A Multi-Center Biologic Assignment Trial Comparing Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients w/Intermediate-2 & High Risk Myelodysplastic Syndrome (BMTCTN1102)
Phase: PHASE2
Conditions: MDS
Sponsor: Medical College of Wisconsin



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PROTOCOL SYNOPSIS - BMT CTN PROTOCOL 1102  
 
A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic 
Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in 
Patients Aged 50-75 with Intermediate-2 and High Risk Myelodysplastic Syndrome 
 
 
Study Chairpersons:  
Ryotaro Nakamura, M.D. and Corey Cutler, M.D., M.P.H., F.R.C.P.(C) 
 
Study Design: 
This study is designed as a multicenter trial, with biological assignment 
to one of two study arms; Arm 1: Reduced intensity conditioning 
allogeneic hematopoietic cell transplantation (RIC-alloHCT), Arm 2: 
Non-Transplant Therapy/Best Supportive Care. 
 
Primary Objective: 
The primary objective is to compare the three-year overall survival (OS) 
probabilities between two treatment arms. 
 
Secondary Objectives: Patients will also be assessed for the following:  
1. Compare leukemia-free survival (LFS) at 3 years from patient 
consent.  
2. Compare Quality of Life (QOL) measures between treatment arms 
3. Compare Cost-Effectiveness measures between treatment arms (see 
Appendix F for ancillary cost-effectiveness protocol) 
 
Accrual Objective: 
The trial will accrue a total of 338 patients if the ratio of HCT vs. 
nonHCT is 6:4 and 400 patients if the ratio of HCT vs. nonHCT is 7:3. 
 
Accrual Period:  
The estimated accrual period is 2.5-3.5 years. 
 
Study Duration: 
Patients will be followed for three years after biological assignment; total 
time from start of accrual will be approximately 5.5-6.5 years. 
 
Eligibility Criteria: 
Patients 50-75 years of age with a history of de novo intermediate-2 or 
high-risk myelodysplastic syndrome (MDS) by the International 
Prognostic Scoring System (IPSS) with < 20% marrow blasts.  MDS 
must be of an acceptable subtype.  Patients must be considered to be 
suitable RIC alloHCT candidates at the time of initial evaluation based 
on medical history, physical examination, and available laboratory tests.  
Specific testing for organ function is not required for eligibility but, if 
available, these tests should be used to judge eligibility.  
 
Patients and physicians must be willing to comply with treatment 
assignment: 

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1. No intent to proceed with alloHCT using donor sources not specified 
in this protocol, including HLA-mismatched related or unrelated 
donors (< 6/6 HLA related matched or < 8/8 HLA unrelated 
matched) or umbilical cord blood unit(s) 
2. No intent to use myeloablative conditioning regimens 
3. Intent to proceed with RIC alloHCT if a matched sibling or matched 
unrelated donor is identified.  There is no requirement as to the 
timing of the transplantation. 
 
To be biologically assigned to the alloHCT arm, patients must have 
either a 6/6 HLA-matched related donor, defined by Class I (HLA-A 
and -B) intermediate resolution or high resolution DNA-based typing 
and Class II (HLA-DRBI) at high resolution DNA-based typing OR an 
8/8 HLA-A, -B, -C, and -DRB1 at high resolution DNA-based typing 
unrelated donor identified within 90 days from the date of consent.  

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STUDY SCHEMA 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Background .................................................................................................................... 1-1 
1.2. 
Myelodysplastic Syndrome ........................................................................................... 1-1 
1.3. 
Allogeneic Hematopoietic Cell Transplantation for MDS ......................................... 1-1 
1.4. 
Hypomethylating Therapy for Treatment of MDS..................................................... 1-3 
1.5. 
Quality of Life ................................................................................................................ 1-5 
1.6. 
Study Rationale .............................................................................................................. 1-5 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Study Objectives............................................................................................................. 2-2 
2.2.1. 
Primary Objective ....................................................................................................... 2-2 
2.2.2. 
Secondary Objectives .................................................................................................. 2-2 
2.3. 
Patient Eligibility ........................................................................................................... 2-2 
2.3.1. 
Patient Inclusion Criteria............................................................................................. 2-2 
2.3.2. 
Patient Exclusion Criteria ........................................................................................... 2-3 
2.4. 
Donor Selection Guidelines ........................................................................................... 2-4 
2.5. 
Study Treatments ........................................................................................................... 2-4 
2.5.1. 
Hypomethylating Therapy – Examples of Standard Therapies .................................. 2-4 
2.5.2. 
Reduced Intensity Conditioning Regimens ................................................................. 2-4 
2.5.3. 
GVHD Prophylaxis Regimen ...................................................................................... 2-4 
2.6. 
Supportive Care ............................................................................................................. 2-5 
2.6.1. 
Post-HCT .................................................................................................................... 2-5 
2.6.2. 
Hypomethylating Therapy/Best Supportive Care ....................................................... 2-5 
2.7. 
Participant Risks ............................................................................................................ 2-5 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 3-1 
3.1. 
Primary Objective and Endpoint ................................................................................. 3-1 
3.2. 
Secondary Objectives and Endpoints........................................................................... 3-1 
3.2.1. 
Three-year Leukemia-free Survival (LFS).................................................................. 3-1 
3.2.2. 
Relapse for HCT Arm ................................................................................................. 3-1 
3.2.3. 
QOL Comparison Between Transplant and Non-Transplant Therapy ....................... 3-1 
3.2.4. 
Cost-Effectiveness Analysis ....................................................................................... 3-2 
4. 
PATIENT ENROLLMENT AND EVALUATION .................................................... 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.1.1. 
Screening and Eligibility Procedures .......................................................................... 4-1 
4.1.2. 
Evaluations and Research Samples at Enrollment ...................................................... 4-1 
4.1.3. 
Donor Search ............................................................................................................... 4-3 
4.2. 
Treatment Group Assignment ...................................................................................... 4-3 
4.3. 
Methodology and Documentation of Study Events .................................................... 4-4 
4.3.1. 
Approaching Patients, Eligibility, Screening, and Obtaining Consent ....................... 4-4 

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4.3.2. 
Search Commencement ............................................................................................... 4-4 
4.3.3. 
Search End and Assignment to alloHCT versus non-HCT Arm (Donor versus no-Donor)
 ..................................................................................................................................... 4-4 
4.4. 
Study Monitoring ........................................................................................................... 4-5 
4.4.1. 
Follow-up Schedule for non-HCT Arm ...................................................................... 4-5 
4.4.2. 
Follow-up Schedule for HCT Arm ............................................................................. 4-5 
4.4.3. 
Collection of QOL Data .............................................................................................. 4-6 
4.4.4. 
Locating Missing Patients ........................................................................................... 4-6 
4.4.5. 
Adverse Event Reporting ............................................................................................ 4-6 
4.4.6. 
Patient Evaluations prior to HCT Therapy.................................................................. 4-6 
4.5. 
OPTIONAL Research Samples Pre-transplant and at Relapse (RIC alloHCT Arm 
only) ............................................................................................................................ 4-7 
4.6. 
OPTIONAL Cost-Effectiveness Analysis Information............................................... 4-7 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Study Overview .............................................................................................................. 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Biologic Assignment and Randomization ................................................................... 5-2 
5.1.3. 
Intention-to-Treat Principle ......................................................................................... 5-2 
5.2. 
Sample Size and Power Calculations ........................................................................... 5-2 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-3 
5.3.1. 
Interim Analysis for Efficacy ...................................................................................... 5-4 
5.3.2. 
Guideline for Safety Monitoring ................................................................................. 5-6 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-8 
5.5. 
Analysis Plan .................................................................................................................. 5-8 
5.5.1. 
Analysis of the Primary Endpoint ............................................................................... 5-8 
5.5.2. 
Analysis of Secondary Endpoints ............................................................................... 5-8 
5.5.3. 
Subgroup Analyses ..................................................................................................... 5-9 
5.5.4. 
Secondary Analyses of RIC alloHCT Arm ............................................................... 5-10 
5.5.5. 
Exploratory Analysis of Non-transplant Therapy Arm ............................................. 5-10 
 
 
LIST OF APPENDICES 
 
APPENDIX A: HUMAN SUBJECTS 
APPENDIX B: 
INFORMED CONSENT 
APPENDIX C: LABORATORY PROCEDURES 
APPENDIX D: KARNOFSKY AND ECOG PERFORMANCE STATUS SCALES 
APPENDIX E: 
IPSS/IPSS-R SCORE 
APPENDIX F: 
ANCILLARY COST-EFFECTIVENESS ANALYSIS PROTOCOL 
APPENDIX G: REFERENCES 

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CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
 
A subject of clinical urgency for researchers, clinicians, patients, and health care underwriters such 
as Medicare, is the role of allogeneic hematopoietic cell transplantation (alloHCT) in the treatment 
of older patients with higher risk myelodysplastic syndromes (MDS).  The use of reduced intensity 
conditioning (RIC) regimens has extended HCT to the care of older patients with acute 
myelogenous leukemia (AML) and lymphoma and a number of retrospective and phase II trials 
for patients with MDS now show the curative potential of RIC alloHCT in selected patients.1, 2, 3, 
4, 5, 6, 7  Concomitantly, new drugs have been developed for nontransplant therapy of MDS, 
including hypomethylating agents, which result in improved hematopoietic function and delayed 
transformation to acute leukemia.8  While it is believed that RIC alloHCT provides a survival 
advantage over hypomethylating therapy because of its curative potential, RIC alloHCT also 
carries the risk of early transplant-related mortality and the relative effectiveness of the two 
approaches is uncertain, particularly in older patients.  This protocol is designed to evaluate the 
relative benefits of RIC alloHCT compared to non-transplant therapies focusing on overall 
survival.  The hypothesis to be tested is that RIC alloHCT improves overall survival in patients 
with higher risk MDS compared to patients who receive only hypomethylating therapy or best 
supportive care.  The study is a prospective, multi-center, biologic assignment trial of 
hypomethylating therapy or other best supportive care versus RIC alloHCT from HLA-matched 
related and unrelated donors in patients aged 50.0 to 75.0 years with higher-risk MDS. 
 
1.2. 
Myelodysplastic Syndrome 
 
MDS is a clonal disorder of hematopoietic precursors and stem cells, which may evolve to a 
terminal phase resembling acute leukemia.  Alternatively, patients may suffer progressive 
peripheral blood cytopenias and hematopoietic failure, eventually succumbing to complications of 
bleeding and infection.  The international prognostic scoring system (IPSS) for MDS assesses 
patients’ risk for transformation and survival at the time of diagnosis and is based on analysis of 
bone marrow blasts, karyotype, and cytopenias.9  Median survival for patients with low-risk 
disease is approximately 5.7 years; it is 11.8 years for low-risk patients younger than 60.  Among 
patients with intermediate-2 disease (composite score 1.5-2), median survival is 1.2 years for all 
patients and 1.8 years for those younger than 60.  In patients with high risk disease, however, the 
prognosis is measured in months in both younger and older patients.10  A newer iteration of the 
IPSS score was recently proposed but has not yet been used in clinical trials.11   
 
1.3. 
Allogeneic Hematopoietic Cell Transplantation for MDS 
 
AlloHCT is the only curative treatment modality for MDS, but the use and timing of 
transplantation remain controversial, particularly in older patients.  The relatively chronic course 
of MDS often leads to reluctance to accept the risks associated with HCT where non-relapse 
mortality (NRM) rates are in the range of 20-35%, related to organ toxicity, graft-versus-host 

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disease (GVHD), and infections.  Recently, an HCT-specific co-morbidity index has provided a 
useful guide for HCT risk assessment of HCT and can be applied to transplantation candidates 
with a variety of disorders, including MDS.12  The IPSS is also useful in determining the timing 
of transplantation in younger patients who have HLA-identical siblings.13, 14, 15  Several studies 
indicate that patients in the intermediate-2 and high risk IPSS groups have longer life expectancy 
when transplanted early, with delay of HCT resulting in loss of life years.  In contrast, patients in 
the low-risk group have the best life expectancy if HCT is delayed until there is evidence of disease 
progression.  Optimal timing for patients in the intermediate-1 risk category is less clear.14  A 
recent study extended a Markov decision model to elderly MDS patients and showed for de novo 
MDS patients aged 60–70 years with low/intermediate-1 disease, early transplantation was not the 
preferred strategy unless MDS-associated QOL impairment was substantial.  For intermediate-
2/high IPSS risk, early RIC alloHCT offered a life expectancy benefit, with quality adjusted 
survival benefit detectable earlier.16  While no prospective controlled study has been published, a 
retrospective study comparing alloHCT and treatments with hypomethylating agents suggests a 
survival advantage for alloHCT compared with azacytidine therapy in medically fit patients with 
high-risk MDS age 60-70 years.17 
 
Conventional high dose conditioning regimens include myeloablative doses of chemotherapy 
and/or radiation.  These regimens are often poorly tolerated by older patients or those with 
significant comorbidities and are generally offered to patients under the age of 50 years with good 
performance status.  The introduction of RIC regimens over the last decade has allowed expansion 
of the upper age for alloHCT, with patients above age 70 transplanted successfully.  Unfortunately, 
though treatment-related mortality is lower, some studies suggest higher incidences of relapse with 
lower intensity regimens.  Patients with the low disease burden tend to have the best success rates 
with this approach.  For this reason, some have recommended the use of cytoreductive 
chemotherapy prior to RIC alloHCT, but no controlled trials of this strategy have been 
conducted.18, 19. 
 
Over the last several years, multiple groups have used RIC alloHCT to treat MDS with two to 
three-year overall survival rates ranging from 27% to 70% depending on cohort and regimen 
characteristics.1, 3, 4, 5, 20  Lim et al analyzed a group of 1,333 patients reported to the European 
Group for Blood and Marrow Transplantation (EBMT), ages 50 to 74 (median 62); 62% received 
RIC.  The four-year survival rate was 31%, the NRM rate was 39% and the relapse rate was 36%.6  
No significant impact of age or transplantation regimen on outcomes was noted.  Advanced disease 
stage at transplantation was the major independent predictor of poor outcomes.  McClune et al 
reported data on 181 patients to the Center for International Blood and Marrow Transplant 
Research (CIBMTR), aged 40 to ≥ 65 (median 67); 68% received RIC.  The two-year survival rate 
for this group was 45%, the NRM rate was 35%, and the relapse rate was 29%.7  As in the EBMT 
study, the CIBMTR data showed no significant impact of age on outcomes.  These two recent 
registry-based studies of older patients transplanted for MDS reflect results in the community-at-
large and support the safety of alloHCT for older patients with MDS. 
 
More recently, a study from the CIBMTR evaluated the outcomes of 701 adult MDS patients who 
underwent allogeneic HCT between 2002 and 2006.  This study focused its analyses on the type 
of HCT donors (matched-related donor [MRD], n=176; 8/8 HLA allele matched unrelated donor 
[MUD], n=413; 7/8 MUD, n=112).  The median age was 53 years (range, 22-78).  Sixty-five 

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percent had advanced disease at HCT and 19% had therapy-related MDS.  Seventy-seven percent 
received peripheral blood stem cells, and 40% received RIC regimens.  The 100-day cumulative 
incidence of grades B-D acute GVHD was significantly lower in MRD HCT recipients than 8/8 
MUD and 7/8 MUD HCT recipients (42%, 54%, and 57%, respectively; p=.009).  The 
corresponding adjusted three-year disease free survival (DFS)/survival estimates were 40%/47% 
for MRD, 35%/38% for 8/8 MUD, and 29%/31% for 7/8 MUD HCT recipients.  In multivariate 
analysis, adjusting for patient-related (age, gender, KPS), disease-related (IPSS stage at diagnosis, 
WBC count at diagnosis, therapy-related MDS, and disease status at HCT), and HCT-related 
variables (time between diagnosis and HCT, donor-recipient CMV and gender match, graft type, 
conditioning and GVHD prophylaxis regimens), 8/8 MUD HCT recipients had similar DFS and 
survival rates compared to MRD HCT recipients (relative risk [RR] 1.11 (95% confidence 
intervals [CI] 0.89-1.39) and 1.24 (95% CI 0.98-1.56), respectively).  7/8 MUD HCT recipients 
had an inferior DFS and survival compared to MRD HCT recipients (RR 1.43 (95% CI 1.08-1.91) 
and 1.62 (95% CI 1.21-2.17), respectively), and 8/8 MUD HCT recipients (RR 1.29 (95% CI 1.00-
1.65) and 1.30 (95% CI 1.01-1.68), respectively).  Differences in outcome were largely related to 
excess TRM (RR 1.37 and 1.71 for 8/8 MUD and 7/8 MUD respectively, p < 0.05 for both 
comparisons).  Unrelated donor status or mismatch was not associated with less relapse (overall p 
value=0.33).  In patients with MDS, transplantation from 8/8 MUD and MRD donors produce 
similar survival; however, 7/8 MUD HCT is associated with inferior outcomes.21 
 
1.4. 
Hypomethylating Therapy for Treatment of MDS 
 
Azacytidine (5-azacytidine) and decitabine (5-aza-2’-deoxycytidine) are two hypomethylating 
agents approved by the Food and Drug Administration for treatment of MDS.  The rationale for 
hypomethylation therapy is the observation that aberrant DNA methylation is frequently seen in 
patients with MDS.  These drugs indirectly deplete methylcytosine and cause hypomethylation of 
target gene promoters involved in disease initiation or progression, making them appropriate 
targets for pharmacologic therapy. 
 
Azacytidine was first synthesized in 1963 and demonstrated activity in four AML trials in the 
1970s, resulting in complete remission in 17% to 36% of patients.22  The registration study leading 
to FDA approval for azacytidine for all MDS subtypes was a phase III trial in which transfusion-
dependent MDS patients were randomized to receive azacytidine or supportive care.  Patients in 
the supportive care arm were allowed to cross over to the treatment arm at time of disease 
progression.8  Ninety-nine patients were randomized to the treatment arm, in which azacytidine 
was administered at 75 mg/m2 daily for 7 days of a 28-day cycle, and 92 to the supportive care 
arm, of whom 49 crossed over to receive active therapy.  When these and other CALGB data were 
analyzed using international working group (IWG) criteria, Silverman et al reported response rates 
of 14% complete response (CR) + partial response (PR) and 30% hematologic improvement.8  
There was a significant delay in transformation to AML or death, but not a significant prolongation 
of survival in the treatment arm.  Major toxicities included cytopenias.  Patients also reported 
nausea and injection site-related complications. 
 
Azacytidine was next explored in a Phase III trial in which higher-risk patients with MDS were 
randomized to receive azacytidine, at the dose used in the registration study, versus conventional 
care including: best supportive care, low-dose cytarabine, or intensive AML-type induction 

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chemotherapy, as selected by investigators prior to randomization.23  Of 358 patients, 179 were 
randomized to azacytidine and 179 to conventional care, with the majority (n=105) receiving best 
supportive care.  Overall response rates (ORR) with azacytidine were significantly greater than 
with conventional care, 29% versus 21%.  With a median follow-up of 21.1 months, median 
survival was 24.5 months for the azacytidine arm and 15 months for the conventional care arm 
(hazard ratio .58, P = .0001).  The superior activity of azacytidine in this study, compared with 
both conventional care and previous azacytidine studies, is credited to an appropriately selected 
population of higher-risk patients with MDS and to a median duration of therapy of more than 9 
months. 
 
Decitabine, developed in 1964, was also first explored in AML populations.  The Phase III 
registration trial for MDS randomized 89 patients to receive the drug, 81 to receive supportive 
care.24  Patients received decitabine at a dose of 15 mg/m2 every 8 hours over 3 days, with a cycle 
repeated every 6 weeks.  Using IWG criteria, CRs occurred in 9%, PRs in 8%, and hematologic 
improvement in 13% of patients, for an ORR of 30%.  As with 5-azacytidine, the major toxicities 
were hematologic.  Unlike with azacytidine, there was not a significant delay in transformation to 
AML or death in this study.  Since the two drugs are biologically similar, this difference is often 
attributed to variation in the patient population enrolled to each study (more early MDS patients 
in the decitabine study) and to an inadequate number of cycles of decitabine given (median of 2).  
Alternate dosing schedules, including once-daily dosing of decitabine over 5 days every 28-day 
cycle, were explored in higher-risk patients given a median of > 5 cycles of therapy, and yielded 
CR rates equivalent or better than those seen with azacytidine.25, 26  A Phase III survival study in 
higher-risk patients with MDS was conducted in Europe, comparing 119 patients treated with 
decitabine at the registration study dosing schedule, to 114 patients randomized to best supportive 
care.  While the CR+PR rate was 23% (similar to azacytidine), the study was unable to demonstrate 
a survival advantage, with patients randomized to drug living a median of 10.1 months and those 
randomized to best supportive care living a median of 5.8 months (hazard ratio 0.88, P = .38).  
Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), 
was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, 
respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, 
respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24).  AML transformation was significantly (P 
= .036) reduced at 1 year (from 33% with BSC to 22% with decitabine).  
 
Combination therapy has also been explored.  A phase II trial of azacytidine (75 mg/m2/d x 5 days) 
in combination with lenalidomide (10 mg/d x 21 days (28-day cycle)) was conducted in patients 
with higher-risk MDS.27  This study demonstrated the overall response rate (per modified MDS 
IWG criteria) of 72% (CR: 44%), median CR duration of 17+ months (range, 3-39+) and median 
overall survival of 37+ months (range, 7-55+) for CR patients, 13.6 months for the entire cohort 
(range, 3-55).  Another phase I study evaluated the combination of azacytidine and vorinostat in 
MDS and AML patients.  There were no serious non-hematologic toxicities, and responses were 
seen in up to 86% of patients.28  The Southwest Oncology Group (SWOG) has recently begun 
accrual to a 3-arm randomized phase II study of a) azacytidine + lenalidomide versus b) 
azacytidine + vorinostat versus c) azacytidine alone for higher risk myelodysplastic syndromes.29  
 
Although these results from hypomethylating therapy represent an important advance for patients 
with MDS, 40% to 50% of patients did not respond to therapy, and most responders experienced 

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disease progression within 2 years of response.23  In a recent study,30 435 patients with high-risk 
MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated 
for outcome after azacytidine failure.  The cohort of patients included four data sets (i.e., AZA001, 
J9950, and J0443 trials and the French compassionate use program).  With the median follow-up 
after azacytidine failure of 15 months, the median overall survival was 5.6 months, and the 2-year 
survival probability was 15%.  Data on treatment administered after azacytidine failure were 
available for 270 patients, demonstrating a better outcome associated with allogeneic HCT and 
investigational agents compared with conventional clinical care.  
 
