Phase III Randomized Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard Daunorubicin &Amp; Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute Myeloid Leukemia in Older Adults (Age >/= 60 Years)
Phase: PHASE3
Conditions: Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia
Sponsor: ECOG-ACRIN Cancer Research Group

E2906 
 
1 
Phase III Randomized Trial of Clofarabine as Induction 
and Post-Remission Therapy vs. Standard Daunorubicin 
& Cytarabine Induction and Intermediate Dose Cytarabine 
Post-Remission Therapy, Followed by Decitabine 
Maintenance vs. Observation in Newly-Diagnosed Acute 
Myeloid Leukemia in Older Adults (Age ≥ 60 Years) 
 
STUDY CHAIR: James M Foran, MD FRCPC 
Rev. 2/13 
ECOG-ACRIN CO-CHAIR: Martin Tallman, MD 
Rev. 2/13 
SWOG CO-CHAIR: John E Godwin, MD,MS 
 
STUDY STATISTICIAN: Zhuoxin Sun, PhD 
 
BMT CO-CHAIR: David Claxton, MD 
Hillard Lazarus, MD 
 
 
Rev. 2/12 
LABORATORY CO-CHAIRS: Ari Melnick, MD 
Elisabeth Paietta, PhD 
Ross Levine, MD 
Rev. 2/12 
PATHOLOGY CHAIR: Daniel Arber, MD 
Rev. 2/12, 8/13 
CYTOGENETIC COMMITTEE CHAIR: Yanming Zhang, MD 
Rev. 2/12, 12/13 
LEUKEMIA COMMITTEE CHAIR: Mark Litzow, MD 
 
QUALITY OF LIFE CHAIR: Mary Thomas, RN, MS, AOCN 
Version Date:  November 27, 2018 
NCI Update Date:  July 25, 2013 
STUDY PARTICIPANTS 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology – US Sites Only December 28, 2010 
NRG / NRG Oncology Foundation, Inc – US Sites Only 
Addendum #1 – Prior to Activation 
SWOG / SWOG – US Sites Only 
Addendum #2 – Prior to Activation 
Shaare Zedek Medical Center 
Update #1 – Prior to Activation 
Rambam Medical Center 
Update #2 – 4/11 
NOTE: This study is supported by the NCI Cancer Trials Support 
Unit (CTSU). Institutions not aligned with ECOG-ACRIN 
will participate through the CTSU mechanism. 
Update #3 – 7/11 
Addendum #3 – 2/12 
Update #4 – 6/12 
Addendum #4 – 2/13 
 
Addendum #5 – 2/13 
 
Update #5 – 2/13 
 
Addendum #6 – 8/13 
 
Update #6 – 7/13 
Addendum #7 – 12/13 
 
Addendum #8 – 7/14 
 
Addendum #9 – 5/17 
Clofarabine will be provided by Genzyme 
Decitabine will be provided by Eisai Inc. 
Rev. 7/14 
Rev. 4/11 
 
Rev. 4/11 
Rev. 2/13 
Rev. 4/11 
Rev. 4/11

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Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ...................................................................................................... 11 
1.1 
Clofarabine .............................................................................................. 13 
1.2 
Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for 
AML ......................................................................................................... 17 
1.3 
Decitabine in AML ................................................................................... 19 
1.4 
Non-Inferiority Trial Design ..................................................................... 21 
1.5 
Quality of Life Assessment ...................................................................... 21 
1.6 
Additional Correlative Studies ................................................................ 23 
2. Objectives ......................................................................................................... 30 
2.1 
Primary Objective .................................................................................... 30 
2.2 
Secondary Objectives .............................................................................. 30 
2.3 
Quality of Life Objectives ........................................................................ 31 
3. Selection of Patients ......................................................................................... 32 
3.1 
Pre-Registration ...................................................................................... 32 
3.2 
Eligibility Criteria ..................................................................................... 32 
4. Registration Procedures .................................................................................... 38 
4.1 
Pre-registration ....................................................................................... 41 
4.2 
Step 1: Randomization to Induction (ARMS A or B) ................................ 42 
4.3 
Step 2: Registration to Consolidation (ARMS C or D) .............................. 43 
4.4 
Step 3: 2nd Randomization-Maintenance (Arms E or F), or Registration 
to Transplant (Arm G) ............................................................................. 44 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment45 
4.6 
Investigator’s Drug Brochure and Safety Alerts ...................................... 46 
4.7 
IND Status ................................................................................................ 46 
5. Treatment Plan ................................................................................................. 47 
5.1 
Induction Therapy and Premedications .................................................. 47 
5.2 
Adverse Event Reporting Requirements ................................................. 55 
5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Decitabine (5-aza-2'-deoxycytidine) (NSC  127716) ................................ 59 
5.4 
Dose Modifications ................................................................................. 63 
5.5 
Supportive Care ....................................................................................... 65 
5.6 
Duration of Therapy ................................................................................ 72 
5.7 
Duration of Follow-up ............................................................................. 73 
6. Measurement of Effect ..................................................................................... 74 
6.1 
Complete Remission (CR) ........................................................................ 74 
6.2 
Complete Remission incomplete (CRi) .................................................... 74 
6.3 
Partial Remission (PR) ............................................................................. 74 
6.4 
Relapse .................................................................................................... 74 
6.5 
Leukemia Free State ................................................................................ 75 
6.6 
Quality of Life Measurement .................................................................. 75 

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6.7 
Timing of QOL Assessment ..................................................................... 78 
6.8 
Timing of “ALESE” Questionnaire (see Appendix V) ............................... 78 
7. Study Parameters .............................................................................................. 79 
7.1 
Therapeutic Parameters .......................................................................... 79 
7.2 
Arm G Only (Allogeneic Stem Cell Transplantation) ............................... 82 
7.3 
Biological Sample Submissions ............................................................... 84 
8. Drug Formulation and Procurement ................................................................. 86 
8.1 
Cytarabine ............................................................................................... 86 
8.2 
Daunorubicin ........................................................................................... 87 
8.3 
Decitabine ............................................................................................... 89 
8.4 
Clofarabine .............................................................................................. 91 
8.5 
Fludarabine Monophosphate (Fludara®) ................................................ 95 
8.6 
Tacrolimus (Prograf®) .............................................................................. 96 
8.7 
Methotrexate (Amethopterin®; MTX) .................................................... 98 
8.8 
Filgrastim (r-met HuG-CSF, G-CSF: Granulocyte Colony-Stimulating 
Factor, Neupogen®) ................................................................................ 99 
8.9 
Busulfan (Busulfex®) ............................................................................... 99 
8.10 Antithymocyte Globulin (Rabbit) (Thymoglobulin®; rabbit ATG) ......... 100 
9. Statistical Considerations ................................................................................ 102 
9.1 
Original Design Overview ...................................................................... 102 
9.2 
Primary Endpoint and Sample Size ....................................................... 103 
9.3 
Interim Analyses of Primary Endpoint .................................................. 104 
9.4 
Secondary Objectives ............................................................................ 105 
9.5 
Design Changes ..................................................................................... 107 
9.6 
AML Clinical Epidemiology .................................................................... 108 
9.7 
Quality of Life ........................................................................................ 108 
9.8 
Correlative Studies ................................................................................ 111 
9.9 
Accrual ................................................................................................... 113 
9.10 Anticipated Accrual by Gender and Ethnicity ....................................... 114 
9.11 Study Monitoring .................................................................................. 114 
10. Correlative Studies .......................................................................................... 115 
10.1 Immunophenotype and Molecular Genetics ........................................ 115 
10.2 Cytogenetic Review ............................................................................... 120 
10.3 Epigenetics ............................................................................................ 121 
10.4 Somatic Mutation Analysis .................................................................... 122 
10.5 AML Prognostic Factors & Mechanisms of Resistance ......................... 123 
10.6 Array CGH Studies ................................................................................. 123 
10.7 ECOG-ACRIN Sample Tracking System .................................................. 125 
10.8 Sample Inventory Submission Guidelines ............................................. 125 
10.9 Lab Data Transfer Guidelines ................................................................ 126 
10.10 Banking .................................................................................................. 126 
11. Records to Be Kept .......................................................................................... 127 
11.1 Records Retention ................................................................................. 127 

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12. Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents.Patient Consent and Peer Judgment ......................... 127 
13. References ...................................................................................................... 127 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #5] ............................................................ 138 
 Appendix II  Patient Thank You Letter .................................................................. 139 
 Appendix III  E2906 Clofarabine Study Drug Request Form ................................. 140 
Appendix IV  E2906 Decitabine Study Drug Request Form ................................... 142 
Appendix V  ALESE Baseline Questionnaire........................................................... 143 
 

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STUDY CHAIR 
ECOG-ACRIN CO-CHAIR 
James M Foran, MD FRCPC 
Division of Hematology & Oncology 
Mayo Clinic 
4500 San Pablo Road 
Jacksonville, FL 32224 
Tel: 904.953.7292 
Fax: 904.953.2315 
Email: foran.james@mayo.edu 
Martin S. Tallman, MD 
Memorial Sloan Kettering Cancer Center 
Weill Cornell Medical College 
1275 York Avenue 
New York, NY 10065 
Tel: 212.639.3842 
Fax: 212.639.3841 
Email: tallmanm@mskcc.org  
STUDY CHAIR LIAISON 
SWOG CO-CHAIR 
Susan V. Sumrall, RN BSN OCN CCRP 
Supervisor 
Cancer Clinical Studies Unit 
Mayo Clinic 
4500 San Pablo Road 
Jacksonville, FL 32224 
Tel: 904.953.6188 
Fax: 904.953.6870 
Email: Sumrall.susan@mayo.edu 
 
John E Godwin, MD,MS, FACP 
Providence Cancer Center Oncology & 
Hematology Care Eastside  
Robert W. Franz Cancer Research Center 
Earle A. Chiles Research Institute 
4805 NE Glisan, Suite 6N40 
Portland, OR 97213 
Tel: 503.215.3878 
Fax: 503.215.6841 
Email: john.godwin@providence.org 
 
Rev. 2/13 
Rev. 2/13 
Rev. 2/12 
Rev. 7/11 
Rev. 8/13 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site 
registration documents: 
For patient enrollments:  
Submit study data  directly to 
the Lead Cooperative Group 
unless otherwise specified in 
the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 
1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206  
Email: 
CTSURegulatory@ctsu.co
ccg.org (for submitting 
regulatory documents only) 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Netwok (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org.  
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com 
ECOG-ACRIN Operations 
Office - Boston 
28 State St, Suite 1100  
Boston, MA 02109 
(ATTN: DATA). 
Phone # 857-504-2900 
Fax # 617-589-0914 
Data should be sent via postal 
mail. 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy the 
CTSU on data submissions.   
The most current version of the study protocol and all supportingdocuments must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
The CTSU Web site is located at   https://www.ctsu.org 
 
Rev. 7/14, 
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Schema 
 
Rev. 7/14 

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NON-ABLATIVE ALLOGENEIC STEM CELL TRANSPLANTATION TREATMENT SCHEMA 
ELIGIBLE PATIENTS AFTER INDUCTION WITH MATCHED DONOR 
Preferred Patient Preparative Regimen & Stem Cell Infusion 
Prior to initiating therapy, placement of a multi-lumen, indwelling Silastic catheter is required. 
F
B
ATG
A
for patients with a history of herpes simplex (see below) to Day +100 
T
begin taper between Day +90 - +120 to stop between Day +150 - +180
PBSCT
M
M
M
M
Fluconazole 
through Day +100
G-CSF
Day
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
Cotrimoxazole BID two days weekly beginning on Day +28 through Day +100 (see below).
 
F  
 
Fludarabine 30 mg/m2/day IV over 30 minutes x 5 days on Days -7 through -3. 
B  
Busulfan 0.8 mg/kg IV over 2 hours q 6 hours x 8 doses on Days -4 and -3.  
ATG 
Rabbit antithymocyte globulin (thymoglobulin) 2.5 mg/kg/day IV over 6 hours x 3 
doses on Days -4 through -2. After the first dose, thymoglobulin may be 
administered over 4 hours.  
A  
Acyclovir 200-400 P0 TID on Days -3 through Day +100 for patients with a 
history of herpes simplex infection or seropositivity. Valacyclovir 500 mg P0 QD 
may be used instead of acyclovir. Prophylaxis may be extended beyond Day 
+100 at the discretion of the treating physician.  
TMP/SMX DS TMP/SMX DS (Bactrim DS) BID on 2 days weekly beginning on Day +28 through 
Day +100. If, at this time, CD4 lymphocytes are < 200/µL, then prophylaxis 
should continue until CD4 lymphocytes ≥200/µL. In patients who develop chronic 
GVHD, PCP prophylaxis should be extended at the discretion of the physician. 
T  
Tacrolimus target serum levels are 5-10 ng/mL. Serum levels are not to exceed 
15 ng/mL. The suggested starting dose is 0.03 mg/kg P0 BID beginning on Day -
2. Begin tapering between Day +90 to +120 with a goal of stopping by Day +150 
to +180. 
PBSCT 
Peripheral Blood Stem Cell Transplant. On Day 0 a minimum total CD34+ cell 
dose of 2 x 106/kg (actual weight - recipient) and a maximum of 8 x 106/kg (actual 
weight - recipient) will be infused.  
M 
Methotrexate 5 mg/m2/day IV on Days +1, +3, +6 and +11. Hydrate intravenously 
and induce diuresis . 
Fluconazole Fluconazole or itraconazole 200-400 mg P0 daily or voriconazole 200-300 mg P0 
twice daily (or 3-6 mg/kg IV q 12 hours) on Days -2 through +100 based on 
institutional standard. Low-dose amphotericin B (10-20 mg/day IV) also may be 
used. 
G-CSF 
 Recipients will receive 5 mcg/kg G-CSF SQ daily beginning on Day +12 and 
continuing until ANC >1500/µL for two consecutive days or> 5000/µL for one 
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day. If ANC decreases to < 1000/µL then resume G-CSF at 5 mcg/kg/day. 
HLA-Identical Sibling Donor Stem Cell Collection 
 
 
 
G-CSF 
Donors will receive 10 mcg/kg SQ on Days-5 through-2 (and, if necessary -1). 
Donor Pheresis  On Days -1 (and 0) donors will undergo leukapheresis for 1-2 days to achieve 
a CD34+ cell dose of 2-8 x 106/kg (actual weight - recipient). If the yield of 
CD34+ cells is less than 2 x 106/kg on Day -1, an additional pheresis will be 
performed on Day 0 to achieve a total or set dose of 2-8 x l06/kg CD34+ cells. 
 
Day
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
G-CSF---see below -----
Donor
Pheresis

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1. 
Introduction 
There have been significant advances in the management of acute myeloid leukemia 
(AML) in younger adults (age <60 years). The strategy of intensive remission induction 
therapy (sometimes comprising high dose cytarabine) to achieve a complete remission 
(CR), followed by post-remission therapy with high-dose cytosine arabinoside 
(cytarabine; Ara-C) or autologous or allogeneic blood or marrow transplantation has 
been developed progressively over the past 20 years, and has achieved measurable 
improvements in survival, particularly for favorable risk groups. A recent review of the 
ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) experience demonstrated a 
significant improvement in 5-year survival for younger AML patients from 11% in 1973-
79, to 37% from 1989-97 1,2(see Figure 1).  
However, similar progress has not been achieved in older patients (≥ 60 yrs), where the 
median survival in those receiving therapy is approximately 7 months, and the 5 year 
survival over the past three decades remains <15%  2-6(Figure 1). The poor survival in 
this population is predominantly on the basis of de novo chemo-resistance, manifest in a 
substantially lower rate of CR following induction chemotherapy (approximately 40-50% 
in most series, compared with 70-80% CR rate in younger adults), and early relapse 2,6,7. 
Older patients with AML also have a significantly higher incidence of adverse prognostic 
and karyotypic features, which are associated with a worse outcome8-12. Other factors 
that contribute to the poor response to induction chemotherapy include the expression 
and function of multi-drug resistance proteins, such as p-glycoprotein, which is 
expressed in the majority (approx. 70%) of older patients presenting with AML12, and 
which confers chemo-resistance.  
It must be noted that some older patients presenting with a ‘favorable’ karyotypic 
abnormality (albeit rare – incidence ≤5%) may be cured with standard therapy (long-term 
disease-free survival approximately 20-30%)13. It is not known whether intensified Ara-C-
based consolidation regimens are of benefit in this small subgroup of patients11. 
Figure 1. Overall survival of newly-diagnosed AML patients treated on ECOG protocols 
1973-1997.  
(A: all patients; B: patients age ≤55 yrs; C: patients >55 yrs)14 
In addition, older patients with AML tolerate intensive treatment less well, with a reported 
treatment-related mortality (TRM) ranging from 15-25%5,6. In a recent ECOG study, the 
TRM was 13% for patients age 55-70 yrs, and 22% for patients age >70 years15. Similar 
retrospective data in older adults (> 55-65 years) receiving intensive therapy have 
recently been published from the MD Anderson Cancer Center (n=998), CALGB (n=635) 
and SWOG (n=968), demonstrating the limitations of intensive chemotherapy10,11,16. The 

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SWOG analysis in particular highlights the importance of performance status in 
predicting induction mortality, with 30 day induction mortality rates of approximately 50% 
in patients age 65-75 with ECOG PS > 2, or in patients age > 75 years with PS > 110, 
suggesting that intensive therapy regimens in that population are inappropriate. 
In addition to the issue of increased induction mortality and de novo chemotherapy 
resistance (characterized by low CR rates), early relapse from CR also remains a major 
problem in those patients who do achieve CR. The median duration of response 
following CR is short (approximately 7-8 months), and there are very few long-term 
survivors (<15% at 5 years)10,11,15,16. 
This experience is particularly relevant as AML is a disease of older adults, with a 
median age of over 65 years. It is clear therefore that older adults with AML do not 
benefit from the advances in therapy demonstrated for younger adults, and are 
considered by many to have a disease similar to secondary or relapsed AML in younger 
patients2,5,6. 
Recent studies have attempted to address the problems of poor CR rate, excess 
treatment-related mortality, and high relapse rate in older patients, with little 
success4,15,17-26. As in younger adults, Ara-C remains the most important 
chemotherapeutic agent in the treatment of AML in older adults27. Recent studies 
replacing Ara-C with etoposide have been disappointing. Despite encouraging phase II 
results, a randomized study conducted by the Southwest Oncology Group comparing 
mitoxantrone & etoposide to standard daunorubicin and Ara-C demonstrated no 
advantage to the etoposide combination, and in fact suggested an inferior overall 
survival17. Similarly, older patients do not appear to benefit from the substitution of 
idarubicin for daunorubicin in remission induction therapy15,28, or from pre-chemotherapy 
priming with GM-CSF15, and derive no survival advantage from replacing daunorubicin 
with mitoxantrone18.  The addition of 6-thioguanine improved the rate of CR in one study 
to 62%, but did not influence survival20. Similarly, efforts to reverse the effects of p-
glycoprotein with agents such as PSC-833 have been largely unsuccessful, and in some 
cases have been associated with excess toxicity29. ECOG has recently completed a 
randomized study (E3999) evaluating the MDR inhibitor zosuquidar trihydrochloride 
(LY335979) in older patients with AML receiving standard remission induction therapy, 
and unfortunately there was no improvement in overall survival30. The incorporation of 
newer anti-leukemic agents, such as gemtuzumab-ozogamicin (humanized anti-CD33–
calicheamicin immunotoxin), with or without interleukin-11 support, has also failed to 
improve the CR rate in older patients21. Despite a significant decrease in the duration of 
neutropenia, the use of the hematopoietic growth factors G-CSF and GM-CSF after 
chemotherapy has little overall impact on treatment-related mortality, and with the 
exception of the ECOG experience22 has demonstrated no effect on survival 4,23-25. 
Unlike younger patients, intensified Ara-C in consolidation ± mitoxantrone does not 
improve survival, and very high doses of Ara-C in induction are in general poorly 
tolerated in this population3,26,31. In contrast, previous ECOG studies have shown that 
intermediate dose (ID) Ara-C given as consolidation therapy is remarkably well tolerated 
in older patients in remission, and while there is no clear survival advantage ID Ara-C 
continues to be a standard ECOG consolidation therapy even for older patients 15,22,30. 
Prolonged therapy with standard chemotherapy has also been evaluated, but similarly 
does not appear to improve survival20,32.  
It is nevertheless important to note that in general older patients do still benefit from 
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appropriate19,33, it was recently demonstrated in a randomized study from the UK that 
even in older patients considered ‘unfit for chemotherapy‘ there was a survival benefit 
associated with low intensity treatment with low dose Ara-C (LDAC) over supportive care 
alone34. In an analysis from the Swedish Leukemia Registry, there was a superior 2-year 
survival for patients age 70-79 who were treated with the intent to induce remission, 
suggesting that more patients may indeed benefit from therapy than who actually receive 
it at present35. Current estimates in the United States are that despite evidence of a 
survival advantage with treatment, only approximately 35% of AML patients over the age 
of 65 years receive chemotherapy131. 
In summary, AML in older patients (≥60 years) is characterized by lower complete 
remission rates, shorter remission duration, and a very poor prognosis despite therapy. 
This represents a significant barrier to treatment, and there is therefore a clear need for 
AML therapy that is both less toxic and of superior efficacy, particularly in high risk 
subgroups (such as poor-risk cytogenetics). In view of the lack of progress in this group, 
older patients, who constitute more than 50% of adults with AML, represent an ideal 
group in whom novel treatment strategies should be evaluated. 
1.1 
Clofarabine 
Clofarabine ([2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-adenine]; Cl-F-
ara-A) is a rationally designed, second-generation purine nucleoside analog.  
Designed as a hybrid molecule to overcome the limitations and incorporate the 
best qualities of fludarabine phosphate and cladribine, clofarabine has a chloro 
group at the 2-position of adenine, and its chemical structure therefore more 
closely resembles CdA than F-ara-A.  Halogenation at the 2-position of adenine 
renders this class of compounds resistant to cellular degradation by the enzyme 
adenine deaminase36.   
Clofarabine is cytotoxic to CCRF-CEM (human T-lymphoblast leukemia) cells in 
vitro in a time and concentration dependent manner37. It is a more efficient 
substrate for deoxycytidine kinase (dCK; rate-limiting step in intracellular 
phosphorylation of purine nucleosides) than the natural substrate deoxycytidine, 
and phosphorylated clofarabine is incorporated in the DNA of cells, the degree of 
incorporation correlating with cytotoxicity.  There is no apparent cell-cycle 
specificity for the accumulation of clofarabine nucleotide metabolites. Compared 
to cladribine, there is prolonged intracellular retention of clofarabine-triphosphate, 
which exerts its cytotoxic activity38. Furthermore, clofarabine-triphosphate inhibits 
both DNA polymerase α and ribonucleotide reductase (RNR), and is superior to 
cladribine in inhibition of DNA synthesis at similar concentration36,38,39. 
Widely distributed in murine tissue, clofarabine is bound to plasma proteins 
(approx. 47% in humans). There is limited human pharmacokinetic (PK) data 
available, although in recent phase I studies the concentrations at the end of 
infusion appeared to be dose-proportional across all doses40-42. Clofarabine 
exhibits biphasic kinetics, with an effective t½ of about 1.5hrs, and a terminal t½ 
of about 7hrs41. Based upon phase II data, clofarabine has been approved by the 
FDA for the treatment of relapsed and refractory acute lymphoblastic leukemia in 
pediatric patients40,43. 
1.1.1 
Clofarabine in Relapse/Refractory AML 
Clofarabine has significant activity in AML. In a phase I study 
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with relapsed and refractory acute leukemia, the dose-limiting toxicity 
was hepatotoxicity, and the maximum tolerated dose (MTD) was 
established as 40mg/m2/day x 5 days as a short intravenous infusion. 
Importantly, objective responses were seen, including complete 
remission in 2 patients with AML41.  
To confirm its activity a phase II study was subsequently performed in 
patients with high grade myeloid malignancy, including 31 patients 
with relapsed and refractory AML44. Thirteen of the 22 patients 
achieved a CR (42%), and 4 further patients achieved CR with 
incomplete platelet recovery (‘CRp’), for an overall response rate (RR) 
of 55%. The median duration of response was almost 6 months. 
Significant (≥ grade III) toxicity included rash (n=6), reversible 
elevation of hepatic transaminases (n=5), and nausea/vomiting (n=1). 
A concurrent multi-institutional phase II study was performed in 40 
patients with early relapse (within 12 months of achieving CR) or 
refractory AML, of whom 29 were evaluable and had complete clinical 
data45. This included patients with primary refractory disease (n=9), 
and those with an initial remission of either <6 months duration (n=14) 
or 6-12 months duration (n=8), thus representing a group with high 
risk disease and a very poor prognosis. The median age was 63 years 
(range 19-78). 
At interim analysis, the response rate was substantially lower in this 
refractory AML population than that reported in relapsed disease, 
particularly those with longer duration of 1st CR who had been shown 
to have a higher chance of responding44. Only 1/21 evaluable patients 
achieved a complete remission (4 months duration), and another 
achieved a partial remission (duration 2 months). Most patients 
received only a single treatment course with clofarabine, although 8 
patients received a 2nd course, and 1 patient each received a 3rd and 
4th course. Grade III/IV hematologic toxicity was common, including 
neutropenia (29/29), anemia (24/29) and thrombocytopenia (29/29). 
Grade III/IV non-hematologic toxicity in the latter study included 
elevated AST (n=8) or bilirubin (n=4). Other toxicity included 
paresthesiae (20), nausea and vomiting (19), confusion (10), diarrhea 
(8), fatigue (5), hand-foot syndrome (3), and pancreatitis in 1 patient. 
There were 2 treatment-related deaths due to sepsis (n=1) and multi-
organ failure (n=1). These results demonstrate that clofarabine alone 
is not active in refractory AML, but rather suggest that it is more likely 
to exert clinical activity earlier in the course of the disease. 
1.1.2 
Clofarabine in Newly-Diagnosed AML 
Much more encouraging are the results of a recent phase II study 
performed by the UK Medical Research Council (MRC) employing 
clofarabine as a single agent as remission induction therapy and post-
remission therapy for older adults who were considered ‘unfit’ for 
intensive induction therapy46. In this trial, thirty patients with newly-
diagnosed AML were treated (median age 72 yrs, range 61-82), 
including 17 with ‘intermediate risk’ and 7 with ‘high risk’ cytogenetics. 
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30mg/m2/day x 5, every 4-5 wks for 2-4 cycles. Remarkably, 13 
patients achieved CR (43%), and 4 others achieved CRp (13%). 
There were 4 treatment-related deaths (13%). Toxicity (≥ grade III) 
was predictable, and consisted predominantly of reversible 
hepatotoxicity (↑ALT 24%, ↑ bilirubin 15%), handfoot syndrome (11%), 
rash (10%), and nausea and vomiting (3%).  
Based upon the encouraging MRC experience in newly-diagnosed 
patients, a follow-up multicenter phase II trial was recently completed 
in Europe to confirm the activity of single agent clofarabine as 
induction and consolidation therapy in patents age ≥65 years (n=66) 
who were considered unsuitable for chemotherapy on the basis of 
age, comorbidity or performance status47,48. Clofarabine was given for 
2-4 courses at 30mg/m2/day on days 1-5, however most patients were 
only able to receive 2 courses due to toxicity with consolidation; the 
last 16 patients were treated at a lower clofarabine dose of 
20mg/m2/day beginning with the 2nd course, and the treatment was 
much better tolerated (A. Burnett, personal communication). The 
activity of single agent clofarabine was confirmed in this study, with an 
overall CR rate of 48%, and similar TRM to that reported in the initial 
MRC trial referenced above (9% clofarabine-related early death rate). 
Importantly, significant activity was noted in high-risk patient subsets, 
including those with ‘poor risk’ cytogenetics (CR 46%), and in those 
>70 years (CR 44%). The median disease-free survival was 6 
months, and the median overall survival was 5 months (A. Burnett, 
personal communication). 
In Summary, the experience in older AML patients considered 
‘unsuitable’ for standard intensive therapy suggest that single agent 
clofarabine may be better tolerated than standard therapy, and that it 
has significant single agent activity particularly in high risk populations 
where standard therapy has been demonstrated to be inadequate. 
Clofarabine therefore represents an excellent candidate drug for study 
in newly-diagnosed patients who are candidates for intensive therapy, 
in whom the activity would likely be equivalent or better, to address 
the clinical problems of low CR rates and high induction mortality 
encountered with standard daunorubicin & cytarabine. 
1.1.3 
Clofarabine & Ara-C in AML 
Clofarabine inhibits RNR, and is a superior substrate for dCK, with 
increased cytotoxic effects in vitro compared to fludarabine and 
cladribine, and therefore may be an appropriate combination agent 
with Ara-C36,38,39. In vitro studies suggest that clofarabine is more 
effective at increasing Ara-CTP in leukemic blasts than fludarabine49. 
Therefore, the combination of clofarabine and Ara-C is theoretically 
attractive, and several such combinations have been studied in AML 
in both the relapse/refractory and newly-diagnosed populations. 
An MDACC phase I/II pilot study of clofarabine & ‘intermediate dose’ 
Ara-C (1g/m2/day x 5) in relapsed/refractory AML patients 
demonstrated that the combination was reasonably well tolerated, 
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20%), rash (n=2, 10%), impaired liver function (n=2, 10%), hand-foot 
syndrome (n=1, 5%) and palpitations/arrhythmia (n=1, 5%). A febrile 
episode associated with myelosuppression was experienced by 20 
patients (63%) including 1 treatment-related death from bacterial 
sepsis. The overall response rate was 38%50.  
The combination of clofarabine & intermediate-dose Ara-C was 
subsequently evaluated in a phase II study in 60 newly-diagnosed 
patients with AML and high grade MDS at the MTD of clofarabine 
(40mg/m2 d1-5)51. The median age was 61 years (range 50-74). 
Myelosuppression following treatment was ‘ubiquitous’, and there 
were 9 deaths on study (15%), virtually all related to infectious 
complications. The most frequent side effects were diarrhea, emesis, 
palmoplantar erythrodysesthesia, and reversible liver function test 
abnormalities (most commonly grade III/IV hyperbilirubunemia and 
elevation in transaminases). The CR rate was 52%, and another 5 
achieved CRp (8%). At a median follow-up of 18 months, the median 
duration of CR and CRp were 8 months and <2 months, respectively. 
Median overall survival was 10 months, while the median survival of 
patients achieving CR was almost 2 years.  
A phase I study of clofarabine (starting dose 30mg/m2 d1-5) with 
‘standard dose’ cytarabine (100mg/m2 by 24hr continuous infusion d1-
7) is ongoing at the University of Alabama at Birmingham 
Comprehensive Cancer Center in newly-diagnosed AML patients, 
although dose-limiting toxicity has been encountered at the starting 
dose necessitating 2 consecutive clofarabine dose reductions to 
15mg/m2/day x 5 days52. That study is currently continuing in phase I, 
and the maximum tolerated dose has not yet been established. 
Therefore, while feasible in selected patients, the clinical results and 
toxicity of clofarabine combined with infusional Ara-C (at either 
standard or intermediate dose) do not presently support the 
incorporation of this intensive treatment strategy into phase III trials in 
elderly patients. 
Investigators at MDACC have recently completed a small randomized 
phase II study comparing clofarabine to clofarabine & subcutaneous 
low-dose Ara-C (LDAC) in patients age ≥60 years with newly-
diagnosed AML53. Using a Bayesian (adaptive) randomization, which 
progressively favors the treatment arm with higher CR rate, 76 
patients (median age 76 years, range 60-83) were randomized to 
either clofarabine alone (30 mg/m2 d1-5 induction; d1-3 consolidation) 
(n=16); or to clofarabine combined with LDAC (20mg/m2 SQ d1-14 
induction; d1-7 consolidation) (n=60). The overall CR rate was 57%, 
with 20% induction deaths. Interestingly, there was a difference in the 
CR rate observed between the clofarabine (CR 31%) and clofarabine 
& LDAC (CR 63%, p<0.05), although strangely there was an increase 
in induction deaths noted with the single agent clofarabine (TRM 31%) 
compared with the more intensive combination (TRM 17%). 
Unfortunately the unbalanced randomization (only n=16 in the 
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single agent clofarabine arm (which would have been predicted to be 
less toxic) confound the interpretation of this single center study. In 
addition, the low CR rate with single agent clofarabine in this trial is at 
odds with 2 multicenter European studies with n=95 patients46,48, 
probably reflecting patient selection and the small number of patients 
randomized to the single agent arm. There was not a statistically 
significant difference in overall survival between the 2 arms. 
In summary, the available experience of combination clofarabine and 
cytarabine, despite representing a more intensive therapy (particularly 
for infusional Ara-C), does not demonstrate a clear benefit in survival 
over single agent clofarabine and appears substantially more toxic. 
These results therefore do not justify incorporating Ara-C (either 
infusional or subcutaneous LDAC) into comparative trials of 
clofarabine versus standard therapy at this time. 
In Summary, these findings indicate that single agent clofarabine has 
significant activity in newly-diagnosed AML in the elderly population, 
particularly in high risk populations, and may be better tolerated than 
‘standard’ therapy. These data strongly support the rationale for a 
randomized trial comparing clofarabine as both remission induction 
and post-remission therapy versus ‘standard’ daunorubicin & 
cytarabine consolidation to determine its effect on overall survival. 
1.2 
Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for AML 
Allogeneic hematopoietic stem cell transplantation (AlloSCT) is curative for many 
younger patients with relapsed or poor prognosis acute myeloid leukemia.  This 
treatment modality has until recently had only a small impact on overall AML 
survival given that the median age of diagnosis with AML is beyond that at which 
ablative transplants are generally offered.  A number of publications have 
documented the activity of reduced intensity conditioning regimens in advanced 
AML54-58.  Non-ablative conditioning has reportedly been successful for treatment 
of patients in remission59,60. The composite experience suggests that GVHD risks 
are lower following AlloSCT with reduced intensity conditioning 130.Using a low-
dose total body irradiation (TBI) ± fludarabine non-ablative conditioning regimen, 
investigators in Seattle have recently reported a 2-year disease-free & overall 
survival of 44% and 48%, respectively, for a cohort of  n=122 patients (median 
age 57.5 yrs, range 17-74) with AML undergoing allogeneic transplantation from 
matched related or unrelated donors61. The 100 day and 1-year non-relapse 
mortality (NRM) was 3% and 14%, respectively (higher in those with an unrelated 
donor). Using a graft-versus-host disease (GVHD) prophylaxis regimen of 
mycophenolate mofetil and cyclosporine, with the former being tapered beginning 
day 40 and the latter beginning day 10062, the incidence of acute GVHD was 
40%, and the incidence of chronic GVHD (cGVHD) was 36% at 2 years. 
Importantly, for the 51 patients transplanted in 1st complete remission the 2-year 
survival was 51%. In a similar experience, in a cohort of n=112 patients (median 
age 55 yrs, range 22-74) with AML or MDS undergoing allogeneic transplantation 
following reduced intensity conditioning with melphalan & fludarabine at the 
MDACC, the 2-year survival was 66% for those patients in remission at the time 
of transplant63. The 100 day and 2-year NRM was 0% and 20%, respectively. 
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reduced intensity conditioning in 34 patients with AML in 1st CR demonstrated a 
2-year disease-free and overall survival of 56% (95% confidence intervals (CI) 
39-71%) and 68% (95% CI 50-81%), respectively64. There were 3 deaths from 
acute GVHD (9%), and the 12 month chronic GVHD rate was low at 24%. Most 
survivors were reported to have an excellent performance status. 
Recently, Claxton et al66 reported the use of allogeneic hematopoietic transplant 
following non-ablative conditioning with fludarabine & cyclophosphamide (Flu-Cy) 
combined with sirolimus and tacrolimus as GVHD prophylaxis. In this strategy, to 
facilitate GVL, tacrolimus was tapered early in patients without graft versus host 
disease at day 30, the intent being to leave sirolimus, an agent with know anti-
leukemic activity, as the only immunosuppressive agent. In an update of that 
experience, n=91 patients have undergone AlloSCT using Flu-Cy conditioning, 
including patients with advanced AML. The median age was 60 years, and all 
patients achieved successful engraftment (full donor chimerism in peripheral 
blood in majority). Only n=2 of 39 patients of all diagnoses receiving matched 
sibling transplants have suffered NRM (non-relapse related mortality), at day 295 
& day 567 respectively.  Thus 100 day TRM has been 0%, and 2 year TRM has 
been ~5%.  For 52 unrelated donor recipients, many with advanced and multiply 
pretreated malignancy and most with <10/10 matched donors, there were 5 
transplant-related deaths by day 100 (10%) and 13/52 (23%) by 2 years. (D. 
Claxton, personal communication). Therefore, using an immunosuppressive 
conditioning regimen that does not require pharmacokinetic targeting or the use 
of TBI, effective donor engraftment with low NRM can be achieved in an older 
patient population. 
These experiences demonstrate that non-ablative AlloSCT with reduced-intensity 
conditioning (RIC) is both feasible in a multicenter fashion, and associated with 
improved outcomes in selected patients, predominantly through a graft-versus-
leukemia (GVL) effect. In contrast more intensive preparative regimens have 
often been substantially more toxic58,67. However a recent single center feasibility 
analysis from MDACC suggests that this strategy may have only limited 
applicability in this population, and that only a small number of older AML 
patients may ultimately benefit from AlloSCT65. In that prospective single center 
study, only 26 of 259 (10%) newly-diagnosed patients age ≥50yrs with AML or 
high-grade myelodysplastic syndrome achieved CR, had a BMT consultation, 
and had a matched donor identified. Furthermore, only 14/26 (~5% of cohort) 
ultimately proceeded to AlloSCT. Therefore, a critical question remains as to the 
true feasibility and impact of an AlloSCT strategy in older AML patients, and 
whether the benefits of AlloSCT can be effectively extended to an older 
population in a multicenter study. The present study (E2906) affords a unique 
opportunity to evaluate the role and impact of AlloSCT in the management of 
older patients with AML by formally incorporating a ‘biological randomization’ to 
AlloSCT into the primary treatment strategy. Specifically, employing a ‘donor vs. 
no donor’ analysis, this strategy allows a true estimate of the ‘denominator’ of 
newly-diagnosed older AML patients who may be considered for AlloSCT, 
thereby accounting for the apparent selection bias of patients who actually 
proceed to AlloSCT inherent in such reports in this population. 
Based upon the favorable experience and tolerability of the Reduced Intensity 
Conditioning (RIC) regimen employed in the recently completed prospective 
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CR1 (personal communication, Drs. S. Devine & H. Lazarus), we plan to employ 
an identical busulfan-fludarabine conditioning regimen with similar GVHD 
prophylaxis. This will allow comparability of our AlloSCT results with those of the 
BMT CTN 0502 study, but in a more uniformly-treated population. However, the 
systematic early consideration of AlloSCT from the time of diagnosis in E2906, 
and inclusion of HLA-typing at presentation, has an important advantage over 
previous pilot RIC studies, and will allow a more definitive evaluation of the role 
of AlloSCT in this population. 
The non-ablative Flu-Cy conditioning regimen has limited anti-leukemic activity, 
and although the same may be said for other regimens the proposed reduced-
intensity busulfan-fludarabine regimen has the advantage of having been used 
successfully in a recent multi-center study. Both regimens share low morbidity 
and non-relapse-related mortality (NRM), and both share the intent of inducing 
early engraftment and a GVL effect.   
As applied to better matched, less heavily-treated AML patients in CR after only 
1 regimen as proposed in E2906, we may expect superior results. In contrast 
more intensive preparative regimens have often been substantially more 
toxic58,67. 
1.2.1 
In Summary, these observations strongly suggest that allogeneic 
hematopoietic transplantation may yield durable remissions in older 
AML patients who would without transplant have died of their 
leukemia.  Thus the formal testing of this therapy in a large series of 
patients ‘biologically’ randomized to receive or not to receive 
transplantation based on donor availability is logical and timely.  
Disease free and overall survival will be examined in these treatment 
groups in comparison with patients who are treated with 
chemotherapy in a ‘donor vs. no donor’ analysis. 
1.3 
Decitabine in AML 
Early relapse from complete remission remains a significant problem in AML in 
the elderly, with fewer than 15% long-term disease-free survivors among those 
who actually achieve CR. Previous maintenance strategies with low-dose Ara-C 
alone or LDAC-based regimens have unfortunately failed to improve the survival 
of older patients with AML18,32.Therefore, an effective and well tolerated 
maintenance strategy is urgently needed.  
Decitabine (5-aza-2׳-deoxycytidine; DAC) is a deoxycytidine analog which 
requires DNA synthesis for activity. Cytotoxic at high doses, low-dose DAC 
inhibits DNA methyltransferase, and is associated with gene hypomethylation 
and reactivation of target gene expression, favoring differentiation, reduced 
proliferation, and/or increased apoptosis68,69. Phase I studies have demonstrated 
that low-dose daily DAC was well tolerated and had significant activity in patients 
with AML70 and myelodysplastic syndrome (MDS) (overall response rate 32%)69. 
The degree of DNA hypomethylation in vivo correlated with response in AML 
patients treated with low dose DAC; interestingly, there was a dose-response 
relationship, with a linear decrease in methylation with increasing DAC dose from 
5 to 20mg/m2/day, although no further decrease in methylation was noted at 
doses higher than 20mg/m2 71. 

