CHOA-AML: A Pilot Study for Newly Diagnosed Pediatric Patients With Acute Myeloid Leukemia (AML)
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, AML, Childhood
Sponsor: Emory University

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AflacLL1901 
CHOA-AML: A Pilot Study for Newly Diagnosed Pediatric Patients with Acute Myeloid 
Leukemia (AML) 
 
NCT04326439 
 
Version Date: March 1st, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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AflacLL1901 
CHOA-AML: A Pilot Study for Newly Diagnosed Pediatric Patients with Acute Myeloid 
Leukemia (AML) 
 
 
Study Chair 
 
Himalee Sabnis, MD, MSc 
Assistant Professor, Pediatric Hematology Oncology 
ECC - 426J, Emory Children’s Center 
2015 Uppergate Drive 
Atlanta, GA 30322 
Phone: 404-727-3285 
Fax: 404-785-9248 
Email: 
 
 
 
Study Vice Chair 
 
Frank Keller, MD 
Associate Professor, Pediatric Hematology Oncology 
1405 Clifton Rd, NE 
Atlanta, GA 30322 
Phone: 404-785-3124 
Fax: 404-785-9248 
Email:

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Contents 
STUDY COMMITTEE ................................................................................................................................... 4 
EXPERIMENTAL DESIGN SCHEMA ..................................................................................................... 7 
1.1 
GOALS AND OBJECTIVES ......................................................................................................... 8 
1.2 
Primary Objective .................................................................................................................... 8 
1.3 
Secondary Objectives ............................................................................................................... 8 
1.4 
Exploratory Objectives ........................................................................................................... 8 
2.1 
BACKGROUND ............................................................................................................................... 9 
2.2 
Introduction and rationale for development of chemotherapy backbone for 
de novo AML ................................................................................................................................ 9 
2.3 
Rationale for incorporation of Gemtuzumab Ozogamicin (GO) ................................. 13 
2.4 
Rationale for use of Dexrazoxane with anthracyclines ................................................. 14 
2.5 
Use of FLT3-ITD inhibitors in AML ...................................................................................... 15 
2.6 
Genomic testing in de-novo AML ........................................................................................ 16 
3.1 
STUDY DESIGN AND POPULATION ...................................................................................... 16 
3.2 
Patient Inclusion Criteria ....................................................................................................... 16 
3.3 
Patient Exclusion Criteria ...................................................................................................... 17 
3.4 
Definitions .................................................................................................................................. 18 
3.3 
Protection of Human Subjects ............................................................................................. 18 
3.4 
Aflac Office Monitoring Schedule ...................................................................................... 18 
4.0 
RISK STRATIFICATION ................................................................................................................ 19 
5.1 
TREATMENT PROGRAM ........................................................................................................... 20 
5.2 
Induction 1 – ADE (10+3+5) with GO ................................................................................. 20 
5.3 
Induction 1 for FLT3-ITD patients – ADE (10+3+5) with GO with Sorafenib ............ 21 
5.4 
Induction II – MA .................................................................................................................... 22 
5.5 
Induction II for FLT3-ITD patients – MA with Sorafenib ............................................... 23 
5.6 
Intensification I – AE ............................................................................................................. 24 
5.7 
Intensification I for FLT3-ITD patients – AE with sorafenib ......................................... 25 
5.8 
Intensification II – HD ARAC/LASP ..................................................................................... 26 
5.9 
Intensification II for FLT3-ITD patients – HD ARAC/LASP with sorafenib ............... 27 
6.1 
DOSE MODIFICATION FOR TOXICITIES ............................................................................. 27 
Common Terminology Criteria for Adverse Events (CTCAE) .............................................. 27 
6.2 
Allergy to Asparaginase ......................................................................................................... 28 
6.3 
Allergy to Etoposide .............................................................................................................. 28 

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6.4 
Cardiac Toxicity ........................................................................................................................ 28 
6.5 
Coagulopathy ............................................................................................................................ 29 
6.6 
Hepatic Toxicity ........................................................................................................................ 29 
6.7 
Neurologic Toxicity ............................................................................................................... 30 
6.8 
Pancreatitis .............................................................................................................................. 30 
6.9 
Renal Toxicity ............................................................................................................................ 30 
6.10 Thrombosis ................................................................................................................................ 31 
6.11 Sinusoidal Obstruction Syndrome (SOS, formerly VOD) of the Liver ...................... 31 
6.12 Palmar-Plantar Erythrodysesthesia Syndrome, Skin Pain that impacts 
ADLs or Rash Maculo-Papular ........................................................................................... 31 
7.1 
SUPPORTIVE CARE ...................................................................................................................... 32 
7.2 
General Guidelines .................................................................................................................. 32 
7.3 
Infection Prophylaxis ............................................................................................................ 33 
8.1 
EVALUATIONS/DATA TO BE ACCESSIONED ....................................................................... 34 
8.2 
Data Collection .......................................................................................................................... 34 
8.3 
Data Confidentiality ................................................................................................................. 34 
8.4 
Data and Safety Monitoring ................................................................................................... 35 
9.1 
AGENT INFORMATION .............................................................................................................. 36 
9.2 
CYTARABINE - ALL ROUTES ............................................................................................... 36 
9.3 
DAUNORUBICIN ....................................................................................................................... 39 
9.4 
ETOPOSIDE INJECTION ....................................................................................................... 40 
9.5 
GEMTUZUMAB OZOGAMICIN ............................................................................................... 42 
9.6 
ASPARAGINASE (ERWINIA CHRYSANTHEMI) ............................................................... 44 
9.7 
SORAFENIB TOSYLATE ......................................................................................................... 46 
10.1 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA ......................................................................................................................................... 50 
10.2 Criteria for Removal from Protocol Therapy .................................................................... 50 
10.3 Off Study Criteria ...................................................................................................................... 51 
11.0 STATISTICAL CONSIDERATIONS ............................................................................................ 51 
APPENDIX I – SORAFENIB DOSING NOMOGRAM ......................................................................... 53 
APPENDIX II – CYP3A4 INDUCERS AND INHIBITORS ................................................................... 54 
REFERENCES ............................................................................................................................................ 55 

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STUDY COMMITTEE 
 
Himalee Sabnis, MD, MSc 
Assistant Professor, Pediatric Oncology 
426J Emory Children’s Center 
2015 Uppergate Drive 
Atlanta, GA 30322 
Phone: 404-727-3285 
Fax: 404-785-9248 
Email:  
 
Kristen Allen, MPH 
Research Epidemiologist 
Children’s Healthcare of Atlanta 
W342 Health Sciences Research Building 
1760 Haygood Drive NE 
Atlanta, GA 30322 
Phone: 404-785-5437 Ext 14001 
Email:  
 
Frank Keller, MD 
Associate Professor, Pediatric Oncology 
1405 Clifton Rd, NE 
Atlanta, GA 30322 
Phone: 404-785-3124 
Email:  
Nia Moyer 
Study Coordinator 
1001 Johnson Ferry Road, NE 
Atlanta, Georgia 30342 
Phone: 404-785-1007 
Email:  
 
Sharon M. Castellino, MD, MSc 
Associate Professor, Pediatric Oncology 
5455 Meridian Mark Road, Suite 400 
Atlanta, Georgia 30342 
Phone: 404-785-3616 
Email:  
 
William Woods, MD 
Professor, Pediatric Oncology 
W358 Health Sciences Research Building 
1760 Haygood Drive NE 
Atlanta, GA 30322 
Phone: 404-785-6171 
Email:  
 
Melinda Pauly, MD 
Assistant Professor, Pediatric Oncology 
W-350, Heath Sciences Research Building 
1760 Haygood Drive 
Atlanta, GA 30322 
Phone: 404-785-3730 
Fax: 404-727-4455 
Email: 
 
Tamara Miller, MD, MSCE 
Assistant Professor, Pediatric Oncology 
Emory + Children’s Pediatric Institute 
1405 Clifton Road NE 
Atlanta, GA 30322 
Phone: 404-785-4112 
Email:  
Kathryn Murray 
Study Coordinator 
1001 Johnson Ferry Road, NE 
Atlanta, Georgia 30342 
Phone: 404-785-9946 
Email:  
 
Anna Bennett, RN, MSN, CPNP 
Children’s Healthcare of Atlanta 
1405 Clifton Rd, NE 
Atlanta, GA 30322 
Phone: 404-785-1742 
Email:  
 
