Clinical trial NCT01366612
Conditions: Myeloid Malignancies Acute Myelogenous Leukemia Chronic Myelogenous Leukemia Myeloproliferative Disorders Myelodysplastic Syndrome
Keywords: Allogeneic Stem Cell Transplant AML CML MDS
Sponsor: Hackensack Meridian Health
Start date: 2010-06-16; Completion date: 2020-08-18
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a single institution study of fludarabine and busulfan versus fludarabine, busulfan and low dose total body irradiation in patients undergoing allogeneic stem cell transplantation. A study population of 80 subjects will be enrolled from The John Theurer Cancer Center at Hackensack University Medical Center. Subjects who are eligible to receive allogeneic hematopoietic stem cell transplantation according to the eligibility criteria will be consented and enrolled. Subjects will be randomly assigned to receive one of 2 conditioning regimen: fludarabine and busulfan, or fludarabine busulfan and low dose total body irradiation (TBI). Subjects will be followed until 1 year post transplantation to assess the relapse rate in each arm and transplant-related toxicity.

The combination of fludarabine and busulfan is the current standard of care for patients with myeloid malignancies (AML, CML and other myeloproliferative disorders, or MDS) undergoing allogeneic transplantation at HUMC. In this study we will be comparing in a randomized fashion the standard regimen to a regimen of fludarabine, busulfan and TBI.

Detailed description:
This is a single institution study of fludarabine and busulfan versus fludarabine, busulfan and low dose total body irradiation in patients undergoing allogeneic stem cell transplantation. A study population of 80 subjects will be enrolled from The John Theurer Cancer Center at Hackensack University Medical Center. Subjects who are eligible to receive allogeneic hematopoietic stem cell transplantation according to the eligibility criteria will be consented and enrolled. Subjects will be randomly assigned to receive one of 2 conditioning regimen: fludarabine and busulfan, or fludarabine busulfan and low dose total body irradiation (TBI). Subjects will be followed until 1 year post transplantation to assess the relapse rate in each arm and transplant-related toxicity.

The combination of fludarabine and busulfan is the current standard of care for patients with myeloid malignancies (myelogenous leukemia, chronic myelogenous leukemia, other myeloproliferative disorder, or myelodysplastic syndrome) undergoing allogeneic transplantation at HUMC. In this study we will be comparing in a randomized fashion the standard regimen to a regimen of fludarabine, busulfan and TBI.

Primary Objective The primary objective is to compare the relapse rate at 1 year of patients with myeloid malignancies receiving each regimen.

Secondary Objectives The secondary objective is to compare the toxicity of each regimen

Arms: arm 1: FLUDARABINE AND BUSULFAN arm 2: FLUDARABINE, BUSULFAN AND LOW DOSE TOTAL BODY IRRADIATION
Interventions: intervention 1: Fludarabine and Busulfan plus/minus Total Body Irradiation (low dose) intervention 2: Fludarabine and Busulfan + Low Dose Total Body Irradiation (LD TBI)
Intervention descriptions: intervention 1: Fludarabine 40mg/m2 and Busulfan 130mg/m2 on days -6, -5, -4 and -3 of transplant.

rATG on days -3, -2 and -1 intervention 2: Fludarabine 40mg/m2 and Busulfan 130mg/m2 on days -6, -5, -4 and -3 of transplant.

rATG on days -3, -2 and -1 TBI 200cGY (as randomized) on day -1

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Number <pro00001278> 
A PHASE III STUDY OF FLUDARABINE AND BUSULFAN VERSUS FLUDARABINE, 
BUSULFAN AND LOW DOSE TOTAL BODY IRRADIATION IN PATIENTS RECEIVING 
AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT 
 
Protocol Version:  
 
 
Date of Protocol:      
Original 
 
10Feb2010 
Amendment 1 
 
10Nov2010 
Amendment 2 
Amendment 3 
Amendment 4 
Amendment 5 
Amenement 6 
 
17May2012 
27Dec2012 
17Jul2013 
11Dec2013 
21Dec2015 
 
 
BLOOD AND MARROW TRANSPLANTION PROGRAM 
HACKENSACK UNIVERSITY MEDICAL CENTER  
 
 Principle Investigator:  
Michele Donato, M.D. (551) 996-5900 
Co-Investigators: 
Scott D, Rowley M.D., FACP                                                        Melissa Baker, APN 
Phyllis McKiernan, APN                                                            Mary DiLorenzo, APN 
David Vesole, MD, PhD                                                           Michele Boonstra, APN 
Alan Skarbnik, MD 
 
Statistician: 
Themba Nyirenda, Ph.D. 
 VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in 
the United States and internationally. 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE ............................................................. 5 
1.1 
Allogeneic transplantation for the treatment of myelodysplastic syndrome, 
chronic myelogenous leukemia and other myeloproliferative diseases and acute 
myeloid leukemia ................................................................................................. . 5 
1.2 
Fludarabine and busulfan in conditioning regimen …………………………   7 
2 
STUDY RATIONALE ...................................................................................................... 9 
2.1 
Primary Objective .................................................................................................. 9 
2.2 
Secondary Objectives............................................................................................. 9 
3 
INVESTIGATIONAL PLAN .......................................................................................... 10 
3.1 
Overall Design and Plan of the Study .................................................................. 10 
3.2 
Selection Inclusion and Exclusion Criteria .......................................................... 10 
3.3 
Donor Inclusoin and Exclusion Criteria .............................................................. 11 
3.4 
Patient Evaluation ................................................................................................ 12 
3.5 
Donor Evaluaton .................................................................................................. 13 
3.6 
HSC Product Evaluation ...................................................................................... 13 
3.7 
Post-Transplant Evaluation .................................................................................. 13 
3.8 
Post transplant re-staging of disease .................................................................... 13 
3.9 
Study Medications ............................................................................................... 13 
3.10 
Outline of Treatment Plan .................................................................................... 15 
4 
ADVERSE EVENTS ....................................................................................................... 18 
4.1 
Definitions............................................................................................................ 18 
4.2 
Procedures for AE and SAE Reporting ............................................................... 19 
4.3 
Intensity for each adverse event ........................................................................... 19 
4.4 
Assessment of Toxicity ........................................................................................ 19 
4.5 
Assessment of Causality ...................................................................................... 19 
4.6 
Follow-up of Adverse Experiences ...................................................................... 20 
5 
Statistical Evaluation ....................................................................................................... 21 
5.1 
Primary Objective ................................................................................................ 21 
5.2 
Secondary Endpoints ........................................................................................... 21 
5.3 
Accrual, Registration and Follow-up ................................................................... 22 
5.4 
Sample Size and Power Calculations ................................................................... 22 
5.5 
Efficacy Analysis ................................................................................................. 22 
5.6 
Statistical Hypothesis ........................................................................................... 23 
5.7 
Primary Endpoint ................................................................................................. 23 
5.8 
Secondary Endpoints ........................................................................................... 23 
5.9 
Discontinuation from study.................................................................................. 25 
5.10 
Stopping Rules ..................................................................................................... 26 
5.11 
Monitoring Compliance ....................................................................................... 26 
5.12 
Data Management and Analysis .......................................................................... 26 
6 
ADMINISTRATIVE CONSIDERATIONS .................................................................... 27 
6.1 
Patient and Donor Information and Informed Consent........................................ 27 
 