1.5. 
Quality of Life  
 
In the randomized trials comparing hypomethylating agents and best supportive care, both 
azacytidine and decitabine were associated with an improved self-reported QOL scales, evidenced 
by the reduction of transfusion requirements, decreased rate of infections and hospitalizations, as 
well as improvement of fatigue, dyspnea, and physical functioning in patients receiving 
azacytidine.  Comparisons of QOL between alloHCT and hypomethylating agents/non-HCT 
therapy may be confounded by systematic differences in patients who undergo alloHCT versus 
non-alloHCT therapy.  In a literature review,31 three studies have reported worse QOL after 
alloHCT, including physical, cognitive, emotional, and social functioning as well as overall QOL.  
Four studies reported no statistically significant differences between alloHCT and standard-dose 
chemotherapy.  QOL appears to be better after alloHCT than chemotherapy when patients with 
and without relapse are included.  This pattern of findings suggests that differential rates of relapse 
in alloHCT and chemotherapy patients may influence QOL findings, with higher rates of relapse 
in the chemotherapy group potentially associated with worse QOL in that group.  As MDS patients 
generally require continued treatment and supportive care, the QOL measurements may be 
improved with alloHCT despite the known adverse factor of GVHD.  
 
1.6. 
Study Rationale 
 
Advances in both the understanding of MDS and in the development of alternatives to standard 
leukemia induction therapy in the treatment of MDS, including hypomethylating therapy and RIC 
alloHCT for older patients, lead to questions about the appropriate role and timing of these 
therapies.  This trial will compare RIC alloHCT with hypomethylating/best supportive care in 
patients with higher risk MDS who are referred for transplantation evaluation.  The proposed trial 
is consistent with the National Comprehensive Cancer Center (NCCN) Treatment Guidelines for 
Myelodysplastic Syndromes32 and with suggestions from a recent review article by Giralt et al. 
regarding clinical trials to provide evidence for Medicare coverage of allogeneic transplant for 
MDS.33  The design will use assignment to transplantation, when a donor is available, or best 
supportive care (usually hypomethylating therapy) when a suitable matched related or unrelated 
donor is not available.  Patients with an HLA-matched sibling or unrelated donor will proceed to 
allogeneic transplantation utilizing an institutionally-approved RIC regimen.  Patients without a 
suitable donor will be offered hypomethylating therapy (or other best supportive care).  The 
primary objective is to determine whether there is a meaningful benefit (overall survival 
advantage) among those who undergo RIC alloHCT when compared to those who continue on 
hypomethylating therapy/best supportive care.   
 

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CHAPTER 2 
 
 
2. 
STUDY DESIGN  
 
2.1. 
Study Overview 
 
The study hypothesis is that use of RIC alloHCT will improve three year overall survival in patients 
with Intermediate-2/High risk MDS when compared to DNA hypomethylating therapy / best 
supportive care.  This study is designed as a prospective, comparative biologic assignment trial of 
RIC alloHCT from related and unrelated donors versus hypomethylating therapy / best supportive 
care among patients with Intermediate-2/High risk MDS.  Study subjects will be biologically 
assigned to one of the two treatment arms based on the availability of an HLA-matched related or 
unrelated donor (Figure 2.1).  All subjects are initially assigned to the non-transplant arm.  Subjects 
will be re-assigned to the transplant arm should a suitable donor be identified within 90 days of 
informed consent.  Both the RIC alloHCT regimen and non-transplant therapy/best supportive care 
will be at discretion of the treating physician.  Patients will be evaluated for survival, progression 
to acute leukemia, and quality of life (QOL).  
 
 
 
Figure 2.1: Study Schema 

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2.2. 
Study Objectives 
 
2.2.1. Primary Objective 
 
Compare the three-year overall survival probabilities between the two study arms using an intent-
to-treat analysis.  
Arm 1: RIC alloHCT  
Arm 2: Hypomethylating Therapy / Best Supportive Care 
 
2.2.2. Secondary Objectives 
1. Compare leukemia-free survival (LFS) at 3 years from patient consent 
2. Compare QOL measures between treatment arms 
3. Compare Cost-Effectiveness measures between treatment arms (see Appendix F for 
ancillary cost-effectiveness protocol) 
 
2.3. 
Patient Eligibility 
 
Patients must meet specified eligibility criteria for entry into the study.   
 
2.3.1. Patient Inclusion Criteria  
 
Patients fulfilling the following criteria will be eligible for entry into this study: 
1. Patients with de novo MDS who have, or have previously had, Intermediate-2 or High risk 
disease as determined by the IPSS (see Appendix E)9.  Current Intermediate-2 or High risk 
disease is NOT a requirement.   
2. Patients must have an acceptable MDS subtype: 
• Refractory cytopenia with unilineage dysplasia (RCUD) (includes refractory anemia 
(RA)) 
• Refractory anemia with ringed sideroblasts (RARS) 
• Refractory anemia with excess blasts (RAEB-1) 
• Refractory anemia with excess blasts (RAEB-2) 
• Refractory cytopenia with multilineage dysplasia (RCMD) 
• Myelodysplastic syndrome with isolated del(5q) (5q–syndrome) 
• Myelodysplastic syndrome (MDS), unclassifiable 
3. Patients must have fewer than 20% marrow blasts within 60 days of consent.  
4. Patients may have received prior therapy for the treatment of MDS, including but not 
limited to: growth factor, transfusion support, immunomodulatory (IMID) therapy, DNA 
hypomethylating therapy, or cytotoxic chemotherapy prior to enrollment. 

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5. Age 50.0-75.0 years. 
6. Karnofsky performance status > 70 or ECOG ≤ 1 (see comparison scale in Appendix D). 
7. Patients are eligible if no formal unrelated donor search has been activated prior to date 
of consent.  A formal unrelated donor search begins at the time at which samples are 
requested from potential NMDP donors. Patients who have started a sibling donor search 
or who have found a matched sibling donor are eligible.  
8. Patients and physicians must be willing to comply with treatment assignment: 
a) No intent to proceed with alloHCT using donor sources not specified in this protocol, 
including HLA-mismatched related or unrelated donors (< 6/6 HLA related matched 
or < 8/8 HLA unrelated matched) or umbilical cord blood unit(s). 
b) No intent to use myeloablative conditioning regimens. 
c) Intent to proceed with RIC alloHCT if a matched sibling or matched unrelated donor 
is identified.  There is no requirement as to the timing of the transplantation. 
9. Patients must be considered to be suitable RIC alloHCT candidates at the time of 
enrollment based on medical history, physical examination, and available laboratory tests.  
Specific testing for organ function is not required for eligibility but, if available, these tests 
should be used to judge eligibility.  
10. Signed informed consent 
 
2.3.2. Patient Exclusion Criteria 
 
Patients with the following will be ineligible for enrollment onto this study: 
1. Therapy-related MDS (defined as the occurrence of MDS due to prior exposure to systemic 
chemotherapy and/or radiation) 
2. Current or prior diagnosis of AML 
3. Chronic myelomonocytic leukemia or myelodysplastic/myeloproliferative neoplasm 
(unacceptable MDS subtypes); uncontrolled bacterial, viral or fungal infection (currently 
taking medication and with progression or no clinical improvement) at time of enrollment. 
4. Patients with prior malignancies, except treated non-melanoma skin cancer or treated 
cervical carcinoma in situ.  Cancer treated with curative surgery without 
chemotherapy/radiation therapy > 5 years previously will be allowed. Cancer treated with 
curative surgery < 5 years previously will not be allowed unless approved by the Protocol 
Officer or one of the Protocol Chairs. 
5. Prior autologous or allogeneic HCT 
6. Human Immunodeficiency Virus (HIV) infection 
7. Patients of childbearing potential unwilling to use contraceptive techniques 
8. Patients with psychosocial conditions that would prevent study compliance 
 

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2.4. 
Donor Selection Guidelines 
 
Donors must be a 6/6 HLA-matched related donor, defined by Class I (HLA-A and -B) 
intermediate resolution or high resolution DNA-based typing and Class II (HLA-DRBI) at high 
resolution DNA-based typing (but not monozygotic twins) OR an 8/8 HLA-A, -B, -C, and  
-DRB1 at high resolution DNA-based typing matched unrelated donor identified through the 
National Marrow Donor Program (NMDP).  Donors must meet institutional selection criteria, and 
there is no age restriction for sibling donors.  Allogeneic transplantation using umbilical cord blood 
unit(s), mismatched adult donors (< 6/6 HLA alleles for related and < 8/8 HLA alleles for 
unrelated) or haploidentical donors is not allowed. 
 
2.5. 
Study Treatments  
 
Patients must receive either RIC alloHCT (bone marrow or peripheral blood stem cells) or non-
transplant therapy according to their treatment assignment.  The specific transplant or non-
transplant treatment regimen will be at the discretion of the treating physician.  The following are 
examples of acceptable regimens for non-transplant therapy, conditioning regimens, and GVHD 
prophylaxis regimens.  Hypomethylating therapy is the accepted standard therapy of treatment-
naïve patients with Int-2/High Risk MDS not undergoing transplantation.  Participation in Phase 
II clinical trials of HCT or non-transplant therapy is allowed with the exception of experimental 
graft manipulation studies.  
 
2.5.1. Hypomethylating Therapy – Examples of Standard Therapies 
Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles  
Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles 
Hypomethylating-based therapy on an Intergroup clinical trial (e.g., SWOG S1117) 
 
2.5.2. Reduced Intensity Conditioning Regimens 
 
Institutional standard regimens will be used.  All regimens must be declared by the center as a 
preferred regimen in order to assure that alloHCT is performed according to the institutional 
standard.  Deviations from the preferred regimen must be cleared with the study team.  Institutional 
guidelines for dose modifications for renal impairment, obesity, or other factors are allowed.  As 
a general consideration, the following limits on conditioning dose intensity delineate 
myeloablative regimens: 
1. TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) 
2. Busulfan dose ≥ 9.5 mg/kg 
3. Melphalan ≥ 150 mg/m2  
 
2.5.3. GVHD Prophylaxis Regimen 
 
Institutional standard regimens will be used.  All GHVD regimens must be declared for the center 
as a preferred regimen in order to assure that alloHCT is performed according to the institutional 

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standard.  Deviations from the preferred regimen must be cleared with the study team.  Institutional 
guidelines for dose modifications for renal impairment or other factors are allowed.   
 
Ex vivo T-cell depletion, or in vivo T-cell depletion with ATG or Alemtuzumab regimens are 
allowed when used routinely at an institution.  Highly exploratory phase I trials of ex-vivo T cell 
depletion or other graft manipulations will not be allowed.  The protocol team will review those 
studies. 
 
2.6. 
Supportive Care 
 
2.6.1. Post-HCT 
 
All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) 
and local institutional guidelines.  All patients will receive prophylaxis against bacterial, fungal, 
and viral infections during the post-HCT period according to institutional standards.  
 
2.6.2. Hypomethylating Therapy/Best Supportive Care 
 
All supportive care will be given in keeping with local institutional guidelines. 
 
2.7. 
Participant Risks 
 
AlloHCT recipients incur risks from conditioning and post-HCT complications, which must be 
weighed against the risk of complications in the absence of transplantation during hypomethylating 
therapy/non-HCT therapy.  Major risks common to both transplantation and non-transplantation 
therapies include: 1) Infection, which can be bacterial, viral, parasitic, or fungal, occurs commonly 
after transplantation due to impaired immunologic reconstitution (in MDS, infection occurs due to 
neutropenia and granulocyte dysfunction); 2) Bleeding occurs after transplantation and with non-
transplantation therapy due to thrombocytopenia; 3) Damage of all or any of the major organs may 
occur as a result of reactions to drugs (e.g., chemotherapy, antibiotics, anti-fungal medications), 
and as a result of destructive processes (e.g., infection); and 4) Relapse or progression may occur, 
especially in patients with advanced disease status at time of treatment.  Major risks associated 
with alloHCT can be 1) Acute and chronic GVHD and 2) Graft failure, and both can result in 
significant organ dysfunctions and subsequent mortality.  While expected treatment-related 
mortality (TRM) varies widely in non-HCT therapy depending on its intensity (negligible in 
transfusion support only but up to 5-10% in high-intensity induction therapy), the TRM is expected 
range about 20-30% with RIC alloHCT.  Patients’ QOL can be affected by these clinical 
complications in HCT/non-HCT therapies.  QOL of MDS patients are also known to be reduced 
due to symptoms associated with pancytopenia (infections/bleeding/fatigues) as well as frequent 
need for transfusions.  

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CHAPTER 3 
 
 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
 
3.1. 
Primary Objective and Endpoint 
 
The primary objective for this study is to compare three-year overall survival probabilities between 
two treatment arms (Arm 1: RIC alloHCT and Arm 2: Hypomethylating therapy/best supportive 
care).  Overall survival is calculated for all patients from date of patient consent until death from 
any cause.  Observation is censored at the date of last follow-up for patients last known to be alive.  
 
3.2. 
Secondary Objectives and Endpoints  
 
3.2.1. Three-year Leukemia-free Survival (LFS) 
 
LFS is defined as the time from the date of patient consent to the date of progression to AML or 
death from any cause, whichever comes first.  Observation is censored at the date of last follow-
up for patients known to be alive without leukemia.  Progression to AML is defined as > 20% 
leukemic blasts in bone marrow or in the peripheral blood.  
 
3.2.2. Relapse for HCT Arm  
 
Patients assigned to the HCT arm will be followed for relapse of their MDS. 
 
Disease relapse for patients with MDS: 
• 
Satisfying criteria for evolution into acute leukemia; or, 
• 
Reappearance of pre-transplant morphologic abnormalities, detected in bone 
marrow specimens; 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 (institution of any therapy not 
meant for maintenance or prevention), including withdrawal of immunosuppressive 
therapy or DLI, will be considered evidence of relapse regardless of whether the 
criteria described above are met. 
 
3.2.3. QOL Comparison Between Transplant and Non-Transplant Therapy 
 
The following instruments will be used to assess QOL at study entry, and then serially 6, 12, 18, 
24, and 36 months from enrollment.  Only English- or Spanish-speaking trial participants will be 
included in the QOL studies. 
 

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The FACT-BMT version 4.0 instrument34 is 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.  In this protocol, only the FACT-G will be used, 
which 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 MOS SF-36 instrument35, 36, 37 is a 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.  
 
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). 
 
3.2.4. Cost-Effectiveness Analysis 
 
The primary endpoint for the CEA will be the cost per quality-adjusted life year (QALY) from the 
third party payer perspective with two time horizons: (1) within trial (at 3 years post-enrollment), 
and (2) lifetime using simulating modeling. 
 
The secondary endpoint for the CEA is the cost per QALY from the societal perspective, a broader 
measure that captures health insurer direct medical care costs and patient out-of-pocket direct 
medical and direct non-medical costs. Patient productivity costs (captured as part of QALY 
calculations) will be reported separately. 

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CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. 
Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCSM).  The following procedures should be followed: 
1. After the patient has given informed consent to participate on the study, an authorized user 
at the transplant center completes the BMT CTN 1102 Segment 0 Enrollment Form (patient 
demographic data, and the date that informed consent was signed).  A study number will 
be generated for the patient with the submission of the BMT CTN 1102 Segment 0 
Enrollment Form.   
2. If the patient has bone marrow biopsy results from within the past 60 days, the BMT CTN 
1102 Segment A Enrollment Form should be completed.  If the patient does not have bone 
marrow biopsy results from within the past 60 days, a marrow should be obtained within 
30 days after consent.  The BMT CTN 1102 Segment A Enrollment Form will need to be 
completed once the bone marrow biopsy results are obtained.  Segment A enrollment 
should occur no later than 30 days after Segment 0 enrollment. 
3. Some of the post-transplant outcomes data for this study will be collected through the 
CIBMTR.  If a suitable donor is identified, centers must obtain a CIBMTR Recipient 
Identification (CRID) number at the time of treatment assignment and enter it on the BMT 
CTN 1102 Segment A CIBMTR Recipient ID Form (see CIBMTR Data Collection below). 
 
4.1.2. Evaluations and Research Samples at Enrollment 
 
Since non-HCT patients may not return to the BMT CTN transplant centers after enrollment, the 
baseline demographics and research samples will be collected at this time point.  Patients will have 
a history and physical examination, KPS/ECOG assessment, and baseline laboratory studies 
(CBC/differentials, comprehensive metabolic panel, serum ferritin level) performed as shown in 
Table 4.1.2. 
1.  Disease- and patient-specific data: A modified CIBMTR MDS/MPN Pre-HCT data form 
(CIBMTR Form 2014 MDS) will be used to collect the clinical data at enrollment.  The 
pre-HCT data form (2400) will be used to derive the HCT co-morbidity index.  However, 
it is anticipated that some data may be missing at the time of enrollment (i.e., DLCO, 
FEV1).  Bone marrow data must be current (within 60 days of consent).  If a marrow 
examination is not recent, a bone marrow examination will be repeated for trial entry.  An 
attempt to ascertain the HIGHEST prior IPSS and IPSS-R score should be made by the 
investigator.  Response to prior hypomethylating or other therapies will also be collected 
at the time of enrollment. 

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2. Laboratory tests: See Table 4.1.2. 
3. OPTIONAL research samples: At consent (or within 3 months after consent), a peripheral 
blood sample (50 mL) and buccal swab will be collected for future unspecified research 
from those patients that provide consent to optional research samples.  The BMT CTN 
clinical sites will collect the peripheral blood/buccal swab samples from consenting 
patients prior to receiving study treatment and ship to the BMT CTN repository on the day 
of collection without having to process and freeze (see Appendix C). 
4. QOL data: The baseline QOL survey will be collected within 1 month after Segment A 
enrollment.  QOL interviews will be conducted by the Survey Research Group (SRG).  The 
transplant centers will contact the SRG once a patient is enrolled, either by e-mailing or 
faxing a form with the patient’s contact information.  A separate database will be created 
to house the contact information; no patient contact information will be stored in 
AdvantageEDCSM; it will only contain the 3 QOL questionnaires (FACT-G, MOS SF-36 
and EQ-5D).  Interviewers will call the patient at a day and time that is convenient for 
them, and the interviewers will be trained to enter the data collected into AdvantageEDCSM. 
5. OPTIONAL cost-effectiveness analysis study data: At the time of enrollment, patients 
consenting to the ancillary Cost-Effectiveness analysis study (see Appendix F) will need 
to complete the HIPAA Authorization Form and Patient Contact Information 
Form/Optional Alternate Contact Information Form which will be submitted to the CEA 
study team at Fred Hutchinson Cancer Research Center. 
 
TABLE 4.1.2: REQUIRED PATIENT EVALUATIONS AT TIME OF ENROLLMENT 
Required Studies/Testing 
Informed Consent  
History, Physical Examination, Height and Weight* 
Karnofsky/ECOG Performance Score 
Assessment of HIGHEST IPSS and IPSS-R Score since diagnosis 
CBC with Differential* 
Serum Chemistry Panel with Liver Function Tests* 
Serum Ferritin level* 
HLA Testing 
Bone Marrow Aspiration and Biopsy, Cytogenetic Analysis1 
Patient and MDS Specific Data (CIBMTR Forms 2014 / 2400) 
OPTIONAL Research Samples (Blood / Buccal Swab)  
Quality of Life Assessments2 
HIPAA Authorization Form and Patient Contact Information Form/Optional 
Alternate Contact Information Form for Cost-Effectiveness Analysis Study2,3 
 
Notes:  
1 Review of recently obtained sample (obtained within 60 days prior to consent) is permitted 
2 To be performed by the Survey Research Group 
3 If the patient consents to the Cost-Effectiveness Analysis study 
*Should be taken from the most recent values, preferably within 30 days prior to enrollment 
 

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4.1.3. Donor Search 
 
The transplant coordinator at the transplant center should proceed with their institution’s standard 
procedure to identify a sibling donor, if applicable.  If an unrelated donor search is to be pursued, 
then the coordinator should inform the transplant center’s assigned NMDP coordinator through 
the standard procedure for any unrelated donor. 
 
4.2. 
Treatment Group Assignment 
 
The primary purpose of this study is to compare the outcomes of subjects assigned to 
transplantation with outcomes of those assigned to non-transplant therapy.  Since this is not a 
randomized study, minimizing bias in treatment assignment is critical.  Subjects will be assigned 
to the transplantation arm on the basis of a having an available 6/6 related or 8/8 unrelated matched 
(HLA-A, B, C, DRB1) donor as defined in section 2.4, found within 90 days. 
 
On the date of transplantation evaluation, potential research subjects should be offered 
participation in this clinical trial.  The date of consent should be as close to the date of initial 
transplantation consultation as possible, and optimally on the date of consultation.  Enrollment 
should take place within 30 days from the date of consent.  Once consent has been obtained, and 
the subject has been enrolled, the subject will be assigned to one of the two treatment arms within 
90 days from the date of consent.  All subjects are initially assigned to the non-transplant arm.  
Subjects will be re-assigned to the transplant arm should a suitable donor be identified 
within 90 days of informed consent.  The primary outcome analysis will use the date of consent 
for survival analyses.   
Example 1.  Subject is consented and enrolled.  A transplant donor is identified 30 days 
from consent.  The subject undergoes transplantation 70 days from consent.   
Analysis: Transplantation Arm 
Example 2.  Subject is consented and enrolled.  A transplant donor is identified 30 days 
from consent.  The subject receives 4 cycles of hypomethylating therapy and undergoes 
transplantation 200 days from consent.   
Analysis: Transplantation Arm 
Example 3. Subject is consented and enrolled.  A transplant donor is identified 30 days 
from consent.  The subject receives 4 cycles of hypomethylating therapy and expires 
related to an infection prior to transplantation.  
Analysis: Transplantation Arm 
Example 4. Subject is consented and enrolled.  The patient has an identified sibling donor 
on the date of consent.  The patient eventually declines transplantation. 
Analysis: Transplantation Arm 
Example 5. Subject is consented and enrolled.  A donor search is begun, and the subject 
begins hypomethylating therapy.  The subject expires 80 days after consent without a donor 
being identified. 

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Analysis: Non-Transplantation Arm 
Example 6. Subject is consented and enrolled.  A donor search is begun, and the subject 
begins hypomethylating therapy.  No donor is identified after a 90 day search.  The subject 
continues on hypomethylating therapy. 
Analysis: Non-Transplantation Arm 
Example 7. Subject is consented and enrolled.  A donor search is begun, and the subject 
begins hypomethylating therapy.  No donor is identified after a 90 day search.  The subject 
progresses and undergoes alternative donor transplantation 150 days from consent. 
Analysis: Non-Transplantation Arm 
 
4.3. 
Methodology and Documentation of Study Events 
 
4.3.1. Approaching Patients, Eligibility, Screening, and Obtaining Consent 
 
Subjects will be approached for this study when they are considered to be potential alloHCT 
candidates and the decision to proceed with a donor search is made.  Transplant physicians will 
evaluate the patient eligibility.  Eligible patients willing to participate in the study will sign an 
Institutional Review Board (IRB) approved consent form for this protocol.  Transplant center 
personnel will record the documentation of patient consent in EMMES AdvantageEDCSM 
(Electronic Data Capture, an Internet-based data entry system) and patients will be enrolled 
through the AdvantageEDC..  
 
4.3.2. Search Commencement  
 
Transplant centers will initiate the donor search by testing patients and their siblings’ HLA types 
when potential sibling donors are available.  If no healthy siblings are available or no siblings are 
HLA-match, an unrelated donor search will be performed.  Transplant center will initiate the 
unrelated donor search by submitting patient demographics, HLA, and disease information to the 
NMDP coordinating center using standard NMDP forms.  The date of requesting sibling HLA 
typing and/or unrelated donor search will be recorded if informed consent and enrollment do not 
occur on the same day.  
 
