes 
 
4.3 
Organ function and Performance Status Criteria 
 
4.3.1 Recipients must have a Karnofsky score (adults) ≥ 80 % or Lansky play score  50 
(pediatrics) (appendix II) and have acceptable organ function defined as:  
Renal: creatinine < 2.0 (adults) or creatinine clearance > 40 ml/min (pediatrics),  
Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal,  
Pulmonary function: DLCOcorr > 50% normal,  
Cardiac:  left ventricular ejection fraction > 45%. 
 
4.3.2 Voluntary written consent before performance of any study-related procedure not part of 
normal medical care. 
 
4.4 
Exclusion Criteria 
 
4.4.1 Active infection at time of transplantation (including active infection with Aspergillus 
or other mold within 30 days.) 
 
4.4.2 History of HIV infection 
 
4.4.3 Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus 
and there is no information on the excretion of agents into breast milk.  Females of 
childbearing potential must have a blood test or urine study within 2 weeks prior to 
registration to rule out pregnancy  
 
4.4.4 Chemotherapy refractory large cell and high grade NHL (ie progressive disease after > 
2 salvage regimens)  
 
4.4.5 If  18 years old, prior myeloablative transplant within the last 6 months. If >18 years 
old prior myeloablative allotransplant or autologous transplant 
 
4.4.6 Extensive prior therapy including > 12 months alkylator therapy or > 6 months 
alkylator therapy with extensive radiation. 
 
4.4.7 Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab 
(Bexxar), as part of their salvage therapy are not eligible for myeloablative umbilical 
cord blood transplant. 
 
 
 


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5.0  PATIENT REGISTRATION 
 
To be eligible for registration to this study, the patient must meet each criteria listed on the eligibility 
checklist based on the eligibility assessment documented in the patient’s medical record.   
 
5.1 
Registration with the University of Minnesota Clinical Trials Office (CTO) 
 
Upon completion of the screening evaluation, eligibility confirmation and obtaining written 
consent, the study coordinator or designee will enroll the patient into OnCore. 
 
5.2 
Patients who are registered and do not begin study treatment 
 
If a patient is registered to the study, and is later found not able to begin the planned study 
treatment, for whatever reason, the patient will be removed from study and treated at the 
physician’s discretion.  Study staff will update OnCore of the patient’s non-treatment status.  
Study data will be collected until the time the patient is off study.  The reason for removal 
from study will be clearly indicated on the case report forms.   
 
6.0  TREATMENT PLAN 
 
6.1 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, G-CSF, antimicrobials, etc.). 
 
Day 
Preparative Therapy 
Supportive Care 
-8 
Fludarabine 25 mg/m2 IV over 1 hour 
 
-7 
Fludarabine 25 mg/m2 IV over 1 hour 
Cyclophosphamide 60 mg/kg IV 
 
-6 
Fludarabine 25 mg/m2 IV over 1 hour 
Cyclophosphamide 60 mg/kg IV 
 
-5 
Rest 
-4 
TBI 165 cGy twice daily 
 
-3 
TBI 165 cGy twice daily 
Begin CSA, MMF (section 6.3) 
-2 
TBI 165 cGy twice daily 
 
-1 
TBI 165 cGy twice daily 
 
0 
UCBT 
+1 
 
Begin G-CSF (section 6.5) 
 
 
 


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CPRC #2005LS043   
6.2 
Conditioning Regimen 
 
6.2.1 Fludarabine 
 
Fludarabine 25 mg/m2/day IV x 3 days, total dose 75 mg/m2 (days –8 to –6)  
 
6.2.2 Cyclophosphamide  
 
Cyclophosphamide will be administered as a 2 hour intravenous infusion with a high volume 
fluid flush and mesna per institutional guidelines on days -7 and -6.  
 