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In a randomized study in intermediate and high-risk MDS, DAC (15mg/m2 IV over 
4 hours, q8 hours for 3 days - total dose 135mg/m2) at 6 week intervals 
significantly improved patient outcomes, with 17% overall response rate, and a 
longer median time to AML progression or death in those with higher risk disease 
compared to supportive care (p=0.03)72. Alternative dosing schedules have also 
been evaluated, and a randomized study from MDACC in patients with high 
grade MDS has demonstrated improved CR rate of 39% with a once daily DAC 
dosing schedule (20mg/m2/day IV d1-5)73. DAC is therefore well tolerated and 
active in advanced MDS and AML, and was recently approved by the FDA for the 
treatment of intermediate and high risk MDS. 
Re-treatment or prolonged treatment with DAC has recently been evaluated in 2 
myeloid malignancy studies, including an analysis of re-treatment in high-grade 
MDS (including some patients with AML)74, and more recently as an induction 
and ‘maintenance’ strategy in de novo AML in older adults considered ineligible 
for intensive chemotherapy75. In the earlier trial of 108 patients74, 22 of 65 
responding patients were re-treated with low-dose DAC at the time of 
progression (a median of 11 months (range 3-27) from completion of initial DAC 
therapy). A 2nd response of short duration (median 4 months) was achieved in 
10/22 (45%). In the opinion of the investigators, this experience highlighted the 
importance of extended or ‘maintenance’ therapy with DAC in responding 
patients to prolong response and prevent secondary resistance. 
The more recent study more directly addressed the question of both induction 
and maintenance therapy with DAC in older adults (age >60 years) with newly-
diagnosed AML who were not eligible for intensive induction chemotherapy75. In 
this trial, 51 newly-diagnosed AML patients (median age 72, range 63-85 years) 
including those with complex karyotype (65%) and antecedent MDS (51%), were 
treated with standard low-dose DAC (15mg/m2 IV q8 hours d1-3, repeated 
q6weeks) up to 4 courses as induction, followed by maintenance DAC. The 
response rate to induction DAC was 62%, including CR 14%, partial response 
17%, and hematologic benefit 31%. The toxicity was reported to be very similar 
to that described for MDS, and there was only 1 induction death. Maintenance 
DAC 20mg/m2/day d1-3 was then administered as an outpatient every 8 weeks; it 
was reported to be very well tolerated, and there were no hospitalizations during 
maintenance. Remarkably, the median survival was 7.5 months, and the 1 year 
survival was 24%. The investigators concluded that maintenance with DAC was 
associated with prolonged anti-leukemia effect, the occurrence of some late 
responses, and limited hospitalizations, and overall had good feasibility in the 
outpatient setting. 
In a recent update of that experience, the investigators have amended the 
maintenance DAC dosing schedule to address the emergence of secondary 
resistance, decreasing the treatment interval from q8 weeks to q4 weeks. This is 
supported by correlative observations in chronic myeloid leukemia and MDS 
patients receiving decitabine, where re-methylation of LINE1 repeats in 
peripheral blood mononuclear cells occurred about 4 weeks after initial 
dosing73,76. The study has continued to accrue (n=>100), and the 4 week 
interval has been well tolerated (M. Lübbert personal communication). 
The present proposed study therefore represents a unique opportunity to 
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CR following both standard and experimental therapy. In view of the promising 
phase II German experience with prolonged DAC, we therefore propose to 
prospectively evaluate this novel maintenance strategy by adding a second 
randomization to observation (standard) or low-dose decitabine (experimental) in 
patients who remain in CR following completion of assigned consolidation 
therapy. 
1.3.1 
In Summary, AML in older adults is characterized by early relapse, 
with < 15% long-term disease-free survival. Prolonged low dose 
decitabine therapy has demonstrated apparent anti-leukemia activity 
is both feasible and well tolerated in the outpatient setting, and there 
is a suggestion that it may prolong remission duration. We therefore 
propose to incorporate a 2nd randomization following completion of 
consolidation to decitabine versus observation to evaluate the effect 
of prolonged decitabine maintenance on disease-free survival 
following completion of therapy. 
1.3.2 
Gender and Ethnicity 
Entry to this study is open to both men and women, and to persons of 
any racial or ethnic group. Previous ECOG studies in this patient 
population enrolled 56% men, 44% women, 95% white, 4% black and 
1% other from institutions. We anticipate that entry of women and 
minorities to this study will show similar proportions. 
We are aware of no data that would lead us to expect differential 
treatment effects by gender and ethnicity and therefore have not 
incorporated separate accrual goals for these subgroups. 
1.4 
Non-Inferiority Trial Design 
As reviewed extensively above, standard chemotherapy treatment is both toxic 
and ineffective for most older AML patients, and in particular for those who have 
poor performance status, comorbidities, or poor-risk cytogenetics. These poor 
results represent de facto a significant barrier to treatment for older AML patients, 
as evidenced by current estimates that only approximately 35% of those over 
age 65 years currently receive chemotherapy (131). The preliminary data 
suggest that clofarabine may have a similar complete remission rate with lower 
induction mortality compared with standard chemotherapy, and that it may have 
greater activity in those with poor-risk cytogenetics. This suggests that if 
clofarabine has a similar overall survival to standard therapy but with less toxicity 
or with lower induction mortality, it may allow the possibility of extending therapy 
to a larger population of older AML patients than who presently receive 
treatment. Considering the impact on both induction mortality and overall 
survival, E2906 is therefore designed to test both non-inferiority of clofarabine 
compared with standard induction chemotherapy, and if found to be non-inferior 
than to test its superiority. 
1.5 
Quality of Life Assessment 
1.5.1 
Background and Significance 
Quality of life (QOL) is an important concept in the oncology patient 
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trials.  However, with the exception of some studies of patients who 
received bone marrow transplant, there is a striking lack of published 
data that captures QOL in the AML patient population.  Moreover, 
those published are fraught with small sample sizes, high attrition 
rates, and thus, inconclusive findings. 
QOL has been compared in elderly AML patients receiving intensive 
versus low intensity therapy.   In a small non randomized trial, no 
differences were noted between baseline assessment and 6 weeks 
later or between treatment arms [88].  However, these patients scored 
lower overall in QOL measurement than the general population and 
scored higher in depression. Another study of 60 patients also noted 
stability in QOL assessments over a six month time period in patients 
receiving either induction therapy or low intensity therapy [89]   Yet in 
a study of 28 younger patients who successfully completed a full 
course of AML treatment (induction, consolidation, and two cycles of 
maintenance therapy), patients reported an improvement in QOL and 
a decrease in symptoms [90].  
Fatigue is an important component of QOL [91] and can be significant 
in patients with AML.  In two studies of AML patients, fatigue was 
common [92], persistent over time [93], and inversely correlated with 
QOL [92,93], and  with self-reported activities of daily living [93]. 
The elderly AML patient may be more susceptible to complications 
from disease as well as from treatment. The complications that arise 
may be influenced by physiologic changes associated with aging [94].  
Nutritional deficiencies are common in both the elderly as well as in 
the patient with AML [94,95].  The etiology for these deficiencies 
varies and the resultant physiologic and emotional consequences can 
be profound.  Cognitive changes also occur with normal aging and 
have the potential to affect an elderly AML patient’s ability to make 
informed treatment choices, understand prognosis, and treatment-
related side effects [94].  Such cognitive changes were found in a one 
study of AML and MDS patients [96].  In contrast, level of available 
social support has been shown to be a significant predictor of 
improved QOL [97] and even survival [98] in AML survivors. 
The ability to fully assess an elderly patient’s functional status is 
crucial to better anticipate potential problems and identify those who 
are at greater risk for complications.  To date, there are is only one 
published study describing a fully comprehensive geriatric 
assessment in individuals with AML [89].    
For the elderly patient, increasing or maintaining QOL can be viewed 
as more important than prolonged survival [99]. This viewpoint was 
also demonstrated in a group of elderly patients with AML [88].  Yet 
how to best improve or maintain QOL is not yet known.  Clearly more 
research is needed in this area. 
1.5.2 
Rationale for QOL 
The proposed study provides the unique opportunity to assess QOL 
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are randomized to two different treatment arms.  The toxicity profile of 
each treatment varies considerably; hence the impact of each 
treatment on patients’ symptoms and quality of life is important, 
particularly if efficacy in treating the underlying disease is similar.  
Baseline assessments will serve to further describe QOL and 
functioning in this patient population and the findings will also be used 
to compare with those from subsequent measurements.  Thus 
analysis will be performed both within and between treatment groups. 
Questionnaires to be administered have been carefully selected to 
evaluate the most clinically relevant patient-reported health outcomes.  
The assessment battery includes questionnaires that have been 
previously used with AML patients and/or elderly cancer patients 
(Functional Assessment of Cancer Therapy – Leukemia and FACT 
Fatigue as well as the abbreviated Comprehensive Geriatric 
Assessment (aCGA).  Additional measurements of nutritional status, 
social support, co-morbidity, and sexual function will further enhance 
the aCGA as these areas are known to be problematic in the elderly 
leukemia patient population [94].  
Assessment time-points were selected to capture data on patients’ 
QOL at critical time points in the clinical trial so that the impact of each 
treatment phase can be assessed vis-à-vis QOL.  The first 
assessment will be administered at the time of randomization. The 
second assessment will occur at the time hematopoietic nadir (~ two 
weeks after beginning induction therapy).  The third assessment will 
occur 28 days after the patient begins induction therapy.  The fourth 
assessment will occur at the time consolidation therapy is to begin.  
The fifth assessment will occur at the time patients are randomized to 
maintenance treatment or observation.  Efforts will be made to obtain 
QOL assessments at the time a patient is removed from the study. 
For the subset of patients who are is eligible for transplant, QOL 
assessments will be made at the time of conditioning therapy, and 
100 days post transplant. 
1.6 
Additional Correlative Studies 
1.6.1 
Mechanisms of Resistance to Therapy 
MDR1/P-glycoprotein expression is an established adverse prognostic 
factor in AML, particularly in older adults [12,118]. ECOG-ACRIN has 
extensive experience in the evaluation of MDR status, unfortunately 
recent efforts to target MDR have failed to impact on clinical outcomes 
[86,119]. Nevertheless, it remains an important prognostic factor in 
AML, and important preliminary studies suggest that clofarabine is not 
an MDR substrate and that the mechanisms of resistance to 
clofarabine appear to be different than cytarabine in vitro [120]. We 
therefore plan to prospectively evaluate P-glycoprotein expression by 
flow cytometry [86,119] to determine its effect on the CR rate and on 
overall survival. 
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1.6.2 
CXCR4 Expression  
The intensity of CXCR4 expression by AML blasts has recently been 
associated with inferior survival in retrospective studies in younger 
adults [87], but its relevance has not been evaluated in older adults 
nor in a large prospective study. We therefore plan to evaluate 
CXCR4 expression prospectively by flow cytometry in order to better 
characterize its prognostic impact (in terms of CR, disease-free 
survival & overall survival) in relation to other established prognostic 
factors, in particular cytogenetics. 
1.6.3 
Epigenetics 
E2906 incorporates a randomization to maintenance therapy with 
decitabine, a methyltransferase inhibitor, and affords a unique 
opportunity to study the epigenetic phenotype in AML at presentation 
and in remission. The following clinical & basic hypotheses will be 
studied: 
1.6.3.1 
Clinical 
Our preliminary data show that AML comes in different 
epigenetic subtypes, and that a phenotype of epigenetic 
instability seems to correlate with responsiveness with 
DNA methylransferase inhibitors. In addition to the 
epigenetic unstable phenotype, many of the more defined 
AML epigenetic subtypes had different medical outcomes 
in retrospective studies and so may be highly clinically 
relevant. Interestingly, gene expression profiling failed to 
identify several of these subtypes alone, demonstrating the 
power of epigenetic analysis to capture important biological 
differences in AML. Finally, the integration of gene 
expression and epigenetic signatures were shown to 
synergistically capture biological differences between 
patients with leukemia. 
Based on these data we predict that patients who present 
with AML and epigenetic instability will be the better 
candidates to respond to decitabine maintenance. 
Therefore we propose to perform expression and 
methylation profiling on all patients enrolled in 2906 and 
correlate their integrated epigenetic signatures with 
response to decitabine. Of equal importance we also 
predict that specific integrated epigenetic subtypes 
associated with differential clinical outcomes will be 
confirmed in this prospective study and could lead to an 
important advance in leukemia classification. The 
integrated signatures captured upon enrollment of these 
patients will be used to prospectively validate, confirm and 
possibly expand our ability to accurately segregate 
patients into biologically distinct cohorts. We plan to use 
these data to direct the design of future ECOG-ACRIN 
clinical trials. 
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1.6.3.2 
Basic 
Data from the published literature and our laboratory 
indicate that progressive alteration of epigenetic signatures 
in bone marrow cells occurs during normal aging. We 
hypothesize that certain epigenetic signatures associated 
with aging might constitute an epigenetic field defect that 
could result in leukemogenesis.  We will examine the 
epigenetic profiles of remission marrow in patients 
randomized to observation vs decitabine in E2906 to 
determine whether epigenetic signature of apparently 
morphologically normal bone marrow is predictive of 
relapse or response to decitabine maintenance. Our data 
performed in fractionated vs unfractionated marrow from 
the same individuals indicate that epigenetic signatures 
indicative of aberrant epigenetic programming are equally 
readily evident in either case, and are readily 
distinguishable between normal and abnormal samples. 
Therefore, we expect our experimental approach to 
successfully capture indications of epigenetic field defects 
in this patient cohort. 
1.6.4 
Somatic Mutation Analysis 
1.6.4.1 
Background 
Somatic mutation analyses have been extensively studied 
in younger AML cohorts; the biologic and therapeutic 
complexity in the elderly, where the disease is most 
common, has been less extensively investigated. Any 
previous studies have not been sufficiently broad in scope 
or of sufficiently high resolution to elucidate in any detail 
the spectrum of somatic alterations in elderly AML patients 
and to determine which altered pathways are the major 
determinants of chemoresistance and of adverse outcome 
in this disease. The constellation of genetic lesions that 
collectively mediate the chemoresistant phenotype are 
likely heterogenous in nature and require integrated, high-
resolution exploration in a sufficiently large number of 
cases in order to identify recurrently perturbed biologic 
pathways with clinical, prognostic, and therapeutic 
relevance. While it is possible that thousands of coding 
and non-coding genes are affected by mutations, these 
genes often have in common the perturbation of common 
pathways, such as DNA repair, RNA splicing, etc. 
Discovering which pathways contribute to chemoresistance 
and how they are perturbed is fundamentally important to 
address this important clinical phenomenon. 
1.6.4.2 
Genetic Characterization of E2906 Leukemias 
This study will perform a complete genetic characterization 
of patient leukemia cells using state of the art next 
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generation sequencing methods. The entire spectrum of 
somatic coding mutations will be identified, using Agilent 
Sure-Select exome capture followed by Illumina 
HiSeq2000 sequencing, the most powerful and economical 
approach for sequencing the coding sequence of genomes 
on a large scale. DNA from the patients’ own T-
lymphocytes or remission cells will be used as the matched 
germline control, using whole genome amplification to 
amplify small amounts of DNA that will be generated from 
these control cells, in order to distinguish true somatic 
variants. In addition, we will perform base-pair resolution 
DNA methylation sequencing across gene regulatory 
regions encompassing > four million individual cytosine 
residues. This will be achieved using an improved version 
of the reduced representation bisulfate sequencing 
protocol followed by Illumina HiSeq2000 sequencing. All 
mutations detected will be validated by repeat PCR and 
sequencing on the unamplified diagnostic sample. 
Wherever possible, matched control DNA (remission or T-
lymphocyte DNA) will be resequenced to determine if 
candidate disease alleles are somatic or present in 
germline. 
1.6.5 
Epidemiology of AML & Clinical Outcomes in E2906 
The etiology of AML is poorly understood and in the large majority of 
cases is unknown. Similarly, with the exception of therapy-related 
AML, the impact of prior exposures or lifestyle factors which may have 
contributed to its development on subsequent AML survival is also not 
known. In addition to rare cases of “familial” leukemia (associated with 
familial monosomy 7, GATA-1 mutations, germline CEBPA mutation, 
and others) and well-characterized genetic syndromes more closely 
associated with childhood disease (e.g. Down’s syndrome, Bloom’s 
syndrome, Schwachman-Diamond syndrome, Kostmann syndrome, 
etc.)132,1332, observational and case-control studies have identified 
several factors strongly associated with the development of AML. 
Among the best characterized of these is prior exposure to cytotoxic 
chemotherapy (in particular alkylating agents & topoisomerase II 
inhibitors) and/or ionizing or therapeutic radiation – so-called therapy-
related AML (t-AML) - which is associated with inferior survival134. 
However more recent studies have identified important lifestyle and 
occupational exposures that are significantly associated with 
increased relative risk (RR) of developing AML. These include 
obesity135 (approximately 2-fold RR of developing AML), regular 
acetaminophen use136 (RR 1.5), and smoking137 (RR 1.2) which has 
been particularly linked with the t(8;21) cytogenetic abnormality. In 
addition, benzene exposure132 and living in a rural/farm environment 
(personal communication, J. Ross) have also been strongly linked 
with an increased risk of developing AML in some studies. A recently 
completed NIH-funded population-based case-control study (the 
“Predictors of Acute Leukemia Minnesota” - PALM - study) designed 
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and run by Dr. Julie Ross at the University of Minnesota identified  
> 600 new cases of myeloid leukemia (including n=393 AML) and 682 
controls. The PALM study employed a straightforward self-
administered questionnaire, and preliminary analyses confirm the 
significant association between prior regular aspirin (RR 0.6 in 
women) and acetaminophen (RR 1.5) use and development of AML 
(in press, Ross JA, et al Cancer Epi Biom Prev, July 2011), and has 
also identified prior obesity at ages 35 & 50 years with an increased 
risk of adult AML138 (RR ~ 2). Importantly, a significant association 
between both previous medical history139 and family history and the 
development of AML has been identified from the PALM study, 
although that data is still being analyzed and has not yet been 
presented. The prevalence of common exposures among n=682 
controls from the PALM study is included in the Table (below). 
Table: Prevalence of common exposure from PALM study control 
population (personal communication, Dr. J. Ross, Univ. of Minnesota) 
Exposure 
PALM Question # 
Prevalence in Controls 
(n=682) 
Benzene  
85c 
 7% 
Ever Smoked in lifetime 
10 
48% 
Aspirin* 
31a 
27% 
Rural/Farm – ever lived 
67 
**58% 
* more than occasionally 
** Rural/Farm is expected to be significantly lower in ECOG trial, as PALM 
study included only Minnesota residents 
While some of these factors are potentially modifiable, a critical 
question remains as to the impact of these common exposures on 
subsequent AML survival. Patients with t-AML have been shown to 
have an inferior outcome, although this is highly dependent on the 
specific cytogenetic abnormality134. However, the impact of other 
potential etiologic factors (in particular prior exposures, lifestyle 
factors, and medical/family history) on survival after AML is not 
known. The PALM study was itself not designed to study subsequent 
leukemia clinical outcomes. 
A large multicenter cooperative group study affords a unique and 
highly attractive opportunity to prospectively study the impact of these 
established prior exposures/potential etiologic factors on AML survival 
in a controlled clinical setting. Indeed, E2906 is uniquely positioned to 
prospectively study their impact on AML survival for several reasons: 
it is a large prospective trial; it is focused on the largest group of 
patients with AML (age >60 years) and is broadly inclusive; the clinical 
endpoints are well-defined; genetic and molecular subtypes of AML 
will be extremely well-characterized; and it controls strictly for therapy. 
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(unless significant farm exposures - 20-30 minutes), and will add 
minimal additional burden to site research personnel and patients 
during their initial 1-month hospitalization. 
We therefore propose to formally study the impact of underlying 
exposures and lifestyle factors associated with AML development on 
subsequent clinical outcomes, and specifically on overall survival. 
Adapting the self-administered PALM tool for use in E2906 in 
collaboration with Dr. Julie Ross, Univ. of Minnesota (the “Acute 
Leukemia Epidemiology & Survival in ECOG” - “ALESE” 
questionnaire), we will offer patients the opportunity to participate in a 
prospective study which will evaluate the presence of these 
previously-identified exposures/potential etiologic factors among AML 
patients and study their impact on subsequent survival after therapy 
with curative intent. The use of the ALESE tool will allow an 
opportunity to normalize our case data from E2906 with the results of 
the PALM Minnesota population-based case-control study to 
determine important similarities and differences, in order to better 
understand the prevalence of individual exposures & lifestyle factors 
in the broader AML population receiving therapy with curative intent. 
In addition, the availability of this prospective clinical data on lifestyle, 
family/medical history & exposure will be an invaluable resource in the 
future for the correlation of specific exposures with well-characterized 
genetic & molecular subgroups of AML (as will be performed in 
E2906), allowing a planned future study of the molecular 
epidemiology of AML & clinical outcomes. 
METHODS 
Data coordination (including QA & secure data entry) will be 
performed in the Cancer Epidemiology program at Mayo Clinic, 
Florida. Patients will be given the self-administered ALESE 
questionnaire to complete within the first week of hospitalization on 
E2906, and the site research coordinator will return it to the 
investigator. A contact e-mail & telephone number will be provided in 
the questionnaire for questions and assistance to patients or site 
research personnel. While the ALESE questionnaire does not need to 
be completed immediately at baseline prior to initiating therapy (unlike 
the QOL correlative studies) - as it pertains to previous exposures and 
lifestyle/medical/family history factors which are stable - we will ask 
them to complete it in the first week of hospitalization to ensure that 
we can QA the questionnaire during their initial 1-month 
hospitalization. Also the ALESE questionnaire should optimally be 
completed within the first week of initiating therapy to minimize any 
potential bias of early mortality on the analysis. 
High patient participation rates are anticipated, as in the earlier PALM 
study the case Cooperation Rate with the questionnaire was 83% 
(personal communication, Dr. J. Ross). Similarly, in E1Z03 (an 
unrelated QOL study) the compliance (with the help of close 
coordination and follow-up by a clinical coordinator) was >90% 
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significant additional burden for patients, and based on the experience 
from the PALM study it is anticipated that most patients will be able to 
complete the self-directed questionnaire in <20 minutes with minimal 
or no help (personal communication, Dr. J. Ross) unless they have 
extensive farm exposures (20-30 minutes). Indeed in the PALM study 
there was significant enthusiasm among patients to participate in the 
study (personal communication, Dr. J. Ross), and a similar response 
is anticipated in E2906. No additional laboratory or genetic studies are 
required, as appropriate leukemia & germline samples are already 
being collected. 
ALESE Questionnaires will be returned directly to the Investigator in 
stamped sealed envelope where QA & secure data entry (using 
scanning or double-key entry) will be performed by a trained clinical 
coordinator in the Cancer Epidemiology program at Mayo Clinic 
Florida under the supervision of Investigator. A detailed analysis plan 
will include clinical (treatment, induction mortality, remission, survival) 
& cytogenetic data as part of a dedicated grant application including 
collaboration with the ECOG-ACRIN Patient Outcomes Committee, 
Cytogenetic, and Leukemia Lab Committees, and Dr. Ross. 
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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To evaluate the effect of clofarabine induction and consolidation 
therapy on overall survival in comparison with standard therapy 
(daunorubicin & cytarabine) in newly-diagnosed AML patients age ≥ 
60 years. 
2.2 
Secondary Objectives 
2.2.1 
To evaluate complete remission (CR) rates, duration of remission, and 
toxicity/treatment-related mortality of clofarabine in comparison with 
standard therapy (daunorubicin & cytarabine) in newly-diagnosed 
AML patients age ≥60 years.  
2.2.2 
To evaluate the feasibility of consolidation with reduced-intensity 
conditioning and allogeneic hematopoietic stem cell transplantation 
from HLA-identical donors in patients who achieve a response to 
induction therapy, including the incidence of successful engraftment, 
acute and chronic graft-versus-host disease, transplant-related 
mortality, and its impact on overall survival in comparison to patients 
receiving chemotherapy. 
2.2.3 
To evaluate the duration of remission and disease-free survival of 
patients in complete remission following completion of consolidation 
therapy who are subsequently randomized to receive scheduled low-
dose decitabine maintenance in comparison with observation. 
2.2.4 
To perform expression and methylation profiling on all patients 
receiving decitabine and to correlate their integrated epigenetic 
signatures with response to decitabine.  
2.2.5 
To examine the epigenetic profiles of remission marrow in patients 
randomized to observation vs. decitabine to determine whether 
epigenetic signature of apparently morphologically normal bone 
marrow is predictive of relapse or response to decitabine 
maintenance.  
2.2.6 
To explore the possible association of response to clofarabine with 
ABC-transporter P-glycoprotein (Pgp).  
2.2.7 
To assess the intensity of expression of CXCR4 on diagnostic 
leukemia cells and to correlate this parameter with other established 
prognostic factors 
2.2.8 
To assess the entire spectrum of somatic mutations and affected 
pathways at diagnosis of AML and elucidate the association between 
gene mutation and outcome. 
2.2.9 
To examine the impact of smoking, obesity, regular acetaminophen 
use, regular aspirin use, benzene exposure, living in a rural/farm 
environment and some other underlying exposures and lifestyle 
factors associated with AML development on OS. 
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2.2.10 
To investigate potential correlative results between array CGH 
findings and acute myeloid leukemia patient characteristics. 
2.3 
Quality of Life Objectives 
2.3.1 
To compare health-related QOL (physical, functional, leukemia-
specific well-being) and fatigue in elderly AML patients receiving 
standard induction therapy with those receiving clofarabine. 
2.3.2 
To measure the change in health-related QOL that occurs over time 
(within treatment groups). 
2.3.3 
To comprehensively assess patient function at the time of study 
enrollment. 
2.3.4 
To determine if components of a comprehensive geriatric assessment 
or QOL scales predict ability to complete AML treatment. 
2.3.5 
To describe the impact of transplant on QOL in AML patients above 
age 60. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All questions regarding eligibility should be directed to the study chair or 
study chair liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE:  
This study involves pre-registration (see Section 4).  Bone marrow and 
peripheral blood specimens must be submitted for centralized 
immunophenotyping and results will determine the patient’s eligibility. 
3.1 
Pre-Registration 
Diagnostic bone marrow and peripheral blood specimens must be submitted for 
eligibility testing by multiparameter flow cytometry. Testing will be performed by 
the ECOG-ACRIN Leukemia Translational Studies Laboratory and reported to 
the institution. 
3.2 
Eligibility Criteria 
3.2.1 
Age ≥ 60 years. 
3.2.2 
Sexually active males must be strongly advised to use an accepted 
and effective method of contraception.  
3.2.3 
AST, ALT, total bilirubin ≤ Grade 1. 
AST: _____ Date of test: ______ ULN: ______ 
ALT: _____ Date of test: ______ ULN: ______ 
Total bilirubin: _____ Date of test: ______ ULN: ______ 
NOTE: 
If total bilirubin is 2 to 3 mg/dL, but direct bilirubin is 
normal, then the patient will be considered eligible. 
3.2.4 
Patient must not have a concurrent active malignancy for which they 
are receiving treatment (other than MDS). 
3.2.5 
Patient must not have an active, uncontrolled infection. 
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3.2.6 
Additional Induction Eligibility Criteria 
3.2.6.1 
Newly-diagnosed AML patients according to WHO 
classification who are considered candidates for intensive 
chemotherapy based upon examination of peripheral blood 
or bone marrow aspirate specimens or touch preparations 
of the bone marrow biopsy obtained within two weeks prior 
to randomization. A bone marrow aspirate is required for 
enrollment. However, on occasion there is discordance 
between percentage of myeloblasts on the differential of 
the peripheral blood or aspirate. The peripheral blood 
criteria are sufficient for diagnosis. Confirmatory 
immunophenotyping will be performed centrally. 
3.2.6.2 
ECOG performance status 0-3 (restricted to ECOG PS 0-2 
if age ≥70 years)  
3.2.6.3 
Patients with APL confirmed either by the presence of 
t(15;17)(q22;q21) or PML/RAR∀ transcripts will be 
excluded 
3.2.6.4 
Patients must not have blastic transformation of chronic 
myelogenous leukemia. 
3.2.6.5 
Patients with secondary AML are eligible for enrollment 
onto the trial.  Secondary AML is defined as AML that has 
developed in a person with a history of antecedent blood 
count abnormalities, or myelodysplastic syndrome (MDS), 
or a myeloproliferative disorder (excluding Chronic Myeloid 
Leukemia); or a history of prior chemotherapy or radiation 
therapy for a disease other than AML. 
NOTE: 
Prior therapy of MDS with decitabine, low-dose 
cytarabine, or azacitidine is excluded. 
3.2.6.6 
Patients may not have received prior chemotherapy for 
AML with the exception of hydroxyurea for increased blast 
count or leukapheresis for leukocytosis. Patients who have 
received a limited and short-term exposure of ATRA (all 
trans retinoic acid) while AML-M3 (Acute Promyelocytic 
Leukemia) was being ruled out, and which has been 
discontinued, will be eligible. 
3.2.6.7 
Patients must have a total serum bilirubin ≤ 1.5 X ULN (grade 
≤ 1) and a serum creatinine ≤ 1 mg/dL. If total bilirubin is 2 to 3 
mg/dL, but direct bilirubin is normal, then the patient will be 
considered eligible. Patients with a serum creatinine >1 are 
eligible if they have a calculated GFR of ≥ 60 mL/min (i.e. 
class I or class II chronic kidney disease) using the MDRD 
formula [77,78]. The values must be obtained within 48 
hours prior to randomization (for MDRD extended version 
with defaults to SI units please refer to http://mdrd.com). 
NOTE: 
Daily creatinine and MDRD formula are only for 
the 1st induction cycle. 
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3.2.6.8 
Patients must have a cardiac ejection fraction of ≥ 45% or 
within institutional normal limits.  A nuclear medicine gated 
blood pool examination is preferred.  A 2-D ECHO scan is 
acceptable if a calculated ejection fraction is obtained and 
follow-up measurement of the cardiac ejection fraction will 
also be performed by echocardiography.  Measurement of 
cardiac ejection fraction should be within two weeks prior 
to receiving treatment. 
NOTE: 
When a MUGA or echocardiogram cannot be 
obtained due to weekend or holiday, then 
patients may be enrolled provided there is no 
history of significant cardiovascular disease and 
a measurement of cardiac ejection fraction will 
be performed within 5 days of study enrollment. 
3.2.6.9 
Patients with suspected CNS involvement should undergo 
lumbar puncture.  Those with documented CNS 
involvement will be excluded.  
3.2.6.10 
Cytogenetic analysis must be performed from diagnostic 
bone marrow (preferred) or if adequate number of 
circulating blasts (>109/l) from peripheral blood.  
3.2.6.11 
Patients who have received previous treatment for AHD 
with 5-azacitidine, decitabine, or low dose cytarabine will 
be excluded. 
3.2.6.12 
Patients with known HIV infection are excluded due to the 
potential immunosuppressive effects of clofarabine and 
allogeneic transplantation. 
3.2.6.13 
HLA typing should be performed at registration, if possible. 
3.2.6.14 
Diagnostic bone marrow and peripheral blood specimens 
must be submitted for immunophenotyping and selected 
molecular testing. 
3.2.7 
Consolidation Criteria, Step 2 for Arms C and D 
NOTE: 
All patients achieving CR or CRi will receive consolidation 
when fit. 
NOTE:  
Patients proceeding to transplant are allowed up to one 
cycle of consolidation treatment. 
3.2.7.1 
Consolidation Cycle 1 must commence within sixty days of 
the bone marrow aspirate and biopsy that confirmed the 
presence of a CR or CRi. 
3.2.7.2 
Patients must have achieved a CR or Cri (or morphologic 
leukemia-free state for those patients proceeding to Arm G 
transplant) as defined in Section 6.   
3.2.7.3 
Patients who have achieved a CR or CRi must have 
maintained peripheral blood evidence of a CR or CRi as 
defined in Section 6. 
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3.2.7.4 
Patients must have an ECOG performance status of 0-2. 
3.2.7.5 
Patients must have resolved any serious infectious 
complications related to induction. 
NOTE: 
Patients with an HLA-matched donor and 
proceeding to transplant will be allowed up to 
one cycle of consolidation treatment. 
3.2.7.6 
Any significant medical complications related to induction 
must have resolved. 
3.2.7.7 
Patients must have a creatinine and AST ≤ grade 1 (refer to 
Section 5.4 for dose modifications). The values must be 
obtained within 48 hours prior to registration. 
3.2.8 
Maintenance Criteria, Step 3 for Arms E and F 
3.2.8.1 
Maintenance should commence within 60 days of recovery 
of peripheral blood counts after Consolidation Cycle 2.  
Patients must begin Consolidation Cycle 2 within 60 days 
of recovery to be eligible for further therapy. 
3.2.8.2 
Patients must have maintained peripheral blood evidence 
of a remission as defined in Section 6 and must have a CR 
or CRi, confirmed on restaging BM aspirate and biopsy 
and cytogenetic analysis.  
3.2.8.3 
Patients must have an ECOG performance status of 0 -2. 
3.2.8.4 
Patients must have resolved any serious infectious 
complications related to Consolidation Cycle 2. 
3.2.8.5 
Any significant medical complications related to 
Consolidation Cycle 2 must have resolved. 
3.2.8.6 
Patients must have a total serum bilirubin ≤ 1.5 x ULN and a 
serum creatinine ≤ grade 1. The values must be obtained 
within 48 hours prior to randomization. 
NOTE: 
If total bilirubin is 2-3 mg/dL, but direct bilirubin 
is normal, then the patient will be considered 
eligible. 
3.2.8.7 
The ANC must be > 1000 mm3 and the platelet count > 
75,000 mm3 prior to starting every cycle of treatment with 
decitabine. Decitabine may be delayed for up to 4 weeks 
between cycles (i.e. may be administered as infrequently 
as q8 weeks) while waiting for counts to recover. 
3.2.9 
Allogeneic Transplantation, Step 3 for Arm G 
3.2.9.1 
Patients must be > 28 days from the start of induction or 
re-induction chemotherapy, or from the start Consolidation 
Cycle 1 (if received) and < 90 days following recovery from 
most recent treatment; and they must have achieved and 
maintained a response to induction therapy (CR, CRi, or 
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“morphologic disease-free state”) in accordance with 
Section 6 of the protocol. 
3.2.9.2 
Patients must have recovered from the effects of induction, 
re-induction, or consolidation chemotherapy (all toxicities ≤ 
grade I with the exception of reversible electrolyte 
abnormalities), and have no ongoing active infection 
requiring treatment. 
3.2.9.3 
Patients must have a total serum bilirubin ≤ 1.5 x ULN 
(grade ≤ 1) and a serum creatinine ≤ grade1. The values 
must be obtained within 48 hours prior to registration. 
3.2.9.4 
An eligible HLA-identical donor (either related or unrelated) 
should be available. In sibling donors, low resolution HLA 
typing (A,B,DR) will be considered sufficient. In the case of 
unrelated donors, high-resolution class I and II typing 
(A,B,C,DRB1 and DQ) should be matched at all 10 loci. 
Donors must be willing and able to undergo peripheral 
blood progenitor mobilization.  
• 
HLA-Identical Sibling (6/6): The donor must be 
determined to be an HLA-identical sibling (6/6) by 
serologic typing for class (A, B) and low resolution 
molecular typing for class II (DRB1). 
• 
Matched Unrelated Donor (10/10): High resolution 
molecular typing at the following loci is required: HLA-
A, -B, -C, -DRBL, and –DQB1. 
NOTE: 
For matched donors – will allow select 1 
antigen mismatched sibling donors and 
unrelated donors in accordance with site 
institutional standard, as long as matched at 
HLA-A, HLA-B, HLA-C, and DRB1, and with 
advanced discussion/approval by the Study 
Chair and the BMT co-chair. 
3.2.9.5 
Patients must be considered reliable enough to comply 
with the medication regimen and follow-up, and have social 
support necessary to allow this compliance. 
3.2.9.6 
Patients must have a cardiac ejection fraction of > 40%, or 
within institutional normal limits.  A nuclear medicine gated 
blood pool examination is preferred.  A 2-D ECHO scan is 
acceptable if a calculated ejection fraction is obtained and 
follow-up measurement of the cardiac ejection fraction will 
also be performed by echocardiography. Measurement of 
cardiac ejection fraction should be within two weeks prior 
to allogeneic transplantation. 
3.2.9.7 
DLCO > 40% with no symptomatic pulmonary disease. 
3.2.9.8 
No known hypersensitivity to E.coli-derived products 
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3.2.9.9 
No HIV infection. Patients with immune dysfunction are at 
a significantly higher risk of toxicities from intensive 
immunosuppressive therapies. 
3.2.9.10 
Initial Required Laboratory Data 
Creatinine  
≤ Grade 1 
Bilirubin* 
 