4.3.3. Search End and Assignment to alloHCT versus non-HCT Arm (Donor versus no-Donor) 
 
Search end is defined as the date when a 6/6 matched related or 8/8 matched unrelated donor as 
defined in section 2.4 is identified (confirmation of HLA match is completed).  The assignment 
(biologic allocation) to alloHCT occurs on this date.  If a 6/6 matched related or 8/8 matched 
unrelated donor has not been identified within 90 days of consent, the patient will be assigned to 
the non-HCT arm (no donor). 
 
Patients must receive either RIC alloHCT or non-HCT therapy according to their treatment 
assignment.  The specific transplant or non-transplant therapy will be at the discretion of the 
treating physician.  Patients assigned to the alloHCT arm will receive more information about the 
specific transplant procedures and will be required to sign the institution’s consent form which 

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outlines the risks and benefits of the transplant procedure they will undergo.  Patients assigned to 
the non-HCT arm will receive more information about the non-transplant therapy options 
including hypomethylating therapy and will sign a consent form if deemed appropriate.  Non-
transplant patients may return to their primary hematologists for therapy. 
 
4.4. 
Study Monitoring 
 
4.4.1. Follow-up Schedule for non-HCT Arm 
 
Subjects who are assigned to the non-HCT donor arm will be followed by their primary 
hematologists.  The HCT centers which enrolled and registered the patients will be responsible for 
periodic contact (every 3 months for Year 1 and 2: +/- 1 month; every 6 months in Year 3: +/- 2 
months) with the primary hematologists.  When feasible, a recent CBC/differentials and bone 
marrow report should be obtained at each time point.  Documentation of transformation to AML 
should be obtained, when applicable, as well as treatment history.  Vital status (death or alive), 
concurrent therapy (for the first year), and date of the last follow up or death will be recorded.  The 
primary endpoint of this study is 3 year overall survival, which is not affected by ascertainment 
bias. 
 
Should a subject on the non-HCT donor arm eventually undergo alternative donor transplantation, 
long-term outcome reporting will be per Section 4.4.2 using CIBMTR forms.  All patients, 
including those assigned to the non-HCT arm will be registered with the CIBMTR and receive a 
CRID ID to be recorded in AdvantageEDC upon assignment to a study arm. 
 
4.4.2. Follow-up Schedule for HCT Arm 
 
Patients in the HCT arm will be followed according to each HCT center’s institutional standard 
and data will be reported every 3 months for Year 1 and 2 (+/- 1 month) and every 6 months in 
Year 3 (+/- 2 months) in AdvantageEDC.  
 
CIBMTR Data Reporting: Centers participating in BMT CTN trials must register pre- and post-
transplant outcomes on all consecutive hematopoietic cell transplantations done at their institution 
during their time of participation to the 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 alloHCT recipients.)  Intended enrollment on BMT CTN 
1102 must be indicated on the SCTOD pre-transplant registration form.  CIBMTR pre- and post-
transplant comprehensive 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.  
 
In the event that patients with donors DO NOT undergo transplantation, the follow up will remain 
the responsibility of the transplant center, with a schedule of contact and required information as 
in Section 4.4.1. 
 
 
 

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4.4.3. Collection of QOL Data 
 
QOL interviews will be conducted by the Survey Research Group (SRG).  The transplant centers 
will contact the SRG once a patient is enrolled in Segment A, either by e-mailing or faxing a form 
with the patient’s contact information.  A separate database will be created to house the contact 
information; no patient contact information will be stored in AdvantageEDCSM; it will only contain 
the 3 QOL questionnaires (FACT-G, MOS SF-36 and EQ-5D).  Interviewers will call the patient 
at a day and time that is convenient for them, and the interviewers will be trained to enter the data 
collected into AdvantageEDCSM. 
 
The baseline QOL survey will be collected within 1 month after Segment A enrollment.  For each 
subsequent interview, they may occur within the following windows, calculated from month since 
Segment A enrollment.   
• 6 months: +/- 1 month 
• 12 months: +/- 1 month 
• 18 months: +/- 1 month 
• 24 months: +/- 2 month 
• 36 months: +/- 2 month 
 
At the conclusion of each survey administration, patients will be reminded of the next date of 
contact and the procedures that will be followed.  The clinical contact person associated with the 
patient will notify the SRG if a patient’s contact information has changed or if a patient has died. 
 
4.4.4. Locating Missing Patients 
 
If patients cannot be located through the contact information provided, or through the transplant 
center, then Accurint, a government website accessible to only those with permission will be used 
by the SRG to locate the patient.  Patients give their permission for the SRG to use this site when 
they sign the informed consent. 
 
4.4.5. Adverse Event Reporting 
 
Only adverse events related to the study consent process, collection of the optional research 
samples, or completing QOL Surveys will be reported.  Since no other therapy is mandated in this 
study, adverse events associated with transplantation or non-transplantation will not be collected 
nor reported for this protocol.  
 
4.4.6. Patient Evaluations prior to HCT Therapy 
 
Pre-HCT testing will be performed per institutional standards.  The CIBMTR MDS/MPN Pre-
HCT data form (CIBMTR Form 2014 MDS) will be used to collect the clinical data pre-HCT.  The 

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standard CIBMTR pre-HCT data form (2400) will also be used to derive HCT co-morbidity index 
at the time of transplantation.  
 
4.5. 
OPTIONAL Research Samples Pre-transplant and at Relapse (RIC alloHCT Arm 
only) 
 
In addition to research samples at enrollment (Section 4.1.2) collected from consenting patients, a 
pre-transplant bone marrow sample (1 mL) will be collected for those assigned to the alloHCT arm 
(within 3 months prior to transplant).  This sample is asked for only when a clinically indicated 
bone marrow aspirate is performed at BMT CTN centers.  Additionally, at the time of disease 
relapse for those patients assigned to the alloHCT arm, an additional peripheral blood sample (50 
mL, or specified amount based on weight if < 50 kg) and bone marrow sample (1 mL) will be 
collected if possible. 
 
4.6. 
OPTIONAL Cost-Effectiveness Analysis Information 
 
Patients consenting to the optional Cost-Effectiveness Analysis ancillary study (see Appendix F) 
will be interviewed by the Survey Research Group (SRG) at 1, 7, and 19 months after enrollment 
to gather information about their out-of-pocket costs. 

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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Overview 
 
This study is designed as a multicenter trial, with biological assignment to one of two study arms; 
Arm 1: Reduced intensity allogeneic hematopoietic cell transplantation (RIC alloHCT), Arm 2: 
non-transplant therapy / best supportive care.  Patients with an HLA-matched related or unrelated 
donor found within 90 days will be assigned to the RIC alloHCT arm.  Patients without a matched 
donor in that time period will be assigned to the non-transplant therapy arm.  
 
The primary objective is to compare the three-year overall survival (OS) probabilities between the 
RIC alloHCT arm versus the non-transplant arm.  The primary analysis will include all enrolled 
subjects, classified according to their biological treatment assignment, irrespective of treatment 
actually received (intent-to-treat analysis).  (See Section 4.2.)  
 
5.1.1. Accrual 
 
The length of time required to accrue the targeted sample size for this study depends on the 
proportion of enrolled patients with a matched related or matched unrelated donor.  Although this 
proportion is not exactly known, it is believed that 60% - 70% of patients will have a matched 
donor.  To ensure the study is sufficiently powered to detect a 15% improvement in three-year 
overall survival, accrual will remain open until 135 patients are assigned to the non-transplant arm 
if the proportion of patients with a matched donor is 60% and until 120 patients are assigned to the 
nonHCT therapy arm if the proportion with a matched donor is 70%.  The sample size and power 
calculations are given in Section 5.2. 
 
Based on historical CIBMTR data, it is estimated that 420 MDS patients receive RIC alloHCT 
from a matched sibling or matched unrelated donor per year.  Further assuming that at least 50% 
of these patients have had Intermediate-2 or high risk IPSS, approximately 210 patients will be 
eligible to enroll in the RIC alloHCT arm.  Assuming an accrual rate of 40%, we expect annual 
enrollment of 84 patients to the RIC alloHCT arm.  Table 5.1 provides estimated annual accruals 
for various proportions of donor availability. 
 
Table 5.1: ESTIMATED ANNUAL ACCRUAL 
 
Donor Availability 
60% 
70% 
Donor 
84 
84 
No Donor 
56 
36 
Total 
140 
120 
 
Based on these assumptions, it is estimated that 2.5 - 3.5 years of accrual will be necessary to 
enroll the targeted sample size if 60% - 70% of patients have a matched donor.   

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5.1.2. Biologic Assignment and Randomization 
 
This is a biologic assignment trial.  There will be no randomization.  All patients enrolled in the 
study are initially assigned to the non-transplant therapy arm.  Patients with a matched related or 
matched unrelated donor as defined in section 2.4 will be assigned to the RIC alloHCT arm when 
a donor is identified.  To prevent bias resulting from biological assignment, patients are eligible if 
no formal unrelated donor search has been activated prior to informed consent.  Patients who have 
started a sibling donor search or who have found a matched sibling donor are eligible.  Final 
assignment for all patients will be made within 90 days from study consent.  Patients without a 
donor identified in the first 90 days will stay in the non-transplant arm.  Patients without a donor 
identified who die before 90 days will be analyzed in the non-transplant arm, although this number 
is expected to be small.  
 
There are many possible sources of heterogeneity in a multi-center clinical trial.37  In a large 
randomized trial, chance ensures balance on average of both known and unknown risk factors 
across treatment arms.  A non-randomized study is vulnerable to differential assignment of higher 
risk patients to one or the other treatment arm.  Potential sources of heterogeneity include: degrees 
of compliance with biological assignment, differences in baseline characteristics such as age, race, 
gender, performance status, and disease risk status.  To address these concerns, the DCC will 
monitor compliance rate throughout the study and the final analysis will adjust for baseline 
characteristics potentially affecting outcomes.   
 
5.1.3. Intention-to-Treat Principle 
 
In the primary analysis of overall survival at three years post-consent, patients will be classified 
according to their biologic assignment regardless of their actual treatment in accordance with the 
intent-to-treat principle.  Secondary analyses using an as-treated principle will be considered.  
 
5.2. 
Sample Size and Power Calculations 
 
The primary analysis will compare three-year OS probabilities between arms using adjusted 
survival estimates provided by the method of Zhang et al38 to account for potential differences in 
baseline covariates.  Without censoring or covariates, the three-year OS probabilities reduce to 
simple binomial proportions.  A point-wise comparison of survival at three years is proposed for 
the primary analysis rather than the Cox proportional hazards model because of the potential for 
crossing hazards.  The Cox model would have lower power to detect a difference between two 
groups in the presence of crossing hazards.  The sample size calculations were based on a two-
sample Z test of binomial proportions.   
 
The targeted sample size is specified in terms of minimal number of patients without a matched 
donor whose final assignment is non-transplant therapy.  Data from the CIBMTR suggests a three-
year OS probability after transplant for high-risk MDS patients older than 50 to be approximately 
35%-40%.  Three-year OS for the non-transplant group based on data from European patients 
under a compassionate use program of AZA39 are estimated to range between 20% and 25%.  From 
these estimates, we propose a design with sufficient power to detect a 15% increase in three-year 
OS probability in the RIC alloHCT arm compared to the non-transplant arm.  The sample size was 

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estimated assuming 10% loss to follow up at the end of three years.  Table 5.2 give the estimated 
sample size and power to detect a 15% increase in three-year overall survival for various 
combinations of baseline survival probability and donor availability.  If 60% of patients will have 
a matched donor, the study will require 135 patients in the non-transplant arm to provide sufficient 
power to detect a 15% increase in three-year survival probability in the RIC alloHCT arm.  If 70% 
will 
have 
a 
matched 
donor, 
120 
patients 
in 
the 
non-HCT 
arm 
will 
provide sufficient power to detect a 15% increase in three-year survival probabilities as shown in 
Table 5.2.  
 
TABLE 5.2: POWER TO DETECT 15% INCREASE IN OS PROBABILITY IN THE 
TRANSPLANT ARM FOR VARIOUS SURVIVAL PROBABILITIES AND 
PROPORTIONS OF DONOR AVAILABILITY 
  
Donor Availability 
Total Sample size 
(HCT, Non-HCT) 
Three-year OS 
Power 
HCT 
Non-HCT 
60% 
338 
(203, 135) 
35% 
20% 
83% 
40% 
25% 
80% 
62% 
343 
(213, 130) 
35% 
20% 
85% 
40% 
25% 
81% 
64% 
355 
(227, 128) 
35% 
20% 
86% 
40% 
25% 
81% 
66% 
368 
(243, 125) 
35% 
20% 
84% 
40% 
25% 
81% 
68% 
380 
(258, 122) 
35% 
20% 
85% 
40% 
25% 
81% 
70% 
400 
(280, 120) 
35% 
20% 
84% 
40% 
25% 
81% 
 
 
5.3. 
Interim Analysis and Stopping Guidelines 
 
Since the true proportion of donor availability is not known, we recommend monitoring treatment 
assignment to assess the proportion of donor availability and to ensure enough patients will be 
enrolled in each arm to have sufficient power to detect the specified treatment effect.  If the 
proportion of donor availability reaches 90%, an action plan will be developed to address future 
accrual.  The DCC will also monitor compliance rate throughout the study to ensure patients will 
receive their assigned treatment.  Noncompliance in the non-transplant arm is defined as a patient 
without a matched donor identified receiving alternative donor HCT within the first 90 days or a 

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patient not having a donor identified in the first 90 days after consent receiving a transplant within 
six months from the final assignment.  Noncompliance in the transplant arm is defined as a patient 
with a matched donor identified not receiving a transplant within six months from the final 
assignment.  If noncompliance in each arm exceeds 25%, an action plan will be developed to 
address future accrual. 
 
In addition to monitoring for compliance and enrollment imbalance between assignment arms, we 
recommend monitoring the proportion of patients enrolled by age group (< 65 years of age vs. ≥ 
65) to ensure sufficient number of patients will be available in each age group for secondary 
subgroup analysis.   
 
We do not recommend interim analysis for futility for two reasons.  First, we expect the risk of 
mortality in the early period to be higher after HCT and in the later period to be higher with non-
transplant therapy, resulting in crossing hazards.  Although we expect the survival curves to cross 
approximately two years after enrollment, no data exist to estimate the crossing point.  If the 
survival curves happen to cross later than two years, we do not want to prematurely stop the study 
for futility.  Secondly, the investigators are also interested in using the lower bound of the 
confidence interval of the survival difference at three years 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.   
 
We recommend interim analysis for efficacy after accrual is complete starting at 4 years from the 
beginning of the study and every year thereafter to allow the investigators to report the study results 
earlier when there is sufficient evidence to conclude one treatment results in superior three-year 
survival.  Interim analysis for efficacy will be conducted at times that coincide 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.  Toxicity, adverse events, and other safety endpoints will be 
monitored regularly and reported to the DSMB at each interim analysis.  These 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 the study enrollment.   
 
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 statistic used at each interim analysis will be the 
difference between treatment arms in adjusted estimates of three year overall survival.  All patients 
enrolled prior to the time of the interim analyses will be used to compute these adjusted probability 
estimates.  If the test statistic exceeds the critical value, the DSMB will discuss whether the trial 
should continue. 
 
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 

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0.05.  The actual critical values and nominal p-values will be computed using statistical methods 
for group sequential testing with Haybittle-Peto boundaries40,41.  Because differences in adjusted 
survival estimates are not known to follow an independent increments structure asymptotically, a 
Bonferroni adjustment will be used to ensure that the overall type I error rate does not exceed 0.05.  
Letting 𝐾𝐾 denote the total number of analyses and 𝜋𝜋𝑗𝑗 the nominal type I error rate for the analysis 
performed at analysis 𝑗𝑗, the overall type I error rate will not exceed 0.05 if these are chosen such 
that ∑
𝜋𝜋𝑗𝑗 
𝐾𝐾
𝑗𝑗=1
= 0.05.  The Haybittle-Peto design uses a critical value of 3.00 at each intermediate 
analysis, giving 𝜋𝜋𝑗𝑗= 2[1 −Φ(3)] = 0.0027 for stages 𝑗𝑗< 𝐾𝐾 and 𝜋𝜋𝐾𝐾= 0.05 −2(K −1)[1 −
Φ(3)] for the final analysis, where Φ is the standard normal cumulative distribution function. The 
critical value for the final analysis, then, is Φ−1(1 −𝜋𝜋𝐾𝐾/2).  
 
We recommend interim analyses starting four years after the beginning of the study and yearly 
thereafter, until the last patient has been followed for three years.  Four years was chosen as the 
time of the first interim analysis to ensure enough patients have reached the primary endpoint to 
provide reasonable estimates of three-year survival.  The number of subsequent analyses depends 
on the length of time required to complete accrual.  
 
Assuming donor availability rate of 60%, the total accrual time is estimated to be 2.5 years.  With 
3 years of follow up, the study can be completed within 6 years.  In this case, analyses will be 
conducted at the end of year 4, 5, and 6.  Table 5.3.A shows the critical values, nominal Type I 
error, cumulative Type I error, and the probability of stopping to reject the null hypothesis at each 
analysis conducted at the end of year 4, 5, and 6.  This is estimated using a simulation study with 
two different survival probability scenarios, uniform accrual over 2.5 years, and assuming 
exponential censoring with 10% rate by 3 years; we use an unadjusted test statistic for simulation 
study purposes, even though the primary analysis will use the difference in adjusted survival 
probabilities at 3 years.  The power at each look is the probability of stopping and rejecting the 
null hypothesis at that look if the true increase in OS at three years is 15% in the HCT arm 
compared to the non-HCT arm.  In particular, there is 32% power to detect a 15% improvement in 
three-year survival by the first look, 51% by the second look, and 83% by the final look if the true 
survival probabilities were 35% vs. 20%.  There is 29% power to detect the same improvement by 
the first look, 46% by the second look, and 79% power by the final look if the true survival 
probabilities were 40% vs. 25%. 
 
TABLE 5.3.A: CRITICAL VALUES AND OPERATING CHARACTERISTICS; DONOR 
AVAILABILITY RATE OF 60% 
Calendar 
Time since 
Study Start 
Critical 
Value 
Nominal 
Type I Error 
Rate 
Cumulative 
Type I Error 
Rate Upper 
Bound 
Cumulative Probability 
of Stopping under Ha 
35% vs. 
20% 
40% vs. 
25% 
4 years 
3.00 
0.0027 
0.0027 
0.3238 
0.2892 
5 years 
3.00 
0.0027 
0.0054 
0.5096 
0.4562 
6 years 
2.01 
0.0446 
0.0500 
0.8272 
0.7906 
 
 

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Assuming donor availability rate of 70%, the total accrual time is estimated to be 3.5 years.  With 
3 years of follow up, the study can be completed within 7 years.  In this case, analyses will be 
conducted at the end of year 4, 5, 6, and 7.  Table 5.3.B shows the critical values, nominal and 
cumulative Type I error, and the power to reject the null hypothesis by each look conducted at the 
end of year 4, 5, 6, and 7.  This is estimated using a simulation study with two different survival 
probability scenarios, uniform accrual over 3.5 years, and assuming exponential censoring with 
10% rate by 3 years; we use an unadjusted test statistic for simulation study purposes, even though 
the primary analysis will use the difference in adjusted survival probabilities at 3 years.  In 
particular, there is 46% power to detect a 15% improvement in three-year survival by the second 
look and 85% by the final look if the true survival probabilities were 35% vs. 20%.  There is 41% 
power to detect the same improvement by the second look and 81% power by the final look if the 
true survival probabilities were 40% vs. 25%. 
 
TABLE 5.3.B: CRITICAL VALUES AND OPERATING CHARACTERISTICS; DONOR 
AVAILABILITY RATE OF 70% 
Calendar 
Time since 
Study Start 
Critical 
Value 
Nominal 
Type I Error 
Rate 
Cumulative 
Type I Error 
Rate Upper 
Bound 
Cumulative Probability 
of Stopping under Ha 
35% vs. 
20% 
40% vs. 
25% 
4 years 
3.00 
0.0027 
0.0027 
0.2538 
0.2226 
5 years 
3.00 
0.0027 
0.0054 
0.4564 
0.4058 
6 years 
3.00 
0.0027 
0.0081 
0.5636 
0.5124 
7 years 
2.03 
0.0419 
0.0500 
0.8476 
0.8084 
 
5.3.2. Guideline for Safety Monitoring  
 
Treatment-related mortality, a key safety endpoint for patients receiving RIC alloHCT, will be 
monitored up to 100 days post-transplant.  A truncated Sequential Probability Ratio Test (SPRT) 
based on a binomial test of proportions for treatment-related mortality will be used as described 
below.  This sequential testing procedure conserves type I error across all of the monitoring looks 
for TRM.  The SPRT can be represented graphically.  At each interim analysis, the number of 
patients received HCT is plotted against the total number of patients who have experienced TRM 
by day 100 post transplant.  The continuation region of the SPRT is defined by two parallel lines.  
Only the upper boundary will be used for monitoring to protect against excessive TRM.  If the 
graph falls above the upper boundary, the SPRT rejects the null hypothesis, and concludes that 
there are more TRM than predicted by the number of HCT patients.  Otherwise, the SPRT 
continues until enrollment reaches the target goal. 
 
The usual measures of performance of an SPRT are the error probabilities α and β of rejecting H0 
when θ = θ0 and of accepting H1 when θ = θ1, respectively, and the expected sample size E(N|θi).  
Note that since the test uses only the upper boundary, and is truncated by a finite sample size, the 
size of the test will be slightly lower than the nominal level.  The test to be used in this protocol 
was developed from the following SPRT:   

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• An SPRT contrasting 20% versus 30% TRM, with nominal type I and II errors of 5% and 
20%, respectively.   
• The slope of the parallel lines for monitoring TRM is 0.248 and the intercepts are –2.891 
and 5.144. 
Graph of the stopping boundary is given in Figure 5.3.   
 
 
Figure 5.3: Stopping Boundary 
 
The actual operating characteristics of the truncated test, shown in Table 5.3.C, were determined 
in a simulation study.  The simulation assumed uniform accrual of 280 patients over a period of 
three and a half years.   
 
TABLE 5.3.C: OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR 100-DAY TRM FROM A SIMULATION STUDY  
WITH 10,000 REPLICATIONS 
True 100-day rate 
20% 
25% 
28% 
30% 
Probability reject the null hypothesis 
0.05 
0.49 
0.84 
0.95 
Mean month stopped 
42.0 
31.9 
22.5 
17.5 
Mean # endpoints 
54.2 
50.3 
37.7 
30.0 
Mean patients with 100 days follow-up 
271.1 
200.8 
134.8 
99.9 
0
10
20
30
40
50
60
70
80
0
50
100
150
200
250
Total number of observed events
Total number of patients received HCT
Monitoring Boundary for 100-Day TRM
continuation
pausing region
region 

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Treatment-related mortality is monitored in all patients receiving RIC alloHCT.  The SPRT rejects 
the null hypothesis in favor of the alternative 5% of the time when the true 100-day TRM is 20%, 
and 95% of the time when the true 100-day TRM is 30%.  This corresponds to a type I error rate 
of α=0.05 and a type II error rate of β=0.05.  When the true 100-day TRM rate is 30%, on average, 
the DSMB will be consulted 17.5 months after opening, when 30 events have been observed in 
100 patients.  Note that the SPRT procedure is adequately powered to distinguish between a TRM 
rate of 20% and 30%. 
 