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6.2 
Institutional Review Board Review ..................................................................... 27 
6.3 
Data and Safety Monitoring Board ...................................................................... 27 
REFERENCES ............................................................................................................................ 28 
  


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ABBREVIATIONS LIST 
Abbreviation 
Definition 
°C 
degrees Celsius 
µM 
Micromolar 
20S 
20S proteasome subunit 
AE 
adverse event 
ANC 
absolute neutrophil count 
Bc1-2 
B-cell lymphoma-2; a gene that inhibits apoptosis 
BSA 
body surface area 
Bu 
busulfan 
CAM 
cell adhesion molecules  
cm 
Centimeter 
CR 
Complete Response 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
FDA 
Food and Drug Administration 
Flu 
fludarabine 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
ht 
Height 
IκB 
I kappa B kinase; cytokine response kinase that activates 
transcription factor NF-kappa b at serine 32 and 36 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
IκBα 
I kappa B alpha-associated protein kinase 
kg 
Kilogram 
Ki 
inhibitory constant 
lbs 
Pounds 


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Abbreviation 
Definition 
m2 
square meters 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm3 
cubic millimeters 
mmol 
Millimole 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NF-κB 
nuclear factor-κB 
ng 
Nanogram 
nM 
Nanomole 
p21 
p21(ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
SAE 
serious adverse event 
TBI 
total body irradiation 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
wt 
Weight 
 
 
1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
Allogeneic transplantation for the treatment of myelodysplastic syndrome, chronic 
myelogenous leukemia and other myeloproliferative disorders, and acute myeloid 
leukemia: 
The myelodysplastic syndromes are a heterogeneous group of clonal hematologic disorders 
characterized by bone marrow failure and proliferation of myeloblastic leukemia cells.  
Patients with MDS develop cytopenias as a result of ineffective hematopoiesis.  These 
cytopenias are believed to be a result of an increase in apoptosis resulting in an increase in 
futile cell cycling.  In addition, the apparently mature and differentiated hematopoietic cells 
in patients with MDS are functionally impaired.  Granulocytes have decreased 
myeloperoxidase activity (1,2) and platelets have impaired function.  Therapy for MDS 
includes supportive care geared mostly to tranfusional support.  Allogeneic transplantation 
has been shown to offer the possibility of long-term remission and remains the only 
curative option for patients with MDS.  The development of reduced intensity conditioning 


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regimens expanded the scope of allogeneic transplantation for older patients with MDS.  A 
very large retrospective analysis by the European Blood and Marrow Transplantation 
Group (3) compared the outcome of 836 patients with MDS treated with either a reduced-
intensity conditioning regimen or a conventional regimen before allogeneic transplantation.  
The 3-year probabilities of progression-free and overall survival were similar in both 
groups, with a 3-year relapse rate being significantly higher in the reduced-conditioning 
group, offset by a significantly reduced probability of non-relapse mortality.  This 
demonstrates the importance of the preparative regimen in preventing relapse in this 
setting.    
Acute myeloid leukemia accounts for over 9,000 deaths yearly in the United States.  The 
WHO classification of AML incorporates and interrelated morphology, cytogenetics, 
molecular genetics and immunologic markers in an attempt to construct a classification that 
is clinically and prognostically valid.  Under this classification the requisite blast 
percentage in the marrow is > 20%.  Hematopoietic stem cell transplantation is an 
established 
therapeutic 
modality 
in 
patients 
with 
AML. 
 
An 
alloreactive 
immunotherapeutic effect of donor cells has been demonstrated.   
No other established therapy applied during complete remission offers as strong an anti-
leukemic effect.  Transplant-related morbidity and mortality, however, remain obstacles in 
the successful application of this treatment.  More recently, reduced-intensity conditioning 
has been applied as a therapy for AML.  Reduced-intensity conditioning, which includes 
potent immunosuppressive agents in addition to anti-leukemic agents, effectively permits 
engraftment of donor hematopoietic stem cells.  Several studies have demonstrated that the 
morbidity and mortality are less with these regimens compared to myeloablative 
conditioning (4) (5).  While the reduced intensity of the conditioning regimen has resulted 
in reduced non-relapse mortality in patients with AML, some studies have suggested a 
concomitant increase in relapse as a consequence of lowering the intensity of the cytotoxic 
agents(6).  New conditioning regimens that increase the anti-leukemic effect while 
maintaining a low regimen toxicity profile, are therefore needed.  
 
Chronic myeloid leukemia (CML) was the first neoplastic disease associated with a 
chromosomal aberration. The Philadelphia chromosome is a reciprocal t(9;22)(q34;q11) 
translocation that results in the production of the Bcr-Abl1 fusion protein (previously 
termed Bcr-Abl), a constitutively active tyrosine kinase. Elucidation of the molecular 
pathogenesis of CML led to the development of the tyrosine kinase inhibitor (TKI) STI-
571, now known as imatinib mesylate. The Food and Drug Administration first approved 
imatinib in May 2001 for the treatment of patients with chronic-phase (CP) CML after 
failure of interferon alfa therapy and for the treatment of advanced CML. In December 
2002, after positive results from the International Randomized Study of Interferon vs 
STI571 (IRIS), imatinib was approved for the treatment of patients with newly diagnosed 
CP-CML. Use of imatinib as first-line therapy has resulted in complete cytogenetic 
responses (CCyRs) in 65% to 85% of patients with CML. Despite the successes of imatinib 
in treating CML, some patients' responses to treatment are inadequate. In the IRIS trial, 
approximately 30% of patients with newly diagnosed CP-CML who were randomized to 
receive imatinib did not achieve a CCyR within 1 year of treatment. In addition, 
approximately 10% of patients experienced relapse during 5 years of follow-up, including 