Lois Chukoian, RN, MSN, CPNP 
Children’s Healthcare of Atlanta 
5455 Meridian Mark Road 
Atlanta, GA 30342 
Phone: 404-785-3240 
Email: 
 
Stephanie Bernardo, RN, CPNP 
Children’s Healthcare of Atlanta 
1405 Clifton Rd, NE 
Atlanta, GA 30322 
Phone: 404-785-1742 
Email:  

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Waitman Aumann, MD 
Assistant Professor, Pediatric Oncology 
Emory + Children’s Pediatric Institute 
1405 Clifton Road NE 
Atlanta, GA 30322 
Phone: 404-785-1112 
Email:  
Jeff Switchenko, PhD, MS 
Assistant Research Professor 
Biostats and Bioinformatics 
718 Gatewood Road 
Atlanta , GA 30322 
Phone: 404-778-4157 
Email:  
 
Ryan Summers, MD 
Instructor, Pediatric Oncology 
E365 Health Sciences Research Building 
1760 Haygood Drive NE 
Atlanta, GA 30322 
Phone: 404-727-9183 
Email:  
 
Ritu Sachdeva, MD, FACC, FASE, FAAP 
Professor, Pediatric Cardiology 
1405 Clifton Road 
Atlanta, GA 30322 
Phone: 404-694-9318 
Email: 

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ABSTRACT 
 
Advances in risk stratification and therapy, have improved the event-free survival (EFS) and 
overall survival (OS) for pediatric acute myeloid leukemia (AML) to approximately 50% and 65% 
respectively, with current treatment strategies. Patients with good response to induction and/or 
those who lack high-risk cytogenetic and molecular features [classified as low-risk AML (LR-AML)] 
have even better outcomes with EFS and OS approaching 70% and 85% respectively; however, 
treatment-related toxicities remain a major concern. Anthracycline-based therapeutic regimens 
expose patients to the risk of anthracycline-induced cardiotoxicity. Therefore, strategies that 
reduce cardiac toxicities using tailored approaches while maintaining and/or improving outcomes 
are needed for all patients with AML. The Children’s Oncology Group (COG) regimens AAML1031 
and AAML0531 utilized an anthracycline-intensive backbone for LR-AML with cumulative 
anthracycline doxorubicin-equivalent doses of up to 492mg/m2. However, high-risk patients 
treated with chemotherapy alone received an intensified induction chemotherapy (using 
mitoxantrone-cytarabine) but with overall reduced doses of anthracycline-equivalent (342mg/m2). 
We piloted an institutional practice to treat all LR-AML patients with four cycle regimen (Aflac- 
AML) with the goal of reducing cumulative anthracycline exposure, thereby reducing the risk of 
cardiotoxicity, while providing three high-dose cytarabine courses. In this pilot institutional 
experience with this approach, we were able to maintain excellent outcomes for this low-risk group 
with 3-year event-free survival (EFS) and OS of 70.0% ± 0.1% and 85.5% ± 0.08% respectively, 
from end of course 1. Recent evolution in cytogenetic classification has further delineated risk 
groups in AML. Gemtuzumab ozogamicin (GO), an antibody-drug conjugate was shown to reduce 
relapse risk in patients with CC genotype with de-novo AML on COG study AAML0531. We 
propose to study the inclusion of gemtuzumab ozogamicin with our Aflac-AML chemotherapy 
backbone prospectively to validate its use in all pediatric AML and to further evaluate the approach 
with a cardiac-sparing goal in an expanded experience for low risk AML. 

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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Gemtuzumab ozogamicin (GO) dosing to be determined by SNP testing 
Risk Stratification – refer Section 4.0 
De-novo non-Down syndrome AML 
Induction 1 – ADE 10+3+5 with/without GO* 
Risk Assignment – Low/high 
Low Risk/ High Risk with 
no donor options 
High Risk 
• 
Plan for BMT in CR1 likely after 2 or 3 cycles 
depending on timing 
• 
Add FLT3 inhibitor in FLT3-ITD patients 
Induction 2 – Mitoxantrone/AraC 
BMT 
Induction 2 – Mitoxantrone/AraC 
Intensification 1 – AraC/Etoposide 
Intensification 1 
AraC/Etoposide or Capizzi AraC 
(HD AraC + Asparaginase) 
Intensification 2 – Capizzi AraC 
(HD AraC + Asparaginase) 

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1.0 
GOALS AND OBJECTIVES 
 
1.1 
Primary Objective 
To estimate the event-free survival (EFS) for newly diagnosed patients with pediatric acute 
myeloid leukemia using a risk stratified approach, including a modified chemotherapy regimen 
alone for subjects with low-risk features and allogeneic bone marrow transplantation for those 
with high risk features. 
 
1.2 
Secondary Objectives 
1. To estimate the overall survival (OS) for newly diagnosed patients with pediatric 
acute myeloid leukemia 
 
2. To estimate frequency of minimal residual disease (MRD) negative status after one 
cycle of induction chemotherapy for AML patients who received GO and those that 
did not receive GO. 
 
3. To estimate the disease-free survival (DFS) for patients who are MRD negative after 
induction 1, but lack high risk or lowest risk molecular and cytogenetic features as 
currently classified 
 
4. To estimate the incidence of early and late cardiotoxicity in patients with de novo 
AML that receive the four-cycle Aflac-AML regimen with the inclusion of dexrazoxane 
 
5. To estimate the frequency of infection and/or febrile neutropenia by chemotherapy 
regimen 
 
1.3 
Exploratory Objectives 
To describe the prevalence of molecular abnormalities in de-novo AML samples using 
comprehensive genomic testing. 
 
ENDPOINTS 
Primary Endpoints include the event-free survival defined as the time from on study to death, 
failure to achieve remission or relapse 
 
Secondary Endpoints include 
- 
disease-free survival (DFS) from end of first course of therapy, defined as time from end 
of first course of therapy to death or relapse 
- 
overall survival defined as time from study entry and from end of first course of therapy 
- 
proportion of patients that are in remission (MRD negative) after course 1 in both the GO 
and non-GO groups 
- 
Disease-free survival for patients who are MRD negative but lack high or low risk 
molecular and cytogenetic features, defined as time from end of first course of therapy to 
death or relapse 
- 
Estimate the proportion of patients that develop cardiac ejection fraction <50% (CTCAE 
V5.0 grade 2 or greater dysfunction) either during therapy (early cardiotoxicity) or after 
completion of therapy (late cardiotoxicity) 
- 
Estimate the proportion of patients who develop infection and/or febrile neutropenia 
during each treatment course 
- 
Estimate the effect of infection and/or febrile neutropenia on duration of hospital 
admission for each treatment course 

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Exploratory Endpoints include descriptive analysis of molecular abnormalities in de-novo 
AML. 
 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction and rationale for development of chemotherapy backbone for de 
novo AML 
 
Overall survival (OS) rates in pediatric acute myeloid leukemia (AML) approach 65-70% at three 
years with the current risk adapted chemotherapy and hematopoietic stem cell transplantation 
(HSCT) approach1. The recently concluded Children’s Oncology Group (COG) trial in pediatric 
de-novo AML AAML1031 (2011 – 2017) and its precursor trial AAML0531 (2006 – 2010) used a 
chemotherapy backbone adapted from the Medical Research Council (MRC) AML trials in order 
to improve overall outcomes2-4. This backbone comprised of an induction course of chemotherapy 
with cytarabine, daunorubicin and etoposide. Patients were risk stratified into low, intermediate 
and high risk groups on AAML0531 based on their cytogenetic and molecular features and their 
response at the end of this first cycle of induction chemotherapy1. Patients on AAML0531 received 
5 cycles of chemotherapy if they did not meet criteria for consideration of HSCT in first remission 
(Table 1). In addition, patients were randomized to receiving gemtuzumab ozogamicin (GO) at 
study entry and received this drug along with chemotherapy in Induction 1 and Intensification 2. 
Based on results from the MRC12 trial and preliminary analysis of AAML0531, the fifth course of 
chemotherapy was deleted from the chemotherapy backbone for AAML10313. The risk 
stratification evolved over the years with the improvement in multi-dimensional flow cytometry 
(MDFC) and AAML1031 stratified patients into low and high risk categories using response 
defined by MDFC (measurement of minimal residual disease –MRD) in addition to cytogenetic 
and molecular features5. 
 