≤ Grade 1 
AST 
 
≤ Grade 1 
* If bilirubin is 2-3 mg/dL, but direct bilirubin is normal then patient 
will be considered eligible. 
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4. 
Registration Procedures 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
Registration requires the submission of: 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.  For 
questions, please contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov>. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients. Study centers can 
check the status of their registration packets by querying the Regulatory Support System 
(RSS) site registration status page of the CTSU member web site by entering credentials 
at https://www.ctsu.org. For sites under the CIRB initiative, IRB data will automatically 
load to RSS. 
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Downloading Site Registration Documents   
Site registration forms may be downloaded from the E2906 protocol page located on the 
CTSU members’ website.   
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol E2906 
• 
Click on the Site Registration Documents link 
Requirements for E2906 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS. 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
PHONE: 1-866-651-2878 
FAX: (215) 569-0206  
E-MAIL: CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A. 
CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
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• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patient Enrollment 
Patients must not start protocol treatment prior to registration. 
Treatment should start within five working days after registration. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms. 
Please refer to Section 4.1 for the registration information that will be requested.  
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria has been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable).  
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
The following information will be requested 
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4.1 
Pre-registration 
NOTE: 
  Patients who are only pre-registered must not begin treatment.   
To proceed to randomization, patients must have centralized 
immunophenotyping performed by the ECOG-ACRIN Leukemia Translational 
Studies Laboratory. 
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification 
4.1.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.1.2.2 
Investigator’s name (NCI number) 
4.1.2.3 
Cooperative Group Credit 
4.1.2.4 
Credit Investigator 
4.1.2.5 
Protocol specific contact information 
4.1.3 
Patient Identification 
4.1.3.1 
Patient’s initials (first and last) 
4.1.3.2 
Patient’s Hospital ID and/or Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Gender 
4.1.3.3.2 
Birth date 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
Method of payment 
4.1.3.3.7 
Country of residence 
4.1.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3.1. 
4.1.5 
Additional Requirements 
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.1.5.2 
Bone marrow and peripheral blood specimens must be 
submitted at pre-registration for centralized 
immunophenotyping. 
NOTE: 
Copies of the consent are not collected by the ECOG-
ACRIN Operations Office. However the ECOG-ACRIN 
Leukemia Translational Studies Laboratory (LTSL) 
requires institutions to submit a copy of the E2906 consent 
and a copy of the HIPAA Authorization form. 
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4.2 
Step 1: Randomization to Induction (ARMS A or B) 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
[Deleted in Addendum #4] 
4.2.2.2 
Investigator’s name (NCI number) 
4.2.2.3 
Cooperative Group Credit 
4.2.2.4 
Credit Investigator 
4.2.2.5 
Protocol specific contact information 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (first and last) 
4.2.3.2 
Patient’s Hospital ID and/or Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Gender 
4.2.3.3.2 
Birth date 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.3.7 
Country of residence 
4.2.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.  An eligibility checklist has been appended to the protocol.  A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.2.5 
Stratification  
• 
Age 60-69 vs. ≥ 70 years 
• 
[Deleted in Addendum #3] 
• 
Therapy-related AML (any prior treatment with chemotherapy or 
radiation therapy for another malignancy) 
• 
Antecedent Hematological Disorders (AHD) (prior diagnosis of 
MDS, myeloproliferative disorder or other hematologic disorder) 
4.2.6 
Additional Requirements (1st Randomization) 
4.2.6.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.2.6.2 
Baseline and follow-up peripheral blood and buccal swabs 
are to be submitted as outlined in Section 10 for banking, 
per patient consent.  
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4.2.6.3 
Baseline and follow-up karyotypes must be submitted for 
central review as outlined in Section 10. 
NOTE: 
Specimens submitted for mandatory central reviews will 
also be used for the optional correlative studies indicated 
in Section 10 per patient consent. 
NOTE: 
ECOG-ACRIN requires that biological samples submitted 
from patients be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). 
NOTE: 
Institutions outside of the United States and Canada must 
confer with the receiving laboratory and the ECOG-ACRIN 
Operations Office - Boston regarding logistics for 
submission of fresh or frozen samples. 
4.3 
Step 2: Registration to Consolidation (ARMS C or D) 
All patients must register to step 2. Patients who are proceeding to transplant 
and are not receiving consolidation therapy may proceed immediately to 
Registration to Transplant (Step 3). 
4.3.1 
Protocol Number  
4.3.2 
Investigator Identification  
4.3.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.3.2.2 
Investigator’s name (NCI number) 
4.3.2.3 
Cooperative Group Credit 
4.3.2.4 
Credit Investigator 
4.3.2.5 
Protocol specific contact information 
4.3.3 
Patient Identification  
4.3.3.1 
Patient’s initials (first and last) 
4.3.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3.3 
Patient demographics 
4.3.3.3.1 
Gender 
4.3.3.3.2 
Birth date 
4.3.3.3.3 
Race 
4.3.3.3.4 
Ethnicity 
4.3.3.3.5 
Nine-digit ZIP code 
4.3.3.3.6 
Method of payment 
4.3.3.3.7 
Country of residence 
4.3.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.  An eligibility checklist has been appended to the protocol.  A 
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confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.3.5 
Classification 
• 
Induction Treatment (Arm A vs Arm B) 
4.3.6 
Additional Requirements (Randomization) 
4.3.6.1 
Follow-up karyotypes, smears, bone marrow and 
peripheral blood must be submitted for central review as 
outlined in Section 10. 
4.3.6.2 
Follow-up peripheral blood is to be submitted as outlined in 
Section 10 for banking, per patient consent. 
NOTE: 
Specimens submitted for central review will also be used 
for the optional correlative studies outlined in Section 10 
per patient consent. 
NOTE: 
ECOG-ACRIN requires that all biological samples 
submitted be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). 
4.4 
Step 3: 2nd Randomization-Maintenance (Arms E or F), or Registration to 
Transplant (Arm G) 
4.4.1 
Protocol Number  
4.4.2 
Investigator Identification  
4.4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.4.2.2 
Investigator’s name (NCI number) 
4.4.2.3 
Cooperative Group Credit 
4.4.2.4 
Credit Investigator 
4.4.2.5 
Protocol specific contact information 
4.4.3 
Patient Identification  
4.4.3.1 
Patient’s initials (first and last) 
4.4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.4.3.3 
Patient demographics 
4.4.3.3.1 
Gender 
4.4.3.3.2 
Birth date 
4.4.3.3.3 
Race 
4.4.3.3.4 
Ethnicity 
4.4.3.3.5 
Nine-digit ZIP code 
4.4.3.3.6 
Method of payment 
4.4.3.3.7 
Country of residence 
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Rev. 12/13 
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4.4.4 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 
3. An eligibility checklist has been appended to the protocol.  A 
confirmation of registration will be forwarded by the ECOG-ACRIN 
Operations Office - Boston. 
4.4.5 
Stratification and Classification Factors 
4.4.5.1 
Classification for Registration to Transplant 
• 
[Deleted in Addendum #4] 
• 
Transplant donor Identified: HLA-Identical Sibling (6/6) 
or Matched Unrelated Donor (10/10) 
NOTE: 
For matched donors – will allow select 1 
antigen mismatched sibling donors and 
unrelated donors in accordance with site 
institutional standard, as long as matched at 
HLA-A, HLB, HLA-C, and DRB1, and with 
advanced discussion/approval by the Study 
Chair and the BMT co-chair. 
4.4.5.2 
Stratification for Randomization to Maintenance 
• 
Age 60-69 vs. ≥ 70 years 
• 
Cytogenetics unfavorable vs. “other” 
• 
Induction Treatment (Arm A vs. B) 
4.4.6 
Additional Requirements (2nd Randomization) 
4.4.6.1 
Follow-up karyotypes, smears, bone marrow and 
peripheral blood must be submitted for central review as 
outlined in Section 10. 
4.4.6.2 
Follow-up peripheral blood is to be submitted as outlined in 
Section 10 for banking, per patient consent. 
NOTE: 
Specimens submitted for central review will also be used 
for the optional correlative studies outlined in Section 10 
per patient consent. 
NOTE: 
ECOG-ACRIN requires that all biological samples 
submitted from patients be entered and tracked via the 
online ECOG-ACRIN Sample Tracking System (STS). 
NOTE: 
FACT (Foundation for the Accreditation of Cellular 
Therapy) credentialing certificate must be submitted to the 
CTSU Patient Registrar at 1-888-691-8039 at time of 
patient registration to Arm G. 
4.5 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E2906 Forms Packet. Document the reason for not starting 
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protocol treatment on the Off Treatment form. Also report the date and type of 
the first non-protocol treatment that the patient receives.  
4.6 
Investigator’s Drug Brochure and Safety Alerts 
A copy of the Investigator’s Drug Brochure (IDB) for Clofarabine and the drug 
package insert for Decitabine are available for download from the ECOG 
webpage.  The IDB and drug package insert provide relevant and current 
scientific information about the drug products.  The IDB and drug package insert 
should be submitted to your IRB/EC according to GCP regulations. The 
Clofarabine IDB, the Decitabine drug package insert and any correspondence to 
the Institutional Review Board (IRB)/Ethics Committee (EC) should be kept in the 
E2906 regulatory files. 
Should any SAE report on this study qualify as a safety alert report requiring 
expedited reporting, the SAE report will be sent by the sponsors to regulatory 
authorities globally (including the FDA) and ECOG-ACRIN.  If applicable, ECOG-
ACRIN will disseminate these safety alert reports to all participating investigators 
in the bimonthly group mailings.  These reports should be forwarded to your 
IRB/EC within 90 days of receipt for review.  Reporting instructions are provided 
with each safety alert. These safety alerts and any correspondence to your 
IRB/EC should be maintained in your E2906 study file. 
4.7 
IND Status 
The use of Clofarabine and Decitabine in this trial is classified as “off-label” or 
unapproved use of FDA-approved drugs.  When a drug or combination of drugs 
is used in an off-label manner as part of a clinical trial, it is, by rule, considered as 
an investigational treatment regimen.  However, while these treatment regimens 
are not approved by the FDA, their use is exempt from the requirements for an 
IND to conduct this study as defined under Title 21 CFR 312.2(b) of the codified 
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5. 
Treatment Plan 
5.1 
Induction Therapy and Premedications 
NOTE: 
Doses to be calculated using actual body weight. 
5.1.1 
Initial Considerations 
Patients should begin treatment with Allopurinol 300 mg/day orally.  
Reversible abnormalities of renal or metabolic function should be 
treated aggressively and corrected prior to institution of therapy.  
Immediate measures to diagnose and begin treatment of infections 
should be instituted prior to induction therapy. 
Patients should be adequately hydrated with NS or equivalent- and 
achieve a target urine output ≥ 100ml/hour average prior to starting 
induction therapy. This should be maintained throughout the first 5-7 
days of induction therapy, with adjustments as clinically indicated to 
maintain volume status and prevent volume overload. Appropriate 
monitoring for evidence of tumor lysis should also be performed for 
the first 3-5 days of induction therapy (e.g. measurement of K+, PO43-, 
serum creatinine, calcium and uric acid q 8-12 hours) 
Patients with high circulating blast cell counts > 50,000/μl, should be 
given hydroxyurea 750 mg/m2 (or more) orally every 6-12 hours until 
the absolute blast count falls < 50,000/μl. 
NOTE:  
Patients who present with a clinically significant increase in the 
peripheral blast count may receive hydroxyurea prior to the start of 
induction.  A suggested dose is 1 to 2 gm po every six hours, at the 
discretion of the physician. The hydroxyurea must be discontinued 
prior to administration of induction. Hydroxurea suggested minimum 
500–1000 mg PO twice a day. Suggested maximum dose is not to 
exceed 4,000 mg twice a day. 
NOTE: 
Patients with M4 or M5 disease and who have CNS signs or 
symptoms should have a lumbar puncture once blasts have cleared 
from the peripheral blood smear. 
NOTE: 
Up to two courses of induction therapy are permitted to achieve 
marrow aplasia.  Patients who have not achieved CR, CRi, or a 
morphologic leukemia-free state after the second cycle of induction 
are taken off study and further treatment is at the discretion of the 
investigator. 
NOTE: 
Allopurinol 300 mg daily or the dose adjusted for renal insufficiency 
should be administered prior to starting induction through the 
completion of the cytarabine infusion during induction. 
Patients will be randomized to one of the following induction therapy arms: 
5.1.2 
ARM A Standard Therapy with “7&3 schedule” 
Daunorubicin 
60 mg/m²/day by 10 - 15 minute intravenous 
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Cytarabine 
100 mg/m²/day by 24 hour continuous intravenous 
infusion for 7 days (days 1-7). 
NOTE: 
There are no dose modifications during initial induction. 
Dexamethasone 10 mg IV QD (or equivalent) and Ondansetron 16 mg 
IV, or PO, or equivalent, is suggested as an anti-emetic. 
Patients with residual AML by morphologic review or who do not 
achieve an aplastic BM on day 12-14 (i.e. < 5% blasts and < 20% 
cellularity or markedly/moderately hypocellular) are eligible to receive 
a 2nd cycle of induction therapy with the same dose & schedule of 
daunorubicin & cytarabine beginning no sooner than day 14. 
5.1.3 
ARM B Clofarabine 
Clofarabine 
30mg/m2/day IV by 1 hour infusion QD x 5 days 
Dexamethasone 10 mg IV QD (or equivalent) and Ondansetron 16 mg 
IV, or PO, or equivalent, is suggested as an anti-emetic. 
Patients with residual AML or who do not achieve an aplastic BM on 
day 12-14 (i.e. < 5% blasts and < 20% cellularity or 
markedly/moderately hypocellular) are eligible to receive a 2nd cycle of 
induction therapy with clofarabine at the lower ‘consolidation’ dose 
of 20mg/m2/day IV QD x 5 days.  
The creatinine must be measured daily during the first cycle of 
clofarabine treatment. Dose adjustments for an increase in serum 
creatinine > grade I during clofarabine treatment will be according to 
Dose Modification, Section 5.4.4. 
NOTE: 
Dose adjustments for the first induction cycle of clofarabine 
will follow Section 5.4.4. 
The 2nd cycle of induction with clofarabine must not commence sooner 
than day 21 and no later than day 56, and must be withheld until 
creatinine, AST & total bilirubin are ≤ grade I (See Section 5.4.4 for 
dose modifications). 
5.1.4 
Restaging 
A restaging BM will be performed on day 12 -14 (+/- 1 day) to 
determine whether patients have achieved an aplastic BM (i.e. < 5% 
blasts and < 20% cellularity, or markedly/moderately hypocellular).  
Patients who achieve an aplastic BM should start GM-CSF or G-CSF, 
or pegfilgrastim (unless contraindicated). Those with residual 
leukemia or who do not achieve an aplastic or markedly/moderately 
hypocellular BM are eligible for re-induction with a 2nd cycle of 
chemotherapy as noted above.  
A repeat BM for outcome will be performed between day 28 – day 56 
from the start of initial therapy after 1st or 2nd induction either when the 
ANC is > 1000 and platelets > 100,000, or if there is evidence of 
delayed hematologic recovery and it is felt that the ANC will not reach 
1000 or the platelet count > 100,000, to document response to 
induction therapy. Those with an HLA-matched donor identified who 
achieve a “morphologic leukemia-free state” on or before day 56 may 
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proceed to allogeneic transplantation if medically appropriate and per 
physician discretion. Patients proceeding to transplant are allowed up 
to 1 cycle of consolidation before the transplant. See Sections 5.1.6 
and 5.1.7. 
5.1.5 
Criteria for Second Induction Cycle 
A bone marrow aspirate and biopsy is performed on day 12-14 (+ 1 
day), i.e. 5-7 days after the completion of the cytarabine infusion or 7-
9 days after completion of clofarabine treatment.  The decision to 
administer a second induction cycle is based on the following criteria: 
NOTE: 
Patients undergoing 2nd induction who do not achieve 
complete response by day 56 of the start of re-induction 
will be taken off protocol treatment. 
5.1.5.1 
If the marrow cellularity is judged to be greater than 20%, 
or not markedly/moderately hypocellular on the marrow 
biopsy, or with > 5% blasts, or the bone marrow is 
indeterminate, then repeat induction is indicated. 
If the marrow cellularity is less than markedly hypocellular, 
or moderately hypocellular, or there are persistent 
circulating blasts, then the patient’s status should be 
followed with a repeat marrow assessment within 5 to 7 
days. 
5.1.5.2 
Second Induction Treatment Dose Arm A & Arm B 
For Arm A, the 2nd induction cycle is a repeat of the initial 
induction and at the same schedule of chemotherapy as 
the 1st induction, however, for Arm B, clofarabine is 
administered at the reduced dose of 20 mg/m2/day IV by 1 
hour infusion days 1-5, and should not start before day 21. 
Prior to administering a 2nd cycle of clofarabine induction, 
abnormalities in hepatic function must have returned < 
grade I. 
5.1.6 
Consolidation  
All patients achieving CR or CRi will receive consolidation therapy 
when fit. Patients with an HLA-matched donor who achieve at least a 
‘morphologic leukemia-free state’ 79 (< 5% blasts without hematologic 
recovery, and negative flow cytometry if performed) will be eligible for 
AlloSCT (see Section 5.1.7). Patients will be assigned to consolidation 
based upon the 1st randomization: those randomized to ‘standard’ 
daunorubicin & cytarabine induction will receive 2 cycles at 4-6 week 
intervals of ‘standard’ intermediate-dose Cytarabine 1500 mg/m2 q 12 
hours for either 12 doses per cycle (age 60-69 years) or 6 doses per 
cycle (age ≥ 70 years); those randomized to ‘clofarabine’ will receive 2 
cycles of clofarabine 20 mg/m2/day x 5 days at 4-6 week intervals. 
Arm C ‘Intermediate-Dose Cytarabine’ Consolidation 
• 
All patients randomized to ‘standard’ daunorubicin & cytarabine 
induction 
Rev. 2/12, 
         2/13 
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• 
2 cycles of consolidation therapy 
• 
Cytarabine 1500 mg/m2 IV over 1 hour stratified by age for either 
twice a day (q 12 hours) 12 doses per cycle (age 60-69 years) or 
once daily days 1-6, 6 doses per cycle (age ≥ 70 years).  
Cycles will be repeated at 4-6 week intervals.  
Arm D ’Clofarabine’ Consolidation 
• 
All patients randomized to clofarabine induction 
• 
2 cycles of consolidation therapy 
• 
Clofarabine 20 mg/m2/day infused over 1 hour x 5 days per cycle 
Cycles will be repeated at 4-6 week intervals. 
NOTE: 
Consolidation for Patients Proceeding to Transplant 
• 
Up to 1 cycle of consolidation treatment is allowed 
• 
Treatment determined by induction 
5.1.6.1 
Consolidation Cycle 1 
Patients who achieve a CR or CRi and have no residual 
significant toxicities from the induction course are eligible 
for further protocol therapy. In general, consolidation 
therapy should start within 1 month of documentation of 
CR/CRi when possible, after the resolution of any non-
hematologic toxicity of previous chemotherapy ( to </= 
grade I), and with recovery of performance status to >/= 
baseline in the judgment of the Investigator.The first cycle 
of post-remission therapy must begin within sixty days of 
documentation of a CR or CRi. A repeat measurement of 
ejection fraction should be performed for patients on Arm C 
and Arm D. Patients on Arm C will receive dose-escalated 
cytarabine. 
The schedule of cytarabine administration is modified 
based upon age < or ≥ 70 years. 
5.1.6.2 
Consolidation Cycle 2 
Patients must have maintained peripheral blood evidence 
of a remission as defined in Section 6.1. Consolidation 
cycle 2 should commence within thirty days of recovery of 
peripheral blood counts after consolidation cycle 1. 
Patients who do not begin consolidation cycle 2 within 60 
days of recovery are ineligible for further protocol therapy.  
5.1.7 
Allogeneic Stem Cell Transplantation with Reduced Intensity 
Conditioning – Arm G 
All patients with an HLA-matched donor identified (either sibling or 
unrelated) are eligible for AlloSCT. HLA typing should be performed 
on all patients and eligible siblings pre-induction treatment.  
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5.1.7.1 
Allogeneic Transplant  
An eligible HLA-identical donor (either related or unrelated) 
should be available. In sibling donors, low resolution HLA 
typing (A,B,DR) will be considered sufficient. In the case of 
unrelated donors, high-resolution class I and II typing 
(A,B,C,DRB1 and DQ) should be matched at all 10 loci. 
Donors must be willing and able to undergo peripheral 
blood progenitor mobilization.  
• 
HLA-Identical Sibling (6/6): The donor must be 
determined to be an HLA-identical sibling (6/6) by 
serologic typing for class (A, B) and low resolution 
molecular typing for class II (DRB1). 
• 
Matched Unrelated Donor (10/10): High resolution 
molecular typing at the following loci is required: HLA-
A, -B, -C, -DRBL, and –DQB1. 
NOTE: 
For matched donors – will allow select 1 
antigen mismatched sibling donors and 
unrelated donors in accordance with site 
institutional standard, as long as matched at 
HLA-A, HLA-B, HLA-C, and DRB1, and with 
advanced discussion/approval by the Study 
Chair and the BMT co-chair. 
 Patients allocated to allogeneic transplant will proceed 
directly to transplant after induction therapy on Arms A or 
B, or after 1 cycle of consolidation (post-remission) therapy 
on Arms C or D.  They will undergo the therapy no sooner 
than 28 days after initiation of induction therapy; after 
documentation of CR, CRi, or morphologic disease-free 
state; and not later than three months after recovery of 
peripheral blood counts following induction and post 
remission therapy, providing all eligibility guidelines in 
Section 3.1.9 are met. 
Those patients not felt to be fit for transplant or who do not 
have a suitable matched donor as above or who decline 
transplant may be allocated to consolidation. 
5.1.7.2 
Selection of Allogeneic Transplant Center 
Eligible patients will be referred to one of the approved 
allogeneic blood and marrow transplant institutions.  
Arrangements will be made by contacting the marrow 
transplant patient coordinator at the chosen institution.   
NOTE: 
ECOG-ACRIN institutions may refer to the 
ECOG website for information about BMT 
centers. 
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5.1.7.3 
Transplant Regimen 
Preferred Preparative Conditioning regimen will consist of: 
Fludarabine 
30 mg/m2 I.V. days -7, -6, -5, -4, -3, (5 
doses) 
Busulfan** 
0.8 mg/kg I.V. q6 hours days -4 thru -3, 
(8 doses) 
Thymoglobulin 2.5 mg/kg/day I.V. days -4, -3, -2, (3 
doses) 
** Busulfan Pharmacokinetic: While not being formally 
tested in E2906, participating BMT centers may perform 
Busulfan (Bu) Pharmacokinetic (PK) testing per 
institutional standards. Busulfan may be dose reduced in 
individual patients in accordance with results of Bu PK 
results only after consultation with the Study Chair or 
BMT Chairs, but may not be dose escalated. Please 
inform Study Chair prior to AlloSCT if Bu PK will be 
performed.  
NOTE: 
Bu-Flu-ATG is the preferred preparative 
conditioning regimen. Alternative equivalent 
reduced-intensity or non-myeloblative 
conditioning regimens may be used at the 
discretion of the investigator only after 
discussion with the Study Chair (or Co-Chair) 
and BMT Co-Chair. 
Allogeneic Stem Cells - Collection from Donors 
HLA-Identical Sibling Donors 
HLA-identical sibling donors should be treated with G-CSF 
10 mcg/kg subcutaneously daily on Days -5, -4, -3, -2 (and 
-1, if the initial collection is inadequate). G-CSF should 
continue throughout mobilization, but will be reduced by 
50% if WBC > 50,000/µL. 
On Day -1 HLA-identical sibling donors will have vein to 
vein apheresis. CD3 and CD34 cells as fractions of the 
peripheral mononuclear (PMN) cells will be determined 
from the established PMN cell collection according to 
institutional flow cytometry. If the yield of CD34+ cells is 
less than 2 x 106/kg (actual weight -recipient) on Day -1, an 
additional apheresis will be performed on Day 0 to achieve 
a total or set dose of 2-8 x 106/kg (actual weight -recipient) 
CD34+ cells. 
The PMN cells will be separated and collected, while all 
the other separated blood components will be returned to 
the donor. 
Cells from the stem cell collection either may be stored 
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Matched Unrelated Donors 
Collection of peripheral blood stem cells will be performed 
on Days -1 (and 0) according to existing NMDP collection 
center protocols (or equivalent for other registries). Donors 
that are unwilling or unable to have PBSC collected will not 
be eligible. Matched unrelated donors are not required to 
complete Donor Consent Form. 
Allogeneic Stem Cells - Infusion to Recipients 
On Days 0 (and +1) a minimum total cell dose of CD34+ 
cells of 2 x 106/kg (actual weight - recipient) and a 
maximum of 8 x 106/kg (actual weight -recipient) will be 
infused. 
G-CSF 5 mcg/kg/day subcutaneously beginning on Day 
+12 and continuing until ANC > 1500/µL for two 
consecutive days or > 5000/µL for one day. If the ANC 
subsequently falls to < l000/µL then resume G-CSF at 5 
mcg/kg/day. 
Patients will be monitored weekly for engraftment and 
toxicity. Chimerism studies should be performed on Days 
+30, +60, +90, + 120, + 180, +270, +365, and at time of 
relapse. 
5.1.7.4 
Infusion of Peripheral Blood Stem Cells 
Infusion of stem cells is to proceed as described below or 
per institutional standards. 
See Section 5.5 for treatment supportive care. 
5.1.7.4.1 
Stem Cells 
2-8 X 106/kg CD34+ cells cryopreserved 
peripheral blood stem cells are rapidly 
thawed at 37
0 C and immediately infused on 
day 0. 
5.1.7.4.2 
Stem Cells 
Cryopreserved stem cells are rapidly 
thawed at 37C and immediately infused 
36-48 hours after the last dose of 
Cyclophosphamide. 
5.1.7.4.3 
PBSC Infusion: The cells are not washed 
before reinfusion, and the osmolality of the 
cell suspension requires the use of a flowing 
central venous catheter.  Before reinfusion 
of PBSC, hydration must be maintained to 
have an output of at least 3 cc/kg/hour.  
Emergency drugs (Benadryl, epinephrine, 
Solu-Medrol) in appropriate doses must be 
at the bedside.  Baseline vital signs, forced 
vital capacity and EKG are recorded.  

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Fifteen minutes prior to administration of the 
thawed PBSC, the patient is to receive: 
• 
50 mL of 25% mannitol solution IV 
• 
50 mg of diphenhydramine IV 
• 
250 mg of hydrocortisone IV 
• 
An antiemetic drug of choice (optional) 
NOTE: 
Institutional standard allowed for 
PBSC pre-meds. 
5.1.8 
Maintenance 
5.1.8.1 
Observation vs. Decitabine Maintenance (2nd 
Randomization) – Arm E and Arm F 
Patients who complete consolidation therapy will undergo 
restaging with a BM aspiration & biopsy and repeat BM 
cytogenetics to confirm CR or CRi. Patients will then be 
randomized to maintenance therapy with decitabine vs. 
monthly observation for 12 months. 
• 
Decitabine 20 mg/m2/day IV over 1 hour QD x 3 days, 
repeated Q4 weeks x 12 months total75, up to 13 
cycles, but not to continue beyond 12 months. 
Regardless of treatment delays, the total duration of 
maintenance therapy will be 12 months. 
• 
There are no planned dose reductions in decitabine. 
Patients unable to receive treatment on schedule (i.e. 
planned q4 weeks, but delays up to 4 weeks allowed) 
due to cytopenias or persistent side effects will 
discontinue decitabine and subsequently be observed 
per the 'observation ' group (Arm E), although they will 
be analyzed on an 'intention to treat' basis as having 
been assigned to Arm F. 
• 
The ANC must be > 1000 mm3 and the platelet count  
> 75,000 mm3 prior to starting every cycle of treatment 
with decitabine. Decitabine may be delayed for up to 4 
weeks between cycles (i.e. may be administered as 
infrequently as q8 weeks) while waiting for counts to 
recover. 
• 
Monthly CBC and examination will be performed on all 
patients assigned to decitabine or observation for 24 
months 
5.1.8.2 
Patients who do not meet eligibility for Randomization to 
Observation vs. Decitabine Maintenance after recovery 
from Consolidation should be followed according to Arm E. 
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5.2 
Adverse Event Reporting Requirements  
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E2906 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting). Additionally, certain adverse events must be reported in an 
expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.2.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: 
Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 will be 
utilized for AE reporting.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A 
copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website (http://ctep.cancer.gov). 
Step 2: 
Grade the event using Version 4.0 of the NCI CTCAE. 
Step 3: 
Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: 
Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or 
the severity of the event is NOT listed in:  
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• 
Arm A, B, C, D and F – the drug package insert or 
protocol   
Step 5: 
Review Section 5.2.6 for E2906 and/or ECOG-ACRIN 
specific requirements for expedited reporting of specific 
adverse events that require special monitoring.   
NOTE: 
For general questions regarding expedited reporting 
requirements, please contact the the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497. 
5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) and 
• 
the FDA (1-800-FDA-1088) 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
When to Report an Event in an Expedited Manner 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Section 5.2.6. 
NOTE: 
Adverse events that meet the reporting requirements in 
Section 5.2.6 and occur within 30 days of the last dose of 
protocol treatment must be reported on an expedited 
adverse event report form (using CTEP-AERS). For any 
adverse events that occur more than 30 days after the last 
dose of treatment, only those that have an attribution of 
possibly, probably, or definitely AND meet the reporting 
requirements in Section 5.2.6 must be reported on an 
expedited adverse event report form (using CTEP-AERS) 
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5.2.5 
Other Recipients of Adverse Event Reports 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
A drug supporter representative may call a site for additional 
information regarding a serious adverse event.  Any additional written 
AE information requested by the drug supporter MUST be submitted 
to BOTH ECOG-ACRIN and the drug supporter. 
5.2.6 
Expedited Reporting for Commercial Agents 
NOTE: 
Although Arms B, D, and F use agents considered to be 
investigational, their use is exempt from the requirements 
for an IND to conduct this study as defined under Title 21 
CFR 312.2(b) of the codified FDA regulations. Please see 
Section 4.6 for IND status information. 
Commercial reporting requirements are provided below. The agents 
used in arms A, B, C, D, and F of this study are Daunorubicin, 
Cytarabine, Decitabine and Clofarabine. 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial 
agents only – Arms A, B, C, D and F. 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
 
Unrelated or 
Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of 
learning of the event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution. NOTE:  Any 
death that occurs > 30 days after the last dose of treatment and is attributed possibly, probably, 
or definitely to the treatment must be reported within 7 calendar days of learning of the event.   
 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial: 
 
Serious Events: Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via 
CTEP-AERS within 7 calendar days of learning of the event.  For instructions on how to 
specifically report these events via CTEP-AERS, please contact the the AEMD Help 
Desk at aemd@tech-res.com or 301-897-7497. These will need to be discussed on a 
case by case basis’ 
 
5.2.7 
Reporting Second Primary Cancers 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
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• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
• 
A secondary malignancy is a cancer CAUSED BY any prior 
anti-cancer treatment (including the treatment on this 
protocol).  Secondary malignancies require both routine and 
expedited reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office - Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy. 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 

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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Decitabine 
(5-aza-2'-deoxycytidine) (NSC  127716) 
The Comprehensive Adverse Events and Potential Risks List (CAEPR) provides 
a thorough and detailed list of reported and/or potential adverse events 
associated with the Decitabine. The CAEPR is developed and continuously 
monitored by the CTEP Investigational Drug Branch (IDB). The information listed 
in the CAEPR below, as well as the other resources described in the 
'Determination of reporting requirements' part of the Adverse Event Reporting 
section in this protocol, can be used to determine expectedness of an event 
when evaluating if the event is reportable via CTEP-AERS.  Frequency is 
provided based on 1658 patients. Below is the CAEPR for Decitabine (5-aza-2'-
deoxycytidine). 
 