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approximately 10% who had achieved a CCyR. Higher rates of treatment failure occur in 
patients with accelerated- or blast-phase disease. 
 Allogeneic SCT is the only potentially curative treatment for CML. However, since the 
development of modern TKIs, allogeneic SCT is more commonly performed after patients 
have received imatinib and second-generation agents and is an important treatment option 
after treatment failure. Prior imatinib treatment does not adversely affect overall survival, 
progression-free survival, or nonrelapse mortality after allogeneic SCT, and second-
generation TKIs do not appear to increase transplant-related toxic effects. Also, allogeneic 
SCT is probably the best available therapy for eligible patients with a T315I mutation. 
1.2 
Fludarabine and busulfan in conditioning regimens: 
The combination of fludarabine and intravenous busulfan (FluBu) has become the most 
commonly used conditioning regimen for allogeneic transplantation. Its safety profile has 
compared favorably to the previous regimens of cyclophosphamide and TBI or 
cyclophosphamide and busulfan (BuCy). Andersson et al. reported on 148 patients 
receiving fludarabine and busulfan for conditioning regimen compared to 67 patients 
receiving BuCy (7). The groups had comparable pretreatment characteristics, except that 
FluBu patients were older (46 versus 39 years, P<0.01), more often had unrelated donors 
(47.3% versus 20.9%, P<0.003), and had shorter median follow-up (39.7 versus 74.6 
months). To account for improved supportive care and other unidentified factors that might 
have affected outcome (“period” effects), 78 acute myelogenous leukemia (AML) patients 
receiving Melphalan-Flu (MF), treated in parallel during this time (1997-2004) were used 
to estimate the period effect. The MF patients’ outcomes worsened during this period. 
Therefore, the period effect was unlikely to have explained the greatly improved outcome 
with FluBu. Patients transplanted with FluBu in their first complete remission (CR1) had a 
3-year overall survival and event-free survival (EFS) of 78% and 74% respectively, 
whereas CR1 patients younger than age 41 had a 3-year EFS of 83%. These results 
supported replacing BuCy with FluBu. Bredeson et al. compared BuCy to FluBu by 
performing a retrospective matched-pair analysis comparing outcomes of adult patients 
treated with either regimen (8). One hundred and twenty cases (FluBu) and 215 matched 
controls (BuCy) were available for comparison. All FluBu patients also received 
antithymocyte globulin (ATG). Patients receiving FluBu had significantly less treatment 
related mortality (12% versus 34%) and grades II-IV acute graft-versus-host disease (15% 
versus 34%, P<0.001) compared to BuCy patients. The risk of relapse however, was higher 
in the FluBu patients (42% versus 20%, P<0.001). The risk of chronic GVHD and disease-
free survival was similar in the cases and controls. In conclusion, the FluBu regimen has 
improved the treatment-related mortality but post-transplant relapse remains the main 
obstacle in the successful treatment of these patients. 
The fludarabine, busulfan, TBI (FluBuTBI) regimen has been established in an effort to 
reduce the relapse rate (9). Russell et al. evaluated a myeloablative regimen of daily 
busulfan, fludarabine, and 400 cGy total-body irradiation given before allogeneic 
transplantation. Sixty-four adults with acute leukemia in first and second remission were 
evaluated. All patients also received ATG. For 31 matched related and 33 alternate donor 
stem cell transplantation the overall treatment-related mortality was 3%. Projected disease-
free and overall survival at 3 years for AML were the same at 83%, and for acute 
lymphoblastic leukemia were 65% and 78% respectively. For the marched related donors 


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the disease free survival was 77% and overall survival 87%, for alternative donors the 
disease free survival and overall survival were 71% and 84% respectively. Overall survival 
and disease free survival in patients without and with high-risk features were 100% versus 
71% and 88% versus 68%, respectively. This combination therefore appears to be well 
tolerated and may offer better disease control than the standard FluBu. 


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2 
STUDY RATIONALE 
The combination of fludarabine and busulfan is the current standard of care for patients with 
myeloid malignancies (AML, CML and other myeloproliferative disorders, or MDS) undergoing 
allogeneic transplantation at HUMC. In this study we will be comparing in a randomized fashion 
the standard regimen to a regimen of fludarabine, busulfan and TBI. 
2.1 
Primary Objective 
The primary objective is to compare the relapse rate at 1 year of patients with myeloid 
malignancies receiving each regimen. 
2.2 
Secondary Objectives 
The secondary objective is to compare the toxicity of each regimen 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Design and Plan of Study 
This is a single institution study of fludarabine and busulfan versus fludarabine, busulfan 
and low dose total body irradiation in patients undergoing allogeneic stem cell 
transplantation.  A study population of 54 subjects will be enrolled from The John Theurer 
Cancer Center at Hackensack University Medical Center.  Subjects who are eligible to 
receive allogeneic hematopoietic stem cell transplantation according to the eligibility 
criteria will be consented and enrolled.  Subjects will be randomly assigned to receive one 
of 2 conditioning regimen: fludarabine and busulfan, or fludarabine busulfan and low dose 
total body irradiation (TBI). Subjects will be followed until 1 year post transplantation to 
assess the relapse rate in each arm and transplant-related toxicity 
3.2 
Patient Inclusion and Exclusion Criteria 
3.2.1 Patient Inclusion Criteria 
3.2.1.1 
Diagnosis of acute myelogenous leukemia, chronic myelogenous leukemia, 
other myeloproliferative disorder, or myelodysplastic syndrome 
3.2.1.2 
Any stage of disease will be considered for transplantation 
3.2.1.3 
Have a suitable related or unrelated donor (Section 3.3) 
3.2.1.4 
Age ≥18 but <70 yrs 
3.2.1.5 
KPS of ≥70% 
3.2.1.6 
Recovery from all hematologic and non-hematology toxicities from 
previous therapies. 
3.2.2 Patient Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
3.2.2.1 
Diagnosis other than acute myelogenous leukemia, myeloproliferative 
disorder, or myelodysplastic syndrome 
3.2.2.2 
Chemotherapy or radiotherapy within 14 days of initiating treatment in this 
study with the exception of lenalidomide, decitabine, azacitidine, imatinib 
mesylate, dasatinib, nilotinib hydrochloride and hydroxyurea.   
3.2.2.3 
Prior dose-intense therapy requiring HSC support within 56 days of 
initiating treatment in this study 
3.2.2.4 
Uncontrolled bacterial, viral, fungal or parasitic infections  
3.2.2.5 
Uncontrolled CNS metastases 
3.2.2.6 
Known amyloid deposition in heart 
3.2.2.7 
Organ dysfunction 
3.2.2.7.1 
LVEF <40% or cardiac failure not responsive to therapy 
3.2.2.7.2 
FVC, FEV1, or DLCO <50% of predicted and/or receiving 
supplementary continuous oxygen 
3.2.2.7.3 
Evidence of hepatic synthetic dysfunction, or total bilirubin >2x or 
AST >3x ULN 


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3.2.2.7.4 
Calculated creatinine clearance <20 ml/min 
3.2.2.8 
Karnofsky score <70%  
3.2.2.9 
Life expectancy limited by another co-morbid illness 
3.2.2.10 
Diagnosed or treated for another malignancy within 3 years of enrollment, 
with the exception of complete resection of basal cell carcinoma or 
squamous cell carcinoma of the skin, an in situ malignancy, or low-risk 
prostate cancer after curative therapy 
3.2.2.11 
Female subject is pregnant or breast-feeding (women) or unwilling to use 
acceptable birth control methods (men or women) for twelve months after 
treatment. Confirmation that the subject is not pregnant must be established 
by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy 
test result obtained during screening.  Pregnancy testing is not required for 
post-menopausal or surgically sterilized women. 
3.2.2.12 
Documented hypersensitivity to fludarabine or melphalan or to bortezomib, 
boron or mannitol or any components of the formulation 
3.2.2.13 
Patients unable or unwilling to provide consent 
3.2.2.14 
Myocardial infarction within 6 months prior to enrollment or has New York 
Heart Association (NYHA) Class III or IV heart failure (see section 8.4), 
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities. Prior to study entry, any ECG abnormality at screening has to 
be documented by the investigator as not medically relevant 
3.2.2.15 
Patient has received other investigational drugs with 14 days before 
enrollment 
3.2.2.16 
Serious medical or psychiatric illness likely to interfere with participation in 
this clinical study 
3.3 
Donor Inclusion and Exclusion Criteria 
3.3.1 Donor Inclusion Criteria: 
3.3.1.1 
HLA 6/6 (HLA-A, B, DrB1) related donor or 7/8 (HLA-A, B, C, DrB1) 
unrelated donor 
3.3.1.2 
Related donors will be evaluated in accordance with HUMC standard 
practice guidelines for the evaluation and management of allogeneic donors 
3.3.1.3 
Unrelated donors will be identified, evaluated, and managed in accordance 
with National Marrow Donor Program standards 
3.3.1.4 
KPS of ≥70% 
3.3.1.5 
Willing to donate bone marrow using standard techniques or peripheral 
blood HSC by leukapheresis 
3.3.1.5.1 
Have adequate veins for apheresis or agree to placement of a central 
venous catheter (femoral, subclavian) if donating peripheral blood 
HSC 
 


