Clinical trial NCT01339910
Conditions: Leukemia, Myelocytic, Acute
Keywords: Acute Myelogenous Leukemia Myelodysplastic Syndrome
Sponsor: Medical College of Wisconsin
Start date: 2011-06-01; Completion date: 2017-10-16
Enrollment: 272 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) regimens.

Detailed description:
Patients randomized to RIC will receive one of two regimen types: the combination of fludarabine (120-180 mg/m\^2) and busulfan (less than or equal to 8 mg/kg or IV equivalent) (Flu/Bu) or fludarabine (120-180 mg/m\^2) and melphalan (less than 150 mg/m\^2) (Flu/Mel). Patient randomized to MAC will receive one of three regimens: busulfan (16 mg/kg oral or 12.8 mg/kg IV equivalent) and cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m\^2) (Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body irradiation (greater than 1200-1420cGy) (CyTBI). A total of 356 patients (178 to each arm) will be accrued on this study over a period of four years. Patients will be followed for up to 18 months from transplantation.

Arms: arm 1: One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan. arm 2: One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation.
Interventions: intervention 1: Fludarabine and Busulfan intervention 2: Fludarabine and Melphalan intervention 3: Busulfan and Fludarabine intervention 4: Busulfan and Cyclophosphamide intervention 5: Cyclophosphamide and Total Body Irradiation
Intervention descriptions: intervention 1: (Flu/Bu)

* Fludarabine: 30 mg/m\^2/day on Days -6 to -2 (total dose of 150 mg/m\^2)
* Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4 intervention 2: (Flu/Mel)

* Fludarabine: 30 mg/m\^2/day on Days -5 to -2 (total dose of 120 mg/m\^2)
* Melphalan: 140 mg/m\^2 on Day -2 intervention 3: (Bu/Flu)

* Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m\^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -5 to -2
* Fludarabine: 30 mg/m\^2/day on Days -5 to -2: Flu (total dose of 120 mg/m\^2) intervention 4: (Bu/Cy)

* Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m\^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -7 to -4
* Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg) intervention 5: (Cy/TBI)

* TBI: 1200-1420 cGy on Days -7 to -4
* Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)

Protocol documents:
Prot_ICF_000.pdf: 
 
 


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Core Study Participants: 
 
 
      Affiliate Study Participants: 
Baylor College of Medicine (Methodist ) 
BMT at Northside Hospital 
Case Western Reserve University Consortia 
Cleveland Clinic Foundation 
Oregon Health and Science University 
University Hospitals of Cleveland 
Dana Farber Cancer Institute 
Duke Medical Center 
Fred Hutchinson Cancer Research Center 
H. Lee Moffitt Cancer Center 
Ohio State University Consortia 
Ohio State 
Roswell Park Cancer Institute 
University of North Carolina/Chapel Hill 
University of Florida Consortia 
Emory University  
University of Florida (Shands) 
University of Minnesota 
University of Nebraska Consortia 
University of Kansas Hospital 
University of Nebraska 
University of Pennsylvania 
 
Barbara Ann Karmanos Cancer Institute  
Baylor University Medical Center (Dallas) 
Colorado Blood Cancer Institute 
Florida Hospital Cancer Institute 
Fox Chase Temple University 
Jewish Hospital 
Mayo Clinic – Phoenix 
Medical College of Wisconsin 
Mount Sinai Medical Center 
Texas Transplant Institute 
Tufts New England Medical Center 
University of California, San Diego 
University of Kentucky 
University of Maryland 
University of Oklahoma  
University of Rochester 
University of Utah 
University of Wisconsin 
West Virginia University Hospital 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS – BMT CTN 0901 PROTOCOL 
 
A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation 
Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or  
Acute Myeloid Leukemia 
Co-Principal Investigators: 
Bart Scott, MD and Mitchell Horwitz, MD 
Study Design: 
The study is designed as a Phase III, multicenter trial comparing 
outcomes 
after 
allogeneic 
hematopoietic 
stem 
cell 
transplantation (HCT) for acute myeloid leukemia (AML) or 
myelodysplastic syndrome (MDS) between patients receiving 
myeloablative conditioning (MAC) versus reduced intensity 
conditioning (RIC) regimens.   
Primary Objective: 
The primary objective of the randomized trial is to compare 18-
month overall survival (OS) rates between the two groups.  The 
hypothesis to be tested is that reducing the intensity of the 
conditioning regimen will decrease treatment-related mortality 
without increasing relapse so that overall survival will be 
improved. 
Secondary Objectives: 
Secondary objectives include comparisons of disease-free 
survival rates after transplantation, rates of transplant-related 
mortality, incidence of relapse, hematologic recovery, kinetics 
of donor cell engraftment, incidence of graft failure, incidence 
and severity of acute and chronic graft-versus-host disease 
(GVHD), quality of life, rates of infectious complications, rates 
of ≥ grade 3 toxicities according to the CTCAE criteria, immune 
reconstitution and quality of life.   
Eligibility Criteria: 
Patients 18-65 years with the diagnosis of acute myeloid 
leukemia or myelodysplasia with less than 5% bone marrow 
blasts by morphology and no circulating leukemic myeloblasts, 
with HCT-specific comorbidity index score ≤ 4 and an available 
related or unrelated bone marrow or peripheral blood donor. 
Sibling donor must be a 6/6 match at HLA-A and –B 
(intermediate or higher resolution) and –DRB1 (at high 
resolution using DNA-based typing). Related donor other than 
sibling must be a 7/8 or 8/8 match for HLA-A, -B, -C (at 
intermediate typing or higher resolution) and –DRB1 (at high 
resolution using DNA-based typing).  Unrelated donor must be 
a 7/8 or 8/8 match at HLA-A, -B, -C and –DRB1 at high 
resolution using DNA-based typing.  There must be at least 30 
days between the start of the most recent cycle of cytotoxic 
therapy for the malignancy and enrollment or, for patients 
treated with hypomethylating agents, at least 10 days between 
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Treatment Description: 
Patients randomized to RIC will receive one of two regimen 
types: the combination of fludarabine (120-180 mg/m2) and 
busulfan (≤ 8 mg/kg or IV equivalent) (Fu/Bu) or fludarabine 
(120-180 mg/m2) and melphalan (< 150 mg/m2) (Flu/Mel).  
Patient randomized to MAC will receive one of three regimens: 
busulfan 
(16 
mg/kg 
oral 
or 
12.8 
mg/kg 
IV) 
and 
cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 
mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m2) 
(Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body 
irradiation (> 1200-1420cGy) (CyTBI).    
Accrual Objective: 
356 patients, 178 to each arm. 
Accrual Period: 
The estimated accrual period is four years. 
Study Duration: 
Patients will be followed for up to 18 months from 
transplantation. 
 


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Outline of Treatment Plan 
 
 
Reduced Intensity Conditioning (RIC) 
Myeloablative Conditioning (MAC) 
A 
Fludarabine/Busulfan (Flu/Bu) 
• Fludarabine (120-180 mg/m2) 
• Busulfan (≤8 mg/kg PO or 6.4 mg/kg IV) 
C 
Busulfan1 /Fludarabine (Bu/Flu) 
• 
Busulfan (16 mg/kg PO or 12.8 mg/kg IV) 
• 
Fludarabine (120-180 mg/m2) 
B 
Fludarabine/Melphalan (Flu/Mel) 
• Fludarabine (120-180 mg/m2) 
• Melphalan (≤150 mg/m2) 
D 
Busulfan1/Cyclophosphamide (Bu/Cy) 
• 
Busulfan (16 mg/kg PO or 12.8 mg/kg IV) 
• 
Cyclophosphamide (120 mg/kg) 
 
 
E 
Cyclophosphamide/Total Body Irradiation 
(Cy/TBI) 
• 
Cyclophosphamide (120 mg/kg) 
• 
TBI (1200-1420 cGy) 
 
1 Bu = PO doses will be adjusted to maintain Bu steady state concentration at 900±100 ng/mL. 
Randomization 
RIC Regimens: 
Flu/Bu 
Flu/Mel 
MAC Regimens: 
Bu/Flu 
Bu/Cy 
Cy/TBI 
18-month Overall Survival 
MDS/AML 
BM<5% blasts 
GVHD Prophylaxis 
T-cell replete per 
Institutional 
guidelines 
 


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Table of Contents 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Introduction .................................................................................................................... 1-1 
1.2. 
Diagnostic and Prognostic Criteria .............................................................................. 1-1 
1.3. 
Conditioning Regimen Intensity ................................................................................... 1-2 
1.3.1. 
Myeloablative Conditioning for MDS/AML .............................................................. 1-2 
1.3.2. 
RIC regimens for MDS and AML .............................................................................. 1-6 
1.3.3. 
Comparative Studies ................................................................................................... 1-8 
1.4. 
Quality of Life associated with RIC and Myeloablative Preparative Regimens .... 1-12 
1.5. 
Summary ....................................................................................................................... 1-13 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Hypothesis and Specific Objectives .............................................................................. 2-1 
2.2.1. 
Hypothesis ................................................................................................................... 2-1 
2.2.2. 
Primary Objective ....................................................................................................... 2-1 
2.2.3. 
Secondary Objectives .................................................................................................. 2-1 
2.3. 
Patient Eligibility ........................................................................................................... 2-2 
2.3.1. 
Inclusion Criteria ......................................................................................................... 2-2 
2.3.2. 
Exclusion Criteria........................................................................................................ 2-2 
2.4. 
Donor Selection Criteria................................................................................................ 2-3 
2.4.1. 
Donor Exclusion Criteria ............................................................................................ 2-3 
2.5. 
Treatment Plan............................................................................................................... 2-3 
2.5.1. 
Recommended Reduced Intensity Conditioning Regimens ........................................ 2-4 
2.5.2. 
Recommended Myeloablative Conditioning Regimens.............................................. 2-5 
2.5.3. 
Conditioning Regimen Administration ....................................................................... 2-5 
2.5.4. 
Additional Drugs ......................................................................................................... 2-7 
2.5.5. 
GVHD Prophylaxis Regimen ...................................................................................... 2-7 
2.5.6. 
Hematopoietic Graft Collection .................................................................................. 2-9 
2.5.7. 
PBPC and Marrow Infusion ...................................................................................... 2-10 
2.6. 
Supportive Care ........................................................................................................... 2-11 
2.6.1. 
Growth Factors .......................................................................................................... 2-11 
2.6.2. 
Blood Products .......................................................................................................... 2-11 
2.6.3. 
Prophylaxis Against Infections ................................................................................. 2-11 
2.6.4. 
Intravenous Immune Globulin (IVIG) ...................................................................... 2-11 
2.6.5. 
Failure to Engraft ...................................................................................................... 2-11 
2.6.6. 
ABO Incompatibility ................................................................................................. 2-11 
2.6.7. 
Anti-seizure Prophylaxis ........................................................................................... 2-12 
2.6.8. 
Antiemetics ............................................................................................................... 2-12 
2.6.9. 
Post-transplant Donor Leukocyte Infusions (DLI) ................................................... 2-12 
2.7. 
Risks and Toxicities ..................................................................................................... 2-12 
2.7.1. 
Busulfan .................................................................................................................... 2-12 
2.7.2. 
Cyclophosphamide .................................................................................................... 2-13 
2.7.3. 
Fludarabine ................................................................................................................ 2-14 


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2.7.4. 
Melphalan .................................................................................................................. 2-14 
2.7.5. 
Total Body Irradiation ............................................................................................... 2-14 
2.8. 
Quality of Life Assessments......................................................................................... 2-15 
2.8.1. 
Instruments ................................................................................................................ 2-15 
2.8.2 
Administration .......................................................................................................... 2-16 
3. 
STUDY ENDPOINTS AND DEFINITION ................................................................. 3-1 
3.1. 
High Risk Disease ........................................................................................................... 3-1 
3.2. 
Disease Status and Disease Response Assessment....................................................... 3-1 
3.3. 
Primary Endpoint .......................................................................................................... 3-2 
3.3.1. 
Overall Survival .......................................................................................................... 3-2 
3.4. 
Secondary Endpoints ..................................................................................................... 3-2 
3.4.1. 
Overall Survival (OS) ................................................................................................. 3-2 
3.4.2. 
Disease-Free Survival (DFS) ...................................................................................... 3-2 
3.4.3. 
Treatment-related Mortality (TRM) ............................................................................ 3-2 
3.4.4. 
Neutrophil and Platelet Engraftment ........................................................................... 3-3 
3.4.5. 
Donor Cell Engraftment .............................................................................................. 3-3 
3.4.6. 
Acute GVHD of Grades II-IV and III-IV ................................................................... 3-3 
3.4.7. 
Chronic GVHD (cGVHD) .......................................................................................... 3-3 
3.4.8. 
Incidence of Primary Graft Failure ............................................................................. 3-4 
3.4.9. 
Incidence of Secondary Graft Failure ......................................................................... 3-4 
3.4.10. 
Incidence of Toxicities Grade  3 ............................................................................... 3-4 
3.4.11. 
Incidence of Infections ................................................................................................ 3-4 
3.4.12. 
Immune Reconstitution ............................................................................................... 3-4 
3.4.13. 
Quality of Life ............................................................................................................. 3-4 
4. 
TREATMENT SCHEMA ............................................................................................. 4-1 
4.1. 
Patient Enrollment and Evaluation .............................................................................. 4-2 
4.2. 
Enrollment Procedures .................................................................................................. 4-2 
4.2.1. 
Screening and Eligibility Procedures .......................................................................... 4-2 
4.3. 
Study Monitoring ........................................................................................................... 4-2 
4.3.1. 
Follow-up Schedule .................................................................................................... 4-2 
4.3.2. 
Adverse Event Reporting ............................................................................................ 4-3 
4.3.3. 
Patient Assessments .................................................................................................... 4-4 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Study Design and Objectives......................................................................................... 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Randomization ............................................................................................................ 5-1 
5.1.3. 
Primary Endpoint ........................................................................................................ 5-1 
5.2. 
Sample Size and Power Calculations ........................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.3.1. 
Interim Analysis for Efficacy ...................................................................................... 5-3 
5.3.2. 
Guidelines for Safety Monitoring ............................................................................... 5-4 
5.4. 
Demographics and Baseline Characteristics ............................................................... 5-4 
5.5. 
Analysis Plan .................................................................................................................. 5-4 
5.5.1. 
Analysis of the Primary Endpoint ............................................................................... 5-4 


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5.5.2. 
Analysis of Secondary Endpoints ............................................................................... 5-5 
 
 
LIST OF APPENDICES 
 
APPENDIX A – WHO CLASSIFICATIONS 
APPENDIX B – CONSENT FORMS 
APPENDIX C – LABORATORY INFORMATION 
APPENDIX D – IPSS FOR PATIENTS WITH MDS  
APPENDIX E – SWOG CYTOGENETIC CLASSIFICATION FOR AML  
APPENDIX F – KARNOFSKY PERFORMANCE SCORE 
APPENDIX G - HCT-SPECIFIC COMORBIDITY INDEX SCORE 
APPENDIX H – HUMAN SUBJECTS 
APPENDIX I – REFERENCES 
 
 


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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Introduction 
 
MDS and AML are predominantly diseases of older patients.  For patients with advanced or 
chemotherapy refractory disease allogeneic hematopoietic cell transplantation (HCT) is currently 
the only strategy that offers cure.  Unfortunately, this modality is currently available only to a 
small proportion of patients.  Many patients do not undergo HCT either because of advanced 
age, because no suitable donor is available, or because of unacceptable risks currently associated 
with HCT. 
 
One major cause of mortality after HCT is toxicity from pretransplant conditioning which 
historically has included high, myeloablative doses of cytotoxic chemotherapy with or without 
radiation.  In recent years, reduced intensity conditioning regimens were introduced in an attempt 
to reduce non-relapse mortality (NRM) so that HCT could be offered to patients who otherwise 
would not be considered candidates.  The encouraging results of initial studies with these 
regimens are of particular interest for patients with MDS or AML diseases that increase in 
frequency with age (Figure 1.1)1, since older patients are at highest risk of severe complications 
from intensive conditioning.  
 
 
Figure 1.1: Incidence of AML by age 
 
Here we propose a phase III multi-center trial to compare outcomes with myeloablative (MAC) 
and reduced intensity (RIC) conditioning regimens in patients undergoing allogeneic HCT for 
MDS and AML. 
 
1.2. 
Diagnostic and Prognostic Criteria 
 
In the past, MDS and AML were classified by the FAB Classification.2  Some modifications 
were introduced by the World Health Organization (WHO) (Appendix A) which currently sets 
20% myeloblasts by marrow morphology as the upper threshold for the diagnosis of MDS.3  This 
classification has eliminated the MDS category RAEB-T, reclassifying these patients as having 


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AML with multilineage dysplasia transformed from MDS (tAML).  The WHO classification 
system also incorporated clinical and biological subgroups of AML on the basis of cytogenetic 
results and presumed etiology (Appendix A). 
 
The International Prognostic Scoring System (IPSS) for patients with MDS (Appendix D) was 
developed on the basis of a retrospective review of 816 patients with primary MDS in an attempt 
to offer prognostic guidance. 4   Three parameters were identified as having prognostic 
significance: number of cell lines showing peripheral blood cytopenias, number of bone marrow 
myeloblasts, and karyotype.  Based on the values for these three parameters, patients were 
assigned to four risk groups: low, intermediate-1 (int-1), int-2 and high risk with median life 
expectancies of 5.7, 3.5, 1.2 and 0.4 years respectively.  These prognostic categories are helpful 
in counseling patients regarding the suggested time and type of therapeutic interventions, 
including HCT.5  
 
The single most valuable prognostic factor in patients with AML is the karyotype at the time of 
diagnosis.  The results of cytogenetic testing impact the choice of post-induction chemotherapy 
consolidation, and patients considered at high risk for relapse are frequently offered HCT in first 
complete remission.  The Southwest Oncology Group (SWOG) has defined a set of cytogenetic 
criteria that predict clinical outcomes (Appendix E).6  The chances of obtaining a complete 
remission with induction chemotherapy differ by SWOG cytogenetic risk group (84%, 76%, and 
55% for favorable, intermediate, and unfavorable risk, respectively).  The relative risks of death 
from any cause for patients with intermediate and unfavorable cytogenetics, as compared to 
those with favorable cytogenetics, were 1.5 and 3.33, respectively.  These advances in the 
classification schemes of both MDS and AML allow improved prediction of relapse risk, and 
subsequently improved selection of appropriate therapy. 
 
1.3. 
Conditioning Regimen Intensity 
 
As discussed above, a major problem with MAC is regimen-related toxicity and resulting NRM. 
Therefore, there are many efforts directed at reducing NRM by reducing conditioning intensity. 
However, conditioning intensity is also considered important in preventing post-HCT relapse 
leading to concern that decreasing the intensity too much may increase the risk of disease 
recurrence.7   Different investigators have taken diverse approaches to modifying conditioning 
regimens to minimize toxicity while maintaining anti-tumor efficacy.8  Consequently, there are 
currently a variety of conditioning regimens in use, ranging from low to high intensity. 
 
1.3.1. Myeloablative Conditioning for MDS/AML 
 
Busulfan (Bu)/Cyclophosphamide (Cy) Regimen: 
Traditionally, myeloablative doses of chemotherapy were given to eradicate clonal stem cells, 
and donor stem cells were necessary to rescue patients from marrow failure.  The FHCRC team 
reported results for 109 patients with MDS conditioned with oral Bu (16 mg/kg), dose adjusted 
to maintain plasma concentrations at steady state (Css) levels of 800-900 ng/mL (targeted Bu 
[tBu]), and cyclophosphamide (Cy) (120 mg/kg)—oral tBu/Cy.9  Patients were 6-66 (median 46) 
years of age.  The Bu Css levels reached were 635-1,140 (median, 883) ng/mL.  Sixty percent of 
patients were in the prescribed target range.  Pre-HCT marrow myeloblast percentage and IPSS 


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score were the most significant predictors of relapse-free survival (RFS) (Figure 1.3.1a).  NRM 
at 100-days and 3-years was 16% and 31%, respectively.  The 3-year RFS was 56% with related 
and 59% with unrelated donors.  The cumulative incidence of acute GVHD was 64% with HLA-
matched related, and 68% for HLA-matched unrelated donors.  Oral tBu/Cy was an effective 
regimen in patients with MDS, particularly those with early stage disease, but with considerable 
NRM.  Similar results have been reported in AML patients.  In a prospective study performed by 
SWOG/ECOG, 233 patients who obtained complete remissions following 2 cycles of induction 
chemotherapy were randomized to autologous HCT (n=116) or high-dose cytarabine (n=117).  
Patients who had achieved complete remissions and had an HLA-matched or single antigen 
mismatch related donor were offered allogeneic HCT (n=116).  The conditioning regimen for 
allogeneic HCT was oral Bu, 16 mg/kg, and Cy 50 mg/kg x 4 days (oral Bu/Cy).10  Among the 
116 first complete remission patients who received related donor allografts following 
myeloablative conditioning, the median relapse-free survival was 32 months with an estimated 4-
year relapse-free survival of 43%.  The median overall survival (OS) was approximately 35 
months, and the estimated 4-year overall survival was 45% (Figure 1.3.1b).  The 100-day NRM 
among patients who did not relapse was 21%.  
 
   
Years after HCT 
 
Figure 1.3.1a: RFS by IPSS grouping after oral 
tBu/Cy conditioning. 
 
Figure 1.3.1b: Relapse-free survival following 
myeloablative conditioning and related donor 
allografting in 116 patients in first complete 
remission. 
 
Fludarabine (Flu)/Bu Regimen:  
In a subsequent trial, Cy was replaced with fludarabine (Flu) (120 mg/m2) followed by oral tBu 
(16 mg/kg) to Css levels of 900±100 ng/mL—Flu/oral tBu.  Forty-two patients (38 with high risk 
MDS and 4 with advanced chronic myeloid leukemia) were enrolled. 11  Engraftment was 
achieved in all patients.  The day-100 NRM was 7%.  After a median follow-up of 18 months, 
overall survival, NRM, and RFS were 42%, 24%, and 35%, respectively (Figure 1.3.1c).  The Bu 
Css levels were 774-1,188 (median, 908) ng/mL.  Fifteen patients had an average Bu exposure 
<900 ng/mL, with 7 relapses and 4 NRM.  Twelve patients had an average Bu exposure of >900 
ng/mL with 2 relapses and 5 NRM.  The use of Flu instead of Cy appeared to permit higher 
average Bu exposure before equivalent toxicity developed.  This might have resulted in greater 
anti-leukemic efficacy.  Thus, myeloablative HCT was effective and potentially curative in 
patients with MDS, but had significant toxicity as evidenced by a NRM of 20-30%. 
 


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Figure 1.3.1c: OS in patients receiving Flu/Bu 
Figure 1.3.1d: OS for patients with MDS/AML 
after Flu/IV Bu conditioning and allogeneic HCT 
(Dotted lines indicate the confidence interval.) 
 
The M.D. Anderson Cancer Center (MDACC) has also reported results using a Flu/Bu regimen.  
regimen consisting of IV fludarabine 40 mg/m2/day and IV busulfan 130 mg/m2/day on Day -6 
to -3 (Flu 160 mg/m2, Bu 520 mg/m2).12  There were a total of 96 patients with MDS or AML 
conditioned with this regimen.  Patients were 19-66 (median 45) years of age.  The regimen 
results in a 1-year overall survival of (65%), NRM of (3%), and RFS of (52%) (Figure 1.3.1d).  
Also, NRM was lower with the Flu/IV Bu regimen when compared to the Flu/oral tBu regimen 
reported above (3% vs.15%, respectively).  The mean and median area under the curve (AUC) of 
IV Bu was 4,891 µmol/min and 4,871 µmol-min, respectively.  This corresponds to a Bu Css of 
836.6 ng/mL, which was only slightly lower than the median level of 908 ng/mL in the Flu/oral 
tBu regimen.13  Consequently, it appears unlikely that the lower NRM observed with Flu/IV Bu 
was attributable solely to a lower Css of Bu.  The route (IV vs. oral) of Bu administration may 
have also been important. 
 
Cy/TBI Regimen: 
Between 1985 and 1998, 161 patients with de novo AML were transplanted at the FHCRC with 
unrelated donor allografts either HLA-matched (n=102) or mismatched (n=59).14  The majority 
of patients (154, 96%) were conditioned with Cy 120 mg/kg and TBI 13.2-15.75 Gy (Cy/TBI).  
Leukemia-free survival was 50% for patients in first complete remission, 28% for patients in 
second complete remission, and 7% for patients in relapse (Figure 1.3.1e).  The 5-year 
cumulative NRM in this cohort was 43%. 
 
A retrospective matched cohort study was performed by the EBMT comparing Bu/Cy vs. 
Cy/TBI MAC allograft HCT performed between 1987 and 1993. 15   Matching parameters 
included disease stage, age, and GVHD prevention.  There were 268 patients with AML who 
received Bu/Cy conditioning matched to 268 patients with AML who received Cy/TBI 
conditioning.  There were no significant differences in NRM, relapse, or RFS between the Bu/Cy 
cohort compared to the Cy/TBI cohort (Figure 1.3.1f).  Based on these results it appears that the 
Cy/TBI regimen offers equivalent relapse free survival in comparison to the Bu/Cy regimen.  
However, this was not a randomized study and while matching was performed to remove some 
of the inherent bias present this does not completely remove the selection bias that may be 
 


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present when patients are offered MAC.  In addition, there was no control for center effects in 
this large non-randomized retrospective EBMT study.  Similar findings from a retrospective 
study at the FHCRC were reported in an MDS population.16  
 
 
Figure 1.3.1e: Leukemia-free survival following 
MAC and unrelated donor allografting by  
disease state at time of  HCT 
Figure 1.3.1f: LFS in AML patients in CR-1 conditioned  
with Bu/Cy vs. Cy/TBI 
 
 
 
1.3.1.1.Busulfan dosing in myeloablative regimens 
 
Several studies demonstrate that Bu dose adjustments to achieve narrowly defined plasma levels 
may reduce regimen-related toxicity and NRM; most of those studies were carried out with oral 
Bu.  Since its FDA approval in 1999, IV Bu is increasingly used in combination with Cy or 
Flu.17, 18, 19, 20  The use of IV Bu may lead to a lower incidence of toxicity compared to oral Bu, 
particularly mucositis and hepatic veno-occlusive-disease (VOD).  One advantage of IV over 
oral Bu is more predictable bioavailability since it avoids the variable gastrointestinal absorption 
and first-pass metabolism rates contributing to high inter-patient variability of Bu levels with the 
oral drug. 21  It also eliminates the need for re-dosing after vomiting. IV Bu was initially 
administered every 6-hours, similar to oral Bu regimens, but recent studies have used the drug 
with once or twice daily administration.  The IV formulation at a dose of 0.8 mg/kg IV every 6 
hours is considered equivalent to the oral formulation at a dose of 1 mg/kg PO every 6 hours.  On 
this basis a regimen using 4 x 0.8 mg/kg=3.2 mg/kg of IV Bu as a single daily dose was 
developed.19, 22 
 
While differences in absorption and, hence, bioavailability, between patients were eliminated 
with IV Bu, the inter-patient variability in the clearance of IV Bu is similar to that with oral Bu. 
After oral Bu, PK sampling at 7 time points over 6-hours after dose 1, and 5 time points after 
doses 5 and 9 allows a predetermined target Css to be achieved reliably.  Results in 10 patients 
who were conditioned with once a day dosing of IV Bu (3.2 mg/kg/day x 4 days) with 
concomitant Flu have been reported.  Virtually no intra-patient variability in the clearance of IV 
Bu, (106.8 ± 16.7 mL/min/m2) after dose 1 vs. after dose 4 (106.9 ± 21.6 mL/min/m2) was 
present.19  Thus, less frequent blood sampling might be sufficient for consistent targeting with IV 
Bu in that (i) more predictable PK parameters are achieved with IV than with the oral 


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administration, and (ii) less intra-patient variability is expected.  These results have been 
confirmed by additional PK analyses performed by the group at MDACC.22   The use of IV Bu is 
one approach to reducing toxicity associated with HCT conditioning.   
 