5.4. 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, disease status, donor type, donor 
gender, all components of IPSS score, co-morbidity index, duration of disease, cytogenetics, prior 
treatment, and response to prior treatment. 
 
5.5. 
Analysis Plan 
 
5.5.1. Analysis of the Primary Endpoint 
 
The primary outcome of the trial is overall survival at three years after consent.  The primary null 
hypothesis of the study is that there is no difference in overall survival between the treatment arms 
at three years post consent.  In the primary analysis, the intent-to-treat principle will be used.  
Because of the potential bias resulting from biological assignment42, the comparisons of overall 
survival will be adjusted for the following pre-specified patient characteristics: age, race/ethnicity, 
performance status, disease status, co-morbidity index, IPSS score, duration of disease (time from 
diagnosis to enrollment), cytogenetics, and response to prior therapy.  The primary analysis will 
be performed using the difference in adjusted overall survival probabilities at three years, using 
the method of Zhang et al38.  In this analysis, the time to event is the time from study consent to 
the time of death from any cause; surviving patients will be censored at last follow-up.  The 
adjusted survival probabilities are estimated using the Cox proportional hazards model stratified 
by treatment.  A 95% confidence interval for the difference in adjusted OS at three years will also 
be constructed.  In addition to a point-wise comparison at three years, adjusted survival curves will 
be constructed and confidence bands for the difference between treatments will be generated to 
compare the survival probabilities across time.  
 
5.5.2. Analysis of Secondary Endpoints 
 
5.5.2.1. 
Overall survival at three years (as treated analysis) 
 
In addition to the primary intent-to-treat analysis, three-year survival probabilities will be 
compared using the adjusted OS probabilities in several exploratory analyses.  In the first one, the 
patients who die or drop out before 90 days without a donor identified will be removed from the 
non-transplant group.  The second analysis will be an as treated analysis, where patients are 
classified by the treatment they actually received.   
 

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5.5.2.2. 
Overall survival post three years 
 
Overall survival post three years will be compared between arms using the linear combination test 
proposed by Logan et al43.  This comparison directly compares the survival curves starting at three 
years, and accounts for patients enrolled early in the study having additional follow-up beyond 
three years.   
 
5.5.2.3. 
Leukemia-free survival at three years 
 
Probabilities of leukemia-free survival three years post consent will be compared between 
treatment groups using the method of Zhang et al.38 adjusting for age, race/ethnicity, performance 
status, disease status, co-morbidity index, IPSS score, duration of disease (time from diagnosis to 
enrollment), cytogenetics, and response to prior therapy.  A 95% confidence interval for the 
difference in adjusted OS at three years will also be constructed.  In addition to a point-wise 
comparison at three years, adjusted survival curves will be constructed and confidence bands for 
the difference between treatments will be generated to compare the leukemia-free survival 
probabilities across time.  An as-treated analysis as described in Section 5.5.2.1 will also be 
conducted to compare leukemia-free survival probabilities at three years.  
 
5.5.2.4. 
Quality of Life 
 
QOL will be described and compared between treatment arms utilizing the FACT-G, the MOS-
SF36 Physical Component Score (PCS) and Mental Component Score (MCS), and the EQ-5D 
utility score.  The questionnaires will be scored according to standard procedures.  The self report 
questionnaires will be completed at enrollment and subsequently at six months, 12 months, 18 
months, 24 months, and 36 months from enrollment.  Only English and Spanish 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 
two-sample t-tests.  In addition, pattern of missing QOL data will be examined using graphical 
techniques and logistic regression models.  At each time point, the difference in QOL between the 
treatment arms conditional on being alive at that time point will be estimated using the inverse 
probability of censoring-weighted generalized estimating equations with independent working 
correlation model of Kurland and Heagerty44.  
 
5.5.3. Subgroup Analyses 
 
Exploratory analyses will be performed to determine the impact of the following factors on 
treatment effect: 
1. Response to hypomethylating therapy (response versus no response), where response is 
defined as achieving complete or partial response or hematologic improvement.  
2. Patient age (< 65 years of age vs. ≥ 65),  
3. Disease duration,  

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4. IPSS, and  
5. Revised-IPSS. 
 
Subgroup analyses will be conducted separately for each factor listed above using the pseudo-
value approach of Klein et al45. Differential impact of each factor on the effect of transplant on 
three-year OS and three-year LFS will be tested for by including an interaction term between the 
factor and the treatment group in the pseudo-value regression models.   
 
5.5.4. Secondary Analyses of RIC alloHCT Arm 
 
The following secondary analyses will be conducted for patients enrolled in the alloHCT arm.  
The time to event for all outcomes in the following analyses starts at the time of transplant.  
 
The impact of the following factors on transplantation outcomes (i.e. OS, disease-free or 
progression-free survival, relapse, TRM, acute/chronic GVHD) will be evaluated: 
1. Response to hypomethylating therapy (complete response, partial response and no 
response), 
2. Patient age (< 65 years of age vs. ≥ 65),  
3. Disease duration,  
4. IPSS,  
5. Revised-IPSS, and 
6. Donor type (HLA-matched sibling donor vs. matched unrelated donor). 
 
Cox proportional hazards models will be performed in these analyses.  The proportional hazards 
assumption will be tested.  When test indicated differential effects over time (non-proportional 
hazards), models will be constructed breaking the post-transplant course into two time periods, 
using the maximized partial likelihood method to find the most appropriate breakpoint. 
 
QOL will be described and compared between age groups (< 65 years of age vs. ≥ 65) utilizing 
the FACT-G using the same approach described in Section 5.5.2.4. 
 
5.5.5. Exploratory Analysis of Non-transplant Therapy Arm 
 
Exploratory analysis of post-enrollment therapy will be conducted for patients assigned to the non-
transplant therapy arm.  Frequency and type of systemic therapy at each periodic contact will be 
summarized.   
 
 

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APPENDIX A 
 
HUMAN SUBJECTS 
 

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APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
Patients will be approached for this study when they are considered to be potential allo RIC HCT 
candidates based on medical history, physical examination and available laboratory tests. A 
conference will be held with the patient and family to discuss this study and alternative treatments 
available for the treatment of the underlying disease. The Principal Investigator or another 
designated physician will conduct the conference. Potential risks associated with HCT should be 
discussed as objectively as possible. Informed consent for this study will be obtained using a form 
approved by the Institutional Review Board of the institution enrolling the patient.  
 
If an appropriate matched related or unrelated donor is found within 90 days of consent, the patient 
will be assigned to the allo RIC HCT treatment arm. The treating physician will review the risks 
and benefits of the institutionally-approved allo RIC HCT regimen with the patient. Informed 
consent for the specific transplant study will be obtained using a separate consent form approved 
by the Institutional Review Board of the institution enrolling the patient. 
 
Patients without suitable donors will be offered standard treatment (hypomethylating therapy) or 
other best supportive care. The treating physician will discuss the options and risks and benefits 
of each therapy. Informed consent for standard treatment will be obtained if required by local IRB 
of the institution treating the patient.  
 
 
2. 
Confidentiality 
 
Confidentiality will be maintained by masking of individual names and assignment of a patient 
identifier code. The identifier code representing the patient’s identity will be kept separately from 
the research file at the center. The ID code will be transmitted to the BMT CTN Data Coordinating 
Center upon enrollment. 
 
 
3. 
Participation of Women and Minorities and Other Populations 
 
Women, ethnic minorities, and other populations will be included in this study. Accrual of women 
and minorities at each center will be monitored to determine whether their rates of enrollment are 
reflective of the distribution of potentially eligible women and minorities expected from data 
reported to the CIBMTR and from published data on the incidence of MDS. Centers will be 
notified if their rates differ significantly from those expected and asked to develop appropriate 
recruitment strategies. 
 

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APPENDIX B 
 
INFORMED CONSENT 
 

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APPENDIX B 
 
Informed Consent to Participate in Research 
 
 
A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic 
Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in 
Patients Age 50 or Older with Intermediate-2 and High Risk Myelodysplastic Syndrome 
 
Your Name:  
________________________________ 
Study Title:  
A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity 
Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or 
Best Supportive Care in Patients Age 50 or Older with Intermediate-2 and 
High Risk Myelodysplastic Syndrome 
 
 
Protocol: 
BMT CTN #1102 
Co-Investigator:  
Ryotaro Nakamura, MD  
 
 
 
 
 
 
City of Hope Medical Center 
1500 East Duarte Road 
Duarte, CA 91010 
Phone: (626) 656-4673 
 
Co-Investigator:  
Corey Cutler, MD MPH FRCP(C) 
 
 
 
 
 
 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
Phone: (617) 632-3470 
Transplant Center 
Investigator:  
________________________ 
(Insert contact information for PI at your site) 
Sponsor:   
The National Institutes of Health (NIH) is sponsoring this study by 
providing financial support through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN).  
 

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1. Introduction 
We invite you to join this clinical trial, also 
known as a research study. You are invited 
to join this study because: 
1) You have myelodysplastic 
syndrome (MDS), also called 
myelodysplasia; 
 
2) Your MDS is at an advanced stage. 
This means that you are at medium 
(intermediate) to high risk for your 
MDS to become acute leukemia or 
cause death; and 
 
3) Your doctor recommends that you 
have an allogeneic stem cell 
transplant (transplant) if a donor is 
found whose DNA or tissue type 
matches your DNA or tissue type. 
We are doing this study because we want to 
find out if patients with MDS who have a 
matched donor and get a reduced-intensity 
conditioning (RIC) transplant do better 
than those who get drugs to treat their MDS 
(no transplant). 
This study also wants to learn more about 
the cost-effectiveness of transplant and 
collect extra blood and tissue samples for 
future studies. 
(See Section 2. Study Background for a 
definition of the bolded terms) 
This study will take about 6.5 years and will 
include about 338 – 400 participants from 
around the United States. We will collect 
information on how you’re doing (your 
health condition and how you feel) for 3 – 4 
years.   
This Consent Form tells you about the 
purpose of the study, the possible risks and 
benefits, other treatment 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 will not benefit from taking part 
on 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].  
 Please ask the study staff questions 
about anything that you don’t 
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 join, 

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please sign and date the end of the 
Consent Form. 
You and your doctor will discuss how to 
best treat your MDS. Joining this study will 
affect your treatment decisions. If you don’t 
want to participate in this study, we will not 
collect information on your health condition 
or how you’re feeling. 
 
2. Study Background 
The National Institutes of Health (NIH), 
through the Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN), are 
providing staff support and money for this 
research study. The BMT CTN will direct 
the research study. The BMT CTN and the 
NIH will make decisions about how to 
manage the study. 
Myelodysplastic Syndrome (MDS), also 
called myelodysplasia, is a disease where 
the bone marrow does not make enough 
normal blood cells for the body. This can 
lead to a fast-growing blood cancer called 
acute leukemia. It mostly affects people who 
are 50 or older.   
There are different ways to treat MDS. 
Some treatments use blood transfusions and 
drugs. These treatments can improve MDS 
and slow it from becoming acute leukemia. 
However, drugs don’t cure MDS.  
Allogeneic stem cell transplant 
(transplant) is another treatment option for 
advanced stage MDS. A transplant uses 
blood-making cells from a family member 
or an unrelated donor to remove and replace 
your abnormal blood cells. It requires a 
close tissue match between you and the 
donor.  
Your donor could be a sibling (a sister or 
brother) or an unrelated person. We use the 
Be The Match® Registry to find unrelated 
donors.   
The best experience with transplant for 
MDS is with well-matched sibling or 
unrelated donors. If you do not have one of 
these donors there may be other potential 
donor options such as umbilical cord blood 
or mismatched donors. Since the outcome 
from transplant with these donors is not as 
good, only well-matched sibling and 
unrelated donors are being offered on this 
trial. 
A transplant first uses chemotherapy and 
radiation to destroy the abnormal blood cells 
or stop them from growing. For your MDS 
and your condition, your doctor wants to use 
lower amounts of chemotherapy and 
radiation. This type of transplant is called 
reduced-intensity conditioning (RIC) or 
non-myeloablative. There are different 
combinations of RIC drugs and radiation. 
Your doctor will decide on the best 
combination for you. 
Because of your age or health problems, you 
may have a higher chance of side effects and 
health problems from a standard transplant 
that uses very high doses of chemotherapy 
and radiation. The possible benefit of RIC is 

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a lower chance of side effects. The possible 
risk of RIC is that the transplant will not 
stop your disease from growing or cure it. 
Your doctor will explain all of the risks and 
side effects of your RIC treatment. 
Transplant cures MDS for some patients, but 
not all patients. However, patients often 
have side effects after both standard and 
RIC transplants. The side effects can be very 
serious, sometimes even causing death. We 
don’t know if patients with MDS in an 
advanced stage do better with transplant or 
with drug therapy only (no transplant). Both 
treatments are common. 
If you don’t find a donor whose DNA or 
tissue type is a close match, you might be 
able to get a transplant that uses a donor 
who isn’t a close match or that uses an 
umbilical cord blood unit (CBU). However, 
other research studies showed that 
transplants that use a less-closely matched 
donor or a CBU don’t treat the disease as 
well, so transplants with these donor types 
are not included in this study. 
 
3. Study Purpose  
We are inviting you to join this study 
because you have MDS and your doctor 
recommends reduced-intensity transplant as 
a treatment option for you (if you find or 
have a matched donor). 
The main goal of this study is to learn if 
MDS patients who have a matched donor 
and receive transplant do better than other 
MDS patients who don’t have a donor and 
only get drugs to treat their MDS (no 
transplant). We want to know how well 
you’re able to do your normal activities after 
your treatment. We will ask you survey 
questions (health evaluations) by phone after 
you start your treatment. 
We also want to learn more about the cost-
effectiveness of transplant (see Ancillary 
Cost-Effectiveness Analysis Informed 
Consent Form (Optional)) and collect 
extra blood and tissue samples for future 
research (see Section 17: Blood and Tissue 
Samples for Future Research). These 
studies are optional. This means you can still 
be part of the main study (health evaluations 
by phone) if you say ‘no’ to these studies.  
 
4. 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 the study or you want to leave the 
study, please contact: 
[insert contact info for site PI] 
Being in this study is voluntary. You can 
choose not to be in this study or leave this 
study at any time. If you choose not to take 
part or to leave this study, it will not affect 
your regular medical care in any way.   

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Your study doctor and study staff will be 
available to answer any questions you may 
have about taking part in or leaving this study.
 
5. Study Treatment and Tests 
We will check your health condition before 
you start treatment and for 3 years after. 
You will not have to make any extra visits to 
your clinic or transplant center to be part of 
this study. 
If you have not had a bone marrow biopsy 
within the last 60 days, you might need to 
have one before you join the study. Your 
doctor will tell you if you need a bone 
marrow biopsy. 
Study Participation 
If you join this study and you don’t have a 
known sibling donor, your doctor will 
determine if you have a suitable matched 
donor. Your donor could be a sibling (sister 
or brother) or an unrelated person. If a donor 
is found within 90 days (about 3 months) of 
your consent to be on this study, you will 
have a transplant as soon as you and your 
doctor feel you are ready for it.  
If we can’t find a matched donor for you, 
you will continue to see your regular cancer 
doctor. Together, you and your doctor will 
decide on the standard treatment or a 
different treatment for your MDS. We will 
be in touch with you and your cancer 
doctor’s office to collect information on how 
you’re doing.  
Once you and your doctor decide on your 
treatment, you will get more information 
about the treatment. 
Health Evaluations 
After you join the study, we will ask you 
questions about your health and how you’re 
feeling over the phone.  
We will also contact you by phone at: 
 6 months 
 1 year (12 months) 
 1 ½ years (18 months) 
 2 years (24 months), and  
 3 years (36 months)   
These phone calls will take approximately 
30 minutes each. These health evaluation 
follow-up phone calls are only for English- 
and Spanish-speaking participants. 
Different treatments can work to treat MDS, 
but they can have different side effects. In 
this study, we want to find out how 
transplant makes people feel compared to 
how drug therapy only makes people feel.  
We will use surveys to collect information 
on how you’re doing. The surveys will ask 
you about: 
 
Your general health 

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 
Any side effects you may have from 
your treatment  
 
How well you can do your normal 
activities 
 
Your feelings 
You do not need to answer all of the 
questions or complete the surveys at all. It is 
okay to only answer the questions you feel 
comfortable answering. If any of the 
questions make you uncomfortable, you can 
skip them. 
If your phone number changes, it’s 
important that you let us know your new 
number so we can reach you. You can call: 
[Insert contact information for site PI] 
If we can’t reach you by phone, we may use 
an Internet search service to find you. By 
agreeing to join this study, you are giving us 
your permission to use search firms to find 
your contact information. The service uses 
public and non-public information to reach 
you.  
We will also give you the choice to provide 
a list of what you and your insurance 
company pay for your treatment (see  
Ancillary Cost-Effectiveness Analysis 
Informed Consent Form (Optional)) and 
extra samples of your blood and tissue for 
future research (see Section 17: Optional 
Blood and Tissue Samples for Future 
Research).
 
6. Risks and Discomforts 
The risks and side effects of transplant are 
the same if you join this study or if you 
don’t join this study. Your doctor will give 
you drugs to help ease side effects, such as 
feeling sick to your stomach (nausea). In 
some cases, side effects can be long lasting 
or never go away. 
a) Risks and side effects of transplant 
If you have a matched donor, the following 
general problems might happen from your 
transplant. Your doctor will explain the 
possible risks and benefits for the drugs used 
with your transplant before you get your 
transplant.  
Anyone who has a transplant will experience 
the risks described below: 
1. Slow recovery of blood counts. You will 
need blood and platelet transfusions after 
your transplant because red blood cells, 
white blood cells, and platelets can be slow 
to recover. This will make you at risk for 
bleeding and infections.  
2. Graft failure. The peripheral blood or 
bone marrow stem cells (the “graft”) may fail 
to grow inside your body. There is a low 
chance of this happening (about 1 out of 10 
people), and can result in low blood counts 
for a long time. If your counts don’t recover, 
you might need another transplant. Graft 
failure can be fatal. 
3. Graft-Versus-Host Disease (GVHD). 
This happens when the graft sees your body 
as foreign and attacks it. Sometimes GVHD 

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is serious or difficult to treat and may lead to 
death. In most cases, GVHD can be 
successfully treated.  
Acute GVHD may produce skin rash, nausea, 
vomiting, diarrhea, stomach pain, 
abnormalities of liver function, and an 
increased risk of infection. Chronic GVHD 
may produce skin rashes, hair loss, thickened 
dry skin, dry eyes, dry mouth, liver disease, 
weight loss, diarrhea, and an increased risk of 
infection. To diagnosis acute or chronic 
GVHD, you may need to have a biopsy (a 
small sample of your tissue for testing) of 
your skin, gut, or liver.  
4. Damage to the vital organs in your body. 
The transplant could cause problems in any 
body organ such as the heart, lungs, liver, gut, 
kidneys and bladder, or brain. The kidneys 
and the liver are most likely to be damaged. 
Some patients will experience serious lung 
problems from infections, or the 
chemotherapy and radiation.  
5. Serious infections. There is an increased 
risk of infections when your immune system 
is recovering. Most infections can be 
successfully treated, but some infections may 
result in death. 
6. Relapse of MDS. Your MDS may come 
back even if the transplant is successful at 
first. 
7. Risk to the unborn. Transplant has not 
been proven to be safe at any stage of 
pregnancy. If you are a woman and can 
become pregnant, it’s very important that 
you aren’t pregnant when you start the study 
and don’t become pregnant while in the 
study. 
8. Reproductive Risks. The drugs used in 
transplant may damage your reproductive 
organs, affect your ability to have children 
or possibly cause birth defects if you take 
them while you are pregnant. It is important 
that a woman is not pregnant or breast-
feeding and does not become pregnant 
during the course of transplant. 
 If you are a woman and can 
become pregnant: 
You will need to take a pregnancy test 
before you start transplant. You should 
discuss ways to prevent pregnancy while 
you are going through transplant.  
 If you are a man: 
Your body may not be able to make 
sperm (become sterile). You should talk 
with your doctor about banking your 
sperm before having a transplant. 
Please check with your doctor to 
understand more about these risks. 
b) Risks and side effects of RIC drugs 
Your doctor decided that a RIC transplant is 
the best treatment for you if you have a 
matched donor.  
The drugs used in RIC transplants are likely 
to cause infection, bleeding, feeling tired 
(fatigue), feeling sick to your stomach 
(nausea), and throwing up (vomiting). You 
might also have diarrhea, feel numb in your 

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hands and feet, or notice changes in your 
eyesight.  
Other side effects that are very rare (but 
serious if they happen) include a lung 
infection (pneumonia), feeling confused, 
coughing and trouble breathing, serious 
brain damage, and death. Your doctor will 
tell you more about the side effects of the 
specific RIC drugs you will receive before 
you get your transplant.    
c) Risks and side effects of drug therapy 
for MDS (no transplant)  
If you don’t have a matched donor, you will 
be treated with drugs for MDS. Your doctor 
will discuss with you more details about the 
side effects, risks, and benefits of these 
drugs. Some of the drugs can cause low 
blood counts, nausea, and stomach upset. 
Drug treatments can improve MDS and slow 
it from becoming leukemia. However, 
because drugs alone don’t cure MDS, the 
risk of your disease coming back is very 
high.  
d) Risks of being in this study  
The 3 main parts to this study are health 
evaluations, optional cost-effectiveness of 
transplant research, and optional blood and 
tissue samples for future research. Each of 
these studies has their own risks. These risks 
are described below:  
1. Health evaluations by phone (see 
Section 5). You may feel uncomfortable 
about some of the questions on the 
surveys. If this happens, you can skip 
these questions. You can also decide not 
to take the entire survey. 
2. Ancillary Cost-Effectiveness Analysis 
(Optional) (see  Ancillary Cost-
Effectiveness Analysis Informed 
Consent Form). The risks to 
participating in the cost-effectiveness 
study are small. A possible risk is the 
loss of confidentiality of your medical 
information, but the chance that this 
information will be given to someone 
else is very small. 
3. Blood and Tissue Samples for Future 
Research (Optional) (see Section 17). 
The risk of injury from having your 
blood taken is very small. If your blood 
samples are collected from your arm, 
you may bleed a little bit and/or develop 
a small bruise. Infection from blood 
draws is rare, but it may happen. If you 
are uncomfortable at the sight of blood, 
you may feel light-headed or faint. The 
risk of injury from having your bone 
marrow taken also is small. You may 
feel stiff or sore for several days 
afterwards. You may bleed a little bit 
and/or develop a bruise. The risk of 
injury from having a cheek swab from 
the inside of your mouth is very small. 
4. Unforeseen risks. New risks might 
appear at any time during the study. We 
may learn new things that might make 
you want to stop being in the study. We 
will let you know if this happens and 
you can decide if you want to stay in the 
study. 
 