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3.3.2 Donor Exclusion Criteria 
3.3.2.1 
Identical twin 
3.3.2.2 
Female donors who are pregnant or breastfeeding 
3.3.2.3 
Infection with HIV or viral hepatitis (B or C) 
3.3.2.4 
Known allergy to filgrastim 
3.3.2.5 
Current serious systemic illness 
3.3.2.6 
Uncontrolled bacterial, viral, or fungal infection 
3.3.2.7 
Receiving experimental therapy or investigational agents 
3.3.2.8 
History of cancer other than treated basal cell cancer of the skin or 
carcinoma in situ of the cervix.  Cancer treated with curative intent >5 yrs 
before donation will be reviewed on a case-by-case basis by the principal 
investigator 
3.4 
Patient Evaluation 
Pre-transplant evaluation must be performed within 30 days of transplantation.   
3.4.1 History with full details of the patient’s prior treatments and responses 
3.4.2 Physical exam with determination of Karnofsky score and findings related to 
underlying malignancy 
3.4.3 Chemistry profile to include serum creatinine, AST, alkaline phosphatase, and 
bilirubin 
3.4.4 CBC with differential 
3.4.5 ABO and Rh 
3.4.6 Serum pregnancy test, if female gender with child-bearing potential  
3.4.7 HIV, Hepatitis B, Hepatitis C, CMV serology 
3.4.8 Disease Staging: 
3.4.8.1 
Bone marrow aspiration and biopsy 
3.4.8.2 
Morphology 
3.4.8.3 
Cytogenetic evaluation 
3.4.8.4 
Fish study for common abnormalities associated with the disease being 
treated (if previously documented negative, need not be repeated to comply 
with this requirement). 
3.4.8.5 
Molecular testing for common abnormalities associated with the disease 
being treated 
 
3.4.9 Pulmonary function tests with DLCO 
3.4.10 MUGA scan or cardiac echo 
3.4.11 EKG 


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3.5 
Donor Evaluation 
Pre-donation evaluation must be performed in accordance with HUMC Standard Operating 
Procedures for the evaluation and management of related HSC donors, or with NMDP 
Standard Operating Procedures for the evaluation and management of unrelated HSC 
donors.  
3.6 
HSC Product Evaluation 
3.6.1 TNC, CD34+, and CD3+ cell counts 
3.6.1.1 
Bone marrow or PBSC products may be cryopreserved 
3.7 
Post-Transplant evaluation 
3.7.1 Physical exam daily until hematological recovery and resolution of serious 
regimen-related complications 
3.7.2 History and physical exam weekly through day 100 after transplantation, then at 6 
months, 9 months, 12 months after transplantation. 
3.7.2.1 
Assessment and staging of acute and chronic GvHD will be performed and 
recorded at these visits and at least weekly through day +100 after 
transplantation 
3.7.2.2 
Once weekly assessment of toxicity in accordance with NCI toxicity 
guidelines from day-1 until resolution of all Grade 3/4 treatment-related 
toxicities, and then at days +28, +56, +84 (all ±7 days) 
3.7.3 CBC daily from day 0 until ANC ≥500/ul on two sequential days after nadir 
reached (engraftment) 
3.7.4 Chemistry profile 2 times per week until documentation of engraftment and then 
weekly through day +100 after transplantation 
3.7.5 Chimerism evaluation at days +28, 56, and 84 (±7 days), at then at 6 months, 9 
months, 12 months (±30 days) after transplantation.  The Chimerism 
assessment will be performed in accordance with the protocol schedule of 
assessments.  If a subject’s insurance denies coverage, the assessment may 
be omitted 
3.7.5.1 
Peripheral blood samples will be separated to allow assessment of CD3+ 
cell chimerism 
3.7.5.2 
Chimerism studies will be obtained at time of relapse  
      3.7.5.3 
Record of all medication administered during inpatient course 
3.8 
Post transplant re-staging of disease 
3.8.1 Bone marrow aspirate and biopsy with cytogenetic evaluations will be obtained: 
3.8.1.1 
Day 84 (±7 days), at one year (±30 days), and whenever there is evidence of 
relapse 
3.9 
Study Medications 
All medications used in this study are commercially available 


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3.9.1 Fludarabine: 
Fludarabine is a fluorinated nucleotide analogue of the antiviral vidarabine. It acts 
as a purine antagonist antimetabolite. Synonyms: 2-F-ara-AMP. Bone-marrow 
suppression from fludarabine is dose-limiting, manifesting as neutropenia, 
thrombocytopenia, and anemia. Other adverse effects include fever, chills, cough, 
Dyspnea, pneumonia, gastrointestinal disturbances, stomatitis, edema, the tumor 
lysis syndrome, skin rashes, auto-immune hemolytic anemia and thrombocytopenia, 
and hemorrhagic cystitis. Neurological disturbances include peripheral neuropathy, 
agitation, confusion, visual disturbances, seizures, and coma; high doses have been 
associated with progressive encephalopathy, blindness, and death. Dosage should 
be reduced in renal impairment and fludarabine should not be given if creatinine 
clearance is less than 30 mL/minute. Intravenous fludarabine phosphate is rapidly 
dephosphorylated to fludarabine, which is taken up by lymphocytes and 
rephosphorylated to the active triphosphate nucleotide. Peak intracellular 
concentrations of fludarabine triphosphate are seen about 4 hours after a dose. 
Fludarabine has a bioavailability of about 50 to 65% after doses of the phosphate by 
mouth. Clearance of fludarabine from the plasma is triphasic with a terminal half-
life of about 20 hours. Elimination is mostly via renal excretion: 60% of a dose is 
excreted in the urine. The pharmacokinetics of fludarabine exhibit considerable 
interindividual variation.  
3.9.2 Busulfan: 
The major adverse effect of busulfan with standard doses is bone-marrow 
suppression, manifest as leucopenia, thrombocytopenia, and sometimes, anemia. 
The nadir of the granulocyte count usually occurs after about 10 to 30 days with 
recovery occurring over up to 5 months, but busulfan has sometimes caused 
irreversible or extremely-prolonged bone-marrow depression. Hyperpigmentation is 
common, and in a few cases after long-term therapy may be part of a syndrome 
simulating Addison's disease. Rarely, progressive interstitial pulmonary fibrosis, 
known as `busulfan lung', can occur on prolonged treatment. Gastrointestinal 
disturbances are rare at usual therapeutic doses but may be dose-limiting where 
high doses are given before bone marrow transplantation. Other rare adverse effects 
include dry skin and other skin reactions, liver damage, gynaecomastia, cataract 
formation, 
and, 
at 
high 
doses, 
CNS 
effects 
including 
convulsions.  
Busulfan may result in impaired fertility and gonadal function. As with other 
alkylating agents, it is potentially carcinogenic, mutagenic, and teratogenic. 
Busulfan is readily absorbed from the gastrointestinal tract and rapidly disappears 
from the blood with a half-life of 2 to 3 hours. It is extensively metabolized and 
excreted in the urine almost entirely as sulfur-containing metabolites. It crosses the 
blood-brain barrier. 
Busulfan is an antineoplastic with a cell-cycle non-specific alkylating action unlike 
that of the nitrogen mustards, and having a selective depressant action on bone 
marrow. In small doses, it depresses granulocytopoiesis and to a lesser extent 


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thrombocytopoiesis but has little effect on lymphocytes. With larger doses, severe 
bone-marrow depression eventually ensues. 
 