2.1.1 Rationale for chemotherapy approach in children with low risk AML 
 
Based on the recent COG AAML1031 chemotherapy backbone, patients with low-risk AML 
received Induction II that is similar to Induction I and two more cycles of consolidation therapy 
which included two high-dose cytarabine (> 1gm/m2 per dose) courses in Intensification 1 and 
Intensification II. Patients with high-risk AML received an intensified second course (Induction II) 
of chemotherapy comprising of mitoxantrone and high dose cytarabine followed by two more high 
dose cytarabine containing courses (Intensification I and II) if allogeneic hematopoietic stem cell 
transplantation was not an option. Thus, these high-risk patients received a total of three courses 
with high-dose cytarabine as opposed to the low-risk patients who only received two. In addition, 
in the COG approach, low-risk AML patients received higher doses of anthracycline (492 mg/m2) 
and etoposide (1.75 g/m2) as compared to high-risk patients who did not receive a stem cell 
transplant2. Exposure to high doses of anthracycline and etoposide results high risk of 
cardiotoxicity and secondary malignancies with the cardiotoxicity risk being highest in patients 
with acute myeloid leukemia6,7. Mertens et al demonstrated that in the Childhood Cancer Survivor 
Study, cardiac causes and secondary malignancies accounted for excess mortality rates in the 
childhood cancer survivors as compared to the general population8. Cumulative anthracycline 
dosage >300 mg/m2 was associated with increased incidence of anthracycline-induced clinical 
heart failure9 thereby raising concerns that exposures as high as 492 mg/m2 in this low-risk cohort 
on AAML1031 could place them at very high risk of heart failure. 

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Patients with low-risk AML have favorable outcomes (3-year EFS and OS - 70% and 85% 
respectively) as compared to patients with high-risk AML (3-year EFS and OS – 30% and 48% 
respectively)1. Regardless of risk, disease relapse still remains the major cause of mortality1. 
Anthracyclines comprise an important component of relapsed AML therapy and higher doses of 
anthracyclines received in upfront AML therapy preclude their use at the time of relapse10. Given 
the concerns for long term toxicity without clear evidence of benefit to additional anthracyclines 
and etoposide in low-risk AML patients, we chose to adopt an institutional approach (Aflac-AML 
regimen) whereby newly diagnosed low-risk AML patients were treated with four cycles of 
chemotherapy that was identical to the high-risk group per AAML1031 which received 
chemotherapy alone. The aim of our regimen was to limit anthracycline exposure to 342 mg/m2 
and etoposide exposure to 1.25 g/m2 in low-risk AML patients while maintaining the same 
favorable outcomes. A comparison of the two regimens is outlined in the table (Table 1) below. 

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Table 1: Therapy regimen for Aflac-AML, AAML0531 and AAML1031 low-risk patients 
 
Aflac-AML 
COG AAML0531 
COG AAML1031 
Induction 1 
Cytarabine 
100 mg/m²/dose 
every 12 hours 
IV Days 1-10 
Cytarabine 
100 
mg/m²/dose 
every 12 hours 
IV 
Days 1-10 
Cytarabine 
100 
mg/m²/dose 
every 12 hours 
IV Days 1-10 
Daunorubicin 
50 mg/m²/dose 
IV Days 1, 3, 5 
Daunorubicin 
50 mg/m²/dose 
IV 
Days 1, 3, 5 
Daunorubicin 
50 mg/m²/dose 
IV Days 1, 3, 5 
Etoposide 
100 mg/m²/dose 
IV 
Days 1-5 
Etoposide 
100 
mg/m²/dose IV 
Days 1-5 
Etoposide 
100 
mg/m²/dose IV 
Days 1-5 
Induction 2 
Cytarabine 
1,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1-4 
Cytarabine 
100 
mg/m²/dose 
every 12 hours 
IV 
Days 1-8 
Cytarabine 
100 
mg/m²/dose 
every 12 hours 
IV 
Days 1-8 
Mitoxantrone 
12 mg/m²/dose 
IV 
Days 3-6 
Etoposide 
100 
mg/m²/dose IV 
Days 1-5 
Etoposide 
100 
mg/m²/dose IV 
Days 1-5 
----- 
----- 
Daunorubicin 
50 mg/m²/dose 
IV 
Days 1, 3, 5 
Daunorubicin 
50 mg/m²/dose 
IV 
Days 1, 3, 5 
Intensification 1 
Cytarabine 
1,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1-5 
Cytarabine 
1,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1-5 
Cytarabine 
1,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1-5 
Etoposide 
150 mg/m²/dose 
IV 
Days 1-5 
Etoposide 
150 
mg/m²/dose IV 
Days 1-5 
Etoposide 
150 
mg/m²/dose IV 
Days 1-5 
Intensification 2 
Cytarabine 
3,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1, 2, 8, 9 
Cytarabine 
1,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1-4 
Cytarabine 
1,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1-4 
Erwinia L- 
Asparignase 
25,000 
International 
Units/m²/dose IM 
Days 2, 9 
Mitoxantrone 
12 mg/m²/dose 
IV 
Days 3-6 
Mitoxantrone 
12 mg/m²/dose 
IV 
Days 3-6 
Intensification 3 
---- 
---- 
Cytarabine 
3,000 
mg/m²/dose 
every 12 hours 
IV 
Days 1, 2, 8, 9 
---- 
---- 
---- 
---- 
E. Coli L- 
Asparignase 
6,000 
mg/m²/dose IM 
Days 2, 9 
---- 
---- 
Abbreviations: COG, Children’s Oncology Group; IM, intramuscular; IV, intravenous 
 
We performed a retrospective review of our institutional cohort of patients with de novo low-risk 
AML between 0-21 years of age at diagnosis and were treated at the Aflac Cancer and Blood 
Disorders Center at Children’s Healthcare of Atlanta (CHOA) between January 1, 2011 and 

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December 31, 2016 (manuscript in progress). LR-AML was defined as the presence of NPM1, 
CEBPA, t(8;21)(q22;q22), inv(16)(p13.1q22), or less than 0.1% blasts (minimal residual disease 
– MRD negative) at end of Induction I, with the absence of unfavorable cytogenetic or molecular 
findings. A total of 27 patients with LR-AML treated per Aflac-AML were eligible for analysis with 
a mean follow up period from time of diagnoses of 3.3 years (SD 2.0). For the study population 
three-year EFS and OS from end of Induction 1 were 70.0% ± 0.1% and 85.5% ± 0.08% (Figure 
1A and B). 
 
Figure 1 A and B: EFS and OS for low-risk patients treated on Aflac-AML regimen 
 
 
Mean time to relapse for the 7 relapsed patients was 1.11 ± 0.16 years and mean survival time 
for the 3 patients who died was 1.18 ± 0.65 years (Table 2). Short-term cardiovascular outcomes 
were determined by echocardiogram measurements taken at diagnosis, between cycles of 
chemotherapy, and at follow-up. Four of 27 patients (14.8%) experienced grade 2 or higher left 
ventricular systolic dysfunction (LVSD) during therapy, two of which were associated with 
bloodstream infection, and 3 of these patients had normal cardiac function at the time of last 
follow-up. One patient had progressive LVSD which ultimately resulted in death (grade 5). We 
examined infectious toxicities, ICU admissions, and time to hematologic recovery in each course 
and compared them to the data available for the precursor AML trial AAML0531 where similar 
courses of treatment were used and found that they were comparable (Table 3). It is important to 
note that our institutional practice changed to include regular Levaquin and voriconazole 
prophylaxis midway through the reporting period for this data. 