Cyclophosphamide 60mg/kg/day IV x 2 days, total dose 120 mg/kg (days –7 and –6) 
 
Dosing is calculated based on Actual Body Weight (ABW) unless ABW > 30 kg above Ideal 
Body Weight (IBW), in which case the dose should be computed using adjusted body weight. 
Ideal body weight is calculated using Devine's formula or per institutional guidelines: 50 kg + 
(2.3 kg x (height in inches - 60)) for men; 45.5 kg + (2.3 kg x (height in inches - 60)) for 
women. Adjusted body weight = IBW + 0.5(ABW - IBW) 
 
6.2.3 Total Body Irradiation (TBI) 
 
The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to –
1).  Recommended TBI Guidelines are described in Appendix III. TBI may be delivered by 
local guidelines provided the effective dose is equivalent to what is recommended in the TBI 
Guidelines.   
 
 
6.3 
Immunosuppressive Therapies 
 
All patients will receive GVHD prophylaxis with 2 drugs as follows: 
 
6.3.1 Cyclosporine (CSA) 
Cyclosporine A (CSA) will start day -3 and will be administered PO/IV maintaining a trough 
level between 200 and 400 ng/mL. For adults the initial dose will be 2.5 mg/kg IV over 1 hour 
every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 1 hour every 8 
hours. 
 
CSA dosing will be monitored and altered as clinically appropriate per institutional pharmacy 
guidelines.  Dose adjustments will be made on the basis of toxicity and/or low CSA levels.  
 
Patients will receive CSA until day +100.  If no GVHD, the dose will be tapered 10% per 
week beginning on day 101, to discontinue at approximately day +180.  
 
 


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CPRC #2005LS043   
6.3.2 Mycophenolate mofetil (MMF) 
 
Mycophenolate mofetil (MMF) 3 gram/day IV/PO for patients who are ≥ 40 kg divided in 2 
or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose 
every 8 hours beginning day -3.  MMF dosing will be monitored and altered as clinically 
appropriate based on institutional guidelines.  Patients will be eligible for MMF dosing and 
pharmacokinetics studies. 
 
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 no donor engraftment, do not stop MMF.  If no evidence of donor engraftment on the day 
+21 bone marrow biopsy, notify URD search coordinator to pursue back-up UCB and arrange 
day +28 bone marrow biopsy per current institutional slow engraftment guidelines. 
 
If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days after 
initiation of systemic therapy for acute GVHD.  
 
6.4 
Umbilical Cord Blood Transplantation (UCBT) 
 
Cord blood products are thawed and filtered (170-micron) in the Molecular and Cellular 
Therapeutics (MCT) Lab using the method of Rubinstein et al.  
 
Infusion will be per current institutional policies.  The infusion of the first UCB unit should 
begin within 15 minutes, and no later than 30 minutes after arrival on the Unit.  If 2 units are 
used, both cords will be infused within 30-60 minutes of each other as deemed clinically safe 
by the BMT attending or designee.  
 
6.5 
Growth Factor  
 
 
All patients will receive G-CSF 5 mcg/kg/day IV (dose rounded to vial size) based on the 
actual body weight IV beginning on day +1 after UCB infusion.  G-CSF will be administered 
daily until the ANC exceeds 2.5 x 109/L for three consecutive days and then discontinued.  If 
the ANC decreases to <1.0 x 109/L, G-CSF will be reinstituted. 
 
6.6 
Treatment Related Toxicities 
 
Potential toxicities associated with preparative therapies 
 
Cyclophosphamide 
Common 
Less Common
Rare
 low white blood cell count 
with increased risk of 
infection  
 hair loss or thinning, 
including face and body hair 
 low platelet count (mild) 
with increased risk of 
bleeding  
 darkening of nail beds  
 heart problems with high doses, with chest 
pain, shortness of breath, or swollen feet 
 severe allergic reactions 
 skin rash  