Version 2.4, January 4, 20171 
 Adverse Events with Possible  
 Relationship to Decitabine (5-aza-2'-deoxycytidine) 
 (CTCAE 4.0 Term) 
[n= 1832] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
 
Febrile neutropenia 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Anal mucositis 
 
 
 
Constipation 
 
 
 
Diarrhea 
 
 
 
Mucositis oral 
 
 
Nausea 
 
 
 
 
Rectal mucositis 
 
 
 
Small intestinal mucositis 
 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
 
Chills 
 
 
 
Edema limbs 
 
 
Fatigue 
 
 
 
Fever 
 
 
 
 
Non-cardiac chest pain 
 
 
 
Pain 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
Autoimmune disorder 
 
 
INFECTIONS AND INFESTATIONS 
 
Infection2 
 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Bruising 
 
 
INVESTIGATIONS 
 
 
Alanine aminotransferase increased 
 
 
 
Aspartate aminotransferase increased  
 
 
Blood bilirubin increased 
 
 
 
Creatinine increased 
 
 
Rev. 2/12,  
8/13, 12/13 
Rev. 12/13, 
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Lymphocyte count decreased 
 
 
Neutrophil count decreased 
 
 
 
Platelet count decreased 
 
 
 
White blood cell decreased 
 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
Hyperglycemia 
 
 
 
Hyperuricemia 
 
 
 
Hypoalbuminemia 
 
 
 
Hypocalcemia 
 
 
 
Hypokalemia 
 
 
 
Hypomagnesemia 
 
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
Bone pain 
 
 
 
Pain in extremity 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Headache 
 
 
 
 
Intracranial hemorrhage 
 
 
Somnolence 
 
 
PSYCHIATRIC DISORDERS 
 
 
Anxiety 
 
 
 
Insomnia 
 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Cough 
 
 
 
Dyspnea 
 
 
 
Laryngeal mucositis 
 
 
 
Pharyngeal mucositis 
 
 
 
Pharyngolaryngeal pain 
 
 
 
Respiratory hemorrhage3 
 
 
 
Tracheal mucositis 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Alopecia 
 
 
 
Pruritus 
 
 
 
Purpura 
 
 
 
Rash maculo-papular 
 
 
VASCULAR DISORDERS 
 
 
Hematoma 
 
 
 
Phlebitis 
 
 
 
Vascular 
disorders 
- 
Other 
(hemorrhage with decreased platelets) 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
3 Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 

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4 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
5 Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal obstruction, 
Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and Small intestinal 
obstruction under the GASTROINTESTINAL DISORDERS SOC. 
Adverse events reported on decitabine (5-aza-2'-deoxycytidine) trials, but for which there 
is insufficient evidence to suggest that there was a reasonable possibility that decitabine 
(5-aza-2'-deoxycytidine) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (coagulaopathy); Blood and lymphatic system disorders - Other (lymphadenopathy); 
Blood and lymphatic system disorders - Other (pancytopenia); Bone marrow hypocellular; 
Hemolysis; Leukocytosis; Spleen disorder 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Atrial flutter; 
Atrioventricular block complete; Cardiac arrest; Cardiac disorders - Other (cardiac murmur); 
Cardiac disorders - Other (dilation atrial); Chest pain - cardiac; Heart failure; Myocardial 
infarction; Restrictive cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular 
tachycardia; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Ear pain; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (eye hemorrhage); Eye disorders - 
Other (eye swelling); Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Dyspepsia; Dysphagia; 
Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (mouth ulceration); Gastrointestinal disorders - Other (oral 
mucosal blistering); Gastrointestinal hemorrhage4; Gastrointestinal obstruction5; Gastrointestinal 
pain; Hemorrhoids; Ileus; Oral pain; Periodontal disease; Proctitis; Rectal pain; Toothache; 
Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Gait 
disturbance; Infusion related reaction; Injection site reaction; Localized edema; Malaise; Multi-
organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other 
(cholethiasis); Hepatobiliary disorders - Other (hepatomegaly) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture; Injury, 
poisoning and procedural complications - Other (catheter site pain); Injury, poisoning and 
procedural complications - Other (hernia); Injury, poisoning and procedural complications - 
Other (procedural pain); Injury, poisoning and procedural complications - Other (stent occlusion) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase 
increased; CPK increased; Cardiac troponin I increased; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; Fibrinogen decreased; GGT increased; INR 
increased; Investigations - Other (blood bicarbonate decreased); Investigations - Other (blood 
bicarbonate increased); Investigations - Other (blood bilrubin decreased); Investigations - Other 
(blood chloride decreased); Investigations - Other (blood chloride increased); Investigations - 

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Other (blood lactate dehydrogenase increased); Investigations - Other (blood urea increased); 
Investigations - Other (elevated ammonia); Investigations - Other (eosinophilia); Investigations - 
Other (platelet count increase); Investigations - Other (protein total decreased); Lipase 
increased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperkalemia; Hypermagnesemia; Hypoglycemia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (hyperphosphatemia); Metabolism and nutrition disorders - Other 
(malnutrition) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Chest wall pain; 
Generalized muscle weakness; Musculoskeletal and connective tissue disorder - Other (muscle 
spasms); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Leukemia secondary to oncology chemotherapy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Aphonia; Ataxia; Cognitive disturbance; 
Dysesthesia; Dysgeusia; Ischemia cerebrovascular; Lethargy; Paresthesia; Peripheral sensory 
neuropathy; Seizure; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Hematuria; 
Urinary fistula; Urinary frequency; Urinary retention; Urinary tract pain; Urinary urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Uterine hemorrhage; 
Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Allergic rhinitis; Atelectasis; Bronchospasm; Hypoxia; Nasal congestion; Pleural 
effusion; Pneumonitis; Postnasal drip; Pulmonary edema; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (breath sounds abnormal/decreased); Respiratory, 
thoracic and mediastinal disorders - Other (crepitations); Respiratory, thoracic and mediastinal 
disorders - Other (pulmonary congestion); Sinus disorder; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Erythema 
multiforme; Hyperhidrosis; Skin and subcutaneous tissue disorders - Other (hyperkeratosis); 
Skin and subcutaneous tissue disorders - Other (Sweet's Syndrome); Skin hyperpigmentation; 
Skin hypopigmentation; Skin ulceration; Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension ;Thromboembolic event; 
Vascular disorders - Other (aortic anyeurism); Vascular disorders - Other (catheter site 
hemorrhage); Vascular disorders - Other (circulatory collapse); Vascular disorders - Other 
(hemorrhage); Vascular disorders - Other (splenic infarct vs hemorrhage/rupture); Vascular 
disorders - Other (veno-occlusive disease); Vasculitis 
NOTE: Decitabine (5-aza-2'-deoxycytidine) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent 
 

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5.4 
Dose Modifications 
All toxicities should be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). . 
5.4.1 
Dose Modification for Cytarabine – Arm C Consolidation 
For patients ≥ 70 years of age the cytarabine dose is identical but the 
patient will receive one dose daily for a total of 6 doses (days 1-6). 
Patients should have a daily creatinine and total bilirubin. The dose of 
cytarabine will be adjusted. The dose of cytarabine will be adjusted if 
there is a change in the serum creatinine or bilirubin during that cycle 
after the start of therapy. 
Serum Creatinine (mg/dL) 
Serum Total Bilirubin 
Dose (mg/m2) 
< 2 
< 3 
1500 
> 2 
(or an increase of > 0.5 mg/dL 
 from baseline) 
< 3 
750 
> 3 
< 3 
500 
Any 
> 3 
500 
Modified from Smith, et al. JCO 15:833 
5.4.2 
Dose Modification for Daunorubicin During Induction Cycle II- Arm A 
Patients who do not achieve aplasia with Cycle I are eligible for a 
second cycle of induction. The total bilirubin should be determined on 
the days of the administration of daunorubicin. The dose of 
daunorubicin is adjusted according to the following table. 
If Total Bilirubin 
Administer % of Daunorubicin Dose 
< 1.5 mg/dL 
100% 
1.5 to 3 mg/dL 
75% 
3.1 to 5 mg/dL 
50% 
> 5 mg/dL 
No Daunorubicin 
Reference: The Chemotherapy Source Book, second edition. Perry, M. 
Publisher: Williams and Wilkins 
5.4.3 
Decitabine Arm F Maintenance 
There are no planned dose reductions in decitabine. Patients unable 
to receive treatment on schedule (i.e. planned q4 weeks, but delays 
up to 4 weeks allowed) due to cytopenias or persistent side effects will 
discontinue decitabine and subsequently be observed per the 
'observation ' group (Arm E), although they will be analyzed on an 
'intention to treat' basis as having been assigned to Arm F. 
5.4.4 
Clofarabine Dose Modifications – Arm B Induction and Re-induction, 
and Arm D 
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5.4.4.1 
Hematologic (Blood/Bone Marrow) Toxicity 
Patients who achieve a CR or CRi should receive the 
consolidation cycle no sooner than 28 days from Day 1 of 
the previous induction or re-induction cycle, provided their 
peripheral blood counts have recovered (ANC ≥ 1.0 × 109/l 
and platelet count ≥ 100 × 109/l (or ≥ 50 x 109/l if previously 
achieved CRi).  If the peripheral count recovery is delayed 
beyond Day 42 from Day 1 of the prior induction or 
re-induction cycle and the delay is presumed to be 
secondary to the induction or re-induction therapy, the 
clofarabine dose for the consolidation cycle, if 
administered, must be reduced by 25% for all subsequent 
doses. 
5.4.4.2 
Non-Hematologic Toxicity 
Dose Modifications During the Treatment Period 
(Intracycle Dose Modifications) 
Patients who experience a grade 3 or greater drug-related 
non-hematologic toxicity or asymptomatic grade 2 serum 
creatinine or serum total bilirubin during clofarabine 
administration should have clofarabine withheld until 
recovery to baseline or grade 1 before resuming treatment.  
Dose omissions due to the above noted toxicities that 
occur during the drug administration period will only be 
made up if the toxicity resolves such that a dose delay 
does not exceed 48 hours.  If study drug administration 
resumes, proceed at 25% dose reduction for all 
subsequent doses and cycles of clofarabine. Only one 
interruption during study drug(s) administration is allowed 
per treatment cycle.  Excluded from this rule are:  
• 
Grade 3 or greater anorexia, rash/desquamation, 
infection, transient isolated elevations in hepatic 
transaminases (AST and ALT) or alkaline phosphatase 
do not require withholding or reducing clofarabine. 
• 
Grade 3 or greater nausea, vomiting, diarrhea, or 
mucositis may require that the clofarabine be withheld.  
This decision should be guided by the investigator 
based on best clinical judgment. If clofarabine is  being 
held it can be restarted if, for these toxicities, recovery 
to grade 2 or less occurs within 48 hours (with or 
without supportive care) These toxicities do not require 
dose reduction of clofarabine. 
5.4.5 
Dose Modifications for Subsequent Cycles of Study Treatment  
Clofarabine doses for re-induction and consolidation cycles will be 
modified (delayed/reduced) or discontinued for non-hematologic 
toxicity according to the criteria listed in the table: 
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Criteria for Treatment Clofarabine Delays, Dose Reductions, and Discontinuations in 
Patients Experiencing Non-Hematologic Toxicities for Re-Induction and Consolidation 
Cycles 
Non-Hematologic Toxicities 
Description of Event 
Treatment Delays, Dose Reductions, or Discontinuations 
Infection any grade 
Re-induction Cycle: No delay is required. 
Consolidation Cycle: If a patient develops a clinically significant infection of 
any grade, consideration should be given to delaying the consolidation 
cycle until the infection is clinically controlled (defined as improvement of 
signs/symptoms related to the infection with appropriate antibiotics or other 
treatment)—however, the judgment ultimately rests with the investigator. 
Treatment (ie, subsequent cycle) may then resume without dose reduction.  
At the discretion of the investigator, prophylactic therapy to prevent 
recurrence of infection may be instituted as clinically indicated. 
Drug-related non-
infectious event(s): 
Grade 2 toxicity 
Re-induction and Consolidation Cycles: Initiation of a treatment cycle will 
be delayed until returned to baseline or ≤ Grade 1.  If this has not occurred 
by Day 56 from Day 1 of the treatment cycle, further study drug treatment 
cannot be administered.  No dose reduction is required for subsequent 
cycles after recovery of Grade 2 toxicities to ≤ Grade 1. 
Drug-related non-
infectious event(s): ≥ 
Grade 2 neurologic 
toxicity 
Re-induction and Consolidation Cycles: The patient’s study drug doses are 
to be re-evaluated in consultation with the PI, and may be reduced or 
discontinued according to the parameters below defined for a drug-related 
Grade 2 or higher toxicity.  
Drug-related non-
infectious,  
non-neurologic 
event(s):  Grade 3 
toxicity 
Re-induction and Consolidation Cycles: 
If toxicity recovers to baseline or Grade 1 by Day 56 from Day 1 of the 
treatment cycle, study treatment is to be restarted at a 25% dose reduction 
with no alteration in schedule for clofarabine for all subsequent cycles.  If 
treatment has not resumed by Day 56 from Day 1 of the treatment cycle, 
further clofarabine cannot be administered. 
Drug-related non-
infectious event: 
Grade 4 toxicity 
Re-induction and Consolidation Cycles: The patient must not receive 
additional clofarabine except under extraordinary circumstances and only 
after consultation with the PI.  If study treatment is restarted, toxicity must 
recover to baseline or Grade 1 by Day 56 from Day 1 of the treatment 
cycle, and either a 25% or 50% dose reduction with no alteration in 
schedule for clofarabine should be instituted for all subsequent cycles. 
5.5 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
5.5.1 
Cytarabine Consolidation- Arm C- Cycles 1 and 2 
Patients must receive corticosteroid eye drops, 2 drops in each eye at 
least 4 times a day starting on day 1 before the first dose of 
cytarabine and continuing until at least 48 hours after completion of 
cytarabine, i.e. for a minimum of 8 days. 
Cytarabine 
Age 60-69 1500 mg/m² as a one hour intravenous 
infusion every 12 hours for a total of 12 doses 
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Age ≥ 70 1500 mg/m2 as a one hour intravenous 
infusion every 24 hours for a total of 6 doses (days 
1-6) times 2 cycles. 
Corticosteroid 
2 drops in each eye, 4 times a day for 10 days. The 
eye drops should be applied within one hour of the 
administration of high dose cytarabine.  
GM-CSF 
250 mcg/m²/day by intravenous or subcutaneous 
injection starting one day after the last dose of 
cytarabine through recovery of absolute neutrophil 
count (ANC) ≥ 500 cells/mcL is sustained for 3 
consecutive days. The dose may be rounded to the 
nearest vial size. 
OR 
G-CSF 
5 mcg/kg/day by either intravenous or 
subcutaneous injection starting one day after the 
last dose of cytarabine, through recovery of 
absolute neutrophil count (ANC) ≥ 500 cells/mcL is 
sustained for 3 consecutive days. The dose may be 
rounded to the nearest vial size. 
OR 
Pegfilgrastim 
6mg SC on day 7 (1 day after completing the last 
dose of cytarabine). 
5.5.2 
Supportive Care with GM-CSF, G-CSF & Prophylactic Antibiotics for 
Restaging Bone Marrow 
Patients who achieve an aplastic BM following the 1st or 2nd course of 
induction therapy should receive cytokine support with GM-CSF 
(LeukineTM) at a dose of 
250 mcg/m2/day subcutaneously every day until calculated ANC ≥ 
5000/mcL or discharge from hospital. Alternatively, patients may 
receive G-CSF at a dose of 5 mcg/kg (rounded to the nearest vial 
size) at the discretion of the treating physician.  
Patients should receive an oral Quinolone, Fluconazole, and Acyclovir 
to prevent infection once the ANC drops below 1000 beginning sooner 
than day 7 of induction. 
5.5.3 
Arm D Clofarabine Consolidation 
Patients should receive an oral Quinolone, Fluconazole or equivalent 
based on institutional standard, and Acyclovir to prevent infection 
once the ANC drops below 1000 mm3. 
GM-CSF 
250 mcg/m²/day by intravenous or subcutaneous 
injection starting one day after the last dose of 
clofarabine through recovery of absolute neutrophil 
count (ANC) > 500 cells/mcL is sustained for 3 
consecutive days. The dose may be rounded to the 
nearest vial size. 
Rev. 2/12 
Rev. 2/12 
Rev. 2/12 
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OR 
G-CSF 
5 mcg/kg/day by either intravenous or 
subcutaneous injection starting one day after the 
last dose of clofarabine, through recovery of 
absolute neutrophil count (ANC) > 500 cells/mcL is 
sustained for 3 consecutive days. The dose may be 
rounded to the nearest vial size. 
OR 
Pegfilgrastim 
6 mg SC on day 6 (1 day after completing the last 
dose of clofarabine). 
5.5.4 
Arm G Supportive Care for Allogeneic Transplant  
NOTE: 
Patients must be premedicated with acetaminophen 650 
mg P0, diphenhydramine 25-50 mg P0/IV prior to 
thymoglobulin, and methylprednisone 1 mg/kg at initiation 
and midway through thymoglobulin administration each 
day. 
Patients will be evaluated on an outpatient basis for evidence of 
toxicity, in particular graft vs. host disease (GVHD) and cytopenias. 
GVHD Prophylaxis 
Tacrolimus dosing is to be based on target serum levels of 5-10 
ng/mL. Serum levels are not to exceed 15 ng/mL. Tacrolimus is to 
be initiated on Day -2 with a suggested starting dose of 0.03 mg/kg P0 
BID (Institutional standard allowed if equivalent). Begin tapering 
between Day +90 to +120 in the absence of GVHD as tolerated with a 
goal of stopping by Day +150 to + 180. The rate of taper will be 
adjusted for the presence of signs and symptoms of GVHD. In 
patients who are unable to take oral tacrolimus, the intravenous dose 
is generally 1/4 to 1/3 of the oral dose. 
Please note that concurrent use of agents such as itraconazole, 
voriconazole or fluconazole (at doses > 200 mg) may inhibit the 
metabolism of tacrolimus. and thus increase tacrolimus levels. Hence, 
it is recommended to check tacrolimus levels twice weekly when 
these agents are initiated concurrently. In addition, the initial dose of 
tacrolimus may be decreased according to institutional policies. 
Methotrexate 5 mg/m2/day IV on Days +1, +3, +6 and Day +11. 
Hydrate intravenously and induce diuresis. Methotrexate will be held if 
the serum creatinine > 3.0 mg/dL. If the creatinine level is > 1.5 
mg/dL, then administer leucovorin 10 mg IV or P0 q6 hours for four 
doses beginning 24 hours after methotrexate. 
Rabbit antithymocyte globulin (Thymoglobulin) at 2.5 mg/kg/day IV 
over 6 hours x 3 doses on Days -4 through -2. Patients must be 
premedicated with acetaminophen 650 mg P0, diphenhydramine 25-
50 mg P0/IV, and methylprednisone 1 mg/kg at initiation and midway 
through thymoglobulin administration each day. After the first dose, 
subsequent administration of antithymocyte globulin may be infused 
over 4 hours. 
Rev. 2/13 
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Patients with progressive disease will have met the primary study 
endpoint and will be removed from protocol therapy. Such patients 
may receive additional treatment at the discretion of the investigator, 
although patients will be followed for response to further therapy, 
survival and new primary malignancies. 
Mucosal Evaluation and Care: Mucositis is expected to be very mild 
with this chemotherapy regimen. Stomatitis and esophagitis due to 
herpes virus may be confused with drug-induced mucositis and viral 
cultures should be obtained frequently. Patients with a history of 
herpes simplex infection or seropositivity will receive acyclovir 200-
400 mg PO TID Days -3 through Day + 100. Valacyclovir 500 mg P0 
QD may be used instead of acyclovir. Prophylaxis may be extended 
beyond Day +100 at the discretion of the treating physician. 
Candida Prophylaxis: Fluconazole or itraconazole 200-400 mg P0 
daily or voriconazole 200-300 mg P0 twice daily (or 3-6 mg/kg IV q12 
hours) on Days -2 through +100 per institutional standards. Low dose 
amphotericin B (10-20 mg/day) IV also may be used. 
Pneumocystis Pneumonia (PCP) Prophylaxis: In an attempt to 
prevent PCP, cotrimoxazole (Bactrim®) will be administered to all 
patients as one double strength tablet BID on 2 days weekly, 
beginning on Day +28 through Day + 100. If, at this time. CD4 
lymphocytes are < 200/µL, then prophylaxis should be continued until 
CD4 lymphocytes are ≥ 200/µL. Patients allergic to cotrimoxazole 
should receive dapsone or inhaled pentamidine instead. In patients 
who develop chronic GVHD, PCP prophylaxis should be extended at 
the discretion of the physician. 
CMV Infections: No routine prophylaxis for CMV will be initiated. 
Surveillance for CMV using CMV Ag (e.g.. immunofluorescence) or 
CMV PCR (or Digene Hybrid Capture® assay or equivalent) is 
required weekly beginning on Day +7 through Day +100, and then 
every other week through Day + 180. Patients with positive CMV PCR 
or positive CMV Ag’emia should receive treatment with ganciclovir 5 
mg/kg IV BID x 14 days (or appropriate doses of valganciclovir or 
foscarnet). 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
Tacrolimus 
Tacrolimus may cause hypertension, renal insufficiency (usually 
reversible), seizures, liver function abnormalities, hemolytic uremic 
syndrome (rare), hyperglycemia, and hypomagnesemia. 
Tacrolimus dose adjustments will be made to achieve target trough 
levels of 5-10 ng/mL. Serum levels are not to exceed 15 ng/mL. 
Methotrexate 
Methotrexate may cause mucositis and cytopenias. In the presence of 
worsening renal insufficiency or the development of effusions or 
ascites, the addition of leucovorin is permitted at the discretion of the 
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physician. If the creatinine is > 1.5 mg/dL, leucovorin 10 mg IV or 
P0 may be given every 6 hours for four doses beginning 24 
hours after methotrexate. Methotrexate will not be given if the 
creatinine is > 3.0 mg/dL. Individual doses of methotrexate will 
not be altered. 
Graft Versus Host Disease 
It is expected that some patients will develop mild-moderate graft 
versus host disease. It is precisely this effect that may be associated 
with an antineoplastic outcome. 
The diagnosis of acute graft versus host disease rests on clinical 
presentation (rash, diarrhea, liver function abnormalities) and 
histopathologic evidence via skin, gastrointestinal, or liver biopsy. 
Chronic GVHD is associated with rash, sicca syndrome, hepatitis. In 
addition grade 2-4 GVHD or extensive chronic GVHD will be treated 
with methylprednisone 2 mg/kg/day and subsequently tapered 
according to institutional standard. The ultimate treatment approach, 
i.e., the addition of cyclosporine, tapering of immunosuppressive 
medications, etc., will be left to the discretion of the transplant or 
hematology/oncology physician according to institutional standard 
allogeneic guidelines for the management of these conditions. The 
following tables should be used for reporting these toxicities. 
Clinical Grading of Acute GVHD 
Organ 
Grade 
Skin Changes 
Bilirubin 
(mg/dL) 
Gut Changes (diarrhea 
[ml/day]) 
0 
No rash 
< 2.0 
None 
1 
Erythematous macular rash over 
< 25% body surface 
2 - <3.0 
> 500 - ≤ 1000 
2 
Over 25-50% of Body surface 
≥ 3 - <6 
> 1000 - ≤ 1500 
3 
≥ 50% body surface 
≥ 6 - < 15 
> 1500 
4 
Bullae, exfoliation  
Ulcerative dermatitis 
≥ 15 
Severe abdominal pain with 
or without ileus 
 
Organ Grade (see table above) 
Skin Changes 
Hepatic 
Gut Changes 
Overall Grade 
0 
1 or 2 
1, 2, 3 
2 or 3 
0 
0 
1 
2 or 3 
0 
0 
1 
2 or 3 
0 
1 
2 
3 
Patients with Grade 4 toxicity in any organ system are considered overall 
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Clinical Grading of Chronic GVHD 
Limited Chronic GVHD: 
1. Localized skin involvement, 
and/or 
2. Hepatic dysfunction due to chronic GVHD. 
Extensive Chronic GVHD: 
1. Generalized skin involvement, 
or 
2. Localized skin involvement and/or hepatic dysfunction due to 
chronic GVHD 
Plus 
3a. Liver histology showing chronic aggressive hepatitis. bridging 
necrosis, or cirrhosis, or 
3b. Involvement of eye (Schirmer’s test with less than 5 mm wetting), 
or 
3c. Involvement of minor salivary glands or oral mucosa 
demonstrated on labial biopsy, or 
3d. Involvement of any other target organ. 
Instructions for Dosing by Corrected Body Weight (Arm G) 
High-dose chemotherapy can adversely impact the outcomes of 
obese patients when dosing is performed according to actual body 
weight. Therefore, all therapy (including methotrexate and 
tacrolimus) and growth factor drug doses will be determined 
using a corrected body weight formula. The corrected body 
weight is calculated based on the following formula with all 
weights in kg: 
Corrected Weight = (0.25)(actual weight - ideal weight)+(ideal 
weight) 
Thus, for patients whose actual weight is > 150% of ideal, their 
“actual” weight will be capped at 150% of ideal (i.e., their 
corrected weight will be 112.5% of ideal). For patients whose 
actual weight is less than ideal, use their actual weight as the 
corrected weight. 
5.5.4.1 
Colony Stimulating Factors 
All patients should receive G-CSF 5 mcg/kg SC daily from 
day 12 until achievement of an ANC of > 1.5 x 109/lt. 
5.5.4.2 
Antimicrobial Supportive Care 
Antibacterial, antifungal and antiviral prophylaxis and 
treatment should follow conventional guidelines or 
institutional protocols. Patients should receive an oral 
Quinolone, Fluconozole, and Acyclovir to prevent infection 
once the ANC drops below 1000 mm3. 
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Management of immunosuppression and donor 
lymphocyte infusions: Therapy will be directed to promote 
engraftment, and minimize GVHD without undue 
immunosuppression. 
5.5.4.3 
Treatment of Acute GVHD 
Patients who develop Grade 2 or greater acute GVHD will 
receive methylprednisolone or prednisone at least 2 mg/kg 
daily and subsequently tapered according to institutional 
standard. Other immunosuppression may be administered 
as needed. 
5.5.4.4 
Immunosuppression 
Patients with < 5% engraftment by day 35 may have 
immunosuppression tapered early in accordance with 
institutional standards. 
5.5.4.5 
Treatment of Residual Disease 
Patients with evidence of residual disease as defined by 
clinical, radiological, cytogenetic or molecular techniques 
may have immunosuppression tapered rapidly and may 
subsequently receive treatment with 106 to 108 CD3+ 
donor lymphocyte cells/kg (“donor lymphocyte infusion”) as 
often as every 6-12 weeks for up to 3 courses at the 
discretion of the treating physician and in accordance with 
institutional standards. 
If a patient experiences a creatinine > 3, Tacrolimus will be 
decreased whenever possible.  If in the judgment of the 
primary investigator Tacrolimus cannot be maintained at 
an adequate level then other immunosuppression should 
be added. 
5.5.4.5.1 
GVHD Prophylaxis 
Standardizing GVHD prophylaxis regimen 
will be utilized comprising ATG, Tacrolimus, 
and methotrexate. See Section 5.5. 
5.5.4.5.2 
Tacrolimus Administration 
Tacrolimus will be started 2 days before the 
marrow infusion at a dose of 0.03 
mg/kg/day intravenously infused 
continuously over a period of 24 hours 
(Institutional standard allowed if equivalent). 
IV tacrolimus can be discontinued when 
patient starts to eat and PO tacrolimus 
substituted at a dose four times the IV dose 
(0.12 mg/kg) in two divided doses.  Monitor 
blood concentrations to keep in therapeutic 
range per institutional guidelines. Unless 
toxicity is encountered, tacrolimus can be 
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continued at the same dose until day 100, 
after which the drug can be tapered and 
discontinued on day 180 after grafting. 
5.5.4.5.3 
Methotrexate Administration 
Methotrexate is to be administered at doses 
of 5 mg/m² I.V. on days 1, 3, 6 and 11. 
5.6 
Duration of Therapy  
Patients will receive protocol therapy unless: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
E2906 Forms Packet. 
• 
Patient withdraws consent. 
5.6.1 
Induction 
The induction phase is considered to include the period of time from 
when a patient is enrolled on trial until one of the following endpoints: 
• 
Death. 
• 
Failure to achieve marrow aplasia after two courses of induction 
therapy or after one course of induction and judged to be unable 
to receive any further therapy. 
• 
Achievement of CR and discharge from the hospital.  Any repeat 
hospitalization within two weeks of induction needs to be reported. 
• 
Patients who fail to experience recovery of peripheral blood 
counts to remission status by day 56 will undergo a repeat marrow 
aspirate and biopsy.  Patients should be followed, at a minimum, 
with weekly CBCs until it is determined that there is recovery of 
peripheral blood counts, refractory AML, or death. 
• 
Patient withdraws consent. 
• 
A toxicity which in the opinion of the investigator precludes further 
protocol therapy.  The patient should be followed until resolution of 
the toxicity. 
5.6.2 
Consolidation Cycle 1 
Consolidation I is considered to include the period of time from when 
a patient receives therapy until one of the following endpoints: 
• 
Death 
• 
Recovery of peripheral blood counts and discharge from the 
hospital.  Any repeat hospitalization within two weeks of discharge 
after Consolidation I needs to be reported 
Patients who do not begin Consolidation II within 60 days of recovery 
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5.6.3 
Consolidation Cycle 2 
The Second Consolidation Cycle is considered to include the period of 
time from when a patient receives therapy until one of the following 
endpoints: 
• 
Death. 
• 
Recovery of peripheral blood counts and discharge from the 
hospital.  Any repeat hospitalization within two weeks of discharge 
after Consolidation II needs to be reported. 
5.7 
Duration of Follow-up  
Surviving patients will be followed for at least 5 years. Following completion of 
consolidation, all patients will have a CBC performed monthly as well as a BM 
biopsy/aspirate performed every 3 months, for the first 24 months (including 
12 months of observation or maintenance decitabine in 2nd randomization), then 
q3 months for the next 2 years, then q6 months. Following 5 years, patients will 
have a CBC performed annually and followed for survival. 
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until progression, even if non-protocol therapy 
is initiated, and for survival for 5 years from the date of registration. All patients 
must also be followed through completion of all protocol therapy.
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6. 
Measurement of Effect 
6.1 
Complete Remission (CR)  
Requires that all of the following be present: 
6.1.1 
Peripheral Blood Counts  
6.1.1.1 
Neutrophil count > 1.0 x 109 /L. 
6.1.1.2 
Platelet count ≥ 100 x 109 /L. 
6.1.1.3 
Reduced hemoglobin concentration or hematocrit has no 
bearing on remission status. 
6.1.1.4 
Leukemic blasts must not be present in the peripheral 
blood. 
6.1.2 
Bone Marrow Aspirate and Biopsy  
6.1.2.1 
Cellularity of bone marrow biopsy must be > 20% with 
maturation of all cell lines. 
6.1.2.2 
< 5% blasts by morphologic review. 
6.1.2.3 
Auer rods must not be detectable. 
6.1.3 
Extramedullary leukemia, such as CNS or soft tissue involvement, 
must not be present. 
6.2 
Complete Remission incomplete (CRi) 
All the same response criteria in peripheral blood and bone marrow as CR with 
the exception that there is incomplete platelet recovery (platelets > 50 x 109/L 
independent of platelet transfusions) over a period of observation without 
evidence of ongoing platelet recovery and no sooner than day 35 after the 
preceding cycle of treatment. 
6.2.1 
Patients who achieve criteria for CR or CRi and who have recovered 
from the effects of therapy but who have < 20% cellularity in BM will 
be deemed a "Hypocellular CR/CRi" and will be allowed to continue 
protocol therapy at the discretion of the Investigator and after 
discussion with the Study Chair as long as they meet other eligibility 
criteria for Step 2 
6.3 
Partial Remission (PR)  
6.3.1 
Requires that all of the criteria for complete remission be satisfied 
except that the bone marrow may contain > 5% blasts but < 25% 
blasts. 
6.3.2 
If all other criteria for CR are met, then a value of ≤5% blasts with 
Auer rods or abnormal morphology is considered a partial remission. 
6.4 
Relapse  
Relapse following complete remission is defined as: 
6.4.1 
Peripheral Blood Counts  
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6.4.1.1 
Reappearance of blasts in the blood. 
6.4.2 
Bone Marrow Aspirate and Biopsy  
6.4.2.1 
Presence of > 5% blasts, not attributable to another cause 
(e.g., bone marrow regeneration). 
6.4.2.2 
If there are no circulating blasts and the bone marrow 
contains 5% to 20% blasts, then a repeat bone marrow 
performed ≥ 1 week later documenting more than 5% 
blasts is necessary to meet the criteria for relapse. 
6.5 
Leukemia Free State 
6.5.1 
Peripheral Blood Counts 
6.5.1.1 
No circulating blasts in peripheral blood by morphologic 
review. 
6.5.2 
Bone Marrow Aspirate & Biopsy 
6.5.2.1 
< 5% blasts, without clustering of blasts, and without Auer 
rods by morphologic review. 
6.5.3 
Flow Cytometry of BM Aspirate 
6.5.3.1 
If one or more unique leukemia-associated 
immunophenotypes (LAIP) were identified at diagnosis, 
minimal residual disease (MRD) levels will be analyzed by 
multiparameter flow cytometry. 
6.5.3.2 
Immunologic MRD must be below the level of detection  
(< 0.001) to qualify for “Leukemia-Free State”. 
6.5.3.3 
Any detectable immunologic MRD levels will be quantified 
and retrospectively correlated with relapse-free and overall 
survival. 
6.5.4 
Extramedullary leukemia must not be present. 
6.5.5 
If indeterminant, the BM Aspirate & biopsy should be repeated 1 week 
later. 
6.6 
Quality of Life Measurement 
6.6.1 
Assessment Battery 
Patient reported outcomes measuring health related quality of life, 
physical and functional well-being, and fatigue are important 
components of a clinical trial. As the population of interest is elderly, it 
is also appropriate to perform a comprehensive geriatric assessment. 
Moreover, as the leukemia experience results in unique issues and 
concerns for patients, it is useful to choose an instrument that 
captures these unique issues. 
6.6.2 
Health-related Quality of Life  
QOL will be assessed using the Functional Assessment of Cancer 
Therapy – Leukemia. This instrument combines the General version 
of the Functional Assessment of Cancer Therapy (FACT-G) with a 
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leukemia-specific subscale [100]. The FACT-G is intended to be a 
self-administered questionnaire that assesses four QOL domains: 
physical, social/family, emotional, and functional well being [101]. The 
FACT has been tested for reliability and validity. Test-retest 
correlation coefficients ranged from .82 (emotional well-being) to .88 
(functional well-being) and .92 (total score) [101].  Convergent and 
discriminant validity were evaluated as well as construct validity.  The 
FACT has good reliability and validity data, and has been shown to 
discriminate patients based on their stage of disease and 
performance rating as well as demonstrated sensitivity in detecting 
changes in QOL over time. 
For this study, the Leukemia subscale will also be added to the FACT-
G [100]. Comprised of 17 items, this subscale examines issues and 
concerns typically experienced by the leukemia patient population, 
such as “I am bothered by fevers; I worry about getting infections; and 
I feel isolated from others because of my illness or treatment.” The 
Leukemia subscale is scored in the same manner as the FACT-G, so 
that higher scores reflect greater well-being; scores range from 0 – 
68. Internal consistency is good (Cronbach’s alpha 0.86-0.88). The 
Leukemia subscale was also successful in discriminating patients 
based on ECOG Performance status ratings, including the ability to 
detect changes in performance status over time. 
The FACT Fatigue Scale has been developed by Cella and 
colleagues to assess the impact of fatigue on the multiple dimensions 
of QOL and will provide additional important QOL data in these 
patients [102]. The FACT Fatigue scale has been tested for reliability 
and validity with good results. Internal consistency was strong (alpha 
coefficient = .93-.95); convergent and discriminant validity were 
demonstrated by a strong positive relationship with other measures of 
fatigue and a strong negative relationship with vigor. 
6.6.3 
Comprehensive Geriatric Assessment  
The abbreviated Comprehensive Geriatric Assessment (aCGA) is a 
brief, 15-item instrument developed from instruments used in the 
Comprehensive Geriatric Assessment: [103].  Specific items taken 
from known valid and widely used instruments:  the Geriatric 
Depression Scale, the Activities of Daily Living, Instrumental Activities 
of Daily Living, and Mini-mental Status Examination; thus functional, 
emotional, and cognitive domains are represented.  Specific item 
selection was based on highest item-to-total correlations in a 
retrospective review of 500 elderly cancer patients who had a 
Comprehensive Geriatric Assessment performed.  Cronbach’s α was 
0.70-0.93.  The aCGA is designed to function as a screening tool for 
use in the outpatient setting; patients who test positive should have 
more comprehensive testing [104].  Feasibility within the context of a 
clinical trial is high and can better capture the functionality of this 
patient population beyond the inclusion and exclusion criteria for this 
clinical trial.  Moreover, it takes only 5 minutes to complete.  For the 
proposed study, the aCGA will be augmented with the following 

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components:  a brief nutritional assessment, social support 
assessment, co-morbidity, and sexual function.   
6.6.4 
Nutritional Status  
Body Mass Index, a well-known and clinically used tool will be used to 
assess nutritional status for this trial.  In a study of 214 elderly adults 
living in a community setting, a low BMI (< 22 kg/m2) was associated 
with dependency in ADLs and decreased survival at one year [105].   
6.6.5 
Unintentional Weight Loss 
The percentage of unintentional weight loss is well documented as a 
prognostic factor in the context of chemotherapy treatment.  Such 
weight loss occurring during the six months proceeding chemotherapy 
treatment was associated with a lower response rate to treatment, 
decreased performance status, and poorer survival [106,107].   
6.6.6 
Social Support 
Medical Outcomes Study Social Support Survey:  
Emotional/Information and Tangible subscales 
These subscales from the MOS Social Support Survey [108] assess 
the expression of empathetic understanding and positive affect; the 
offering of information, advice, feedback, or guidance 
(emotional/information) and behavioral assistance or access to 
material aid (tangible). Twelve items, they are two of four subscales 
from the larger instrument. They have excellent internal consistency 
(Cronbach alpha ? 0.90); convergent validity was also demonstrated.  
All but one item uses a 5-point Likert scale. These scales were 
chosen as they are brief, relevant, and moreover, are part of the 
comprehensive cancer-specific geriatric assessment battery 
developed by Hurria and colleagues [109]. 
6.6.7 
Co-Morbidity 
The Comorbitiy Questionnaire [110].  This instrument is a modification 
of the well-established Charlson Comorbidity Index (CCI) [111].  
Designed to be a self-administered questionnaire; it identifies several 
medical conditions commonly encountered in the elderly patient 
population.  It is scored like the CCI, which reflects not only the 
number of conditions, but the seriousness of each.  Test-retest 
reliability was 0.91 (and 0.92 for the CCI [110].  The scale correlated 
significantly with health professionals’ ratings via the CCI (Spearman 
correlation = 0.70) with item-specific agreement 90 – 100%, excluding 
the presence of tumor [110].  This instrument has not been 
extensively used in the elderly, nor in the oncology patient population, 
but the original Charlson Comorbidity Index has [112-114].  The CCI 
has demonstrated predictive value for evaluating tolerance for cancer 
treatment [112,113] an, in some studies, cancer survival [114].  For 
this study, the instrument will be modified to include some additional 
commonly occurring conditions (e.g. back pain, osteoporosis, 
depression, anemia) as well as some that commonly cause 
complications with AML management (chronic sinus infection, poor 

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dentition).  The questionnaire will be further modified by asking the 
respondent to identify the number of medications taken, both 
prescribed and over-the-counter.   
6.6.8 
Sexual Function 
Clinically, it has been observed that elderly AML patients who remain 
sexually active may better tolerate the rigor associated with induction 
therapy [115]. A literature review did not provide any data to support 
or refute this observation.  Therefore, two additional questions related 
to sexual activity will be added to the Geriatric Assessment Battery 
but scored separately to address this important question.   
6.7 
Timing of QOL Assessment 
The Geriatric Assessment Battery will be administered at the time of 
randomization for a baseline assessment. This battery includes the aCGA, Body 
Mass Index, Unintentional Weight Loss, MOS Social Support Survey 
(Emotional/Information and Tangible Subscales only), Comorbidity Questionnaire 
and Sexual Function. 
The FACT-Leukemia and FACT –Fatigue instruments will be administered at the 
following time points: 
T1: Baseline before induction. (Beginning Step 1) 
T2: At day 14 (+/- 2 days) following 1st induction. (Nadir of Step 1) 
T3: Following the outcome restaging BM (day 35-56) prior to 
consolidation therapy. (End of Step 1, beginning Step 2) 
T4: At the beginning of randomization to Arm E or F. (Beginning Step 3) 
T5: At the end of the observation/maintenance decitabine (i.e. after 12 
months) after randomization to Arm E or F). (End of Step 3) 
NOTE: 
QOL is to be assessed at any time the patient is removed from or 
elects to withdraw from the study 
For those patients who are eligible and elect to go on to transplant, the FACT-
Leukemia and FACT Fatigue instruments will be administered at the following 
time points: 
T1tx: At the beginning of the conditioning regimen 
T2tx: 100 days (± 14 days) post transplant 
6.8 
Timing of “ALESE” Questionnaire (see Appendix V) 
The ALESE questionnaire will be administered at patient registration, or during 
the first week of induction therapy, whenever possible. 
Administration of the ALESE questionnaire at later dates is permissible in 
surviving patients. 
NOTE: 
Return instructions for sites are in Appendix V on page 34. 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays used to assess all measurable or non-measurable 
sites of disease must be done within 4 weeks prior to 
randomization/registration. 
2. Prestudy CBC (with differential and platelet count) should be done ≤ 4 weeks 
before randomization/ registration.  
3. All required prestudy chemistries, as outlined in Section 1.6, should be done  
≤ 4 weeks before randomization/registration – unless specifically required on 
Day 1 as per protocol.  
4. The diagnostic bone marrow aspirate must be obtained within two weeks 
prior to randomization. 
5. The required prestudy chemistries, as enumerated in Section 3, should be 
obtained within forty-eight hours prior to randomization. Please note that the 
dose of daunorubicin is adjusted, for cycle 2 induction only, based upon the 
total bilirubin as indicated in Section 5.4.2. 
6. Prestudy CBC should be repeated ≤ 48 hours prior to randomization. 
7. The cardiac ejection fraction will be determined prior to induction 
chemotherapy, and prior to re-induction (if required). The cardiac ejection 
fractions should be determined by either MUGA or echocardiography 
throughout the study. 
 