1.3.2. 
RIC regimens for MDS and AML  
 
Another approach to reduce NRM associated pre-transplant conditioning is to reduce the overall 
intensity of the conditioning regimen.  The definition of reduced intensity conditioning is related 
to the dose of the agent and specific combination.  The consensus criteria were utilized for the 
threshold definition of a reduced intensity conditioning23.  Busulfan dose of less than 9 mg/kg, 
melphalan dose of less than 150 mg/m2 and irradiation dose of less than 500 cGy unfractionated 
or less than 800 cGy fractionated are defined as RIC.  The major concern with RIC regimens are 
an increased probability of relapse.  
 
Flu/Bu Regimen: 
A RIC regimen consisting of fludarabine and busulfan was first reported by Slavin et al. The 
authors treated 26 consecutive patients with a variety of malignant and nonmalignant conditions 
with fludarabine 180 mg/m2 and oral busulfan 8 mg/kg.  The overall survival, after a median 
follow-up of 8 months, was 85% and 81% of patients were disease-free.  Since then several 
investigators have further explored this regimen in myeloid malignancies.24  For example, a 
conditioning regimen of Flu (150 mg/m2), oral Bu (8 mg/kg), and anti-CD52 antibody-
alemtuzumab (100 mg) was used in 62 patients with MDS (all WHO categories), chronic 
myelomonocytic leukemia, or tAML.25  Patients were 22-70 (median 53) years of age.  The 
predicted 1-year overall survival (74%), NRM (15%), and RFS (62%) were encouraging and 
suggest that reduced-intensity regimens should be explored further.  Importantly, however, a 
large proportion of these patients required donor lymphocyte infusion (DLI) to achieve complete 
chimerism and remissions post-HCT.  The plasma Bu concentrations were not reported in this 
analysis.  Investigators in France published results using a Flu (180 mg/m2) and oral Bu (8 
mg/kg) with ATG in 101 patients undergoing HCT.26  DLI was given to 4 patients to establish 
full donor chimerism and to 33 patients secondary to relapse.  In patients who received HCT for 
hematologic malignancies the RFS at 2 years was 57%. 
 
Long-term results of a Flu/Bu RIC regimen in 59 patients with AML and 34 patients with MDS 
were recently reported.27  The conditioning regimen consisted of Flu 150 mg/m2 and Bu 8-10 
mg/kg.  Patients were 21-70 (median 56) years of age.  Forty-nine percent of the patients were in 
complete remission at the time of transplant.  The 4-year probability of survival was 47% in the 
entire cohort, 42 % for AML patients, and 49% for MDS patients (Figure 1.3.2a).  Eighteen 
patients died secondary to NRM at a median of 4.3 months post-transplant.  The 1 year 
cumulative incidence of NRM was 16%.  In multivariate analysis only the presence of chronic 
GVHD improved overall survival.  The authors demonstrated that the RIC Flu/Bu regimen 
resulted in long-term remission with relatively low NRM.  Further the development of chronic 
GVHD was important in reducing relapse and improving overall survival28.   
 


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Flu/Mel Regimen: 
Investigators at MDACC first reported results with a RIC regimen consisting of Flu 125 mg/m2 
and melphalan (Mel) 100-140 mg/m2 in 78 patients with a variety of hematologic malignancies. 
The Day 100 NRM was 37.4%.  The RFS was 57% for patients in first remission or chronic 
phase disease.  This regimen has subsequently been investigated at other centers yielding similar 
results 29. 
 
Long-term results of the Flu/Mel regimen in patients with AML or MDS have been reported.  
One hundred twelve patients with AML or MDS were conditioned with Flu 100-150 mg/m2 and 
Mel 100-180 mg/m2.  The majority of patients were not in remission at the time of HCT and the 
median age was 55 (range, 22-74) years.  The median follow-up was 29.4 (range, 22-74) months.  
There were no differences in survival or risk of progression between patients who received Mel 
140 mg/m2 vs. Mel 180 mg/m2.  The cumulative incidence of Day 100 and 2-year NRM was 0% 
and 20%, respectively.  The estimated 2-year survival was 66% for patients in remission at time 
of transplant and 40% for patients with active disease but without circulating blasts (Figure 
1.3.2b).30  Results using a RIC regimen of Flu/Mel have also been reported from the City of 
Hope Comprehensive Cancer Center.  Investigators conditioned 43 MDS patients with Flu 125 
mg/m2 and Mel 140 mg/m2.  The median age was 58 (range, 30-71) years and the majority of 
patients had int-2 or high risk MDS.  The 2-year overall survival and NRM was 53.5% and 
35.2%, respectively.31  The results of these studies demonstrate reliable engraftment following a 
RIC regimen of Flu/Mel and that the NRM and overall survival are comparable to the historical 
results of MAC regimens.   
 
 
Figure 1.3.2a: Overall survival in MDS and AML 
patients treated with a RIC regimen of Flu/Bu 


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1.3.3. 
Comparative Studies 
 
Retrospective Studies: 
Despite the above studies, the benefits of reduced intensity conditioning regimens in comparison 
to standard myeloablative regimens remain undetermined.  A retrospective analysis from the 
Dana-Farber Cancer Institute compared outcomes with nonmyeloablative and myeloablative 
conditioning regimens in patients over the age of 50 years, transplanted for various diagnoses 
(non-Hodgkin lymphoma, AML, acute lymphocytic leukemia, chronic myelogenous leukemia, 
chronic lymphocytic leukemia, MDS, CMML). 32  The RIC regimen was used in 71 patients and 
consisted of Flu 120 mg/m2, and IV Bu 3.2 mg/kg, and the MAC regimen used in 81 patients 
consisted of either Cy, 1800 mg/m2 given over 2 days with either 14 Gy fractionated TBI or oral 
Bu, 16 mg/kg over 4 days, and Cy 1800 mg/m2.  The analysis showed a trend towards 
improvement in overall survival with RIC vs. MAC (39% vs. 29%, P=0.056) at 2 years, but no 
significant differences were seen in relapse-free survivals (27% vs. 25%, P=0.24) or incidences 
of grades II-IV GVHD (28% vs. 27%).  Furthermore, while NRM was significantly reduced with 
RIC conditioning (32% vs. 50%, P=0.01), there was an increase in relapse incidence (46% vs. 
30%, P=0.052).  As a result, relapse-free survival was identical for the two groups.  Because of 
many patient and disease related variables in that study, conclusions in regards to outcomes 
among patients with specific diagnoses could not be drawn.  The same investigators 
subsequently published a similar retrospective review focused on patients with AML or MDS 
conditioned with the same RIC and MAC as detailed above. 33   Ninety-seven patients received a 
MAC regimen and 39 patients received a RIC regimen.  Patients who received a RIC regimen 
were more likely to be older and to have received a previous HCT compared to the patients who 
received a MAC regimen.  There were no significant differences between the cohorts in regards 
to disease type, stage of disease, type of donor, or stem cell source.  There were no differences 
between the cohorts in regards to the incidence of acute GVHD; however, the RIC cohort was 
more likely to develop extensive chronic GVHD compared to the MAC cohort.  The cumulative 
incidence for NRM was 26% and 33% in patient transplanted with a RIC regimen and MAC 
regimen, respectively.  There was a significantly increased cumulative incidence in relapse 
among patients who received a RIC regimen (61%) compared to patients who received a MAC 
 
Fig. 1.3.2b: Overall survival by disease status at time 
of HCT using a RIC of Flu/Mel. 


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regimen (38%).  There was no difference in overall survival or RFS between the 2 cohorts 
(Figure 1.3.3a).  The 2-year estimated overall survival was 28% for the RIC cohort and 34% for 
the MAC cohort.  Among patients who received a RIC regimen, donor chimerism ≥ 90% was 
associated with improved survival.  In this retrospective review, there was no significant 
difference in NRM but the relapse rate was significantly higher in the RIC cohort. Despite this 
the overall survival was similar between the RIC and MAC regimens.  This finding was 
remarkable given that patients who received a RIC regimen were older and more likely to have 
received a prior HCT.  
 
 
 
Figure 1.3.3a: Probability of overall survival in 
patients with AML or MDS who underwent HCT 
with RIC (n=39) or MAC (n=97) regimens 
Fig. 1.3.3b: Overall survival in AML patients ≥ 50 
years conditioned with MA (n=407) or RIC (n=315) 
 
 
A large retrospective study by the EBMT compared outcomes in patients with AML aged ≥ 50 
years at time of HCT and who where conditioned with MAC vs. RIC regimens 34.  MAC 
regimens consisted of TBI ≥ 10 Gy or Bu > 8 mg/kg; RIC regimens consisted of TBI < 3 Gy or 
Bu ≤ 8 mg/kg.  A total of 407 patients received MAC regimens and 315 patients received RIC 
regimens.  Patients who received a RIC regimen were more likely to be older, have older donors, 
to be male and have a later date of HCT in comparison to patients who received a MAC regimen.  
There were no significant differences between the two groups in regards to FAB classification, 
disease status at time of HCT, and cytogenetic risk.  The cumulative incidence of 2-year NRM 
was 32% and 18% for MAC and RIC HCT, respectively.  However, the cumulative incidence of 
relapse was higher for the RIC (41%) compared to the MAC regimen (24%).  Therefore, there 
was no significant difference in 2-year overall survival (40% vs. 47%) or RFS (44% vs. 46%) 
between the RIC and MAC cohorts, respectively (Figure 1.3.3b).  The EBMT performed a 
similar retrospective analysis in patients with MDS35.  There were no age restrictions placed on 
this analysis and the definition of RIC and MAC regimens was slightly different. RIC regimens 
consisted of TBI 2-4 Gy, oral Bu 8-10 mg/kg, Mel 80-140 mg/m2, Cy 60-120 mg/m2 or thiotepa 
5-10 mg/kg.  MAC regimens consisted of TBI ≥ 8 Gy, oral Bu 16 mg/kg or “equivalent” IV Bu.  
A total of 621 patients received a MAC regimen and 215 patients received a RIC regimen. 
Patients who received a RIC regimen were more likely to be older, have secondary AML, have 
untreated disease, have received a prior auto HCT, and to have received PBSCT grafts.  Clearly 
there was an intrinsic disadvantage in the RIC cohort compared to the MAC cohort.  The 3-year 
relapse rate was significantly increased in the RIC cohort (HR=1.64, p=0.001), but the 3-year 


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NRM rate was decreased (HR=0.61, p=0.015).  There was no difference in 3-year probability of 
RFS or overall survival (39% vs. 34% and 45% vs. 41%) between the MAC and RIC regimens, 
respectively (Figure 1.3.3c).   
 
 
 
Specific doses of Bu have been compared by investigators at the Chaim Sheba Medical Center.36  
In this retrospective review 112 consecutive patients with AML/ MDS were conditioned with a 
MAC regimen of IV Bu 12.8 mg/kg and Cy 120 mg/kg (BuCy n=45), a MAC regimen of IV Bu 
12.8 mg/kg and Flu150-160 mg/m2 (FB4 n=26), or a RIC regimen of IV Bu 6.4 mg/kg and Flu 
150-160 mg/m2 (FB2 n=41).  The patients who received the RIC regimen were more likely to be 
older, to have unrelated grafts, and to be in remission at time of HCT in comparison to patients 
who received the MAC regimens.  In agreement with the previous retrospective studies the 
investigators found that the MAC regimens were associated with a higher NRM but a lower 
relapse rate.  The overall survival at 2 years was 50, 49, and 47% for BuCy, FB4 and FB2 
regimens, respectively.  However if patients had active disease at time of HCT, there was a 
difference in overall survival between the MAC and RIC regimens (Figure 1.33d).   
 
 
Figure 1.3.3c: Overall survival with MAC and RIC regimens by disease status at time of HCT. 


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Another study from the same group at Chaim Sheba Medical Center compared outcomes 
between different RIC regimens.37  The authors compared the Flu 150 mg/m2 + Mel 100-140 
mg/m2 regimen to the Flu 150 mg/m2 + IV Bu 6.4 mg/kg regimen.  There were 72 patients 
conditioned with Flu/Bu and 79 patients conditioned with Flu/Mel.  All patients had hematologic 
malignancies.  The patients who received Flu/Mel were younger, more likely to have multiple 
myeloma rather than AML, more likely to have received a prior auto HCT, and more likely to 
have received a related donor graft in comparison to patients who received the Flu/Bu regimen.  
While the NRM was significantly higher with the Flu/Mel regimen (40% vs. 16%, p=0.003), 
(Figure 1.3.3e) there was no difference in overall survival between the two regimens.  For 
patients in remission, there was a survival advantage with the FB regimen compared to the FM 
regimen (72% vs. 36%, p=0.03), respectively.  The survival advantage with the FB regimen in 
patients in remission at time of HCT was chiefly related to a reduced NRM.  While these 
observations are intriguing they could be explained by selection bias at time of HCT; therefore, 
these observations should be confirmed in a prospective randomized study. 
 
 
 
Figure 1.3.3d: Overall survival by conditioning regimen for 
patients with (a) active disease at time of HCT (n=58)  
or with (b) remission at time of HCT (n=54) 


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Prospective Studies: 
A prospective study comparing RIC vs. MAC consecutively enrolled patients with AML/MDS 
who underwent HLA-identical sibling HCT has been completed.38  Patients ≤ 50 years of age 
were schedule to receive a MAC regimen, and patients > 50 years of age were scheduled to 
receive a RIC regimen.  Forty patients were scheduled to receive a MAC regimen of Cy/TBI and 
47 patients were scheduled to receive a RIC regimen of Flu/Bu (10 mg/kg).  The choice of 
conditioning intensity was not randomized, but as stated was based on age.  Patients who 
received a RIC regimen were more likely to be older, have MDS as opposed to AML, have poor 
risk cytogenetics, and have a higher co-morbidity index in comparison to patients who received a 
MAC regimen.  The 4-year NRM was 19 and 20% for the MAC and RIC regimens, respectively.  
There was no difference in relapse or overall survival between the MAC and RIC regimens.  The 
major limitation of this analysis is that the choice of conditioning regimen was based on age and 
that this decision was made prior to the administration of induction chemotherapy.  Thus, there 
were some dropouts between the decision to proceed to HCT and the start of conditioning.  
Despite these limitations this was one of the first prospective studies conducted, and the results 
confirm the findings of the retrospective studies presented above.  
 
1.4. 
Quality of Life associated with RIC and Myeloablative Preparative Regimens 
 
As there have been no randomized studies comparing RIC and MAC treatment approaches, 
relative effects on health related quality of life (QOL) are extrapolated from observational 
studies.  Bevans and colleagues studied 41 RIC and 35 MAC recipients and concluded that the 
trajectory of QOL post-transplant was similar between RIC and MAC patients.39  Andersson and 
colleagues studied 32 RIC and 25 MAC patients and reported greater deterioration in 
functioning, more symptoms, and slower recovery in the MAC group, although the groups return 
to baseline and are similar at one year. 
 
Measurement of QOL in allogeneic HCT has used a variety of self-reported instruments 
including the Medical Outcomes Study Short Form 36 (SF-36), the Functional Assessment of 
Cancer Therapies-Bone Marrow Transplant module (FACT-BMT), the European Organization 
 
Fig 1.3.3e: OS in patients in remission at time of HCT 


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for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQC30).  
The CTN Quality of Life and Late Effect Subcommittee has recommended at a minimum that 
the SF36 and the FACT-BMT be collected in CTN trials at the time of enrollment prior to 
protocol treatment and at the time of the primary endpoint assessment. 
 
1.5. 
Summary 
 
Several investigators have published results with a variety of RIC regimens.  It is clear that these 
regimens do allow for engraftment of both related and unrelated donor stem cells.  The primary 
benefits of these RIC regimens are a reduction in NRM and the potential to extend curative HCT 
to a broader patient population.  Several retrospective studies have demonstrated a reduction in 
NRM with the use of RIC, but with an increased risk of relapse post-transplant.  This is 
particularly relevant when the disease status at time of transplant is considered.  For patients who 
do not have adequate disease control at time of transplant there appears to be an advantage using 
MAC; however, for patients in remission at time of HCT there was no difference in relapse risk 
between the MAC and RIC cohorts.  The majority of data collected to date indicate that there is 
no significant difference in overall survival between RIC and MAC regimens.  However, most of 
the patients enrolled into the RIC are considered higher risk in comparison to the patients 
enrolled into the MAC regimens.  The patients who receive RIC regimens tend to be older, to 
have higher risk disease, and have higher co-morbidity scores.  Therefore, it is plausible that RIC 
regimens may offer an advantage over MAC regimens in a select population of patients who are 
at lower risk of relapse post-transplant.  Multiple studies have documented that disease status at 
time of transplant is an important predictor of the risk of post-transplant relapse.   
 
Based on the data presented, we anticipate that patients with MDS or AML who have < 5% 
marrow myeloblasts at the time of HCT will have similar rates of relapse irrespective of 
conditioning intensity.  We anticipate that there will be a significant reduction in NRM with RIC.  
Overall we anticipate that there will be a survival benefit with the use of RIC in comparison to 
MAC.  Given the above background we propose a prospective comparison of a MAC regimen 
(using myeloablative doses of BU or TBI) to a RIC regimen (Flu/Mel, Flu/Bu) in patients with 
MDS or AML with < 5% marrow myeloblasts at time of HCT. 
 


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CHAPTER 2 
 
 
2. 
STUDY DESIGN 
 
2.1. 
Study Overview 
 
This prospective, multi-center, Phase III trial is designed to assess the impact of regimen 
intensity on outcome after allogeneic stem cell transplantation for MDS or AML.  Each study 
arm will include either a myeloablative (MAC) or reduced intensity conditioning (RIC) regimen.  
Prior to randomization, the investigator will choose one RIC and one MAC regimen, and a stem 
cell source (peripheral blood or bone marrow stem cells).  The investigator will also commit to a 
GVHD prophylaxis regimen that will be paired with the chosen conditioning regimen.  The 
investigator is encouraged to choose from a list of recommended conditioning regimens and 
accompanying GVHD prophylaxis regimens; however alternative regimens will be permitted if 
they meet specified criteria.  The investigator will also commit to using, or not using, anti-
thymocyte globulin, irrespective of the treatment assignment. 
 
2.2. 
Hypothesis and Specific Objectives 
 
2.2.1. Hypothesis 
 
Hematopoietic cell transplantation with RIC is superior to transplantation with MAC for patients 
with AML and MDS in remission at the time of transplantation.  The premise is that reducing the 
intensity of the conditioning regimen will decrease treatment-related mortality without increasing 
relapse so that overall survival will be improved. 
 
2.2.2. Primary Objective 
 
The primary objective of the trial is to compare 18 month overall survival rates of the two groups 
of patients starting from the time of randomization to the RIC or MAC arms.   
 
2.2.3. Secondary Objectives 
 
Secondary objectives are to compare patients receiving an RIC conditioning regimen with those 
patients receiving an MAC conditioning regimen for:  
1. Disease-free survival rates after transplantation; 
2. Rates of transplant-related mortality;  
3. Incidence of relapse; 
4. Incidence of neutrophil and platelet engraftment;  
5. Kinetics of donor cell engraftment;  
6. Incidence of graft failure;  
7. Incidence and severity of acute and chronic graft-versus-host disease (GVHD);  


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8. Immune reconstitution;  
9. Rates of infectious complications;  
10. Rates of ≥ grade 3 toxicities according to the CTCAE criteria; and, 
11. Quality of life.  
 
2.3. 
Patient Eligibility  
 
The diagnosis of MDS or AML will be based on WHO criteria (Appendix A).  
 
2.3.1. Inclusion Criteria 
1. Age ≤ 65 years and ≥ 18 years. 
2. Patients with the diagnosis of MDS or AML with fewer than 5% myeloblasts in the bone 
marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis 
performed within 30 days of enrollment.  
3. For patients receiving treatment of their MDS or AML prior to transplantation: 
• Interval between the start of the most recent cycle of conventional cytotoxic 
chemotherapy and enrollment must be at least 30 days.  
• Interval between completing treatment with a hypomethylating agent or other 
non-cytotoxic chemotherapy and enrollment must be at least 10 days. 
4. Patients must have a related or unrelated bone marrow or peripheral blood donor.  
a) Sibling donor must be a 6/6 match at HLA-A and – B (intermediate or higher 
resolution) and –DRB1 (at high resolution using DNA-based typing). 
b) Related donor other than sibling must be a 7/8 or 8/8 match at HLA-A, -B, -C (at 
intermediate or higher resolution) and –DRB1 (at high resolution using DNA-
based typing). 
c) Unrelated donor must be a 7/8 or 8/8 match at HLA-A, -B, -C, and –DRB1 at 
high resolution using DNA-based typing. 
5. HCT-Specific Comorbidity Index Score (HCT-CI) ≤ 4 (Appendix G). 
6. Organ function: 
• Cardiac function: Ejection fraction ≥ 40%. 
• Hepatic function: total bilirubin ≤ 2x the upper limit of normal and ALT and AST      
≤ 3x the upper limit of normal.  
• Pulmonary function: DLCO (corrected for hemoglobin) ≥ 40% and FEV1 ≥ 50%   
7. Estimated creatinine clearance ≥ 50mL/min/based on the Cockcroft-Gault formula. 
8. Signed informed consent. 
 
2.3.2. Exclusion Criteria 
1. Prior allograft or prior autograft. 


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2. Symptomatic coronary artery disease. 
3.  Leukemia involvement in the CNS within 4 weeks of enrollment for patients with a 
history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in 
the cerebral spinal fluid). 
4. Karnofsky Performance Score < 70 (Appendix F). 
5. Patients receiving supplemental oxygen. 
6. Planned use of DLI therapy. 
7. Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate 
treatment and with progression of clinical symptoms). 
8. Patients seropositive for the human immunodeficiency virus (HIV). 
9. Patients with prior malignancies, except resected basal cell carcinoma or treated cervical 
carcinoma in situ.  Cancer treated with curative intent > 5 years previously will be 
allowed.  Cancer treated with curative intent < 5 years previously will not be allowed 
unless approved by the Protocol Officer or one of the Protocol Chairs.   
10. Females who are pregnant or breastfeeding. 
11. Fertile men and women unwilling to use contraceptive techniques during and for 12 
months following treatment. 
 
2.4. 
Donor Selection Criteria 
 
Related and unrelated donors will be identified according to institutional guidelines. Peripheral 
blood progenitor cells will be requested, but the use of bone marrow will be allowed according to 
donor preferences and/or institutional guidelines for pediatric donors.   
 
2.4.1. Donor Exclusion Criteria 
1. Donors will be excluded if they are an identical twin of the recipient. 
2. Females who are pregnant (positive serum β HCG) or uninterruptible breastfeeding will 
be excluded. 
3. HIV seropositive donors will be excluded. 
4. Donors receiving experimental therapy or investigational agents will be excluded unless 
approved by the protocol chairs and protocol officer. 
 
2.5. 
Treatment Plan 
 
Centers will declare one MAC and one RIC regimen to be used in each patient at time of 
enrollment prior to randomization.  There are two options for RIC regimens and three for MAC 
regimens, these regimens are listed in Table 2.5. 
 


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TABLE 2.5: CONDITIONING REGIMENS 
Reduced Intensity Conditioning (RIC) 
Myeloablative Conditioning (MAC) 
A 
Fludarabine/Busulfan (Flu/Bu) 
• 
Fludarabine (120-180 mg/m2) 
• 
Busulfan (≤ 8 mg/kg PO or 6.4 mg/kg 
IV) 
C 
Busulfan1 /Fludarabine (Bu/Flu) 
• 
Busulfan (16 mg/kg PO or 12.8 mg/kg IV) 
• 
Fludarabine (120-180 mg/m2) 
B 
Fludarabine/Melphalan (Flu/Mel) 
• 
Fludarabine (120-180 mg/m2) 
• 
Melphalan (≤ 150 mg/m2) 
D 
Busulfan1/Cyclophosphamide (Bu/Cy) 
• 
Busulfan (16 mg/kg PO or 12.8 mg/kg IV) 
• 
Cyclophosphamide (120 mg/kg) 
 
 
E 
Cyclophosphamide/Total Body Irradiation 
(Cy/TBI) 
• 
Cyclophosphamide (120 mg/kg) 
• 
TBI (1200-1420 cGy) 
 
1 Bu PO doses will be adjusted to maintain Bu steady state concentration at 900±100 ng/mL. 
 
 
2.5.1. Recommended Reduced Intensity Conditioning Regimens 
 
2.5.1.1.RIC: Fludarabine and Busulfan (Flu/Bu) 
 
The recommended Flu/Bu regimen is the following:  
• Fludarabine: 30 mg/m2/day on Day -6 to -2 (total dose of 150 mg/m2) 
• Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day IV (total dose of 8 mg/kg or 6.4 mg/kg, 
respectively) on Day -5 to -4. 
 