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CPRC #2005LS043   
Cyclophosphamide 
Common 
Less Common 
Rare 
(usually grows back after 
treatment)  
 nausea  
 vomiting  
 loss of appetite  
 sores in mouth or on lips  
 bleeding from bladder, with 
blood in urine  
 diarrhea 
 long-term or short-term 
infertility in women and men  
 
 acne  
 tiredness  
 infection 
 fetal changes if 
pregnancy occurs while 
taking cyclophosphamide 
 
 scarring of bladder 
 kidney damage (renal tubular necrosis) 
which can lead to kidney failure 
 heart damage, with trouble getting your 
breath, swelling of feet, rapid weight gain 
 scarring of lung tissue, with cough and 
shortness of breath 
 second cancer, which can happen years 
after taking this drug 
 death from infection, bleeding, heart 
failure, allergic reaction, 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 
 
 
 
Total Body Irradiation (TBI) 
Common 
Less Common 
Rare 
 nausea and vomiting 
 diarrhea 
 cataracts 
 sterility 
 endocrinopathies 
 growth failure 
 intestinal cramps 
 mucositis 
 parotitis 
 interstitial pneumonitis 
 generalized mild erythema 
 veno-occlusive disease 
 dysphagia 
 vertebral deformities 
 nephropathy 
 risk of 2nd malignancy years later (when given 
along with chemotherapy) 


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CPRC #2005LS043   
6.6.2 Toxicities potentially associated with the infusion of the UCB graft 
 
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) 
 
graft-versus-host-disease (GVHD) 
 
veno-occlusive disease  
 
infections (sepsis)  
 
acute hemolytic reactions 
 
febrile nonhemolytic reactions 
 
anaphylactoid or anaphylactic reactions 
 
transfusion-related acute lung injury (TRALI) 
 
DMSO toxicity 
 
transmission of bacterial, viral or protozoal infection 
 
transfusion-associated circulatory overload (TACO) 
 
hypothermia 
 
non-immunologic hemolysis 
 
granulocyte-related complications 
 
cardiotoxicity   
 
6.6.3 Potential Toxicities Associated with Immunosuppressive Therapies 
Cyclosporine A (CSA) can cause high blood pressure, abnormalities in blood chemicals, 
seizures, headaches and kidney problems. The effect of CSA on the kidneys ranges from mild 
(noted only on blood tests) to severe (requiring dialysis). Blood levels of CSA and kidney 
function tests will be monitored closely to minimize side effects. 
 
Mycophenolate mofetil (MMF) can cause nausea and vomiting, diarrhea or constipation, a 
lowering of blood counts, leg cramps, skin rash, difficulty sleeping, chemical imbalances 
including high blood sugar, headaches, dizziness and high blood pressure. 
 
6.6.4 Toxicities associated with Neupogen (G-CSF) 
 
bone pain 
 
headaches 
 
body aches 
 
fatigue  
 
nausea/vomiting 
 
insomnia 
 
dyspnea 
 
rash 
 
edema 
 
6.7 
Supportive Care Guidelines 
Supportive care will be provided per University Of Minnesota institutional guidelines for 
transplant patients including any supportive care research protocols. 
 
All patients will receive standard supportive transfusion care according to transfusion 
committee guidelines or as modified based on clinical parameters. 
 


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CPRC #2005LS043   
Antimicrobial prophylaxis directed towards bacteria, fungi and viruses will be per University 
Of Minnesota current institutional guidelines for transplant patients.  
7.0   STUDY PARAMETERS 
Scheduled evaluations for days 21, 28 may be performed (+/-3 days) from the targeted date; 
assessments to be performed on day 60 and 100 may be done on  (+/-) 7 days of the targeted date; 
assessments on day 180, 1 year, 2 years and 3 years may be performed (+/- 30) days of the targeted 
date.  In addition, targeted days may be altered as clinically appropriate. 
 