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Table 2: Details of patients who relapsed on Aflac-AML regimen 
 
Pt # 
Karyotype/ FISH/molecular 
Time to relapse (from EOI) 
Current status 
1 
Inv 16 
1.31 yr 
Alive, CR2 >4yr 
2 
Inv 16 
1.4 yr 
Alive, CR2 >3yr 
3 
CEPBA mutation 
2.8 yr 
Alive, CR2 
4 
t(1;11)(p36,1;q23); complex 
0.35yr 
Died in relapse 
5 
t(x;21)(11.2;q13;p13) 
1.4 yr (MRD+) 
Died in second MRD+ 
relapse (no HSCT)* 
6 
t(9;11)(p22;q23) 
0.34 yr 
Died in relapse 
7 
t(11;19)(p23;p13.1) 
0.72 
Alive, relapse post BMT 
*developed severe irreversible cardiomyopathy during intensification 1 
 
 
Table 3: Comparison of infectious rate between Aflac-AML and AAML0531 regimens 
 
Induction I 
Induction II 
Intensification 
I 
Intensification 
II 
Intensification 
III 
Aflac 
0531 
Aflac 
0531 
Aflac 
0531 
Aflac 
0531 
Aflac 
0531 
ADE 
ADE 
MA 
ADE 
AE 
AE 
Capizzi 
MA 
Capizzi 
Documented 
infection 
32% 
35% 
60% 
37% 
29% 
49% 
60% 
69% 
N/A 
67% 
Neutropenic 
fever* 
52% 
31% 
16% 
22% 
20% 
23% 
17% 
23% 
N/A 
18% 
*in absence of documented infection 
Comparable regimens represented with like colors 
 
Given that our rates of treatment associated infection are comparable to published standards 
along with similar favorable outcomes, we will plan to use our described four cycle cytarabine- 
intensive regimen piloted in 27 patients as the chemotherapy backbone for this trial. All patients 
regardless of risk status will receive mitoxantrone-cytarabine as their second course of therapy 
(Induction II). This will be followed by Intensification I (cytarabine-etoposide) and Intensification II 
(Capizzi-AraC) for low-risk patients. Patients with high-risk disease will receive an allogeneic 
HSCT typically after two or three courses of chemotherapy. The third course could be either 
cytarabine-etoposide or Capizzi-AraC at the treating physician’s discretion. High-risk patients 
unable to receive a HSCT will receive treatment per the Aflac-AML regimen with four cycles of 
chemotherapy similar to low-risk AML patients. 
 
2.2 
Rationale for incorporation of Gemtuzumab Ozogamicin (GO) 
 
Gemtuzumab Ozogamicin (GO, MylotargTM) is an antibody-drug conjugate (ADC) chemotherapy 
agent that is composed of a recombinant humanized IgG4, kappa antibody to CD33 conjugated 
with a cytotoxic antitumor antibiotic, calicheamicin11. It binds to CD33 after which the complex is 
endocytosed and undergoes dissociation in the lysosome. The detached calicheamicin then binds 
to the minor groove of cellular DNA causing damage and apoptosis12. It received accelerated 
approval in May 2000 by the US FDA for treatment of older adults with CD33 positive AML in first 
relapse not considered candidates for cytotoxic therapy13. CD33 expression is absent on normal 

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hematopoietic stem cells and is limited to leukemic blasts, thus making it an attractive therapeutic 
target14. 
 
Though GO was initially approved for use in patients experiencing first relapse of AML who were 
unable to tolerate any other chemotherapy, it was subsequently given both as monotherapy and 
in combination with other chemotherapy agents for patients with de novo AML15-18. 
Myelosuppression, infections, hyperbilirubinemia and elevated liver enzymes were the major side 
effects reported19. Hepatic veno-occlusive disease (VOD) was reported in patients who received 
the drug even in the absence of stem cell transplantation 20. However, the Southwest Oncology 
Group (SWOG) study S0106 which prospectively compared the benefit of adding GO to a 
standard induction regimen of cytarabine and daunorubicin failed to show any survival benefit and 
reported a 5% induction mortality in the GO group as compared to the non-GO group (1% 
mortality)21. Results of this study led to the withdrawal of the drug from the market in June 2010. 
Four subsequent studies demonstrated contrasting results showing efficacy of GO in patients with 
newly diagnosed AML, supporting the consideration for re-approval of GO in AML22. In the 
Children’s Oncology Group (COG) randomized phase III trial for pediatric patients with de novo 
AML (AAML0531), GO significantly improved the 3-year event free survival (EFS) by reducing the 
relapse risk (RR), but had no impact on overall survival1. Specifically in patients with FLT3-ITD 
positive disease, exposure to GO prior to HSCT reduced the risk of relapse significantly compared 
to those that had not received GO (15% versus 55%, p=0.007) 23. Following the overwhelming 
support for the use of GO in AML, the US FDA granted approval for the drug in de-novo and 
relapsed or refractory disease in September 2017. 
 
Pollard et al divided all patients on AAML0531 based on their CD33 expression into quartiles. 
Patients with high CD33 expression (Q2-4) had significantly improved EFS and relapse risk 24. 
Single nucleotide polymorphisms (SNPs) in CD33 (specifically resulting in increased number of T 
alleles) showed a positive correlation with poorer response to GO-containing regimens25. On the 
COG AML pilot study AAML 03P1, coding SNPs in CD33 (rs35112940 and rs12459419) were 
associated with better risk disease and improved outcomes compared to other genotypes26. 
Further characterization and testing in a larger cohort of patients on AAML0531 (n=816) showed 
that patients with CC genotype (rs12459419) have a significant response to GO as compared to 
CT or TT genotypes27. When genotyping data was correlated with expression, it was found that 
the presence of T allele (CT/TT) genotype strongly correlates with low expression of CD33. There 
are 256/816 patients (31%) who had either CT or TT genotype and were in the high expression 
(Q2-4) group on AAML0531. In this group, addition of GO did not improve relapse risk. 
Conversely, there were 61/816 individuals (7%) who were CC genotype that showed low quartile 
(Q1) CD33 expression. The RR even in this small group was still improved significantly with GO 
through the p-value was just shy of statistical significance (p=0.055)27. While determination of 
CD33 expression is universally possible with routine multi-dimensional flow cytometry, division of 
the data acquired into quartiles that are validated and can be compared between institutions is 
challenging. Given that the CD33 genotyping shows strong correlation with relapse risk regardless 
of CD33 expression, we will be obtaining CD33 genotyping on all patients at the time of diagnosis. 
We expect the turn-around time for this testing to be approximately 4-5 days, allowing for a single 
3 mg/m2 dose of GO to be administered between days 6-10 during Induction I for patients with 
CC genotype. 
 
 
2.3 
Rationale for use of Dexrazoxane with anthracyclines 
 
Cumulative incidence of heart failure and other cardiac events in patients with acute leukemias 
ranges from 4-10% at 10-20 years from diagnosis 28,29. While late cardiotoxicity has been 

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described well following anthracycline exposure above 250-300 mg/m2 doxorubicin equivalents, 
early cardiotoxicity is a growing concern30. Evaluation of cardiotoxicity (defined as grade 2 or 
higher left ventricular dysfunction per CTCAE version 5.0) on COG AAML0531 showed an 
incidence of 12% over a five-year follow-up period with most of the events occurring while on 
protocol therapy. Black, older patients (>1 year age) and concurrent infection were risk factors 
associated with worse cardiac outcomes30. 
 
Dexrazoxane is a bis-dioxopiperazine compound that was introduced in the early 1990’s and has 
been shown to reduce cardiotoxicity related to anthracyclines initially in animal models and later 
in clinical studies31,32. While the exact mechanism is poorly understood, it is believed that 
anthracyclines form complexes with heavy metals specifically iron and generate free radicals that 
cause cardiac damage33. Dexrazoxane binds to iron and prevents the generation of free radicals 
thereby reducing cardiotoxicity. Dexrazoxane has been used successfully in combination with 
various chemotherapy regimens with acceptable toxicity and enhanced cardio-protection34,35. 
While there was concern regarding development of secondary malignancies with exposure to 
dexrazoxane, recent literature has not supported this side-effect36. In this study, all patients will 
receive dexrazoxane in anthracycline-containing treatment courses. We will closely monitor for 
infection, cardiac, hepatic and hematologic toxicities as well as development of secondary 
malignancies. In addition, we will obtain more precise measurements of cardiac function using 
echocardiogram at the end of each course (Section 8.0) as noted in Table 4. 
 