The sequence of fludarabine and busulfan administration in RIC regimens will be done 
according to institutional standards as long as the prescribed doses are the same as the 
recommended regimen above. 
 
2.5.1.2.RIC: Fludarabine and Melphalan (Flu/Mel) 
 
The recommended Flu/Mel is the following: 
• Fludarabine: 30 mg/m2/day on Day -5 to -2 (total dose of 120 mg/m2) 
• Melphalan: 140 mg/m2 on Day -2 
 
The sequence of fludarabine and melphalan administration in RIC regimens will be done 
according to institutional standards as long as the prescribed doses are the same as the 
recommended regimen above.  Dividing the dose of melphalan in two days is allowed.  
 


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2.5.2. Recommended Myeloablative Conditioning Regimens 
 
2.5.2.1.MAC: Busulfan and Fludarabine (Bu/Flu) 
 
The recommended Bu/Flu regimen is the following: 
• Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m2/day with Bu steady state 
concentration 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m2, 
respectively) on Day -5 to -2 
• Fludarabine: 30 mg/m2/day on Day -5 to -2 (total dose of 120 mg/m2) 
 
The sequence of busulfan and fludarabine administration in MAC regimens will be done 
according to institutional standards as long as the prescribed doses are the same as the 
recommended regimen above. 
 
2.5.2.2.MAC: Busulfan and Cyclophosphamide (Bu/Cy) 
 
The recommended Bu/Cy regimen is the following: 
• Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m2/day with Bu steady state 
concentration 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m2, 
respectively) on Day -7 to -4  
• Cyclophosphamide: 60 mg/kg/day on Day -3 to -2 (total dose of 120 mg/kg) 
 
2.5.2.3.MAC: Cyclophosphamide and Total Body Irradiation (Cy/TBI) 
 
The recommended Cy/TBI regimen is the following: 
• TBI:  1200-1420 cGy on Day -7 to -4 
• Cyclophosphamide: 60 mg/kg/day on Day -3 to -2 (total dose of 120 mg/kg) 
 
The sequence of cyclophosphamide, busulfan and TBI administration practices in MAC 
regimens will be done according to institutional standards as long as the prescribed doses are the 
same as the recommended regimen above. 
 
2.5.3. Conditioning Regimen Administration 
Ideal Body Weight (IBW) Formulas: 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
 
Adjusted Ideal Body Weight (AIBW) Formula: 
where ABW = actual body weight  
AIBW = IBW + [(0.25) x (ABW - IBW)] 
 


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2.5.3.1.Busulfan administration 
 
RIC Regimens: 
Busulfan can be administered orally in four divided doses or intravenously once daily or in four 
divided doses according to institutional preferences.  Pharmacokinetic analysis with the intent of 
dose adjustment is not required for busulfan with total doses lower than 9 mg/kg.  Blood 
collection for pharmacokinetic analysis will be performed as an ancillary study, regardless of the 
busulfan dose (Appendix C). 
 
Patients < 100% of ideal body weight will be dosed according to actual body weight.  Patients > 
100% of ideal body weight will be dosed according to their adjusted ideal body weight.  If 
adjusted body weight is greater than the actual weight, then actual weight should be used.  
Formulas are available in §2.5.3. 
 
MAC Regimens: 
Participating centers will have the option of using oral or intravenous busulfan.  Oral busulfan 
will be administered at 4 mg/kg/day for four days (1 mg/kg every 6 hours).  Patients < 100% of 
ideal body weight will be dosed according to actual body weight.  Patients > 100% of ideal body 
weight will be dosed according to their adjusted ideal body weight.  If adjusted body weight is 
greater than the actual weight, then actual weight should be used.  Formulas are available in 
§2.5.3.  If the center is administering busulfan orally, pharmacokinetics analysis and targeting 
the dose to 900+100 ng/mL must be performed.  Pharmacokinetics on oral Bu will be performed 
according to institutional guidelines. 
 
Intravenous busulfan is administered at a dose of 3.2 mg/kg/day or 130 mg/m2/day for four days 
either in four divided doses (0.8 mg/kg) or once daily (3.2 mg/kg or 130 mg/m2).  Target dosing 
through pharmacokinetic assays for busulfan intravenous administration is not required under the 
protocol.  Patients < 100% of ideal body weight will be dosed according to actual body weight.  
Patients > 100% of ideal body weight will be dosed according to their adjusted ideal body 
weight.  If adjusted body weight is greater than the actual weight, then actual weight should be 
used.  Formulas are available in §2.5.3. 
 
2.5.3.2.Cyclophosphamide administration 
 
Cyclophosphamide (Cy) will be administered on Day -3 and Day -2 at a dose of 60 mg/kg per 
day IV.  Doses ≥ 5,000 mg must be infused IV over 2 hours.  Lower doses may be administered 
over one hour.  Patients < 100% of ideal body weight will be dosed according to actual body 
weight.  Patients > 100% of ideal body weight will be dosed according to their adjusted ideal 
body weight.  If adjusted body weight is greater than the actual weight, then actual weight should 
be used.  Formulas are available in §2.5.3. 
 
2.5.3.3.Fludarabine administration 
 
Fludarabine will be administered intravenously at a minimum total dose of 120 mg/m2 divided 
into three or more daily doses according to institutional practices.  Since patients with creatinine 
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be performed.  Patients < 100% of ideal body weight will be dosed according to actual body 
weight.  Patients > 100% of ideal body weight will be dosed according to their adjusted ideal 
body weight.  If adjusted body weight is greater than the actual weight, then actual weight should 
be used.  Formulas are available in §2.5.3. 
 
2.5.3.4.Melphalan administration 
 
Melphalan will be infused once daily intravenously to a total dose not greater than 150 mg/m2. 
Dose of melphalan might be reduced to 100 mg/m2 at the discretion of the treating physician, in 
the setting of renal insufficiency or other co-morbidities.  Patients < 100% of ideal body weight 
will be dosed according to actual body weight.  Patients > 100% of ideal body weight will be 
dosed according to their adjusted ideal body weight.  If adjusted body weight is greater than the 
actual weight, then actual weight should be used.  Formulas are available in §2.5.3.  
 
2.5.3.5.Total body irradiation administration (TBI) 
 
Fractionated TBI will be administered according to institutional practice.  Radiation sources, 
dose rates, details of lung shielding, and sites receiving boost radiation will also be defined by 
the institution.  TBI may be delivered from either linear accelerator or Cobalt sources.   
 
2.5.4. Additional Drugs 
 
2.5.4.1.Allopurinol 
 
The use of allopurinol will be allowed according to institutional guidelines.  A common regimen 
employs allopurinol at the daily dose of 300 mg, beginning at least six hours before the start of 
conditioning and until the day before marrow or PBSC infusion. 
 
2.5.4.2.Antithymocyte globulin (ATG) 
 
The use of ATG (Thymoglobulin or ATGAM) is not part of the conditioning regimens studied in 
this clinical trial but is permitted. The dose and schedule of ATG will be administered according 
to institutional standards.  Plans for the use of ATG must be disclosed prior to randomization, 
and must be used irrespective of the outcome of the randomization.  The Physician Desk 
Reference’s manufacturer’s guidelines should be followed for administration of ATG. 
 
2.5.5. GVHD Prophylaxis Regimen 
 
Transplant centers are encouraged to utilize the recommended GVHD prophylaxis regimens 
listed in Table 2.5.5.  Alternative GVHD prophylaxis regimens are permitted as per standard 
institutional practice with the following stipulations: 
a) The regimen includes a calcineurin inhibitor that is continued for a minimum of 6 months 
(therapeutic blood levels for a minimum of 4 months) 
b) Ex-vivo T-cell depletion is not performed 
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d) Investigational GVHD prophylaxis regimens may be allowed if co-enrollment with BMT 
CTN 0901 is approved by the protocol chairs.  
Recommendations for the administration of the GVHD agents are listed in Sections 2.5.5.1, 
2.5.5.2, and Table 2.5.5. 
 
 
Table 2.5.5 RECOMMENDED GVHD PROPHYLAXIS REGIMENS 
 
Tacrolimus 
▪ 
Blood trough levels 5-15ng/mL 
▪ 
Continue for minimum 6 months (taper may begin 4 
months post transplantation 
Methotrexate  
▪ 
10-15 mg/m2 Day 1 
▪ 
5-10 mg/m2 Day 3, 6 and 11 
Tacrolimus 
▪ 
Blood trough levels 5-15ng/mL 
▪ 
Continue for minimum 6 months (taper may begin 4 
months post transplantation 
Methotrexate  
▪ 
10 mg/m2 Day 1 
▪ 
5-10 mg/m2 Day 3, 6 and 11 
Other regimens may include: 
▪ 
Cyclosporine/Methotrexate  
▪ 
Tacrolimus/Sirolimus1 
▪ 
Cyclosporine/Mycophenolate Mofetil 
▪ 
Any other combination of agents that meet the criteria 
outlined in section 2.5.5. 
1Sirolimus given with myeloablative doses of busulfan is associated with increased 
risk of hepatic veno-occlusive disease. 
 
2.5.5.1.Tacrolimus  
 
Tacrolimus for GVHD prophylaxis is administered beginning at least one day before 
transplantation for a minimum of six months.  The initial dose should be based on the ideal body 
weight of the recipient to achieve an intravenous daily dose of 0.03 mg/kg/day.  Subsequent 
doses are targeted to achieve whole blood levels between 5 and 15 ng/mL.  When a patient is 
switched from intravenous to oral tacrolimus, the dose is increased by 3-4 fold to adjust for the 
lower bioavailability of oral compared to intravenous tacrolimus.  Determinations of blood levels 
should be performed at least once weekly for the initial three months.  Dose reductions should be 
made if toxicity is present or whole blood levels are above the recommended range, in the 
absence of toxicity.  Dose reductions for high levels without toxicity should be conservative, e.g. 
25%, to avoid inadequate immunosuppression. 
 


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If there is nausea and vomiting, the drug should be given intravenously.  Patients with severe 
intolerance of tacrolimus may be placed on cyclosporine. 
 
 
Drugs that may affect tacrolimus levels are: 
1. Caspofungin, phenobarbital, phenytoin, rifampin, carbamazepine, rifabutin, St. John’s 
Wort (lowers levels); 
2. Glucocorticoids, fluconazole, voriconazole, ketoconazole, itraconazole, grapefruit juice, 
amprenavir, bromocriptine, chloramphenicol, cimetidine, cisapride, clarithromycin, 
clotrimazole, danazol, diltiazem, erythromycin, ethinyl estradiol, metoclopramide, 
metronidazole, 
mibefradil, 
nefazodone, 
nelfinavir, 
nifedipine, 
omeprazole, 
quinupristin/dalfopristin, ritonavir, saquinavir, theophylline, troleandomycin, verapamil 
(increases levels). 
For patients who are taking both tacrolimus and sirolimus it is recommended that serum trough 
levels of tacrolimus do not exceed 10 ng/mL. 
 
Per the tacrolimus package insert, when initiating therapy with voriconazole in patients already 
receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to one-third of the 
original dose and followed with frequent monitoring of the tacrolimus blood levels.  Increased 
tacrolimus levels have been associated with nephrotoxicity.  When voriconazole is discontinued, 
tacrolimus levels should be carefully monitored and the dose increased as necessary.  
 
2.5.5.2.Methotrexate 
 
The regimen of methotrexate for GVHD prophylaxis will employ intravenous doses of 10 or 
15 mg per m2 on Day 1 post-transplant, and 10 or 5 mg/m2 on Day 3, 6, and 11 post-transplant 
according to institutional standards.  Third space syndromes with large accumulation of ascites 
or pleural effusions are a contraindication to the use of methotrexate.  Dose reductions should be 
made for renal, hepatic and mucosal toxicity.  Determinations of blood levels are indicated 24-72 
hours after administration in patients with impaired renal function.  Leucovorin rescue should be 
considered in patients with decreased clearance, severe toxicity or fluid accumulation/effusions. 
 
Drugs that may increase methotrexate levels are: 
1. Non-steroidal anti inflammatory drugs 
2. Penicillins 
3. Diuretics 
 
2.5.6. Hematopoietic Graft Collection 
 
Bone marrow and mobilized peripheral blood progenitor cells are the graft sources in this study. 
The graft source collection depends on donor preference and institutional practices. Umbilical 
cord blood units are not a permitted graft source, per protocol. 
 


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2.5.6.1.Peripheral Blood Progenitor Cells (PBPC) Mobilization and Collection 
 
PBPC mobilization and collection will be done according to institutional guidelines.  It is 
recommended the following mobilization and collection: 
- 
Donors will receive G-CSF (filgrastim) at a dose of 10 mcg/kg/day subcutaneously for 5 
consecutive days.  Daily dose will not exceed 1200 mcg/day, and volume per injection 
site will not exceed 2.0 mL.  G-CSF should be administered at approximately the same 
time each day.  The fifth dose will be given at least one hour prior to apheresis.   
- 
Apheresis will begin on Day 5 of G-CSF administration. The recommended method for 
apheresis is through a continuous-flow apheresis device and ideally bilateral peripheral 
venous access. Donors with insufficient peripheral access will undergo placement of a 
central venous catheter.   
 
Target CD34 cell dose is 5 x 106 per kg recipient body weight.   
 
2.5.6.2.Bone marrow collection 
 
It is recommended bone marrow donors undergo harvest on Day 0.  The protocol officer and 
protocol chairs should be consulted regarding the use of cryopreserved bone marrow.  Either 
general or regional (epidural, spinal) anesthesia may be used.  The bone marrow cell dose 
recommended is approximately 4 x 108 nucleated cells per kg of recipient body weight.  This 
dose will be unattainable for many recipients because of donor and/or recipient factors, e.g., 
body size mismatches.  The volume of marrow shall not exceed 20 mL per kg donor weight.  The 
estimated cell dose and a planned donor marrow volume shall be agreed upon by the donor and 
transplant centers for unrelated donors and between the transplant physician and cell processing 
laboratory for related donors before initiation of the transplant conditioning regimen.   
 
Bone marrow processing, other than anticoagulation, filtration, packaging, and labeling in 
preparation for transportation, should not be performed by the collection center.  Processing of 
bone marrow for reduction of volume, plasma, red blood cells, or fat, should be performed by the 
transplant center according to institutional guidelines. 
 
The transportation of bone marrow from unrelated donors shall be done in accordance with 
institutional guidelines.  
 
2.5.7. PBPC and Marrow Infusion 
 
PBPC or BM grafts will be infused through an appropriate central catheter, according to 
institutional guidelines at Day 0.  For recipients of related donor PBPC, whose donors require a 
third day of collection (Day +1), these cells will be infused separately from the Day –1 and Day 
0 collections on Day +1.   
 


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2.6. 
Supportive Care 
 
All supportive care will be given in keeping with BMT CTN MOP and local institutional 
practice. 
 
2.6.1. Growth Factors 
 
It is recommended that patients not receive post-transplant growth factors before Day 21, except 
in the case of serious infection where hastening neutrophil recovery by 1-3 days may be critical 
for survival.  After Day 21, G-CSF or granulocyte-macrophage colony stimulating factor (GM-
CSF) should be given for severe neutropenia (ANC < 500/µL), or as necessary to keep ANC 
> 1000/µL. 
 
2.6.2. Blood Products 
 
Transfusion thresholds for blood product support will be consistent with BMT CTN MOP and 
standard institutional guidelines.  All cellular blood products will be irradiated.  Patients who are 
CMV negative will receive CMV negative or filtered blood products from study entry. 
 
2.6.3. Prophylaxis Against Infections 
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the 
peritransplant period according to the BMT CTN MOP and institutional practices.   
 
Routine CMV antigenemia/viral load testing by hybrid capture or PCR based methods per 
institutional guidelines (with preemptive ganciclovir or valganciclovir therapy in patients who 
develop a positive assay, as per institutional guidelines).  CMV testing is recommended weekly 
through at least Day +100 post transplant. 
 
2.6.4. Intravenous Immune Globulin (IVIG) 
 
IVIG administration will be left to local institutional standard practice. 
 
2.6.5. Failure to Engraft 
 
If the ANC has not reached 500/µL by Day 21, G-CSF, GM-CSF or other cytokines may be 
utilized.  If the ANC is < 100/µL on Day 28 post-transplant, the patient should be considered for 
a second infusion of stem cells from the original donor or retransplantation from a different 
donor using appropriate institutional guidelines.   
 
2.6.6. ABO Incompatibility 
 
All patients with ABO incompatibility should be evaluated and treated per standard practice at 
the individual centers.  Recommended approach is detailed in the BMT CTN MOP. 
 


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2.6.7. Anti-seizure Prophylaxis 
 
Phenytoin or levetiracetam (Keppra) should be used with busulfan in accordance with standard 
practice at individual centers.  
 
2.6.8. Antiemetics  
 
Anti-emetics should be administered in accordance with institutional guidelines.  
 
2.6.9. Post-transplant Donor Leukocyte Infusions (DLI) 
 
DLI may be given to patients for a recurrent or a second malignancy according to institutional 
practice, if the donor is available and provides consent. The protocol officer and protocol chairs 
should be consulted regarding the use of DLI for recurrent disease, loss of chimerism and 
secondary malignancy.  The use of planned DLI therapy is NOT permitted per protocol.   
 
2.7. 
Risks and Toxicities 
 
2.7.1. Busulfan 
 
Since its FDA approval in 1999, IV busulfan has been used increasingly in combination with 
cyclophosphamide or fludarabine.17, 18, 19, 20  IV busulfan was initially administered every 6-
hours, similar to oral busulfan.  However, several studies have used the drug with once or twice 
daily administration.  In terms of safety, IV busulfan and oral busulfan appear to have similar 
toxicity profiles.  It has been proposed that sinusoidal obstruction syndrome and mucositis may 
be reduced in incidence and severity with IV busulfan.21  The IV formulation at a dose of 0.8 
mg/kg IV every 6-hrs is considered equivalent to the oral formulation at a dose of 1 mg/kg PO 
every 6 hrs in conditioning regimens.  On this basis a regimen using 4x0.8 = 3.2 mg/kg as a 
single daily dose has been developed.19, 22  
 
Pharmacokinetic parameters have been determined for different schedules of IV Bu, including a 
standard four times daily for a total of 16 doses, as with oral busulfan, and two dosing schedules 
of once or twice daily for four days.  The inter-patient variability in the clearance of IV busulfan 
is similar to that of oral busulfan.  After oral busulfan (given every 6 hours), pharmacokinetic 
sampling at 7 time points over 6-hours after dose 1, and 5 blood samples after doses 5 and 9 
allows a target Css to be achieved reliably.  In a limited number of patients (N=10), a low intra-
patient variability was present in the clearance of IV busulfan dosed every 24 hours with 
fludarabine (106.8 ± 16.7 mL/min/m2 after dose 1 vs. 106.9 ± 21.6 mL/min/m2 after dose 4).1519  
Thus, less frequent blood sampling may be possible with IV busulfan in that: (i) more predictable 
pharmacokinetics after IV administration should permit for fewer samples per Css determination, 
and (ii) less intra-patient variability may lead to fewer Css determinations per patient.  In this 
protocol, we will obtain pharmacokinetic samples after a single busulfan dose in patients at 
participating centers and compare overall exposure to treatment outcomes, such as toxicity, 
treatment-related mortality, and disease relapse (see Appendix C). 
 


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Toxicities associated with busulfan administration include: 
a.) Gastrointestinal: nausea, vomiting, constipation, diarrhea, abdominal discomfort, 
anorexia, dyspepsia and mucositis. 
b.) Hepatobiliary: busulfan is associated with the development of hepatic veno-occlusive 
disease. Pharmacokinetic dose targeting and intravenous formulation decrease the risk of 
this complication. Co-administration of sirolimus as GVHD prophylaxis has been shown 
to accentuate the risk for this complication.  
c.) Neurologic: Busulfan decreases the seizure and concomitant use of prophylactic use of 
anti-seizure medication successfully reduces the risk of this complication. Other 
neurologic side effects related to Bu include headache and insomnia. 
d.) Cardiovascular: Bu is associated with hypertension, hypotension and tachycardia.   
e.) Other toxicities: 
- 
Rhinorrhea 
- 
Hypermagnesemia, hyperglycemia and hyperphosphatemia 
- 
Amenorrhea 
- 
Infertility 
- 
Skin rashes 
- 
Cataracts 
- 
Dyspnea 
- 
Lung fibrosis 
 
2.7.2. Cyclophosphamide  
 
Cyclophosphamide is frequently used as a cytotoxic agent.  Cyclophosphamide is converted to 
its active form in vivo by hepatic enzymes.  After a single dose, tissue enzymes degrade most of 
the active metabolites.  After high doses (> 40 mg/kg), the alkylating activity in the plasma is 
minimal by 24 hours.  Several of the metabolites appear to have toxic actions.  One of the 
metabolic products, acrolein (CH2=CH-CHO), is known to be toxic to the bladder urothelium 
and can cause hemorrhagic cystitis when Cy is administered at high doses.  
• 
Fluid Retention: Cyclophosphamide can cause an antidiuretic effect with development of 
inappropriate ADH secretion. 
• 
Cardiomyopathy: within 0-10 days after high-dose cyclophosphamide a clinical 
syndrome of severe CHF has been observed (usually in patients given doses of 200 
mg/kg), Characterized by cardiomegaly, pericardial effusions, diffuse voltage decrease on 
ECG and decreased LVEF. Mortality is >50%. There are nine retrospective studies of 
post-HCT cardiomyopathy published in 1976-2001. In the four studies with >100 
patients, incidence was 0.4 – 4%.  
• 
Hemorrhagic Cystitis: Cyclophosphamide can cause hemorrhagic cystitis. To prevent the 
development of hemorrhagic cystitis, patients are kept well hydrated, and mesna therapy 


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or bladder irrigation is used per institutional guidelines. The recommended prophylaxis 
is mesna therapy unless contraindicated clinically, e.g., bladder outlet obstruction as in 
prostatic hypertrophy. 
• 
Nausea/Vomiting/Anorexia. 
• 
Other Toxicities: 
- Myelosuppression 
- Gonadal function impairment 
- Alopecia 
- Rare pulmonary toxicity 
 
2.7.3. Fludarabine 
 
Fludarabine can lower the white blood cell count, in particular the CD4+ T-cells.  The 
immunosuppression observed with the use of fludarabine increases the risk of infection, which 
can be life threatening.  Hematopoietic suppression and immunosuppression are expected to 
occur as a direct effect of the antimetabolite.  The most serious toxicity of fludarabine is 
neurological, and may consist of both peripheral neuropathy and encephalopathy.  Toxicity can 
be manifested by fatigue, weakness, paresthesias, visual disturbances, somnolence and coma, 
that usually develop between 30 and 60 days from therapy.  The incidence of serious 
neurological toxicity has been 36% in patients treated with > 96 mg/m2 per day for 5-7 days,40 a 
dose > 3 times higher than used in this protocol.  Other adverse effects include fever, nausea, 
vomiting, diarrhea, stomatitis, skin rash, cough and idiopathic pneumonitis. 
 
2.7.4. Melphalan 
 
High-dose melphalan is well tolerated by patients when they are supported with blood 
component transfusions, PBSC/marrow transplantation and broad-spectrum antibiotics.  The 
duration of profound bone marrow suppression decreases with the use of PBSC infusion and 
colony stimulating factors.  Gastrointestinal toxicity, which includes severe stomatitis, 
esophagitis and diarrhea, can be severe or life-threatening.  Most patients receiving high-dose 
melphalan will require parental narcotics for mucositis-related pain, IV hydration; may require 
IV alimentation and broad spectrum IV antibiotics.  Despite moderate to severe symptoms in 
many patients, recovery is the norm, coincident with recovery of granulocytes.  Other toxicities 
reported include pulmonary fibrosis and interstitial pneumonitis, skin hypersensitivity, vasculitis, 
alopecia, hemolytic anemia, and allergic reactions. 
 
See the FDA-approved package insert for a comprehensive list of adverse events. 
 
2.7.5. Total Body Irradiation 
 
TBI given in myeloablative doses can be given with or without lung shielding according to 
institutional guidelines.  The toxicities associated with irradiation include marrow suppression, 
gastrointestinal mucosal toxicity, fever, nausea, vomiting, diarrhea, parotiditis, reversible skin 
pigmentation, alopecia among others.  Dosimetry calculations are performed by the radiation 


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physicist.  Late effects may include cataract formation, growth retardation, pulmonary damage, 
carcinogenesis, and sterilization. 
2.8. Quality of Life Assessments 
2.8.1. Instruments 
 
FACT-BMT: The Functional Assessment of Cancer Therapy – Bone Marrow Transplant 
subscale41 version 4.0 instrument is a 37 item scale comprised of a general core questionnaire, 
the FACT-G, that evaluates the health-related quality of life (HQL) of patients receiving 
treatment for cancer, and a specific module, BMT Concerns, that addresses disease and 
treatment-related questions specific to bone marrow transplant.  The FACT-G consists of four 
subscales developed and normed in cancer patients:  Physical Well-being, Social/Family Well-
being, Emotional Well-being, and Functional Well-being.  Each subscale is positively scored, 
with higher scores indicating better functioning.  The FACT-BMT Trial Outcome Index, 
comprised of the physical well being scale, the functional well being scale and the BMT specific 
items, will be used as the outcome measure in summarizing the FACT-BMT data.  The FACT-
BMT takes 6 minutes to complete, and is being collected in BMT CTN 0201 and 0801.  
 
MOS SF-36: The Medical Outcomes Study Short Form 36 is a 36 item general assessment of 
health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, 
General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health 
Index.  Each domain is positively scored, indicating that higher scores are associated with 
positive outcome.  This scale has been widely applied in a variety of outcome studies and is 
being used in this protocol as a generic measure of quality of life.  To facilitate comparison of 
the results with published norms, the Physical Component Summary (PCS) and Mental 
Component Summary (MCS) will be used as the outcome measures in summarizing the SF-36 
data. These summary scores are derived by multiplying the z-score for each scale by its 
respective physical or mental factor score coefficient and summing the products.  Resulting 
scores are then transformed into T-scores (mean=50; standard deviation=10). The SF-36 takes 6 
minutes to complete, and is being collected in BMT CTN 0801.42, 43 
 
MDASI: The MD Anderson Symptom Inventory is a 19 item instrument that captures 13 
symptoms (0=“not present” to 10=“as bad as you can imagine”) and 6 items measuring 
interference with life from 0 (“did not interfere”) to 10 (“interfered completely”). It provides two 
summary scales: symptoms and interference. 44  The MDASI takes less than 5 minutes to 
complete, and is current being collected in BMT CTN 0802 trial of acute GVHD treatment.  
 