Screen 
Day 1 to engraftment 
Days 31-100 
Follow-up 
daily 
weekly 
Day +21  
Day +28  
weekly 
Day 
+60 
 
Day 
+100  
6 months, 1 
and 2 years 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
Physical exam 
X 
X 
 
 
 
X 
 
 
X 
Performance status 
X 
 
 
 
 
 
 
X 
X 
Height/Weight 
X 
 
 
 
 
 
 
 
 
GVHD evaluation 
 
X 
X 
 
 
X 
 
 
X 
CMV Surveillance 
 
 
X 
 
 
X 
 
 
prn 
Severe Adverse event 
notation 
 
X 
 
 
 
X 
 
 
X 
Laboratory 
CBC, diff  
X 
X3 
 
 
 
X 
 
 
X 
Platelet 
X 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
Serum chemistries 
X 
 
 
 
 
 
 
 
 
Creatinine, Na, K, HCO3 
X 
X 
 
 
 
 
 
 
 
Viral tests  
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
prn 
 
 
 
 
 
 
Urine pregnancy test 
X1 
 
 
 
 
 
 
 
 
Bone marrow bx/asp 
X 
 
 
X 
 
 
 
X 
X 
Chimerism – BM 
X 
 
 
X 
 
 
 
X 
X 
Chimerism – PB 
 
 
 
 
X 
 
X 
 
 
Procedures 
EKG 
X 
 
prn 
 
 
prn 
 
 
prn 
MUGA or 
echocardiogram5 
X 
 
prn 
 
 
prn 
 
 
prn 
Chest x-ray or CT 
X2 
 
prn 
 
 
prn 
 
 
prn 
PFT’s5 
 
 
prn 
 
 
prn 
 
 
prn 
Disease evaluation 
X 
 
X 
 
 
 
 
X 
X 
1- within 14 days of registration in females of childbearing potential 
2- CT without contrast to exclude occult infection for patients with a history of the following:  
 
MDS/CML blast crisis 
 
2 or more consecutive leukemia inductions 
 
prolonged neutropenia, as defined as ≥ 4 weeks of neutropenia within the 2 months prior to BMT 
3- Complete blood count with leukocyte differential daily until the absolute neutrophil count (ANC) > 5 X 108/L for 3 
consecutive measurements  
4- Continue longer if clinically indicated 
5- Pediatric pre-transplant evaluation qualification: for children that are not able to cooperate to have a MUGA and/or 
pulmonary function tests, an echocardiogram should be attempted and pulse oxymetry with exercise tolerance obtained.  
If not possible at all, it should clearly be documented in the physicians note. 
 
 
7.1 
UCB Engraftment Evaluation 
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months 1 year 
and 2 years. In cases of slow engraftment a BM biopsy may be repeated on day +28. Preparative 


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CPRC #2005LS043   
therapy for a second graft should not be commenced prior to day +30. Subsequently, if the patient's 
peripheral blood counts drop after an initial recovery, the peripheral blood and bone marrow should 
again be evaluated unless a cause has been determined (e.g., use of Ganciclovir for treatment of 
CMV).  Patients diagnosed with graft failure (failure of ANC > 5 x 108/L of donor origin by day +42) 
must be reported to the Principal Investigator. 
 
7.2 
GVHD Evaluation 
GVHD evaluations will be done at least weekly until discharge and at each follow-up visit and 
continue at each follow-up using the current institutional criteria (acute GVHD appendix II and 
consensus for late acute and chronic GVHD).    
 
7.3 
Residual/Recurrent Disease Evaluation 
Patients will be evaluated routinely for evidence of recurrent malignancy.  If at any time the attending 
physician suspects recurrent disease, additional analyses will be performed as clinically indicated.   
 