 

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7. Alternative Treatments
It is your choice to join this study. If you 
choose not to take part, you may still receive 
an allogeneic transplant to treat your MDS. 
Your treatment and evaluations could be 
very similar to what you would receive if 
you join this study.  
The best experience with transplant for 
MDS is with well-matched sibling or 
unrelated donors. If you do not have a 
matched donor, you might be able to get a 
transplant that uses a donor who isn’t a close 
match or that uses an umbilical cord blood 
unit (CBU). Since the outcome from 
transplant with these donors is not as good, 
only well-matched sibling and unrelated 
donors are being offered on this trial. 
Your study doctor will talk with you about 
your options. If you decide not to join this 
study, your medical care will not be affected 
in any way.
 
8. Possible Benefits
You will not benefit from taking part in this 
study. Your participation in this study 
allows us to collect specific information 
about your treatment for MDS. You can still 
receive the same or similar treatments if you 
don’t take part in this study. 
Information from this study will help 
doctors learn more about treatments for 
MDS. This information could help people 
with MDS who may need a transplant in the 
future.
 
9. New Information Available During the Study 
During this study, the study doctors may learn 
new information about the risks and benefits 
of the study. If this happens, they will tell you 
about the new information.  
The new information may mean that you can 
no longer take part in the study, or that you 
may not want to continue in the study.   
If this happens, the study doctor will stop 
your participation and offer you all available 
care to meet your needs and medical 
conditions. 
 
10. Privacy, Confidentiality and Use of Information 
Your confidentiality is one of our main 
concerns. We will do our best to make sure 

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that the personal information in your medical 
record will be kept private. However, we 
can’t guarantee total privacy.   
All your medical and demographic 
information (such as race and ethnicity, 
gender and household income) will be kept 
private and confidential. (Name of 
Transplant Center) and the organizations 
listed below will not disclose your 
participation by any means of 
communication to any person or 
organization, except by your written request, 
or permission, or unless required by federal, 
state or local laws, or regulatory agencies. 
Individuals authorized by the organizations 
below will have access to your research and 
medical information. They may use this 
information for inspections or audits to 
study the outcomes of your treatment. In 
agreeing to participate, you consent to such 
inspections and to the copying of parts of 
your records, if required by these 
organizations. 
We may give out your personal information 
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.  
Information about your transplant from your 
original medical records may be seen or sent 
to national and international transplant 
registries, including: 
 /Institution/Transplant center 
 The National Institutes of Health 
(NIH) 
 The National Heart, Lung, and Blood 
Institute (NHLBI)  
 The National Cancer Institute (NCI) 
 Office of Human Research Protection 
(OHRP) 
 The Food and Drug Administration 
(FDA)  
 Institutional Review Boards (IRBs) 
responsible for this study 
 Data and Safety Monitoring Board 
(DSMB), not part of /Institution/ 
 Blood and Marrow Transplant 
Clinical Trials Network (BMT CTN), 
including the Center for International 
Blood and Marrow Transplant 
Research (CIBMTR), the National 
Marrow Donor Program (NMDP) and 
the EMMES Corporation who are 
coordinating the studies of the BMT 
CTN 
 Study investigators, Ryotaro 
Nakamura, MD and Corey Cutler, 
MD MPH FRCP(C) 
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.   
Your privacy is very important to us.  The 
study doctors will make every effort to 

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protect it.  The study doctors have a privacy 
permit to help protect your records if there is 
a court case.  However, some of your medical 
information may be given out if required by 
law.  If this should happen, the study doctors 
will do their best to make sure that any 
information that goes out to others will not 
identify who you are. 
Data regarding your clinical situation, 
including follow-up after 3-4 years, may 
be obtained from the CIBMTR, which 
captures information on all US transplants. 
For questions about access to your medical 
records, please contact /name/at/number. 
11. Ending Your Participation
The study doctor or the study sponsor may 
stop the study at any time, and we may ask 
you to leave the study.  
 
If we ask you 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.  
 The study is stopped for any reason. 
Even if you withdraw from the study, the 
information collected from your participation 
will be included in the study.
 
12. Physical Injury as a Result of Participation 
It is important to tell your study doctor 
[investigator's name(s)] or study staff if you 
feel that you have been hurt or injured from 
taking part in this study.  You can tell the 
doctor in person or call [telephone number]. 
You will get all available medical treatment if 
you are injured from 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 you are injured in this study, you 
don’t lose any of your legal rights to receive 
payment by signing this consent form. 
 

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13. Compensation or Payment
You will not be paid for taking part in this 
study. You will not be compensated or 
reimbursed for any extra costs (for example, 
travel and meals) from taking part in this 
study. 
 
14. Costs and Reimbursements 
The clinic visits for this study are standard 
medical care for transplant or the standard 
treatment. You and/or your health 
plan/insurance will need to pay for the costs 
of transplant or standard treatment in this 
study. 
Some health plans will not pay these costs 
for people taking part in studies. Check with 
your health plan or insurance company to 
find out if they will pay.  
For questions about your costs, financial 
responsibilities, and/or medical insurance 
coverage for your transplant and this study, 
please contact /Center/ Financial Counselor 
at /Number/. 
For more information on clinical trials and 
insurance coverage, you can visit the 
National Cancer Institute’s Web site at 
http://cancer.gov/clinicaltrials/understanding
/insurance-coverage. You can print a copy 
of the “Clinical Trials and Insurance 
Coverage” information from this Web site. 
Another way to get the information is to call 
1-800-4-CANCER (1-800-422-6237) and 
ask them to send you a free copy.  
 
15. For More Information
If you want more information about this 
study, or if you have problems while taking 
part in this study, you can contact the study 
doctor or study staff. 
They can be reached at the telephone numbers 
listed here: 
[Insert contact information for site PI]. 
 
16. Contact Someone about Your Rights 
If you wish to speak to someone not directly 
involved in the study, or if you have any 
complaints about the project, or any questions 
about your rights as a research participant, 
you may contact:  
[Insert appropriate contact details]. 
The ethical aspects of this research study have 
been reviewed and approved by [name of 
IRB]. 

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B-14 
For questions about your rights while taking 
part in this study, call the __________[name 
of center] Institutional Review Board (a 
group of people who review the research to 
protect your rights) at __________________ 
(telephone number).  
 
17. Blood and Tissue Samples for Future Research (Optional) 
This section of the consent form is about 
future research studies that will use blood 
and tissue (blood, cheek cells, and bone 
marrow) samples from people who are 
taking part in the main study. You may 
choose to give blood and tissue samples for 
these future studies if you want to. You or 
your insurance will not be charged for these 
research samples. 
You can still be a part of the main study 
(health evaluations by phone) even if you 
say ‘no’ to give blood and tissue samples for 
future studies. 
The risk of injury from having your blood 
taken is very small. If your blood samples 
are collected from your arm, you may bleed 
a little bit and/or develop a small bruise. 
Infection from blood draws is rare, but it 
may happen.  
If you are uncomfortable at the sight of 
blood, you may feel light-headed or faint. 
Only trained people will draw your blood. 
The risk of injury from having your bone 
marrow taken is small. You may feel stiff or 
sore for several days after the aspiration. 
You may bleed a little bit and/or develop a 
bruise. Only trained people will collect your 
bone marrow. 
 
The risk of injury from having a cheek swab 
from the inside of your mouth is very small.   
If you agree to provide blood and tissue 
samples, this is what will happen: 
a.) We will collect 1 extra blood sample at 
the same time you have routine blood 
tests done before you start your 
treatment. We will collect about 4 
tablespoons (50 mL). If you weigh less 
than 110 pounds (50 kg), the amount of 
blood we collect will be based on your 
weight.  
b.) We will also collect cells from your 
mouth by gently rubbing a cotton swab 
on the inside of your cheek. 
c.) Additionally, if you are going to get a 
transplant, we will also collect about ¼ 
teaspoon (1 mL) of bone marrow fluid 
and cells through a needle put into your 
bone (aspiration, if you and your doctor 
choose to perform this procedure) before 
you get your transplant.  
 
The skin will be cleaned with a special 
solution and a medicine (local 
anesthetic) will be used to numb the 
area. Then the aspiration needle will be 
put through your skin and into your bone 
to reach the bone marrow. During an 
aspiration, you may feel a quick, 
shooting pain as the sample is taken. 

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B-15 
d.) If you get a transplant and your MDS 
comes back: 
a. We will collect another blood sample 
(no more than 4 tablespoons).  
b. We will collect another ¼ teaspoon 
(1 mL) of bone marrow fluid and 
cells through a needle put into your 
bone (if you and your doctor choose 
to perform this procedure). 
 
e.) The blood and tissue samples will be 
sent to the BMT CTN Repository for 
processing and storage. A repository is 
a place that protects, stores, and sends 
out samples for approved research 
studies. All research samples will be 
given a number that cannot be linked to 
you.  
f.) Samples stored in the Repository will be 
used mainly by doctors and researchers 
in the BMT CTN network. In the future, 
the unused blood and tissue samples and 
health information will be made 
available outside of this network (see 
sections ‘g’ below).  
g.) Researchers can apply to study the 
health information and blood and tissue 
samples in the Repository. The BMT 
CTN Steering Committee and/or the 
BMT CTN Executive Committee must 
approve each request before they will 
share samples or information with 
researchers. This is to make sure that the 
investigators requesting the samples are 
qualified, and that the research is of high 
quality. 
h.) DNA from your stored blood and tissue 
samples might be used in genome-wide 
association (GWA) 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 find genes that have 
a role in human disease or treatment. 
Each study can look at millions of 
genetic changes at the same time. 
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 
although the results of genetic studies 
could theoretically include identifying 
information about you.  
Your name and other information that could 
directly identify you (such as address or 
social security number) will not be placed 
into any scientific database. However, 
because your genetic information is unique 
to you, there is a small chance that someone 
could trace it back to you. The risk of this 
happening is small, but may grow in the 
future. Researchers have a duty to protect 
your privacy and to keep your information 
confidential. 
Some general things you should know about 
letting us store your blood and tissue 
samples for research are: 

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B-16 
 We will only store samples from people 
who give us permission. 
 Research is meant to gain knowledge that 
my help people in the future. You will not 
get any direct benefit from taking part. 
Additionally, you or your doctor will not 
be given results and they will not be 
added to your medical record. 
 A possible risk is the loss of 
confidentiality about your medical 
information. We will use safety measures 
with both your samples and health 
information to make sure that your 
personal information will be kept private. 
It’s very unlikely that your personal 
information will be given to someone else.   
 Your blood and tissue will be used only 
for research and will not be sold. The 
research done with your blood may help 
to develop new products in the future. 
You will not get paid for any samples or 
for any products that may be developed 
from current or future research. 
You can change your mind at any time 
about allowing us to use your samples and 
health information for research.  
If you do not want us to use your blood and 
tissue samples or health information for 
research, we ask that you contact: [Principal 
Investigator] in writing. The mailing address 
is on the first page of this form.  
However, samples and information that have 
already been shared with other researchers 
cannot be taken back or destroyed.  
Making Your Choice  
Please read each sentence below and think 
about your choice. After reading each 
sentence, please indicate your choice below. 
If you have any questions, please talk to 
your doctor or nurse, or call our research 
review board at: [contact information for 
site PI]. ___________________.  
No matter what you decide to do, it will not 
affect your care. 
 
 
 

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B-17 
Statement of Consent for Optional Blood and Tissue Research Samples 
The purpose of storing blood and tissue 
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 and tissue for 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, tissue, 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 clinical information may or may 
not be used in genome-wide association 
studies.
 
Blood and cheek samples 
 I agree to allow my blood and cheek samples to be stored for research. 
 I do not agree to allow my blood and cheek samples to be stored for research. 
Bone marrow samples 
 I agree to allow my bone marrow samples to be stored for research. 
 I do not agree to allow my bone marrow samples to be stored for research. 
 
 
 
 
 
 
 
Signature 
 
 
Date
 
 
 
 
 
 
 

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B-18 
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 Multi-Center Biologic Assignment Trial 
Comparing Reduced Intensity Allogeneic 
Hematopoietic Cell Transplant to 
Hypomethylating Therapy or Best 
Supportive Care in Patients Age 50 or Older 
with Intermediate-2 and High Risk 
Myelodysplastic Syndrome 
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). 
                                                 
 
 
 
 
1 HIPAA is the Health Insurance Portability and 
Accountability Act of 1996, a federal law related to 
privacy of health information 
 Findings from physical exams. 
 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]. 

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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. Ryotaro Nakamura, Co-Principal 
Investigator  
Dr. Corey Cutler, 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 as 
required by law and would no longer be 
protected. 
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. 

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B-20 
TITLE: A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic 
Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in 
Patients Age 50 or Older with Intermediate-2 and High Risk Myelodysplastic Syndrome 
PROTOCOL NUMBER: BMT CTN 1102 
PRINCIPAL INVESTIGATORS:  
Ryotaro Nakamura, MD  
City of Hope Medical Center 
1500 East Duarte Road 
Duarte, CA 91010 
Phone: (626) 656-4673 
 
Corey Cutler, MD MPH FRCP(C) 
Dana-Farber Cancer Institute 
450 Brookline Ave 
Boston, MA 02215 
Phone: (617) 632-3470 
 
 I have read and understood this Consent 
Form. The nature and purpose of the 
research study has been explained to me.  
 I understand that I will have a transplant 
if a matched donor is found. If I don’t 
have a matched donor, I will get the 
standard treatment.   
 I have had the chance to ask questions, 
and I understand the answers I have been 
given. I understand that I may ask 
questions at any time during the study. 
 I freely agree to take part in the study. 
 I understand that I will 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 to keep.

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B-21 
 
 
 
 
 
 
 
Participant Name 
 
 
Date 
 
 
 
 
 
 
Signature 
 
 
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. 
 
 
 
 
 
 
Name of Counseling Physician 
 
 
Date 
 
 
 
 
 
 
 
Signature of Counseling Physician 
 
 
Date 
 
 
 
 
 
 
 
 
Name of Interpreter 
 
 
Date 
 
 
 
 
 
 
 
Signature of Interpreter 
 
 
Date 
 
 

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C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 

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C-2 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
1. OPTIONAL RESEARCH SPECIMENS 
 
Patients consenting to the optional future research will have samples collected for future, 
undefined research supporting the protocol.  All research sample aliquots will be given unique bar 
code designations that cannot be linked back to the participant’s name or other identifying 
information.  Laboratory test results, clinical information, etc., associated with the coded samples 
are provided to the Investigator only after completion of the protocol.  Samples sent to researchers 
cannot be linked with any remaining samples at the repository. 
 
Patient peripheral blood and buccal swab samples will be collected at enrollment for both arms.  
Peripheral blood (and bone marrow samples if available) will also be collected from patients 
assigned to the HCT arm who experience relapse at the time of relapse and stored to support future 
research studies.  If available, bone marrow will be collected pre-transplant for the patients 
assigned to the HCT arm.  All research samples will be collected and shipped same-day to the 
BMT CTN Repository for processing and sample aliquot storage.  Sample collection and shipping 
procedures are detailed in the BMT CTN 1102 Laboratory Sample Guide. 
 
 
 

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C-3 
 
Subject 
Optional Research Samples 
Research 
Sample 
Type 
Time Points 
[Total Blood 
Volume] 
Sample 
Quantity 
Stored 
Material 
Sample 
Processing 
& Storage 
Site 
Aliquots Stored 
Purpose 
Non-transplant 
Therapy/Best 
Supportive 
Care 
 
120 Patients 
Peripheral 
Blood 
Enrollment  
50 mL 
5 mL 
EDTA 
Plasma 
BMT CTN 
Repository 
Maximum 
5 aliquots 
0.5 mL aliquots; 
stored at -80º C 
Undefined Future Research 
(Proteomic) 
6 mL 
EDTA 
Whole 
Blood 
BMT CTN 
Repository 
Maximum 
6 aliquots 
1.0 mL aliquots; 
stored at -80º C 
Undefined Future Research 
(Genomic) 
29 mL 
Heparin 
Viable 
PBMC 
BMT CTN 
Repository 
Maximum 
6 aliquots 
1.0 mL aliquots 
containing ~ 2.5-
5.0 x 106 PBMC; 
controlled-rate 
frozen and stored 
in LN2 
Undefined Future Research 
(Cell-Functional & Gene 
Expression) 
10 mL 
PAXgene 
Whole 
Blood 
BMT CTN 
Repository 
Maximum 
4 aliquots 
2.5 mL-fill 
PAXgene tubes; 
stored at -80º C 
Undefined Future Research 
(Gene Expression) 
Buccal 
Swabs 
Enrollment 
4 swabs 
Buccal Cells 
BMT CTN 
Repository 
4 cryovials each 
containing a 
swab; stored at -
80º C 
Undefined Future Research 
(Genomic) 
 
 

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C-4 
Subject 
Optional Research Samples 
Research 
Sample 
Type 
Time Points 
[Total Blood 
Volume] 
Sample 
Quantity 
Stored 
Material 
Sample 
Processing & 
Storage Site 
Aliquots Stored 
Purpose 
Reduced 
Intensity 
Conditioning 
Allogeneic 
Transplant 
 
280 Patients 
Peripheral 
Blood 
Enrollment  
280 patients* 
 
and 
 
Disease 
Relapse 
(event-
driven) 
84 patients* 
 
50 mL 
5 mL 
EDTA 
Plasma 
BMT CTN 
Repository 
Maximum 
5 aliquots 
0.5 mL aliquots; stored at -80º 
C 
Undefined Future 
Research 
(Proteomic) 
6 mL 
EDTA 
Whole 
Blood 
BMT CTN 
Repository 
Maximum 
6 aliquots 
1.0 mL aliquots; stored at -80º 
C 
Undefined Future 
Research 
(Genomic) 
29 mL 
Heparin 
Viable 
PBMC 
BMT CTN 
Repository 
Maximum 
6 aliquots 
1.0 mL aliquots containing ~ 
2.5-5.0 x 106 PBMC; 
controlled-rate frozen and 
stored in LN2 
Undefined Future 
Research 
(Cell-Functional & 
Gene Expression) 
10 mL 
PAXgene 
Whole 
Blood 
BMT CTN 
Repository 
Maximum 
4 aliquots 
2.5 mL-fill PAXgene tubes; 
stored at -80º C 
Undefined Future 
Research 
(Gene Expression) 
Buccal 
Swabs 
Enrollment 
4 swabs 
Buccal Cells 
BMT CTN 
Repository 
4 cryovials each containing a 
swab; stored at -80º C 
Undefined Future 
Research 
(Genomic) 
 
 
 

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C-5 
Subject 
Optional Research Samples 
Research 
Sample 
Type 
Time Points 
[Total Blood 
Volume] 
Sample 
Quantity 
Stored 
Material 
Sample 
Processing & 
Storage Site 
Aliquots Stored 
Purpose 
 
Bone 
Marrow 
Aspirate 
 
Pre-
transplant 
(if available) 
280 patients* 
 
and 
 
Disease 
Relapse 
(event-
driven) 
84 patients* 
 
1-3 mL 
Bone 
Marrow 
BMT CTN 
Repository 
Maximum 
4 aliquots 
0.5 to 0.75 mL BM aliquots 
added to equal volume RPMI 
freezing solution; controlled-
rate frozen and stored in LN2 
Undefined Future 
Research 
(Genomic) 
*Estimated patient numbers 
 
 
 

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D-1 
APPENDIX D 
 
KARNOFSKY AND ECOG  
PERFORMANCE STATUS SCALES 
 

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D-2 
APPENDIX D 
 
KARNOFSKY AND ECOG PERFORMANCE STATUS SCALES 
 
Karnofsky 
Scale % 
Karnofsky 
Description 
ECOG 
Scale* 
ECOG 
Description 
SWOG 
Scale 
100 
Normal, no complaints, no 
evidence of disease. 
0 
Fully active, able to carry on all 
pre-disease activities without 
restriction. 
0 
90 
Able to carry on normal 
activity, minor symptoms or 
signs of disease. 
80 
Normal activity with effort, 
some signs or symptoms of 
disease. 
1 
Restricted 
in 
physically 
strenuous 
activity 
but 
ambulatory and able to carry 
out work of a light or sedentary 
nature e.g. light house work 
office work.  
1 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work. 
60 
Requires occasional assistance, 
but is able to care for most of 
own needs. 
2 
Ambulatory and capable of all 
self care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours  
2 
50 
Requires 
considerable 
assistance and frequent medical 
care. 
40 
Disabled, requires special care 
and assistance. 
3 
Capable of only limited  self 
care, confined to bed or chair 
more than 50% of waking hours  
3 
30 
Severely 
disabled, 
hospitalization 
is 
indicated 
although death is not imminent. 
20 
Hospitalization necessary, very 
sick, 
active 
supportive 
treatment necessary. 
4 
Completely disabled. Cannot 
carry on any self care. Totally 
confined to bed or chair  
4 
10 
Moribund, fatal processes 
Dead 
 
Dead 
 
5 
*also known as Zubrod or WHO scale 
 
 
 
 
 

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E-1 
APPENDIX E 
 
INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS)  
AND 
REVISED INTERNATIONAL PROGNOSTIC SCORING 
SYSTEM  
(IPSS-R) 

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E-2 
APPENDIX E 
 
INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS)  
AND 
REVISED INTERNATIONAL PROGNOSTIC SCORING SYSTEM  
(IPSS-R) FOR PATIENTS WITH MDS 
 
 
International prognostic scoring system (IPSS)* for MDS: 
 
Prognostic 
Variable 
Score 
0 
0.5 
1.0 
1.5 
2.0 
BM blasts (%) 
< 5 
5 - 10 
- 
11 - 20 
21 - 30 
Karyotype** 
Good 
Intermediate 
Poor 
 
 
Cytopenias^ 
0 or 1 
2 or 3 
 
 
 
 
Score for risk groups are as follows: 
 
Risk Group 
IPSS Score 
Low 
0 
Intermediate - 1 
0.5 - 1.0 
Intermediate - 2 
1.5 - 2.0 
High 
> 2.5 
 
*International Prognostic Scoring System [21] 
**Good: normal, -Y, del(5q), del(20q); Poor: complex (≥3 abnormalities) or chromosome 7 
anomalies; Intermediate: other abnormalities 
^Red blood cells: Hemoglobin <10 g/dL (100g/L); White blood cells: Absolute neutrophil count 
<1800/microL; Platelets: Platelet count <100,000/microL 
 
 
 

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E-3 
Revised international prognostic scoring system (IPSS-R) in MDS: 
 
Prognostic 
Variable 
Score 
0 
0.5 
1.0 
1.5 
2.0 
3.0 
4.0 
Cytogenetics* 
Very good 
- 
Good 
- 
Intermediate 
Poor 
Very poor 
Bone marrow 
blasts (%) 
≤ 2 
- 
> 2 to < 5 
- 
5 - 10 
> 10 
 