Global QOL: Four standard questions will assess patient self-assessed Karnofsky performance 
status, overall health and overall quality of life, (excellent, very good, good, fair, poor) and a 
rating scale for overall quality of life (where 0 equals death and 100 equals perfect quality of 
life).  In addition, the presence and severity of chronic GVHD will be assessed (mild, moderate, 
severe).  These questions take 1 minute to complete and are being collected in BMT CTN 0201 
and 0801. 
 


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Occupational functioning: Occupational functioning will be measured using 6 items that assess 
current job status, type of work (will be captured using Hollingshead categories), number of 
hours of paid and unpaid work, school, importance of work and change in work goals. The same 
scale has been used in NHLBI-sponsored HCT studies and BMT CTN protocol 0201 
(randomized peripheral blood vs. marrow for unrelated transplantation). 
 
EQ-5D: The EQ-5D will collect data that may be used to calculate patient-reported utilities for 
cost-utility analyses. The EQ-5D contains a five item survey with three response levels per item 
measuring mobility, self-care, usual activities, pain/discomfort and anxiety/depression.  The EQ-
5D takes approximately 1 minute to complete (Agency for Healthcare Research and Quality, 
2005). 
 
2.8.2 
Administration 
 
The self report questionnaires will be completed prior to transplantation and subsequently at 100 
days, 12 months, and 18 months from randomization or until death.  Only English speaking 
patients are eligible to participate in the HQL component of this trial.  Surveys are completed by 
participants using self-completed instruments as a first choice.  If this method of data collection 
is not possible, then surveys and response options may be read verbatim to participants, either in 
person or over the phone, to collect data.  The method of survey completion, the date, and the 
language will be recorded in the database.  Surveys may not be completed by surrogates. 
 
 
Table 2.8. – Required Patient-Reported Outcomes Data Collection 
 
Instrument 
N 
items 
Pre 
100 
days 
12 and 
18 mos 
Socio-demographics 
8 
X 
 
 
Global quality of life 
4 
X 
X 
X 
FACT-BMT 
37 
X 
X 
X 
MOS SF-36 
36 
X 
X 
X 
MDASI 
19 
X 
X 
X 
Occupational functioning 
6 
X 
X 
X 
Chronic GVHD 
2 
 
 
X 
EQ-5D 
5 
X 
X 
X 
Alternative contacts 
2 
X 
 
X 
 
 
 
 
 
TOTAL N ITEMS 
 
117 
107 
111 
ANTICIPATED TIME 
 
30 min 
25 min 
30 min 
 


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3-1 
CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS AND DEFINITION 
 
3.1. 
High Risk Disease 
 
Patients enrolled in this trial will be identified as high or standard risk disease.  High-risk AML 
is defined according to cytogenetic and certain molecular abnormalities identified prior to 
transplantation.  Poor-risk cytogenetics according to the ECOG/SWOG cytogenetic classification 
will be considered high-risk AML (Appendix E).  Additionally, patients with FLT-3 internal 
tandem duplication mutation, regardless of cytogenetic abnormalities and patients in CR ≥ 3 will 
be considered high risk for disease.  High-risk MDS is defined as patients with intermediate-II or 
high International Prognostic Scoring System (IPSS) (Appendix D).    
 
3.2. 
Disease Status and Disease Response Assessment 
 
Assessment after transplantation response will be assessment as follows: 
 
Complete Remission: 
• 
Bone Marrow Myeloblasts < 5% by morphologic assessment; 
• 
No circulating leukemic myeloblasts; 
• 
Neutrophil count  ≥ 1,000/µL; 
• 
Absence of previous cytogenetic or molecular abnormality identified prior to 
transplantation in the bone marrow aspirate.  
 
Disease Relapse for Patients with AML: 
• 
Increase in bone marrow blast to ≥ 5% by morphologic assessment not attributed to other 
causes (e.g., bone marrow regeneration); or if < 5%, reappearance of blasts with the same 
leukemia phenotype as present at diagnosis.  
• 
Reappearance of blasts with aberrant phenotype by Flow Cytometry. 
• 
Reappearance of leukemic blasts in the peripheral blood. 
• 
Reappearance of previous cytogenetic or molecular marker of disease present prior to 
transplantation.  
• 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid. 
• 
Institution of any therapy to treat relapsed disease, including withdrawal of 
immunosuppressive therapy or DLI, will be considered evidence of relapse regardless of 
whether the criteria described above are met. 
 
 


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Disease Relapse for patients with MDS: 
• 
Satisfying above criteria for evolution into acute leukemia; or, 
• 
Reappearance of pre-transplant morphologic abnormalities, detected in two 
consecutive bone marrow specimens taken at least one month apart; or,  
• 
Reappearance of pre-transplant cytogenetic abnormality in at least one metaphase 
on each of two separate consecutive examinations at least one month apart, 
regardless of the number of metaphases analyzed. 
• 
Institution of any therapy to treat relapsed disease, including withdrawal of 
immunosuppressive therapy or DLI, will be considered evidence of relapse 
regardless of whether the criteria described above are met. 
 
3.3. 
Primary Endpoint 
 
3.3.1. Overall Survival  
 
The primary endpoint is to compare the 18 month overall survival probabilities between 
treatment arms.  Patients are considered a failure of the primary endpoint if they die from any 
cause.  The time to this event is the time from randomization to death, loss to follow up or end of 
study whichever comes first.  
 
3.4. 
Secondary Endpoints  
 
3.4.1. Overall Survival (OS) 
 
OS probabilities will be compared between treatment arms, adjusting for disease risk (defined in 
Section 3.1), donor type, and significantly imbalanced covariates.  Patients are considered a 
failure of this endpoint if they die from any cause.  The time to this event is the time from 
randomization to death, loss to follow up or end of study whichever comes first.   
 
3.4.2. Disease-Free Survival (DFS)  
 
DFS at different time points will be included as a secondary endpoint.  Patients are considered a 
failure of this endpoint if they die or suffer from disease relapse.  The time to this event is the 
time from randomization to relapse, death, initiation of non-protocol AML or MDS therapy, loss 
to follow up or end of study whichever comes first. 
 
3.4.3. Treatment-related Mortality (TRM)  
 
TRM is defined as death occurring in a patient from causes other than disease relapse.  
Individuals who relapse are censored for the event of TRM.  
 


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3.4.4. Neutrophil and Platelet Engraftment 
 
The kinetics of post-transplant recovery of both neutrophil and platelet engraftment post 
transplantation and compared between treatment arms.  Neutrophil engraftment is defined as 
achieving an absolute neutrophil count (ANC) > 500 µL for three consecutive measurements on 
different days.  The first of the three days will be designated the day of neutrophil engraftment.   
 
ANC = Total WBC x (%Neutrophils + %Bands) 
 
Platelet engraftment is defined as a platelet count > 20,000/µL for three consecutive 
measurements over three or more days without requiring platelet transfusions.  The first of the 
three days will be designated the day of platelet engraftment.  Subjects must not have had 
platelet transfusions during the preceding 7 days.  The time to a platelet count > 50,000/µL will 
be collected as well.  This endpoint will be evaluated through 100 days.   
 
3.4.5. Donor Cell Engraftment 
 
The kinetics and extent of donor cell engraftment will be assessed by donor/recipient chimerism 
studies.  Bone marrow is the preferred source for chimerism analysis, which will be performed, 
at minimum, on Day 28, 100 and 18 months post transplantation (Table4.3). 
 
Additionally donor cell engraftment will be assessed by donor recipient chimerism studies.  For 
the purposes of this protocol, mixed chimerism will be defined as the presence of donor cells, as 
a proportion of the total population of < 95% in the peripheral blood or bone marrow.  Full 
donor chimerism is defined as > 95% donor cells.  Mixed or full donor chimerism will be 
evidence of donor engraftment.  For the purposes of this protocol, graft rejection is defined as 
the inability to detect or loss of detection of greater than 5% donor cells as a proportion of the 
total population. 
 
3.4.6. Acute GVHD of Grades II-IV and III-IV 
 
Acute GVHD is graded according to the BMT CTN MOP.  The first day of acute GVHD onset at 
a certain grade will be used to calculate cumulative incidence curves for that GVHD grade (e.g., 
if the onset of grade I acute GVHD is on Day 19 post-transplant and onset of grade III is on Day 
70 post-transplant, time to grade III is Day 70).  This endpoint will be evaluated through 100 
days and compared between treatment arms. 
 
3.4.7. Chronic GVHD (cGVHD) 
 
Chronic GVHD is scored according to the BMT CTN MOP.  The first day of cGVHD onset will 
be used to calculate cumulative incidence curves.  Rates and severity of cGVHD will be 
compared between treatment arms. 
 


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3.4.8. Incidence of Primary Graft Failure 
 
This is defined by lack of neutrophil engraftment by 28 days.  Rates of primary graft failure will 
be compared between treatment arms. 
 
3.4.9. Incidence of Secondary Graft Failure 
 
This is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil 
counts < 500/µL unresponsive to growth factor therapy.  Rates of secondary graft failure will be 
compared between treatment arms.  
 
3.4.10. Incidence of Toxicities Grade  3  
 
All Grade  3 toxicities will be tabulated by grade for each treatment arm, by type of toxicity as 
well as the peak grade overall.  Toxicity frequencies will be described for each time interval as 
well as cumulative over time.   
 
3.4.11. Incidence of Infections 
 
The number of infections and the number of patients experiencing infections will be tabulated by 
type of infection, severity, and time period after transplant.  The cumulative incidence of severe, 
life-threatening, or fatal infections will be compared between the two treatment arms at 6, 12, 
and 18 months from transplant or until death.  
 
3.4.12. Immune Reconstitution 
 
Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19 and CD56 positive 
lymphocytes will be done through flow cytometric analysis at baseline, 100 days, 12 months and 
18 months post transplantation.  Results will be tabulated according to time from transplant.   
 
3.4.13. Quality of Life 
 
The instruments will be scored according to the recommendations of the developers.  See Section 
2.8.1 for detailed descriptions of the instruments.  The FACT-BMT instrument will be 
summarized by the Trial Outcome Index, comprised of the physical, functional and BMT-
specific items.  The MOS SF-36 will be summarized by the Physical Component Summary 
(PCS) and Mental Component Summary (MCS).  The MDASI will be summarized by the 
interference and symptoms scores.  The EQ-5D utility score will be calculated. 
 
HQL will be described and compared between the two treatment arms over time.  The self report 
questionnaires will be completed prior to transplantation and subsequently at 100 days, 12, and 
18 months from randomization or until death.  Only English speaking patients are eligible to 
participate in the HQL component of this trial. 
 
 


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4-1 
CHAPTER 4 
 
 
4. 
TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PATIENT IDENTIFICATION 
CONFIRM ELIGIBILITY 
PATIENT CONSENT 
COMPLETION OF PATIENT SURVEYS 
CENTER DESIGNATES A 
MYELOABLATIVE AND A REDUCED 
INTENSITY REGIMEN TABLE 2.5), A 
GVHD PROPHYLAXIS REGIMEN (TABLE 
2.5.5) AND A STEM CELL SOURCE 
ENDPOINT ASSESSMENT 
18 MO OVERALL SURVIVAL 
18 MO DISEASE-FREE SURVIVAL 
RANDOMIZATION 


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4.1. 
Patient Enrollment and Evaluation 
 
4.2. 
Enrollment Procedures 
 
4.2.1. Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCSM).  The following procedures should be followed: 
1.  Within the 14 days prior to initiation of the conditioning regimen, an authorized user at 
the transplant center enters the patient demographics and completes the Segment 0 
Enrollment Form in AdvantageEDC.  The Segment 0 form includes a question 
confirming that the patient (or legally authorized representative) signed the informed 
consent.  The patient will be assigned a study number at this time.  Additionally, Segment 
0 requires completion of the Regimen Intensity HLA-typing form (patient and donor) to 
confirm that the HLA-typing meets protocol criteria.  Upon successful completion of the 
two Segment 0 forms, the authorized user will proceed to Segment A and complete the 
Segment A enrollment form in which the chosen RIC and MAC regimens, the GVHD 
prophylaxis regimen and graft source will be indicated.  In addition, the transplant center 
must commit to using or not using anti-thymocyte globulin irrespective of the treatment 
assignment. 
2. If the patient is eligible, a treatment assignment is displayed upon completion of the 
Segment A Enrollment Form.  The user should make a copy of this form to keep in the 
patient record. 
3. A visit schedule based on treatment start date is displayed for printing and is referred to 
as ‘Segment A Follow-up.’ 
 
4.3. Study Monitoring 
 
4.3.1. Follow-up Schedule 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.3.1.  A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide. 
 
 
TABLE 4.3.1:  FOLLOW-UP SCHEDULE 
 
Study Visit 
Target Day Post-Transplant 
1 week 
7  2 days 
2 week 
14  2 days 
3 week 
21  2 days 
4 week 
28  2 days 
5 week 
35  2 days 
6 week 
42  2 days 


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Study Visit 
Target Day Post-Transplant 
7 week 
49  2 days 
8 week 
56  2 days 
9 week 
63  2 days 
10 week 
70  2 days 
11 week 
77  2 days 
12 week 
84  2 days 
100 day 
100 14 days 
6 month 
180  28 days 
12 month 
365  28 days 
18 month 
540  28 days 
 
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook and User’s Guide.  Forms that are not entered into 
AdvantageEDC within the specified time will be considered delinquent.  A missing form will 
continue to be requested either until the form is entered into the AdvantageEDC and integrated 
into the Data Coordinating Center’s (DCC) master database, or until an exception is granted and 
entered into the Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Reporting Patient Deaths: Recipient death information must be entered into AdvantageEDC 
within 24 hours of knowledge of the patient’s death.  If the cause of death is unknown at that 
time, it need not be recorded at that time.  However, once the cause of death is determined, the 
form must be updated in AdvantageEDC. 
 
CIBMTR Data Reporting: Centers participating in BMT CTN trials must register pre and post-
transplant outcomes on all consecutive hematopoietic stem cell transplants done at their 
institution during their time of participation to the Center for International Blood and Marrow 
Transplant Research (CIBMTR).  Registration is done using procedures and forms of the Stem 
Cell Transplant Outcomes Database (SCTOD).  (Note: Federal legislation requires submission of 
these forms for all US allotransplant recipients.)  Enrollment of BMT CTN #0901 must be 
indicated on the SCTOD pre-transplant registration form, if applicable.  Additionally, CIBMTR 
pre- and post- transplant Report Forms must also be submitted for all patients enrolled on this 
trial.  CIBMTR forms will be submitted directly to the CIBMTR at the times specified on the 
Form Submission Schedule. 
 
Weekly GVHD Monitoring:  GVHD should be monitored in accordance with BMT CTN 
guidelines as specified in the Manual of Procedures.  Patients should be assessed weekly until 
Day 100 post-transplant for GVHD.  Patients will also be assessed at each follow-up visit (6, 12 
and 18 months) for the presence of GVHD.   
 
4.3.2. Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of 


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knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business days 
of knowledge of the event.  Expected AEs will be reported using NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form 
Submission Schedule. 
 
4.3.3. Patient Assessments 
 
Table 4.3 summarizes patient clinical assessments over the course of the study. 
 
4.3.3.1.Pre-transplant evaluations 
 
The following observations are considered standard evaluations for transplant eligibility and 
should be performed ≤ 4 weeks of enrollment. 
1. History, physical examination, height and weight. 
2. HCT-specific comorbidity index (Appendix G). 
3. Karnofsky performance score (Appendix F). 
4. CBC with differential and platelet count, serum creatinine, bilirubin, alkaline 
phosphatase, ALT, and AST. 
5. CMV antibody test, hepatitis panel (HepA Ab, HepB Sab, HepB Sag, HepB Core Ab, 
HepC Ab), herpes simplex, syphilis, HIV and HTLV1 I/II antibody, and varicella zoster 
virus. 
6. Cerebral spinal fluid assessment (for patients with prior leukemia CNS involvement). 
7. For sibling donors, HLA typing at HLA–A and –B (intermediate or higher resolution) 
and –DRB1 (at high resolution using DNA-based typing). For related donors other than a 
sibling, HLA–A, –B, –C (at intermediate or higher resolution) and –DRB1 (at high 
resolution using DNA-based typing)..  For unrelated donors, HLA typing at HLA-A, -B, -
C, and –DRB1 at high resolution using DNA-based typing if not already performed.  
8. Left ventricular ejection fraction or shortening fraction (preferably ≤ 4 weeks from 
enrollment and must not be more than 8 weeks prior to enrollment). 
9. DLCO and FEV1 (preferably ≤ 4 weeks from enrollment and must not be more than 8 
weeks prior to enrollment). 
10. Bone marrow biopsy and/or aspirate for pathology, flow cytometry (if available) and 
cytogenetics and analysis of peripheral blood.  These assessments must also occur ≤ 30 
days from initiation of conditioning for patients with AML or high grade MDS (≥ 5% 
myeloblasts at any time) and ≤ 50 days from initiation of conditioning for patients with 
low grade MDS (bone marrow myeloblasts never ≥ 5%); otherwise, must be repeated. 
11. β-HCG serum pregnancy test for females of childbearing potential. 
12. Chest x-ray. 
13. Blood for pre-transplant chimerism assay. 


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14. Blood samples for evaluation of immune reconstitution by flow cytometry (CD3, CD4, 
CD8, CD19, and CD56+).   
15. Optional blood sample for future research to be shipped to the Repository. 
16. Health Quality of Life Instruments to be completed by English speaking patients. 
 
4.3.3.2.Post-transplant evaluations 
 
The following evaluations are considered standard evaluations for transplant recipients: 
1. History and physical exam to assess GVHD and other morbidity weekly until Day 100 
post-transplant, then at six months, one year and 18 months post-transplant. GVHD 
evaluation and grading to be in keeping with BMT CTN MOP. 
2. CBC at least three times a week from Day 0 until ANC > 500 µL for 3 days after nadir 
reached.  Thereafter CBC twice per week until Day 28, then weekly until 12 weeks, then 
six months, one year and 18 months post-transplant. 
3. CBC with differential and platelet count, serum creatinine, bilirubin, alkaline 
phosphatase, ALT, and AST twice a week until Day 28 (or four weeks) and then weekly 
until 12 weeks, and then at six months, one year and 18 months post-transplant. 
4.  Blood quantitative assessment of CD3, CD4, CD8, CD19 and CD56 positive cells at Day 
100, 12 months and 18 months. 
5. Blood or bone marrow aspirate sample for post-transplant T-cell and myeloid chimerism 
assay collected at Day 28, 100, and 18 months.  Whole bone marrow chimerism is an 
acceptable alternative if lineage-specific chimerism analysis is not available.  Peripheral 
blood chimerism can be substituted for bone marrow chimerism if bone marrow sample 
is not available. 
6. Bone marrow biopsy and/or aspirate at Day 100 ± 30 days, and 18 months ± 30 days.  All 
follow-up studies should include relevant cytogenetic or molecular testing to assess for 
residual disease. 
7. Toxicity assessments at Day 28, 56, 100, 6 months and 12 months.  
8. Busulfan pharmacokinetics at 6-7 time points after the first dose of Bu for patients 
receiving busulfan only at centers participating in this ancillary study (see Appendix C). 
9. Health Quality of Life Instruments to be completed by English speaking patients at 100 
days, 12 months, and 18 months post-transplant. 
 
  


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TABLE 4.3.:  SUMMARY OF PATIENT CLINICAL ASSESSMENTS 
 
 
 
 
DAYS POST-TRANSPLANT 
Study Assessments/Testing* 
Baseline 
Day 7 
Day 
14 
Day 
21 
Day 
28 
Day 
35 
Day 
42 
Day 
49 
Day 
56 
Day 
63 
Day 
70 
Day 
77 
Day 
84 
Day 
91 
Day 
100 
6 
mo 
12 
mo 
18 
mo 
History, physical exam, height, 
weight1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCT-specific comorbidity index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Karnofsky performance score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC2, differential, platelet count, and 
blood chemistries3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CSF4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 LVEF or shortening fraction 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO and FEV1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow biopsy and/or aspirate 
for pathology, flow cytometry and 
relevant cytogenetics and molecular 
studies 5,6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ß-HCG serum pregnancy test (females 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune reconstitution assays7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
GVHD and other morbidity 
assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessments 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
Blood or Bone Marrow for Myeloid 
and T-cell Chimerism8 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Health Quality of Life9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Optional blood sample for research10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for busulfan 
pharmacokinetics11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All evaluations are standard of care for treatment or transplantation of patients with AML and MDS.  Quality of life assessments are not considered standard of care. 
 


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4-1 
Table 4.3 Notes: 
1 Height is only required at baseline. 
2 CBC performed at least three times a week from Day 0 until ANC >500 µL for three days after nadir.  CBC performed twice weekly until Day 28. CBC performed weekly after Day 
28 until 12 weeks post-transplant. 
3 A standard chemistry panel to include: CBC with differential and platelet count, serum creatinine, bilirubin, alkaline phosphatase, ALT, and AST twice a week until Day 28 (or four 
weeks) and then weekly until 12 weeks post transplant, and then at six months, one year and 18 months post-transplant. 
4 CSF assessment for patients with prior leukemia CNS involvement only. 
5 Flow cytometry is optional if not available at the treatment center. 
6 Baseline bone marrow biopsy and/or aspirate to be performed ≤ 30 days of initiation of conditioning for patients with AML or high grade MDS (as defined in Section 4.3.3.1) and ≤ 
50 days of initiation of conditioning for patients with low grade MDS (as defined in Section 4.3.3.1); otherwise, it must be repeated.   
7 Quantitative assessment of peripheral blood CD3, CD4, CD8, CD19 and CD56 to be performed by local institutional or reference laboratory.  
8 Chimerism will be measured by RFLP or microsatellite on bone marrow aspirate sample.  Lineage-specific chimerism is highly preferred, but whole blood chimerism can be 
substituted if not available at treatment center.  Peripheral blood chimerism can be substituted for bone marrow chimerism if bone marrow sample not available.  
9 Only English speaking patients will complete the Health QOL assessments.   
10 Single blood sample to be shipped to the repository.   
11 Only in patients who receive Bu at centers participating in this ancillary study.  


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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Design and Objectives 
 
The study is designed as a Phase III, randomized, multicenter prospective comparative study of  
myeloablative (MAC) versus reduced intensity (RIC) conditioning regimens in allogeneic 
hematopoietic stem cell transplantation (HCT) for AML or MDS.  The premise is that reducing 
the intensity of the conditioning regimen will decrease treatment-related mortality without 
increasing relapse so that overall survival will be improved.  The target enrollment is 356 
patients, 178 for each arm. 
 
5.1.1. Accrual 
 
It is estimated that four years of accrual will be necessary to enroll the targeted sample size. 
 
5.1.2. Randomization 
 
Patients will be randomized at a ratio of 1:1 between the treatment arms using permuted blocks 
of random sizes.  Randomization will be stratified by center.  
 
5.1.3. Primary Endpoint 
 
The primary endpoint of this study is overall survival (OS) at 18 months post-randomization.  
The 18-month time point was chosen based on a retrospective analysis of data from the Center 
for International Blood and Marrow Transplant Research (CIBMTR) where more than 80% of 
events had occurred by this time.  The primary analysis will be performed using the intention-to-
treat principle so that all randomized patients will be included in the analysis.  Death from any 
cause will be considered events for this endpoint. 
 
5.2. 
Sample Size and Power Calculations 
 
The primary analysis will be done using a group sequential comparison of the 18 month survival 
probabilities using the difference in Kaplan-Meier estimates (see Gu et al. 45); sequential 
monitoring is described further in section 5.3.  Since with no censoring prior to 18 months, the 
18 month survival probabilities reduce to simple binomial proportions, we approximated the 
sample size calculations  based on a group sequential  analysis  using a two-sample Z test of 
binomial proportions. The final patient enrolled will be followed up for a minimum of 18 
months.  We anticipate minimal (<3%) censoring for survival prior to 18 months, because the 
primary endpoint involves survival rather than a disease assessment and because transplant 
centers are required to report survival data on all allogeneic transplant recipients to the CIBMTR 
as part of the Stem Cell Therapeutic Outcomes Database (SCTOD).  A pointwise comparison of 
survival at 18 months is proposed for the primary analysis rather than a log-rank test because of 


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the potential for crossing hazards; the logrank test would have poor power to detect a difference 
between these two groups if the hazards cross.   
 
The sample size is 356, 178 per treatment arm.  Assuming 3% loss to follow-up 18 months post 
randomization, complete survival information would be available for 346 patients.  Even with 
3% loss to follow-up, the targeted sample size of 356 is sufficient to maintain Type I error of 5% 
across all planned interim analyses while providing 80% power for a two-sided test to detect an 
increase in OS at 18 months from 45% in the MAC arm to 60% in the RIC arm.  This sample 
size provides sufficient power to detect a 15% increase in OS at 18 months between treatment 
arms for various true survival probabilities in the MAC arm as shown in Table 5.2.1, even with 
3% loss to follow-up.   
 
TABLE 5.2.1 POWER TO DETECT 15% INCREASE IN OS PROBABILITY IN THE 
RIC ARM FOR VARIOUS SURVIVAL PROBABILITIES IN THE MAC ARM,  
AS A FUNCTION OF THE PROPORTION OF PATIENTS LOST TO  
FOLLOW-UP BY 18 MONTHS 
 
 
Power 
True 18-month OS probability in the 
MAC arm 
0% loss to fu 
3% loss to fu 
.25 
86 
85 
.35 
81 
80 
.45 
81 
80 
.55 
83 
82 
.65 
89 
88 
 
5.3. 
Interim Analysis and Stopping Guidelines 
 
We recommend no interim analyses for futility because the investigators are also interested in 
using the lower bound of the confidence interval for the survival difference at 18 months to learn 
about the magnitude of the survival difference.  Stopping early for futility would result in 
substantially wider confidence intervals, leading to greater uncertainty about the magnitude of 
the survival difference when it is not likely to be as large as targeted.   
 
Interim analysis for efficacy will be conducted at times coincident with regularly scheduled 
meetings of the NHLBI-appointed Data and Safety Monitoring Board (DSMB) at approximately 
one year intervals.  Policies and composition of the DSMB are described in the BMT CTN’s 
Manual of Procedures.  The stopping guidelines serve as a trigger for consultation with the 
DSMB for additional review and are not formal “stopping rules” that would mandate automatic 
closure of study enrollment.  Toxicity, adverse events, and other safety endpoints will be 
monitored regularly and reported to the DSMB at each interim analysis. 
 