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Induction &  
Re-Induction 
Consolidation 
I and II 
Maintenance 
Observation vs. 
Decitabine 
Follow-Up 
 
Prior 
Daily 
Weekly 
Prior 
Daily 
Monthly 
Monthly 
Quarterly 
Annually 
History and Physical 
X 
X1 
 
X1 
X1 
X2 
X12 
 
 
Weight, Height (baseline) 
X 
X1 
 
X1 
X1 
 
 
 
 
CBC 
X1 
X1 
 
X1 
X1 
X2 
X16 
 
 
HLA Typing 
X11 
 
 
 
 
 
 
 
 
Serum Potassium, Calcium, Creatinine, Serum 
Phosphorus, Serum Uric Acid 
 
X10 
 
 
 
 
 
 
 
Serum Creatinine, Uric Acid, Bilirubin, SGPT, (ALT) 
LDH, Alk Phosphatase, SGOT (AST) Mg 
X 
X3 
X3 
X3 
X3 
 
 
 
 
EKG 
X 
 
 
X 
 
 
 
 
 
Bone Marrow Aspirate, Biopsy and Cytogenetics 9,4 
X 
 
X4 
X19 
 
X8 
 
X17 
X13 
Cardiac Ejection Fraction (MUGA/Echocardiogram) 
X5,7 
 
 
X7 
 
X7 
 
 
 
Cerebellar Neuro Checks 
 
 
 
 
X6 
 
 
 
 
QOL14 
X 
X15 
 
 
 
X 
 
 
 
Geriatric Assessment18 
X 
 
 
 
 
 
 
 
 
ALESE Questionnaire 
X20 
 
 
 
 
 
 
 
 
1 
The daily evaluations should be performed until discharge from the hospital.  If the patient is discharged prior to recovery of ANC or platelet 
count the values should be obtained no less than twice weekly until the outcome BM is performed 
2 
It is required that complete blood counts be obtained every 4 weeks for the first twenty-four months after the conclusion of consolidation 
therapy. Complete blood counts should be obtained every three months in the third year.  The frequency in subsequent years is at the 
discretion of the investigator. 
3 
During the administration of daunorubicin or high-dose cytarabine the serum creatinine and total bilirubin are required daily to adjust dose of 
medications.  After the administration of chemotherapy the values must be determined and reported at least weekly or more frequently as 
clinically indicated. 
4 
A bone marrow is required on day 12-14 (+/- 1 day) to assess whether the patient has achieved an aplastic BM and will receive GM-CSF or 
G-CSF or a repeat course of induction.  Subsequent marrows until recovery of peripheral blood counts are at the discretion of the treating 
physician. An outcome BM must be performed no sooner than day 28 and no later than day 56 to determine response to induction therapy at 
the time of recovery of ANC to >1000 & platelets (>100,000) or if the patients is suspected to have residual AML, or if no further recovery is 
expected (e.g. plateau in platelet recovery). 
5 
If the cardiac ejection fraction cannot be obtained due to weekend or holiday then patients may be enrolled provided there are no clinical 
signs or there is no history of significant cardiovascular disease and a measurement of cardiac ejection fraction will be performed within 5 
days of study enrollment. 
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6 
Prior to each dose of cytarabine during consolidation for patients randomized to Arms A and C. 
7 
The Cardiac Ejection Fraction must be measured prior to Induction. For patients on Arm A, a repeat measurement is recommended before 
receiving re-induction (if indicated). Repeat measurement prior to Consolidation Cycle 1 (Arms C & D) is recommended per institutional 
guidelines and as clinically indicated. For patients who proceed to Arm G (Allogeneic stem cell transplantation) a repeat measurement 
of Cardiac Ejection Fraction must be performed after recovery from last cycle of chemotherapy and prior to start of transplant 
conditioning regimen 
8 
Routine bone marrow aspirate and biopsy is required every 3 months during maintenance and observation (Arms E and F) for first 24 
months. 
9 
A repeat bone marrow to confirm the maintenance of a CR prior to Consolidation II is not required provided a complete blood count with 
differential and platelet count remains within the range anticipated during a CR. Bone marrow (or peripheral blood if bone marrow is 
unavailable) should be sent to the institution’s local cytogenetics laboratory for analysis. Please refer to the table in Section 7.3 for the time 
points for the submission of karyotypes for central review. 
10 Monitoring for tumor lysis syndrome at the initiation of induction therapy is strongly suggested at least every 8-12 hours for at least the first 3-
5 days of treatment, and at further intervals at the discretion of the investigator. 
11. HLA -typing (Class I & Class II) should be performed prior to therapy on all patients and on siblings who are eligible donors. The number of 
full siblings with ages and reason for ineligibility (including refusal) must be noted. 
12. Physical only 
13. If clinical or hematological evidence of relapse. 
14. QOL must be presented to all patients that consented to the QOL componentat the following time points: 
• 
Baseline before induction. (Beginning Step 1) 
• 
At day 14 (+/- 2 days) following 1st induction. (Nadir of Step 1) 
• 
Following the outcome restaging BM (day 35-56) prior to consolidation therapy. (End of Step 1, beginning Step 2) 
• 
At the beginning of randomization to Arm E or F. (Beginning of Step 3) 
• 
At the end of the observation/maintenance decitabine (i.e. after 12 months after randomization to Arm E or F). (End of Step 3) 
NOTE: QOL is also to be assessed at the time a patient is removed from or elects to withdraw from the study. 
15. QOL should be done at day 14 nadir and following the outcome restaging BM (day 35-56). These must presented to all patients that 
consented to the QOL component of the protocol. 
16. Monthly after 2nd randomization for 2 years, every 3 months for 2 years, every 6 months for a year and annually afterwards up to five years. 
17. A surveillance BM aspirate and biopsy every 3 months for 2 years beginning at the time of the second randomization, and after that, when 
clinically indicated (e.g., symptoms of relapse or abnormal CBC). 
18. Geriatric Assessment will be measured at Baseline before Induction. 
19. BM required prior to consolidation cycle 1 only. 
20. ALESE: “Acute Leukemia Epidemiology and Survival in ECOG-ACRIN” Questionnaire should be administered early during induction therapy, 
preferably in the first week whenever possible. (See Section 1.6.6, 6.8, and Appendix V). For instructions on returning the questionnaire, 
please refer to Appendix V, page 34. 
Rev. 2/13 
Rev. 2/12 
Rev. 2/13 
Rev. 2/13 
Rev. 2/13 
Rev. 8/13 
12/13 
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7.2 
Arm G Only (Allogeneic Stem Cell Transplantation) 
 
Prior to AlloSCT 
Twice a week to Day +28 
Weekly to Day +100 
Monthly to Day +365 
Restaging* 
Post-treatment Follow-Up** 
Tests & Observation 
 
 
 
 
History & Progress Notes 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
Vital Signs & Weight 
X 
X 
X 
X 
BSA 
X 
 
 
 
ECOG PS 
X 
X 
X 
X 
Toxicity Assessment 
 
X 
X 
X 
QOL1 
 
 
 
 
Lab Studies 
 
 
 
 
CBC, Diff, Plts 
X 
X 
X 
X 
Serum creatinine, BUN 
X 
X 
 
X 
Creat. Clearance & Urinalysis 
X 
 
 
 
Serum Electrolytes 
X 
X 
 
 
AST, Alk Phos, Bilirubin 
X 
X 
 
X 
Total Protein, Albumin 
X 
 
 
 
EKG 
X 
 
 
 
MUGA or Echo 
X 
 
 
 
PFT (Lung Function) 
X 
 
 
 
Hepatitis screen, CMV, HIV, EBV, HSV 
X 
 
 
 
CMV Ag or PCR 
 
A 
 
 
Tacrolimus  
 
D 
 
 
Serologies & HLA Typing (donor & recipient) 
X 
 
 
 
Staging 
 
 
 
 
CXR (PA/Lat) 
X 
 
 
 
BM Asp. & Biopsy 
X 
 
C 
X2 
Chimerism Samples (+/- 7 days) 
B 
B 
B 
B 
* 
Restaging will occur between days +90-100, and +150-180, then q3 months for the 1st year. 
** 
After restaging, at least q6 months for a maximum of 5 years from AlloSCT. 
1.  
QOL will be performed at the following time points: At the beginning of the conditioning regimen and 100 days (+/- 14 days) post 
transplant- TOTAL 2 time points.  
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2. 
Within 1 month after Allo SCT 
A 
Weekly beginning day +7 through day +100, then every other week until day +180. 
B 
Samples to be collected prior to study (from both donor & recipient), and form recipient on days+30, +60, +90, +120, +180, +270, +365, 
and at relapse. 
C 
BM aspirate & biopsy (& cytogenetics & flow cytometry) will be required at days +90-100, and day +150-180, then q3 months for 2 
years, then as clinically indicated. 
D Twice weekly beginning days -2 until day+28, then weekly until day +150 or until drug stopped. 
 

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7.3 
Biological Sample Submissions 
1. 
Peripheral blood, bone marrow, and smears must be submitted for centralized immunophenotyping during pre-
registration for eligibility testing 
2. 
Karyotypes must be submitted at baseline for central review as outlined in Section 10. 
3. 
Follow-up karyotypes, smears, bone marrow, and peripheral blood must be submitted for review. 
4. 
Peripheral blood and buccal swabs/rinse are to be submitted for banking per patient consent. 
NOTE: 
It is required that biological sample submissions be logged into the ECOG-ACRIN Sample Tracking 
System (STS) (see Section 10.6) for purposes of monitoring compliance. 
Rev. 12/13 
 
Pre-
registraion 
Step 1 - 
Randomization 
(Baseline)1 
Time of Outcome 
Following 
Induction (Prior to 
Consolidation)8 
End of 
Consolidation 
(Prior to 2nd 
Randomization -  
Step 3)4 
Relapse 
Send 
To 
 
MANDATORY – Submissions required for central review 
 
Karyotypes 
 
X 
X 
X 
X 
Cyto 
lab2 
 
Bone Marrow/ Peripheral Blood Smears (Wright-Giemsa stained) 
X 
 
X 
X 
X 
LTSL3 
Rev. 2/13 
Bone Marrow Aspirate (heparin, FIRST PULL)6,9 
X 
 
X 
X 
X 
 
Peripheral Blood (heparin, green or EDTA purple top tubes, (4) 
10 mL tubes, 30-40 mL)6 
X 
 
X 
X 
X 
 
From patients who answer “YES” to “I agree to provide additional specimens for research.” 
 
Peripheral Blood (red top tubes, (2) 10 mL tubes, 15-20 mL) 
 
X 
X 
X 
X 
LTSL3 
 
Buccal Rinse (preferred) or Swab7 
 
X 
 
 
 
LTSL3 
1. 
Pre-study bone marrow, peripheral blood, and smears must be submitted for centralized immunophenotyping to determine patient eligibility. 
This testing is mandatory for participation in this study.  
2. 
Submit to the ECOG-ACRIN Cytogenetic laboratory at Mayo Clinic. 
3. 
Submit to the ECOG-ACRIN Leukemia Translational Studies Laboratory (LTSL). Signed E2906 patient consents and HIPAA authorizations 
must be submitted to the LTSL prior to or at time of submission of pre-registration specimens to the LTSL. 
4. 
At time of evaluation response. 
5. 
[Deleted in Addendumn #8] 
6. 
Bone marrow and peripheral blood will also be used for the optional correlative studies per patient consent. 
7. 
Buccal rinse (preferred) or swabs are strongly encouraged to be collected at baseline, but can be collected at any other time during the 
study, if necessary. 
8. 
At time of response assessment or off-study, whichever occurs first.  
Rev. 2/12, 8/13, 7/14 
Rev. 2/13, 12/13 
Rev. 2/13, 
8/13, 12/13 
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9. 
The laboratory will accept any amount as long as it represents a first pull. It is imperative that aspirate from a separate first pull be 
submitted. DO NOT SUBMIT THE SECOND OR THIRD PULL OF ASPIRATE FROM THE SAME ASPIRATION SITE. 

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8. 
Drug Formulation and Procurement 
8.1 
Cytarabine 
8.1.1 
Other Names 
Cytosar-U‚, Ara-C, Arabinosyl, cytosine arabinoside. 
8.1.2 
Classification 
Antimetabolite. 
8.1.3 
Mode of Action 
Converted to cytarabine triphosphate (Ara-CTP), a competitive 
inhibitor of DNA polymerase.  The drug is also incorporated into 
cellular DNA and RNA.  It is active against cells in S-phase and is 
considered to be phase specific. 
8.1.4 
Storage and Stability 
The dry powder is stored at room temperature.  Solutions 
reconstituted with sterile water without preservative should be used 
immediately; solutions reconstituted with Bacteriostatic of Water are 
stable up to 48 hours at controlled room temperature (15o to 30oC).  
Solutions with a slight haze should be discarded. 
8.1.5 
Dose Specifics 
Induction Arm A 
100 mg/m²/day by 24 hour continuous infusion for 7 days (days 1-7). 
Consolidation I 
1500 mg/m² as a one hour intravenous infusion every 12 hours for a 
total of 12 doses (days 1-6) for patients < 70 years of age, or a total of 
6 doses for patients ≥ 70 years of age. See Section 5.4.1 for dose 
modifications for Consolidation I. See Section 5.6.3 for duration of 
Consolidation II therapy. 
8.1.6 
Preparation 
For IV use, reconstitute the 100 mg vial with 5 mL bacteriostatic water 
for injection to achieve a concentration of 20 mg/mL.  Add 10 mL of 
bacteriostatic water to the 500 mg vial to achieve a final concentration 
of 50 mg/mL.  Add 10 and 20 mL of bacteriostatic water to the 1 and 2 
gm vials respectively to achieve a final concentration of 100 mg/mL.  
For subcutaneous use, reconstitute the powder with sterile water or 
saline to a concentration of 50-100 mg/mL.  For IT use, mix with 
lactated Ringer's solution or normal saline without preservatives. 
8.1.7 
Administration 
IV push, IV continuous infusion, subcutaneous, or IT.  Cytarabine is 
not absorbed when given orally. 

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8.1.8 
Incompatibilities 
Possible interaction with fluorouracil. 
8.1.9 
Compatibilities 
Cytarabine (0.25 mg/mL), daunorubicin (0.03 mg/mL) and etoposide 
(0.4 mg/mL) are stable in D5/0.45% NaCl for 72 hours at room 
temperature.  Cytarabine is also compatible with sodium chloride, 
potassium chloride, calcium, and magnesium sulfate.  
8.1.10 
Availability 
Commercially available in 100 mg, 500 mg, 1 gm, and 2 gm vials. 
8.1.11 
Side Effects 
1. Hematologic:  Leukopenia, thrombocytopenia, anemia, and 
phlebitis.  Nadir occurs in 5-7 days with recovery in 2-3 weeks. 
2. Dermatologic:  Rash, alopecia. 
3. Gastrointestinal:  Nausea, vomiting, diarrhea, dysphagia, mucositis, 
anorexia. 
4. Hepatic:  Transient increase in liver enzymes. 
5. Renal:  Urinary retention. 
6. Other:  Flu-like syndrome, fever.  Profound hyperuricemia may 
occur in leukemia patients with high white blood counts. 
Conjunctivitis, dizziness, shortness of breath, headache, urticaria, 
pruritis, abdominal pain, pericarditis. 
7. After intrathecal administration, the most common side effects are 
nausea, vomiting, fever, and headache, usually mild and self-
limiting.  Meningism, paresthesia, paraplegia, seizures, blindness, 
necrotizing encephalopathy have occurred. 
8.2 
Daunorubicin 
8.2.1 
Other Names 
Daunomycin, Rubidomycin, Cerubidine. 
8.2.2 
Classification 
Anthracycline antibiotic. 
8.2.3 
Mode of Action 
Anthracycline mechanism of action results in a very tight binding of 
the drug to the DNA molecule.  The ultimate effect is interference with 
nucleic acid synthesis, both RNA and DNA. 
8.2.4 
Storage and Stability 
Intact vials are stored at room temperature and protected from direct 
sunlight.  Reconstituted solutions are stable for 48 hours when 
refrigerated and 24 hours at room temperature, when protected from 
sunlight. 

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8.2.5 
Dose Specifics Induction Arm A 
60 mg/m²/day by 10-15 minute intravenous infusion for 3 days (days 
1, 2 and 3). 
NOTE: 
No dose modification during initial induction. See Section 
5.4.2 for dose modification during induction cycle II.   
Doses should be reduced in presence of impaired hepatic or renal 
function.  Patients with serum bilirubin of 1.5 to 3 mg/dl should receive 
75% of the usual dose; patients with serum bilirubin or serum 
creatinine 3.1 to 5 mg/dl should receive 50% of the usual dose. 
8.2.6 
Preparation 
Each 20 mg vial is reconstituted with 4 mL of sterile water to give a 
final concentration of 5 mg/mL.  The desired dose is drawn into a 
syringe containing  
10-15 mL of normal saline.  Protect from sunlight. 
8.2.7 
Administration 
10-15 minute intravenous infusion. 
8.2.8 
Incompatibilities 
Sodium heparin. 
8.2.9 
Availability 
Commercially available in 20 mg glass vials of red colored lyophilized 
drug. Also available in 50 mg vials. 
8.2.10 
Side Effects 
1.  Hematologic:  Myelosuppression (leukopenia with a nadir between 
1-2 weeks). 
2.  Dermatologic:  Rash; alopecia; chemical thrombophlebitis or local 
necrosis if extravasation occurs. 
3.  Gastrointestinal:  Nausea, vomiting, commonly occurring one hour 
after a dose and lasting for several hours; diarrhea, stomatitis. 
4.  Cardiovascular:  Arrhythmias, usually transient; congestive 
cardiomyopathy; maximum total (lifetime) dose of 500-600 mg/m² 
is recommended because of cumulative cardiotoxicity. 
5. Renal:  Red urine; not hematuria. 
6.  Other: Fever; transient elevations in serum bilirubin, AST, alkaline 
phosphatase. 
8.2.11 
Nursing Implications 
1. Vesicant - avoid extravasation.  Refer to extravasation protocol if 
inadvertent infiltration occurs. 
2. Monitor CBC, platelet counts. 
3. Advise patient of red coloration of urine. 
4. Administer antiemetics as needed. 

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8.2.12 
References 
Von Hoff DD, Rozencweig M, Layard M, et al.  Daunomycin-induced 
cardiotoxicity in children and adults:  A review of 110 cases.  Am J 
Med 1977; 62:200-208. 
Yates J, Glidewell O, Wiernik P, et al.  Cytosine arabinoside with 
daunorubicin or Adriamycin for therapy of acute myelocytic leukemia:  
A CALGB study.  Blood 1982; 60:454-462. 
8.3 
Decitabine 
8.3.1 
Other Names  
Dacogen®, 5-aza-2’-deoxycytidine, 5-aza-CdR 
8.3.2 
Classification  
Antineoplastic, DNA hypomethylating agent 
8.3.3 
Mode of Action  
A cytosine nucleoside analog.The drug inhibits DNA 
methyltransferase at low doses promoting DNA hypomethylation and 
reactivation of previously silenced genes.  At higher doses, the drug 
has a direct cytotoxic effect. It is an S-phase specific agent. 
8.3.4 
Storage and Stability  
Intact vials are stored at room temperature. Unless used within 15 
minutes of reconstitution, diluted decitabine solution must be prepared 
using cold (2o to 8oC) infusion fluids and stored at 2o to 8oC for up to a 
maximum of 7 hours until administration. 
8.3.5 
Dose Specifics  
Decitabine 20 mg/m²/day IV over 1 hour QD x 3 days, repeated Q 4 
weeks x 12 months total. See Section 5.4.3 for duration. 
In the absence of a hypoplastic marrow (5% or less cellularity), clearly 
progressive increase in bone marrow blast count, febrile neutropenia, 
or unresolved systemic neutropenic infection, dosing should be 
continued at the recommended dose without delay. In the event of 
delayed recovery to pre-dose ANC and platelet counts for more than 
two cycles, the dose should be reduced by approximately 25% upon 
restarting therapy. 
8.3.6 
Preparation  
Each vial should be reconstituted with 10 mL of sterile water giving a 
final concentration of 5 mg/mL. Immediately after reconstitution, the 
solution should be further diluted with 0.9% sodium chloride injection, 
5% dextrose injection or lactated ringer’s injection to a final drug 
concentration of 0.1-1 mg/mL. Unless used within 15 minutes of 
reconstitution, the diluted decitabine solution must be prepared using 
cold (2°C to 8°C) infusion fluids and stored at 2°C to 8°C (36°F-46°F) 
for up to a maximum of 7 hours until administration. 

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8.3.7 
Route of Administration  
Intravenous infusion over 1 hour.  
8.3.8 
Compatibilities  
Compatible with 0.9% sodium chloride injection, 5% dextrose injection 
or lactated ringer’s injection. 
8.3.9 
Availability  
Decitabine is an investigational agent available free of charge from 
Eisai Inc. and distributed by Fisher Clinical Services. Decitabine will 
be available in 50 mg vials.   Decitabine should only be requested 
for patients who are treated on Arm F of the Maintenance step. 
Initial Drug Orders for Each Patient 
Following randomization to Arm F a supply of Decitabine may be 
ordered. Investigators must email a completed E2906 Decitabine 
Study Drug Request Form (See Appendix IV) to the ECOG-ACRIN 
Drug Team at 900.drugorder@jimmy.harvard.edu who will then 
forward the drug request to Fisher Clinical Services. If email is not 
available, the completed form may be faxed to ATTN: ECOG-ACRIN 
Drug Team at 617-632-2063. No starter supplies are available for 
this protocol.  
Decitabine will be shipped to a responsible person (e.g., a 
pharmacist) at the investigator’s institution. Drug is ambient and will 
use a normal ambient shipper. Quantities must be ordered per cycle 
(keeping in mind that you will need 3 vials per cycle.  
NOTE: 
Decitabine is provided in kits that contain 5 vials per kit. 
Each order should cover, at minimum, 2 cycles - 10 vials. 
Institutions should allow 3-4 business days for shipment of drug 
from Fisher Clinical Services from receipt of the E2906 
Decitabine Drug Request Form by the ECOG-ACRIN Drug Team. 
Shipments will be made fromFisher Clinical Services. on Monday 
through Thursday for delivery onsite Tuesday through Friday.  There 
will be no weekend or holiday delivery of drugs. The E2906 
Decitabine Drug Request Form can be downloaded from the ECOG 
website in WORD format. 
IMPORTANT REORDER INSTRUCTIONS  
Once it is determined that the patient will continue treatment, please 
reorder 2 cycles of study drug immediately. Institutions should keep 
in mind the number of vials used per cycle, and that decitabine kits 
contain 5 vials per kit. 
Institutions should allow 3-4 business days for shipment of drug from 
Fisher Clinical Services from receipt of the E2906 Decitabine Drug 
Request Form by the ECOG-ACRIN Drug Team. Shipments will be 
made fromFisher Clinical Services. on Monday through Thursday for 
delivery onsite Tuesday through Friday.  There will be no weekend or 
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holiday delivery of drugs. The E2906 Decitabine Drug Request Form 
can be downloaded from the ECOG website in WORD format. 
Drug Destruction and Return 
At the completion of all patients’ treatment randomized to Arm F at 
your institution, all unused drugs, partially used, or empty containers 
must be destroyed at the site according to the institution’s policy for 
drug destruction.  Please maintain appropriate records of the disposal, 
including dates and quantities.  
Drug Inventory Records 
Investigational Product Records at Investigational Site(s): It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried. 
8.3.10 
Side Effects  
See CAEPR (Section 5.3) 
8.3.11 
Nursing/Patient Implications  
1. Monitor CBC, platelet counts. 
2. Obtain liver chemistries and serum creatinine prior to initiation of 
treatment. 
3. Premedicate with antiemetics as needed (emetogenic potential: 
minimal risk, < 10%).  
4. Not an irritant or vesicant. 
8.3.12 
References  
Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized 
study of three schedules of low-dose decitabine in higher risk 
myelodysplastic syndrome and chronic myelomonocytic leukemia. 
Blood. 2007;109:52-57. 
Kantarjian HM, Issa JP, Rosenfeld CS, et al. Decitabine improves 
patient outcomes in myelodysplastic syndromes: results of a phase III 
randomized study. Cancer. 2006;106:1794-1803. 
Data on file, MGI PHARMA, INC. 
Dacogen [package insert]. Bloomington, MN: MGI PHARMA, INC; 
2006. 
8.4 
Clofarabine  
8.4.1 
Other Names 
CLOLARTM, Cl-F-Ara-A, 2-chloro-9-(2-deoxy-2-fluoro-β-D-
arabinofuranosyl)adenine 
8.4.2 
Classification 
Purine nucleoside analog, anti-metabolite\ 

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8.4.3 
Mode of Action 
Converted to clofarabine triphosphate, a competitive inhibitor of DNA 
synthesis, and inhibitor of DNA polymerse α and ribonucleotide 
reductase. It is not cell cycle specific 
8.4.4 
Storage & Stability 
Clofarabine is formulated at a concentration of 1 mg/mL in sodium 
chloride (9 mg/mL), United States Pharmacopeia (USP), and Water 
for Injection, USP, quantity sufficient (qs) to 1 mL. Clofarabine is 
supplied in one vial size:  a 20-mL clear, glass vial with gray stopper 
and blue flip off seal.The 20-mL vial contains 20 mL (20 mg)of 
solution with a pH range of 4.5 to 7.5. The solution is sterile, clear and 
practically colorless, is preservative-free, and is free from foreign 
matter. 
8.4.5 
Dose Specifics 
Arm B Induction Cycle I: 30 mg/m²/day IV by 1 hour infusion QD x 5 
days. See Section 5.1.3. 
Arm B Induction Cycle II: 20 mg/m²/day IV by 1 hour infusion QD x 5 
days. This cycle should not begin before day 21. See Sections 5.1.3 
and 5.1.5. 
Arm D Consolidation: 20 mg/m²/day x 5 days. See Section 5.1.6. 
8.4.6 
Preparation 
Clofarabine for injection should be filtered through a sterile 0.2 mcm 
syringe filter and then further diluted with 5% dextrose injection USP 
(D5W) or 0.9% sodium chloride injection USP (normal saline [NS]) 
prior to IVI.  If the use of a 0.2 mcm syringe filter is not feasible then 
clofarabine should be either pre-filtered with a 5 mcm filter, or 
administered through a 0.2 or a 0.22 mcm in-line filter. Clofarabine 
can be further diluted in D5W or NS.  Recommended total volume is 
up to 250 mL. The resulting admixture may be stored at room 
temperature, but must be used within 24 hours of preparation. The 
final concentration of the solution should be between 0.15 mg/mL to 
0.4 mg/mL. 
8.4.7 
Route of Administration 
Clofarabine should be administered by daily intravenous infusion over 
1 hour. 
8.4.8 
Incompatibilities 
To prevent drug incompatibilities, no other medication should be 
administered through the same IV line.   
8.4.9 
Drug Availability  
Clofarabine is distributed free of charge from Genzyme CPRS. Refer 
to Section 4.0 for regulatory documents required prior to study entry.  
Be sure to allow ample time for processing of the regulatory packet 
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and drug request.  Clofarabine should only be ordered for patients 
randomized to Arm B on Induction and Arm D on Consolidation. 
 
 
Initial Drug Orders for Each Patient 
Following submission and approval of the required regulatory 
documents and patient registration, a supply of Clofarabine may be 
ordered from Genzyme Oncology.   Investigators must email a 
completed E2906 Clofarabine Study Drug Request Form (See 
Appendix III) to Genzyme at GTOdrugorders@genzyme.com or fax 
to (210) 949-8484. Clofarabine should only be ordered for patients 
randomized to Arm B on Induction and Arm D on Consolidation. 
If needed, starter supplies may be requested. Please indicate on 
the drug request form that a starter supply is being ordered. 
Clofarabine will be shipped to a responsible person (e.g., a 
pharmacist) at the investigator’s institution, who will document the 
amount and condition of the drug and enter these data into forms 
provided by the drug distributor. A suggested initial shipment is 30 
vials (1.5 cycles). Allow 5 business days from date of receipt of the 
E2906 Drug Request Form to the date of receipt of clofarabine at the. 
Please note the date by which clofarabine is needed and Genzyme 
will attempt to accommodate more rapid delivery as necessary.  The 
Drug Supply Shipment Form can be downloaded from the ECOG 
website in WORD format. 
IMPORTANT REORDER INSTRUCTIONS  
Once it is determined that the patient will continue treatment, please 
reorder study drug immediately. Institutions should keep in mind the 
number of vials used per cycle, and that shipments may take 5 
business days from the date Genzyme receives the request. 
Shipments will be made from Genzyme CPRS on Monday through 
Thursday for delivery onsite Tuesday through Friday.  There will be no 
weekend or holiday delivery of drugs.   
Clofarabine Quality and Complaints Handling 
Genzyme has requested that the pharmacist or pharmacy designee 
report any issues related to the quality of Clofarabine to Genzyme 
Clinical Pharmacy Research Services (CPRS) via fax at 508-424-
4484 or 877-237-1292 (toll-free). The company’s CPRS Fax is 
available for Clofarabine handling and complaint reporting on a 24-
hour basis.  Complaints are reviewed during normal business hours. 
Where possible, once a complaint has been logged with CPRSP, the 
Clofarabine in question should be stored as instructed on the label in 
a limited access area until otherwise instructed by Genzyme. 
Questions regarding quality issues can be addressed to CPRS by 
calling 800-326-7002 or e-mailing 
CPRSProductComplaints@genzyme.com. 
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Drug Destruction and Return 
At the completion of the patient’s treatment at your institution, all 
unused drugs, partially used, or empty containers must be destroyed 
at the site according to the institution’s policy for drug destruction.  
Please maintain appropriate records of the disposal, including dates 
and quantities. 
Drug Inventory Records 
Investigational Product Records at Investigational Site(s):  It is the 
responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site 
where investigational product is inventoried. 
8.4.10 
Side Effects (for a more complete list of side effects see Section 4 of 
the IB) 
1. Most frequently reported: Nausea, asthenia, diarrhea, myalgia. 
2. Body as a whole: Fever, malaise, asthenia, abdominal pain, back 
pain, extremity pain, sepsis, pain. 
3. Gastrointestinal: Nausea, vomiting, anorexia, diarrhea, stomatitis, 
GI disorder, GI hemorrhage, liver damage, liver function 
abnormalities.  
4. Musculoskeletal: Myalgia, arthralgia. 
5. Cardiovascular: Hemorrhage, chest pain, cardiac dysrhythmia, 
hypotension, heart failure, hypertension. Cardiac insufficiency and 
cardiomyopathy have been observed in rats treated with 
clofarabine. 
6. Respiratory: Dyspnea, lung disorder, cough. 
7. Dermatologic: Rash, urticaria. 
8. Neurologic: Headache, CNS disorder. 
9. Hematologic: Leukopenia, neutropenia, thrombocytopenia. 
8.4.11 
Interactions 
Unknown; no other medication should be administered through the 
same IV line.   
8.4.12 
Nursing/Patient Implications 
1. Educate patient/support person(s) about potential side effects, 
particularly related to myelosuppression & immunosuppression. 
2. Follow protocol guidelines for discontinuing monitoring WBC, 
neutrophil and platelet count. 
3. Administer antiemetics and analgesics as ordered/needed: 
Prophylactic use of antiemetics is recommended. See Section 5.3. 
4. Monitor for signs of infection, bleeding, hand-foot syndrome. 
5. Monitor renal and hepatic function with clofarabine administration.

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8.5 
Fludarabine Monophosphate (Fludara®) 
8.5.1 
Availability 
Fludarabine monophosphate is commercially available as FLUDARA 
IV as a white, lyophilized powder. Each vial contains 50 mg of 
fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to 
adjust pH. Store at 15-30°C (59-86°F). Please refer to the agent’s 
package insert for additional information. 
8.5.2 
Storage & Stability 
Reconstituted FLUDARA IV is chemically and physically stable for 24 
hours at room temperature or 48 hours if refrigerated. In addition, 
reconstituted FLUDARA IV contains no antimicrobial preservative and 
thus care must be taken to assure the sterility of the prepared 
solutions and should be discarded eight hours after initial entry. 
8.5.3 
Preparation 
FLUDARA IV should be prepared for parenteral use only by 
aseptically adding Sterile Water for Injection, USP. When 
reconstituted with 2 ml of Sterile Water for Injection, USP, each ml of 
the resulting solution will contain 25 mg of Fludarabine Phosphate, 25 
mg of mannitol, and sodium hydroxide to adjust the pH to 7-8.5. The 
product may be further diluted for intravenous administration to a 
concentration of 1 mg/ml in 5% Dextrose for Injection USP or in 0.9% 
Sodium Chloride, USP. 
8.5.4 
Administration 
Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration. Fludarabine will be 
delivered as a piggy-back via an ongoing IV line, over a period of 30 
minutes. 
8.5.5 
Toxicity 
Myelosuppression (dose limiting toxicity), fever, nausea, vomiting, 
stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin 
rashes, myalgia, headache, agitation, hearing loss, transient episodes 
of somnolence and fatigue, autoimmune hemolytic anemia, 
autoimmune thrombocytopenia, paresthesias, peripheral neuropathy, 
renal and pulmonary toxicity (interstitial pneumonitis). Severe fatal 
CNS toxicity presenting with loss of vision and progressive 
deterioration of mental status were encountered almost exclusively 
after very high doses of fludarabine monophosphate. Such toxicity 
has only been rarely demonstrated at the 25-30 mg dosage of 
fludarabine monophosphate. Very rarely described complications 
include transfusion-associated graft versus host disease, thrombotic 
thrombocytopenic purpura, and liver failure. Tumor lysis syndrome, 
complicating fludarabine monophosphate therapy has been observed, 
especially in patients with advanced bulky disease. Opportunistic 
infections (protozoan, viral, fungal, and bacterial) have been observed 
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receiving fludarabine combined with other agents (corticosteroids, 
mitoxantrone, and cyclophosphamide). 
8.6 
Tacrolimus (Prograf®) 
8.6.1 
Availability 
Tacrolimus is a commercially available macrolide compound with 
potent immunosuppressant properties. Tacrolimus is available for oral 
administration as capsules containing the equivalent of 0.5 mg, 1 mg, 
or 5 mg of anhydrous tacrolimus. For IV use, tacrolimus is available 
as a sterile solution in 1mL ampules containing the equivalent of 5 mg 
of anhydrous tacrolimus per mL. 
The oral absorption of tacrolimus is erratic and incomplete; absolute 
bioavailability is approximately 25%; peak serum levels are seen 1 to 
3 hours after an oral dose, and therapeutic trough blood 
concentrations have ranged from 5 to 20 ng/mL; tacrolimus is 
extensively metabolized in the liver, with only small amounts of 
unchanged drug (2% or less) being recovered in the urine; the 
elimination half-life of tacrolimus is approximately 10 hours.  
Tacrolimus suppresses both humoral (antibody) and cell-mediated 
immune responses. The compound is chemically distinct from 
cyclosporine but both agents elicit similar immunosuppressant effects. 
The immunosuppressive activity of tacrolimus is, however, more 
marked than that of cyclosporine.  
Please refer to the agent’s package insert for additional information. 
8.6.2 
Preparation -- For IV use 
Tacrolimus concentrate for injection must be diluted prior to IV 
infusion. For IV infusion, the concentrate is diluted with 0.9% sodium 
chloride or 5% dextrose injection to a concentration of 4-20 µg/mL. 
Preparation of the solution in polyethylene or glass containers allows 
storage for 24 hours beyond which unused solution should be 
discarded. A plasticized polyvinyl chloride (PVC) container should not 
be used because stability of the solution is decreased and polyoxyl 60 
hydrogenated castor oil contained in the formulation may leach 
phthalates from PVC containers. Tacrolimus concentrate for injection 
and diluted solutions of the drug should be inspected visually for 
particulate matter and discoloration prior to administration whenever 
solution and container permit. 
8.6.3 
Administration 
Tacrolimus is to be initiated on Day -2. Begin tapering between Day 
+90 to +120 in the absence of GVHD as tolerated with a goal of 
stopping by Day +150 to +180. See protocol text for tapering 
instructions, and for instructions for patients who are unable to take 
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8.6.4 
Storage & Stability 
Store tacrolimus capsules at controlled room temperature, 15-30°C 
(59-86°F) (Prod Info Prograf®, 1997). An extemporaneous suspension 
of tacrolimus with a final concentration of 0.5 milligrams/milliliter was 
stable for 56 days when it was stored at 24-26°C in glass or plastic 
amber prescription bottles. 
8.6.5 
Toxicity 
In patients receiving tacrolimus, 5% to 47% experienced anemia, 8% 
to 32% experienced leukocytosis, and 14% to 24% experienced 
thrombocytopenia. Rare cases of microangiopathic hemolytic anemia 
have been reported. Mild to moderate hypertension was reported in 
38% to 50% of patients receiving tacrolimus. Mild to moderate 
hypertension is a common adverse effect associated with tacrolimus 
therapy. Chest pain was reported in 19%. Antihypertensive therapy 
may be required. The most common adverse effects of tacrolimus 
have involved the central nervous system, and include headache 
(37% to 64%), tremors (48% to 56%), insomnia (32% to 64%), 
paresthesia (17% to 40%); and dizziness (19%). Tremor and 
headache may respond to a dosage reduction. Agitation, anxiety, 
confusion, seizures, depression, hallucinations, myoclonus, 
neuropathy, psychosis, incoordination, and abnormal dreams have 
been reported in 3% to 15% of tacrolimus-treated patients. 
Hyperkalemia (13% to 45%), hypokalemia (13% to 29%), 
hypophosphatemia (49%), and hypomagnesemia (16% to 48%) have 
been associated with tacrolimus therapy. In addition, hirsutism occurs 
only rarely with tacrolimus. Hyperuricemia has been reported in 
greater than 3% of tacrolimus-treated patients. Gastrointestinal 
adverse effects of tacrolimus have included nausea (32% to 46%), 
vomiting (14% to 29%), anorexia (7% to 34%), constipation (23% to 
35%) and diarrhea (37% to 72%). Gingival hyperplasia observed in 
patients treated with cyclosporine has not been reported with 
tacrolimus therapy. Nephrotoxicity was reported in 36% to 40% and 
52% of liver and kidney transplant patients receiving tacrolimus. Overt 
nephrotoxicity is usually seen early after transplantation and is 
characterized by an increased serum creatinine and a decrease in 
urine output. Hematuria has been reported in greater than 3% of 
tacrolimus-treated patients (Prod Info Prograf®, 1997). Abnormal liver 
function tests have been reported in 6% to 36% of patients receiving 
tacrolimus; ascites was reported in 7% to 27% of these patients.  
Other miscellaneous effects that have occurred in clinical trials include 
pain (24% to 63%), fever (19% to 48%), asthenia (11% to 52%), back 
pain (17% to 30%), and peripheral edema (12% to 36%). The 
incidence of hyperglycemia is 17% and may require therapy with 
insulin. Other less frequently occurring effects (greater than 3%) 
include abscess, chills, peritonitis, and photosensitivity reactions. 
Anaphylaxis has been reported in a few patients receiving intravenous 
tacrolimus. Tacrolimus contains castor oil which has been associated 
with anaphylaxis in other drugs containing castor oil derivatives.  