 
8.0 
STUDY ENDPOINTS 
 
8.1 
Primary Objective 
Survival at 1 year as measured from date of UCBT 
 
8.2 
Secondary objectives 
Based on clinical and laboratory evaluations the following will be recorded for each subject: 
8.2.1 Incidence of transplant-related mortality (TRM) at 6 months after UCBT 
8.2.2 Pattern of chimerism after double UCBT - Chimerism studies will be performed on the 
bone marrow on days 21 and 100 and at 6 months 1 year and 2 years. 
8.2.3 Incidence of neutrophil engraftment at day 42 after UCBT  
8.2.4 Incidence of platelet engraftment at 1 year after UCBT 
8.2.5 Acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day 100 after 
UCBT 
8.2.6 Chronic GVHD at 1 year after UCBT  
8.2.7 Disease free survival at 1 and 2 years after UCBT  
8.2.78 Relapse at 1 and 2 years after UCBT  
 
9.0  ADVERSE EVENT MONITORING and REPORTING 
 
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria for 
Adverse Events V 3.0 (CTCAE) and reported on the schedule below.   A copy of the CTCAE can be 
downloaded from the CTEP home page http://www.eortc.be/services/doc/ctc/ctcaev3.pdf 
9.1 
Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 Part 312.32 
(21CFR312.32(a)). 
 
 


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CPRC #2005LS043   
Adverse Event:  Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
 
Suspected Adverse Reaction:  Any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  
 
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse Reaction: An 
adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. 
   
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 A congenital anomaly/birth defect.  
 
Unanticipated (unexpected) problems/events as defined by the University Of Minnesota 
IRB 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. 
 
Event Attribution Categories: 
CTCAE does not define an AE as necessarily ‘caused by a therapeutic intervention.’ The 
clinical investigator must assign attribution for an adverse event after naming and grading of 
the event. 
 
Attribution 
Description 
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   
 
UPIRTSO: Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the 
IRB to ensure that researchers promptly report “any unanticipated problems involving risk to 
subjects or others” (UPIRTSOs).  The University of Minnesota IRB defines a UPIRTSO as 
any problem or event which in the opinion of the local researcher was unanticipated, reflects 
new or increased risk to the subjects and at least possibly related to the research procedures.  
 
In addition, the IRB has defined the following problems/events as reportable within 10 
working days using the UPRITSO form found on the IRB website: 


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CPRC #2005LS043   
 Any accidental or unintentional change to the IRB-approved protocol that increases 
risk or has the potential to recur  
 Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject  
 Any publication in the literature, safety monitoring report (including Data and Safety 
Monitoring Reports), interim result or other finding that indicates an unexpected 
change to the risk/benefit ratio of the research  
 Any breach in confidentiality that may involve risk to the subject or others  
 Any complaint of a subject that cannot be resolved by the research staff  
 Any other possibly related event which in the opinion of the investigator constitutes an 
unanticipated risk  
 
Expedited (Rapid) Reporting: Certain events may require rapid notification to entities 
providing patient safety oversight (e.g. IRB) as detailed in section 9.2.  For the IRB this is 10 
working days.   
 
9.2 
Adverse Event Monitoring  
All subjects will be monitored from the initiation of any study treatment through day 100 as it 
is expected that most serious adverse events will occur during this period.   
 
After day 100, monitoring for adverse events will become less frequent based on the schedule 
in section 7.0.  However, the investigator is obligated, upon knowledge of, to report any event 
meeting the definition of UPIRTSO and requires expedited reporting per section 9.3. 
 
9.3 
Required Reporting  
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. 
 
The SAE Coordinator will provide the 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). 
 
FOR UNLICENSED UCB UNITS ONLY:  Selected expected adverse reactions determined 
to be caused by or at least possibly caused by the UCB unit based on objective evidence will 
be reported in an expedited manner to the FDA under University of Minnesota IND BB-
14797 (C. Brunstein, MD, PhD – sponsor/investigator). 
Agency 
Criteria for reporting 
Timeframe 
Form to Use 
Submission address/ 
fax numbers 
Copy AE to: 
U of MN 
IRB 
UPIRTSO: any event which is 
unanticipated, involved new or 
increased risk to subjects, and 
was at least possibly related to 
study procedures 
10 Working 
Days 
 
UMCC SAE 
University Of Minnesota 
IRB 
MMC 820 
Masonic Cancer Center 
SAE Coordinator 
mcc-saes@umn.edu 
Other Problems or Events 
meeting the definition of 
UPIRTSO in section 9.1 
UPIRTSO 
form 
 