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5.3.1. Interim Analysis for Efficacy 
 
Analyses will be performed as described below for the primary endpoint. At the time of each 
interim analysis, a two-sided test to detect either an increase or decrease in the proportion of 
patients surviving will be performed.  The test statistics will be based on the Kaplan-Meier 
proportions, which have independent increments as described in Gu et al45.  All patients 
randomized prior to the time of the interim analyses will be used to compute the Kaplan-Meier 
estimate of overall survival at 18 months.  If the test statistic exceeds the critical value, the 
DSMB will discuss the continuation of the trial. 
 
In order the preserve the overall Type I error rate at 5%, the critical value for the test statistic will 
be inflated above 1.96, the value that would be used if no repeated testing were used.  
Equivalently, the nominal p-value at which an observed difference is declared significant will be 
reduced below 0.05.  The actual critical values and nominal p-values will be computed using 
statistical methods for group sequential testing with O’Brien Fleming boundaries.  Information is 
defined as the reciprocal of the variance of the difference in Kaplan-Meier estimates between the 
two treatments.  The final information at the end of the study reduces to the reciprocal of the 
variance of the difference in two binomial proportions, assuming no censoring prior to 18 
months, computed as 365.13.  Then the information fraction is the ratio of the information at an 
interim analysis to the final information at the end of the study.  
 
As an example, Table 5.3.1 shows the critical values and nominal p-values for tests conducted 
after four equally spaced information increments, starting when 25% of the information is 
accrued.  Table 5.3.1 shows the critical values and cumulative Type I error at each analysis along 
with the power to reject the null hypothesis by each look.  The power at each look is the 
probability of stopping to reject the null hypothesis at that look if the true increase in OS at 18 
months is 15% in the RIC arm compared to the MAC arm.  In particular, there is 55% power to 
detect a 15% improvement in 18-month survival by the third look and there is 80% power to 
detect the same improvement by the final look. 
   
TABLE 5.3.1 CRITICAL VALUES AND OPERATING CHARACTERISTICS 
Information 
Fraction 
Critical Value 
Nominal 
Type I 
Error 
Cumulative 
Type I 
Error 
Cumulative Probability 
of Stopping under Ha 
0.25 
4.049 
0.0000 
0.0000 
0.0043 
0.50 
2.863 
0.0042 
0.0042 
0.1956 
0.75 
2.337 
0.0167 
0.0209 
0.5521 
1.00 
2.024 
0.0291 
0.0500 
0.8000 
 
To permit necessary flexibility in scheduling interim analyses, the critical values will be 
recomputed to correspond to the actual available statistical information using the “use-function” 
approach of Lan and DeMets. 
 


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5.3.2. Guidelines for Safety Monitoring 
 
There will be no pre-specified stopping guidelines for safety monitoring for two reasons.  First, 
the toxicity and mortality profiles are expected to be somewhat different, with lower early 
transplant-related mortality (TRM) in the RIC arm accompanied by possibly higher late relapse 
risk.  We feel that long-term follow-up using the primary endpoint of 18 month overall survival 
is the best way to assess and compare these treatments.  If the trial were stopped early due to 
excessive early treatment-related mortality, this would limit our ability to assess the crucial 
tradeoff between relapse and TRM for these conditioning regimens.  Second, myeloablative and 
reduced intensity conditioning regimens are common procedures in HCT, and the specific 
regimens included in each of these groups are the ones used most frequently in practice.  The 
toxicities associated with each type of conditioning regimen are well established and not likely to 
be different in this study.  However, even though we are not including pre-specified stopping 
guidelines, toxicity, adverse events, and other safety endpoints will be monitored regularly and 
reported to the DSMB at each interim analysis. 
 
5.4. 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, Karnofsky/Lansky performance status, HCT-
comorbidity index, disease, disease status at transplant, time from diagnosis to transplantation, 
cytogenetic at diagnosis, AML risk stratification (Section 3.1), IPSS (Appendix D), HLA 
matching, conditioning regimen, use of ATG, GVHD prophylaxis, graft source, donor type, 
donor age, donor/recipient gender match, donor recipient CMV status.  Between groups 
comparisons will be performed for continuous variables via a Kruskal-Wallis test and for 
categorical variables, via the chi-square test.  Demographic and baseline characteristics which 
are statistically different between treatment arms will be adjusted for in secondary analysis for all 
outcome comparisons.   
 
5.5. 
Analysis Plan 
 
5.5.1. Analysis of the Primary Endpoint 
 
The primary outcome of the trial is overall survival at 18 months after randomization.  The 
primary null hypothesis of the study is that there is no difference in overall survival between the 
treatment arms at 18 months post transplantation.  In the primary analysis, the intention-to-treat 
principle will be used.  The primary analysis will be performed using the difference in Kaplan-
Meier estimates for overall survival at 18 months.  A 95% confidence interval for the difference 
in OS at 18 months will also be constructed.  In addition to a point-wise comparison at 18 
months, Kaplan-Meier curves will also be constructed and confidence bands for the difference 
between treatments will be generated to compare the survival probabilities.  
 
 


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5.5.2. Analysis of Secondary Endpoints 
 
5.5.2.1.Overall Survival (OS) at 18 months (adjusted comparison) 
 
In this analysis, the 18-month OS probabilities will be compared using the adjusted OS 
probabilities proposed by Zhang et al.46  The adjusted survival probabilities are estimated using 
the Cox proportional hazards model stratified by treatment.  Disease risk, donor type and all 
demographic and baseline characteristic shown to be significantly different between treatment 
arms will be included in the Cox model to adjust for potential imbalances. 
 
5.5.2.2.Disease-free survival 
 
The event is relapse or death.  The time to this event is the time from randomization to relapse, 
death, initiation of non-protocol AML or MDS therapy, loss to follow up or end of study 
whichever comes first.  Disease-free survival curves will be estimated using Kaplan-Meier 
estimator.  Kaplan Meier estimates of DFS at 18 months will be compared between treatment 
arms.  In addition to a pointwise comparison at 18 months, confidence bands for the difference 
between treatments will be generated to compare the entire DFS curves.  A secondary analysis of 
DFS will be performed by comparing the adjusted DFS probabilities at 18 months using the 
same method described in 5.5.2.1.  
 
5.5.2.3.Treatment-related mortality (TRM) 
 
The event is death occurring from causes other than relapse.  Incidence of TRM will be 
estimated using cumulative incidence function, treating relapse as a competing risk.  Incidence of 
TRM will be compared between the treatment arms using Gray’s test48.  In a secondary analysis, 
TRM will be compared between arms using a Cox proportional hazards model with treatment as 
the main effect.  Disease risk, donor type and baseline characteristics which are significantly 
different between arms will be included as covariates in the Cox model to adjust for potential 
imbalances.  The proportional hazards assumption will be checked for all covariates.  If there are 
indications of differential effects over time, the final model will be stratified by factors with non-
proportionality. 
 
5.5.2.4.Relapse 
 
Incidence of relapse will be estimated using cumulative incidence function, treating death in 
remission as a competing risk.  Incidence of relapse will be compared between the treatment 
arms using Gray’s test48.  In a secondary analysis, relapse rates will be compared using a Cox 
proportional hazards model with treatment as the main effect.  Disease risk, donor type and 
significantly imbalanced characteristics will be adjusted for as described in 5.5.2.4.  
 
5.5.2.5.Neutrophil and Platelet Engraftment 
 
Incidence of neutrophil and platelet engraftment will be estimated using the cumulative 
incidence function with death prior to engraftment as the competing risk.  Incidence of 
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compared between the treatment arms using a pointwise comparison of the cumulative incidence 
probabilities.  
 
5.5.2.6.Donor cell engraftment 
 
Donor chimerism at 100 days and 18 months will be described in each treatment arm, according 
to proportions with full (>95%), mixed (5-95% donor cells), graft rejection (<5%), or death prior 
to assessment of donor chimerism.  These proportions will be compared between the two groups 
at each time point using the chi-square test. 
 
5.5.2.7.Acute GVHD of Grades II-IV and III-IV 
 
Cumulative incidence of acute GVHD will be estimated using the cumulative incidence function, 
treating death prior to aGVHD as the competing risk.  Cumulative incidence of aGVHD will be 
compared between treatment arms using Gray’s test.4  
 
5.5.2.8.Chronic GVHD (cGVHD)  
 
Cumulative incidence of cGVHD will be estimated using the cumulative incidence function, 
treating death prior to aGVHD as the competing risk.  Cumulative incidence of cGVHD will be 
compared between treatment arms using Gray’s test.48 
 
5.5.2.9.Incidence of Primary Graft Failure  
 
The proportions of patients alive at Day 28 but with primary graft failure will be described and 
compared between the treatment arms using the chi-square test or Fisher’s exact test as 
appropriate.   
 
5.5.2.10. 
Incidence of Secondary Graft Failure 
 
The cumulative incidence of secondary graft failure out of those who had initial engraftment will 
be described using the cumulative incidence estimator, treating death prior to secondary graft 
failure as a competing event.  
 
5.5.2.11. 
Incidence of Toxicities Grade  3  
 
All Grade  3 toxicities will be tabulated by grade for each treatment arm, by type of toxicity as 
well as the peak grade overall.  Toxicity frequencies will be described for each time interval as 
well as cumulative over time.   
 
The cumulative incidence of Grade  3 toxicity will be compared between treatment arms at 1, 3, 
6, 12, and 18 months.  
 


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5.5.2.12. 
Incidence of Infections 
 
The number of infections and the number of patients experiencing infections will be tabulated by 
type of infection, severity, and time period after transplant.  The cumulative incidence of severe, 
life-threatening, or fatal infections, treating death as a competing event, will be compared 
between the two treatment arms at 6, 12, and 18 months. 
 
5.5.2.13. 
Immune Reconstitution 
 
Quantitative assessment of peripheral blood CD3, CD4, CD8, CD19 and CD56 by flow 
cytometric analysis will be tabulated by time period after transplant.  The concentration of 
lymphocyte subsets will be compared between treatment arms at 100 days, 12 and 18 months 
from transplant using a nonparametric Mann-Whitney test.  To account for potential imbalances 
caused by differences in survival probabilities, the concentration of lymphocyte subsets for 
patients who died prior to the assessment period will be assigned as zero. 
 
5.5.2.14. 
Quality of Life 
 
QOL will be described and compared between all treatment arms utilizing the FACT-BMT Trial 
Outcome Index, the MOS-SF36 Physical Component Score (PCS) and Mental Component Score 
(MCS), the MDASI interference and symptom subscales, the EQ-5D utility score, and the 
categorical components of the occupational functioning, global quality of life, and chronic 
GVHD self reported scales.  The questionnaires will be scored according to standard procedures.  
The self report questionnaires will be completed prior to transplantation and subsequently at 100 
days, 12 months, and 18 months from randomization or until death.  Only English speaking 
patients are eligible to participate in the HQL component of this trial.  
 
Differences in quality of life will be assessed in several ways.  For the descriptive analysis, only 
QOL scores for survivors at specific time points will be compared between treatment arms using 
simple T-tests.  In the primary analysis, linear mixed models will be used to assess differences in 
QOL scores over time and to explore covariates associated with QOL in survivors.  Additional 
secondary analysis to account for differences in survival rates between treatment groups will be 
performed using the Integrated Quality Adjusted Survival49.  The Integrated Quality Adjusted 
Survival approach aggregates QOL over the entire period of observation.  Finally, if missing data 
occur for survivors, mechanism and patterns of missing data will be analyzed.  In addition, the 
joint mixed-effects model for informatively censored longitudinal data developed by 
Schluchter50 will be explored to identify clinical events associated with changes in QOL 
overtime. 
 


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APPENDIX A 
 
WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATIONS 
 


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APPENDIX A 
 
WORLD HEALTH ORGANIZATION CLASSIFICATIONS 
 
 
WHO CLASSIFICATION OF ACUTE MYELOID LEUKEMIA 
 
Acute myeloid leukemia with recurrent genetic abnormalities  
• 
Acute myeloid leukemia with t(8;21)(q22;q22), (AML1/ETO)  
• 
Acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16)(p13q22) or 
t(16;16)(p13;q22), (CBF /MYH11)  
• 
Acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RAR ) and variants  
• 
Acute myeloid leukemia with 11q23 (MLL) abnormalities  
Acute myeloid leukemia with multilineage dysplasia  
• 
Following MDS or MDS/MPD  
• 
Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 
or more myeloid lineages  
Acute myeloid leukemia and myelodysplastic syndromes, therapy related  
• 
Alkylating agent/radiation-related type  
• 
Topoisomerase II inhibitor-related type (some may be lymphoid)  
• 
Others  
Acute myeloid leukemia, not otherwise categorized  
• 
Acute myeloid leukemia, minimally differentiated  
• 
Acute myeloid leukemia without maturation  
• 
Acute myeloid leukemia with maturation  
• 
Acute myelomonocytic leukemia  
• 
Acute monoblastic/acute monocytic leukemia  
• 
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)  
• 
Acute megakaryoblastic leukemia  
• 
Acute basophilic leukemia  
• 
Acute panmyelosis with myelofibrosis  
• 
Myeloid sarcoma 
 
 
 


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WHO CLASSIFICATION AND CRITERIA FOR THE MYELODYSPLASTIC 
SYNDROMES 
 
 
 
 
 


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APPENDIX B 
 
PATIENT INFORMED CONSENTS 
 
 


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Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
 
Your Name:   
__________________________________________________ 
 
Study: 
BMT CTN 0901: A Randomized, Multi-Center, Phase III Study of 
Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in 
Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia 
 
Co-Investigator: 
Bart Scott, MD 
 
 
 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North, D1-100 
Seattle, WA 98109-1023 
Phone: (206) 667-1990 
 
Co-Investigator: 
Mitchell Horwitz, MD 
 
 
 
Duke University 
2400 Pratt Street, DUMC 3961 
Durham, NC 27710 
Phone: (919) 668-1045 
 
Transplant Center 
Investigator:  
__________________________________________________ 
 
Sponsor: 
The National Institutes of Health (NIH) gave financial support for this research 
study through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). 


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Introduction 
We are inviting you to join a research study.  The main goals of the study are to:  
▪ Compare two kinds of treatments used to destroy diseased cells and prepare your body 
for transplant.  This process is also called a conditioning regimen. 
▪ Measure how well your disease (acute myeloid leukemia or myelodysplastic syndrome) 
responds to the treatment.  
Combinations of chemotherapy and sometimes radiation are used as a treatment to destroy 
cancer cells and help donor cells start to grow in your bone marrow.  Depending on the 
combination used, each treatment (or conditioning regimen) can have a different intensity or 
strength.  
▪ High intensity treatment uses high doses of chemotherapy or radiation.  
▪ Reduced intensity treatment uses lower doses of chemotherapy or radiation.  
Both kinds of treatments are used by stem cell transplant doctors around the world and are not 
experimental.  Our goal is to see if one kind of treatment is better than the other for people who 
have a stem cell transplant to treat either their acute myeloid leukemia (AML) or 
myelodysplastic syndromes (MDS). 
If you volunteer to join this study, we will randomly assign you to receive either a high intensity 
or a reduced intensity treatment before you receive the stem cells from your donor.   
We believe this study will last about 18 months for most patients who decide to join.  About 356 
patients will take part in the study at transplant centers around the United States.  We will 
explain the two different treatments in this consent form.  Every participating clinic will report 
their results, so we can compare and share the results at the end of the study. 
This consent form tells you about the study, its possible risks and benefits, other options 
available to you, and your rights as a participant in the study.  Please take your time to make 
your decision.  
Everyone who takes part in research at [insert facility name] should know that: 
▪ Being in any research study is voluntary. 
▪ You may or may not benefit from being in the study.  Knowledge we gain from this study 
may benefit others. 
▪ If you join the study, you can quit the study at any time.   
▪ If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 


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▪ Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 
▪ You can ask questions now or any time during the study. 
▪ Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends.  It is your decision to be in the study.  If you decide to take part, 
please sign and date the end of the Consent Form. 
You and your doctor will discuss other treatment choices if you do not want to participate 
in this study. 
 
Background 
This research study is sponsored by The National Institutes of Health (NIH) through the Blood 
and Marrow Transplant Clinical Trials Network (BMT CTN).   
Conditioning Regimen 
The conditioning regimen is a combination of chemotherapy and/or radiation given to patients 
before the donor cells are infused.  This treatment allows donor cells to engraft and start growing 
in your bone marrow.  The treatment also helps to kill cancer cells that might not be detectable.  
Different chemotherapy drugs can be used as part of the conditioning regimen.  Some common 
combinations of chemotherapy drugs used for transplant are: 
▪ Busulfan + cyclophosphamide or fludarabine 
▪ Fludarabine + melphalan 
▪ Radiation + cyclophosphamide  
Each combination of chemotherapy drugs or radiation has a different strength.  This strength can 
also be described as the treatment “intensity.” 
Stem cell transplant destroys cancer in two ways.  
▪ The treatment (or conditioning regimen) destroys cancer cells. 
▪ The immune cells from the donor can recognize cancer cells and kill them.  
High intensity treatments are also known as myeloablative conditioning (MAC) regimens.  These 
treatments work well to destroy cancer cells because they use very high amounts of 
chemotherapy or radiation.  High intensity treatments can also have more side effects during and 
after transplant.  
Using a lower or “reduced” intensity treatment before transplant can have fewer serious 
problems from the chemotherapy drugs.  While the cancer killing effects may also be lower, 


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studies show that immune cells given during the transplant can help destroy remaining cancer 
cells.  Transplants with reduced intensity conditioning (RIC) regimens are often used for people 
who cannot have high doses of chemotherapy drugs or radiation because of their age or other 
medical problems.  
This study will compare high intensity and reduced intensity treatments used to destroy cancer 
cells and prepare bone marrow for transplant.  Our goal is to see if one kind of treatment is better 
than the other for people who have a stem cell transplant to treat either their AML or MDS. 
Purpose 
You are invited to join this research study because you have AML or MDS and are currently 
being evaluated for an allogeneic transplant.  The main goal of this study is to see if patients with 
AML or MDS have better results with transplants using reduced intensity treatment compared to 
high intensity treatment. 
 
Right to ask Questions and/or Withdraw 
You have the right to ask questions about the study at any time.  If you have questions about 
your rights as a participant or you want to leave the study, please contact [insert contact info]. 
Being in this study is voluntary.  You can choose to not be in this study, or leave this study at 
any time.   
If you choose to not take part or to leave this study, your regular medical care will not be 
affected in any way.  The conditioning regimen of your transplant will be the standard of care.  If 
you decide to leave this study after taking the study treatment, or are asked to leave by your 
doctor for medical reasons, you will be asked to come back to the doctor’s office for tests for 
your safety and as part of your routine medical care.   
▪ Even if you withdraw from the study, the information collected from your participation will 
be included in the study evaluation, unless you specifically ask that it not be included. 
▪ Your study doctor and study staff will be available to answer any questions that you may 
have about your participation in, or your withdrawal from this study. 
Procedures 
Before you join the study, we will evaluate your general health, medical history, and your current 
medications. 


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Study Participation 
You will need to go to clinic at least once before the study begins.  Your participation in the 
study starts after your sign this consent form.  After your transplant you will have weekly 
evaluations for the first 3 months of this study.  After 3 months, you will have an evaluation at 6, 
12 and 18 months after your transplant.  
These evaluations will be done if you are in the hospital ward or clinic, or if your disease 
becomes active again after the transplant.  
 
Before You Start Your Treatment 
You will have at least one clinic visit before you begin the study.  This visit will collect 
information about your: 
▪ 
Physical health (including history, height, weight and temperature); 
▪ 
Heart, lung and kidney function; 
▪ 
Chest x-ray; 
▪ 
Bone marrow biopsy and aspirate; 
▪ 
Routine blood tests, including cell counts, liver and kidney function; 
▪ 
Routine markers of infectious diseases, including hepatitis, herpes, HIV, syphilis, 
varicella zoster (shingles) among others; 
▪ 
Pregnancy test (if it applies to you); 
▪ 
HLA typing for you and your donor; and, 
▪ 
Health quality of life for English speaking patients (see below). 
 
Randomization 
We selected five different treatment options based on the ones that are most often used by 
transplant centers.  The treatment options are listed in Table 1.  
Your doctor will choose one reduced intensity treatment (A or B in the table below) and one high 
intensity treatment (C, D or E in the table below) to use for this study.  These are often the most 
commonly used at [insert Institution name].  A computer program will then assign you by chance 
to either the reduced intensity or the high intensity treatment option.  
You will have an equal chance of being placed in either group.  This means that half of the 
people in the study will be in the reduced intensity group and half will be in the high intensity 
group. 


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TABLE 1: TREATMENT OPTIONS (CONDITIONING REGIMENS) 
Reduced Intensity Treatments  
 
High Intensity Treatments 
A 
Fludarabine + Busulfan (Flu/Bu) 
 
C 
Busulfan  + Fludarabine (Bu/Flu) 
B 
Fludarabine + Melphalan (Flu/Mel) 
 
D 
Busulfan + Cyclophosphamide (Bu/Cy) 
 
 
 
E 
Cyclophosphamide + Total Body 
Irradiation (Cy/TBI) 
 
Study Evaluations 
We will measure your health at specific times during your study participation.  These tests and 
how often they are scheduled are standard for what we do for all patients receiving an allogeneic 
transplant.  We would do them even if you were not part of this study. 
▪ History, physical exam and weight: weekly for 3 months, 6, 12 and 18 months. 
▪ Routine blood tests, including cell counts, liver and kidney function: weekly for 3 
months, 6, 12 and 18 months.  
▪ Bone marrow biopsy and/or aspirate: at Day 100 and 18 months. 
▪ Graft-versus-host disease (GVHD) and infections monitoring: weekly for 3 months, 6, 
12 and 18 months. 
▪ Side effects or toxicity: monthly for the first 3 months, then at 6, 12 and 18 months. 
▪ Blood or bone marrow tests to find out the proportion of donor cells present in the 
recipient (chimerism) at 1, 3 and 18 months.  
▪ Blood samples to determine the level of busulfan in your blood after the first dose (if you 
received busulfan as part of your treatment) only if your transplant center is participating 
in the ancillary study. 
▪ Health quality of life for English speaking patients (see below) at 3, 12 and 18 months. 
 
⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ 
Blood Samples for Busulfan Pharmacokinetics 
 
Some transplant centers may be participating in this ancillary study. 
 
Researchers are trying to learn more about how your body breaks down one of the drugs 
(busulfan) given as part of the conditioning regimen in this study.  Samples for this test will be 
collected from you only if you receive this drug and your transplant center is participating in this 
ancillary study.  These tests measure how much busulfan is concentrated in the blood.  Busulfan 


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levels are already done routinely in some settings in order to avoid too high levels.  Every patient 
can have different levels of this drug after receiving the same dose of busulfan.  
 
The goal of this study is to see if these levels can be tied to the success of the transplant.  
This study will explore the levels of busulfan in these two treatment intensities and compare with 
what happens after transplant.   
 
This study will collect up to seven blood samples within 6 to 8 hours after a dose of busulfan was 
given to you.  Each blood sample volume is 3 mL (1/2 teaspoon).  Once all seven blood samples 
are collected from you, they will be sent to a laboratory for testing.  None of your personal 
information will be shared with the laboratory. 
 
The busulfan blood tests are part of this clinical trial at select centers, but your center may repeat 
these tests as part of the routine transplant procedure. If this happens, your doctor will either 
collect 6 mL (1 teaspoon) each time as described above, or collect 3 mL for the research tests on 
another day that busulfan is given. 
 
⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ 
 
Health Quality of Life 
We will ask you about your general health and how well you feel while you participate in this 
study.  Even though different treatments may treat a disease equally well, there might be a 
difference in how patients feel or the side effects they have after their treatment.  This is 
important information for when we evaluate the treatments in this study. 
We will collect information by using surveys.  The surveys will ask about: 
▪ 
How you feel 
▪ 
What symptoms you might have and how they affect you 
▪ 
How well can you do regular daily activities 
 
You will need to fill out the surveys and each survey should take about 30 minutes to finish.  
Your answers will help us understand how your transplant treatment affects how you feel, what 
you can do, and your general quality of life.   
 
Other Treatment Choices 
It is your choice to join this study.  If you decide you do not want to participate, you may still 
receive a transplant for treatment of your disease.  It is possible that you may have a treatment 
and evaluations that are very similar to what would be if you joined this study.  
Your study doctor will discuss these choices with you.  If you decide you do not want to join this 
research study, your medical care will not be affected in any way. 
 


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Risks and Discomforts 
The risks and discomforts of stem cell transplant are the same if you join this study, or if you do 
not join this study.  The differences in side effects from medications are because of the different 
levels of treatment strength.  
High intensity treatments usually have more side effects early after transplant compared to 
reduced intensity treatments.  Other problems with transplant, such as graft-versus-host disease 
(GVHD) and infections happen equally in patients who have high intensity or reduced intensity 
treatments.  
Risks Related to Medications or Radiation Used in Conditioning Regimens  
All chemotherapy and radiation treatments used as conditioning in this study are commonly used 
in allogeneic stem cell transplantation.  The side effects can change based on the amount of drug 
given.  This is true for busulfan, which is used for reduced intensity and high intensity treatments 
but in different amounts.  
 