Table 4: Variables of cardiac function to be determined using echocardiography 
 
Left ventricle (LV) remodeling 
LV thickness to dimension ratio 
LV myocardial deformation 
Strain and Strain rate imaging 
LV systolic function 
LV Ejection Fraction using biplane Simpson method 
LV Shortening fraction using 2D and M-mode 
Mitral and septal S’ 
LV diastolic function 
Early filling peak velocity (E wave) 
Atrial systole filling peak velocity (A wave) 
Mitral E/A ratio 
Isovolumic relaxation time (IVRT) 
Mitral annular tissue doppler (E’ and A’) 
Isovolumic contraction time (IVCT) 
Aortic ejection time (ET) 
LV global function 
Spectral Doppler-derived myocardial performance index  
Tissue Doppler Imaging-derived myocardial performance index 
 
 
2.4 
Use of FLT3-ITD inhibitors in AML 
 
Presence of activating mutations in the FLT3 gene occurs in approximately 15% of pediatric 
patients with de-novo AML37. Patients with FLT-ITD mutations with a high allelic ratio (HAR>0.4) 
have an extremely poor progression-free survival of 16% compared to those with lower allelic 
ratios38 and are therefore categorized in the high risk group post induction. Further analysis of 
FLT3-ITD mutations has suggested an AR>0.1 to be associated with a poor outcome as well 
(COG, internal communication). Several FLT3-ITD inhibitors are currently in clinical trials and 
COG AAML1031 tested the inclusion of one such inhibitor, sorafenib, with the regular 
chemotherapy backbone in FLT3-ITD positive AML in a non-randomized fashion. The results of 
this combination are currently under review; however the combination is believed to be safe 

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(COG, internal communication). In this study, we will use sorafenib as the FLT3 inhibitor of choice 
in patients with FLT3-ITD HAR (>0.1) AML. 
 
 
2.5 
Genomic testing in de-novo AML 
 
The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative 
was launched by the National Cancer Institute to support genomic characterization of pediatric 
cancers with poor outcomes, AML being one of them. As a part of the Target Pediatric AML 
initiative (TpAML), genomic sequencing will be carried out for clinical purposes through the 
Foundation One Heme panel. This panel sequences DNA coding regions of 406 genes and 
selected introns of 31 genes involved in hematologic malignancies. It also performs RNA 
sequencing of 265 genes commonly rearranged in cancer. All patients on this study will have 
Foundation One Heme panel sent at diagnosis and we expect results to be available within 4 
weeks. We will be able to correlate the data obtained from this panel with disease outcomes. 
While this panel includes the genes of interest for risk stratification, it is recognized that other 
investigational sequencing approaches may be options during the course of this trial. 
 
 
 
3.0     STUDY DESIGN AND POPULATION 
 
CHOA-AML is a single-center pilot trial. We will enroll up to 30 newly diagnosed pediatric patients 
with acute myeloid leukemia (AML) at CHOA. 
 
All clinical and laboratory data required for determining eligibility of a patient enrolled must be 
available in the patient's medical/research record which will serve as the source document for 
verification. 
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated. Bone marrow aspiration (BMA)/biopsy must be obtained 
within 2 weeks prior to start of protocol therapy (repeat the BMA/biopsy if necessary). 
 
3.1 
Patient Inclusion Criteria 
 
3.1.1 
Age: Patients must be less than 21 years of age at the time of study enrollment 
 
3.1.2 
Diagnosis: Patients must be newly diagnosed with AML 
 
3.1.1.1 Patients with previously untreated primary AML who meet the customary 
criteria for AML with ≥ 20% bone marrow blasts as set out in the 2016 WHO 
Myeloid Neoplasm Classification are eligible. 
 
3.1.1.2 Attempts to obtain bone marrow either by aspirate or biopsy must be made 
unless clinically prohibitive. In cases where it is clinically prohibitive, peripheral 
blood with an excess of 20% blasts and in which adequate flow cytometric and 
cytogenetics/FISH testing is feasible can be substituted for the marrow exam 
at diagnosis. 
 
3.1.1.3 Patients with <20% bone marrow blasts are eligible if they have: 

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• 
A karyotypic abnormality characteristic of de novo AML (t(8;21)(q22;q22), 
inv(16)(p13q22) or t(16;16)(p13;q22) or, 
• 
the unequivocal presence of megakaryoblasts, or 
• 
Biopsy  proven  isolated  myeloid  sarcoma  (myeloblastoma;  chloroma, 
including leukemia cutis) 
 
3.1.3 
Performance Level: Patients with acceptable organ function and any 
performance status are eligible for enrollment 
 
3.2 
Patient Exclusion Criteria 
 
3.2.1 Patients with any of the following constitutional conditions are not eligible: 
• 
Fanconi anemia 
• 
Shwachman syndrome 
• 
Any other known bone marrow failure syndrome 
• 
Patients with constitutional trisomy 21 or with constitutional mosaicism of 
trisomy 21 
Note: Enrollment may occur, pending results of clinically indicated studies to exclude 
these conditions. 
 
3.2.2 Other Excluded Conditions: 
• 
Any concurrent malignancy 
• 
Juvenile myelomonocytic leukemia (JMML) 
• 
Philadelphia chromosome positive AML 
• 
Biphenotypic or bilineal acute leukemia 
• 
Acute promyelocytic leukemia (APL) 
• 
Acute myeloid leukemia arising after a clearly defined preceding 
myelodysplastic syndrome 
• 
Therapy-related myeloid neoplasms 
 
Note: Enrollment may occur pending results of clinically indicated studies to exclude 
these conditions. 
 
3.2.3 Sexually Active Patients 
 
Sexually active patients of reproductive potential are not eligible unless they have 
agreed to use an effective contraceptive method for the duration of their study 
participation. 
 
3.2.4 Pregnancy and Breast Feeding: 
• 
Female patients of childbearing potential are not eligible unless a 
negative pregnancy test result has been obtained 
• 
Female patients who are pregnant are ineligible since fetal toxicities and 
teratogenic effects have been noted for several of the study drugs. 
• 
Lactating females are not eligible unless they have agreed not to 
breastfeed their infants. 

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3.3 
Definitions 
 
3.3.1 CNS LEUKEMIA AT DIAGNOSIS: 
CNS disease at diagnosis is defined as: 
• 
Any number of blasts on a cytospin prep in an atraumatic (< 100 RBCs) lumbar 
puncture. 
• 
Blasts in a traumatic tap in which the WBC/RBC ratio in the CSF is twice that in 
the peripheral blood. 
• 
Clinical signs of CNS leukemia (such as facial nerve palsy, brain/eye involvement 
or hypothalamic syndrome). Extra-ocular orbital masses are not considered CNS 
leukemia. 
• 
Radiographic evidence of an intracranial, intradural mass consistent with a 
chloroma. 
 
 
3.3.2 Method of Evaluation for Traumatic Lumbar Punctures 
 
If the patient has leukemic cells in the peripheral blood and the lumbar puncture is traumatic and 
contains blasts, the following algorithm should be used to diagnose CNS disease: 
 
CSF WBC 
> 2X 
Blood WBC 
CSF RBC 
Blood RBC 
A patient with CSF blasts, whose CSF WBC/RBC is 2X greater than the blood WBC/RBC ratio, 
has CNS disease at diagnosis. Example: CSF WBC = 60/μL; CSF RBC = 1,500/μL; blood WBC 
= 46,000/μL; blood RBC = 3 X 106/μL: 
 
60 
= 0.04 
> 2X 
46,000 
= 0.015 
1,500 
3 X 106 
 
 
3.3 
Protection of Human Subjects 
This protocol will be reviewed and approved by the Emory University Institutional Review Board 
(IRB) prior to study initiation. Prospective participants and their families will be informed of the 
nature of the study and will be given pertinent information as to the intended purpose, possible 
benefits, and possible adverse events. The procedures and possible hazards to which the patient 
will be exposed will be explained, as well as alternatives to participation in this trial will be 
presented in detail to the patient and to the patient’s responsible family members. An approved 
informed consent statement will be read and signed by the patient (or responsible family member 
if under the age of 18) and an investigator. 
 
Verbal assent will be obtained from children ages 6 to 10 and documented in the patients’ medical 
record, as well as being noted in the case report forms. Written assent will be obtained from 
children ages 11 to 17, using an approved assent statement, along with use of the informed 
consent by their parent or guardian. Participants 18 years or older will read/sign the consent form. 
 
3.4 
Aflac Office Monitoring Schedule 
 
The trial will be monitored internally according to the following schedule: 
• 
Study monitoring will occur every 6 months until all subjects have completed intervention; 

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• 
Once all subjects have completed intervention, a final monitoring visit will occur within 90 days 
after the last study related procedures and follow-up are completed for all patients enrolled; 
• 
Additional monitoring may be performed in the event of serious adverse event(s), if deemed 
necessary by the monitoring committee or if requested by the Principal Investigator. 
 
 
 
4.0 
RISK STRATIFICATION 
 
After completion of first course of chemotherapy (Induction I), patients will be classified into low 
or high-risk groups. 
 