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The incidence of bloodstream infection is 22%. Most infections are 
due to bacteria (81%), followed by candidemia (14%), and 
cryptococcemia (5%). The source of bloodstream infection was 
primarily intravascular catheter, accounting for 39% of cases. 
8.7 
Methotrexate (Amethopterin®; MTX) 
8.7.1 
Availability 
Commercially available in 2 mL, 4 mL, 8 mL, 10 mL vials, or 1 g vials 
or preserved with benzyl alcohol. Please refer to the agent’s package 
insert for additional information. 
8.7.2 
Preparation 
The 1 gm vial may be diluted in 100 mL of saline or D5W. 
8.7.3 
Compatibility 
Additive incompatibility: bleomycin, prednisone. 
8.7.4 
Storage & Stability 
Stability and compatibility of methotrexate sodium solutions depend 
on several factors including the formulation of methotrexate sodium 
used, presence of preservatives, concentration of drug, specific 
diluents used, resulting pH, and temperature; the manufacturer’s 
labeling and specialized references should be consulted for specific 
information. Methotrexate sodium solutions should be inspected 
visually for particulate matter and discoloration whenever solution or 
container permits. 
8.7.5 
Administration 
Administer via slow IV push. Hydrate intravenously and induce 
diuresis. 
8.7.6 
Toxicity 
Hematologic including leukopenia (1.5%), thrombocytopenia (5%; 
nadir 5-12 days; recovery 15-27 days), anemia (nadir 6-13 days), 
pancytopenia (1.5%); gingivitis, glossitis, pharyngitis, stomatitis, 
enteritis; nausea/vomiting, anorexia, diarrhea; hematemesis, melena; 
acute and chronic hepatotoxicity; transaminases increase 1-3 days 
after administration, hepatic fibrosis and cirrhosis with long-term 
therapy; pulmonary toxicity including pneumonitis, pulmonary fibrosis 
that is not dose-dependent and may not be fully reversible; pruritis, 
urticaria, photosensitivity; CNS: drowsiness, blurred vision, tinnitus, 
malaise, seizures; nephropathy: cystitis, dysuria, azotemia, hematuria, 
renal failure; diabetes; when administered it may cause headache, 
back pain, rigidity. 
8.7.7 
Drug Interactions 
Aminoglycosides may cause decreased absorption of methotrexate, 
and increased renal toxicity. Folic acid may decrease response to 
methotrexate. The use of NSAIDs may increase methotrexate levels. 
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toxic effect of methotrexate. Procarbazine can cause increased 
nephrotoxicity. Theophylline may increase plasma levels. Alcohol may 
result in increased hepatotoxicity. Thiazides may cause 
granulocytopenia. Food will delay absorption, and decreases 
methotrexate peak. 
8.8 
Filgrastim (r-met HuG-CSF, G-CSF: Granulocyte Colony-Stimulating Factor, 
Neupogen®) 
8.8.1 
Availability 
r-met HuG-CSF is commercially available in 1.0 and 1.6 mL vials 
containing 300 µg and 480 µg G-CSF, respectively. Please refer to 
the agent’s package insert for additional information. 
8.8.2 
Storage & Stability 
G-CSF is available as a sterile buffered protein solution and must be 
stored at 2-8°C. DO NOT ALLOW THE DRUG TO FREEZE. 
8.8.3 
Administration 
Each vial should be entered only once, and the remainder of the vial 
discarded and not re-entered a second time. The daily dose should be 
injected subcutaneously in one or two sites. Standard dosing is 5 
µg/kg daily as a subcutaneous injection. Higher dosing (10 µg/kg) will 
be used for donors in this protocol. 
8.8.4 
Toxicity 
Chills, nausea, anorexia, myalgias, bone pain, local injection site pain 
or inflammation, abnormal liver function tests, thinning of hair, and 
enlargement of the spleen. Rarely fluid retention and pericardial 
effusion. All of these are generally reversible when the drug is 
discontinued. 
8.9 
Busulfan (Busulfex®) 
8.9.1 
Availability 
Busulfan is commercially available as 60 mg/10 mL ampuls. Please 
refer to the agent’s package insert for additional information. 
8.9.2 
Preparation 
Dilute busulfan injection in 0.9% sodium chloride injection or dextrose 
5% in water. The dilution volume should be ten times the volume of 
busulfan injection, ensuring that the final concentration of busulfan is 
≥ 0.5 mg/mL. 
8.9.3 
Storage & Stability 
Store unopened ampuls under refrigeration at 2°C to 8°C. The diluted 
solution is stable for up to 8 hours at room temperature (25°C) but the 
infusion must also be completed within that 8-hour time frame. 
Dilution of busulfan injection in 0.9% sodium chloride is stable for up 
to 12 hours at refrigeration (2°C-8°C) but the infusion must also be 
completed within that 12-hour time frame. 

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8.9.4 
Administration 
Intravenous busulfan should be administered via a central venous 
catheter as a 2-hour infusion every 6 hours for 2 consecutive days for 
a total of 8 doses. 
8.9.5 
Toxicity 
Severe myelosuppression with marrow ablation, alopecia, and mild 
nausea/vomiting are expected. Alopecia may not be completely 
reversible. Liver toxicity including severe or fatal veno-occlusive 
disease (<5%) may occur. Pulmonary toxicity is rare in this schedule. 
In combination with etoposide, busulfan causes severe mucositis, 
esophagitis, and possible enteritis. It is expected that patients will 
require mouth care including narcotic analgesia, and may require 
parenteral nutrition. In combination with etoposide, busulfan may 
cause skin toxicity including painful desquamation, and this may 
require local care and narcotic analgesia. Darkening of the skin may 
occur and may last several months. Seizures may occur (<5%). 
Busulfan causes immunosuppression and risk of opportunistic 
infection even after resolution of neutropenia. Busulfan is expected to 
cause nearly universal infertility in the doses used, although men may 
occasionally father children. 
8.9.6 
Nursing Implications 
1. GI toxicities leading to alteration in nutritional status. Patients 
require daily mouth care regimen which may include narcotic 
analgesic and potentially parenteral nutrition. 
2. Painful desquamation may require local care and narcotic 
analgesics. 
8.10 
Antithymocyte Globulin (Rabbit) (Thymoglobulin®; rabbit ATG) 
8.10.1 
Availability 
Antithymocyte globulin is commercially available as a lyophilized 
powder for reconstitution containing 25 mg per vial. Each vial of 
powder is supplied with 5 mL diluent. 
8.10.2 
Storage & Stability 
Intact vials should be stored under refrigeration and protected from 
light. Do not freeze. Reconstituted solutions should be used within 4 
hours. Further diluted solutions for infusion should be used 
immediately after dilution. 
8.10.3 
Preparation 
Remove the ATG rabbit plus diluent from the refrigerator and allow 
them to reach room temperature prior to reconstitution. Reconstitute 
each 25 mg vial with 5 mL of the diluent provided (sterile water for 
injection, USP). Rotate the vial gently to dissolve the powder. The 
resultant solution contains 5 mg/mL of ATG rabbit. Withdraw the 
calculate dose and inject into D5W or NS for IV infusion. The final 

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concentration should be 0.5 mg/mL. The solution should be 
administered through a 0.22 micron filter. 
8.10.4 
Administration 
ATG rabbit will be administered IV at a dose of 2.5 mg/kg/day for 3 
days (on Days -4, -3, and -2). The first dose should be infused over at 
least six hours, and subsequent doses over at least 4 hours. Infuse 
through a 0.22 micron in-line filter. Acetaminophen 650 mg PO, 
diphenhydramine 25-50 mg PO/IV, and methylprednisolone 1 mg/kg 
IV should be administered at the initiation and midway through each 
antithymocyte globulin (rabbit) infusion to minimize infusion reactions. 
8.10.5 
Toxicity 
Infusion reactions such as fever and chills are common, occurring in 
more than 10% of patients. Steroids, antihistamines and 
acetaminophen will be given, as described above, to minimize 
infusion reactions. Hypersensitivity reactions, including anaphylaxis, 
occur less frequently and may also be minimized with steroids and 
antihistamines. 
Immunosuppression from antithymocyte globulin (rabbit) is associated 
with an increase in opportunistic infections, including fungal, viral, and 
pneumocystis infections. 
 

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9. 
Statistical Considerations 
9.1 
Original Design Overview 
In this study, 747 patients will be stratified by age (60 to 69 vs. over 70), therapy-
related AML, and the presence of AHD (antecedent hematologic disorder) at the 
time of diagnosis of AML, then randomized to receive either the standard therapy 
induction treatment or clofarabine induction treatment. If achieving CR or CRi, 
these patients will continue to receive standard or clofarabine consolidation 
treatments. Patients who have a matched sibling donor and who achieve a 
'morphologic leukemia-free state' will undergo non-myeloablative allogeneic 
transplant. For the patients who do not undergo non-myeloablative allogeneic 
transplant, after receiving the induction and consolidation therapies, if patients 
are still in CR or CRi, they will be randomized to receive either decitabine 
maintenance treatment or observation, stratified on the induction and 
consolidation therapy, cytogenetics and age. We anticipate that approximately 
8% of patients will undergo allogenic transplant. We assume 25% of patients who 
do not receive allogenic transplant go through the second randomization. 
The primary objective of this trial is to determine the effect of clofarabine on 
overall survival (OS) in comparison with standard therapy (daunorubicin & 
cytarabine in induction and cytarabine in consolidation) in newly-diagnosed AML 
patients with age over 60 years. Since clofarabine is believed to be less toxic and 
also clofarabine is expected to prolong OS, a non-inferiority design with 
superiority alternative is preferred. If clofarabine turns out to be non-inferior to the 
standard therapy, the superiority of clofarabine will be tested. Another main 
endpoint of interest in this study is the 30-day mortality rate. It is suspected that 
clofarabine has a lower early mortality rate. The 30-day mortality rate will be 
tested after the inferiority of overall survival of clofarabine is rejected. The non-
inferiority test of OS, the superiority test of OS and the mortality endpoints fit into 
a hierarchical framework, since the superiority test of OS and the mortality 
endpoint will both be tested only conditional on inferiority of OS being rejected.  
Therefore, non-inferiority of OS will be tested at a one-sided 0.025 level, and 
superiority of OS and 30 day mortality rate will both be tested at a nominal level 
of 0.0125 (one-sided). The overall type I error rate of all three tests is still 
controlled at 0.025.  
As one of secondary endpoints, the induction complete response (CR) rates 
between clofarabine arm and the standard treatment arm will be compared. A 
non-inferiority test with superiority alternative at a one-sided significance level of 
0.025 will be used. If the inferiority of CR rate of clofarabine is rejected, the 
superiority test will be performed at a one-sided 0.025 significance level.  
At each interim analysis, the study will be monitored for early stopping in favor of 
either superior OS on the clofarabine arm or inferior OS on the clofarabine arm in 
the context of the non-inferiority test of OS. Meanwhile, the study will also be 
monitored for early stopping in favor of an inferior CR rate on the clofarabine 
arm.  In the event that at an interim analysis the criterion for inferiority of CR 
rates is met, but there is a trend towards superiority of survival, the DMC may 
decide to continue the study in spite of the inferiority of the CR rate. 
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As other secondary endpoints, we want to determine the effect of decitabine on 
disease free survival (DFS) as a maintenance therapy in comparison with 
observation. Also in this study, we want to evaluate the impact of consolidation 
with non-ablative conditioning and allogeneic hematopoietic stem cell 
transplantation with an HLA-identical sibling on overall survival in patients who 
achieve a ‘morphologic leukemia-free state’. 
9.2 
Primary Endpoint and Sample Size 
The primary objective of this trial is to determine the effect of clofarabine on 
overall survival in comparison with standard therapy. The primary endpoint is 
overall survival (OS). OS is defined as the time between randomization and 
death from any cause. Patients last known to be alive at the time of an analysis 
will be censored. 
The primary comparison of OS will be based on the treatment assignment 
received at randomization. To reduce potential bias of the primary comparison 
from the alloSCT arm, the patients will be censored at the time of allogeneic 
transplant for the primary analysis. Due to the potential confounding by 
maintenance therapy on the induction comparison, a weighted analysis 
(weighted Cox regression) (121,122,123) will be used for the primary analysis. 
Let π denote the actual proportion randomized to the observation arm of all 
patients entering on maintenance randomization. In the weighted analysis, 
patients who do not enter maintenance randomization get weight 1; Observation 
maintenance arm patients get weight 1/ π. Decitabine maintenance arm patients 
get weight 0. Thus, patients on the observed maintenance arm represent 
themselves as well as the response of (1/ π -1) similar patients in the decitabine 
maintenance arm. A robust variance estimator that correctly accounts for the 
weights will be used in this setting. 
Because long-term cures have been observed in previous studies with the same 
patient population, we assume a cure rate mixture distribution for the standard 
arm, with the distribution on the clofarabine arm given by a proportional hazards 
shift from the standard arm, to calculate power. Based on a previous ECOG 
study, E3999, we assume that the long-term cure rate in the standard treatment 
arms will be 10% and median survival among the non-cured group will be about 
9 month, i.e., the survival model for the standard treatment arm S0(t) = 0.1+0.9 
exp(-t*log(2)/9).  The study team would consider clofarabine to be acceptable if 
the long-term cure rate in the clofarabine arms will be no lower than 8% and 
median survival among the non-cured group will be no less than 8 months, which 
is approximately a less than 12% increase in hazard rate. Therefore, our null 
hypothesis is that the hazard ratio for clofarabine/standard is no less than 1.12. 
The alternative is that the hazard ratio for clofarabine/standard is no more than 
0.86. The non-inferiority of clofarabine will be tested at a one-sided significance 
level of 0.025. 
We assume that 8% of those patients will undergo allogeneic transplant. We also 
assume that 25% of patients who do not receive allogeneic transplant go through 
the second randomization. Adjusted for the sequential monitoring described 
below and based on the weighted analysis previously described, with 685 
patients, the study will have approximately 80% power to reject the null 
hypothesis of inferiority of clofarabine at the one-sided significance level of 0.025 
under the alternative above, assuming 5 years of accrual and 2 years of follow-

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up after the completion of accrual. The size and power of the study will not be 
affected even if the proportions of patients receiving maintenance are 
imbalanced between the induction arms. The full information needed is 507 
events. This information is the expected number of deaths among the non-allo 
non-decitabine patients under the alternative. Deaths on the decitabine 
maintenance arm do not contribute information to this comparison. Since the allo 
transplant patients are censored at the time of transplant, they do not contribute 
events. Therefore, the overall sample size was increased by 1/(1-.08), around 
9%, to make up for the loss of information. A total accrual of 747 patients is 
planned for this study.  
If criteria for early stopping given in Section 9.3 are not met, the final analysis will 
be performed when 507 non-allo non-decitabine patients have died, which is 
anticipated to occur 7 years after the study begins active accrual. A two-sided 
95% confidence interval on the log hazard ratio (clofarabine/standard) will be 
provided based on the weighted analysis as previously described, with age (60 to 
69 vs. over 70), therapy-related AML, and the presence of AHD at the time of 
diagnosis of AML as the stratification factors. 
If the 95% confidence interval on the log hazard ratio lies entirely below 
log(1.12), the non-inferiority of clofarabine treatment will be accepted. This 
analysis will be conducted in two ways: (1) comparing the treatments based on 
treatment assignment received at randomization and censoring the allo 
transplant patients at the time of transplant; and (2) comparing the treatment 
based on actual treatment received and again censoring the allo transplant 
patients (the weighted analysis removing the effect of maintenance decitabine 
will be used for both). The results will be credible only if the two analyses are 
reasonably consistent.   
If clofarabine turns out to be non-inferior to the standard therapy, a two-sided 
97.5% confidence interval on the log hazard ratio (clofarabine/standard) will be 
provided for the superiority test of OS. If the 97.5% confidence interval lies 
entirely below log(1), then clofarabine will be considered superior to the standard 
treatment. A p-value for superiority based on the weighted analysis will be 
presented to allow assessment of the strength of the evidence. The superiority 
test will be based on the ITT (intention-to-treat) principle), including all 
randomized patients and censoring the allo transplant patients at the time of 
transplant.  
9.3 
Interim Analyses of Primary Endpoint 
Interim analysis of the study will be performed for all semi-annual DMC meetings 
beginning when approximately 25% of planned full information (126 events) has 
occurred. Table 1 gives the expected timing of the analyses and the expected 
number of events under the alternative at each interim analysis. Because of 
delays in initiation of accrual and delays in data submission and processing, it is 
likely the actual analysis time will be 6-12 months later.  
The study will be monitored for early stopping in favor of either the alternative 
hypothesis of superior OS on the clofarabine arm or the null hypothesis of inferior 
OS on the clofarabine arm using the repeated confidence interval (RCI) 
methodology similar to that described by Jennison and Turnbull (124). At each 
interim analysis, a two-sided 95% RCI on the log hazard ratio 
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(clofarabine/standard) will be computed, using the partial likelihood estimate and 
their truncated O’Brien-Fleming critical points listed in Table 1. The partial 
likelihood estimate of log hazard ratio and its robust variance estimator will be 
obtained using the weighted analysis described in Section 9.2. Since we do not 
want to stop the trial and declare the inferiority or superiority of clofarabine unless 
the results are convincing, a hazard ratio of 1 is pre-specified. If at any of the 
interim analyses, the 95% confidence interval of the log hazard ratio lies entirely 
below log(1), we may consider stopping the trial for the superiority of clofarabine; 
if the 95% confidence interval lies entirely above log(1), the study may need to be 
stopped due to the inferiority of clofarabine. 
Table 1: The Interim Analyses for the Primary OS Comparison 
Real Time (Years) 
Information Time 
Events Under the 
alternative 
Truncated O-F 
critical points 
2.2 
0.25 
127 
3.2905 
2.7 
0.34 
175 
3.2905 
3.2 
0.44 
224 
3.2905 
3.7 
0.54 
274 
2.9491 
4.2 
0.64 
325 
2.6418 
4.7 
0.74 
377 
2.4402 
5.2 
0.85 
429 
2.2623 
5.7 
0.92 
465 
2.1928 
7.0 
1.00 
507 
2.0974 
9.4 
Secondary Objectives 
As a secondary objectives of this trial, we will evaluate the 30-day mortality rate 
(all-cause mortality within 30 days of first dose) of clofarabine in comparison with 
standard treatment (daunorubicin & cytosine arabinoside) in newly diagnosed 
AML patients age > 60 years. Based on the results from E3999, we assume the 
30-day mortality of standard treatment is 10%. With 747 patients in total, we will 
have 80% power, at the one-sided 0.0125 significance level, to detect a 6% 
reduction in the 30-day mortality rate in the clofarabine arm using Fisher’s exact 
test. 
In this trial, we will also compare the induction complete response (CR) rates 
between the clofarabine arm and the standard treatment arm. Based on the 
results from E3999, we assume the CR rate of standard treatment is about 40%. 
The study team would consider clofarabine to be acceptable if the CR rate is no 
more than 10% less than the standard treatment. A non-inferiority test was used 
for this endpoint. Our null hypothesis is that the difference in the CR rates 
between the standard treatment arm and the clofarabine arm (CR rate of 
standard treatment – CR rate of clofarabine) is more than 10% and the 
alternative is that the difference of CR rates between the standard treatment arm 
and the clofarabine arm (CR rate of standard treatment – CR rate of clofarabine) 
is less than -1%. With 747 patients in total, the study will have 85% power to 
reject the null hypothesis of inferiority of clofarabine at the one-sided significance 
level of 0.025, adjusting for the sequential monitoring described below. At the 
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end of the study, the 95% confidence interval on the difference in the CR rates 
(CR rate of standard treatment – CR rate of clofarabine) will be computed based 
on the normal approximation to the difference of two independent binomial 
proportions. If the 95% confidence interval lies entirely below 0.1, the non-
inferiority of clofarabine in CR rate will be accepted. If the 95% confidence 
interval lies entirely below 0, then clofarabine is superior to the standard 
treatment in CR rate. 
The induction CR rates will be monitored to allow for early stopping in favor of 
inferiority using the repeated confidence interval methodology described by 
Jennison and Turnbull (123). Interim analyses will be conducted for induction CR 
rates when induction response data is available on 25%, 45%, 65%, 85% and 
100% of patients. At each interim analysis, the two-sided 95% repeated 
confidence interval on the difference of CR rate (CR rate of standard treatment – 
CR rate of clofarabine) will be computed. This repeated confidence interval uses 
the critical value from a truncated O’Brien-Fleming error spending rate function 
with an overall one-sided 2.5% error rate. If the confidence interval lies entirely 
above 0, the induction randomization may need to be stopped due to the 
inferiority of clofarabine and subsequent patients will directly be assigned to 
standard treatment arm.  
Another objective of this trial is to determine the effect of decitabine on disease 
free survival (DFS) as a maintenance therapy in comparison with observation. 
DFS is defined as the time from the second randomization to relapse or death 
without relapse. If 25% of patients who do not receive allogeneic transplant go 
through the second randomization, there will be 172 patients = randomized to 
either the decitabine arm or the observation arm. 
We assume that the long-term cure rate for the observation arm is 10% and the 
median DFS in the non-cured group is 7 months. The study will have 90% power 
to detect approximately a 36% reduction in the DFS hazard rate in the decitabine 
maintenance therapy arm. This power calculation is based on a one-sided log-
rank test at the significance level of 0.1 and assumes 5 years of accrual and 2 
years of follow-up after the completion of the accrual. The number of DFS events 
needed is 140. The primary analysis of DFS will be an intention-to-treat analysis 
and will use a one-sided log rank test stratified on the induction and consolidation 
therapy and on patient age and cytogenetics.  
Another secondary objective of this study is to evaluate the impact of 
consolidation with non-ablative conditioning and allogeneic hematopoietic stem 
cell transplantation with an HLA-identical sibling on overall survival in patients 
who achieve a ‘morphologic leukemia-free state’. 
The intention–to-treat approach will be used in this analysis. Patients with donors 
who choose not to have AlloSCT (or are unable due to insurance issues) need to 
be included in the AlloSCT arm for analysis. Assuming that 50% of patients 
receiving chemotherapy in induction and consolidation achieve a ‘morphologic 
leukemia-free state’ and 25% of those patients have a donor, 94 patients from 
the allogeneic transplant arm and 280 patients from the chemotherapy arms will 
be available for this OS comparison.   
For the chemotherapy arms, we assume that the long-term cure rate will be 10% 
and median survival among the non-cured group will be about 9 months. The 
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study will have 82% power to detect approximately a 32% reduction in the OS 
hazard rate in the allogenic transplant arm using one-sided log-rank test at the 
significance level of 0.025. This power calculation assumes 5 years of accrual 
and 2 years of follow-up after the completion of accrual. Full information needed 
is 292 deaths. The analysis of this secondary objective will use a one-sided log 
rank test stratified on age, therapy-related AML, the presence of AHD at the time 
of diagnosis of AML, and the induction therapy they received. 
9.5 
Design Changes 
Following a pre-planned interim analysis of primary endpoint OS, accrual to Step 
1 of this study was suspended on February 23, 2015 based on DSMC’s 
recommendation, due to differences in overall survival favoring standard 
daunorubicin and cytarabine compared to clofarabine for induction and 
consolidation. By that time, 727 patients had been accrued to this study.  
Among those 727 patients, 120 (16.5%) entered the second randomization. The 
original protocol design requires 172 patients to be randomized to either the 
decitabine arm or the observation arm (number of DFS events needed 140), in 
order to have 90% power to detect approximately a 36% reduction in the DFS 
hazard rate in the decitabine maintenance therapy arm at the significance level of 
0.1.  
We plan to reopen the study to accrue additional 52 patients to the second 
randomization, to finish the accrual goal of 172 patients. This requires about 74 
CR/CRi Patients to be pre-registered after their induction therapy.  Patients will 
receive consolidation while on study and then will be randomized to receive 
either decitabine maintenance treatment or observation, stratified on the 
induction therapy, cytogenetics and age. Based on the accrual rate of the first 
120 randomized patients, we anticipate the additional accrual could be 
completed within 1.8 years. The final analysis will be performed at 2 years of 
follow-up after the completion of the accrual. Based on the event rate observed, 
at that time, 125 DFS events could occur. The study will have approximately 90% 
power to detect a 37% reduction in the DFS hazard rate in the decitabine 
maintenance therapy arm, using a one-sided log-rank test at the significance 
level of 0.1. The half width of two-sided 80% confidence interval on the log 
hazard ratio (decitabine /observation) will be about 0.23. The half width of two-
sided 95% confidence interval on the log hazard ratio (decitabine /observation) 
will be about 0.35. 
Prior to the study reopen, as the study has reached 60% information for the 
maintenance comparison (Arms E vs. F), an interim analysis will be performed 
and the maintenance randomization will be monitored for early stopping in favor 
of null hypothesis by computing the conditional power. The conditional power will 
be calculated given the current data, assuming the study will continue until 125 
events of the maintenance comparison is reached. If the conditional power is 
higher than 0.7, the study will be reopen to pre-register 74 CR/CRi patients and 
accrue additional 52 patients to the second randomization. The cutoff of 
conditional power is set high, as we want to reopen the study only if there is a 
good chance of a positive result.   
If the conditional power is lower than 0.7, the study will be closed permanently. 
No more patients will be accrued. Based on the current event rate of the 120 
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patients, the events are anticipated to be accumulated very slowly. Therefore, the 
final analysis of the maintenance comparison will be performed at six months 
after the interim analysis. Based on the current event rate, at that time, we 
assume 90 DFS events could be observed. With 90 events, the study will have 
approximately 85% power to detect a 36% reduction in the DFS hazard rate in 
the decitabine maintenance therapy arm, using a one-sided log-rank test at the 
significance level of 0.15. The half width of two-sided 70% confidence interval on 
the log hazard ratio (decitabine /observation) will be about 0.22. The half width of 
two-sided 95% confidence interval on the log hazard ratio (decitabine 
/observation) will be about 0.41. 
9.6 
AML Clinical Epidemiology 
We assume that approximately 600 (82% of all 727 registered to Step 1) patients 
will complete the ALESE questionnaire. The proportions of obese patients and 
patients who had benzene exposure, ever smoked in their lifetime, took aspirin 
regularly, took acetaminophen regularly, ever lived in rural/farm environments, or 
had other exposures or lifestyle factors will be calculated separately, along with 
their 95% CIs. With 600 patients, the width of the 95% CI will be no wider than 
0.08. 
We will examine the impact of smoking, obesity, regular acetaminophen use, 
regular aspirin use, benzene exposure, and living in a rural/farm environment on 
OS. The impact of some other exposures or lifestyle factors on OS will also be 
explored. Assume 50% patients ever smoked in lifetime and assume for those 
patients a 10% long-term cure rate and 8-month median overall survival in the 
non-cured group. With treatment arms combined, the study will have 
approximately 80% power to detect a 22% reduction in the hazard rate in non-
smoking patients, using a one-sided log rank test at the significance level of 
0.025 and assuming 2 years of follow-up. The number of events needed is 502. 
Assume 20% patients had benzene exposure and assume those patients have a 
10% long-term cure rate and 7.5 -month median overall survival in the non-cured 
group. With treatment arms combined, the study will have approximately 80% 
power to detect a 27% reduction in the hazard rate in non- benzene- exposure 
patients, using a one-sided log rank test at the significance level of 0.025 and 
assuming 2 years of follow-up. The number of events needed is 482. When data 
are available, a one-sided log-rank test stratified by induction treatment effect will 
be used to evaluate the impact of those exposures or lifestyle factors on OS.  
Moreover, the weighted analysis as described in Section 9.2 will also be used in 
order to reduce the potential bias from the maintenance therapy. Patients 
receiving alloSCT will be included in this analysis. 
9.7 
Quality of Life 
9.7.1 
Primary Endpoint 
Quality of life (QOL) will be assessed using the FACT-Leukemia and 
FACIT Fatigue instruments as well as the Geriatric Assessment 
Battery. The FACT-Leukemia and FACIT –Fatigue instruments will be 
administered at the following time points: at the time of randomization, 
two weeks after beginning induction therapy (at the time of nadir), at 
28 – 30 days after beginning induction therapy, at the time of 
beginning consolidation therapy, at the time of randomization to 
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maintenance therapy or observation, and also at the time the patient 
discontinues treatment. The Geriatric Assessment Battery will be 
administered at the time of induction randomization for a baseline 
assessment.  The primary objective of the QOL study is to compare 
health-related QOL in elderly AML patients receiving standard 
induction therapy with those receiving clofarabine. Of primary interest 
are the scores on the FACT-Leu TOI (combines Physical Well-Being 
+ Functional Well-Being components of FACT-G and leukemia-
specific subscales) and FACIT Fatigue score. The FACT-Leu TOI has 
31 items and the score ranges from 0-124. The FACIT Fatigue has 13 
items and the score ranges from 0-52. The primary endpoints will be 
defined as the change of the FACT-Leu TOI score and change of 
FACIT Fatigue scores from time of randomization to day 28 – 30 after 
beginning induction therapy. The changes of the FACT-Leu TOI score 
and changes of FACIT Fatigue scores will both be tested at a nominal 
level of 0.025 (two-sided) to adjust for multiple comparisons. 
The FACT-Leu TOI is reported to have a standard deviation (SD) 
ranging from 18.1-21.7. Differences in FACT-Leu TOI mean change 
scores between the standard treatment arm and the clofarabine arm 
from time of randomization to day 28 – 30 after beginning induction 
therapy that can be detected with 80% power at two-sided 
significance level of 0.025 are presented in the following table. The 
expected survival models for each treatment arm specified in Section 
9.2 were used to establish the estimated number of patients alive at 
day 28 – 30 after beginning induction therapy. A sensitivity analysis 
for the % of patients assumed alive to complete the questionnaire at 
day 28 – 30 after beginning induction therapy (65%, 80%), allowing 
for slightly less and more variability in the instrument (18.0, 20.0, 22.0) 
and assuming different correlation (0.4, 0.6) between repeated 
measures was performed. For example, assuming a SD of 22.0 for 
the FACT-Leu TOI, a correlation between repeated measures of 0.6 
and using a two-sided t-test with a 0.025 significance level, there is 
sufficient power to detect a true difference in the FACT-Leu TOI mean 
change score between the two arms of 5.1-5.7. 
Table 2: Differences in FACT-Leu TOI Mean Change Scores 
Standard 
deviation 
(SD) 
Correlation 
SD of 
change 
Difference between treatment arms in mean 
change score from time of randomization to 
day 28 – 30 after beginning induction  
65% compliance 
(n=456) 
80% compliance 
(n=561) 
18.0 
0.4 
19.7 
5.7 
5.1 
 
0.6 
16.1 
4.7 
4.2 
20.0 
0.4 
21.9 
6.3 
5.7 
 
0.6 
17.9 
5.2 
4.7 
22.0 
0.4 
24.1 
7.0 
6.3 
 
0.6 
19.7 
5.7 
5.1 
The FACIT Fatigue scores are reported to have a standard deviation 
(SD) ranging from 9.4-13.6. Differences in FACIT Fatigue mean 

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change scores between the treatment arms from time of 
randomization to day 28 – 30 after beginning induction therapy that 
can be detected with 80% power at two-sided significance level of 
0.025 are presented in following table. For example, assuming a SD 
of 12.5 for the FACIT Fatigue, a correlation between repeated 
measures of 0.6 and using a two-sided t-test with a 0.025 significance 
level, there is sufficient power to detect a true difference in the FACIT 
Fatigue mean change score between the two arms of 2.9-3.2.  
Table 3: Differences in FACIT Fatigue Mean Change Scores 
Standard 
deviation 
(SD) 
Correlation 
SD of 
change 
Difference between treatment arms in mean 
change score from time of randomization to 
day 28 – 30 after beginning induction 
65% compliance 
(n=456) 
80% compliance 
(n=561) 
9.5 
0.4 
10.4 
3.0 
2.7 
 