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TABLE 2 – ADVERSE EVENTS 
 
Cyclophosphamide 
Likely Side Effects 
(May happen in more 
than 20% of patients) 
Less Likely  
(May happen in less 
than 20% of patients) 
Rare  
(May happen in less 
than 2% of patients) 
 
Damage to male 
(testes) and female 
(ovaries) sex glands 
Diarrhea 
Fluid retention 
Hair loss 
Infertility 
Irregular or no 
menstrual cycles 
Loss of appetite  
Nausea, Vomiting 
Suppression of the 
immune system 
Bleeding in the bladder 
Inflammation of the 
heart muscle (heart 
failure) 
Shortness of breath 
 
Allergic reaction 
Lung fibrosis 
Serious skin rashes 
 
 
 
 
Fludarabine 
Likely Side Effects 
(May happen in more 
than 20% of patients) 
Less Likely  
(May happen in less 
than 20% of patients) 
Rare  
(May happen in less 
than 2% of patients) 
 
Diarrhea 
Mouth sores  
Nausea and vomiting 
Suppression of the 
immune system 
 
Fever 
Numbness in the 
extremities 
Sleepiness 
Visual changes 
Weakness 
 
Coma 
Cough 
Inflammation of the 
lung 
Interstitial Pneumonia 
Skin rash 
 


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TABLE 2 – ADVERSE EVENTS, continued 
 
Busulfan 
Likely Side Effects 
(May happen in more 
than 20% of patients) 
Less Likely  
(May happen in less 
than 20% of patients) 
Rare  
(May happen in less 
than 2% of patients) 
 
Abdominal discomfort 
Constipation 
Diarrhea 
Dizziness 
Fluid retention 
Headache 
Heartburn 
Insomnia 
Lack of appetite 
Mouth sores  
Nausea and vomiting 
Running nose 
Skin rashes 
Irregular or no 
menstrual cycles 
Tachycardia 
Cough 
Hepatic Veno-
occlusive disease  
High blood pressure 
High magnesium and 
phosphorus levels in 
the blood 
High sugar levels in 
the blood 
Infertility 
Low blood pressure 
Seizures 
Cataracts 
Lung fibrosis 
 
 
Melphalan 
Likely Side Effects 
(May happen in more 
than 20% of patients) 
Less Likely  
(May happen in less 
than 20% of patients) 
Rare  
(May happen in less 
than 2% of patients) 
 
Constipation 
Diarrhea 
Hair loss 
Mucositis 
Nausea and vomiting 
Heart rhythm 
abnormalities 
Hepatitis 
Kidney failure 
Allergic reaction 
Interstitial Pneumonia 
Seizure 
Lung fibrosis 
 
 
 
 


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Total Body Irradiation (TBI): 
 
Likely 
(“Likely” refers to a side effect 
that is expected to occur in more 
than 20% of patients.)  
Less Likely 
(“Less likely” refers to a side 
effect that is expected to occur in 
20% or fewer patients.) 
Rare, but Serious 
(These possible risks have been 
reported in rare occurrences, 
typically less than 2% of patients.  
They may be serious if they occur.) 
Diarrhea 
Nausea 
Stomach cramps 
Vomiting (throwing up) 
Painful swelling of the 
salivary glands under the ears 
for a few days 
Short-term hair loss 
Anemia 
Infection 
Bleeding 
Cataracts 
Sterility (inability to have 
children) 
Slow growth  
Hormone problems (such as 
thyroid disease or diabetes) 
Mouth sores 
Lung inflammation 
Pneumonia 
Redness of the skin 
Serious liver problems 
Risk of developing other cancers 
in the future  
Difficulty swallowing 
Back problems 
Kidney problems 
Learning problems 
 
 
 
Risks Related to the Medication Used to Help Prevent Graft-versus-Host Disease  
 
Graft-versus-Host Disease (GVHD) is a medical condition that can become serious enough to 
cause death.  GVHD is a common development after allogeneic stem cell transplant. It happens 
when the donor cells attack and damage your organ tissues after transplant.  GVHD can cause:  
▪ 
Skin rashes 
▪ 
Feeling sick to your stomach (nausea) 
▪ 
Throwing up (vomiting) 
▪ 
Abdominal pain 
▪ 
Diarrhea  
▪ 
Liver damage or jaundice (yellowing of the skin or eyes)   


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Your doctor will prescribe medication to prevent GVHD.  You will start GVHD prevention 
around the time you get your donor cells, and it can last many months after the transplant.  These 
medications do not completely prevent GVHD and more drugs might be needed to manage this 
complication.  
Your doctor will decide which GVHD prevention treatment is the best choice for you.  This 
decision is not part of the research study.  Your doctor will also decide your medications based 
on what is regularly used for transplant in this hospital or clinic.  Below is a list of commonly 
used drugs used to prevent GVHD.  Your doctor may choose to use other medications than what 
is listed here.  
▪ Tacrolimus:  This drug is used to try to prevent GVHD.  Early side effects you may have 
include: feeling sick to your stomach (nausea) or throwing up (vomiting) after you 
swallow.  Other side effects include high blood pressure (hypertension), shaking hands 
(tremor), increased hair growth and possibly how clearly you can think or make decisions 
(mental function).   
If you have these effects, they generally go away if your doctor lowers the amount of 
medication you take.  A few patients have had a seizure while on this medication.   
Your liver or kidneys might not work as well as they did before.  If this happens, your 
doctor may lower the amount of drug you take or stop giving the drug completely.  You 
might be more likely to have kidney problems if you need to take other medications at the 
same time.  This is especially true for drugs that we know might cause kidney problems, 
such as antibiotics.  Sometimes, the kidney damage caused is serious enough for you to 
need an artificial kidney machine (hemodialysis). 
Some patients given tacrolimus develop diabetes and must take insulin while taking 
tacrolimus. 
It is very important that you do not eat grapefruit or drink grapefruit juice.  
Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs, including tacrolimus, used in this study.  Common soft drinks that 
have bergamottin are Fresca, Squirt and Sunny Delight. 
▪ Methotrexate:  This is also a medication used to try to prevent GVHD.  Methotrexate 
causes damage to cells and can affect many different parts of your body.  It may cause 
mouth sores or mouth inflammation. Or if you already have these problems from your 
treatments and other medications, they can get worse.   
Methotrexate may slow down the recovery of blood cells after transplantation.  
Methotrexate can also cause kidney damage.  If your kidneys are already damaged for 


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other reasons, it can make your kidneys worse.  If kidney damage does happen, your 
doctor might give you a lower dose of methotrexate, or stop giving it completely. 
▪ Tacrolimus and Methotrexate:  These medications can affect your body’s immune 
system and make it easier for you to get infections.  Even simple infections can become 
very serious and even life-threatening.  As a result, you might have more infections for 
several months after transplant, especially viral infections and pneumonia. 
▪ Risks Related to the Transplant Procedure: The following risks are part of the 
transplant process and not connected to any one medication or the transplanted donor 
cells. 
- Bleeding: Platelets help your blood to clot.  When you have low amounts of 
platelets, you may have bleeding problems.  Once your new bone marrow starts to 
grow, your platelets will increase and your blood will start to clot normally again.  
Bleeding problems can range from minor bleeding, such as nosebleeds or 
bruising, to more serious bleeding in your brain and lungs.  Serious bleeding can 
be very dangerous and can happen if your platelet levels stay low.  Usually, we 
can prevent major bleeding problems with transfusions of platelets.  However, if 
your body does not respond well to transfused platelets, you may be at serious 
risk for bleeding.  
- Veno-occlusive Disease (VOD): High dose chemotherapy, radiation therapy and 
medications used to prevent GVHD can cause veno-occlusive disease (VOD).  
VOD causes severe damage to the liver.  Symptoms include jaundice (yellowing 
of the skin and eyes), weight gain, and extra fluid build-up in the belly (abdominal 
cavity) and other parts of the body.  We can usually manage veno-occlusive 
disease very well, to the point where it goes away.  However, complications can 
happen with VOD that may put your life in danger. 
- Mouth Sores and Diarrhea: The large doses of chemotherapy and radiation 
cause irritation in the lining of the mouth and intestines.  This can result in painful 
mouth sores and diarrhea.  If you have severe mouth sores, we will give you 
medicine to help control the pain.  If your mouth sores are very bad, you may not 
be able to eat normally until the sores are healed.  Mouth sores get better when 
your white blood count starts to rise, and your donor cells start to grow (also 
called engraftment). 
- Capillary Leak Syndrome: This can happen from your chemotherapy and 
radiation treatments.  The blood vessels may become ‘leaky’ and fluid enters your 
abdomen, lungs, and other tissues.  You may gain water weight and not go to the 
bathroom as often as you normally do.  Capillary leak syndrome can be difficult 


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to manage if extra fluid enters your lungs and makes it hard to breathe.  You may 
die if fluid continues to build up in your lungs.  
- Unexpected Organ Damage and Other Side Effects: You might have 
unexpected, life-threatening heart, lung, kidney, or liver damage as a result of 
your transplant.  High doses of chemotherapy and radiation can cause very bad 
lung damage that may not get better with time or medications.  If this happens, 
you may need to use oxygen or even a respirator.  The lung damage may get 
worse and be life-threatening.  Rarely, multiple organ failure (such as lung and 
kidney failure) can happen, which can lead to death. 
- Fluid Build-up: We will give you intravenous (IV) fluids during the transplant 
process and it can be hard for your body to eliminate this fluid.  We will also give 
you Furosemide, which is a medication that can help your body get rid of the 
extra fluid.  One risk of Furosamide is hearing loss.  Some side effects may be 
loss of body chemicals such as potassium and sodium. 
- Late Effects: You may have side effects happen a few months to many years 
after your transplant.   
• 
You may have problems with your thyroid gland that require you to take 
thyroid medication.   
• 
You may get cataracts earlier in life compared to a person who has not had 
a transplant.  If you develop cataracts (cloudiness in the eyes) they may 
need treatment.  
• 
Your kidneys could be affected and cause anemia (low red blood cell 
count) or high blood pressure.   
• 
You may develop a second cancer as a result of the chemotherapy, 
radiation and/or underlying disease.  If secondary cancers happen they 
generally do not develop until 10 to15 years after your transplant.   
• 
We do not know the long-term effects of transplant on your heart, lungs 
and brain. 
 
- Unforeseen Risks: New risks might appear at any time during the study that are 
different from the risks listed in this Consent Form. We will promptly tell you of 
any new information that may affect your decision to participate. 
 


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▪ Risk to the unborn: The treatments in this study have NOT been proven to be safe at 
any stage of pregnancy.  Therefore, if you are pregnant or nursing, you are not eligible 
for this study.  Women who have the potential of becoming pregnant must use some form 
of effective birth control while receiving chemotherapy, TBI, and GVHD prophylaxis.  
Effective birth control is defined as the following:  
• Refraining from all acts of vaginal intercourse (ABSTINENCE)  
• Consistent use of birth control pills 
• Injectable birth control methods (Depro-Provera, Norplant) 
• Tubal sterilization or male partner who has undergone a vasectomy 
• Placement of an IUD (intrauterine device) 
• Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or 
condoms with contraceptive foam. 
• Sterility and future childbearing potential for men and women.  Chemotherapy 
and/or irradiation may affect your ability to have children.  Male patients may 
become sterile (unable to produce sperm) and should discuss with their doctor 
regarding sperm banking prior to transplantation.  Female patients who have 
attained puberty may find that their menstrual cycle becomes irregular or stops 
permanently.  However, this DOES NOT MEAN THAT YOU CANNOT 
BECOME PREGNANT, and you must use some effective method of birth control 
during transplant and afterwards until you are off GVHD prophylaxis.  Damage to 
reproductive tissue may result in infertility (inability to have children).  It is not 
known if the damage could result in birth defects.  You should discuss these risks 
and options in detail with your doctor before entering this study. 
 
Possible Benefits 
 
Taking part in this study may or may not make your health better compared to receiving the 
transplant through your routine medical care.  We do know that the information from this study 
will help doctors learn more about selection of conditioning regimen intensities.  This 
information could help patients in the future who are in need of an allogeneic transplant.  
 
What if I change my mind? 
 
You can change your mind at any time about allowing us to use your samples and health 
information for research.  We ask that you contact [Principal Investigator] in writing and let 
him/her know you do not want us to use your research samples or health information for 
research.  His/her mailing address is on the first page of this form.   
If you withdraw yourself from this protocol, even if you allowed your samples to be used for 
research, your samples will not be used from that point and they will be discarded.  However, 


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samples and information that have already been shared with other researchers cannot be taken 
back or destroyed.  
 
New Information Available During the Study 
 
During this research study, new information about the study drug or the risks and benefits of the 
study may become known to the study doctors.  If this happens, they will tell you about the new 
information.   
 
The new information may mean that you can no longer participate in the study, or that you may not 
want to continue in the study.  If this happens, the study doctor will stop your participation in the 
study and you will be offered all available care to suit your needs and medical conditions. 
 
Privacy, Confidentiality and Use of Information 
 
Your confidentiality is one of our main concerns.  We will do our best to make sure that the 
personal information in your medical and research records remains confidential.  We will not 
discuss or publish information about your health with any unauthorized person or persons.  
However, we cannot guarantee total privacy.   
 
Your personal information may be given out if required by law.  If information from this study is 
published or presented at scientific meetings, your name and other personal information will not be 
used.  Your study number is not related to your name, social security number or medical record 
number at [insert facility name]. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
Information about your transplant from your original medical records may be seen or sent to 
national and international transplant registries, including:  
▪ The Center for International Blood and Marrow Transplant Research (CIBMTR) 
▪ The National Marrow Donor Program (NMDP) 
▪ The Food and Drug Administration (FDA) 
▪ The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
▪ Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN), and  
▪ Other authorized study organizations 
 
We will not identify you by name in any publications or reports that come from these organizations 
or groups. 
 


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Ending Your Participation 
 
The study doctor or the study sponsor may stop the study at any time, and you may be asked to 
leave the study.  We may ask you to leave the study if you do not follow directions or if you 
suffer from side effects of the treatment.   
 
The study sponsor may decide to end the study at any time.  If you are asked to leave the study, 
the reasons will be discussed with you. 
 
Possible reasons to end your participation in this study include: 
▪ You do not meet the study requirements.   
▪ You need a medical treatment not allowed in this study. 
▪ The study doctor decides that it would be harmful to you to stay in the study. 
▪ You are having serious side effects. 
▪ You become pregnant. 
▪ You cannot keep appointments or take study drugs as directed. 
▪ The study is stopped for any reason. 
 
Physical Injury as a Result of Participation 
 
It is important that you tell your study doctor or study staff if you feel that you have been hurt or 
injured because of taking part in this study.  You will get medical treatment if you are injured as a 
result of taking part in this study.  You and/or your health plan will be charged for this treatment.  
The study will not pay for this treatment. 
 
In case of injury resulting from this study, you do not lose any of your legal rights to seek payment 
by signing this form. 
 
Compensation or Payment 
 
You will not be paid for your participation in the research study.  You will not get compensation or 
reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation 
on this trial. 
 
Costs & Reimbursements 
 
Most of the visits for this research study are standard medical care for patients undergoing 
allogeneic transplants and will be billed to your insurance company.  You and/or your health 
plan/insurance company will need to pay for some or all of the costs of standard treatment in this 
study.   
 
You or your insurance will not be charged for the busulfan blood samples required for the study or 
the optional blood sample for research on this study. 


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Ethical Review 
 
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 
 
Further Information 
 
If you need any information about this study, or if you have any problems while you are 
participating in this study you can contact the study doctor or his/her staff.  They may be contacted 
at the telephone numbers listed below. 
[Insert name and contact details]. 
 
Independent Contact 
 
If you wish to speak to someone not directly involved in the study, or if you have any complaints 
about any aspect of the project, the way it is being conducted or any questions about your rights as a 
research participant, then you may contact  
 
[Insert appropriate contact details]. 
 
 
Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purposes 
 
A. Purpose:   
As a research participant, I authorize the Principal Investigators and the researcher’s staff to 
use and disclose my individual health information for the purpose of conducting the research 
study:  
A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation 
Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid 
Leukemia 
 
B. Individual Health Information to be Used or Disclosed:  
My individual health information that may be used or disclosed to do this research includes:  
▪ Demographic information (for example: date of birth, sex, weight).  
▪ Medical history (for example: diagnosis, complications with prior treatment). 
▪ Findings from physical exams. 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


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▪ Laboratory test results obtained at the time of work up and after transplant (for example: 
blood tests, biopsy results).  
 
C. Parties Who May Disclose My Individual Health Information:  
The researcher and the researcher’s staff may collect my individual health information from: 
[List hospitals, clinics or providers from which health care information can be requested]. 
 
D. Parties Who May Receive or Use My Individual Health Information:  
The individual health information disclosed by parties listed in item c and information 
disclosed by me during the course of the research may be received and used by the following 
parties: 
▪ Principal Investigator and the researcher’s staff: 
Dr. Bart Scott, Co-Principal Investigator  
Dr. Mitchell Horwitz, Co-Principal Investigator  
▪ National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH),  
▪ Study sponsors: Blood and Marrow Transplant Clinical Trials Network (BMT CTN), 
Data and Coordinating Center 
▪ U.S. government agencies that are responsible for overseeing research such as the Food 
and Drug Administration (FDA) and the Office of Human Research Protections (OHRP) 
▪ U.S. government agencies that are responsible for overseeing public health concerns such 
as the Centers for Disease Control (CDC) and federal, state and local health departments. 
 
E. Right to Refuse to Sign this Authorization:  
I do not have to sign this Authorization.  If I decide not to sign the Authorization, I will not 
be allowed to participate in this study or receive any treatment related to research that is 
provided through the study.   
My decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
 
F. Right to Revoke:   
I can change my mind and withdraw this authorization at any time by sending a written 
notice to the Principal Investigator to inform the researcher of my decision. 
If I withdraw this authorization, the researcher may only use and disclose the protected health 
information already collected for this research study.  No further health information about me 
will be collected by or disclosed to the researcher for this study. 
 
G. Potential for Re-disclosure:  
My individual health information disclosed under this authorization may be subject to re-
disclosure outside the research study and no longer protected. 


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Examples include potential disclosures for law enforcement purposes, mandated reporting or 
abuse or neglect, judicial proceedings, health oversight activities and public health measures. 
 
H. This authorization does not have an expiration date. 
 
Blood Samples for Future Research (optional) 
 
Researchers also want to learn how to better predict possible health problems and how to make 
transplants more successful.  Much of this research is done using human tissue or blood.   
We would like to store a sample of your blood for use in future research studies.  Your blood 
would be collected at your transplant center before your transplant.  We would keep the sample 
at a central place called the BMT CTN Research Sample Repository (this will be called the 
“Repository” in the rest of the consent form).  A Repository is a place that protects, stores and 
sends out samples for approved research studies.   
Some general things you should know about letting us store your blood samples for research are: 
▪ We will only store samples from people who give us permission.  You should feel free to 
talk over your decision with your family, friends, doctor, and health care team.  If you 
decide to not let us store research samples now or in the future, it will not affect your 
medical care.  
▪ Research is meant to gain knowledge that may help people in the future.  You will not get 
any direct benefit from taking part.  
▪ All testing done on your blood is for research purposes.  You or your doctor will not be 
given results and they will not be added to your medical record. 
▪ You will not get paid for any samples or for any products that may be developed from 
current or future research. 
If you agree to provide a blood sample, here is what will happen: 
1. A single 6 mL sample of your blood (approximately 1 teaspoon) will be collected before 
your transplant and stored solely for research purposes.  The collection will be done at the 
same time as the routine blood collection done for the study. 
2. The research sample will be given unique bar code designation that cannot be linked to 
you by the researcher testing your samples.  
3. Researchers can apply to study the materials stored in the Repository.  
4. Materials stored in the Repository will be used mainly by clinicians and researchers in the 
BMT CTN network.  In the future, the remaining research samples and clinical data will 
be made available outside of this network.  Researchers from other universities, the 


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government, and drug or health-related companies can apply to use the samples and 
information.  Only skilled researchers will be allowed to use the samples and 
information. 
5. The BMT CTN Steering Committee or the BMT CTN Biomarkers Committee must 
approve each study application before they will share samples or information with 
researchers.  This kind of review is to make sure that the investigators requesting the 
samples are qualified, and that the research they propose has a high potential of success 
and for contribution of scientific knowledge. 
6. DNA from your stored blood sample might be used in genome-wide association (GWA) 
or pharmacogenomics studies for a future project either done or supported by the 
National Institutes of Health (NIH). Genome-wide association studies are a way for 
scientists to identify genes involved in human disease.  This method searches the genome 
for small genetic changes that are more common in people with a particular disease than 
in people without the disease. Each study can look at hundreds of thousands of genetic 
changes at the same time. Researchers use data from this type of study to find genes that 
may add to a person’s risk of developing a certain disease.  Pharmacogenomics studies 
are similar genetic tests but look specifically at genes related to how the body breaks 
down medications.  
If your coded samples are used in such a study, the researcher is required to add your test 
results and sample information into a shared, public research database.  This public 
database is called the NIH Genotype and Phenotype Database and it is managed by the 
National Center for Biotechnology Information (NCBI).  The NCBI will never have any 
information that would identify you, or link you to your information or research samples.  
7. A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA) 
generally makes it illegal for health insurance companies, group health plans, and 
employers of 15 or more persons to discriminate against you based on your genetic 
information.  Health insurance companies and group health plans may not request your 
genetic information that we get from this research.  This means that they must not use 
your genetic information when making decisions regarding insurability.  Be aware that 
this new federal law will not protect you against genetic discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance. 


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Statement of Consent 
The purpose of storing blood samples, the procedures involved, and the risks and benefits have 
been explained to me.  I have asked all the questions I have at this time and I have been told 
whom to contact if I have more questions.  I have been told that I will be given a signed copy of 
this consent form to keep. 
I understand that I do not have to allow the use of my blood for future research.  If I decide to not 
let you store research samples now or in the future, it will not affect my medical care in any way. 
I voluntarily agree that my blood and information can be stored indefinitely by the BMT CTN 
and/or NHLBI Repositories for research to learn about, prevent, or treat health problems.  I also 
understand that my DNA and health information may or may not be used in genome-wide 
association studies. 
❑ I agree to allow my blood samples to be stored for research. 
❑ I do not agree to allow my blood samples to be stored for research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 


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TITLE: 
BMT CTN 0901: A Randomized, Multi-Center, Phase III Study of Allogeneic Stem 
Cell Transplantation Comparing Regimen Intensity in Patients with Myelodysplastic 
Syndrome or Acute Myeloid Leukemia 
 
CO-INVESTIGATOR: 
 
Bart Scott, MD 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North, D1-100 
Seattle, WA 98109-1023 
Phone: (206) 667-1990 
CO-INVESTIGATOR: 
 
Mitchell Horwitz, MD 
Duke University 
2400 Pratt St. DUMC 3961 
Durham, NC 27710 
Phone: (919) 668-1045 
 
▪ I have read and understood this Consent Form.  The nature and purpose of the research study 
has been explained to me. 
▪ I understand that the transplant intensity will be randomly assigned to me. 
▪ I have had the chance to ask questions, and understand the answers I have been given.  I 
understand that I may ask questions at any time during the study. 
▪ I freely agree to be a participant in the study. 
▪ I understand that I may not directly benefit from taking part in the study. 
▪ I understand that, while information gained during the study may be published, I will not be 
identified and my personal results will stay confidential. 
▪ I have had the chance to discuss my participation in this research study with a family member 
or friend. 
▪ I understand that I can leave this study at any time, and doing so will not affect my current 
care or prevent me from receiving future treatment. 
▪ I understand that I will be given a copy of this signed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Signature  
 
Print Name 
                                                Date    
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks.  I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
                                                                              
    
Signature of Counseling Physician 
 
    
 
 
 
       
Date 
 
 
 
 
 
 
 
                                                                              
    
Signature of Interpreter 
 
 
 
 
    
 
       
Date 
 


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C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
 


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Version 5.0 dated March 3, 2014 
 
 
C-2 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
1. BUSULFAN PHARMACOKINETICS (PK) STUDIES 
 
Patients receiving busulfan (Bu) as part of the conditioning regimen regardless of the 
intensity will participate in this ancillary study if their transplant center agrees to participate 
in this study.  Even though Bu PK is routinely done in some instances to optimize Bu 
exposure and minimize toxicity with myeloablative Bu doses, this practice is not done in 
patients who receive reduced intensity Bu doses.  This study will analyze Bu PK in all 
eligible patients at a central laboratory with the objective of correlating PK results with post-
transplant outcomes, including rates of relapse, treatment-related mortality, disease-free and 
overall survival.  Patients who receive Bu will be asked to provide up to 7 peripheral blood 
samples, using a pre-set sampling strategy after the first dose of Bu.  Samples will be 
collected up to 8 hours post administration of Bu.  Patients who already have Bu PK 
performed as part of their routine clinical care will need additional samples to be analyzed at 
a central laboratory for this study.  They can be collected on the same day or another day 
busulfan is given. 
 
Samples Required 
One 3 mL peripheral blood sample will be collected in a 6 mL-fill, sodium heparin-
containing Vacutainer® tubes at up to seven scheduled post-Bu dose sample collection time 
points for a total of 6 or 7 samples (21 mL maximum).  Peripheral blood samples will be 
placed on ice immediately after collection, centrifuged at 1000 g at 4ºC for 5 minutes for 
plasma separation.  The plasma will be removed from each vacutainer and placed in a single 
polypropylene cryovial corresponding for each time point.  The cryovials will be labeled and 
frozen at -70ºC.  The plasma samples must be well frozen prior to shipping to the project 
laboratory. 
 
Samples Shipment 
Samples will collected at 6-7 different time points depending on the route of Bu 
administration and Bu dosing schedule.  The table below outlines the proposed sampling 
strategy after the first dose of Bu.  The final schedule will be provided in the BMT CTN 
0901 Laboratory Sample Guide. 
 


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Dosing 
Schedule 
Bu Sample Collection Time Points 
#1 
#2 
#3 
#4 
#5 
#6 
#7 
IV 
Q6 hours 
End of Infusion 
(EOI)1 
EOI+ 
15 min 
EOI+ 
30 min 
240 min 
(4hrs)2 
300 min     
(5 hrs)2 
360 min 
(6 hrs)2 
--- 
IV 
Q24 Hours 
End of Infusion 
(EOI) 1 
EOI+ 
15 min 
240 min 
(4 hrs)2 
300 min     
(5 hrs) 2 
360 min     
(6 hrs)2 
480 min 
(8hrs)2 
--- 
Oral 
Busulfan 
(suspension) 
15 min 
30 min 
60 min  
(1 hrs) 
120 min  
(2 hrs) 
240 min     
(4 hrs) 
300 min 
(5 hrs) 
360 min 
(6 hrs) 
Oral 
Busulfan 
(tablet) 
30 min 
60 min 
(1 hr) 
90 min 
(1.5 hrs) 
120 min  
(2 hrs) 
240 min     
(4 hrs) 
300 min 
(5 hrs) 
360 min 
(6 hrs) 
1 For the initial EOI sample, be sure all of the drug has been delivered and the lines have been thoroughly 
flushed by Saline before drawing the end of infusion (EOI) sample. 
2 From the start of the infusion. 
 
Samples Shipment and Test Result Reporting 
Clinical centers will ship the set of six or seven frozen plasma cryovials in 5 kg of dry ice by 
priority overnight FedEx either on (1) the day of collection (Monday through Thursday) or 
(2) on the day following collection if sample collection is performed Monday through 
Wednesday.  If the sample collection occurs Friday through Sunday, the samples will need to 
be stored for Monday shipment.  Testing results will be provided by the Project Laboratory to 
the submitting clinical center, for subsequent entry into the Advantage EDC study data 
system. 
 