Low risk 
t(8;21)(q21.3;q22) – CBF (RUNX1-RUNX1T1) 
inv(16)/t(16;16)(p13.1q22.1) – CBF (CBFB-MYH11) 
NPM1 positive without associated FLT3 mutation 
Biallelic CEBPA positive 
No High-Risk Prognostic Markers/MRD negative (<0.05%) at end of 1st induction 
CBF, CEBPa, NPM positive and MRD positive at the end of 1st Induction 
 
 
 
 
High risk 
 
 
t(3;21)(26.2;q22) 
t(3;5)(q25;q34) 
t(6;9)(p23;q34.1)(DEK-NUP214) 
t(8;16)(p11.2;p13.3) KAT6A(8p11.21) Fusion (for patients who are 90 days or older) 
t(16;21)(p11;q22) FUS-ERG) 
Inv(16) (p13.3q24.3) CBFA2T3-GLIS2 
Monosomy 7 
Monosomy 5/5q-[EGR1(5q31) deleted] 
KMT2A(MLL) (11q23.3) 
- 
t(4;11)(q21;q23) 
- 
t(6;11)(q27;q23) 
- 
t(10;11)(p11.2;q23) 
- 
t(10;11)(p12;q23) 
- 
t(11;19)(q23;p13.3) 
11p15 rearrangement - NUP98 (11p15.5) 
12p 13.2 rearrangement - ETV6 – any partner gene 
Deletion 12p to include 12p13.2 
FLT3 High Allelic Ratio mutations (AR >0.1) 
 
RAM phenotype (high CD56, dim-to-negative expression CD45 & CD38, no HLA-DR) 
MRD positive (>0.05%) at end of 1st induction, excluding those with CBF, CEBPa, NPM 
inv(3)(q21q26.3) MECOM-RPN1 fusion 
10p12.3 rearrangement - Non-KMT2A MLLT10 Fusions 

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5.0 
TREATMENT PROGRAM 
 
Dexrazoxane will be administered per institutional standard during all anthracycline-  
containing courses of this protocol 
 
5.1 
Induction 1 – ADE (10+3+5) with GO 
The following therapy guidelines are for patients during Induction I. Patients on Induction I will 
receive gemtuzumab in addition to ADE therapy based on GO genotyping. Induction I lasts a 
total of 28 days. 
 
Intrathecal Cytarabine: IT 
Given at time of diagnostic lumbar puncture or Day 1. 
Age-based dosing: 
Age (yrs) 
Dose 
0-0.99 
20 mg 
1-1.99 
30 mg 
2-2.99 
50 mg 
≥ 3 
70 mg 
 
For CNS positive patients: add twice weekly IT AraC doses until CNS is clear, plus two 
additional treatments. A minimum of four intrathecal treatments are to be administered during 
the period of three weeks following diagnosis. 
 
Cytarabine: Slow IV Push (e.g., over 1-2 minutes) 
100 mg/m2/dose (3.3 mg/kg/dose if BSA < 0.6 m2) every 12 hours (total of 20 doses) on Days 1- 
10. 
 
Daunorubicin (DAUN): IV over 15 minutes) 
50 mg/m2/dose (1.67 mg/kg/dose if BSA < 0.6 m2) every other day (total of 3 doses) on Days 1, 
3, 5. 
See Section 6 if direct bilirubin is > 2. 
 
Etoposide (ETOP): IV over 60 – 120 minutes 
100 mg/m2/dose (3.3 mg/kg/dose if BSA < 0.6 m2) daily (total of 5 doses) on Days 1-5. 
See Section 6 if direct bilirubin is > 2. 
 
Gemtuzumab Ozogamicin (GO): IV over 2 hours 
3 mg/m2/dose (0.1 mg/kg/dose if BSA < 0.6 m2) once (total of 1 dose) on Day 6 through10. 
 
GO to be given once when GO genotyping demonstrates CC genotype. It can be given on 
any day between days 6-10 of Induction 1. 
 
Pre-medicate with an antihistamine such as diphenhydramine, 1 mg/kg IV (max 50 mg), 
acetaminophen 10-15 mg/kg PO (max 650 mg) and methylprednisolone (1mg/kg) PO/IV. 
Repeat every 4 hours as needed to prevent post infusion complications. 

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Following Induction I, the next course (Induction II) starts on Day 29 or when blood count 
parameters and clinical condition are acceptable (whichever occurs later). This should not 
precede the end of course marrow exam. 
 
5.2 
Induction 1 for FLT3-ITD patients – ADE (10+3+5) with GO with Sorafenib 
The following therapy guidelines are for patients during Induction I with FLT3-ITD mutation. 
Patients on Induction I will receive gemtuzumab in addition to ADE therapy based on GO 
genotyping. Induction I lasts a total of 28 days. 
 
Intrathecal Cytarabine: IT 
Given at time of diagnostic lumbar puncture or Day 1. 
 
Age-based dosing:  
Age (yrs) 
Dose 
0-0.99 
20 mg 
1-1.99 
30 mg 
2-2.99 
50 mg 
≥ 3 
70 mg 
 
For CNS positive patients: add twice weekly IT AraC doses until CNS is clear, plus two 
additional treatments. A minimum of four intrathecal treatments are to be administered during 
the period of three weeks following diagnosis. 
 
Cytarabine: Slow IV Push (e.g., over 1-2 minutes) 
100 mg/m2/dose (3.3 mg/kg/dose if BSA < 0.6 m2) every 12 hours (total of 20 doses) on Days 1- 
10. 
 
Daunorubicin (DAUN): IV over 15 minutes 
50 mg/m2/dose (1.67 mg/kg/dose if BSA < 0.6 m2) every other day (total of 3 doses) on Days 1, 
3, 5. 
See Section 6 if direct bilirubin is > 2. 
 
Etoposide (ETOP): IV over 60 – 120 minutes 
100 mg/m2/dose (3.3 mg/kg/dose if BSA < 0.6 m2) daily (total of 5 doses) on Days 1-5. 
See Section 6 if direct bilirubin is > 2. 
 
Gemtuzumab Ozogamicin (GO): IV over 2 hours 
3 mg/m2/dose (0.1 mg/kg/dose if BSA < 0.6 m2) once (total of 1 dose) on Day 6 through10. 
 
GO to be given once when GO genotyping demonstrates CC genotype. It can be given on 
any day between days 6-10 of Induction 1. 
 
Pre-medicate with an antihistamine such as diphenhydramine, 1 mg/kg IV (max 50 mg), 
acetaminophen 10-15 mg/kg PO (max 650 mg) and methylprednisolone (1mg/kg) PO/IV. 
Repeat every 4 hours as needed to prevent post infusion complications. 
 
Sorafenib (SORAF): PO 
Days: 11 through 28. 
Dose: 200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 
400 mg. Dose will be administered per dosing nomogram in Appendix I. 

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Note: Sorafenib tablets should be taken at least 1 hour before or 2 hours after food. Tablets should 
be taken with clear liquids (approximately 2 to 4 ounces for children < 12 years and 4 to 8 ounces 
for ≥ 12 years). If taken with food, sorafenib should be taken with a moderate to low fat meal. 
Tablets should not be crushed and should be swallowed whole. However, sorafenib tablets can 
be dispersed in water to facilitate the administration to subjects that cannot swallow tablets 
 
Following Induction I, the next course (Induction II) starts on Day 29 or when blood count 
parameters and clinical condition are acceptable (whichever occurs later). This should not 
precede the end of course marrow exam. 
5.3 
Induction II – MA 
The following therapy guidelines are for patients during Induction II. Induction II lasts 28 days or 
longer. 
 
Progression to Induction II should await disease response determination (MRD and 
extramedullary disease) in order to correctly assign risk stratum. Patients with high or low risk 
cytogenetic/molecular features may proceed on to Induction II therapy before disease response 
results are available. By the beginning of Induction II, patients should have been classified as Low 
or High risk. If a patient is classified as High risk at the end of Induction I and no family HLA 
match is found, initiation of an unrelated donor search should occur. 
 
Intrathecal Cytarabine (IT ARAC): IT 
IT ARAC may be administered on Day 1 of Induction II or with the bone marrow evaluation at 
the end of Induction I. 
Age-based dosing:  
Age (yrs) 
Dose 
0 - 0.99 
20 mg 
1 - 1.99 
30 mg 
2 - 2.99 
50 mg 
≥ 3 
70 mg 
 
For newly detected CNS positive patients who were CNS negative at diagnosis: IT cytarabine is 
to be administered twice weekly until the CSF is clear. A minimum of 4 intrathecal treatments 
must be given and a maximum of 6 intrathecal treatments may be given. Patients whose CSF is 
clear at the second spinal tap will receive 3 intrathecal treatments once the CSF is clear and all 
other patients will receive 2 intrathecal treatments once the CSF is clear. Patients with refractory 
CNS leukemia following 6 doses of therapy will be taken off protocol therapy. 
 