Hemoglobin 
(g/dL) 
≥ 10 
- 
8 to < 10 
< 8 
 
 
 
Platelets 
(cells/microL) 
≥ 100 
50 - 100 
< 50 
 
 
 
 
Absolute 
neutrophil count 
(cells/microL) 
≥ 0.8 
< 0.8 
 
 
 
 
 
 
Score for risk groups are as follows: 
 
Risk Group 
IPSS-R Score 
Very low 
≤ 1.5 
Low 
> 1.5 to 3.0 
Intermediate 
> 3 to 4.5 
High 
> 4.5 to 6 
Very high 
> 6 
 
**Very good: -Y, del(11q); Good: Normal, del(5q), del(12p), del(20q), double including del(5q); 
Intermediate: del(7q), +8, +19, i(17q), any other single or double independent clones; Poor:-7, 
inv(3)/t3q)/del(3q), double including -7/def(7q), complex 3 abnormalities; Very poor: complex, 
≥3 abnormalities 
 
 

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F-1 
APPENDIX F 
 
ANCILLARY COST-EFFECTIVENESS ANALYSIS PROTOCOL 
 

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F-2 
Ancillary Cost-Effectiveness Analysis to: 
A Multi-Center Biologic Assignment Trial Comparing Reduced 
Intensity Allogeneic Hematopoietic Cell Transplant to 
Hypomethylating Therapy or Best Supportive Care in Patients Aged 
50-75 with Intermediate-2 and High Risk Myelodysplastic Syndrome 
BMT CTN 1102 
 
 
BMT CTN PROTOCOL 1102 
CEA VERSION 2.0 
 
 
 
CEA Study Investigators 
Scott Ramsey, M.D., Ph.D. 
Catherine Richards, Ph.D., M.P.H 
Bart Scott, MD 
 
Parent Study Investigators 
Wael Saber, MD 
Corey Cutler, M.D., M.P.H., F.R.C.P.(C) 
Ryotaro Nakamura, MD 
 
 
CEA Study Team 
Adam Mendizabal, PhD 
Alyssa Ramirez 
Deborah Mattila 
Rebecca Drexler 
 
 
 
 
 

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F-3 
LIST OF ABBREVIATIONS  
 
 
Abbreviation 
Definition  
alloHCT 
Allogeneic hematopoietic stem cell transplant 
BMT 
Bone marrow transplant 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
CEA 
Cost-effectiveness analysis 
CIBMTR 
Center for International Blood and Marrow Transplant 
Research 
GVHD 
Graft versus host disease 
HMA 
Hypomethylating agents 
ICER 
Incremental cost effectiveness ratio 
MDS 
Myelodysplastic syndromes 
OS 
Overall survival 
PFS 
Progression free survival 
QALY 
Quality adjusted life year 
QoL 
Quality of life 
RIC 
Reduced intensity conditioning  
SRG 
Survey Research Group  
 
 
 

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PROTOCOL SYNOPSIS 
 
Myelodysplastic syndrome (MDS) is a heterogeneous group of acquired malignant bone marrow 
disorders with an annual incidence rate of approximately 4 per 100,000.1,2 MDS most commonly 
occurs in older individuals, with 80% diagnosed at ≥65 years of age in the United States.3 
Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only curative treatment 
modality for MDS, and with the introduction of reduced intensity conditioning (RIC) regimens, 
alloHCT is now a viable treatment option for many older patients. Hypomethylating agents 
([HMA] azacitadine and decitabine) also on average improve progression free (PFS) and overall 
survival (OS) in patients with MDS and, unlike transplantation, these agents do not require the 
demanding preparation or carry the risk of graft versus host disease (GVHD) and other 
transplant related morbidity and mortality.  BMT CTN 1102 is a controlled trial designed to 
evaluate the comparative effectiveness of alloHCT relative to treatment with HMA or best 
supportive care in patients with MDS aged 50-75. Although alloHCT is the only curative modality 
for MDS, clinical equipoise exists given the considerable mortality and long term morbidity risk 
associated with transplant. Moreover, the relative survival, quality of life, and cost impacts of 
these alternative treatment approaches in older adults remains uncertain.  
 
This protocol describes an ancillary cost-effectiveness analysis to be conducted alongside BMT 
CTN 1102. Consenting patients will provide health insurance information to allow calculation of 
direct medical costs from reimbursement records, and will provide out-of-pocket costs, time 
costs, through paper-based surveys. These outcomes will inform a cost-effectiveness analysis 
comparing the outcomes of alloHCT and HMA or best supportive care from patient, payer, and 
societal perspectives. The results of this analysis will be the first to provide a comprehensive 
evaluation of the comparative effectiveness of these MDS treatment approaches from multiple 
perspectives. 
 
 
 
 
 
 

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Table of Contents 
1. 
BACKGROUND AND RATIONALE ........................................................................ 7 
1.1 
Background ................................................................................................................ 7 
1.2 
Rationale for Cost-Effectiveness Analysis ......................................................... 8 
2. 
STUDY OBJECTIVES ................................................................................................ 9 
2.1 
Objective 1 .................................................................................................................. 9 
2.2 
Objective 2 ................................................................................................................ 10 
2.3 
Objective 3 ................................................................................................................ 10 
2.4 
Objective 4 ................................................................................................................ 10 
3. 
METHODS .................................................................................................................. 10 
3.1 
Study Design ............................................................................................................ 10 
3.2 
Study Population ..................................................................................................... 11 
3.2.1 
Inclusion Criteria ..................................................................................................... 11 
3.2.2 
Exclusion Criteria .................................................................................................... 11 
3.2.3 
Enrollment Procedures .......................................................................................... 11 
3.3 
Study Period ............................................................................................................. 12 
3.3.1 
Coordination between BMT 1102 Clinical Centers, Survey Research 
Group, and CEA Coordinating Center ............................................................... 12 
3.3.2 
Index Date for Assessment Surveys and Study Arm Assignment ............ 12 
3.4 
Data Sources ............................................................................................................ 15 
3.4.1 
Direct Medical Care Costs Payer: Health Insurance Reimbursements .... 15 
3.4.2 
Out-of-Pocket Costs ............................................................................................... 15 
3.4.3 
Indirect costs: Work Loss Related to Illness and Treatment (Productivity 
Costs) ......................................................................................................................... 16 
3.4.4 
Valuing Patient Work Loss ................................................................................... 16 
3.4.5 
Financial Hardship .................................................................................................. 16 
3.4.6 
Cost Data Collection Mechanisms ..................................................................... 16 
3.4.7 
Measuring Quality Adjusted Life Years ............................................................. 17 
3.5 
Outcomes/Endpoints ............................................................................................. 17 
3.5.1 
Primary Endpoint .................................................................................................... 17 
3.5.2 
Secondary Endpoints ............................................................................................. 17 
4. 
STATISTICAL CONSIDERATIONS ...................................................................... 17 

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4.1 
Analysis of Costs .................................................................................................... 17 
4.1.1 
Study Perspective and the use of Health Insurer Reimbursements ......... 17 
4.1.2 
Direct Medical Care Costs Payer ........................................................................ 18 
4.1.3 
Out-of-pocket and Personal Costs ..................................................................... 19 
4.2 
Analysis of Effectiveness: Quality Adjusted Life Years ............................... 19 
4.3 
Analysis of Incremental Cost Effectiveness .................................................... 19 
4.4 
Lifetime Horizon and Simulation Modeling ...................................................... 19 
4.4.1 
Uncertainty Analysis .............................................................................................. 20 
4.5 
Base Year Cost Counting and Discounting ..................................................... 21 
4.6 
Missing Data ............................................................................................................. 21 
4.7 
Sample Size and Power ......................................................................................... 21 
5 
REFERENCES .......................................................................................................... 23 
 
 
LIST OF TABLES AND FIGURES 
 
 
Figure 1 Study schema for patients enrolled in BMT 1102 
Table 1 Summary of Cost Information to be Collected 
Table 2 Cost Data Collection 
Table 3 Power Calculations 
 
 

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1. 
BACKGROUND AND RATIONALE  
1.1 
Background 
MDS is a clonal disorder of hematopoietic stem cells, which may progress to acute myeloid 
leukemia (AML). Data from the Surveillance Epidemiology and End Results (SEER) national 
cancer registries estimate that approximately 10,000 new cases of MDS are diagnosed 
annually.4 However, this may be a substantial underestimate given the diagnostic challenges of 
identifying MDS.5 Using linked SEER-Medicare records, Cogle et al estimated an annual 
incidence of 75 per 100,000 among persons aged 65 and older, compared to an incidence of 20 
per 100,000 for the same age group when only SEER records were used.6 The median age at 
diagnosis is 67 years and incidence rises sharply with age.4 MDS is more common among 
males than females, and while a significantly higher incidence has been observed in non-
Hispanics than among Hispanics, significant differences by 
race have not been observed.4 
 
The International Prognostic Scoring System (IPSS) is used 
to classify MDS into four risk groups (low, intermediate-1, 
intermediate-2, and high). Table 1 shows the median survival 
for each risk group, as published by Greenberg et al.7 Low-
risk MDS patients are often not treated until they become 
transfusion-dependent,5 while patients with high-risk MDS (intermediate-2, and high) are 
considered for alloHCT.8,9 Despite advances in alloHCT, including the use of RIC preparative 
regimens, the use of alloHCT remains low among older patients. For example, records from the 
Center for International Blood and Marrow Transplant Research (CIBMTR) show that out of a 
total of 3,101 alloHCTs performed in the US between 2000 and 2010 for MDS, only 232 (7.5%) 
were among persons aged ≥65 years (personal communication, W. Saber). HMA, including 
azactidine and decidabine, are recommended for the treatment of high-risk MDS patients who 
are not candidates for or are not willing or able to undergo alloHCT.8,9 According to a study from 
the CIBMTR,10 three-year disease-free survival for patients receiving alloHCT is approximately 
40% (95% CI 36%-45%). This is better than the median time to AML progression of 18 months, 
and median time of AML transformation or death of 21 months observed for azacitidine in two 
randomized controlled trials,11,12 however it should be noted that the cumulative incidence of 
transplant-related mortality at 3-years in the CIBMTR study was 37% (95% CI 32%-42%).10 The 
substantial risk of morbidity (including graft versus host disease and post-alloHCT infection) and 
mortality associated with transplant undoubtedly tips the balance for some physicians and 
patients considering alloHCT, especially for elderly patients with comorbidities. A biologic 
assignment, non-randomized trial is currently underway in Europe comparing non-transplant 
therapies to alloHCT based on availability of a human leukocyte antigen (HLA) matched donor, 
but results are not expected until June 2017. The BMT CTN clinical study recently opened in the 
United States, providing the opportunity to collect clinical and ancillary economic data to 
address the use of alloHCT in older patients in a multi-payer system. If the results of BMT CTN 
1102 demonstrate superior survival at 3-years for the alloHCT group, as hypothesized by the 
study investigators, it is likely that the demand for alloHCT will grow and CMS and other payers 
will have to weigh both the clinical and economic evidence when making coverage decisions. 
However, there is already evidence that suggests that the use of alloHCT in older MDS patients 
is increasing rapidly. For example, since 2010, the year CMS issued the Coverage with 
Evidence decision for alloHCT, the number of alloHCTs performed in the US among patients 
age ≥65 years rose nearly 3.5 fold, from 65 to 220 respectively (personal communication, W. 
Saber). Given that this still represents a small proportion of eligible MDS patients, it is expected 
Table 1. Median survival estimates 
based on the IPSS  
Risk Category  
Median 
Survival (y) 
Low 
5.7 
Intermediate-1 
3.5 
Intermediate-2 
1.2 
High 
0.4 

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that the demand would rise even more dramatically if alloHCT was covered outside of clinical 
trial settings.  
  
An analysis of the ten most costly inpatient hospital procedures published by the Agency for 
Health Care Research and Quality found that bone marrow transplant was the most expensive 
procedure ($1.3 billion 2007 USD in inpatient hospital costs), and required an equivalent 
number of hospital stays as the other top 9 procedures combined.13 Additionally, the process of 
searching for a donor, harvesting of donor cells, and immunosuppressive conditioning to 
prepare the patient for alloHCT transplant is extremely resource intensive. Likewise, in the post-
transplant period, patients must be closely monitored to reduce the high risk of morbidity and 
mortality discussed above. The total first-year direct medical care costs of alloHCT have been 
estimated to be between $96,000 and $204,000 2012 USD.14 The authors of the cited review of 
HCT costs note that few studies take a societal approach, meaning that these cost estimates do 
not include direct nonmedical costs (transportation, food, lodging) or indirect nonmedical costs 
(lost wages and productivity). These additional costs can be especially burdensome for older 
MDS patients receiving alloHCT, as they may need extensive caregiver support and may be 
living on fixed incomes that cannot absorb the financial shock of unexpected medical expenses. 
Direct medical costs can be obtained retrospectively from insurance claims, and are thus often 
the only data available to compare the economic impact of treatment strategies, however the 
Public Health Service’s Panel of Cost Effectiveness in Health and Medicine and the 
International Society for Pharmaceutical Outcomes Research Randomized Control Trials – cost-
effectiveness analysis (CEA) Task Force both recommend that a societal perspective be taken 
to comprehensively assess the economic consequences of alternative treatments.15,16  
 
BMT CTN 1102 Trial 
Given this knowledge gap and as a response to the Centers for Medicare & Medicaid Services 
(CMS) Coverage-with-Evidence-Development (CED) for National Coverage Determination 
(NCD) of Stem Cell Transplantation,17 the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN) launched the BMT CTN 1102.18 This study is a prospective biologic assignment trial 
to compare RIC alloHCT to non-transplant therapies based on suitable donor availability. 
Suitable donor is defined as either a human leukocyte antigen (HLA)-matched related donor, or 
an 8/8 (HLA-A, -B, -C, and -DRB1) well matched unrelated donor. If no suitable donor is 
identified during a 90-day interval (from enrollment), subjects will be permanently assigned to 
the no donor arm. The 90-day interval was chosen based on the likelihood that a donor will be 
found, according to the median search times reported by the National Marrow Donor Program 
(NMDP). Four hundred patients will be enrolled over roughly 3 years at 30 centers throughout 
the United States. Secondary outcomes include leukemia-free survival, quality of life, and cost-
effectiveness and planned subgroup analyses will evaluate key biologic questions, such as the 
impact of age & response to HMA on treatment effects. Figure 1 depicts the overall study 
schema.    
 
1.2 
Rationale for Cost-Effectiveness Analysis 
Cost-effectiveness analyses can be particularly informative when conducted alongside 
randomized controlled trials. In this setting, CEA can provide timely economic evidence about 
the relative value of alternative medical strategies with a high level of internal validity.19 In the 
case of the BMT CTN 1102 trial, conducting an ancillary CEA study provides the opportunity to 
precisely measure a range of quality of life and expenditure endpoints to complement the 
clinical endpoints evaluated in the parent trial, providing a comprehensive view of the tradeoffs 
of managing MDS with either alloHCT or HMA and best supportive care. Findings from this 

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study potentially may set a new standard of care for older patients with high risk MDS who are 
considered candidates for alloHCT. 
 
This study is particularly important because alloHCT is the only potentially curative treatment for 
MDS, but is also among the most expensive medical procedures in the United States. For 
example, in pilot data from 38 MDS patients undergoing alloHCT at the Medical College of 
Wisconsin, the average total cost per patient was $212,069 for the first two years post-
transplant (range $45,619 – $528,572). (Wael Saber, Personal communication)  
 
This study will provide important information about the comparative effectiveness of alloHCT 
relative to standard care with HMA or best supportive care. The outcome measures include life 
years, quality-adjusted life years, health plan direct medical expenditure and patient out of 
pocket expenditure, and productivity impact. The primary analysis will calculate the incremental 
cost-effectiveness ratio (ICER), a measure that reflects expenditure per QALY gained. Results 
will be calculated over the plausible range of willingness to pay in the United States (from 
$20,000 to $200,000 per QALY gained).20-22 
 
Several prior studies have evaluated cost and quality of life outcomes for MDS patients treated 
with alloHCT23-31 and non-transplant therapy32-35. However, none of the previous studies 
included patients as old as age 75, or long-term tracking of outcomes. As a result, the findings 
of this ancillary study will be an important contribution to the literature by providing outcomes for 
older patients (age 50-75), and tracking outcomes for up to 3 years post-enrollment. 
 
In addition, no prior studies of alloHCT or non-transplant therapy have attempted to quantify a 
comprehensive range of economic outcomes that includes patient out of pocket medical 
expenditures and work productivity impact. . This is particularly important in the case of the 
treatments compared in BMT CTN 1102 because alloHCT requires substantial hospital stays 
and non-medical costs for patients and their families can be substantial. Although many 
transplant centers provide subsidized housing to families, costs associated with transportation 
and living away from home, plus associated work loss, may pose significant burdens for patients 
and families. Moreover, patients may face the possibility of exceeding lifetime insurance caps, 
exposing them to the full cost of care thereafter. For older patients who may be retired and living 
off of a fixed income, the financial burden of alloHCT may be especially pronounced.  
 
By prospectively collecting data on costs and productivity loss of patients and their families 
participating in the BMT CTN 1102 clinical trial, this CEA of alloHCT versus HMA or best 
supportive care presents a time sensitive opportunity to comprehensively determine the cost-
effectiveness of these two alternative options. 
 
 
2. 
STUDY OBJECTIVES  
2.1 
Objective 1  
From the perspective of the payer (health insurer), to determine direct medical expenditure 
associated with alloHCT and HMA or best supportive care over the course of the trial. 
a. Based on trial results, use modeling to estimate lifetime direct medical expenditures  
 
Hypothesis 1: Direct medical expenditure will be significantly greater for patients who receive 
alloHCT compared to those who receive HMA or best supportive care.  

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2.2 
Objective 2   
From the patient perspective, estimate and compare the economic hardship associated with use 
of alloHCT and HMA or best supportive care over 18 months, by directly surveying patients..  
a. Estimate the proportion of patients/families that experience economic hardship as 
defined by out-of-pocket-costs, financial hardship(a composite measure of the 
inability to pay bills, recent income loss, need to borrow money or current debt) and 
loss of work productivity. 
 
Hypothesis 2: Out-of-pocket expenditures will be significantly greater for patients who receive 
alloHCT compared to those who receive HMA or best supportive care. 
 
Hypothesis 3: The likelihood of financial hardship will be higher for patients who receive alloHCT 
compared to those who receive HMA or best supportive care. 
 
Hypothesis 4: Patients who receive alloHCT will experience a greater loss of work productivity 
compared to those who receive HMA or best supportive care  
 
2.3 
Objective 3 
To estimate short-term and lifetime quality adjusted life years (QALYs) associated with alloHCT 
and HMA or best supportive care. Short-term QALYs will be estimated directly from the trial 
while lifetime QALYS will be estimated through modeling. 
 
Hypothesis 5: Patients receiving alloHCT will have significantly more QALYs than patients 
receiving HMA or best supportive care. 
 
2.4 
Objective 4   
Using the information from objectives 1-3, to estimate the cost-effectiveness of alloHCT 
compared to HMA or best supportive care from the societal and health insurer perspective.  
 
Hypothesis 6: AlloHCT will be more cost effective than HMA or best supportive care, from both 
a health insurer and a societal perspective, at a cost-effectiveness threshold of $100,000US per 
QALY.  
 
 
3. 
METHODS 
3.1 
Study Design 
This ancillary CEA assesses the relative value of RIC alloHCT versus HMA or best supportive 
care through the incremental cost effectiveness ratio (ICER). The ICER is equal to costs divided 
by quality-adjusted life years (QALY), resulting in the cost per quality-adjusted life year. Costs 
for this study will be measured using cost diary surveys administered to patients at 1 month, 7 
months and 19 months from the date of study enrollment.  A QALY is a metric that measures 
the duration and quality of life based on health state utility data collected from quality of life 
surveys administered in the parent BMT CTN 1102 study. The ICER, as a cost-effectiveness 
endpoint, is recommended by numerous groups, including the US Preventive Services Task 
Force on Cost-Effectiveness in Health and Medicine.36 
 

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3.2 
Study Population  
Patients eligible to participate in the BMT CTN 1102.  A biologic assignment trial open to 
patients age 50 – 75 with MDS.  
 
3.2.1 
Inclusion Criteria 
• 
Any patient who provided consent to participate in the parent study BMT CTN1102 is 
eligible to participate in the CEA study. In addition, patients enrolled in the CEA study 
must:  
- Sign the CEA research consent form 
-Complete the patient contact information form with a mailing address for the cost diary 
surveys 
- Have a bone marrow biopsy that indicates they are eligible for HCT 
 
3.2.2 
Exclusion Criteria 
• 
Primary language spoken: Languages other than English  
 
3.2.3 
Enrollment Procedures 
1) Eligible patients presented with the option of participating in BMT CTN 1102, will at the 
same time be given the option to participate in the parallel CEA. Patients will be 
informed that they can have a caregiver/family member/alternate contact help with 
completing the surveybut an alternate contact is not required to participate in the CEA 
study.  
 
2) For participants providing consent to participate in BMT CTN 1102 and the CEA, the 
Transplant Center Study Coordinator will complete the following CEA forms with the 
patient within 14 days of the patient’s enrollment date. The Study Coordinator will: 
 
a) Complete HIPAA Authorization Form (See Appendix F) with patient. 
b) Complete Patient Contact Information Form/Optional Alternate Contact 
Information Form (See Appendix F) with patient. 
c) Complete CEA Consent Form with patient (See Appendix F)  
 
d) Securely send, by Email or fax, items a,b and c to SRG. Email: 
1102SRGTeam@nmdp.org; Fax: 612-294-4370 
 
Note: Transplant Center Study Coordinators will also be responsible for emailing or 
faxing immediate notification to SRG if a patient withdraws from the study or dies.  
 
3) CEA Coordinating Center staff located at Fred Hutchinson Cancer Research Center will: 
a) Receive email notifications from The Emmes Corporation when a patient has 
enrolled to the CEA study and follow-up with transplant coordinators who have not 
submitted patient CEA enrollment forms. 
Obtainthe HIPAA Authorization Form and CEA Consent Form from SRG to 
request health insurance claims data from health insurers after completion of the 
study. 
 
4) The SRG team located at CIBMTR will:  

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b) Call the alternate contact/caregiver to address any questions they may have in 
assisting the patient in completing the survey for the CEA study and confirming 
contact information. Add patients and agreeing alternate contacts to system to track 
mailing and receipt of cost diary surveys.  
 
3.3 
Study Period 
3.3.1 
Coordination between BMT 1102 Clinical Centers, Survey Research Group, 
and CEA Coordinating Center  
Following enrollment in the BMT CTN 1102 parent trial, patients will have 30 days to be enrolled 
in the ancillary CEA. This will involve a cooperative effort between transplant coordinators, CEA 
coordinating center staff at the Fred Hutchinson, and the SRG at CIBMTR.  
 
The SRG is already conducting the Quality of Life (QoL) assessments to be used in both the 
clinical study and the CEA. Therefore, communication about those patients enrolled in both 
studies will be necessary for the SRG to administer the additional surveys ascertaining cost 
data for the CEA.  
 