 
2. OPTIONAL SAMPLE FOR UNDEFINED FUTURE RESEARCH 
 
Patients consenting to provide optional research samples to be submitted to the BMT CTN 
Research Sample Repository for future testing will have an additional baseline peripheral 
blood sample collected. 
 
Samples Required 
A 6 mL peripheral blood sample will be collected at within 30 days of the initiation of 
preparative regimen in a 6 mL-fill, EDTA containing Vacutainer® tube (lavender).  The 
peripheral blood sample will be stored upright in a rack at room temperature while preparing 
to ship the sample on the same day to the BMT CTN Research Sample Repository.  Centers 
should arrange to have these patient samples collected on Monday-Thursday for receipt at the 
repository on Tuesday-Friday. 
 
Sample Shipment 
Clinical centers will ship the peripheral blood tube at ambient temperature by priority 
overnight FedEx on the day of collection directly to the BMT CTN Research Sample 
Repository for processing and long-term storage of whole blood aliquots. 


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C-4 
SCHEDULE OF LABORATORY EVALUATIONS 
 
 
RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
PURPOSE 
TYPE OF  
SAMPLE 
SAMPLE 
COLLECTION, 
PROCESSING AND 
STORAGE 
REQUIREMENTS 
SAMPLE 
COLLECTION 
TIME POINTS 
SHIPPING SPECIFICATIONS 
Busulfan 
Pharmacokine
tics Studies1 
Serial 
Busulfan 
Levels 
Up to seven 3 mL 
peripheral blood 
samples collected 
in 6 mL sodium 
heparin 
containing, green-
top vacutainer 
tube. 
Gently mix blood with 
heparin by inverting the 
tube 8-10 times. Centrifuge 
at 1000 g at 4ºC to separate 
plasma. Freeze the plasma 
in polypropylene cryovials. 
Ship the complete set of PK 
samples to Project 
Laboratory. 
Up to 7 time 
points from 
completion of the 
first dose of Bu 
until 6-8 hours 
later. 
Cryovials set will be shipped frozen in 
5 kg on dry ice directly to the Project 
Laboratory by priority overnight Fed 
Ex delivery for processing and 
busulfan testing.  Guidelines for the 
final specimen collection schedule, 
handling and shipment to the Project 
Laboratory is detailed in the BMT 
CTN 0901 Laboratory Research 
Sample Guide. 
(Optional) 
Investigational 
Future 
Research 
Sample2 
Undefined 
Future  
Studies 
One 6 mL 
peripheral blood 
sample collected 
in an EDTA 
containing, 
lavender-top 
vacutainer tube. 
Gently mix blood with 
EDTA by inverting the tube 
8-10 times.  Store upright in 
a rack at room temperature 
while preparing to ship to 
the BMT CTN Research 
Sample Repository. 
Pre-transplant 
Within 30 days of 
the initiation of 
preparative 
regimen.  
Peripheral blood tube will be shipped 
at ambient temperature on the day of 
collection, directly to the BMT CTN 
Research Sample Repository by 
priority overnight Fed Ex delivery for 
processing and long-term storage of 
whole blood aliquots. Guidelines for 
specimen handling and shipment to 
the Repository are detailed in the 
BMT CTN 0901 Laboratory Research 
Sample Guide. 
1 To be collected only from patients receiving busulfan at participating transplant centers. 
2 To be collected only from patients consenting to future research sample. 
 
 


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D-1 
APPENDIX D 
 
INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS)  
FOR PATIENTS WITH MDS 
 
 


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D-2 
APPENDIX D 
 
INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS)  
FOR PATIENTS WITH MDS 
 
 
 
 
 
 


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E-1 
APPENDIX E 
 
SWOG CYTOGENETIC CLASSIFICATION FOR AML 
 
 


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E-2 
APPENDIX E 
 
SWOG CYTOGENETIC CLASSIFICATION FOR AML 
 
 
 
 
 
 
 


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F-1 
APPENDIX F 
 
KARNOFSKY PERFORMANCE SCORE 
 
 


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F-2 
APPENDIX F 
 
KARNOFSKY PERFORMANCE STATUS SCALE 
 
 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of disease. 
 
Able to carry on normal activity; no 
special care needed. 
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 
Care for self, unable to carry on normal activity 
or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, varying amount of assistance 
needed. 
60 
Requires occasional assistance from others but 
able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, requires special care and assistance. 
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
 
30 
Severely disabled, hospitalization indicated, but 
death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead 
 
 


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G-1 
APPENDIX G 
 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
 


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Version 5.0 dated March 3, 2014 
 
 
G-2 
APPENDIX G 
 
HCT-SPECIFIC COMORBIDITY INDEX SCORE 
 
 
Comorbidities 
Definition 
Score 
Migraine/headache 
 
0 
Osteoporosis 
 
0 
Osteoarthritis 
 
0 
Hypertension 
 
0 
Gastrointestinal 
Including inflammatory bowel disease 
0 
Mild pulmonary 
DLCo and/or FEV1 >80% or 
Dyspnea on moderate activity 
0 
Mild renal 
Serum creatinine 1.2-2 mg/dl 
0 
Endocrine 
 
0 
Bleeding 
 
0 
Coagulopathy 
Deep venous thrombosis or pulmonary embolism 
0 
Asthma 
 
0 
Arrhythmia 
 
1 
Myocardial 
Coronary artery disease, congestive HF, history of 
medically documented MI, EF50% 
1 
Mild hepatic 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, or 
AST/ALT >ULN-2.5XULN 
1 
Cerebro-vascular 
accident 
History of transient ischemic attack or cerebro-vascular 
accident 
1 
Morbid obesity 
 
1 
Diabetes 
Requiring treatment 
1 
Depression/anxiety 
 
1 
Infection 
Requiring continuation of treatment after Day 0 
1 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD, polymyalgia 
rheumatica 
 
2 
Moderate pulmonary 
DLCo and/or FEV1 66-80% or 
Dyspnea on slight activity 
2 
Peptic ulcer 
Patients who have required treatment 
2 
Moderate-severe renal 
Serum creatinine >2 mg/dl, on dialysis, or prior renal 
transplantation 
2 
Valvular heart disease 
Except mitral valve prolapse 
3 
Prior solid tumor 
Requiring treatment with chemotherapy 
3 
Moderate-severe hepatic 
Liver cirrhosis, Bilirubin >1.5 X ULN, or AST/ALT 
>2.5XULN 
3 
Severe pulmonary 
DLCo and/or FEV1 65% or 
Dyspnea at rest or requiring oxygen 
3 
Total score is the sum of all comorbidities present at time of transplantation. 


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Version 5.0 dated March 3, 2014 
 
 
H-1 
APPENDIX H 
 
HUMAN SUBJECTS 
 


BMT CLINICAL TRIALS NETWORK 
 
RIC vs. MAC – Protocol # 0901 
 
Version 5.0 dated March 3, 2014 
 
 
H-2 
APPENDIX H 
 
HUMAN SUBJECTS 
 
 
Subject consent: Candidates for the study will be identified as described in Chapter 4 of the 
protocol.  The Principal Investigator or his/her designee at each transplant center will contact the 
candidates and enroll them onto the study.  The study coordinator at each center will provide the 
patient with information about the purpose of the study and obtain consent.  The Network will 
provide a template of the consent form to each center.  Each center will customize the template 
according to their local requirements and submit it for review by the local Internal Review Board 
(IRB).  The DCC will verify the adequacy of the consent forms.  Each center must provide 
evidence of IRB approval.  
 
 
Confidentiality: Confidentiality will be maintained by individual names being masked and 
assigned a patient identifier code.  The code relaying the patient’s identity with the ID code will 
be kept separately at the center.  The ID code will be transmitted to the network.   
 
 
Participation of women, children, minorities and other populations: Women and ethnic 
minorities will be included in this study.  Children will not be included. 
 
 
Accrual will be monitored within each center with the expectation that the enrolled patient 
population is representative of the transplanted patient population at each center.  Representation 
will be examined by comparing gender, race, ethnicity, and age distributions.  Accrual of 
minority patients will be expected to be in proportion to the number of minority patients 
transplanted at each center.  The DCC and NHLBI will discuss enrollment anomalies with the 
centers. 
 
 
 


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RIC vs. MAC – Protocol # 0901 
 
Version 5.0 dated March 3, 2014 
 
 
I-1 
APPENDIX I 
 
REFERENCES 
 


BMT CLINICAL TRIALS NETWORK 
 
RIC vs. MAC – Protocol # 0901 
 
Version 5.0 dated March 3, 2014 
 
 
I-2 
APPENDIX I 
 
REFERENCES 
 
 
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I-3 
 
13 Bornhäuser M, Storer B, Slattery JT, et al.  Conditioning with fludarabine and targeted 
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20 Andersson BS, Thall PF, Madden T, et al.  Busulfan systemic exposure relative to regimen-
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22 Madden T, de Lima M, Thapar N, et al.  Pharmacokinetics of once-daily IV busulfan as part of 
pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. 
Biol Blood Marrow Transplant 2007;13(1):56-64. 
23 Bacigalupo A, Ballen K, Rizzo D, et al.  Defining the intensity of conditioning regimens: 
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24 Slavin S, Nagler A, Naparstek E, et al.  Nonmyeloablative stem cell transplantation and cell 
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25 Kroger N, Schetelig J, Zabelina T, et al.  A fludarabine-based dose-reduced conditioning 
regimen followed by allogeneic stem cell transplantation from related or unrelated donors in 
patients with myelodysplastic syndrome. Bone Marrow Transplant 2001;28(7):643-647. 
26 Ho AYL, Pagliuca A, Kenyon M, et al.  Reduced-intensity allogeneic hematopoietic stem cell 
transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage 
dysplasia using fludarabine, busulphan and alemtuzumab (FBC) conditioning. Blood 
2004;104(6):1616-1623. 
27  Mohty M, Bay JO, Faucher C, et al.  Graft-versus-host disease following allogeneic 
transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-
intensity preparative regimen. Blood 2003;102(2):470-476. 
28 Valcarcel D, Martino R, Caballero D, et al.  Sustained remissions of high-risk acute myeloid 
leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic 
hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor 
improving survival. J Clin Oncol 2008;26(4):577-584. 
29 Giralt S, Thall PF, Khouri I, et al.  Melphalan and purine analog-containing preparative 
regimens: reduced-intensity conditioning for patients with hematologic malignancies 
undergoing allogeneic progenitor cell transplantation. Blood 2001;97(3):631-637. 
30 Oran B, Giralt S, Saliba R, Hosing C, Popat U, Khouri I, et al. Allogeneic hematopoietic stem 
cell transplantation for the treatment of high-risk acute myelogenous leukemia and 
myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and 
melphalan. Biol Blood Marrow Transplant. 2007 Apr;13(4):454-62. 
31 Nakamura R, Rodriguez R, Palmer J, Stein A, Naing A, Tsai N, et al. Reduced-intensity 
conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and 
melphalan is associated with durable disease control in myelodysplastic syndrome. Bone 
Marrow Transplant. 2007 Nov;40(9):843-50. 
32  Alyea EP, Kim HT, Ho V, et al.  Comparative outcome of nonmyeloablative and 
myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of 
age. Blood 2005;105(4):1810-1814. 
33 Alyea EP, Kim HT, Ho V, et al.  Impact of conditioning regimen intensity on outcome of 
allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and 
myelodysplastic syndrome. Biol Blood Marrow Transplant 2006;12(10):1047-1055. 
34 Aoudjhane M, Labopin M, Gorin NC, et al.  Comparative outcome of reduced intensity and 
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35 Martino R, Iacobelli S, Brand R, et al.  Retrospective comparison of reduced-intensity 
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36 Shimoni A, Hardan I, Shem-Tov N, et al.  Allogeneic hematopoietic stem-cell transplantation 
in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose 
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37 Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R, et al. Comparison 
between two fludarabine-based reduced-intensity conditioning regimens before allogeneic 
hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher 
incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of 
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38 Martino R, Valcarcel D, Brunet S, Sureda A, Sierra J.  Comparable non-relapse mortality and 
survival after HLA-identical sibling blood stem cell transplantation with reduced or 
conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid 
leukemia in first remission. Bone Marrow Transplant 2008;41(1):33-38. 
39 Bevans MF, Marden S, Leidy NK, et al.  Health-related quality of life in patients receiving 
reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Bone 
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40 Grever M, Leiby J, Kraut E, et al.  A comprehensive phase I and II clinical investigation of 
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50 Schluchter MD Methods for the analysis of informatively censored longitudinal data. Statistics 
in Medicine. 1992, 11:1861-70.  
 

SAP_001.pdf: 
1 
 
BMT CTN #0901 Statistical Analysis Plan (SAP) 
Drafted by: Maggie Wu on 5/5/15, Reviewed by: Brent Logan 5/8/15  
Finalized after the team call on 5/11/15 
 
Protocol:  
BMTCTN #0901 Full vs. RIC in MDS/AML 
 
Protocol Synopsis:  
The BMT CTN protocol #0901 titled “A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation 
Comparing Regimen Intensity in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia” is a Phase III, multicenter trial 
comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or 
myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning 
(RIC) regimens.  The primary objective is to compare 18-month overall survival (OS) rates between the two groups.  Secondary 
objectives include comparisons of disease-free survival rates, rates of transplant-related mortality, incidence of relapse, hematologic 
recovery, kinetics of donor cell engraftment, incidence of graft failure, incidence and severity of acute and chronic graft-versus-host 
disease (GVHD), rates of infectious complications, rates of ≥ grade 3 toxicities, immune reconstitution and quality of life. Per the 
original study design, the target sample size is 356 patients with 178 on each arm and patients will be followed for up to 18 months 
post-transplantation on the study. 
Study Status and Publication Plan: 
The study opened to accrual in June 2011 and closed accrual in April 2014 per DSMB recommendation. By the time of accrual 
closure, 272 patients were enrolled to the study.  All patients have completed 1-year follow up by May 1, 2015.  It is expected that all 
except 30 patients would have completed 18-month follow up by June 2015. And it is expected that the last 30 patients would 
complete 18-month follow up per protocol by the end of October 2015.  The Endpoint Review Committee (ERC) has reviewed the 
primary endpoint and some secondary endpoints including relapse/progression and GVHD for all the study patients with the available 
data and it is expected that ERC process including data QC will be completed by early June 2015.  Data lock is planned on June 5, 
2015 to generate the preliminary analysis report.  Analysis report will be updated in October to include the result of the primary 
endpoint.  The analysis report will be provided to the team within 2 weeks of the data lock.  The writing team will prepare a late-
breaking ASH abstract (submission deadline in October 2015) and also work on the manuscript for a simultaneous publication of 
ASH presentation and manuscript. 


2 
 
Primary Endpoint and Final Analysis: 
The primary endpoint of BMT CTN 0901 is overall survival (OS) at 18 months from the time of randomization.  The hypothesis to be 
tested is that reducing the intensity of the conditioning regimen will decrease treatment-related mortality without increasing relapse so 
that overall survival will be improved.  Participants are considered a failure if they die post randomization and time to this event is the 
time from randomization to death or last follow-up, whichever comes first. The primary analysis is a pointwise comparison of the 
survival proportions between treatment arms.  
Three interim analyses on the primary endpoint were conducted and reviewed by the BMT CTN Data and Safety Monitoring Board.  
It was approved by DSMB that the final analysis of the primary endpoint would be conducted when all patients have completed the 
18-month follow up per the protocol, as expected to be October 2015. The final boundary to be used for the final analysis was 
recomputed from the original study design since the study did not reach the target sample size of 356 when the accrual was closed.  
The actual maximum information was less than the target maximum information and the re-computation is to ensure the cumulative 
type I error alpha as 0.05 at the end of the study after the previously conducted interim analyses. The secondary endpoints may have 
minor changes using the fully mature data in October from the June data but we do not expect major changes. 
Patients to Include: 
The study enrolled a total of 272 patients.  Two hundred and sixty-five patients received a transplant per study.  All the patients will 
be included for the primary endpoint using intent-to-treat principle.  For some secondary endpoints, only transplanted patients will be 
included to evaluate the post-transplant outcomes, which will be specified below for each. 
 
Additional data source and data analysis: 
 
Also the long-term follow-up data (beyond 18 months, up to 2 or 3 years depending on data availability) will be retrieved from 
CIBTMR data system to evaluate the long-term survival between the two treatment arms in an exploratory analysis. 
 
Table of Contents 
 
Data Summary 
EXHIBIT 0901-1: DEMOGRAPHICS AND BASELINE CHARACTERISTICS BY TREATMENT ARM 
EXHIBIT 0901-2: OVERALL SURVIVAL BY TREATMENT ARM 
 
EXHIBIT 0901-3: DISEASE-FREE SURVIVAL BY TREATMENT ARM 


3 
 
EXHIBIT 0901-4: RELAPSE/PROGRESSION BY TREATMENT ARM 
  
EXHIBIT 0901-5: TREATMENT-RELATED MORTALITY BY TREATMENT ARM 
EXHIBIT 0901-6: PRIMARY CAUSE OF DEATH BY TREATMENT ARM  
EXHIBIT 0901-7: NEUTROPHIL RECOVERY BY TREATMENT ARM 
EXHIBIT 0901-8: PLATELET RECOVERY BY TREATMENT ARM 
EXHIBIT 0901-9: GRAFT FAILURE BY TREATMENT ARM 
EXHIBIT 0901-10: DONOR CELL ENGRAFTMENT BY TREATMENT ARM 
EXHIBIT 0901-11: ACUTE GVHD BY TREATMENT ARM 
EXHIBIT 0901-12: CHRONIC GVHD BY TREATMENT ARM 
EXHIBIT 0901-13: UNEXPECTED GRADES 3-5 ADVERSE EVENTS 
EXHIBIT 0901-14: CORE AND PROTOCOL-SPECIFIC TOXICITY (GRADE > 2) BY TREATMENT ARM 
EXHIBIT 0901-15: INFECTION SUMMARY BY TREATMENT ARM 
EXHIBIT 0901-16: IMMUNE RECONSTITUTION BY TREATMENT ARM  
EXHIBIT 0901-17: QUALITY OF LIFE BY TREATMENT ARM 
EXHIBIT 0901-18: ACCRUAL OVER TIME  
EXHIBIT 0901-19: SIGNIFICANT PROTOCOL DEVIATIONS 
EXHIBIT 0901-20: MULTIVARIATE ANALYSIS FOR PRIMARY AND SECONDARY ENDPOINTS 
EXHIBIT 0901-21: SUBGROUP ANALYSES OF PRIMARY ENDPOINT BY CONDITIONING REGIMEN 
 
 
DATA SUMMARY:  
Brief summary for the report being provided. Descriptions for each exhibit are shown below in order. 
 
 
EXHIBIT 0901-1: DEMOGRAPHICS AND BASELINE CHARACTERISTICS BY TREATMENT ARM 
These will be described in a table as below.  Frequencies and percents for categorical covariates, using Fisher’s test for treatment comparison.  
Median and range for continuous covariates, using T test for treatment comparison.  
 
 
 


4 
 
Table 1 
 
Treatment Arm 
 
 
 
MAC 
(N=) 
N (%) 
RIC 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
P-value 
Total Transplanted 
 
 
 
 
Gender 
 
 
 
 
Female 
 
 
 
 
Male 
 
 
 
 
Ethnicity 
 
 
 
 
Hispanic or Latino 
 
 
 
 
Not Hispanic or Latino 
 
 
 
 
Unknown 
 
 
 
 
Not Answered 
 
 
 
 
Race 
 
 
 
 
American Indian/Alaskan Native 
 
 
 
 
Asian 
 
 
 
 
Hawaiian/Pacific Islander 
 
 
 
 
Black or African American 
 
 
 
 
White 
 
 
 
 
More than One Race 
 
 
 
 
Other, Specify 
 
 
 
 
Unknown 
 
 
 
 
Not Answered 
 
 
 
 
Age, yrs 
 
 
 
 
Mean (Std. Dev.) 
 
 
 
 
Median (range) 
 
 
 
 
        18-29 
 
 
 
 
        30-39 
       
 
 
 
        40-49 
 
 
 
 
        50-65 
 
 
 
 
 


5 
 
Table 1 (cont’d) 
 
 
Treatment Arm 
 
 
 
MAC 
(N=) 
N (%) 
RIC 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
P-value 
Total Transplanted 
 
 
 
 
Primary Diagnosis 
 
 
 
 
Myelodysplastic Syndrome (MDS) 
 
 
 
 
Acute Myelogenous Leukemia (AML) 
 
 
 
 
Conditioning Regimen 
 
 
 
 
Busulfan/Fludarabine (Flu/Bu) 
 
 
 
 
Busulfan/Cyclophosphamide (Bu/Cy) 
 
 
 
 
Cyclophosphamide/Total Body Irradiation (Cy/TBI) 
 
 
 
 
Fludarabine/Melphalan (Flu/Mel) 
 
 
 
 
Conditioning Regimen for AML/MDS 
 
 
 
 
MDS 
 
 
 
 
    Busulfan/Fludarabine (Flu/Bu) 
 
 
 
 
    Busulfan/Cyclophosphamide (Bu/Cy) 
 
 
 
 
    Cyclophosphamide/Total Body Irradiation (Cy/TBI) 
 
 
 
 
    Fludarabine/Melphalan (Flu/Mel) 
 
 
 
 
AML 
 
 
 
 
    Busulfan/Fludarabine (Flu/Bu) 
 
 
 
 
    Busulfan/Cyclophosphamide (Bu/Cy) 
 
 
 
 
    Cyclophosphamide/Total Body Irradiation (Cy/TBI) 
 
 
 
 
    Fludarabine/Melphalan (Flu/Mel) 
 
 
 
 
 
 
 
 


6 
 
Table 1 (cont’d) 
 
 
Treatment Arm 
 
 
 
MAC 
(N=) 
N (%) 
RIC 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
P-value 
Total Transplanted 
 
 
 
 
MDS WHO Classification 
 
 
 
 
Refractory Anemia 
 
 
 
 
Refractory Anemia with Ringed Sideroblasts 
 
 
 
 
Refractory Cytopenia with Multilineage Dysplasia 
 
 
 
 
Refractory Cytopenia with Multilineage Dysplasia and Ringed 
Sideroblasts 
 
 
 
 
Refractory Anemia with Excess Blasts-1 (5-10% blasts) 
 
 
 
 
Refractory Anemia with Excess Blasts-2 (10-20% blasts) 
 
 
 
 
Myelodysplastic Syndrome, Unclassified 
 
 
 
 
MDS Associated with Isolated Del(5q) 
 
 
 
 
AML WHO Classification 
 
 
 
 
AML with recurrent genetic abnormalities 
 
 
 
 
AML with multilineage dysplasia 
 
 
 
 
AML and myelodysplastic syndromes, therapy related 
 
 
 
 
AML, not otherwise categorized 
 
 
 
 
Antithymocyte Globulin Used as Part of Conditioning Regimen 
 
 
 
 
Yes 
 
 
 
 
No 
 
 
 
 
GVHD prophylaxis 
 
 
 
 
Tacrolimus/Methotrexate 
 
 
 
 
Sirolimus/Tacrolimus 
 
 
 
 
Tacrolimus/MMF 
 
 
 
 
Cyclosporine/MMF 
 
 
 
 
Cyclosporine/Methotrexate 
 
 
 
 
Other 
 
 
 
 


7 
 
Table 1 (cont’d) 
 
 
Treatment Arm 
 
 
 
MAC 
(N=) 
N (%) 
RIC 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
P-value 
Total Transplanted 
 
 
 
 
# Non-transplant 
 
 
 
 
# Treatment Crossover 
 
 
 
 
 
 
 
 
 
Donor Type and HLA Match 
 
 
 
 
Sibling Donor 
 
 
 
 
Related Donor 7/8 
 
 
 
 
Related Donoe 8/8 
 
 
 
 
Unrelated Donor 7/8 
 
 
 
 
Unrelated Donor 8/8 
 
 
 
 
Karnofsky Performance Score 
 
 
 
 
100 
 
 
 
 
90 
 
 
 
 
80 
 
 
 
 
70 
 
 
 
 
Donor Source 
 
 
 
 
Peripheral Blood 
 
 
 
 
Bone Marrow 
 
 
 
 
CMV Status  
 
 
 
 
Positive 
 
 
 
 
Negative 
 
 
 
 
 


8 
 
Table 1 (cont’d) 
 
 
Treatment Arm 
 
 
 
MAC 
(N=) 
N (%) 
RIC 
(N=) 
N (%) 
Total 
(N=) 
N (%) 
P-value 
Total Transplanted 
 
 
 
 
 
 
 
 
 
Risk Status 
 
 
 
 
Standard 
 
 
 
 
High 
 
 
 
 
Unknown 
 
 
 
 
   Total 
 
 
 
 
AML Risk Status 
 
 
 
 
Standard 
 
 
 
 
High 
 
 
 
 
Unknown 
 
 
 
 
Total AML patients 
 
 
 
 
MDS Risk Status 
 
 
 
 
Standard 
 
 
 
 
High 
 
 
 
 
Total MDS patients 
 
 
 
 
 
Notes: Risk status data will be provided by CIBMTR,  AML risk status evaluated based on cytogenetics tests. MDS risk status based on IPSS score.                                        
IPSS = International Prognostic Scoring System.  High-risk MDS is defined as patients with intermediate-II or high IPSS. 
Other baseline data including HCT-CI, time from diagnosis to transplant will also be provided for each treatment arm, and 
these data also need to be retrieved from CIBTMR data system. 
 


9 
 
EXHIBIT 0901-2: OVERALL SURVIVAL BY TREATMENT ARM  
The primary objective is to compare 18-month overall survival (OS) rates between the two groups.  Overall survival (OS) curve will be plotted by 
treatment arm.  OS curve will show the Kaplan-Meier estimates of OS from the time of transplant to 18 months, where death from any cause are 
treated as events.  Kaplan-Meier estimate at 18 months be provided with 95% confidence intervals.  All patients will be included for the primary 
endpoint. The time to this event is the time from randomization to death, loss to follow up or end of study whichever comes first. 
The test statistic is the standardized difference in the Kaplan Meier estimates of overall survival, and is written as  
 
 
  
 
 
 
where 
)
18
(
ˆ
m
SMAC
and
)
18
(
ˆ
m
SRIC
 are the product limit estimates of the survival function for the MAC and the RIC at 18 months post 
randomization, respectively, while 
)
18
(
ˆ
(ˆ
m
S
V
MAC
)  and 
)
18
(
ˆ
(ˆ
m
S
V
RIC
)  are the variances (per Greenwood’s formula) of the  product limit 
estimates at 18 months.  The critical values and type I error for the interim analyses are shown in below table. 
 