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CPRC #2005LS043   
10.0 DATA AND SAFETY MONITORING PLAN 
This study’s Data and Safety Monitoring Plan will be in compliance with the University of Minnesota 
Masonic Cancer Center's Data & Safety Monitoring Plan, which can be accessed at 
http://www.cancer.umn.edu/exfiles/research/dandsmplan.pdf 
 
For the purposes of data and safety monitoring, this study is classified as moderate risk.  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 more frequent 
reporting may be required by the Cancer Protocol Review Committee. 
• 
The PI will comply with at least twice yearly monitoring of the project by the Masonic Cancer 
Center monitoring services. 
• 
The PI will oversee the reporting of all adverse events meeting the definition of reportable in 
section 9.3 to the University Of Minnesota IRB and the Masonic Cancer Center SAE 
Coordinator.   
 
At the time of the University of Minnesota IRB continuing review, the Principal Investigator will 
submit to the CPRC a copy of all documentation submitted to the IRB for continuing review.  
 
11.0  STATISTICAL CONSIDERATIONS 
 
11.1 Objectives 
 
11.1.1 Primary objective 
The principal aim of this study is to estimate one year overall survival of UCBT after a 
myeloablative preparative regimen for the combined experience of single unit UCB 
transplants and double unit UCB transplants. 
 
11.1.2 Secondary objectives 
 the incidence of transplant-related mortality (TRM) at 6 months after UCBT 
 the pattern of chimerism at multiple time points after double UCBT 
 the incidence of neutrophil engraftment at day 42 after UCBT  
 the incidence of platelet engraftment at 1 year after UCBT 
 the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-
IV at day 100 after UCBT 
 the incidence of chronic GVHD at 1 year after UCBT  
 the disease free survival at 1 and 2 years after UCBT  
 the incidence relapse at 1 and 2 years after UCB T  
 
11.2 
Statistical Analysis 
Survival and progression-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 using competing risk methods. 95% confidence intervals will be used to show 
precision for the estimates. 


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CPRC #2005LS043   
 
In order to show that survival after double unit UCB transplants are no worse than single unit UCB 
transplants, a non-inferiority test will be performed. The null and alternative hypotheses will be: 
 
Ho: 1 year survival for double UCB ≤ 1 year survival for single UCB – 0.2 (20%) 
Ha: 1 year survival for double UCB  1 year survival for single UCB – 0.2 (20%) 
 
Comparison of the single UCB cohort will be made to a historical cohort using a superiority test. 
 
Ho: 1 year survival for new cohort = 1 year survival for old cohort 
Ha: 1 year survival for new cohort > 1 year survival for old cohort by at least 0.2(20%) 
 
For inferences of 1 year survival among patients that have been followed for at least 1 year, 
comparisons will be made by a normalized Z-test for non-inferiority. A Chi-square test will be used 
for the superiority comparison. Comparisons in which patients have not been followed for the 
complete follow-up period will be completed by the Log-rank test. Univariate comparisons of factors 
other than the number of units will be stratified by the number of units. Cox regression will be 
utilized to correct for any potential confounders.  
 
11.3 
Rationale for Sample Size 
In order to achieve a precise estimate of the probability of survival at one year post transplant we 
would like to have an estimate of survival with a 95% confidence interval that has a band width of 
less than 0.10. We expect to enroll approximately 300 patients over the 10 year study period. We will 
also be able to use 40 patients from the previous study using this same conditioning regimen. 
Assuming that the proportion surviving at one year is 65%, the 95% confidence interval should have 
a band width of approximately 0.08. This is assuming that there are no patients lost to follow-up and 
that all patients have been followed for at least one year post transplant at the time of analysis.  
 
Based on the accrual goal of 300 patients, the equivalence test will have a power of 97% and a type I 
error of 5%. The superiority test will have a power of 83% and a type I error of 5%. 
 