3.3.2 
Index Date for Assessment Surveys and Study Arm Assignment 
The biologic assignment design of the BMT CTN 1102 necessitates a waiting period of up to 90 
days between enrollment in the trial and assignment to the non-transplant HMA or best 
supportive care arm of the study. This poses several methodological challenges for data 
collection. While the date of transplantation provides a clinically meaningful date for patients to 
reference when providing estimates of costs incurred, no such date occurs for individuals 
assigned to the non-transplant HMA or best supportive care arm. Many of these patients will 
enter the study having already received treatment for MDS, making the date of treatment 
initiation an imperfect reference date that if used only for the non-transplant arm could bias the 
results of the CEA by allowing more follow-up time over which costs could accrue. Bias in the 
opposite direction could occur if the 90-day mark is used as a reference for non-transplant 
patients.  
 
To overcome potential biases by use of a natural reference date, individuals in both arms of the 
study will be assigned the date of enrolment into BMT CTN 1102 as the baseline reference 
date.  
 
There may be a lag of up to 30 days between when a patient signs a consent form and when 
they are enrolled in the BMT CTN 1102 CEA ancillary study. This is due to the enrollment 
process in the parent study. After a patient signs their consent form for the 1102 parent study, 
they have up to 60 days to complete a bone marrow biopsy to determine their eligibility for HCT. 
Search for a donor also begins at the time a patient signs their BMT CTN 1102 study consent 
form. If the patient’s bone marrow biopsy indicates they are not eligible for HCT, then they are 
not enrolled in the study, even though they have signed a consent form. If the patient’s bone 
marrow biopsy indicates they are eligible for HCT, the patient’s transplant center completes an 
enrollment form. The parent study’s Quality of Life (QOL) survey time points are then based on 
that enrollment date, post-bone marrow biopsy.  
 
The enrollment date for the CEA ancillary study will also be the date a transplant center 
completes a parent study enrollment form, which may be up to 30 days after signing the consent 
forms for both the parent and ancillary studies. To be enrolled in the BMT CTN 1102 ancillary 

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CEA study, patients must sign the parent study consent form, the ancillary study consent form, 
have a bone marrow biopsy that indicates they are eligible for HCT, and have an enrollment 
form completed by their transplant center. The 1-month, 7-month and 19-month CEA survey 
dates will be based off of the enrollment date to the 1102 parent study, and not the date a 
patient signs their consent form.  
 
The biologic assignment design of the patient to the HCT or best supportive care arm in the 
BMT CTN 1102 study occurs naturally when a patient finds a suitable donor for HCT or if they 
are unable to find a suitable donor within 90 days of signing their BMT CTN 1102 study consent 
form. The BMT CTN 1102 CEA ancillary study will use the biologic assignment of the parent 
study. 

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Figure 1 Study schema for patients enrolled in BMT 1102 
MDS patients, age 
50 - 74, suitable RIC 
alloHCT candidates, 
fewer than 20% 
marrow blasts , 
performance status 
> 70
Donor match 
found within 90 
days
Biologic 
assignment to 
alloHCT
No suitable 
donor found 
within 90 days
Biologic 
assignment to 
HMA
Within 30 days of enrollment into 
clinical study Transplant Center Study 
Coordinator identifies English 
speaking patients consenting to 
participate in CEA
Transplant Center Study Coordinator 
a) Collects - HIPAA AUTHORIZATION
FORM
b) Collects - ALTERNATE CONTACT
INFORMATION     FORM
c) Copies - CEA CONSENT FORM
d) Prepares - Fax cover sheet including study
site and contact person
e) Faxes - items a, b and c to SRG
f) Immediately sends fax to SRG
CEA Coordinating Center
a) Collect health insurance claims data using the HIPAA
AUTHORIZATION FORM

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3.4 
Data Sources 
To comprehensively evaluate the cost-effectiveness of RIC alloHCT versus HMA or best 
supportive care, this study uses information from three separate data sources: 
I.
Health insurance reimbursement records
II.
Mail-out survey
a. Cost diary
b. Work Productivity and Activity Impairment Questionnaire (WPAI)
III.
Previously collected QOL data
Cost information will be collected in four distinct areas (Table 1). 
Table 3 Summary of Cost Information to be Collected 
Cost Category 
Description 
Providing Information 
1.
Direct medical care costs
Health insurance reimbursements 
Health insurer 
2.
Out-of-pocket costs
Direct medical care costs 
Copays, deductibles, uncovered 
medical bills 
Patient 
Direct non-medical costs 
Transportation, accommodation, 
child care…. 
Patient 
3.
Indirect costs
Lost productivity 
Patient 
4. 
3.4.1 
Direct Medical Care Costs Payer: Health Insurance Reimbursements 
Participants who consent to participate in BMT CTN 1102 will be given the option to participate 
in the parallel economic analysis. Those providing consent will be asked to provide the name(s) 
of their health insurer(s), the policy holder’s name and date of birth, the health insurance group 
number(s) and policy identification number(s) (we anticipate that some patients will have 
multiple insurance plans).  
This information will be used to request health care claims records from insurers for the period 
beginning 12-months prior to the date of enrollment, through 3-years following enrollment. To 
account for administrative delays in claims data processing, requests will be made at least 42-
months following the date of enrollment. Claims will be requested from health insurers in 
batches with batch size dependent on patient accrual to the parent study and subsequent 
accrual into the CEA. Requests will be made regardless of outcome (i.e. for patients who remain 
in remission, relapse, or die).  
3.4.2 
Out-of-Pocket Costs 
In addition to health insurance expenditure, the study will collect out of pocket expenditures 
directly from patients and/or the alternate contact nominated by the patient. Patients and 
contacts are invited to jointly participate because: there may be periods where patients are 
unable to provide information due to illness; patients usually have a team of people supporting 
them in different capacities and at different times; and to encourage discussion, recall, and 
reconciliation of potential expenses. These costs will include direct medical care costs for 
patients (e.g. copays, deductibles and uncovered medical bills) and direct non-medical patient 

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costs: transportation costs, travel time and distance, and accommodation costs. The survey is 
an adaptation of the cost diary method used by Goossens and colleagues. 37 
 
Patients will be mailed paper surveys by SRG and will return them to SRG at 1, 7 and 19 
months post enrollment. SRG will contact patients and alternate contacts by phone to 
encourage returning the surveys if not received 14 days after sending.  
 
3.4.3 
Indirect costs: Work Loss Related to Illness and Treatment (Productivity 
Costs) 
Patient time spent away from work will be estimated using the Work Productivity and Activity 
Impairment Questionnaire (WPAI). The WPAI measures work time missed as well as work and 
activity impairment due to a specific health issue.38 The WPAI’s validity has been established in 
a number of diseases and has proven a useful tool for measuring relative differences between 
treatment groups in clinical trials, including cancer, in patients with and without disease.  
 
3.4.4 
Valuing Patient Work Loss  
The value of hours recorded for patient work loss will be estimated using wages from the 
Bureau of Labor Statistics for the sex, age, location and employment category of patients.  
 
3.4.5 
Financial Hardship 
Financial hardship experienced by the patient will be captured by a set of four questions that 
capture the inability to pay bills, recent income loss, need to borrow money or current debt. The 
responses to these four questions will be combined into a composite index of financial hardship. 
This measure of financial hardship has been previously used and validated by Shankaran et al.39 
 
3.4.6 
Cost Data Collection Mechanisms 
Hard copy surveys mailed out by SRG will be used to collect data on costs and work 
productivity.  Using the cost diary method and WPAI methods described in previous sections, a 
SRG staff member will mail the patient a cost diary at 1 month, 7 months and 19 months from 
the date of study enrollment. We selected the first survey time point to be 1 month after patient 
enrollment in order to improve the likelihood that the patient or alternate contact will be able to 
collect and track their cost and time data (4).  
 
Table 4 Cost Data Collection 
 
Instrument 
N items 
 
Month Post-enrollment 
1 
7 
19 
Cost diary 
10 
X 
X 
X 
Patient WPAI 
7 
X 
X 
X 
Financial Hardship 
4 
X 
X 
X 
TOTAL N ITEMS 
21 
 
 
ANTICIPATED TIME PATIENT 
15-30 min 
 
 
 
Given that the SRG is already contacting patients in BMT CTN 1102 to collect QoL data at 
specified time points, the CEA will contract with SRG to collect the additional economic data at 1 
month, 7 months and 19 months follow-up. This approach is likely to improve participant 

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response by making SRG the single point of contact for study participants while avoiding the 
need for an internet connection or fluency with filling out online surveys.   
 
3.4.7 
Measuring Quality Adjusted Life Years  
Quality of life and clinical data collected from the parent study will be used for the CEA study to 
provide an estimate for quality adjusted life years (QALYs). QALYs make up the denominator of 
the ICER, the cost effectiveness measure for this study.  
 
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.  Since there are 5 
dimensions with 3 levels there are a total of 720 different health states, each with their own 
health utility value.  The health utility value is then multiplied by the length of time spent in that 
health state to determine each patient’s QALY. SF-36 scores will also be converted to health 
state utilities using the SF6D algorithm in order to calculate QALYs per patient.40 We will 
estimate and compare results using the QALYs (and health utility values) estimated from both 
instruments since there is no single agreed upon “best” way to measure health state utilities. 
Measuring QALYs using these two approaches will allow us to evaluate the stability of estimates 
as a function of survey instrument selection.   
 
3.5 
Outcomes/Endpoints  
3.5.1 
Primary Endpoint 
The primary end-point for the analysis will be the cost per QALY from the third party payer 
perspective with two time horizons: (1) within trial (at 3 years post enrollment), and (2) lifetime 
using simulation modeling.  
 
3.5.2 
Secondary Endpoints 
The secondary end-point is the cost per quality-adjusted life year from the societal perspective, 
a broader measure that captures health insurer direct medical care costs and patient out-of-
pocket direct medical and direct non-medical costs.19,41 Patient productivity costs (captured as 
part of QALY calculations) will be reported separately. 
 
 
4. 
STATISTICAL CONSIDERATIONS 
4.1 
Analysis of Costs 
4.1.1 
Study Perspective and the use of Health Insurer Reimbursements 
It is recommended that the comparative analysis of costs in CEAs be conducted from both a 
health system perspective and a broader societal perspective.15,16 For the evaluation of the 
costs of alloHCT and HMA or best supportive care, the primary analysis will take the third party 
payer perspective where only payer direct medical expenditures are considered. 
 
CTotal = CDirect Medical Expenditures  
 
Reimbursement records will be used to measure health plan expenditure for MDS care. The trial 
includes MDS patients that are age 50 – 75, and a substantial proportion are expected to be 

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enrolled in Medicare plans. All public and private insurance records will be requested and 
included in the primary analysis.   
 
A secondary analysis will be to evaluate cost-effectiveness from a broader societal perspective 
that includes health plan expenditure, patient out of pocket expenditure, and patient productivity 
costs. 
 
CTotal = CDirect Medical Care Payer + CDirect Medical Care Patient + CDirect Non-Medical Patient  
 
To avoid double counting, indirect productivity costs for patients will not be included in the ICER 
calculations but recorded separately (patient indirect productivity costs are captured in the 
QALY).  
 
4.1.2 
Direct Medical Care Costs Payer 
The null hypothesis is that there is no difference between the total costs of direct medical care 
for patients who receive alloHCT versus HMA or best supportive care. 
 
For the base case analysis, the mean difference in disaggregate costs and total cost between 
patients (i.e. the incremental cost) who receive alloHCT and hypomethylating therapy or 
standard or care will be analyzed. In order to estimate potential differences in cost in the two 
arms of the BMT CTN 1102 clinical trial, first the arithmetic mean of total per patient costs will 
be calculated for each arm of the trial. Differences in the arithmetic mean cost for each arm of 
the trial will be compared using a t-test. While in practice, the t-test is fairly robust to non-
normality owing to the central limit theorem,42 cost data are often highly skewed (e.g., small 
portions with very high costs), which calls into question the validity of a direct comparison of 
arithmetic means. Therefore, we will also evaluate differences in total costs of the two treatment 
strategies using non-parametric bootstrap methods42 and the Kaplan-Meier Sample Average 
estimation (KMSA) technique.43 These nonparametric techniques minimize bias due to the 
problems of censoring and skewed data.  
 
Using cost histories from the patients in each study arm, the KMSA technique determines the 
mean cost (M) over the time period of interest as: 
 
 
 
where Si denotes the probability of the event occurring in the ith month and 
 is the average 
cost among patients who are alive at the beginning of the ith month and 
is the estimated 
survival probability obtained from the Kaplan-Meier curve.  Specifically, 
is the estimated 
probability of being alive at the beginning of the ith month. Lin et al.43 demonstrate that the 
KMSA estimator is unbiased and consistent as long as (i) censoring is independent in time and 
(ii) the time intervals for the cost analysis are sufficiently narrow. The design of the treatment 
trial is consistent with independent censoring and the time intervals incorporated into cost data 
collection provide appropriately narrow time intervals. Lin et al. also show that the KMSA 
estimator is asymptotically normal with easily estimated variances, permitting standard two-
sample parametric testing.43 For the purposes of this analysis, monthly time intervals will be 
used. 
∑
=
i
i
iC
S
M



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Finally, a regression-based KMSA model developed by Lin will be used account for baseline 
patient characteristics that could influence costs, to account for clustering within study centers, 
and to evaluate the uncertainty provided by the use of these different analytic techniques as an 
analytic sensitivity analysis.37,44,45 
 
4.1.3 
Out-of-pocket and Personal Costs 
The same analytic approach described in section 4.2.2 will be used for out-of-pocket and 
indirect costs. Direct medical costs paid by patients will be based on patient information 
ascertained through the online or telephone surveys. Direct non-medical costs will be 
disaggregated into transportation, accommodation, telecommunication, and other costs. These 
costs will then be combined to calculate the total out-of-pocket costs incurred. Indirect costs for 
patients will be presented separately.   
 
4.2 
Analysis of Effectiveness: Quality Adjusted Life Years 
Health state utilities derived from the EQ-5D. Secondary analyses will use the SF-36 (using the 
SF-6D algorithm)40,46 to derive utilities. Utility scores will be combined with survival data from 
BMT CTN 1102, to calculate QALYs using the area under the curve method.44 The analysis of 
QALYs will follow the same analytic approach used for the analysis of; using KMSA for the base 
case followed by mixed effects modeling. Baseline health state utilities will be included as a 
covariate in multivariate analysis of the difference in QALYs between alloHCT and HMA or best 
supportive care to account for possible differences in baseline utility between groups.47 
 
4.3 
Analysis of Incremental Cost Effectiveness  
If objectives 1 and 3 show either treatment alternative is less costly and more effective (greater 
QALYs) than the other alternative, it is said to dominate and no numerical estimate of 
incremental cost-effectiveness is required. Instead the estimated reduction in cost and 
improvement in quality-adjusted survival, and the associated uncertainty in these estimates, will 
be reported. If no strategy dominates, the incremental difference in cost and/or QALYs, and the 
associated uncertainty in these estimates, will be reported. 
 
The incremental cost-effectiveness of one alternative over another is derived using the following 
formula:  
 
Incremental cost-effectivenessA = (CA – CB )/(EA –EB) 
 
Where CA and CB refer to average total costs of each alternative and EA and EB refer to average 
total effectiveness for each alternative, respectively. The resulting incremental cost-
effectiveness ratio (ICER) can then be used to make a judgment on the value provided by 
alternative A when compared to alternative B as it represents the investment required for each 
additional unit of effect gained.  
 
All analyses of cost and effectiveness will be completed on an intent-to-treat basis.  
 
4.4 
Lifetime Horizon and Simulation Modeling  
Mean costs and mean QALYs as estimated using data collected by objectives 1-3, will be used 
as input in a health economic simulation model. The model will be used to project lifetime health 
outcomes based on within-trial (ie. 3-year) overall survival (OS), quality of life, and medical 

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expenditure trends. Different parametric survival functions will be considered to extrapolate 
within trial results, including: Weibull, Gompertz, exponential, log-normal and generalized 
gamma distributions.48 The base case analysis survival function will be selected using the 
Akaike Information Criterion (AIC).49 Cox-Snell residuals will be plotted as a confirmatory test to 
identify the function with the best fit to the observed data.50 The mean number of life-years for 
patients in each group will be estimated as the area under the OS curve.51 QALYs will be 
estimated from OS by weighting with utility values obtained from the analysis of utility data. 
Projected utility weights for long-term survivors will be based on monthly trends in utility as 
observed for those who survive the year following treatment initiation or transplant.  Projected 
utility weights for the last 6 months of life will be based on utilities for the last 6 months of life for 
persons who die during the year following treatment initiation or transplant. In the case where 
insufficient numbers of persons have died within 6 months of their survey, we will use patient’s 
baseline utility scores as an estimate for quality of life in the last 6 months of life. 
 
Similarly, for those who survive through the end of the study observation period, we will project 
costs over a lifetime horizon modeled as described above, dividing costs into two periods: 
continuing care and death costs. Continuing care costs will be based on monthly trends in costs 
observed for those who have survived the year following treatment initiation or transplant. Death 
costs, defined as costs of care during the last 6 months of life for persons who have died, will be 
based on costs of care observed for those who die during the year following treatment initiation 
or transplant. Costs will be modeled based on projected survival (see above).  
 
4.4.1 
Uncertainty Analysis 
One-way and probabilistic uncertainty analyses will be conducted to characterize uncertainty 
around the base case results. In one-way uncertainty analyses, we will calculate incremental 
QALYs, incremental expenditure, and the incremental cost-effectiveness ratio using low and 
high survival, quality of life, and expenditure values derived from the 95% confidence interval 
bounds. This procedure demonstrates the influence of each input on incremental outcomes, and 
will be plotted in the form tornado diagrams. In probabilistic uncertainty analyses, we will 
evaluate the joint uncertainty in outcomes by sampling from the distributions all model inputs, 
propagating those values through the model, and obtaining the resulting distribution of 
incremental QALYs, incremental expenditure, and the incremental cost-effectiveness ratio. In 
this procedure we will assign mathematical distributions to all of the model inputs (hazard 
ratio=log-normal, expenditure=normal, quality of life=beta), conduct 10,000 Monte Carlo 
simulations, and results will be used to calculate 95% credible intervals for life years, QALYs, 
and expenditures.52 Uncertainty in the primary CEA endpoint will be evaluated using cost-
effectiveness acceptability curve (CEAC) plots.53  
 
In the case where an incremental cost-effectiveness ratio is computed (higher costs, higher 
QALYs), cost-effectiveness acceptability curves will be created to characterize the level of 
probability that the intervention is cost-effective at different willingness-to-pay thresholds (e.g., 
$50,000, $100,000 per QALY).54  
 
One-way sensitivity analyses will be conducted on all parameters to determine their individual 
impact on results with parameters varied within one standard deviation or error from their base 
case value.  
 

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4.5 
Base Year Cost Counting and Discounting  
All costs will be converted to base year costs (2014, the year 1102 began enrolling patients). 
The medical consumer price index55 and the US Consumer Price Index for All Urban 
Consumers56 will be used to covert direct medical costs and non-medical costs, respectively. 
Costs and outcomes that occur 12-months post study entry, will be discounted at a rate of 3% 
annually with sensitivity analyses completed with discount rates of 1% and 5%.16 
 
4.6 
Missing Data 
Missing direct medical care costs (payer) data is not anticipated. However, missing quality of 
life, out-of-pocket, productivity and caregiving cost data may occur for several reasons including 
entire surveys being incomplete due to censoring due to death or loss to follow up or intermittent 
patient non-response. If the amount of missing data exceeds 10% for any particular item, we will 
explore the mechanism of missingness. Random effects models will be used if data is missing 
completely at random (MCAR) and the presence of informative missingness is assumed. Under 
the assumption that the data are missing at random (MAR),57 we will impute missing data using 
multiple imputation.77  
 
4.7 
Sample Size and Power  
The targeted sample size for this ancillary cost-effectiveness analysis is determined by the 
number of patients enrolling in the parent study, BMT CTN 1102 and by the percent of patients 
who do not find a matched donor within 90 days of enrollment in the parent study. Assuming 
that 80% of BMT CTN 1102 participants agree to enroll in the economic study, and a 10% loss 
to follow up over the study period, the targeted sample size is 270 (162 alloHCT, 108 non-HCT) 
if donor availability is 60%. If donor availability is 70%, the targeted sample size is 320 (224 
alloHCT, 96 non-HCT).  
 
The primary research question is whether costs and/or effects, measured as QALYs, differ 
between MDS patients age 50 – 74 years receiving either alloHCT or HMA or best supportive 
care. Table 3 presents the power associated with each objective and the CEA using the sample 
size assumptions described above.  Other parameter assumptions used in these calculations 
include the difference in mean disease-attributable direct medical expenditure between a 
sample of 38 patients receiving alloHCT at the Medical College of Wisconsin ($172,532 (95% 
CI: $79,618-$265,446), SD=$92,914) and the mean disease-attributable direct medical 
expenditure of MDS patients receiving HMA presented in Wang et al.58 Minimally clinically 
important difference in QALYs based on utility values provided by the EQ-5D and SF-6D (0.147, 
SD 0.294) were used to estimate the expected difference in effects,59 and for ICER calculations, 
we used a correlation between cost and effect of 0.25.  
 
Estimates of power for ICERs use the Incremental Net Benefit (INB) method to calculate the 
point estimate and confidence interval.60 This approach is derived from the statistical test of 
whether the net monetary benefit is significantly different from zero by performing a sensitivity 
analysis of the willingness to pay (WTP) threshold. Because there is not an explicit WTP 
threshold in the United States, we will evaluate INB over a plausible range of WTP values 
ranging from $50,000 to $200,000 (Table 3).  
The results of the power calculations show that regardless of the assumptions used, the 
difference in costs and effects between the treatments with the target sample size results in 
power of >0.98 for all analyses.  
 