High Dose Cytarabine (HD ARAC): IV over 1 - 3 hours 
Days:  1 through 4. 
Dose:  1000 mg/m2/dose, every 12 hours (i.e., 2000 mg/m2/day, divided BID) or 
33 mg/kg/dose, every 12 hours (i.e., 66 mg/kg/day, divided BID) if BSA < 0.6 m2. 
 
Suggested premedications and supportive care: Administer steroid eye drops (0.1% 
dexamethasone or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 
hours, beginning immediately before the first dose and continuing for 24 hours after the 
last dose. If patient does not tolerate steroid eye drops, may administer artificial tears on 
an every 2-4 hour schedule. 

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Patients in whom serum creatinine is > 2 mg/dL or > 2 x normal for age, must have a CrCl 
performed (Day 1) and doses of cytarabine adjusted as outlined. 
 
MitoXANTRONE (MITOX): IV over 15 - 30 minutes 
Days:  3 through 6. 
Dose:  12 mg/m2/dose or 
0.4 mg/kg/dose if BSA < 0.6 m2. 
 
Note: Administer through the tubing of a rapidly infusing solution of D5W or 0.9% NaCl. Avoid 
extravasation; the use of a central line is suggested. On the Days 3 and 4, mitoXANTRONE 
should be given 8 hours after the 5th and 7th high dose cytarabine infusions are complete. 
 
Patients with high risk status may proceed to best allogenic donor SCT or alternative donor 
SCT following Induction II. Depending on timing, these patients may receive a third course  
of chemotherapy (Intensification I) prior to HSCT. This course could be either AE or HD 
ARAC/LASP. 
 
Patients with low risk status who had low risk markers and were MRD positive at the end 
of Induction I and continue to be MRD positive after Induction II will come off protocol. 
 
 
5.4 
Induction II for FLT3-ITD patients – MA with Sorafenib 
The following therapy guidelines are for patients during Induction II with FLT3-ITD AML. Induction 
II lasts 28 days or longer. 
 
Progression to Induction II should await disease response determination (MRD and 
extramedullary disease) in order to correctly assign risk stratum. Patients with high or low risk 
cytogenetic/molecular features may proceed on to Induction II therapy before disease response 
results are available. By the beginning of Induction II, patients should have been classified as Low 
or High risk. If a patient is classified as High risk at the end of Induction I and no family HLA 
match is found, initiation of an unrelated donor search should occur. 
 
Intrathecal Cytarabine (IT ARAC): IT 
IT ARAC may be administered on Day 1 of Induction II or with the bone marrow evaluation at the 
end of Induction I. 
Age-based dosing:  
Age (yrs) 
Dose 
0 - 0.99 
20 mg 
1 - 1.99 
30 mg 
2 - 2.99 
50 mg 
≥ 3 
70 mg 
 
For newly detected CNS positive patients who were CNS negative at diagnosis: IT cytarabine is 
to be administered twice weekly until the CSF is clear. A minimum of 4 intrathecal treatments 
must be given and a maximum of 6 intrathecal treatments may be given. Patients whose CSF is 
clear at the second spinal tap will receive 3 intrathecal treatments once the CSF is clear and all 
other patients will receive 2 intrathecal treatments once the CSF is clear. Patients with refractory 
CNS leukemia following 6 doses of therapy will be taken off protocol therapy. 

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High Dose Cytarabine (HD ARAC): IV over 1 - 3 hours 
Days:  1 through 4. 
Dose:  1000 mg/m2/dose, every 12 hours (i.e., 2000 mg/m2/day, divided BID) or 
33 mg/kg/dose, every 12 hours (i.e., 66 mg/kg/day, divided BID) if BSA < 0.6 m2. 
 
Suggested premedications and supportive care: Patients in whom serum creatinine is > 2 mg/dL 
or > 2 x normal for age, must have a CrCl performed (Day 1) and doses of cytarabine adjusted 
as outlined. 
 
MitoXANTRONE (MITOX): IV over 15 - 30 minutes 
Days:  3 through 6. 
Dose:  12 mg/m2/dose or 
0.4 mg/kg/dose if BSA < 0.6 m2. 
 
Note: Administer through the tubing of a rapidly infusing solution of D5W or 0.9% NaCl. Avoid 
extravasation; the use of a central line is suggested. On the Days 3 and 4, mitoXANTRONE 
should be given 8 hours after the 5th and 7th high dose cytarabine infusions are complete. 
 
 
Sorafenib (SORAF): PO 
Days: 7 through 34. 
Dose: 200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 
400 mg. 
Dose to be administered per dosing nomogram in Appendix I. 
 
Note: Sorafenib tablets should be taken at least 1 hour before or 2 hours after food. Tablets should 
be taken with clear liquids (approximately 2 to 4 ounces for children < 12 years and 4 to 8 ounces 
for ≥ 12 years). If taken with food, sorafenib should be taken with a moderate to low fat meal. 
Tablets should not be crushed and should be swallowed whole. However, sorafenib tablets can 
be dispersed in water to facilitate the administration to subjects that cannot swallow tablets. 
 
 
Patients with FLT3-ITD AML may proceed to best allogenic donor SCT or alternative donor  
SCT following Induction II. Depending on timing, these patients may receive a third course  
of chemotherapy (Intensification I) prior to HSCT. This course could be either AE or HD 
ARAC/LASP with sorafenib. 
 
 
5.5 
Intensification I – AE 
The following Intensification I therapy guidelines are for low risk patients and for patients with high 
risk disease who do not have an appropriate donor for SCT. Intensification I will last for 28 days 
or longer. It is suggested, but not required, that patients have an ANC > 1,000/μL and a platelet 
count > 75,000/μL before proceeding with Intensification I therapy. 
 
Intrathecal Cytarabine (IT ARAC): IT 
IT ARAC may be administered on Day 1 of Intensification I or with the bone marrow evaluation 
at the end of Induction II. 
 
Age-based dosing:  
Age (yrs) 
Dose 

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0 - 0.99 
20 mg 
1 - 1.99 
30 mg 
2 - 2.99 
50 mg 
≥ 3 
70 mg 
 
High Dose Cytarabine (HD ARAC): IV over 1 - 3 hours 
Days:  1 through 5. 
Dose:  1000 mg/m2/dose, every 12 hours, (i.e., 2000 mg/m2/day, divided BID), or 
33 mg/kg/dose, every 12 hours (i.e., 66 mg/kg/day, divided BID) if BSA < 0.6 m2. 
 
Suggested premedications and supportive care: Administer steroid eye drops (0.1% 
dexamethasone or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 hours, 
beginning immediately before the first dose and continuing for 24 hours after the last dose. If 
patient does not tolerate steroid eye drops, may administer artificial tears on an every 2-4 hour 
schedule. Patients in whom serum creatinine is > 2 mg/dL or > 2 x normal for age, must have a 
CrCl performed (Day 1) and doses of cytarabine adjusted as outlined. 
 
Etoposide (ETOP): IV over 60 - 120 minutes 
Days:  1 through 5. 
Dose:  150 mg/m2/dose, or 
5 mg/kg/dose if BSA < 0.6 m2. 
 
Note: Slow rate of administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested. Each dose of etoposide should immediately follow the 1st, 3rd, 5th, 7th 
and 9th doses of cytarabine. 
 
5.6 
Intensification I for FLT3-ITD patients – AE with sorafenib 
The following Intensification I therapy guidelines are for patients with FLT3-ITD AML who do not 
have an appropriate donor for SCT. Intensification I will last for 28 days or longer. It is 
suggested, but not required, that patients have an ANC > 1,000/μL and a platelet count > 
75,000/μL before proceeding with Intensification I therapy. 
 