We expect 50% to be double unit UCBT.  
 
11.4 
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.  
 
12.0 RECORDS 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 has been closed with the 


MT2005-10: UCBT Using A Myeloablative Prep 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 23 of 26 
 
 
CPRC #2005LS043   
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. 
 
13.0 REFERENCES 
 
1. 
Blume, K., S.J. Forman, and F.R. Appelbaum, Thoma's Hematopoietic Cell Transplantation. 
3nd ed. 2004, Malden, MA: Blackwell Science, Inc. 
2. 
Confer, D.L., Unrelated marrow donor registries. Curr Opin Hematol, 1997. 4(6): 408-12. 
3. 
Wagner, J.E., N.A. Kernan, M. Steinbuch, et al., Allogeneic sibling umbilical-cord-blood 
transplantation in children with malignant and non-malignant disease. Lancet, 1995. 
346(8969): 214-9. 
4. 
Wagner, J.E., J. Rosenthal, R. Sweetman, et al., Successful transplantation of HLA-matched 
and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment 
and acute graft-versus-host disease. Blood, 1996. 88(3): 795-802. 
5. 
Kurtzberg, J., M. Laughlin, M.L. Graham, et al., Placental blood as a source of hematopoietic 
stem cells for transplantation into unrelated recipients. N Engl J Med, 1996. 335(3): 157-66. 
6. 
Gluckman, E., V. Rocha, A. Boyer-Chammard, et al., Outcome of cord-blood transplantation 
from related and unrelated donors. Eurocord Transplant Group and the European Blood and 
Marrow Transplantation Group. N Engl J Med, 1997. 337(6): 373-81. 
7. 
Rubinstein, P., C. Carrier, A. Scaradavou, et al., Outcomes among 562 recipients of placental-
blood transplants from unrelated donors. N Engl J Med, 1998. 339(22): 1565-77. 
8. 
Laughlin, M.J., J. Barker, B. Bambach, et al., Hematopoietic engraftment and survival in 
adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med, 2001. 344(24): 
1815-22. 
9. 
Laughlin, M.J., M. Eapen, P. Rubinstein, et al., Outcomes after transplantation of cord blood 
or bone marrow from unrelated donors in adults with leukemia. N Engl J Med, 2004. 
351(22): 2265-75. 
10. 
Rocha, V., M. Labopin, G. Sanz, et al., Transplants of umbilical-cord blood or bone marrow 
from unrelated donors in adults with acute leukemia. N Engl J Med, 2004. 351(22): 2276-85. 
11. 
Wagner, J.E., J.N. Barker, T.E. DeFor, 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, 2002. 100(5): 
1611-8. 
12. 
Barker, J.N., D.J. Weisdorf, T.E. DeFor, et al., Transplantation of 2 partially HLA-matched 
umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. 
Blood, 2005. 105(3): 1343-7. 
13. 
Le, C., Study Designs, in Introductory Biostatistics, C. Le, Editor. 2003, John Wiley & Sons: 
Hoboken, NJ. p. 445-482. 
 
 
 


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CPRC #2005LS043   
Appendix I ‐ Diagnosis and Treatment Of Acute Graft Versus Host Disease 
 
Patients will be considered evaluable acute GVHD if they demonstrate donor cell engraftment and 
survive to day 28.  Organ involvement will be staged using the criteria outlined in the table below.  
Biopsy of each organ site at diagnosis or major change in disease activity will be performed unless 
clinical circumstances make it impossible. 
 