 

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Table 3 Power Calculations 
Scenario 
Hypotheses 
CEA Sample Size 
Power 
for 
Costs 
Power 
for 
QALYs* 
Power 
for 
ICERs 
Specific Aim 1 – Costs Direct Medical Payer (CDMP) 
 
 
Ho: CDMPalloHCT = CDMPHMA 
Ha: CDMPalloHCT > CDMPHMA 
(162 alloHCT, 108 HMA) 
0.999 
 
 
(224 alloHCT, 96 HMA) 
0.999 
 
 
Specific Aim 2 – Costs Out-of-Pocket and Indirect (COOPI) 
 
 
Ho: COOPIalloHCT = COOPIHMA 
Ha: COOPIalloHCT > COOPIHMA 
(162 alloHCT, 108 HMA) 
0.999 
 
 
(224 alloHCT, 96 HMA) 
0.999 
 
 
Specific Aim 3 – Effectiveness: QALYS (E) 
 
 
Ho: EalloHCT = EHMA 
Ha: EalloHCT > EHMA 
(162 alloHCT, 108 HMA) 
 
0.996 
 
(224 alloHCT, 96 HMA) 
 
0.981 
 
1- WTP= $50,000 
𝐻𝐻𝑜𝑜:          NB = 0 
 
𝐻𝐻𝑎𝑎:          NB ≠0 
 
(162 alloHCT, 108 HMA) 
0.999 
0.996 
0.999 
(224 alloHCT, 96 HMA) 
0.999 
0.981 
0.999 
2- WTP= 
$100,000 
𝐻𝐻𝑜𝑜:          NB = 0 
 
𝐻𝐻𝑎𝑎:          NB ≠0 
 
(162 alloHCT, 108 HMA) 
0.999 
0.996 
0.999 
(224 alloHCT, 96 HMA) 
0.999 
0.981 
0.999 
3- WTP= 
$150,000 
 
𝐻𝐻𝑜𝑜:          NB = 0 
 
𝐻𝐻𝑎𝑎:          NB ≠0 
 
(162 alloHCT, 108 HMA) 
0.999 
0.996 
0.999 
(224 alloHCT, 96 HMA) 
0.999 
0.981 
0.998 
4- WTP=$200,000 
𝐻𝐻𝑜𝑜:          NB = 0 
 
𝐻𝐻𝑎𝑎:          NB ≠0 
 
(162 alloHCT, 108 HMA) 
0.999 
0.996 
0.999 
(224 alloHCT, 96 HMA) 
0.999 
0.981 
0.999 
 
 

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49. Akaike H. A new look at the statistical model identification. IEEE Trans Automat Contr 
1974;19:716-23. 
50. Cleves M, Gould W, Gutierrez R, Marchenko Y, eds. An introduction to survival analysis 
using STATA. 2nd ed. College Station, TX: Stata Press; 2008. 
51. Willan A, Briggs A. Statistical Analysis of Cost-Effectiveness Data. Chichester, UK: John 
Wiley & Sons; 2006. 

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52. Briggs AH, O'Brien BJ, Blackhouse G. Thinking outside the box: recent advances in the 
analysis and presentation of uncertainty in cost-effectiveness studies. Annu Rev Public 
Health 2002;23:377-401. 
53. Fenwick E, O'Brien BJ, Briggs A. Cost-effectiveness acceptability curves--facts, fallacies 
and frequently asked questions. Health economics 2004;13:405-15. 
54. Shiroiwa T, Sung Y, Fukuda T, Lang H, Bae S, Tsutani K. Internation survey on 
willingness-to-pay (WTP) for one additional QALY gained: what is the threshold of cost-
effectiveness? . Health economics 2010;19:422-37. 
55. Arzykulov Z, Chichua N, Smagulova K, Khamidullina G, Mukanova S, Suriya K. 
Effectiveness of Chemotherapy with Oxaliplatin, Capecitabine and Bevacizumab (Xelox Plus 
Bev) in Second Line Therapy of Metastatic Colorectal Cancer (Mcrc). Ann Oncol 
2010;21:32-. 
56. Guan Z, Xu J, Luo R, et al. Bevacizumab Plus Chemotherapy in Chinese Patients with 
Metastatic Colorectal Cancer: Efficacy and Tolerability Results from the Artist Study. Ann 
Oncol 2010;21:22-. 
57. Missing data in longitudinal studies: a review. Pensylvania State Univeristy, 2005. 
(Accessed March 31, 2009, at http://www.stat.psu.edu/~jls/.) 
58. Wang R, Gross CP, Frick K, et al. The impact of hypomethylating agents on the cost of 
care and survival of elderly patients with myelodysplastic syndromes. Leukemia research 
2012;36:1370-5. 
59. Walters SJ, Brazier JE. Comparison of the minimally important difference for two health 
state utility measures: EQ-5D and SF-6D. Quality of life research : an international journal 
of quality of life aspects of treatment, care and rehabilitation 2005;14:1523-32. 
60. Willan AR. Analysis, sample size, and power for estimating incremental net health 
benefit from clinical trial data. Controlled clinical trials 2001;22:228-37. 
 
 
 
 

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Cost-Effectiveness Research  
 
INFORMED CONSENT
Study Title: Ancillary Cost-Effectiveness Study to BMT CTN 1102 
 
Principal Investigator: Scott Ramsey, MD, PhD; Email: sramsey@fhcrc.org;  
Tel: (206) 667-7846 
 
Mailing Address: 1100 Fairview Ave N, MS: M3-B232; Seattle, WA 98109 
 
Cost-Effectiveness Research (Optional) 
This section of the consent form is about 
cost-effectiveness research that will look at 
how much you and your insurance pay for 
your treatment. The researchers want to 
understand how much different therapies 
cost. You may choose to let the researchers 
collect information on the cost of your 
treatment for this study if you want to.  
You can still be a part of the main study 
(health evaluations by phone) even if you 
say 'no' to give information on the cost of 
your treatment. 
Study purpose: The study doctors want to 
learn more about the costs of the two types of 
treatments that are being compared in the 
main study: 1) transplant from a well 
matched family donor or unrelated donor; 
and, 2) blood transfusion and drug therapy 
only (no transplant).  
This research will help doctors understand 
the cost-effectiveness of these treatments. In 
particular, researchers want to know if costs 
are a problem for patients and their families. 
They also want to know how out-of-pocket 
financial costs (costs not covered by your 
insurance) differ by treatment type and by 
type of insurance. This will help them 
understand cost barriers for patients with 
different treatments.  
Lead study doctor: Scott Ramsey of the 
Fred Hutchinson Cancer Research Center in 
Seattle is the lead study doctor for the cost-
effectiveness research. Dr. Ramsey is a 
medical doctor and well-known health 
economist who has studied costs of many 
different cancer treatments.  
Your health insurance and out-of-pocket 
medical costs: If you agree to join this study, 
we will ask for the following information 
about your health insurance: 
1) Type 
2) Provider 
3) Policy number 
4) Group number 
5) Policy holder’s name and date of birth. 
We will also want to know about your out-of-
pocket costs. The out-of-pocket costs you and 

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your family have to cover are important in 
understanding the overall cost of medical 
care, so we want to collect this information as 
well. For example, we want to know how 
much you spend on: 
1) Medical costs (for example, co-pays, 
prescriptions) 
2) Travel and lodging  
3) Cost of time away from work  
Your health insurance and out-of-pocket 
information is called the ‘study data’ in this 
consent form. 
How we will use your health insurance 
information: After you finish the study, we 
will use your insurance information to learn 
about the payments your health insurer made. 
We will calculate the cost of your medical 
care (both groups that are being compared, 
the transplant group and the no transplant 
group). Because treatment (either transplant 
or non-transplant therapies) can impact your 
health for many years after you join the 
study, we want to collect insurance payment 
information for the 12 months before you 
joined the study, and for 3 years after your 
treatment start date.   
Privacy, confidentiality and use of 
information: Only the study doctors at the 
Fred Hutchinson Cancer Research Center 
(FHCRC) will have access to your health 
insurance information and out-of-pocket cost 
information (study data). The FHCRC will 
contract with the Survey Research Group 
(SRG) at the CIBMTR to collect out-of-
pocket cost data, who are also administering 
the telephone health surveys as part of the 
parent study. To maintain your 
confidentiality, we will not link your name to 
the study data. Also, all of the study doctors 
signed a confidentiality agreement and 
promised to keep electronic data protected 
under passwords and physical data (paper or 
other media such as CDs) in secure facilities 
(for example, on-campus locked offices and 
locked filing cabinets).   
Collecting the study data: We will collect 
your health insurance information at the time 
of study enrollment. Out-of-pocket cost data 
will be collected by mail-out survey. The 
mail-out surveys were designed to be very 
user friendly, but we will help you with the 
cost diary over the phone if needed. We will 
also place phone call reminders. 
We will ask you about your out-of-pocket 
costs only 3 times during the course of the 
study: at 1, 7 and 19 months after enrollment. 
We think each questionnaire will take 
between 10 and 30 minutes to complete, but 
this depends on how much information there 
is to enter.  
Alternate contact: We ask that you give us 
the name of an alternate contact. This may be 
your spouse, partner, parent, adult child or 
sibling, or friend. You may not feel like 
answering the questionnaires or need help 
gathering cost information, so we ask that 
this individual help with this information    
Risks to participating: The risks to 
participating in the cost-effectiveness study 
are small. A possible risk is the loss of 
confidentiality about your medical 
information, but the chance that this 

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information will be given to someone else is 
very small.  
Payment and costs: You will not get paid 
for participating in this study. You will not 
be charged for taking part in this study.   
Right to ask questions and/or withdraw: 
You do not have to be part of the cost-
effectiveness research study. Your 
participation is voluntary. If you decide not 
to be part of this study, it will not affect your 
regular medical care or services. You can 
quit the study at any time.  
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.  
 
For more information:  Contact the Study 
Coordinator at the Fred Hutchinson Cancer 
Research Center at (844) 840-2731 or email: 
1102-CEA@fredhutch.org 
Making Your Choice  
Please read each sentence below and think 
about your choice. After reading each 
sentence, please indicate your choice below. 
If you have any questions, please talk to 
your doctor or nurse, or call Karen Hansen, 
Director at the FHCRC research review 
board at: (206) 667-4867. 
No matter what you decide to do, it will not 
affect your care.
Statement of Consent for Cost-Effectiveness Research Study (Optional) 
The purpose of the cost effectiveness research, 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 participate in the cost effectiveness research. If I decide to not 
participate, it will not affect my medical care in any way. 
 I agree to be part of the cost-effectiveness research.  
 I do not agree to be part of the cost-effectiveness research.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
 
 
 
 
 
 
Date 
 
(Version date 1/30/15) 

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IR number:  9159  
 
 
 
Protocol number:  1.0 
 
Title of Research Study:  Ancillary Cost-Effectiveness Analysis to: A Multi-Center Biologic 
Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to 
Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Intermediate-2 
and High Risk Myelodysplastic Syndrome BMT CTN 1102 
 
The research study named above and described more fully in the informed consent form that you 
sign (“Research Consent”) requires that the researchers have access to health insurance 
information about you (also called “Protected Health Information” or “PHI”).  By law, your health 
insurance provider (the “Insurer”) must protect the confidentiality of your PHI.   The researchers 
can obtain your PHI from the Insurer and use it for research only if you authorize and direct the 
Insurer to share it with them..  
 
This authorization form (“form”) describes what types of PHI the researchers need and what they 
will do with it as part of the research study. Please read it carefully. If you agree with it, please 
sign your name at the bottom. You will be given a copy of this form after you have signed it. 
  
If you sign this form, your PHI will be shared with Fred Hutchinson Cancer Research Center, its 
staff, and others who work with them. In this form, the term for all these people is “Researchers” 
and they are described more fully in the Research Consent. The Researchers will use the PHI 
only for the purposes described in the Research Consent and in this form. 
 
1. The protected health information to be obtained and used by the Researchers for the 
Study includes:  
 
• 
All health insurance information including the type of health insurance, provider, 
policy number, group number and the policy holder’s name and date of birth. It also 
includes information about health care costs and health care claims information as 
well as reimbursements made by your health insurer(s).   
 
• 
The specific protected health information that will be obtained from the Insurer and 
used for the Research is described below:  
 
• 
Dates and codes associated with medical service and diagnoses 
• 
Location of medical service 
• 
Provider of medical service 
 
 
 
 
Institutional Review Board 
HIPAA Authorization for the Use of Member 
Protected Health Information for Research 

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2. What the Researchers will do with your Protected Heath Information. 
 
The Researchers will use your PHI only in the ways described in the Research Consent 
form that you sign and as described here. They may also share your PHI with certain 
people and groups. These may include: 
 
 
 
 
 
• 
The sponsor of the Study, The National Heart, Lung and Blood Institute.  The 
sponsor reviews the Study. Government agencies, review boards, and others who 
watch over the safety, effectiveness and conduct of the research 
 
• 
Others, if the law requires. 
 
By law, the Researchers are required to protect the confidentiality of your PHI.  The 
Research Consent form you sign describes in more detail how your PHI will be protected.  
You may ask questions about what the Researchers will do with your information and how 
they will protect it. Privacy laws do not always require the receiver of your information to 
keep your information confidential.  After your information is given to others, there is a risk 
that it could be shared without your permission. 
 
You are free to refuse to allow the Researchers access to your PHI.  If you refuse, you will 
not be able to participate in this research study but your refusal will not affect your health 
insurance eligibility or coverage. 
 
 
3. 
How long the permission will last? 
 
 
The permission for the Researchers to obtain and use your protected health information 
will end when the Researchers complete the research study AND any review of the 
research study is completed.    
 
4. Canceling your permission. 
 
You may change your mind and take back your permission anytime. To take back your 
permission, please send a written request to the research study coordinator, Lisel Koepl, 
at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, M/S M3-B232, 
Seattle, Washington 98109-1074.   If you do this, you may no longer be allowed to be in 
the research study. The Researchers may still keep and use any Protected Health 
Information they already have.  But they can’t obtain more PHI about you for the research 
study unless it is required by a federal agency that reviews the research.  
 
 
 

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5.   
Giving permission 
You give your permission for the use of your protected health information by signing this 
form. 
 
Signature 
 
I authorize and direct the Insurer   to provide access to my protected health information to the 
Researchers as described in this authorization form.   
 
 
 
 
 
 
 
 
 
___________________ 
Signature of participant or participant’s Legal  
Date 
Representative 
 
 
 
 
___________________________________________ 
________________________ 
Printed name of participant or participant’s   
Representative’s relationship 
Legal Representative  
 
 
 
to participant 
 

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Primary insurance (if any): 
Health Insurer: ______________________ Type of Insurance: ___________________________ 
Policy Number: ______________________ Group Number: _____________________________ 
Policy Holder’s Name: _________________________Policy Holder’s Date of Birth: ___________ 
 
Additional insurance (if any): 
Health Insurer: ______________________ Type of Insurance: ___________________________ 
Policy Number: ______________________ Group Number: _____________________________ 
Policy Holder’s Name: _________________________Policy Holder’s Date of Birth: ___________ 
 
If more than 2 insurance providers, please add additional insurance information below: 
 
Health Insurer:______________________ Type of Insurance: ____________________________ 
 
 

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APPENDIX G 
 
REFERENCES 

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APPENDIX G 
 
REFERENCES 
 
 
1 Martino R, Perez-Simon JA, Moreno E, Queralto JM, Caballero D, Mateos M, et al. Reduced-
intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral 
busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid 
leukemia ineligible for conventional conditioning. Biol Blood Marrow Transplant. 
2005;11(6):437-47. 
2 van Besien K, Artz A, Smith S, Cao D, Rich S, Godley L, et al. Fludarabine, melphalan, and 
alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and 
myelodysplastic syndrome. J Clin Oncol. 2005;23(24):5728-38. 
3 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;40(9):843-50. 
4 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;13(4):454-62. 
5 Laport GG, Sandmaier BM, Storer BE, Scott BL, Stuart MJ, Lange T, et al. Reduced-intensity 
conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with 
myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant. 
2008;14(2):246-55. PMCID: 2259225. 
6 Lim Z, Brand R, Martino R, van Biezen A, Finke J, Bacigalupo A, et al. Allogeneic 
Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic 
Syndromes or Secondary Acute Myeloid Leukemia. Journal of Clinical Oncology. 
2010;28(3):405-11. 
7 McClune BL, Weisdorf DJ, Pedersen TL, Tunes da Silva G, Tallman MS, Sierra J, et al. Effect 
of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients 
With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic 
Syndrome. Journal of Clinical Oncology. 2010;28(11):1878-87. 
8 Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et 
al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a 
study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429-40. 
9 Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system 
for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079-88. 
                                                 
 

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10 Sanz GF, Sanz MA, Greenberg PL. Prognostic factors and scoring systems in myelodysplastic 
syndromes. Haematologica. 1998;83(4):358-68. 
11 Greenberg et al, Blood in press, 2012. 
12 Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG, et al. Comorbidity 
and disease status based risk stratification of outcomes among patients with acute myeloid 
leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin 
Oncol. 2007;25(27):4246-54. 
13 Runde V, de Witte T, Arnold R, Gratwohl A, Hermans J, van Biezen A, et al. Bone marrow 
transplantation from HLA-identical siblings as first-line treatment in patients with 
myelodysplastic syndromes: early transplantation is associated with improved outcome. 
Chronic Leukemia Working Party of the European Group for Blood and Marrow 
Transplantation. Bone Marrow Transplant. 1998;21(3):255-61. 
14 Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C, et al. A decision analysis of 
allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed 
transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 
2004;104(2):579-85. 
15 Oliansky DM, Antin JH, Bennett JM, Deeg HJ, Engelhardt C, Heptinstall KV, et al. The role of 
cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic 
syndromes: an evidence-based review. Biol Blood Marrow Transplant. 2009;15(2):137-72. 
16 Koreth J, Pidala J, Perez WS, Deeg HJ, Garcia-Manero G, Malcovati L, Cazzola M, Park S, 
Itzykson R, Ades L, Fenaux P, Jädersten M, Hellstrom-Lindberg E, Gale RP, Beach CL, 
Greenberg PL, Tallman MS, DiPersio JF, Bunjes D, Weisdorf DJ, and Cutler CS. A Decision 
Analysis of Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell 
Transplantation for Older Patients with De-Novo Myelodysplastic Syndrome (MDS): Early 
Transplantation Offers Survival Benefit in Higher-Risk MDS ASH Annual Meeting Abstracts 
2011 118:115. 
17 Platzbecker et al. Biol Blood Marrow Transplant 18: 1415-1421 (2012) 
18 Nakai K, Kanda Y, Fukuhara S, Sakamaki H, Okamoto S, Kodera Y, et al. Value of 
chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical 
sibling donor for myelodysplastic syndrome. Leukemia. 2005;19(3):396-401. 
19 Scott BL, Storer B, Loken MR, Storb R, Appelbaum FR, Deeg HJ. Pretransplantation induction 
chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic 
syndrome. Biol Blood Marrow Transplant. 2005;11(1):65-73. 
20 Nakamura R, Palmer JM, Stiller T, Chao J, Parker P, Pullarkat V, et al. Improved outcome after 
reduced intensity allogeneic hematopoietic stem cell transplant (RI-HCT) for MDS using 
tacrolimus/sirolimus as GVHD prophylaxis. . submitted. 2011. 
21 Saber W, Cutler CS, Nakamura R, Zhang MJ, Atallah E, Rizzo JD, Maziarz RT, Cortes J, 
Kalaycio ME, Horowitz MM. Impact of donor source on hematopoietic cell transplantation 
outcomes for patients with myelodysplastic syndromes (MDS). Blood. 2013 Jul 11. [Epub 
ahead of print]. PMID: 23847196. 
22 Saiki JH, McCredie KB, Vietti TJ, Hewlett JS, Morrison FS, Costanzi JJ, et al. 5-azacytidine in 

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acute leukemia. Cancer. 1978;42(5):2111-4. 
23 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy 
of azacitidine compared with that of conventional care regimens in the treatment of higher-risk 
myelodysplastic syndromes: a randomised, open-label, phase III study. The lancet oncology. 
2009;10(3):223-32. 
24 Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine 
improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized 
study. Cancer. 2006;106(8):1794-803. 
25 Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, et al. Results of a  
randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic 
syndrome and chronic myelomonocytic leukemia. Blood. 2007;109(1):52-7 
26 Steensma DP, Baer MR, Slack JL, Buckstein R, Godley L, Larsen JS, et al. Preliminary Results 
of a Phase II Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults with 
Myelodysplastic 
Syndrome 
(MDS). 
Blood 
(ASH 
Annual 
Meeting 
Abstracts). 
2007;110(11):1450 
27 Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M, et al. Phase 2 study of the 
lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic 
syndromes. Blood. 2012;120(25):4945-51. 
28 Silverman LR, Verma A, Odchimar-Reissig R, LeBlanc A, Najfeld V, Gabrilove J et al. A Phase 
I Trial of the Epigenetic Modulators Vorinostat, in Combination with Azacitidine (azaC) in 
Patients with the Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): A 
Study of the New York Cancer Consortium Blood (ASH Annual Meeting Abstracts) 2008 112: 
Abstract 3656. 
29 http://clinicaltrials.gov/ct2/show/NCT01522976 
30 Prébet T, Gore SD, Esterni B, Gardin C, Itzykson R, Thepot S, Outcome of high-risk 
myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29(24):3322-
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31 Pidara et al. Blood. 2009;114:7-19. 
32 The NCCN 2.2011 Myelodysplastic Syndromes Clinical Practice Guidelines in Oncology Fort 
Washington, PA; 2011 2011 Contract No.: Document Number|. 
33 Giralt SA, Horowitz M, Weisdorf D, Cutler C. Review of stem-cell transplantation for 
myelodysplastic syndromes in older patients in the context of the Decision Memo for 
Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome emanating 
from the Centers for Medicare and Medicaid Services. J Clin Oncol. 2011;29(5):566-72. 
34 McQuellon RP, Russell GB, Cella DF, Craven BL, Brady M, Bonomi A, et al. Quality of life 
measurement in bone marrow transplantation: development of the Functional Assessment of 
Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Bone Marrow Transplant. 
1997;19(4):357-68. 

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35 McHorney CA, Ware JE, Jr., Lu JF, Sherbourne CD. The MOS 36-item Short-Form Health 
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patient groups. Med Care. 1994;32(1):40-66. 
36 McHorney CA, Ware JE, Jr., Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-
36): II. Psychometric and clinical tests of validity in measuring physical and mental health 
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37 Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
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38 Zhang X, Loberiza FR, Klein JP, and Zhang, MJ. A SAS macro for estimation of direct adjusted 
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39 Raphael Itzykson, Sylvain Thépot, Bruno Quesnel, Francois Dreyfus, Odile Beyne-Rauzy, 
Pascal Turlure, Norbert Vey, Christian Recher, Caroline Dartigeas, Laurence Legros, Jacques 
Delaunay, Célia Salanoubat, Sorin Visanica, Aspasia Stamatoullas, Francoise Isnard, Anne 
Marfaing-Koka, Stephane de Botton, Youcef Chelghoum, Anne-Laure Taksin, Isabelle Plantier, 
Shanti Ame, Simone Boehrer, Claude Gardin, C. L. Beach, Lionel Adès, Pierre Fenaux and on 
behalf of the Groupe Francophone des Myelodysplasies (GFM).  Prognostic factors for response 
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Blood 2011, 117: 403-41 
40 Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. British Journal 
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41 Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV,  et al. Design and analysis of 
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42 Logan B, Leifer E, Bredeson C, Horowitz M, Ewell M, Carter S, et al. Use of biological 
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2008;5(6):607-1 
43 Zhang X, Loberiza FR, Klein JP, and Zhang, MJ. A SAS macro for estimation of direct adjusted 
survival curves based on a stratified Cox regression model. Computer Methods and Programs 
in Biomedicine 2007; 88: 95-101. 
43 Logan BR, Klein JP and Zhang MJ. Comparing treatments in the presence of crossing survival 
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44 Kurland BF and Heagerty PJ. Directly parameterized regression conditioning on being alive: 
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45 Klein JP, Logan B, Harhoff M, and Andersen PK. Analyzing survival curves at a fixed point in 
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