 
3.9.3 Rabbit antithymocyte globulin: 
Antithymocyte globulins are antibodies, which act against lymphocytes, and in 
particular against T-cells, to produce suppression of cell-mediated immunity.  
Common adverse reactions include fever, chills, and skin reactions including rash, 
pruritus, and urticaria, which may be manifestations of hypersensitivity. Dyspnea, 
hypotension, chest, back or flank pain may indicate anaphylaxis, which can occur in 
up to 1% of patients. Rashes and arthralgia may represent serum sickness, 
especially in patients with aplastic anemia. Use with other immunosuppressants 
may reduce the incidence or severity of hypersensitivity but increase the risk of 
acquired systemic infections, such as CMV or herpes simplex. Enhanced 
immunosuppression may also increase the incidence of post-transplant 
lymphoproliferative 
disease 
or 
other 
malignancies. 
Leucopenia 
and 
thrombocytopenia are also common. Although usually transient, dosage adjustment 
may be necessary if they become severe or prolonged, and if unremitting, they may 
warrant stopping therapy. Other adverse effects include headache, abdominal pain, 
gastrointestinal 
disturbances, 
hypertension, 
peripheral 
edema, 
asthenia, 
hyperkalaemia, and tachycardia. Nephrotoxicity has been reported. 
3.10 Outline of Treatment Plan 
Eligible patients who have signed informed consent will undergo pre-transplant evaluation 
and clearance as per current transplant program standard operating procedures.  Patients 
will be admitted to Hackensack University Medical Center for the administration of the 
fludarabine, busulfan, TBI and for the transplant procedures 
Table 1: Treatment Schema for Conditioning Regimen 
 
Day of Transplant 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
+3 
+6 
+9 
+11 
Fludarabine 40mg/m2 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Busulfan 130 mg.m2 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
rATG  
 
 
 
X 
X 
X 
 
 
 
 
 
 
TBI 200 cGY (as 
randomized) 
 
 
 
 
 
X/
X 
 
 
 
 
 
 
Tacrolimus 
 
 
 
 
X→ 
 
 
 
 
 
 
 
Stem cell infusion 
 
 
 
 
 
 
X 
 
 
 
 
 
Methotrexate 5 mg/m2 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Filgrastim 5 ug/kg 
 
 
 
 
 
 
 
 
 
 
X→ 
 
 
 


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3.10.1 Conditioning Regimens 
Eligible patients who have signed informed consent will be randomized to treatment arm A 
(Flu-Bu) or treatment arm B (Flu-Bu-TBI).  
3.10.2 Treatment arm A: 
3.10.2.1 
Patients must be admitted to HUMC prior to the start of the fludarabine and 
will not be discharged until engraftment has occurred. 
3.10.2.2 
Fludarabine will be administered at a dose of 40/mg/m2 IV daily for 4 days 
starting on transplant day -6. 
3.10.2.3 
Busulfan will be administered immediately following the fludarabine at a 
dose of 130 mg/m2 IV daily for 4 days starting on transplant day -6. 
3.10.2.4 
Patients will also receive rabbit antithymocyte globulin (Thymoglobulin) at 
a dose of 0.5 mg/kg IV on day -3, and 1.5 mg/kg on day -2 and 2 mg/kg on 
day -1 
3.10.2.5 
Hematopoietic cells will be infused on day 0 
3.10.2.6 
Graft versus host disease (GVHD) prophylaxis will consists of tacrolimus 
0.03 mg/kg ( or 0.015 mg/kg for age ≥65) using  ideal body weight, IV total 
daily dose starting on transplant day -2 and adjusted based on blood levels.  
Methotrexate at a dose of 5 mg/m2 IV will be administered on transplant 
days +1, +3, +6 and +11 
3.10.2.7 
Dose adjustment for the fludarabine, busulfan and antithymocyte globulin 
will be as follows: 
3.10.2.7.1 
If patient weighs less than 100% of ideal body weight (IBW), dosing 
is based on actual body weight 
3.10.2.7.2 
If patient weighs 120-150% of IBW, dosing is based on adjusted 
body weight (ABW) 
3.10.2.7.3 
If patient weighs greater than 150% of IBW, actual weight will be 
capped at 150% of ideal body weight, and this will be used in the 
adjusted body weight formula 
3.10.2.8 
Corrected body weight formula: ABW= IBW + [(0.25) x (actual BW-IBW)] 
3.10.3 Treatment arm B: 
3.10.3.1 
Patients must be admitted to HUMC prior to the start of the fludarabine and 
will not be discharged until engraftment has occurred. 
3.10.3.2 
Fludarabine will be administered at a dose of 40/mg/m2 IV daily for 4 days 
starting on transplant day -6. 
3.10.3.3 
Busulfan will be administered immediately following the fludarabine at a 
dose of 130 mg/m2 IV daily for 4 days starting on transplant day -6. 
3.10.3.4 
Total body irradiation will be given in 2 fractions of 200 CGY (total 400 
CGY) on day -1. 


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3.10.3.5 
All patients in treatment arm B will also receive rabbit antithymocyte 
globulin (Thymoglobulin) at a dose of 0.5 mg/kg IV on day -3, and 1.5 
mg/kg on day -2 and 2 mg/kg on day -1.  
3.10.3.6 
Hematopoietic cells will be infused on day 0.  
3.10.3.7 
Graft versus host disease (GVHD) prophylaxis will consists of tacrolimus 
0.03 mg/kg ( or 0.015 mg/kg for age ≥65) using  ideal body weight, IV total 
daily dose starting on transplant day -2 and adjusted based on blood levels.  
Methotrexate at a dose of 5 mg/m2 IV will be administered on transplant 
days +1, +3, +6 and +11.  
3.10.3.8 
Dose adjustment for the fludarabine, busulfan and antithymocyte globulin 
will be as follows: 
3.10.3.8.1 
If patient weighs less than 100% of ideal body weight (IBW), dosing 
is based on actual body weight. 
3.10.3.8.2 
If patient weighs 120-150% of IBW, dosing is based on adjusted 
body weight (ABW). 
3.10.3.8.3 
If patient weighs greater than 150% of IBW, actual weight will be 
capped at 150% of ideal body weight, and this will be used in the 
adjusted body weight formula. 
3.10.3.9 
Corrected body weight formula: ABW= IBW + [(0.25) x (actual BW-IBW)] 
3.10.4 Stem cell infusion: 
Day 0 for purposes of methotrexate administration is defined as the day the HSC 
infusion is completed. The infusion of peripheral blood stem cells will be done in 
accordance with the Blood and Marrow Transplant program standard operating 
procedures 
3.10.5 Graft versus host disease (GVHD) prophylaxis: 
GvHD prophylaxis consists of tacrolimus 0.03 mg/kg ( or 0.015 mg/kg for age ≥65) 
using  ideal body weight, IV total daily dose starting on transplant day -2 and 
adjusted based on blood levels.  Methotrexate at a dose of 5 mg/m2 IV will be 
administered on transplant days +1, +3, +6 and +11 
3.10.6 Supportive care after transplantation 
Supportive care including transfusions, hydration and prophylactic antibiotics will 
be provided as per current transplant program standard operating procedures. 
3.10.7 Post-transplant cytokine administration 
Filgrastim will be administered at a dose of 5 mcg/kg (rounded to vial size) every 
day starting on day+9 until neutrophil engraftment  
3.10.8 GvHD management 
Management of GvHD is not defined in this protocol.  Patients may be treated in 
accordance with usual practices and are encouraged to enroll into clinical studies of 
the management of these complications of transplantation Supportive care including 