0.6 
8.5 
2.5 
2.2 
11.0 
0.4 
12.0 
3.5 
3.1 
 
0.6 
9.8 
2.8 
2.6 
12.5 
0.4 
13.7 
4.0 
3.6 
 
0.6 
11.2 
3.2 
2.9 
14.0 
0.4 
15.3 
4.4 
4.0 
 
0.6 
12.5 
3.6 
3.3 
9.7.2 
Secondary Endpoints 
For the FACT-G, leukemia-specific, FACIT –Fatigue and Geriatric 
Assessment Battery subscales, we will provide descriptive statistics 
and calculate Cronbach’s alpha at each time point to assess reliability. 
Repeated measures analysis techniques will also be utilized to 
examine the treatment effect and time effect on FACT-Leu TOI score 
and FACIT Fatigue score. For patients randomized to the induction 
treatments, the longitudinal scores collected from time of 
randomization, two weeks after beginning induction therapy (at the 
time of nadir),  and at 28 – 30 days after beginning induction therapy, 
will be analyzed according to the methods described in Schluchter5 
and Schluchter, Greene and Beck6. These methods take into account 
the possibility of informative missingness by jointly modeling the 
longitudinal response (QOL scores) and the time to dropout.  
We will also examine whether components of a comprehensive 
geriatric assessment or QOL scale could predict ability to complete 
AML treatment. For patients who received induction therapy, logistic 
regression models on whether patients complete induction treatment 
will be fitted with all those scores (FACT-Leu TOI, FACIT Fatigue, and 
each component of Geriatric Assessment Battery at time of induction 
randomization) as covariates and treatment effect as a factor. For 
patients who received consolidation therapy, logistic regression 
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fitted with FACT-Leu TOI,  and FACIT Fatigue scores at beginning of 
consolidation therapy as covariates and treatment effect as a factor. 
For patients who received decitabine maintenance therapy, logistic 
regression models on whether patients complete maintenance 
treatment will be fitted with FACT-Leu TOI and FACIT Fatigue scores 
at the time of maintenance randomization as covariates.  
For those patients who go to allo transplant, the FACT-Leukemia and 
FACT Fatigue instruments will be administered at the following time 
points: at the beginning of the conditioning regimen and 100 days (+ 
14 days) post transplant. We will provide descriptive statistics of 
FACT-Leukemia and FACT Fatigue subscales at each time point. 
Paired t-tests will be used to examine the impact of allo transplant on 
FACT-Leu TOI and FACIT Fatigue. 
9.8 
Correlative Studies 
The first goal of the correlative studies is to perform expression and methylation 
profiling on all patients receiving decitabine and to correlate their integrated 
epigenetic signatures with response to decitabine. The second goal is to examine 
the epigenetic profiles of remission marrow in patients randomized to observation 
vs. decitabine in E2906 to determine whether the epigenetic signature of 
apparently morphologically normal bone marrow is predictive of relapse or 
response to decitabine maintenance. These analyses will be exploratory in 
nature. Assume that 86 patients will receive decitabine maintenance treatment 
and 86 patients will be randomized to the observation arm. Among them, 45%-
50% will submit samples and have sufficient material for expression and 
methylation profiling. Genomic microarrays will be used to study DNA 
methylation, and gene expression arrays will be used to study expression.  Both 
types of arrays are made by the NimbleGen company. The assay for DNA 
methylation is HELP (HpaII tiny fragment enrichment by ligation-mediated PCR). 
DNA is digested in parallel with MspI (resistant to DNA methylation), and then the 
HpaII and MspI products are amplified by ligation-mediated PCR and hybridized 
using separate fluorochromes to a customized array. The analysis of HELP data 
involves quality analysis and normalization. The methods described in Thompson 
et.al (127) will be used to identify epigenetics signatures which are different 
between patients who relapsed and patients who did not relapse. Signatures 
identified by epigenetic analysis will be correlated with DFS using a 
LARS/LASSO approach (128,129) for each maintenance arm. For the gene 
expression data, we will use Dchip software to normalize the expression levels 
and generate model-based expression intensities. Genes will be filtered by 
examining ratios of standard deviation to the mean. Genes will be hierarchically 
clustered to find genes with high/low fold change/differences. Supervised 
analyses will be used to identify genes that are differentially expressed between 
patients who relapsed and patients who did not relapsed. Genes or epigenetic 
signatures identified by gene expression or epigenetic analysis will be correlated 
with DFS using LARS/LASSO approach (128,129).  
A third goal is to study how genetic lesions cooperate to induce the resistant 
phenotype and to confer an adverse prognosis to elderly patients with AML. 
These analyses aim at elucidating in detail the spectrum of somatic alterations in 
elderly AML and at determining which alterations or pathways are the major 
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determinants of chemoresistance in this disease. While it is possible that 
thousands of coding and non-coding genes are affected by mutations or 
epigenetic lesions, these genes often have in common the perturbation of 
common pathways, such as DNA repair, RNA splicing, etc. This goal also aims at 
determining the biological functions perturbed by genetic lesions, using bio-
assays and animal models. The E2906 patient cohort will allow a comparison 
between somatic mutations in leukemia oncogenes and tumor suppressor genes 
previously identified in younger AML patients accrued to E1900 with those 
dominating in elderly AML. 
We assume that 635 patients (87% of 727 patients) will submit samples and 
have sufficient material for mutation analysis. We estimate about 20 mutations 
will be examined. For a mutation with 50% prevalence, we assume for those 
mutated patients a 10% long-term cure rate and 7.5-month median overall 
survival in the non-cured group. With treatment arms combined, the study will 
have approximately 81% power to detect a 29% reduction in the hazard rate in 
wild-type patients, assuming 2 years of follow-up. The number of events needed 
is 528. For a mutation with 20% prevalence, we assume those mutated patients 
have a 10% long-term cure rate and 6.3-month median overall survival in the 
non-cured group. With treatment arms combined, the study will have 
approximately 81% power to detect a 35% reduction in the hazard rate in wild-
type patients, assuming 2 years of follow-up. The number of events needed is 
501. Those power calculations were based on a two-sided log rank test with the 
family-wise type I error rate controlled at 0.05 using the Bonferroni correction. For 
each mutation we will perform a stratified log-rank test (using the strata at 
randomization) adjusted for multiple testing using resampling and the min-p 
method of Westfall and Young (1993) as implemented in the R package multtest. 
In addition we will perform tests for interaction between treatment assignment 
and mutational status to identify potential predictive mutations.  We will begin 
these analyses by assessing the prognostic relevance of known mutations on 
overall survival and response to therapy, including FLT3, DNMT3A, IDH1, IDH2, 
TET2, ASXL1, WT1, and MLL, and we will also include novel mutations identified 
in our discovery studies and by other efforts (including the AML TCGA project) to 
determine if novel mutations affect outcomes in this cohort of elderly patients with 
AML. 
We will also identify prognostic risk groups by using recursive partitioning and 
logistic regression, both of which are highly suitable for binary predictors. We 
plan to use a randomly chosen subsample of 423 (2/3 of 635) patients for training 
these models and the remaining 212 for validation. 
Another goal of the correlative studies is to explore the possible association of 
response to clofarabine with ABC-transporter P-glycoprotein (Pgp). We 
hypothesize that the relative expression of Pgp will determine differential activity 
of clofarabine in subsets of patients who overexpress Pgp, and will manifest itself 
in the CR rate. An aliquot of bone marrow or peripheral blood from pre-treatment 
samples will be evaluated for Pgp protein expression by flow cytometric 
assessment of binding of anti-Pgp antibody, MRK-16. In E3999, MRK-16 binding 
significantly correlated with P-glycoprotein function as a drug-efflux pump. We 
assume that 360 patients will receive clofarabine and 87% of those patients will 
submit samples and will have sufficient material for analysis. We assume about 
20% of patients will overexpress Pgp and the CR rate of the patients who 
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overexpress Pgp is 30%. With 63 patients who overexpress Pgp the study will 
have 80% power to detect an effect size of 0.80 at the two-sided significance 
level of 0.05 using a Wilcoxon rank sum test. Effect size is defined as the 
difference of the expression of Pgp between CR patients and non-CR patients 
divided by the common standard deviation of the two groups. Table 4 presents 
the effect size to be detected with 80% power under various percentages of 
patients overexpress Pgp and various CR rates of those patients.  
Table 4: Effect Size of the Expression of Pgp between CR Patients and non-CR 
Patients (two-sided α =0.05, power=80%) 
CR rate of the patients who 
overexpress transporter 
Percentages of patients 
overexpress transporter 
Effect size to be detected 
30% 
40% 
0.56 
30% 
0.65 
20% 
0.80 
35% 
40% 
0.54 
30% 
0.62 
20% 
0.76 
In addition, expression of CXCR4, will be assessed in this study by flow 
cytometric assay to correlate the intensity of its expression with other established 
prognostic factors (in particular with cytogenetics) in patients receiving induction 
treatments. Expression intensity of CXCR4 will be divided into three groups (low, 
intermediate, high). Based on results of Spoo, et al 87, it is anticipated that 
high/intermediate CXCR4 expression is associated with inferior clinical outcomes 
of response or survival. Therefore, the grading will be further simplified as 
high/intermediate vs. low. Data will be first analyzed by induction treatment arms. 
We assume 315 patients will receive induction therapy in each arm and have 
sufficient material for analysis, and among them, 35% of patients will have low 
expression of CXCR487.  Assuming 40% overall CR rate in that treatment arm, 
there will be 85% power to detect a difference in CR rate if the CR rate in the low 
expression of CXCR4 group is 52% and 34% in the high/intermediate expression 
of CXCR4 group. Alternatively, assuming 45% overall CR rate in that treatment 
arm, there will be 81% power if the CR rate in the low expression of CXCR4 
group is 56% and 39% in the high/intermediate expression of CXCR4 group. This 
power calculation is based on Fisher’s exact test at two-sided significance level 
of 0.05. When data are available, logistic and Cox regression analysis, adjusted 
by treatment effect and prognostic factors (including cytogenetics), will be used 
to assess whether CXCR4 expression level is an independent predictor for 
response or survival. 
9.9 
Accrual 
If the interim analysis of the maintenance comparison (described in Section 9.5) 
demonstrate the study should reopen, we will reopen the study to accrue an 
additional 52 patients to the second randomization, to finish the accrual goal of 
172 patients. This requires about 74 CR/CRi patients to be pre-registered after 
their induction therapy. Based on the accrual rate of the first 120 randomized 
patients, we anticipate the additional accrual could be completed with 1.8 years. 
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9.10 
Anticipated Accrual by Gender and Ethnicity 
Based on previous data from E3999, the anticipated accrual in subgroups 
defined by gender and race is: 
Ethnic Category 
Sex/Gender 
Total 
Females 
Males 
Hispanic or Latino 
11 
7 
18 
Not Hispanic or Latino 
335 
448 
783 
Ethnic Category: Total of all subjects 
346 
455 
801 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
2 
2 
4 
Black or African American 
17 
18 
35 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
327 
435 
762 
Racial Category: Total of all subjects 
346 
455 
801 
9.11 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee 
(DMC). The DMC meets twice each year. For each meeting, all monitored 
studies are reviewed for safety and progress toward completion. When 
appropriate, the DMC will also review interim analyses of outcome data. Copies 
of the toxicity reports prepared for the DMC meetings are included in the study 
reports prepared for the ECOG-ACRIN group meeting (except that for double 
blind studies, the DMC may review unblinded toxicity data, while only pooled or 
blinded data will be made public). These group meeting reports are made 
available to the local investigators, who may provide them to their IRBs. Only the 
study statistician and the DMC members will have access to interim analyses of 
outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DMC. Any DMC recommendations for changes to this 
study will be circulated to the local investigators in the form of addenda to this 
protocol document. A complete copy of the ECOG-ACRIN DMC Policy can be 
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10. 
Correlative Studies 
NOTE:  
ECOG-ACRIN requires that all biological samples submitted be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System.  An STS 
shipping manifest form must be generated and shipped with the sample 
submissions.  See Section 10.8.  
10.1 
Immunophenotype and Molecular Genetics   
Immunophenotyping has become an essential part of the diagnostic work-up of 
all leukemia patients. In fact, the diagnosis of leukemia without 
immunophenotypic characterization is no longer acceptable. ECOG-ACRIN has, 
therefore, developed a model system for antigenic data collection that requests 
specimens from all patients entered on ECOG-ACRIN leukemia treatment trials 
be studied by ECOG-ACRIN's Leukemia Translational Studies Laboratory 
(LTSL). In addition to establishing the leukemia subtype, this centralized testing 
and data collection has allowed that research questions of clinical relevance  be 
applied to a growing database (e.g., definition of prognostically significant antigen 
expression levels to eventually yield specific treatment subcategories). 
Depending on the study protocol and tissue availability, anti-coagulated (heparin, 
EDTA, ACD) peripheral blood or bone marrow or both are to be submitted to the 
LTSL. The dual function of the LTSL in eligibility determination and sample 
processing/banking (ECOG-ACRIN’s Leukemia Tissue Bank), facilitates the 
distribution of fresh or adequately processed specimens to other laboratories 
involved in protocol-embedded correlative studies, such as the analyses of 
epigenetic and genetic lesions. 
In addition to the study of abnormal hematopoietic cells, the focus of research on 
circulating serum factors in patients with leukemia or myelodysplasia has 
increased. Two tubes of coagulated peripheral blood (red top tubes) are 
requested for future research studies that may aim at identifying pathogenetic, 
diagnostic, or prognostic factors associated with leukemia or myelodysplasia.  
Serum and cells from peripheral blood or bone marrow from patients entered on 
studies of hematologic malignancies are stored in ECOG-ACRIN's Leukemia 
Tissue Bank for future laboratory studies. The bank provides the scientific 
community a source of leukemia specimens that are collected, processed, and 
maintained following quality control and quality assurance guidelines. The bank 
will accommodate requests from investigators within and outside ECOG-ACRIN 
in a timely and efficient manner, with respect to tissue type, tissue preparation, 
and most importantly, biologic characteristics of specimens. 
10.1.1 
Sample Collection and Submission Schedule 
Bone marrow, peripheral blood, and smears must be submitted at the 
following time points (Mandatory Submissions): 
• 
Pre-Registration 
• 
Notification to the submitting institution: 
The ECOG-ACRIN Leukemia Translational Studies Laboratory 
will notify the submitting institution of the results of the 
centralized immunophenotyping within 4-6 hours of receipt of 
the samples. 
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• 
Time of Outcome Following Induction – Prior to Consolidation (at 
time of response assessment or off-study, whichever occurs first) 
• 
End of Consolidation (Prior to 2nd Randomization - Step 3) 
• 
Relapse 
Bone marrow and peripheral blood will also be used for the optional 
correlative studies per patient consent. 
Peripheral blood and buccal rinse [preferred] or swabs (baseline only) 
are to be submitted at the above time points for banking per patient 
consent. 
 
Samples are to be shipped on the day they are drawn. If this is not 
possible, call the LTSL. 
If you have questions, contact the LTSL at (718) 920-9992.  
10.1.2 
Sample Preparation Guidelines 
NOTE: 
All cooperative groups should send specimens to the 
ECOG-ACRIN Leukemia Translational Studies Laboratory. 
Dr. Paietta’s institutional regulations require that she receive a copy of 
the patient’s consent and a copy of the HIPAA authorization at time of 
or prior to submission of the pre-study samples.  
All samples must be clearly labeled with the ECOG-ACRIN protocol 
number (E2906), ECOG-ACRIN patient sequence number, patient’s 
initials, date of collection, and sample type. 
10.1.2.1 
The following are to be submitted: 
1. MANDATORY AT ALL TIME POINTS: Heparinized 
bone marrow aspirate. The laboratory will accept any 
amount as long as it represents a first pull. It is 
imperative that aspirate from a separate first pull be 
submitted. DO NOT SUBMIT THE SECOND OR 
THIRD PULL OF ASPIRATE FROM THE SAME 
ASPIRATION SITE. With every pull from the same 
aspiration site, the blast count decreases due to 
hemodilution. Ideally, 2-3 mL of aspirate from a 
separate aspiration site should be submitted 
For patients with an inaspirable bone marrow (“dry 
tap”), or if a bone marrow has been done previously 
and the patient refuses to have another aspiration 
done, call Dr. Paietta's laboratory at (718) 920-9992 to 
discuss the case and the possibility for submitting 
peripheral blood only. Be prepared to report the WBC 
count and the blast count in the peripheral blood at the 
time of the call. 
2. MANDATORY AT ALL TIME POINTS: Heparinized or 
EDTA peripheral blood (four (4) green or purple top 
tubes, 30-40 mL). 
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3. MANDATORY AT ALL TIME POINTS: At least two (2) 
Wright-Giemsa stained bone marrow smears and one 
(1) Wright-Giemsa stained peripheral blood smear. 
NOTE: 
These smears will be forwarded to Dr. 
Daniel Arber at Stanford University for 
morphologic review, if necessary. 
4. MANDATORY AT ALL TIME POINTS: A copy of the 
institutional pathology report on the bone marrow must 
be submitted. If the pathology report is not available at 
the time the samples are mailed to the ECOG-ACRIN 
Leukemia Translational Studies Laboratory, the report 
must be FAXED at a later time to: (718) 920-1161. The 
pathology report must include cytogenetic results and 
any results from fluorescence-in-situ (FISH) 
hybridization and/or molecular studies done at the 
submitting institution. 
5. Two (2) red top serum tubes of peripheral blood (15-
20mLno anticoagulent) 
 
• 
Submit from patients who answer “YES” to “I agree 
to provide additional specimens for research.” 
NOTE: 
If samples designated for banking only are 
not submitted, please note the reason in the 
comments section of the Sample Tracking 
System. 
6. 
Buccal Cell Samples 
Most commonly, institutions will have buccal swab kits 
for the collection of cells for HLA-typing. Alternatively, 
Scope, a commercial brand mouthwash, or normal 
saline in a small sealed bottle can be given to the 
patient for a mouthwash. 
Aseptic techniques must be used to collect buccal 
cells from patients on-site and buccal cells must not 
be contaminated with cells from any other source. 
Patients should not brush their teeth or consume food 
prior to buccal cell collection.   
If a cytobrush is used, the collection end should not be 
touched and the patient should not scrape his/her 
cheek too vigorously. The inside of the cheek should 
be scraped 6 times. Several models of cytobrushes 
are available, such as the Omni swab or Bio-Swab 
from Arrowhead Forensics or the Cyto-Pak CytoSoft 
Brush from Medical Packaging Corp. 
• 
If mouthwash (e.g. Scope) or normal saline is 
used, the patient should pour approximately 10cc 
of mouthwash or saline into his/her mouth and 
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vigorously swish it against the cheeks for 10 
seconds and deliver the solution into a labeled 
15cc polypropylene test tube or a sterile urine cup. 
Among mouthwashes, the Scope brand fares best 
in collecting buccal cells for the preparation of 
high-quality DNA in high yield. 
• 
It is important that buccal cells do not dry out 
during shipping. Institutions are advised to seal the 
container containing the buccal cells tightly. Ship 
containers on ice-packs, together with the patient’s 
peripheral blood and bone marrow specimens. 
• 
Submit from patients who answer “YES” to “I 
agree to provide additional specimens for 
research.” 
NOTE: 
Buccal rinse (preferred) or swabs are 
strongly encouraged to be collected at 
baseline, but can be collected at any 
other time during the study if 
necessary. 
10.1.3 
Shipping Procedures  
Log the shipment into the ECOG-ACRIN STS the day of shipment.  If 
the STS is unavailable, an Generic Specimen Submission Form 
(#2981) must be submitted with the samples.  Once STS is available, 
retroactively log the shipment into STS, using the actual collection and 
shipping dates. 
The LTSL must be notified by telephone the day of shipment. 
 Fax or Email to Dr. Paietta is NOT Acceptable. 
Telephone: (718) 920-9992 
During off hours, all information regarding the shipment should be left 
on the answering machine in the LTSL including: 
E2906 Sequence Number 
Patient’s Initials 
Type of Specimen Shipped 
Name, Telephone Number, and Institution 
Follow the directions given in the phone message. 
For questions regarding the shipment, Dr. Paietta and her staff can be 
reached at the cell phone numbers provided on the recorded 
message. Please always try Dr. Paietta first. Questions can also be 
addressed to Dr. Paietta via e-mail (epaietta@earthlink.net), however, 
please do not use e-mail for shipment notifications. 
Heparinized bone marrow and peripheral blood samples or EDTA 
peripheral blood samples, coagulated blood in red top tubes and 
buccal cells must be sent fresh (on the day of collection) on cool 
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packs (do not freeze and do not use ice cubes) by overnight courier 
(preferably Federal Express) to arrive within 24 hours to: 
Elisabeth Paietta, Ph.D. 
Montefiore Medical Center-North Division (Wakefield) 
600 East 233rd Street 
6th Floor, Immunology Laboratory 
Bronx, New York 10466-2697 
Tel: (718) 920-9992 
FAX: (718) 920-1161 
An STS shipping manifest form must be generated and shipped with 
all sample submissions. 
Please enter all information into the STS, including time and date of 
specimen collection and peripheral blood WBC count and blast count. 
The LTSL is open to receive shipments Monday through Saturday. 
Shipments on Fridays for Saturday delivery must have “Saturday 
Delivery” marked on the overnight courier slip. 
If samples need to be drawn late at night, on Sunday, or on a holiday 
when Federal Express does not operate, keep the samples in a 
refrigerator between 10 and 15 degrees Celsius until the next day 
when it can be shipped. 
In general, always ship specimens the day before a holiday for 
delivery the day after the holiday. 
10.1.3.1 
Sample Processing and Routing 
Samples will be processed in ECOG-ACRIN’s Leukemia 
Translational Studies Laboratory and sent to Dr. Ari 
Melnick’s laboratory as frozen viable cells or isolated DNA 
if viable cells are not available. Dr. Melnick will perform his 
studies (Section 10.3) and/or forward DNA to Dr. Ross 
Levine for Dr. Levine’s studies (Section 10.4).  From the 
remaining specimen, an aliquot will be sent to GenPath for 
Array CGH studies. 
The priority of work is as follows: 1. Melnick  2. Levine  3. 
Array CGH at GenPath.  In some cases, RNA may not be 
available for epigenetic studies (Dr. Melnick), although 
DNA may be available for mutation analysis (Dr. Levine) 
and Array CGH (GenPath).Bone marrow and peripheral 
blood smears may be forwarded to Dr. Daniel Arber at 
Stanford University for morphology review. 
Dr. Elisabeth Paietta’s laboratory will perform the P-
glycoprotein and CXCR4 expression studies as outlined in 
Section 10.5. 
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10.2 
Cytogenetic Review  
The cytogenetic review will be performed at the Mayo Clinic Cytogenetic 
Laboratory. 
10.2.1 
Sample Submission Schedule and Preparation Guidelines 
Karyotypes must be collected and submitted at the following time 
points: 
• 
Enrollment/Baseline 
• 
Time of Outcome Following Induction (Prior to Consolidation) [at 
time of response assessment or off-study, whichever occurs first] 
• 
End of Consolidation (Prior to 2nd Randomization - Step 3) 
• 
Relapse 
NOTE: 
Karyotypes are required at all time points. 
10.2.1.1 
Karyotypes (MANDATORY AT ALL TIME POINTS) 
Within 30 days of specimen collection at each time point, 
investigators must send the two (2) original karyotypes per 
clone, FISH results, institution’s cytogenetic laboratory 
report, the Leukemia Cytogenetic Form (#365R) to the 
ECOG-ACRIN Cytogenetic Committee. 
NOTE: 
If cytogenetic studies are not successful, submit 
the laboratory report and #365R form to Gary 
Hicks by either mail or fax. 
Original karyotypes will be returned, upon written request, 
when the review and analysis are complete. 
10.2.1.2 
Shipping Guidelines 
Log the shipment into the ECOG-ACRIN STS the day of 
shipment.  If the STS is unavailable, an Generic Specimen 
Submission Form (#2981) must be submitted with the 
karyotypes.  Once STS is available, retroactively log the 
shipment into STS, using the actual collection and shipping 
dates. 
Direct questions to Gary Hicks at Tel: (507) 284-2950 or 
Fax: (507) 284-0043. 
The forms and karyotypes are to be shipped to: 
Gary Hicks 
Mayo Clinic Cytogenetic Laboratory 
970 Hilton 
200 First Street, S.W. 
Rochester, MN 55905 
Tel: (507) 284-2950 
Fax: (507) 284-0043 
An STS shipping manifest form must be generated and 
shipped with all submissions. 
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10.3 
Epigenetics  
E2906 incorporates a randomization to maintenance therapy with decitabine, a 
methyltransferase inhibitor, and affords a unique opportunity to study the 
epigenetic phenotype in AML at presentation and in remission. The following 
clinical & basic hypotheses will be studied in Dr. Ari Melnick’s laboratory at Weill 
Cornell Medical College, New York, NY. 
10.3.1 
Clinical 
Our preliminary data show that AML comes in different epigenetic 
subtypes, and that a phenotype of epigenetic instability seems to 
correlate with responsiveness with DNA methylransferase inhibitors. 
In addition to the epigenetic unstable phenotype, many of the more 
defined AML epigenetic subtypes had different medical outcomes in 
retrospective studies and so may be highly clinically relevant. 
Interestingly, gene expression profiling failed to identify several of 
these subtypes alone, demonstrating the power of epigenetic analysis 
to capture important biological differences in AML. Finally, the 
integration of gene expression and epigenetic signatures were shown 
to synergistically capture biological differences between patients with 
leukemia. 
Based on these data we predict that patients who present with AML 
and epigenetic instability will be the better candidates to respond to 
decitabine maintenance. Therefore we propose to perform expression 
and methylation profiling on all patients enrolled in 2906 and correlate 
their integrated epigenetic signatures with response to decitabine. Of 
equal importance we also predict that specific integrated epigenetic 
subtypes associated with differential clinical outcomes will be 
confirmed in this prospective study and could lead to an important 
advance in leukemia classification.  The integrated signatures 
captured upon enrollment of these patients will be used to 
prospectively validate, confirm and possibly expand our ability to 
accurately segregate patients into biologically distinct cohorts. We 
plan to use these data to direct the design of future ECOG-ACRIN 
clinical trials.  
10.3.2 
Basic 
Data from the published literature and our laboratory indicate that 
progressive alteration of epigenetic signatures in bone marrow cells 
occurs during normal aging. We hypothesize that certain epigenetic 
signatures associated with aging might constitute an epigenetic field 
defect that could result in leukemogenesis.  We will examine the 
epigenetic profiles of remission marrow in patients randomized to 
observation vs decitabine in E2906 to determine whether epigenetic 
signature of apparently morphologically normal bone marrow is 
predictive of relapse or response to decitabine maintenance. Our data 
performed in fractionated vs unfractionated marrow from the same 
individuals indicate that epigenetic signatures indicative of aberrant 
epigenetic programming are equally readily evident in either case, and 
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are readily distinguishable between normal and abnormal samples. 
Therefore, we expect our experimental approach to successfully 
capture indications of epigenetic field defects in this patient cohort. 
10.4 
Somatic Mutation Analysis  
Following the model applied to E1900, a study in younger AML, E2906 will 
delineate the full spectrum of genetic lesions occurring in elderly patients with 
AML to discover potential differences dependent on age. The following clinical & 
basic hypotheses will be studied in Dr. Ross Levine’s laboratory at Memorial 
Sloan Kettering Cancer Center, New York, NY. 
10.4.1 
Clinical 
High throughput mutational profiling of patients enrolled in E1900 
allowed us to delineate the somatic mutational frequencies of all 
known leukemia oncogenes and tumor suppressors in a large patient 
cohort who presented with de novo AML <60 years of age. 
Specifically, we found that mutations in ASXL1 and PHF6 are 
associated with an adverse outcome in the entire E1900 cohort and 
with primary induction failure. On the other hand, the IDH R140Q 
mutation was associated with an improved outcome in younger AML. 
In addition, we found that TET2, ASXL1, PHF6, DNMT3A, and WT1 
mutations are associated with an adverse outcome in intermediate 
risk AML, including in patients without FLT3 mutations. Moreover, we 
found that patients with mutated DNMT3A, which occurs in 30% of 
younger AMLs, benefited from randomization to 90mg daunorubicin. 
By contrast, there was no benefit of higher dose chemotherapy for 
patients with wild-type DNMT3A, suggesting that DNMT3A mutations 
represent a novel biomarker with immediate therapeutic relevance. 
Analogous studies are currently underway to determine somatic 
genetic lesions in elderly AML from ECOG trial, E3999.  
10.4.2 
Methodology 
Samples from E2906 will be analyzed as patients are accrued to the 
trial. High quality genomic DNA will be extracted from mononuclear 
cells provided by the LTSL, as done previously for E1900 and E3999 
specimens. Control DNA will be isolated from normal T-cell 
contaminating the leukemia specimens or from remission samples. 
Genomic DNA from blasts and control cells will be subjected to 
Agilent SureSelect sequence capture followed by bar-coding and 
sequencing on our HiSeq2000. Genomic DNA will also be processed 
for reduced representation bisulfate sequencing and examined on the 
HiSeq2000. Excess DNA will be stored and made available to ECOG-
ACRIN for distribution to other approved investigators. Validation will 
be done using amplicon based sequencing on our existing 
resequencing platform (used for E1900 and E3999 mutational studies) 
to facilitate higher throughput candidate gene mutational analysis of 
genomic DNA. Wherever possible, mutations will be analyzed in 
remission or T-cell DNA to ascertain whether specific alterations are 
somatic or in the germline. We will use our suite of computational 
biostatistical tools for identifying candidate somatic mutations. The 
data set will be evaluated for genetic signatures that distinguish 
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patient subtypes using unsupervised methods such as hierarchical 
clustering, principal component analysis, and consensus clustering. 
Signatures of co-occurring lesions will be determined using 
supervised methods including moderated T tests with correction for 
multiple testing, LEMMA, random forest, etc. The biological 
connectivity between gene sets and their genomic features will be 
derived using tools including iPAGE, FIRE, IPA, etc. We will use a 
series of statistical approaches to determine whether lesions in 
specific recurrently affected genes or pathways indicate risk of 
chemotherapy failure, disease recurrence or survival. In addition to 
univariate and multivariate analyses, we will use machine-learning 
algorithms like SuperPC and BDVAL to identify genetic, epigenetic, 
and integrated classifiers. All mutations detected will be validated by 
repeat PCR and sequencing on the unamplified diagnostic sample. 
Wherever possible, matched control DNA (remission or T-lymphocyte 
DNA) will be resequenced to determine if candidate disease alleles 
are somatic or present in germline. 
10.5 
AML Prognostic Factors & Mechanisms of Resistance 
Clofarabine (like cytarabine) requires active cellular uptake by equilibrative or 
concentrative nucleoside transporters, but is not a substrate for P-glycoprotein 
(Pgp). We hypothesize that the relative expression of Pgp will determine 
differential activity of clofarabine in subsets of patients who overexpress these 
transporters, and manifest in the CR rate. An aliquot of BM from pre-treatment 
will be evaluated for Pgp expression by flow cytometric assessment  of the 
binding of antibody MRK-1686, an antibody directed against a cell-surface epitope 
of Pgp. In addition, expression of CXCR4, which has been associated with 
inferior prognosis in retrospective studies in younger patients, will be assessed 
prospectively in this study by flow cytometry in the LTSL to correlate the intensity 
of its expression with other established prognostic factors (in particular with 
cytogenetics)87. 
10.6 
Array CGH Studies 
Cytogenetic analysis provides valuable diagnostic and prognostic information for 
the evaluation of hematologic malignancies and solid tumors.  Traditional and 
new techniques have been applied in clinical oncology with a variable range of 
resolution and sensitivity including chromosome analysis, fluorescence in situ 
hybridization (FISH) and more recently DNA array-based technologies. 
Karyotypic analysis in metaphase cells is considered a routine test for the 
detection of chromosomal aberrations associated with the diagnosis, prognosis 
and treatment of the malignant disorders.  However, many genomic 
abnormalities remain undetected by karyotyping due to its relatively low 
resolution (~5 Mb) and inadequate sensitivity (it depends on the sample cell 
distribution and proliferation).  Alternatively, FISH has been applied for the 
detection of diagnostic/prognostic relevant chromosomal abnormalities in 
interphase nuclei.  Although this technique increases the sensitivity for the 
identification of targeted lesions (~1 Mb), the resolution is still low since the 
detection of unbalanced rearrangements is not well defined.  Recently, the 
application of DNA array-based technologies such as array comparative genomic 
hybridization (aCGH) and single nucleotide polymorphism arrays (SNP-A) have 
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enabled the detection of previously undetected copy number changes (CNC) and 
the more precise determination of genomic break points of regions that are gain 
or loss with an increased resolution and sensitivity. 
The use of aCGH in the identification of CNC and correct mapping of genomic 
aberrations breakpoints is becoming the gold standard for the diagnosis of 
hematological malignancies such as lymphoid, plasma cell and myeloid 
disorders.  The used of aCGH has uncovered the complexity of the CNC 
observed in those malignancies and suggests the need for further investigation.  
Several of these genomic alterations are known to affect oncogenes or tumor 
suppressor genes.  Classical examples include amplification of ERBB2 and MYC 
oncogenes and deletions of RB1, PTEN and CDKN2A tumor suppressor genes. 
Considering the high resolution and sensitivity of aCGH in addition to the 
flexibility of using DNA instead of cultured cells, we developed and clinically 
validated a custom microarray using the Agilent platform.  GenArray™ - 
Molecular Karyotyping is a non-FDA approved test based in aCGH technology 
for the detection of genomic imbalances of diagnostic, prognostic and therapeutic 
significance in hematological malignancies.  The microarray contains 
approximately 64,000 DNA oligonucleotide probes.  The design of the probes is 
based on the human genome sequence build hg18 (NCBI build 36).  The probes 
are spaced at approximately 50 kb intervals across the genome and there is a 
higher probe density in some cancer-relevant regions (1 probe every 10 kb).  The 
current array cannot detect balanced chromosomal rearrangements (reciprocal 
translocations, Robertsonian translocations, balanced inversions and insertions) 
and imbalances of areas not covered by the microarray.  In addition, the 
oligonucleotide probes in this microarray are not designed to detect point 
mutations, epigenetic effects or loss of heterozygosity (LOH) events. 
In order to detect genomic gains and losses, 500ng of genomic DNA from the 
patient and a normal reference DNA are differentially labeled with fluorophores 
(Cy3 and Cy5) and competitively hybridized to the array (40 hours).  Normal 
reference DNA is promega male and female reference DNA which have been 
optimized extensively and CLIA certified for GenPath’s Array CGH assay.  The 
relative fluorescence intensities of the hybridized DNA from each sample (at 
each oligonucleotide probe) is measured by a high-resolution scanner and 
presented as a log (base 2) ratio of the sample/reference intensity signal.  A plot 
of these ratios across the genome sequence displays any variations between the 
patient and reference DNA sample.  The array has a resolution of 250 kb (5 
consecutive probes with a minimum absolute ratio value of 0.25).  The detection 
limit/sensitivity for chromosomal alterations is approximately 20-30% (can be 
detected is present in at least 20-30% of the DNA) with 100% specificity.  DNA 
gains or losses greater than 1 Mb will be reported and alterations less than 1 Mb 
in size will be interpreted at the discretion of the geneticist. 
GenPath’s team of experts in the microarray laboratory has accumulated 
significant experience in Array CGH testing.  GenPath has run the GenArray in 
more than 3,000 cases in hematological malignancies with an overall failure rate 
of less than 1%, primarily due to the poor quality of DNA.  GenPath currently runs 
300 cases a month and the volume continues to grow.  The group has 
discovered novel and recurrent alterations not detected by cytogenetics of FISH 
analyses in myeloid, lymphoid and plasma cell neoplasms with important clinical 
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tumor biology, clarify the cancer classification systems, and help in the 
identification of useful molecular markers of prognostic or therapeutic value. 
All samples will be cross validated by Dr. Melnick’s next-generation sequencing 
and Q-PCR platforms for focused lesions that are of particular interest.  In 
addition, germline DNA will be sequenced as part of Dr. Melnick’s correlative 
study and in cases where germline copy number abnormalities by sequencing 
are detected validation by PCR will be completed.   GenPath may provide further 
validation by running repeat arrays. 
The number of samples tested is contingent upon the number of patient samples 
with sufficient testing material.  Ideally, all patients in E2906 will have Array CGH 
studies completed but that is most likely not possible given specimen constraints. 
10.7 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst  
Important:  Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
10.7.1 
Study Specific Notes 
Generic Specimen Submission Form (#2981) will be required only if 
STS is unavailable at time of sample submission.  Indicate the 
appropriate Lab ID# on the submission form: 
• 
0002 = ECOG-ACRIN Leukemia Translational Studies Laboratory 
• 
0003 = ECOG-ACRIN Cytogenetic Laboratory 
Retroactively enter all specimen collection and shipping information 
when STS is available. 
10.8 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted, and used on the above mentioned 
laboratory correlative studies will be submitted to the ECOG-ACRIN Operations 
Office - Boston on a monthly basis. Inventories will be submitted electronically by 
any laboratory holding and/or using any specimens associated with this study. All 
other correspondence should be addressed to the attention of the Translational 
Science Team. 
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10.9 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory correlative studies will be 
submitted to the ECOG-ACRIN Operations Office - Boston by the central 
laboratory on a quarterly basis. The quarterly cut-off dates are March 31, June 
30, September 30 and December 31. Data is due at the ECOG-ACRIN 
Operations Office - Boston 1 week after these cut-off dates.  
10.10 Banking 
The residuals and/or derivatives of samples collected for this study will be 
retained at the LTSL/ECOG-ACRIN Leukemia Tissue Bank for possible use in 
ECOG-ACRIN approved future studies. If future use is denied or withdrawn by 
the patient, the samples will be removed from consideration for use in any future 
study. 
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11. 
Records to Be Kept 
Please refer to the E2906 Forms Packet for the forms submission schedule and copies 
of all forms. The E2906 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office - Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office - Boston to CTEP by electronic means. 
11.1 
Records Retention  
This study is being conducted under an IND exemption and is not intended to 
support any FDA-related filings. However, ECOG-ACRIN requires clinical 
investigators to retain all trial-related documentation, including source 
documents, for at least one year from the posting of the final technical report of 
the outcome of this trial to support any publication of the data. 
12. 
Please contact the ECOG-ACRIN Operations Office - Boston prior to destroying 
any source documents.Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
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Rowe JM. Treatment of acute myelogenous leukemia in older adults. Leukemia. 
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Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in 
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Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical 
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Dombret H, Chastang C, Fenaux P, et al. A controlled study of recombinant 
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Heil G, Chadid L, Hoelzer D, et al. GM-CSF in a double-blind randomized, 
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Stone RM, Berg DT, George SL, et al. Postremission therapy in older patients 
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TA & Greaves MF (ed 7th edition). Philadelphia: Saunders; 2002. 
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Wheatley K. for the AML Collaborative Group: A systematic collaborative 
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anthracyclines) as induction therapy for acute myeloid leukemia. Br J Haematol. 
1998;103:100-109. 
29. 
Baer MR, George SL, Dodge RK, et al. Phase 3 study of the multidrug resistance 
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30. 
Cripe L, Li, Xiaochun, Litzow, M, et al. A randomized, placebo-controlled, double-
blind trial of the MDR modulator, Zosuquidar, during conventional induction and 
post-remission therapy for pts greater than 60 years of age with newly diagnosed 
acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS): 
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31. 
Rubin EH, Andersen JW, Berg DT, Schiffer CA, Mayer RJ, Stone RM. Risk 
factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and 
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Phase III Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard 
Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission 
Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute 
Myeloid Leukemia in Older Adults (Age ≥ 60 Years) 
 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #5] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #5 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines. 

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Phase III Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard 
Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission 
Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute 
Myeloid Leukemia in Older Adults (Age ≥ 60 Years) 
 
Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and the 
NCI to increase awareness of the importance of clinical trials and improve accrual and follow-
through. We appreciate your help in this effort. 
____________________________________________________________________________ 
PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions remain 
unanswered in cancer.  With the participation of people like you in clinical trials, we will improve 
treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will maintain 
very close contact with you. This will allow me to provide you with the best care while learning 
as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
[PHYSICIAN NAME] 
 
Rev. 7/14 

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Phase III Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard 
Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission 
Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute 
Myeloid Leukemia in Older Adults (Age ≥ 60 Years) 
 
Appendix III 
 
E2906 Clofarabine Study Drug Request Form 
Rev. 6/12 

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Study Drug Request Form: Investigator-Sponsored Trials (ISTs) 
 
 
 
 
 
 
Please email the completed form to: GTOdrugorders@genzyme.com or fax to: 908-635-5941.  
Allow 5-7 business days for initial drug orders and 3-5 business days for drug re-orders from the 
acknowledgement of order receipt to the date of delivery. There are no weekend or Monday deliveries.  
For questions regarding shipments, please contact Jay Tiña @ 908-981-4535 / jay.tina@sanofi.com or 
Joseph Silverman @ 908-981-3981 / joseph.silverman@sanofi.com. 
Do Not Write Below this Line - for Genzyme Use Only 
Medical Affairs 
The following documents are required for initial shipments:             
1. IRB Approval Letter…………………………….
 Y   
 N  
 N/A 
2. Signed Research Agreement………………… 
 Y   
 N  
 N/A 
3. IND Status document…………………………..
 Y   
 N  
 N/A 
4. clinicaltrials.gov listing………………………….
 Y   
 N  
 N/A 
5. IACUC Approval Letter (Pre-clinical only)……
 Y   
 N  
 N/A 
 
Signature: ______________________________  Date: _____________ 
Fax this form to CPRS: 508-424-4484 
CPRS 
Processed by: ___________________  Date: _________ 
Reviewed by:  ___________________  Date: _________
 
Date of  
Request:  
 
Date  
Needed  
By:  
 
Protocol No. / Title:   
 
 
 
 
Attention:  
 
Ship to Address: 
 
 
 
 
 
Phone #:  
 
Fax #:  
 
Email:  
PI:  
Site #:  
 
Institution:  
 
Qty 
Units 
Study Drug Requested 
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
Comments: 
Comments: 
 
POR#: ___________ 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
142 
Phase III Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard 
Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission 
Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute 
Myeloid Leukemia in Older Adults (Age ≥ 60 Years) 
 
Appendix IV 
 
E2906 Decitabine Study Drug Request Form 
Site Instructions: All shaded areas must be completed before forwarding the drug 
request to the ECOG-ACRIN Operations Office - Boston. 
Email completed form as an attachment to 900.drugorder@jimmy.harvard.edu or fax to 
617-632-2063. The ECOG-ACRIN Drug Team will approve and email the order to Fisher 
Clinical Services  
Secondary Contact (Research Nurse/Study Coordinator/Pharmacist): 
Name: 
 
Title: 
 
Telephone: 
 
Email: 
 
Investigator Address  
(Please include contact information): 
Ship Supplies To 
(If different from Investigator Address): 
Institution Name: 
 
Institution Name: 
 
Address: 
 
 
 
 
 
Address: 
 
City, State, Zip: 
 
City, State, Zip: 
 
Telephone: 
 
Telephone: 
 
Email: 
 
Email: 
 
 
Date Requested:  
(MM/DD/YY) 
 
Study Drug: 
Decitabine (50 mg vials) 
Shipment Must Reach Destination By: (MM/DD/YY) -
Deliveries are not made on Mondays 
 
 
ECOG-ACRIN Patient Sequence Number: 
 
# Vials Needed: 
(3 vials needed per cycle, please order 2 cycles at a time) 
NOTE: Vial packages contain 5 vials per package 
 
Materials ID#: 
 
 
To Be Completed By The ECOG-ACRIN Drug Team 
Cgroup/Inst/Affil: 
CTEP ID #: 
IRB Approval Date:  
Regulatory Docs:  
Completed By: 
Date:  
Rev. 2/12 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
143 
Phase III Trial of Clofarabine as Induction and Post-Remission Therapy vs. Standard 
Daunorubicin & Cytarabine Induction and Intermediate Dose Cytarabine Post-Remission 
Therapy, Followed by Decitabine Maintenance vs. Observation in Newly-Diagnosed Acute 
Myeloid Leukemia in Older Adults (Age ≥ 60 Years) 
 
Appendix V 
 
ALESE Baseline Questionnaire 
 
Acute Leukemia Epidemiology & Survival In ECOG (Alese Study) 
 
Dear Patient, 
 
Thank you for taking part in the Acute Leukemia Epidemiology & Survival in ECOG study being 
done by Leukemia researchers as part of the E2906 trial. The purpose of this study is to identify 
environmental, lifestyle, and medical factors related to the development of acute myeloid 
leukemia (AML) in adults and assess the potential impact of those factors on outcomes after 
treatment. 
The study consists of filling out this survey.  This survey asks for general information about you 
as well as information about your personal habits, such as smoking and alcohol use, medical 
history, and environmental and chemical exposures you may have had on the job or in your 
everyday life. It will take about 20-30 minutes to fill out. Please answer every question as best 
you can. If you do not know the answer to a question, please provide your best guess.  
In order to obtain the most valid information possible, it is important that this survey is 
answered by the person it was given to. If you are not able to fill in the survey, you can 
discuss with your physician or research nurse who will assist you. If you have any other 
questions as you fill out this survey, please discuss this with the physician or research nurse 
looking after you. You or they may also contact the Study Chair (Dr. James Foran) with 
questions at foran.james@mayo.edu.  
 