Time of Interim Analysis 
for DSMB Review   
Information 
Fraction 
Critical Value 
Test 
Statistic 
Type I Error 
Cumulative Type I 
Error 
Nov 2013 
0.19 (0.25) 
5.010 
-1.13 
0.00000 
0.00000 
April 2014 
0.45 (0.59) 
3.144 
−2.00 
0.00167 
0.00167 
Nov 2014 
0.71 (0.93) 
2.430 
−2.09 
0.01396 
0.01563 
 
The final boundary was computed to be ±1.964 using group sequential boundaries after accounting for the change in maximum information of the 
study.  The final analysis will compute the test statistic using all available final information based on the 18-months survival estimates.  If the |test 
statistic| would exceed 1.964, significance of efficacy for the primary endpoint would be reached.  
Results for the primary endpoint will be summarized in the below table, besides the OS curve. 
 
 
Primary Endpoint 
18 month OS 
(95% CI) 
Test 
Statistic 
Final 
boundary 
P-value 
MAC:  
RIC: 
 
 
 
 
 
 
))
18
(
ˆ
(ˆ
))
18
(
ˆ
(ˆ
)
18
(
ˆ
)
18
(
ˆ
m
S
V
m
S
V
m
S
m
S
Z
MAC
RIC
MAC
RIC
KM





10 
 
In a secondary analysis, the 18-month OS probabilities will be compared using the adjusted OS probabilities proposed by Zhang et al.  The 
adjusted survival probabilities are estimated using the Cox proportional hazards model stratified by treatment.  Disease risk, donor type and all 
demographic and baseline characteristic shown to be significantly different between treatment arms will be included in the Cox model to adjust for 
potential imbalances.  The proportional hazards assumption will be checked for all covariates.  If there are indications of differential effects over 
time, the final model will be stratified by factors with non-proportionality. Details will be described in the multivariate analysis part. 
Note/Concern: Final p-value will not be available for regular ASH abstract due to the timeline so will submit a late-breaking abstract to ASH.  .  
Multivariate analysis will be conducted after the ASH abstract for the presentation/manuscript.  
 
EXHIBIT 0901-3: DISEASE-FREE SURVIVAL BY TREATMENT ARM 
Disease-Free Survival (DFS) will be analyzed as a secondary endpoint.  Patients are considered a failure of this endpoint if they die or suffer from 
disease relapse or initiate non-protocol AML or MDS therapy.  Per protocol, the time to this event is the time from randomization to relapse, death, 
initiation of non-protocol AML or MDS therapy, loss to follow up or end of study whichever comes first.  Disease-free survival curves will be 
estimated using Kaplan-Meier estimator and 95% confidence interval will be provided.  Kaplan Meier estimates of DFS at 18 months will be 
compared between treatment arms using pointwise comparison.  Relapse before transplant will also be counted as event for this endpoint. 
 
Results for this endpoint will be summarized in the below table, besides the DFS curve. 
 
                                    
Secondary Endpoint: DFS 
Treatment Arm 
             
P-value 
MAC 
RIC 
18 month DFS (95% CI)  
 
 
 
 
 
A secondary analysis of DFS will be performed by comparing the adjusted DFS probabilities at 18 months. This will be described in the 
multivariate analysis part. 
 
 
EXHIBIT 0901-4: RELAPSE/PROGRESSION BY TREATMENT ARM 
  
Incidence of relapse will be estimated using cumulative incidence function, treating death as a competing risk.  Incidence of relapse will be 
compared between the treatment arms using Gray’s test.  18-month incidence rate will be provided with the 95% confidence interval for each 
treatment arm. Per protocol, the time to this event is the time from randomization to relapse, loss to follow up or end of study whichever comes 
first. 
 


11 
 
Results for this endpoint will be summarized in the below table, besides the cumulative incidence curve. 
 
                                      
Secondary Endpoint: Relapse 
Treatment Arm 
             
P-value 
MAC 
RIC 
12 month Incidence Rate (95% CI)  
 
 
 
18 month Incidence Rate (95% CI)  
 
 
 
In a secondary analysis, relapse will be compared between arms using a Cox proportional hazards model with treatment as the main effect.  This 
will be described in the multivariate analysis part. 
 
 
EXHIBIT 0901-5: TREATMENT-RELATED MORTALITY BY TREATMENT ARM 
The event is death occurring from causes other than relapse.  Incidence of Treatment-related Mortality (TRM) will be estimated using cumulative 
incidence function, treating relapse as a competing risk.  Incidence of TRM will be compared between the treatment arms using Gray’s test.  To be 
consistent with the primary endpoint, the time to this event is the time from randomization to death without relapse, loss to follow up or end of 
study whichever comes first. 
 
 
Results for this endpoint will be summarized in the below table, besides the cumulative incidence curve. 
 
                                      
Secondary Endpoint: TRM 
Treatment Arm 
             
P-value 
MAC 
RIC 
12 month Incidence Rate (95% CI)  
 
 
 
18 month Incidence Rate (95% CI)  
 
 
In a secondary analysis, TRM will be compared between arms using a Cox proportional hazards model with treatment as the main effect.  This will 
be described in the multivariate analysis part. 
 
 


12 
 
EXHIBIT 0901-6: PRIMARY CAUSE OF DEATH BY TREATMENT ARM  
Table listing the primary causes of death (COD) by treatment arm.  The ERC adjudicated COD will be used instead of the center-reported COD. 
Results will be shown as below: 
 
 
Treatment Arm 
Total 
MAC  
RIC 
N 
(%) 
N 
(%) 
N 
(%) 
Relapse/Progression 
Graft Failure 
GVHD 
Infection 
Organ Failure 
Secondary Malignancy 
Hemorrhage  
Adult Respiratory Distress Syndrome 
Accidental Death 
Other 
Total 
 
 
 
 
 
 
 
Total Accrual 
Total Death (Percentage %) 
 
EXHIBIT 0901-7: NEUTROPHIL RECOVERY BY TREATMENT ARM 
 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) > 500 µL for three consecutive measurements on different 
days.  The first of the three days will be designated the day of neutrophil engraftment.   


13 
 
Incidence of neutrophil recovery will be estimated using cumulative incidence function, treating death as a competing risk.  Incidence of neutrophil 
recovery will be compared between the treatment arms using Gray’s test.  Incidence rate will be provided with the 95% confidence interval for 
each treatment arm. 
 
Results for this endpoint will be summarized in the below table, besides the cumulative incidence curve. 
 
                                                        
Secondary Endpoint: Neutrophil  Recovery 
Treatment Arm 
             
P-value 
MAC 
RIC 
Day 28 incidence rate (95% CI)  
 
 
 
Day 42 incidence rate (95% CI)  
 
 
Median time to Neutrophil Recovery  
 
 
 
 
EXHIBIT 0901-8: PLATELET RECOVERY BY TREATMENT ARM 
 
Platelet engraftment is defined as a platelet count > 20,000/µL for three consecutive measurements over three or more days without requiring 
platelet transfusions.  The first of the three days will be designated the day of platelet engraftment.  Subjects must not have had platelet 
transfusions during the preceding 7 days.  The time to a platelet count > 50,000/µL will be collected as well.  This endpoint will be evaluated 
through 100 days.   
Incidence of platelet recovery will be estimated using cumulative incidence function, treating death as a competing risk.  Incidence of platelet 
recovery will be compared between the treatment arms using Gray’s test.  Incidence rate will be provided with the 95% confidence interval for 
each treatment arm.  Curve for cumulative incidence of platelet recovery will be displayed for both >20K in panel (A) and >50k in panel (B) 
 
Results for this endpoint will be summarized in the below table, besides the cumulative incidence curve. 
 
                                                        
  Secondary Endpoint:  Platelet Recovery 
Treatment Arm 
             
P-value 
MAC 
RIC 
Platelet Recovery to >20k 
 
 
 


14 
 
        Day 60 incidence rate (95% CI)  
 
 
        Day 100 incidence rate (95% CI)  
 
 
        Median time to Platelet Recovery  
 
 
Platelet Recovery to >50k 
 
 
 
        Day 60 incidence rate (95% CI)  
 
 
        Day 100 incidence rate (95% CI)  
 
 
        Median time to Platelet Recovery  
 
 
 
 
EXHIBIT 0901-9: GRAFT FAILURE BY TREATMENT ARM 
Primary Graft Failure is defined by lack of neutrophil engraftment by 28 days, e.g. no recovery, or late recovery. Secondary graft 
failure is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500/µL unresponsive to 
growth factor therapy.  P-value using Fisher’s test will be provided to compare the numbers of graft failure between the two treatment 
arms.  Results for this endpoint will be summarized in the below table.   
Secondary Endpoint: Graft Failure 
Treatment Arm 
 
Total 
 
P-value 
MAC 
RIC 
N 
(%) 
N 
(%) 
N 
(%) 
Primary Graft Failure  
    ANC count did not recover to >500/µL 
    ANC count recovered late - after Day 28 
 
 
 
 
 
Secondary Graft Failure 
 
 
Total Graft Failure 
 
 
Total Transplanted 
 
 
 


15 
 
 
EXHIBIT 0901-10: DONOR CELL ENGRAFTMENT BY TREATMENT ARM 
 
Donor cell engraftment will be assessed by donor recipient chimerism studies.  For the purposes of this protocol, mixed chimerism will be defined 
as the presence of donor cells, as a proportion of the total population of < 95% in the peripheral blood or bone marrow.  Full donor chimerism is 
defined as > 95% donor cells.  Mixed or full donor chimerism will be evidence of donor engraftment.  Graft rejection is defined as the inability to 
detect or loss of detection of greater than 5% donor cells as a proportion of the total population. Bone marrow is the preferred source for 
chimerism analysis. If not available, will use peripheral blood.  If still not available, will use T cell. P-value using Chi-square test or Fisher’s test will 
be provided to compare the donor chimerism between the two treatment arms.  
 
Results for this endpoint will be summarized in the below table.   
 
Secondary Endpoint: Donor Chimerism 
Treatment Arm 
 
Total 
 
P-value 
MAC 
RIC 
N 
(%) 
N 
(%) 
N 
(%) 
Day 28 Assay 
 
 
 
 
 
        Full donor chimerism (>=95% donor) 
 
 
 
 
        Mixed chimerism (5%<donor<95%) 
 
 
        Graft Rejection (<=5% donor) 
 
 
        Death prior to Assessment 
 
 
        Not done /unknown (due to relapse,          
secondary transplant, missing assay) 
 
 
 
Day 100 Assay 
 
 
 
 
 
        Full donor chimerism (>=95% donor) 
 
 
 
 
        Mixed chimerism (5%<donor<95%) 
 
 
        Graft Rejection (<=5% donor) 
 
 
        Death prior to Assessment 
 
 


16 
 
Secondary Endpoint: Donor Chimerism 
Treatment Arm 
 
Total 
 
P-value 
MAC 
RIC 
N 
(%) 
N 
(%) 
N 
(%) 
        Not done /unknown (due to relapse, 
secondary transplant, missing assay) 
 
 
 
Day 540 Assay 
 
 
 
        Full donor chimerism (>=95% donor) 
 
 
        Mixed chimerism (5%<donor<95%) 
 
 
        Graft Rejection (<=5% donor) 
 
 
        Death prior to Assessment 
 
 
        Not done /unknown (due to relapse, 
secondary transplant, missing assay) 
 
 
 
Total Transplanted 
 
 
 
 
 
EXHIBIT 0901-11: ACUTE GVHD BY TREATMENT ARM 
 
Table to summarize the maximum acute GVHD post transplant.  Plots of cumulative incidence of acute GVHD grade II-IV (Panel A) and acute 
GVHD grade III-IV (Panel B) from the time of transplant.  Provide estimates of cumulative incidence of acute GVHD grade II-IV or III-IV at day 100 
(as well as Day 180) post transplant, with 95% confidence intervals.  Death prior to occurrence of acute GVHD will be considered as a competing 
risk.  Incidence of acute GVHD will be compared between the treatment arms using Gray’s test.   
 
Results for this endpoint will be summarized in the below tables, besides the cumulative incidence curves. 
 
Maximum Acute GVHD Grade 
Treatment Arm 
 
Total 
MAC 
RIC 
N 
(%) 
N 
(%) 
N 
(%) 
Grade 0, No aGVHD 
 
 


17 
 
Maximum Acute GVHD Grade 
Treatment Arm 
 
Total 
MAC 
RIC 
N 
(%) 
N 
(%) 
N 
(%) 
Grade I 
 
 
Grade II 
 
 
Grade III 
 
 
Grade IV 
 
 
Total Transplanted 
 
 
 
                                                      
Secondary Endpoint: Acute GVHD 
Treatment Arm 
           
P-value 
MAC 
RIC 
Day 100 Incidence Rate (95% CI) of Grade II-IV acute GVHD 
 
 
 
Day 100 Incidence Rate (95% CI) of Grade III-IV acute GVHD 
 
 
 
Day 180 Incidence Rate (95% CI) of Grade II-IV acute GVHD 
 
 
 
Day 180 Incidence Rate (95% CI) of Grade III-IV acute GVHD 
 
 
 
 
EXHIBIT 0901-12: CHRONIC GVHD BY TREATMENT ARM 
 
Table to summarize the maximum grade and overall maximum severity of chronic GVHD by treatment arm.  Cumulative incidence of chronic 
GVHD post transplant will be plotted by treatment arm.  Provide incidence rate of chronic GVHD at 1-year and 18 months post transplant, with 
95% confidence intervals.  Death prior to occurrence of chronic GVHD will be considered as a competing risk. Incidence of acute GVHD will be 
compared between the treatment arms using Gray’s test.   
 
Results for this endpoint will be summarized in the below tables, besides the cumulative incidence curves. 
 


18 
 
                                                      
Secondary Endpoint: Chronic GVHD 
Treatment Arm 
           
P-value 
MAC 
RIC 
12 month Incidence Rate (95% CI)  
 
 
 
18 month Incidence Rate (95% CI) 
 
 
Maximum Grade of chronic GVHD 
         Limited 
         Extensive 
 
 
 
Maximum Severity of chronic GVHD 
         Mild 
         Moderate 
         Severe 
 
 
 
 
 
EXHIBIT 0901-13: UNEXPECTED GRADES 3-5 ADVERSE EVENTS 
Table listing the unexpected grades 3-5 adverse events (AEs) including onset date, severity, relationship to protocol and medical 
monitor assessment. 
 
Treatment 
Arm 
Patient 
ID 
Center 
AE Onset 
Date 
Days Since 
Transplant 
Adverse Event Description 
[Medical Monitor 
Description] 
Event 
Severity 
Relationship 
to Protocol 
Effect on 
Therapy/ 
Intervention 
DCC 
Expected
? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EXHIBIT 0901-14: CORE AND PROTOCOL-SPECIFIC TOXICITY (GRADE > 2) BY TREATMENT ARM 
Use bar graphs to show the toxicity frequency within 18 months post transplant for each treatment arm and each assessment period and overall 
from transplant through 18 months. And use scatterplot to show the toxicity rate of each toxicity to compare the two treatment arms. Assessment 
time points include Day 28, Day 56, Day 100, Day 180, Day 365 and Day 540. Also use a summary table to show frequency with maximum toxicity 
of patients experiencing grade 3-5 toxicities and unexpected adverse events classified by system organ class. 
Results for this endpoint will be summarized in the below tables, besides the bar graphs and scatterplots. 


19 
 
 
Maximum Toxicity of Grades 3-5 by System Organ Class 
Treatment Arm 
Total  
MAC  
RIC  
System Organ Class 
Grade 
Blood and lymphatic system disorders 
3 
4 
5 
Grades 3-5 
Cardiac disorders 
3 
4 
5 
Grades 3-5 
Eye disorders 
3 
4 
5 
Grades 3-5 
Gastrointestinal disorders 
3 
4 
5 
Grades 3-5 
General disorders and administration site conditions 
3 
4 
5 
Grades 3-5 
Hepatobiliary disorders 
3 
4 
5 
Grades 3-5 
Immune system disorders 
3 
4 
5 
Grades 3-5 
Infections and infestations 
3 
4 
5 
Grades 3-5 
 


20 
 
 
Maximum Toxicity of Grades 3-5 by System Organ Class 
Treatment Arm 
Total  
MAC  
RIC  
System Organ Class 
Grade 
Injury, poisoning and procedural complications 
3 
4 
5 
Grades 3-5 
Investigations 
3 
4 
5 
Grades 3-5 
Musculoskeletal and connective tissue disorders 
3 
4 
5 
Grades 3-5 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
3 
4 
5 
Grades 3-5 
Nervous system disorders 
3 
4 
5 
Grades 3-5 
Psychiatric disorders 
3 
4 
5 
Grades 3-5 
Renal and urinary disorders 
3 
4 
5 
Grades 3-5 
Renal and urinary disorders/Reproductive system and breast 
disorders 
3 
4 
5 
Grades 3-5 
 


21 
 
Maximum Toxicity of Grades 3-5 by System Organ Class 
Treatment Arm 
Total  
MAC  
RIC  
System Organ Class 
Grade 
Respiratory, thoracic and mediastinal disorders 
3 
4 
5 
Grades 3-5 
Skin and subcutaneous tissue disorders 
3 
4 
5 
Grades 3-5 
Surgical and medical procedures 
3 
4 
5 
Grades 3-5 
Vascular disorders 
3 
4 
5 
Grades 3-5 
Any Organ 
3 
4 
5 
Grades 3-5 
 
 
 
EXHIBIT 0901-15: INFECTION SUMMARY BY TREATMENT ARM 
 
Table to summarize the site-reported infections by treatment arm. Number of infections per patient and maximum severity of infections per patient 
will be tabulated on a per patient basis.  Total number of infections by type of organism will also be tabulated.   
Results for this endpoint will be summarized in the below table. 
 


22 
 
 
Treatment Arm 
Total 
MAC  
RIC  
 
N    %  
N    %  
N    %  
# Patients Transplanted 
 
 
 
# Patients with Infections 
 
 
 
# Patients with Infection Reports 
 
 
 
           =1 
 
 
 
           =2 
 
 
 
           =3 
 
 
 
           =4 
 
 
 
           =5 
 
 
 
           >=6 
 
 
 
Total Infection Events 
 
 
 
Maximum Severity by Patient 
 
 
 
           None 
 
 
 
           Moderate 
 
 
 
           Severe 
 
 
 
           Life Threatening/Fatal 
 
 
 
Infection by Type (# of patients) 
 
 
 
           Bacterial 
 
 
 
           Viral 
 
 
 
           Fungal 
 
 
 
           Protozoal 
 
 
 
           Other 
 
 
 
 
 
 
 
 


23 
 
EXHIBIT 0901-16: IMMUNE RECONSTITUTION BY TREATMENT ARM  
Quantitative assessment of peripheral blood CD3, CD4, CD8, CD19 and CD56 by flow cytometric analysis will be tabulated by time period after 
transplant.  The concentration of lymphocyte subsets will be compared between treatment arms at 100 days, 12 and 18 months from transplant 
using a nonparametric Mann-Whitney test.  To account for potential imbalances caused by differences in survival probabilities, the concentration 
of lymphocyte subsets for patients who died prior to the assessment period will be assigned as zero. 
Table to summarize the descriptive statistics for survivors (mean, standard deviation, median etc.) at each time point. 
Box plots by treatment arm to show the distribution across various time points for each cell, corresponding to the table. 
Results for this endpoint will be summarized in the below table besides the box plots. 
 
 
Treatment Arm 
All 
 
P-value 
MAC 
RIC 
N Mean Std Dev Median N Mean Std Dev Median N Mean Std Dev Median 
CD3 (cells/µL) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 (cells/µL) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD8 (cells/µL) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD19 (cells/µL) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 


24 
 
 
Treatment Arm 
All 
 
P-value 
MAC 
RIC 
N Mean Std Dev Median N Mean Std Dev Median N Mean Std Dev Median 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD56+ (cells/µL) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD45+ (cells/µL) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EXHIBIT 0901-17: QUALITY OF LIFE BY TREATMENT ARM 
 
QOL will be described and compared between the two treatment arms utilizing the FACT-BMT Trial Outcome Index (comprised of the physical, 
functional and BMT-specific items), the MOS-SF36 Physical Component Score (PCS) and Mental Component Score (MCS), the MDASI 
interference and symptom subscales, the EQ-5D utility score, and the categorical components of the occupational functioning, global quality of life, 
and chronic GVHD self reported scales.  The questionnaires will be scored according to standard procedures.  The self report questionnaires will 
be completed prior to transplantation and subsequently at 100 days, 12 months, and 18 months from randomization or until death.  HQL will be 
described and compared between the two treatment arms over time.   


25 
 
Differences in quality of life will be assessed in several ways.  For the descriptive analysis, only QOL scores for survivors at specific time points 
will be compared between treatment arms using simple T-tests.  In the primary analysis, linear mixed models will be used to assess differences in 
QOL scores over time and to explore covariates associated with QOL in survivors.  Additional secondary analysis to account for differences in 
survival rates between treatment groups will be performed using the Integrated Quality Adjusted Survival.  The Integrated Quality Adjusted 
Survival approach aggregates QOL over the entire period of observation.  Finally, if missing data occur for survivors, mechanism and patterns of 
missing data will be analyzed.  In addition, the joint mixed-effects model for informatively censored longitudinal data developed by Schluchter will 
be explored to identify clinical events associated with changes in QOL overtime. 
Results for this endpoint from exploratory analyses will be summarized in the below table. 
 
HQL 
Treatment Arm 
All 
 
P-value 
MAC 
RIC 
N Mean Std Dev Median N Mean Std Dev Median N Mean Std Dev Median 
Global QOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall feeling  
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall health 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT BMT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Well-Being (7 
Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 


26 
 
HQL 
Treatment Arm 
All 
 
P-value 
MAC 
RIC 
N Mean Std Dev Median N Mean Std Dev Median N Mean Std Dev Median 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
Social / Family Well-Being 
(7 Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
Emotional Well-Being (6 
Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional Well-Being (7 
Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT BMT Concerns (10 
Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-G Total (27 Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 


27 
 
HQL 
Treatment Arm 
All 
 
P-value 
MAC 
RIC 
N Mean Std Dev Median N Mean Std Dev Median N Mean Std Dev Median 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-BMT Total (37 
Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-BMT Trial Outcome 
Index (24 Items) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Component 
Score (PCS) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mental Component Score 
(MCS) 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
MDASI interference and 
symptom subscales 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 


28 
 
HQL 
Treatment Arm 
All 
 
P-value 
MAC 
RIC 
N Mean Std Dev Median N Mean Std Dev Median N Mean Std Dev Median 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D utility score 
Day 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 100 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 365 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 540 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes/Concerns: For ASH abstract, will only do exploratory analyses for the abstract.  So the final results from multivariate analysis will be 
provided until the final dataset available to prepare for the manuscript and ASH presentation, or even a secondary paper.   
 
EXHIBIT 0901-18: ACCRUAL OVER TIME  
Table showing accrual numbers for each participating center, actual accrual versus projected accrual number. 
 
EXHIBIT 0901-19: SIGNIFICANT PROTOCOL DEVIATIONS 
Table listing the cumulative significant protocol deviations occurred during the study, including transplant center, patient ID, description of the 
protocol deviations. 
 
EXHIBIT 0901-20: MULTIVARIATE ANALYSIS FOR PRIMARY AND SECONDARY ENDPOINTS 
Will run COX model for the primary endpoint and some secondary endpoints like OS, DFS, relapse and TRM in multivariate analyses. 
Disease risk, donor type, primary disease, conditioning regimen and all demographic and baseline characteristic shown to be significantly different 
between treatment arms will be likely included in the Cox model to adjust for potential imbalances. A gender effect will be examined as well as 
interaction with the treatment arm. The proportional hazards assumption will be checked for all covariates. Treatment arm will be forced to be 
included in the COX model.  Backward selection will be used for model building.  
Notes/Concerns: For ASH abstract, will not do any multivariate analyses.  Multivariate models will not be run until final dataset is closed, which is 
expected to be in October 2015.   So the final results from multivariate analysis will be provided for the manuscript and ASH presentation.   
 


29 
 
EXHIBIT 0901-21: SUBGROUP ANALYSES OF PRIMARY ENDPOINT BY CONDITIONING REGIMEN AND DISEASE 
 
We will utilize the data on conditioning regimen choice pre-specified prior to randomization to examine specific myeloablative conditioning regimen 
comparisons on the primary endpoint - OS.  First we will summarize the 6 different combinations of myeloablative and RIC regimen choices that a 
center might pre-specify prior to randomization as in the table below: 
 
Treatment Arm (per randomization) 
 
Prespecified regimen pair 
(MAC vs. RIC) 
MAC                          
(n, %) 
RIC                           
(n, %) 
Total                          
(n, %) 
Bu/Flu vs. Flu/Bu  
 
 
 
Bu/Flu vs. Flu/Mel 
 
 
 
Bu/Cy vs. Flu/Bu 
 
 
 
Bu/Cy vs. Flu/Mel 
 
 
 
Cy/TBI vs. Flu/Bu 
 
 
 
Cy/TBI vs. Flu/Mel 
 
 
 
Next we will do a forest plot of the difference in survival probabilities at 18 months for each pre-specified regimen pair, showing the difference and 
the confidence interval for each regimen pair.  We will formally assess interaction between conditioning intensity and choice of regimen pairs by 
testing whether the differences in survival probabilities between MAC and RIC are consistent across all regimen pairs. 
 
We will also utilize the data on primary disease to examine if the primary outcome – OS varies by disease (MDS or AML). We will estimate survival 
probabilities at 18 months for each disease with each intensity, will show the difference in survival in a forest plot, and will formally test for 
interaction between conditioning intensity and disease. 
 
Disease 
                          
Primary Endpoint: OS 
Treatment Arm 
             
P-value 
MAC 
RIC 
MDS patients 
18 month OS (95% CI) 
 
 
 
AML patients 
18 month OS (95% CI) 
 
 
 
Note: Analyses in this exhibit are exploratory analyses (not defined in the protocol) and patients number in some groups may be relatively small.  
Additional exploratory subgroup analyses by patient age, performance score, cytogenetics risk and comorbility will also be conducted in a similar 
manner.