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transfusions, hydration and prophylactic antibiotics will be provided as per current 
transplant program standard operating procedures.  


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4 
ADVERSE EVENTS 
4.1 
Definitions 
4.1.1 Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment.  An adverse event can be any unfavorable and unintended sign (eg, including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
the drug, whether or not it is considered to be drug related.  This includes any newly 
occurring event or previous condition that has increased in severity or frequency since the 
administration of drug. 
4.1.2 Serious Adverse Event Definition 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that: 
4.1.2.1 
Results in death. 
4.1.2.2 
Is life-threatening.  Life-threatening means that the patient was at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a 
reaction which hypothetically might have caused death had it occurred in a 
more severe form. 
4.1.2.3 
Requires inpatient hospitalization or prolongation of existing 
hospitalization.  Hospitalization admissions and/or surgical operations 
scheduled to occur during the study period, but planned prior to study entry 
are not considered AEs if the illness or disease existed before the patient 
was enrolled in the trial, provided that it did not deteriorate in an unexpected 
manner during the trial (eg, surgery performed earlier than planned). 
4.1.2.4 
Results in persistent or significant disability/incapacity.  Disability is 
defined as a substantial disruption of a persons’ ability to conduct normal 
life functions. 
4.1.2.5 
Is a congenital anomaly/birth defect. 
4.1.2.6 
Is an important medical event.  An important medical event is an event that 
may not result in death, be life-threatening, or require hospitalization but 
may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.   
 
Clarification should be made between the terms “serious” and “severe” since they ARE 
NOT synonymous.  The term “severe” is often used to describe the intensity (severity) of a 


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specific event (as in mild, moderate, or severe myocardial infarction); the event itself, 
however, may be of relatively minor medical significance (such as a severe headache).  
This is NOT the same as “serious,” which is based on patient/event outcome or action 
criteria described above and are usually associated with events that pose a threat to a 
patient’s life or functioning.  A severe adverse event does not necessarily need to be 
considered serious.  For example, persistent nausea of several hours duration may be 
considered severe nausea but not an SAE.  On the other hand, a stroke resulting in only a 
minor degree of disability may be considered mild, but would be defined as an SAE based 
on the above noted criteria.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
4.2 
Procedures for AE and SAE Reporting 
The Principle Investigator-sponsor must report all serious adverse events (SAE) regardless of 
relationship with any study drug or expectedness to the IRB as required by the institution.  
4.3 
Intensity for each adverse event, including any lab abnormality, will be determined by 
using the NCI CTCAE, version 3.0 (or later version), as a guideline, wherever possible.  
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
4.4 
Assessment of Toxicity 
4.4.1 Common Terminology Criteria for Adverse Events (CTCAE) will be used for the 
assessment and grading of all toxicities experienced by patients enrolled into 
this study (http://ctep.cancer.gov/forms/CTCAE_Index.pdf) 
4.4.1.1 
If the nature of the adverse experience is listed in the CTCAE, the maximum 
grade and time of maximum grade will be reported. 
4.4.1.2 
If the adverse experience is not listed on the NCI CTG Expanded Toxicity 
Criteria Appendix D, report the toxicity grade using the following criteria. 
4.4.1.2.1 
Grade 1 = Mild: an adverse experience which is easily tolerated by 
the patient, causing minimal discomfort and not interfering with 
everyday activities. 
4.4.1.2.2 
Grade 2 = Moderate: an adverse experience which is sufficiently 
discomforting to interfere with normal everyday activities. 
4.4.1.2.3 
Grade 3 = Severe: an adverse experience which is incapacitating 
and prevents normal everyday activities. 
4.4.1.2.4 
Grade 4 = Life Threatening: an adverse experience which places 
the patient at immediate risk of death. 
4.5 
Assessment of Causality 
4.5.1 Every effort should be made by the investigator to explain each adverse experience 
and assess its relationship, if any, to study drug treatment. Causality should 
be assessed using the following categories: Not Related, Unlikely, 
Suspected (Reasonable Possibility), Probable. 


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4.5.1.1 
Not related: The adverse experience is definitely not related to the test 
drug. 
4.5.1.2 
Unlikely:  There are other, more likely causes and the drug is not suspected 
as a cause. 
4.5.1.3 
Suspected (reasonable possibility): A direct cause and effect relationship 
between the drug and the adverse experience has not been demonstrated but 
there is a reasonable possibility that the experience was caused by the drug. 
4.5.1.4 
Probable: There probably is a direct cause and effect relationship between 
the adverse experience and the study drug. 
4.5.2 The degree of certainty with which an adverse experience is attributed to drug 
treatment (or alternative causes, e.g. natural history of the underlying 
diseases, concomitant therapy, etc.) will be determined by how well the 
experience can be understood in terms of one or more of the following: 
4.5.2.1 
Known pharmacology of the drug 
4.5.2.2 
Reaction of similar nature being previously observed with this drug or class 
of drug.  The experience having often been reported in literature for similar 
drugs as drug related e.g. skin rashes, blood dyscrasia.  The experience 
being related by time to drug ingestion terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge 
4.6 
Follow-up of Adverse Experiences 
4.6.1 Patients with Grade 3/4 adverse experiences will be actively followed until the 
event has subsided (disappeared) or until the condition has stabilized. 
4.6.2 Adverse events, both serious and non-serious, and deaths that occur during the 
patient’s study participation will be recorded in the source documents.  All 
SAEs should be monitored until they are resolved or are clearly determined 
to be due to a patient’s stable or chronic condition or intercurrent illness(es) 