Consensus Clinical Stage and Grade of Acute GVHD (Przepiorka et al, 1995) 
Stage 
Skin 
Liver 
Lower 
Gastrointestinal 
Tract 
Upper 
Gastrointestinal 
Tract 
1 
Maculopapular rash 
<25% of body 
surface 
Bilirubin 2.0 – 3.0 
mg/dl 
Diarrhea 500 – 1000 
mL/day or 280 – 555 
mL/m2 
No protracted 
nausea and vomiting 
2 
Maculopapular rash 
25-50% body 
surface 
Bilirubin 3.1 – 6.0 
mg/dl 
Diarrhea 1000 – 1500 
mL/day or 556 – 833 
mL/m2 
Persistent nausea, 
vomiting or anorexia
3 
Generalized 
erythroderma 
Bilirubin 6.1 – 15.0 
mg/dl 
Diarrhea >1500 
mL/day or    >833 
mL/m2 
 
4 
Generalized 
erythroderma with 
bullous formation 
and desquamation 
Bilirubin > 15 
mg/dl 
Severe abdominal 
pain, with or without 
ileus, or stool with 
frank blood or melena 
 
 
Grading for Treatment Criteria 
 
Mild GVHD = Skin stage I-II only (Equivalent to Seattle Grade I). 
 
Moderate GVHD = Skin stage I-III and/or liver I-IV and/or Gastrointestinal tract (GI)   I-III and/or 
Upper GI (UGI).  (Equivalent to Seattle Grade II, III). 
 
Severe GVHD = Any stage IV along with severe clinical illness. 
 
Patients progressing during initial therapy or not improving sufficiently after 2 courses of therapy are 
to be treated as severe GVHD. 
 
Acute GVHD treatment may be by institutional guidelines. The recommended treatment for patients 
demonstrating moderate or severe GVHD (Grade II-IV) is methylprednisolone at 48 mg/m2/day or 
prednisone 60 mg/m2/day followed by a taper which starts a day 8 of acute GVHD therapy.  If there 
is no response in 7 days or there is progression of the disease, ATG 15 mg/kg every 12 hours for 5 
days will be added.  


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CPRC #2005LS043   
Appendix II ‐ Karnofsky and Lansky Performance Status Scales 
 
 
Percentage 
 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled, hospitalization indicated.  Death not imminent 
20 
Very sick, hospitalization necessary, active supportive treatment necessary 
10 
Moribund, fatal processes, progressing rapidly 
0 
Dead 
 
REFERENCE   
 
 
Karnofsky DA:  Meaningful clinical classification of therapeutic responses to anti-cancer drugs.  
Editorial:  Clin Pharmacol Ther 2:709-712, 1961. 
 
LANSKY PLAY PERFORMANCE STATUS SCALE 
 
 
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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CPRC #2005LS043   
Appendix III ‐ Recommended TBI Guidelines 
 
Fractionated Total Body Irradiation (In Lateral Position): 
 
1320 cGy administered in an 8 fractions of 165 cGy each with 2 fractions being given each day. 
 
Total body irradiation is given at a dose rate of 10-19 cGy/minute prescribed to the midplane of the 
patient at the level of the umbilicus. 
 
The total body irradiation will be delivered with right and left lateral fields, with the patient supine on 
a specially designed couch. 
 
Based on measurements of transverse thicknesses, aluminum compensators will be used to ensure 
that the dose homogeneity across the field is within 10 % of the prescribed dose.  Usually head/neck, 
leg and lung compensators are used (although based on calculated mid-mediastinal doses, lung 
compensators are often not needed). 
 
Total body irradiation will be delivered with a linear accelerator using 6, 18, 24 MeV X-rays.  The 
energy used will be based on the calculated dose to the midline at points up and down the patient's 
torso.  The lowest energy that gives 90-100% of the prescription point dose will be used. 
 
A beam "spoiler" will be used to ensure a full skin dose. 
 
Half value layer lung and kidney blocks will not be utilized. 
 
Testicular boosts should be used for all males with ALL (and according to institutional practice for 
other diseases).  The testicular boost is given in a single 400 cGy fraction with either electrons 
prescribed to Dmax or photons prescribed to the midplane of the scrotum.  If electrons are used, the 
energy for the testicular boost depends on the thickness of the testicles and is chosen so that the D90 
corresponds > to the posterior surface of the scrotum.