Warm regards, 
 
 
James M. Foran, MD 
Study Chair, E2906 
 
 
 
 
 
Mayo Clinic  
Jacksonville, Florida  
 
 
 
 
Rev. 2/13 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
144 
 
About You 
 
Thank you for helping with this survey.  Your answers are important. 
 
Please take the time to read and answer each question carefully. 
 
For some questions, you will PUT AN X OR     IN THE BOX that goes with your answer, 
like this: 
 
EXAMPLE 1: 
 
1.  Are you?   1 X Male    2     Female   or     1    Male    2     Female 
 
You will sometimes be told to skip over some questions in this survey.  When this 
happens, you will see an arrow with a note that tells you what questions to answer next, 
like this: 
 
EXAMPLE 2: 
 
     YES              Go to Question 13 
 
 
For some questions, you will enter letters or numbers in boxes.  Please enter one letter 
or number per box and stay within the box, like this: 
 
 
EXAMPLE 3: 
 
 
A    B     2    8   
 
 
 
Today’s date:                 /                / 
                                                                                              
 
 
1.  How old are you?                Years old 
 
 
 
 
 
2.  Are you?   
 
1  
Male 
2  
Female 
 
 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
145 
3.  Are you of Hispanic or Latino origin? 
 
1  
No 
2  
Yes 
 
 
4.  Which best describes your racial background (choose the one you most identify 
with)? 
 
1  
White 
2  
Black or African American 
3  
Native Hawaiian or other Pacific Islander 
4  
Asian  
5  
American Indian/Alaska Native  
6  
Other, please specify: _______________________ 
 
 
5.  What is your marital status? 
 
1  
Married or living in a marriage-like relationship 
2  
Widowed 
3  
Divorced 
4  
Separated 
5  
Never married 
 
 
6.  What is the highest level of schooling you have completed?  (Mark one.) 
 
1  
8th grade or less 
2  
Some high school 
3  
High school graduate 
4  
GED (high school equivalency) 
5  
1 to 3 years vocational education beyond high school 
6  
Some college 
7  
College graduate 
8  
One or more years of graduate or professional school 
9  
Other, please specify:____________________ 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
146 
7.  Thinking back to two years ago, which of the following best describes your total 
household income? 
 
1  
Up to $10,000 
2  
More than $10,000 up to $20,000 
3  
More than $20,000 up to $40,000 
4  
More than $40,000 up to $60,000 
5  
More than $60,000 up to $80,000 
6  
More than $80,000 up to $100,000 
7  
More than $100,000 
 
 
8.    Which State do you live in, and how many years have you lived there?   
 
 
 
 
State           
 
 
 
Years 
 
9.    How many years have you lived in your current residence?    
 
          Years 
 
Lifestyle 
 
 
10.  Have you ever used any tobacco products for six months or longer?  (Please 
include cigarettes, cigars, pipes, snuff, and chewing tobacco.) 
 
1  
No 
 
Go to question 18. 
2  
Yes 
 
 
 
11.  At any time in your life have you smoked cigarettes for six months or longer? 
 
1  
No 
 
Go to question 17. 
2  
Yes 
 
 
 
 
 
12.  If yes, at what age did you start smoking cigarettes? 
               
                     Years old 
 

ECOG-ACRIN 
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Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
147 
 
13.  Do you currently smoke cigarettes? 
 
1  No 
 
15.  Before stopping, how many 
cigarettes did you usually 
smoke per day? 
2  Yes 
 
   
 
14. How many cigarettes do you 
usually smoke per day? 
 
 
                  Cigarettes per day 
                     Cigarettes per day 
 
16.  How old were you when you 
stopped smoking cigarettes? 
 
 
 
 
                      Years old 
 
17.  Going back two years ago and thinking about your life up until that point, did you 
use any of these tobacco products for 12 months or longer? 
 
a.  Cigar 
1  
No 
2 
 Yes 
 
For how many years?              Years 
b.  Pipe 
1  
 
No 
2 
 Yes 
 
For how many years?              Years 
 
c.  Snuff 
1  
No 
2 
 Yes 
 
For how many years?              Years 
d.  Chewing 
Tobacco 
1  
 
No 
2  
Yes 
  
For how many years?              Years 
  
 
 
18.  Not including the past two years, have you ever lived with someone who regularly 
smoked cigarettes around you? 
 
1  
No 
 
 
2  
Yes 
 
 
 
 
 
 
 
 
19.  How many years did they smoke cigarettes around you regularly? 
               
                        Years  
 
 

ECOG-ACRIN 
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Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
148 
20.  Not including the past two years, have you ever worked with someone who 
regularly smoked cigarettes around you? 
 
1  
No 
 
 
2  
Yes 
 
 
 
 
 
21.  How many years did they smoke cigarettes around you regularly? 
               
                        Years  
 
22.  During your entire life, have you had 12 drinks or more of any kind of alcohol?  
(One drink of alcohol is equal to one can of beer, one glass of wine, or one shot of 
liquor, such as whiskey, brandy, or gin.) 
  
1  
No 
 
Go to question 24. 
2  
Yes 
 
 
 
 
23.  If yes, for each age group below, how many drinks of alcohol did you usually have? 
 
 
 
None 
Less 
than 1 
each 
month 
1 to 3 
each 
month 
1 to 2 
each 
week 
3 to 6 
each 
week 
1 to 2 
each 
day 
3 or 
more 
each 
day 
 
 
a.  Less than 18 
years old 
  a. 
  b. 
  c. 
  d. 
  e. 
  f. 
  g. 
 
 
b.  18-22 years old 
  a. 
  b. 
  c. 
  d. 
  e. 
  f. 
  g. 
 
 
c.  23-30 years old 
  a. 
  b. 
  c. 
  d. 
  e. 
  f. 
  g. 
 
 
 
d.  31-49 years old 
  a. 
  b. 
  c. 
  d. 
  e. 
  f. 
  g. 
 
 
 
e.  50-65 years old 
  a. 
  b. 
  c. 
  d. 
  e. 
  f. 
  g. 
 
 
 
f.  66+ years old 
  a. 
  b. 
  c. 
  d. 
  e. 
  f. 
  g. 
 
 
Not that 
age yet 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
149 
Physical Activity 
 
24.  In the past 10 years, thinking about the job you held the longest, which of the 
following categories best describes the activity level at that job: 
 
1  
Sedentary occupation    (You spend most of your time sitting.  Examples: office 
worker, bus/cab driver, etc.) 
 
2 
 
 
Standing occupation      (You spend most of your time standing or walking. 
However, your work does not require intense physical 
effort. Examples: waitress/waiter, flight attendant, shop 
assistant, hairdresser, guard, etc.) 
 
3 
 
 
Physical work                (This involves some physical effort including handling 
of heavy objects and use of tools.  Examples: plumber, 
cleaner, nurse, sports instructor, electrician, carpenter, 
etc.) 
 
4 
 
Heavy manual work       (This involves vigorous physical activity including 
handling of very heavy objects.  Examples: docker, 
miner, bricklayer, construction worker, etc.) 
 
 
25.  During most of your adult life, when walking outside of your home, how often did 
you walk for more than 10 minutes without stopping? 
 
1  
Rarely or never 
 
Go to question 28. 
2  
1 to 3 times each month 
3  
1 time each week 
4  
2 to 3 times each week 
5  
4 to 6 times each week 
6  
7 or more times each week 
 
26.  How many minutes did you usually walk? 
 
                       Minutes 
 
27.  What was your usual speed (check the one which applies most often)?  
1  
Casual (less than 2 miles an hour) 
2  
Average or normal (2 to 3 miles an hour) 
3  
Fairly fast (3 to 4 miles an hour) 
4  
Very fast (more than 4 miles an hour) 
5  
Don’t know 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
150 
 
28.  During most of your adult life, how often did you usually do strenuous or very 
hard exercise?  (Exercise where you work up a sweat and your heart beats fast.  
Do not include walking outside of your home or any physical activity associated with 
any jobs.)  
 
1  
Rarely or never 
2  
1 to 3 days per month 
3  
1 day per week 
4  
2 days per week 
5  
3 to 4 days per week 
6  
5 or more days per week 
 
 
29.  During most of your adult life, how often did you usually do moderate exercise? 
(Exercise that is not exhausting, but your breathing and heart rate are above resting 
levels.  Do not include walking outside of your home or any physical activity 
associated with any jobs.)   
 
1  
Rarely or never 
2  
1 to 3 days per month 
3  
1 day per week 
4  
2 days per week 
5  
3 to 4 days per week 
6  
5 or more days per week 
 
30.  During most of your adult life, how often did you usually do mild exercise?  
(Exercise that is not exhausting.  Do not include walking outside of your home or 
any physical activity associated with any jobs.)   
 
1  
Rarely or never 
2  
1 to 3 days per month 
3  
1 day per week 
4  
2 days per week 
5  
3 to 4 days per week 
6  
5 or more days per week 
Examples: 
aerobics 
aerobic dancing 
jogging 
tennis 
swimming laps 
vigorous yard or housework   
Examples: 
biking outdoors  
using an exercise machine like a stationary bike or 
treadmill 
calisthenics 
easy swimming 
popular or folk dancing 
golfing without a cart 
moderate yard or housework 
Examples: 
slow dancing 
bowling 
golfing with a cart 
hunting 
gardening 
light housework 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
151 
Medical History 
 
31. Not including the past two years, did you regularly take any of the following 
medications?  (Do not include occasional use of less than once per month) 
 
 
Medication 
 
Average days per 
month used 
On days used, 
number of pills taken 
Total number 
of years 
taken 
 
a. 
 
Aspirin (regular or 
extra strength, 163 mg 
or more, e.g., Bufferin, 
Anacin, Bayer, 
Excedrin, Ecotrin, etc.) 
 
 
 
 
 
 
             days per month 
  
 
             
 
 
 
 
             number of pills 
 
 
 
 
 
 
 
             years 
  
 
1  
No 
 
 
2  
Yes 
 
 
3 
 
Not 
sure 
 
What was your main reason for using this? 
 
 
 
 
 
 
__________________________________________________ 
 
b. Aspirin (baby 
or low dose, 
162 mg or 
less) 
 
 
 
   
              days per 
month 
 
 
 
   
              number of pills 
 
 
 
   
              years 
 
 
1  
No 
 
 
2  
Yes  
 
3 
 
Not 
sure 
 
What was your main reason for using this? 
 
 
 
 
 
 
__________________________________________________ 
c. Ibuprofen (e.g., Motrin, 
Advil, Nuprin, Mediprin, 
etc.) 
 
 
 
   
              days per month 
 
 
 
   
              number of 
pills 
 
 
 
   
              
years 
 
 
1 
 
No 
 
 
2  
Yes  
 
3 
 
Not 
sure 
 
What was your main reason for using this? 
 
 
 
 
 
 
__________________________________________________ 
 
(Question 31 continued) 
 
 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
152 
 
Medication 
 
Average days per 
month used 
On days used, 
number of pills 
taken 
Total 
number 
of years 
taken 
 
d. Acetaminophen (e.g., 
Tylenol, Phenaphen, etc.) 
 
 
 
 
              days per month 
  
 
 
 
 
              number of 
pills 
 
 
 
 
 
              
years 
  
 
1 
 
No 
 
 
2  
Yes  
 
3 
 
Not 
sure 
 
What was your main reason for using this? 
 
 
 
 
 
 
__________________________________________________ 
 
 
e. Other anti-
inflammatory 
analgesics (e.g., 
Naprosyn, Anaprox, 
Aleve, Voltaren, 
Feldene, Toradol, 
Indocin, etc.) 
 
       
              days per 
month 
 
 
 
 
   
              number of 
pills 
 
 
 
 
   
              years 
 
 
1  
No 
 
 
2  
Yes  
 
3 
 
Not 
sure 
 
What was your main reason for using this? 
 
 
 
 
 
 
__________________________________________________ 
  
f. COX-2 inhibitors (e.g., 
Celebrex, Vioxx, Bextra, 
etc.) 
 
 
 
   
              days per month 
 
 
 
   
              number of pills 
 
 
 
   
             
years 
 
 
1  
No 
 
 
2  
Yes  
 
3 
 
Not 
sure 
 
What was your main reason for using this? 
 
 
 
 
 
 
__________________________________________________ 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
153 
The following questions are about your height and weight at different 
ages.  If you don’t remember exactly what they were, please give your 
BEST GUESS.  (Women, if you were pregnant at any of these ages, 
please provide your weight when you were not pregnant.) 
 
 
Height 
 
32.  How tall are you (without shoes on)?  (Round up to nearest inch) 
 
       Feet               Inches 
 
 
 
33.  How tall were you (without shoes on) at about age 18?  (Round up to nearest inch) 
 
       Feet               Inches 
 
Weight 
 
34.  How much do you currently weigh? 
                    
                    Pounds 
 
 
35.  What was your weight 2 years ago? 
                    
                    Pounds 
 
 
36.  What was your weight  
 
 
 
a.  at about age 18? 
                    
                    Pounds 
 
 
b.  at about age 35? 
                    
                    Pounds 
 
 
c.  at about age 50? 
                    
                    Pounds 
 
 
d.  at about age 65? 
                    
                    Pounds 
 
Not that 
age yet 
37.  What is your maximum adult weight (the 
most you ever weighed since you were 
18 years old)?  (Remember, do not 
include pregnancy weight.) 
                    
 
 
 
                    Pounds 
 
 
 
38.  Not including the past two years, did you ever have a blood transfusion? 
1  
No  
Go to question 42. 
2  
Yes 
 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
154 
39.  If yes, please list the condition (e.g., neonatal jaundice, anemia, childbirth, trauma) 
or surgical procedure (e.g., heart surgery or hip surgery) for which you had the 
blood transfusion.  (Start with the one when you were the youngest first and fill in as 
many details as you remember.  Please check “Don’t know” if you don’t know.) 
 
Condition or surgical 
procedure 
Age at 
transfusio
n 
Number of 
transfusions 
 How much of this 
blood was your 
own? 
a._____________________ 
 
 
Years old 
 
 
Number 
1  None 
2  Some 
3  All 
4  Don’t know 
b._____________________ 
 
 
Years old 
 
 
Number 
1  None 
2  Some 
3  All 
4  Don’t know 
c._____________________ 
 
 
Years old 
 
 
Number 
1  None 
2  Some 
3  All 
4  Don’t know 
 
 
40.  Were you transfused for more than three conditions or surgical procedures? 
 
1  
No  
Go to question 42. 
2  
Yes 
 
 
41.  If yes, please provide details on the last condition or surgical procedure for 
which you were transfused, excluding the last 12 months. 
 
 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
155 
 
Condition or surgical 
procedure 
Age at 
transfusion 
Number of 
transfusions 
 How much of this 
blood was your own? 
____________________ 
 
 
 
Years old 
 
 
Number 
1  
None 
2  
Some 
3  
All 
4  
Don’t know 
 
 
42.  Did you ever have an organ transplant (including a bone marrow transplant)? 
 
1        No                       Go to question 44. 
2        Yes 
 
 
43.  If yes, what organs were transplanted and what year did you receive them? 
Organ 
a.  
_______________________________________ 
b.  
_______________________________________ 
 
Year received 
 
 
 

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Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
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44.  Were you told by a doctor or other health professional that you had any of the 
following conditions?  (Please mark a box even if you have never had the 
condition.) 
 
Condition 
No 
Yes 
Not Sure 
If yes, age you 
were first 
diagnosed 
A. Hyperthyroidism 
 
 
 
 
B, Hypothyroidism 
 
 
 
 
C. Peptic ulcer 
 
 
 
 
D. Ankylosing 
spondylitis 
 
 
 
 
E. Heart disease, 
angina or heart attack 
 
 
 
 
F. High blood pressure 
 
 
 
 
G. Diabetes mellitus 
(sugar diabetes not 
associated with 
pregnancy) 
 
 
 
 
H. Rheumatoid 
arthritis 
 
 
 
 
I. Osteoarthritis 
(degenerative arthritis) 
 
 
 
 
J. Crohn’s disease 
 
 
 
 
K. Ulcerative colitis 
 
 
 
 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
157 
(Question 44 continued) 
Were you told by a doctor or other health professional that you had any of the following 
conditions? (Please mark a box even if you have never had the condition.) 
 
Condition 
No 
 
Not 
Sure 
Yes 
 
 
If yes, age 
you were 
first 
diagnosed 
l Celiac disease 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
m Sjögren’s disease or sicca 
syndrome 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
n Lupus or Systemic lupus 
erthyomatosis 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
o Polymyositis, dermatomyositis, 
or polymyalgia rheumatica 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
p Eczema 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
q Contact dermatitis 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
r Cirrhosis of the liver or liver 
damage 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
s Infectious mononucleosis 
(“mono”) 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
t Chronic fatigue syndrome 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
u 
Epilepsy (convulsions or 
seizures not related to high 
fever) 
1 
                  
 
2 
                  
 
3 
                  
 
 
 
Years old 
 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
158 
 
45. Have you ever been diagnosed with cancer? (Please do not include your recent 
leukemia diagnosis.)  
1 
 
No 
 
   Go to question 47. 
2 
 
Yes 
46. If yes, please provide: 
 
 
Type of cancer 
Age you were 
first diagnosed 
Treatments received         
(Mark all that apply) 
a. ________________________ 
 
 
 
 
Years old 
 
 Surgery 
 
 Radiation 
 
 Chemotherapy 
 
 Other, specify: 
______________ 
 
 None 
 
 Don’t know 
b. ________________________ 
 
 
 
 
Years old 
 
 
Surgery 
 
 
Radiation 
 
 
Chemotherapy 
 
 
Other, specify: 
______________ 
 
 
None 
 
 
Don’t know 
c. _______________________ 
 
 
 
 
Years old 
 
 
Surgery 
 
 
Radiation 
 
 
Chemotherapy 
 
 
Other, specify: 
______________ 
 
 
None 
 
 
Don’t know 
Rev. 12/13 

ECOG-ACRIN 
E2906 
Cancer Research Group 
Version Date: November 27, 2018 
 
NCI Update Date: July 25, 2013 
159 
 
If male 
 
Go to question 62. 
If female please continue below.  
Female History 
 
47.  At what age did you start having menstrual periods? 
 
                    Years old 
 
48.  Have you ever taken birth control pills for any reason? 
1        No                       Go to question 50. 
2        Yes 
 
49.  Please mark the total number of years you took the pills. 
 
1  
Less than 1 year 
2  
1 to 4 years 
3  
5 to 9 years 
4  
10 to 14 years 
5  
15 to 19 years 
6  
20 to 24 years 
7  
25 or more years 
 
50.  Have you gone through menopause (the change of life) or had surgery that caused 
you to completely stop having menstrual periods? 
 
1        No                         Go to question 53. 
2        Yes                       
3        Not Sure 
 
51.  At what age did you have your last menstrual period?        
 
                     Years old 
 
Rev. 12/13 

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Version Date: November 27, 2018 
 
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52.  What type of menopause did you have? 
 
1  
Natural menopause  
2  
Hysterectomy with uterus and both ovaries removed 
3  
Hysterectomy with uterus and one or neither ovary removed 
4  
Only ovaries removed 
5  
Surgery, but not sure what type 
6  
Other, please specify: _____________________________________ 
 
53.  Have you ever taken any hormones/estrogen, such as Premarin, for symptoms or 
conditions related to menopause (to treat hot flashes, to prevent bone loss, or for 
the change of life)?  (Include pills, skin patches, implants, creams, suppositories, 
and shots.) 
 
1        No          
2        Yes 
 
54. How old were you when you first used hormones/estrogen for symptoms or 
conditions related to menopause? 
 
                 Years old 
 
55. Are you currently taking hormones/estrogen for symptoms or conditions related to 
menopause? 
 
1  
No 
 
2  
Yes 
 
56. How many years altogether did you take hormones/estrogen for symptoms or 
conditions associated with menopause?  (Do not count any time when you 
stopped.) 
 
1  
Less than 1 year 
2  
1 to 3 years 
3  
4 to 5 years 
4  
6 to 10 years 
5  
11 to 15 years 
6  
16 or more years 
 
 
 

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57.  Not including the past two years, did you ever take oral progestins (such as 
Provera) in combination with estrogens for symptoms or conditions related to 
menopause? 
 
1  
No 
 
2  
Yes 
 
58.  Have you ever been pregnant?  (This includes live births, stillbirths, miscarriages, 
tubals [ectopics], and abortions.) 
 
1        No              
2        Yes 
 
59.  How many pregnancies led to live births? 
 
                     Number of pregnancies 
 
60.  How old were you at the birth of your first child? 
 
                     Years old 
 
61.  How old were you at the birth of your last child? 
 
                     Years old 
 
Family History 
Family health history is an important part of learning about the cause and 
prevention of diseases like myeloid leukemia.  We also know that people may not 
know their complete family health history.  As you read these questions, please 
know that we understand this and we hope that you just do the best you can. 
 
 
62.  Were you adopted?    
 
1        No 
2        Yes 
 
Most people in the United States have ancestors who came from other parts of 
the world.  Many people have ancestors who came from more than one country. 
 
 
63.  What country or countries did your biological father’s ancestors come from? 
________________________________________________________________ 
 

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64.  What country or countries did your biological mother’s ancestors come from? 
___________________________________________________________ 
 
65.  Counting only persons related to you by blood (including siblings who are now 
deceased and half siblings), please provide numbers for each of the following.  
 
 
a. How many brothers, including half brothers, 
do/did you have? 
 
 
Brothers 
 
 
 
 
Don’t know 
 
b. How many sisters, including half sisters, 
do/did you have? 
 
 
 
 
Sisters 
 
 
 
 
Don’t know 
 
c. How many of your children are male?  
Include any of those who may have died. 
 
 
 
 
Sons 
 
 
 
d. How many of your children are female?  
Include any of those who may have died. 
 
 
 
 
Daughters  
 
 
66.  Have your parents, brothers, sisters, sons, or daughters related by blood (include 
half brothers and sisters) ever been diagnosed as having cancer?  (Please include 
leukemia, lymphoma, breast cancer, and non-melanoma skin cancer, as well as 
any other cancer.) 
 
1        No                       Go to question 67. 
2        Yes 
2        Not Sure 
 
 
 
 
 
 
 
For each cancer, please mark which relative was diagnosed and their age 
at diagnosis.  
 

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A.  Leukemia 
 
 
  
B.  Lymphoma 
 
Age at 
diagnosis   
Age at 
diagnosis 
  Father  
 
 
 
 
 
Father  
 
  Mother 
 
 
 
 
 
Mother 
 
  Brother 
 
 
 
 
 
Brother 
 
  Sister 
 
 
 
 
 
Sister 
 
  Son  
 
 
 
 
 
Son  
 
  Daughter 
 
 
 
 
 
Daughter 
 
  
Other Blood Relative: 
_____________________ 
 
 
 
 
 
Other Blood Relative: 
______________________ 
 
  Other Blood Relative: 
_____________________ 
 
 
 
 
 
Other Blood Relative: 
______________________ 
 
 
 
C.  Breast Cancer 
 
 
  
D.  Non-melanoma Skin Cancer 
Age at 
diagnosis   
(includes basal cell and 
squamous cell carcinomas) 
Age at 
diagnosis 
 
 
Mother 
 
 
 
  
Father  
 
 
 
Sister 
 
 
 
  
Mother 
 
 
 
Daughter 
 
 
 
  
Brother 
 
 
 
 
 
 
Other Blood Relative: 
_____________________ 
 
 
 
  
Sister 
 
  
Son 
 
 
 
 
 
 
Other Blood Relative: 
_____________________ 
 
 
 
  
Daughter 
 
  
Other Blood Relative: 
_____________________ 
 
 
 
 
 
 
 
  
Other Blood Relative: 
_____________________ 
 
 
 
 

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E.  Other cancer, please 
specify: 
   
F.  Other cancer, please 
specify: 
_____________________ 
Age at 
diagnosis   ____________________ 
Age at 
diagnosis 
 
 
Father  
 
 
 
 
 
Father  
 
 
 
Mother 
 
 
 
 
 
Mother 
 
 
 
Brother 
 
 
 
 
 
Brother 
 
 
 
Sister 
 
 
 
 
 
Sister 
 
 
 
Son  
 
 
 
 
 
Son  
 
 
 
Daughter 
 
 
 
 
 
Daughter 
 
 
 
Other Blood Relative: 
_________________ 
 
 
 
 
 
Other Blood Relative: 
__________________ 
 
 
 
Other Blood Relative: 
_________________ 
 
 
 
 
 
Other Blood Relative: 
__________________ 
 
Farm/Rural Living 
 
67. Have you ever lived on a farm or in a rural area (a community of 1,000 people or 
less)?   
 
1        No                       Go to question 70 below. 
2        Yes 
 
68. For how many years have you lived on a farm or in rural area? 
 
                     Years 
 
69. While you lived on a farm or in a rural area, what was the main source of your 
drinking water? (Check the one that applied most often.) 
 
1  
Municipal water supply 
2  
Private well 
3  
Spring 
4  
Bottled water 
5  
Other, please specify:  _______________________________ 
 

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70.  Have you ever worked or lived on a farm at least half time for more than 1 year? 
 
1  
No 
 
Go to question 78. 
2  
Yes 
 
71.  At any time you worked or lived on a farm, what were the major income-producing 
animals that you raised?  (Mark all that apply) 
 
 
No animals 
 
 
 
 
 
Beef/non-dairy cattle 
 
 
 
 
 
Dairy cattle 
 
 
 
 
 
Hogs/swine 
 
 
 
 
 
Poultry 
 
 
 
 
 
Sheep 
 
 
 
 
 
Eggs 
 
 
 
 
 
Other farm animals:  
______________________________________________ 
 
72.  At any time you worked or lived on a farm, what were the major income-producing 
crops that you raised?  (Mark all that apply) 
 
 
No crops  
 
Cucumbers 
 
Soybeans 
 
Apples 
 
Grapes 
 
Sugar beets 
 
Alfalfa 
 
Green peppers 
 
Strawberries 
 
Blueberries 
 
Hay 
 
Sweet potatoes 
 
Cabbage 
 
Oats 
 
Tomatoes 
 
Corn, popcorn 
 
Peas 
 
Trees 
 
Corn, field corn 
 
Potatoes 
 
Watermelon 
 
Corn, seed corn 
 
Snapbeans 
 
Wheat 
 
Corn, sweet corn 
 
Sorghum 
 
 
 
Other fruit:  
_____________________________________________________ 
 
Other vegetables:  
________________________________________________ 
 
Other small grains:  
_______________________________________________ 
 

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On the Job Pesticide Exposure 
 
73.  Did a veterinarian ever tell you that any livestock on any farm you may have worked 
on had leukemia or lymphoma caused by a virus? 
1        No                       Go to question 78. 
2        Yes 
 
74.  Was it cattle? 
1        No 
2        Yes 
 
75.  When was the first time you recall this happening? 
                                                  Years ago 
 
76.  Was it chickens? 
1        No 
2        Yes 
 
 
77.  When was the first time you recall this happening? 
                                                  Years ago 
 
78.  As part of any job, have you ever personally mixed or applied any pesticides, crop, 
livestock, or structural insecticides, herbicides, fungicides, or fumigants?  Include 
pesticides used for farm use, commercial application, or other workplace that uses 
these chemicals.  (We will ask about your home exposure near the end of the 
survey.) 
 
1        No                       Go to question 83. 
2        Yes 
 
79.  How many years did you personally mix or apply these products? 
 
1  
1 year or less 
2  
2 to 5 years 
3  
6 to 10 years 
4  
11 to 20 years 
5  
21 to 30 years 
6  
31 years or more 
 

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80.  When you personally mixed these products, what additives did you generally use? 
 
1  
Solvents (like diesel fuel) 
2  
Fertilizers 
3  
Other pesticides 
4  
Surfactants, crop oil concentrates 
5  
Other, please specify: ____________________ 
6  
Don’t usually use additives  
 
81.  As part of any job, have you personally mixed or applied any of the following 
pesticides? (Mark all that you have used) 
 
Crop, Nursery, Lawn, and Garden Insecticides 
 
Ambush, Pounce, Asana, or other permethrin 
or pyrethroid products 
 
Dylox 
or 
other 
trichlorfon 
products 
 
Counter or other terbufos products 
 
Furadan, 
Curaterr, 
or 
other 
carbofuran products 
 
Dyfonate or other fonofos products 
 
 
 
Crop/Poultry/Livestock/Animal Confinement Area Insecticides 
 
Lorsban, Dursban, or other chlorpyrifos 
products 
 
Temik or other aldicarb products 
 
Co-Ral or other coumaphos products 
 Thimet, Rampart, or other phorate 
products 
 
Ectiban, Atroban, Permetrina or other 
permethrin products 
 
Aldrin (no longer on the market) 
 
Vapona, Duravos, or other dichlorvos or 
DDVP products 
 
Chlordane (no longer on the market) 
 
Forlin, Gamaphex, or other lindane products 
 
Dieldrin (no longer on the market) 
 
Malathion 
 
DDT (no longer on the market) 
 
Parathion (ethyl or methyl) 
 
Heptachlor (no longer on the market) 
 
Sevin, Carbamine, or other carbaryl products 
 
Toxaphene (no longer on the market) 
 
Spectricide, Dianon, or other diazinon 
products 
 
 
 
Herbicides 
 
AAtrex, Atranex, or other atrazine products 
 
Prowl or other pendimethalin products 

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Banvel, Metambane, or other dicamba 
products 
 
Treflan, Trilin, Commence, or other 
trifluralin products 
 
Bladex, Match, or other cyanazine products 
 
2, 4-D 
 
Dual, Cycle, or other metolachlor products 
 
Classic or other chlorimuron ethyl 
products 
 
Eradicane, Eptam, or other EPTC products 
 
Lexone, Sencor, or other metribuzin 
products 
 
Lasso, Chimiclor, or other alachlor products 
 
Paraquat 
 
Pursuit or other imazethapyr products 
 
Silvex or other 2,4,5 T P products (no 
longer on the market) 
 
Roundup, Jury, or other glyphosate products 
 
2,4,5 T (no longer on the market) 
 
 
(Question 81 continued) 
 
As part of any job, have you personally mixed or applied any of the following pesticides? 
(Mark all that you have used) 
 
 
Fungicides 
 
Bravo, Evade, Daconil 2787, or other 
chlorothalonil products 
 
Manex, Manzate, Dithane Z-78, or other 
maneb or mancozeb products 
 
Orthocide, Clomitane, or other captan 
products 
 
Ridomil, Subdue, or other metalaxyl 
products 
 
Benlate, Tersan, or other benomyl products 
 
Zirex, Corozate, or other ziram products 
 
Fumigants (gases or liquids that turn to gas when released, used in enclosed 
spaces, or to treat soil) 
 
Broom-O-Gas, Brom-O-Sol, or other methyl 
bromide products 
 
Carbon tetrachloride/carbon disulfide 
(80/20 mix) (no longer on the market) 
 
Phostoxin, Gastoxin, or other aluminum 
phosphide products 
 
EDB, E-D-Bee, Bromofume, or other 
ethylene dibromide products (no 
longer on the market) 
 

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82.  Are there any other pesticides you were exposed to? 
1  
No 
2  
Yes (If yes, please list them below and include reason for use.) 
 
 
 
 
83.  What has been your usual job during most of your adult life, that is, the job or type 
of job you have held the longest?  (Please record your job title.  For example: 
gasoline engine assembler, grinder operator, farmer, homemaker, sales manager, 
registered nurse, etc. If military – please include description of job duties and 
highest rank.) 
 
Job Title: 
 
Description: 
 
 
 
84.  For how many years did you work at this job?    
 
              Years 
 
85.  Have you ever been exposed to any of the following substances listed below, for at 
least 8 hours per week for 1 year or more, either on a job or working on a hobby? 
(Check no or yes beside each substance and if yes, write in approximately how 
many years you were exposed in the boxes provided.) 
  
No 
Yes 
Number of Years 
a. Cutting oils, motor vehicle oils 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
b. Asphalt, tar or pitch 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
c. Benzene or other solvents 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
d. Gasoline 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
e. Pesticides 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
f. Herbicides 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 

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(Question 85 continued) 
 
Have you ever been exposed to any of the following substances listed below, for 
at least 8 hours per week for 1 year or more, either on a job or working on a 
hobby? (Check no or yes beside each substance and if yes, write in 
approximately how many years you were exposed.) 
 
  
No 
Yes 
Number of 
Years 
g. Fertilizers 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
h. Arsenic 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
i. Mineral oils 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
j. Soot 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
k. Creosote 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
l. Inks, dyes, tanning solutions 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
m. Dry cleaning agents 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
n. Rubber and rubber products 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
o. Vinyl chloride, plastics 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
p. Acrylic and oil-based paints 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
q. Varnish, lacquers, or glues 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
r. Paraffin waxes 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
s. Coal dust 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
t. Metals (lead, nickel, zinc) 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
u. Radioactive materials 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
v. X-ray machines 
1 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 

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Information About Your Home 
 
We are interested in chemicals that may have been used in places where you 
lived, including inside homes, on lawns/yards, or on family gardens.  Do not 
include use of these chemicals if they were used as part of your job (such as 
farming activities, work at a nursery, or other workplace that uses these 
chemicals). 
 
 
86.  Have insecticides (chemicals that kill insects) ever been used around your home, 
lawn/yard, or family garden at any of the residences where you have lived? 
 
1        No                       Go to question 89. 
2        Yes 
 
87.  If yes, approximately how many years (total) were these products used? 
 
1  
4 years or less 
2  
5 to 15 years 
3  
16 to 30 years 
4  
31 years or more 
 
88.  Did you personally handle any of these products? 
 
1  
No 
2  
Yes  
 
89.  Have fertilizers (not including pesticides) ever been used on lawns/yards at any of 
the residences where you have lived? 
 
1  
No 
 
Go to question 92. 
2  
Yes 
 
90.  Approximately how many years (total) were these products used? 
 
1  
4 years or less 
2  
5 to 15 years 
3  
16 to 30 years 
4  
31 years or more 
 
91.  Did you personally handle any of these products? 
 
1  
No 
2  
Yes  

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92.  Have herbicides (chemicals that kill weeds) ever been used around your home, 
lawn/yard, or family garden at any of the residences where you have lived? 
 
1  
No 
 
Go to question 95. 
2  
Yes 
 
 
93.  If yes, approximately how many years (total) were these products used? 
 
1  
4 years or less 
2  
5 to 15 years 
3  
16 to 30 years 
4  
31 years or more 
 
94.  Did you personally handle any of these products? 
 
1  
No 
2  
Yes  
 
95.  Have pesticides or chemicals to control or prevent termites ever been used at any 
of the residences where you have lived? 
 
1        No                       Go to question 98. 
2        Yes 
 
96.  If yes, approximately how many years (total) were these products used? 
 
1  
4 years or less 
2  
5 to 15 years 
3  
16 to 30 years 
4  
31 years or more 
 
 
97.  Did you personally handle any of these products? 
 
1  
No 
2  
Yes  
 
 
 
 

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98.  Have you ever had cats as pets? 
 
1        No                       Go to comments below. 
2        Yes 
 
99.  If yes, did a veterinarian ever tell you that any of your cats had feline leukemia or 
lymphoma? 
 
1        No                       Go to comments below. 
2        Yes 
 
 
100.  If yes, how many of your cats had feline leukemia or lymphoma?    
 
                              Cats 
  
 
Comments: 
 
Please provide any comments or additional information below. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ALESE Study 
Future Contact 
 
 
 
 
  
A.  How was the survey completed? 
 
1  
I filled it out myself 
2  
Someone helped me fill it out 
 
 
 
3  
Spouse 
 
 
4  
Child 
 
 
5  
Other, please specify: _______________________ 
 
 
B.  What is your date of birth?                 /               / 
 
                                          Month       Day               Year 
 
C.  Would you like to receive any updates or study results? 
 
1  
No 
2  
Yes 
 
D.  We would like to know if it would be okay to contact you in the future to see if 
you have learned anything more about your family health history and to 
record any changes. This would probably be about 3 to 5 years from now.  
Would this be okay?   
 
1  
No 
2  
Yes 
 
Please turn to the next page. 
 
 
 
 
 
To maintain your confidentiality, this page will be stored 
separately from your responses to the survey. 
 

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Please record your name and address so that we may contact you in the future: 
 
 
 
 
 
 
 
 
 
 
 
 
In case you move and we cannot find you, please provide the names, addresses, 
and phone numbers for two people that will always know where you are (such as 
your spouse, siblings, or children). 
 
Person #1 
 
 
 
 
 
 
 
 
 
 
 
Person #2 
Name 
  
Relationship 
to 
you 
  
Street Address 
  
City, State Zip 
  
Phone 
 ( __ __ __ )  __ __ __ - __ __ __ __ 
 
 
Thank you for your time!
Name 
 
 
Street 
Address 
 
 
City, State Zip  
 
Phone 
 
( __ __ __ )  __ __ __ - __ __ __ __ 
Name 
  
Relationship 
to 
you 
  
Street Address 
  
City, State Zip 
  
Phone 
 ( __ __ __ )  __ __ __ - __ __ __ __ 

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Return Instructions for Sites - ALESE Questionnaire 
Optimally, the ALESE Questionnaire will be completed by the patient within the first 
week of the beginning of their treatment on E2906.  
*Please add the Pt. ID number to the top of each page of the questionnaire prior to 
mailing. 
Please mail the questionnaire to the investigator after patient has completed it: 
James M. Foran, M.D. 
Attn: ALESE 
Mayo Clinic, Florida 
Division of Hematology & Medical Oncology 
4500 San Pablo Road 
Jacksonville, FL 32224 
The questionnaire may be scanned and sent directly as pdf to the investigator’s e-mail: 
foran.james@mayo.edu