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5 
STATISTICAL EVALUATION 
5.1 
Primary Objective 
The primary objective of this single institution randomized Phase III trial is to compare the 
1-year relapse rate of myeloid malignancy in patients receiving two different conditioning 
regimens. In this study, subjects will be randomly assigned to one of 2 conditioning 
regimens: fludarabine and busulfan or fludarabine, busulfan and low-dose total body 
irradiation. The myeloid malignancies include acute myeloid leukemia (AML), chronic 
myeloid leukemia (CML) and other myeloproliferative diseases, and myelodysplastic 
syndromes (MDS). 
Primary endpoint will be the 1-year event free survival (EFS) for the two treatment groups, 
where the event is relapse or progression.  Patients are considered a failure with respect to 
EFS if they experience disease relapse or progression.  The time to this event is the time 
from transplant to relapse or progression.  Subjects alive without confirmed disease 
progression will be censored at the time of last disease evaluation.  Patients who die 
without evidence of disease relapse or progression will be censored at time of death and 
death will not be treated as failure for analysis of this primary endpoint. 
5.2 
Secondary Endpoints 
Secondary endpoints will include: 
5.2.1 Overall survival (OS):  Defined as time from the first dose of administration to 
death from any cause. 
5.2.2 Overall response rates: Defined as the composite endpoint of response to treatment 
which includes Complete Response (CR), Partial Response (PR), stable 
disease (SD) as defined in International Response Criteria. We will also 
analyze Complete Response rate.  
5.2.3 Univariate analysis of the risk of progression/relapse and mortality: In addition, 
multivariate analysis of the risk of progression/relapse and overall mortality 
will be conducted to assess influence of variables measured after the start of 
treatment. 
5.2.4 Regimen-related toxicity:  Graded and presented in a descriptive nature. 
Descriptive analysis of baseline characteristics and demographics in this two-treatment 
arms study will be performed in the following manner. Continuous measurements will be 
summarized as mean (SD) or median (inter-quartile range) based on whether or not the data 
come from a normal distribution as validated by Shapiro-Wilks test of normality. 
Categorical measurements will be summarized as frequency (percentage). Proportion of 
overall survival will be estimated by the Kaplan-Meier product limit method. The 
univariate probability of the relapse and treatment–related mortality (TRM) will be 
calculated using cumulative incidence function.   
 
 


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5.3 
Accrual, Registration and Follow-up 
The targeted sample size is 54 subjects.  It is estimated that four years of accrual will be 
necessary to enroll this number of subjects. About 50 patients (49-52) underwent 
allogeneic transplantation at this center, indicating that an appropriate number of subjects 
will be available to complete this study in the time frame anticipated.  Subjects will enroll 
uniformly over the accrual period. The randomization will be stratified by relapse risk 
status (high versus low).  Low relapse will include: AML CR1 and CML chronic phase. All 
other AML, MPD and MDS patients will be considered high relapse risk. An AML CR1 
patient with a history of MDS will be considered high relapse risk. All patients who are 
Flt3/ITD positive at any time will be considered high relapse risk.  Upon establishing 
eligibility, subjects will be randomized in equal numbers to the FluBu and FluBuTBI arms 
using permuted blocks within strata.  
All subjects will be followed for one year from time of transplantation, during which they 
will be monitored for the effects of treatment through regular clinic visits.  Additional 
follow-up data beyond one year of progression-free survival will be obtained from HUMC 
Cancer Center Database. 
5.4 
Sample Size and Power Calculations 
The main objective is to compare the relapse-free surviving proportions at 1 year in 
myeloid malignancy patients who are randomized to either FluBuTBI or FluBu 
conditioning regimen. 
In examining the time to relapse, we consider an analysis of the proportion surviving 
without relapse/progression at the 1 year endpoint.  A comparison of this event between the 
two treatment arms will be conducted using log-rank test statistics at the 5% level of 
significance. Based on this statistic, the calculation of sample size was obtained using 
PASS 2008.  According to the results from previous studies [De Lima et al], the 1-year 
relapse rate in patients with myeloid malignancies being treated with FluBu is 34%.  We 
posit that when the FluBuTBI regimen is used the relapse rate will be reduced to 13.6%, 
which is 40% of the relapse risk in the FluBu regimen arm. Then, a one-sided log-rank test 
will be used to examine evidence for a reduction in disease relapse.  For the nominal power 
of 80%, significance level of 5%, 4 year accrual, 1 year follow-up and 10% drop out rate in 
both FluBuTBI and FluBu treatment arm, 52 patients (26 per arm) will be required to 
detect the 20.4 difference (60% reduction in relapse rate). This calculation achieved 
80.06%. To adjust for balanced samples within the risk status, the study will enroll a 
maximum of 54 patients (27 per arm).   
5.5 
Efficacy Analysis 
This is a phase III study comparing one-year relapse rate after allogeneic HSCT with 
fludarabine, busulfan and total body irradiation regimen and fludarabine and busulfan 
regimen in patients with a diagnosis of myeloid malignancies.   
 
 


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5.6 
Statistical Hypothesis 
The null hypothesis is that the 1 year relapse rate is 34%. It is the goal of this study to show 
that when fludarabine, busulfan and total body irradiation is used as the regimen the risk of 
relapse is 40% that of the flubudarabine and busulfan regimen. Then, we are seeking a 
relapse rate of 13.6 % in the in the FluBuTBI regimen arm which is less than that in FluBu 
regimen arm. Thus, we will evaluate the hypotheses 
HO: θA ≤ θB 
HA: θA > θB 
where θA= rate of relapse in Arm A (FluBu) which is assumed to be 0.34, 
θB= rate of relapse in Arm B (FluBuTBI). 
Due to the lack of homogeneity in the outcome as a result of risk status (low versus high), 
it will be useful to stratified on risk status. Thus, a one-sided log-rank test stratified on risk 
status will be conducted to ascertain if FluBuTBI reduces the relapse rate from that in over 
FluBu using a 5% level of significance.  
5.7 
Primary Endpoint 
The primary analysis will include all randomized subjects, classified according to their 
randomized treatment allocation by the intent-to-treat principle.  The analysis of relapse or 
disease progression is planned at one year after accrual is completed.  The two regimen 
arms will be compared utilizing a one-sided log rank test stratified on risk status, and using 
a level significance level of 0.05.   
5.8 
Secondary Endpoints 
5.8.1 Secondary endpoints will include: 
5.8.1.1 
Overall response rates: Defined as the composite endpoint of response to 
treatment which includes Complete Response (CR), Partial Response (PR), 
stable disease (SD) as defined in International Response Criteria. We will 
also analyze Complete Response rate.  
5.8.1.2 
Overall survival (OS):  Defined as time from the first dose of administration 
to death from any cause. 
5.8.1.3 
Univariate analysis of the risk of progression/relapse and mortality: In 
addition, multivariate analysis of the risk of progression/relapse and overall 
mortality will be conducted to assess influence of variables measured after 
the start of treatment. 
5.8.1.4 
Regimen-related toxicity:  Graded and presented in a descriptive nature. 
5.8.2 Overall Survival 
The event is death from any cause.  The time to this event is the time from 
randomization to death, loss to follow-up or the end of the study, whichever comes 
first.  Patients alive at the time of last observation are considered censored.  The 
Kaplan-Meier estimate of survival will be estimated separately for each treatment-


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group and risk status.  A log-rank test stratified on risk status, conducted at a one-
sided significance level of 0.05 analogous to the analysis of relapse risk described 
above.   
 
5.8.3 Overall Response to Treatment 
A comparative analysis of the response rate to the transplant between the two 
conditioning regimen will also be performed using the incident (CR, PR, SD) as the 
overall response. In addition the CR rate between the treatment arms will also be 
analyzed.  The comparison of the response rate to the transplant with respect to the 
overall and CR component be performed using Mantel-Haenszel Test stratified on 
relapse risk status. 
5.8.4 Event-Free Survival 
The event is death from any cause or relapse/disease progression.  The time to this 
event is the time from randomization to death, relapse or disease progression, loss 
to follow-up or the end of the study, whichever comes first.  Patients alive at the 
time of last observation are considered censored.  The Kaplan-Meier estimate of 
survival will be estimated separately for each treatment-group and risk status.  A 
one-sided log-rank test stratified on risk status will be conducted at the 5% level of 
significance, analogous to the analysis of relapse risk described above. 
5.8.5 Association of Prognostic Factors and Risk of Progression/Relapse and Mortality 
 A comparative analysis of risk outcomes relapse/progression, TRM, and overall 
Mortality will be conducted while adjusting for imbalance in other risk factors 
using a Cox proportional hazards model (1). To fit the multivariate model, a 
stepwise backward selection procedure will be used while considering the type of 
conditioning regimen (FluBuTBI versus FluBu), relapse risk status ( low risk, high 
risk),  age at transplant and  Karnofsky performance score (<90 versus ≥90 ) , 
donor-gender, CMV, HLA match grade, and stem cell source as potential 
covariates. Covariates yielding a p-value of 0.05 or less will be an indication of 
statistical significance. Graft-versus host disease (GVHD) will be entered as a time- 
dependent covariate.  Both acute GVHD and chronic GVHD will be considered as 
subtypes of GVHD.  An examination of the goodness-of-fit will be performed using 
Grambsch-Therneau and Martingale residual plots (2) and lowess smooth of 
Cleveland (3).  The proportionality assumption for Cox regression will be validated 
by introducing a time-dependent covariate for each risk factor and outcome.  Since 
BM blast cell count, presence of peripheral blood blast, and whether or not the 
patient is in CR at transplant are collinear only one variable will be used in single 
model fitting attempt.  Thus, three different models will be considered when 
examining the association risk factors and disease relapse and OS. The results of 
this analysis will be presented in terms of relative risks (RR) along with the 
corresponding p values for each covariate. 
 


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5.8.6 Safety Analysis  
Safety Analysis will be performed on all patients who have at least one dose of 
medication on either treatment arms over the course of this study.  The severity of 
the toxicities will be graded according to the NCI CTCAE v3.0 whenever possible.  
Events during the first 100 days after transplantation will be considered possibly 
related to the transplant for this analysis.  Regimen-related toxicity will be graded 
and presented in a descriptive nature as incidence rates and the corresponding 95% 
confidence intervals.  
5.8.6.1 
Safety Monitoring Endpoints 
 
The incidence of toxicities of grade 3 or higher toxicities (CTCAE version 3.0), the 
incidence of probable viral fungal and bacterial infections, and the incidence of 
treatment-related morality, i.e., from causes other than relapse or progression, will be 
recorded for each patient at set intervals over the course of the study.  Safety data will 
be described in a variety of ways, both graphical and tabular, and incidence will be 
compared across time points and treatment arms.  The Data and Safety Monitoring 
Board will be presented with a comprehensive semi-annual report that will contain both 
solicited and unsolicited adverse event reports. 
5.9 
Discontinuation from study  
5.9.1 Withdrawal of patients 
A patient must be withdrawn from the study under the following circumstances: 
5.9.1.1 
Consent withdrawal at the patient’s own request or at the request of their 
legally authorized representative; 
5.9.1.2 
Toxicity or adverse event requiring treatment that would, in the 
investigator’s opinion, interfere with study endpoints 
5.9.1.3 
Safety reasons requiring discontinuation as determined by the physician(s) 
caring for the patient 
5.9.1.4 
Significant deviation from inclusion/exclusion criteria, in the opinion of the 
investigator; 
5.9.1.5 
If, in the investigator’s opinion, continuation in the study could be 
detrimental to the patient’s well-being; 
5.9.1.6 
Progression of disease (POD) after CR or PR.  
When possible, subjects who are taken-off study or withdraw participation should undergo 
End-of-Study procedures. In addition, patients will be followed for a period of 28 days 
following the day of discontinuation for collection of study related adverse events. 
5.9.2 Replacement of patients 
Patients withdrawn after treatment group assignment may be replaced unless the patient 
discontinued due to as adverse event or the patient met a study endpoint (e.g., disease 
progression). 


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5.10 Stopping Rules 
If the non-relapse mortality rate in the experimental group receiving TBI within the first 3 
month post exceeds 20% then the study will be stopped.  It is assumed that the NRM in the 
standard FluBu conditioning regimen is 10%. Resumption of patient accrual will only be 
permitted after review of interim results by the Institutional Review Board and the Data 
Safety Monitoring Board 
5.11 Monitoring Compliance 
Patients enrolled into the study will be monitored for treatment actually received. Failure to 
comply with study conditioning regimen would first trigger an intervention to improve 
compliance. 
5.12 Data Management and Analysis 
Case report forms will be created for management of data collected during this study.  A 
database in Access will be created based on the case report forms. All study data will be 
imported into SAS and data management will be utilized to flag, and generate queries on 
out of range data issues until they are resolved. All analysis will be performed using SAS 
software version 9.2 (SAS Institute Inc. Cary, NC).    


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6 
ADMINISTRATIVE CONSIDERATIONA 
6.1 
Patient and Donor Information and Informed Consent 
The patient must consent to participate after the nature, scope, and possible 
consequences of the clinical study have been explained in a form understandable to 
him or her. Informed consent documents that include both information about the 
study and the consent form will be given to the patient. Related donor informed 
consent will be obtained in accordance with Standard Operating Practice. This 
document will contain all required regulatory elements. The document must specify 
who informed the patient and the donor.  Informed consent for unrelated donors will 
be in accordance with NMDP standards and procedures and will be obtained by the 
donor center. 
After reading the informed consent document, the patient and donor must give 
consent in writing. The patient’s consent must be confirmed at the time of consent 
by the personally dated signature of the person conducting the informed consent 
discussions. A copy of the signed consent document must be given to the patient or 
the patient’s legally authorized representative. The investigator will retain the 
original signed consent documents in the medical record.  The investigator will not 
undertake any measures specifically required only for the clinical study until valid 
consent has been obtained. 
6.2 
 Institutional Review Board Review 
This study will not be initiated until it is reviewed and approved by the IRB. Any 
modifications to the study must be reviewed and receive written approved by the IRB 
before they can be implemented.  Amendments that are administrative in nature do not 
require IRB approval but will be submitted to the IRB for information purposes. 
6.3 
Data and Safety Monitoring Board  
The HUMC DSMB is responsible for developing and enacting procedures to monitor 
safety of participants in protocols that it oversees. They provide multidisciplinary, 
independent oversight of research studies conducted by HUMC staff and or affiliates, 
focusing on assuring integrity of research and safety of subjects.  The DSMB has the ability 
to require protocol modifications related to participant safety and to recommend suspension 
of termination to the IRB and institutional official of any research protocols that fall within 
its jurisdiction. The DSMB may request that HUMC’s Corporate Compliance Department 
to conduct a periodic audit to assure that data are being collected and recorded according to 
the protocol.  The investigator will submit monitoring reports that include current 
enrollment data, adverse event summary data, and any other data requested by the DSMB.  
The DSMB will meet monthly to review the trial progress, adverse event data, and any 
relevant information such as significant amendments or reviews from IRB submitted by the 
principal investigator.  
 


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7 
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