Intrathecal Cytarabine (IT ARAC): IT 
IT ARAC may be administered on Day 1 of Intensification I or with the bone marrow evaluation 
at the end of Induction II. 
Age-based dosing:  
Age (yrs) 
Dose 
0 - 0.99 
20 mg 
1 - 1.99 
30 mg 
2 - 2.99 
50 mg 
≥ 3 
70 mg 
 
High Dose Cytarabine (HD ARAC): IV over 1 - 3 hours 
Days:  1 through 5. 
Dose:  1000 mg/m2/dose, every 12 hours, (i.e., 2000 mg/m2/day, divided BID), or 
33 mg/kg/dose, every 12 hours (i.e., 66 mg/kg/day, divided BID) if BSA < 0.6 m2. 

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Suggested premedications and supportive care: Administer steroid eye drops (0.1% 
dexamethasone or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 hours, 
beginning immediately before the first dose and continuing for 24 hours after the last dose. If 
patient does not tolerate steroid eye drops, may administer artificial tears on an every 2-4 hour 
schedule. Patients in whom serum creatinine is > 2 mg/dL or > 2 x normal for age, must have a 
CrCl performed (Day 1) and doses of cytarabine adjusted as outlined. 
. 
Etoposide (ETOP): IV over 60 - 120 minutes 
Days:  1 through 5. 
Dose:  150 mg/m2/dose, or 
5 mg/kg/dose if BSA < 0.6 m2. 
 
Note: Slow rate of administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested. Each dose of etoposide should immediately follow the 1st, 3rd, 5th, 7th 
and 9th doses of cytarabine. 
 
Sorafenib (SORAF): PO 
Days: 6 through 33 
Dose: 200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 
400 mg. 
 
Dose to be administered per dosing nomogram in Appendix I. 
 
Note: Sorafenib tablets should be taken at least 1 hour before or 2 hours after food. Tablets 
should be taken with clear liquids (approximately 2 to 4 ounces for children < 12 years and 4 to 
8 ounces for ≥ 12 years). If taken with food, sorafenib should be taken with a moderate to low 
fat meal. Tablets should not be crushed and should be swallowed whole. However, sorafenib 
tablets can be dispersed in water to facilitate the administration to subjects that cannot swallow 
tablets. 
 
5.7 
Intensification II – HD ARAC/LASP 
The following Intensification II therapy guidelines are for low risk patients and for patients with 
high risk disease who do not have an appropriate donor for SCT. Intensification II lasts 28 days 
or longer. 
 
It is suggested, but not required, that patients have an ANC > 1,000/μL and a platelet count > 
75,000/μL before proceeding with therapy. 
 
High Dose Cytarabine (HD ARAC): IV over 3 hours 
Days:  1, 2 and 8, 9 
Dose:  3,000 mg/m2/dose, every 12 hours (i.e., 6,000 mg/m2/day, divided BID), or 
100 mg/kg/dose, every 12 hours (i.e., 200 mg/kg/day, divided BID) if BSA < 0.6 m2. 
 
Suggested premedications and supportive care: Administer steroid eye drops (0.1% 
dexamethasone or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 hours, 
beginning immediately before the first dose and continuing for 24 hours after the last dose. If 
patient does not tolerate steroid eye drops, may administer artificial tears on an every 2-4 hour 
schedule. Patients in whom serum creatinine is > 2 mg/dL or > 2 x normal for age, must have a 
CrCl performed (Days 1 and 8) and doses of cytarabine adjusted as outlined. 

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Erwinia L-asparaginase (Erwinaze): IM (may be given IV over 1 hour) 
Days: 2, 9 (one dose per day, 2 doses total for the entire course) 
Dose: 25,000 IU/m2 (830 IU/kg/dose if BSA < 0.6 m2) 
 
Note: Erwinia asparaginase should be given 6 hours after the start of cytarabine doses 4 and 8. 
If Erwinia asparaginase is not available, pegasparaginase should not be given. Rather, 
asparaginase should be omitted. 
 
5.8 
Intensification II for FLT3-ITD patients – HD ARAC/LASP with sorafenib 
The following Intensification II therapy guidelines are for patients with FLT3-ITD AML who do 
not have an appropriate donor for SCT. Intensification II lasts 28 days or longer. 
 
It is suggested, but not required, that patients have an ANC > 1,000/μL and a platelet count > 
75,000/μL before proceeding with therapy. 
 
High Dose Cytarabine (HD ARAC): IV over 3 hours 
Days:  1, 2 and 8, 9 
Dose:  3,000 mg/m2/dose, every 12 hours (i.e., 6,000 mg/m2/day, divided BID), or 
100 mg/kg/dose, every 12 hours (i.e., 200 mg/kg/day, divided BID) if BSA < 0.6 m2. 
 
Suggested premedications and supportive care: Administer steroid eye drops (0.1% 
dexamethasone or 1% prednisolone ophthalmic solution), 2 drops to each eye every 6 hours, 
beginning immediately before the first dose and continuing for 24 hours after the last dose. If 
patient does not tolerate steroid eye drops, may administer artificial tears on an every 2-4 hour 
schedule. Patients in whom serum creatinine is > 2 mg/dL or > 2 x normal for age, must have a 
CrCl performed (Days 1 and 8) and doses of cytarabine adjusted as outlined. 
 
Erwinia L-asparaginase (Erwinaze): IM (may be given IV over 1 hour) 
Days: 2, 9 (one dose per day, 2 doses total for the entire course) 
Dose: 25,000 IU/m2 (830 IU/kg/dose if BSA < 0.6 m2) 
 
Note: Erwinia asparaginase should be given 6 hours after the start of cytarabine doses 4 and 8. 
If Erwinia asparaginase is not available, pegasparaginase should not be given. Rather, 
asparaginase should be omitted. 
 
Sorafenib (SORAF): PO 
Days: 11 through 28. 
Dose: 200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 
400 mg. Dose will be administered per dosing nomogram in Appendix I. 
 
Note: Sorafenib tablets should be taken at least 1 hour before or 2 hours after food. Tablets 
should be taken with clear liquids (approximately 2 to 4 ounces for children < 12 years and 4 to 
8 ounces for ≥ 12 years). If taken with food, sorafenib should be taken with a moderate to low 
fat meal. Tablets should not be crushed and should be swallowed whole. However, sorafenib 
tablets can be dispersed in water to facilitate the administration to subjects that cannot swallow 
tablets. 
 
 
6.0 
DOSE MODIFICATION FOR TOXICITIES 
 
Common Terminology Criteria for Adverse Events (CTCAE) 

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The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP website (http://ctep.cancer.gov). 
 
6.1 
Allergy to Asparaginase 
6.1.1 Local Reactions (Inflammation at Injection Site, Swelling): 
Continue asparaginase (Erwinia) administration in the presence of Grade 1 allergic 
reaction (transient flushing or rash; drug fever < 38°C). 
 
Premedication with antihistamines to decrease the risk of overt allergy symptoms 
is strongly discouraged since antihistamine use may mask the appearance of 
systemic allergy. Systemic allergy is associated with the presence of asparaginase 
neutralizing antibodies, which render asparaginase therapy ineffective. 
 
6.1.2 Anaphylaxis/Systemic Allergic Reactions: 
Discontinue asparaginase (Erwinia) if the patient develops a systemic allergic 
reaction (urticaria, wheezing, laryngospasm, hypotension, etc.). Should an allergy 
be diagnosed after the first dose given on Day 2 during Intensification II (for high 
risk patients), then the dose due on Day 9 should not be administered. 
 
6.2 
Allergy to Etoposide 
Etoposide allergic reactions may be managed with pre-medications such as diphenhydramine 1 
mg/kg IV (maximum dose 50 mg) or an equivalent H-1 receptor antagonist, ranitidine 1 mg/kg IV 
(maximum dose 50 mg) or an equivalent H-2 receptor antagonist, hydrocortisone 1 - 4 mg/kg IV, 
and by slowing the rate of the infusion OR etoposide phosphate may be substituted in the same 
dose and at the same rate. Premedication for etoposide phosphate is recommended. 
 
6.3 
Cardiac Toxicity 
6.3.1 Left Ventricular Systolic Dysfunction: 
Daunorubicin, mitoxantrone, and sorafenib will be held if there is significant 
evidence of cardiac disease by echocardiogram (shortening fraction < 28% or EF 
< 55%). Cardiac examination with echocardiogram is required prior to the start of 
all chemotherapy courses, at the end of protocol therapy, and in follow up. 
Echocardiogram and cardiac biomarker evaluation (i.e. troponin) are also strongly 
recommended, particularly in clinical scenarios with potential or suspected cardiac 
dysfunction. 
 
6.3.2 Daunorubicin and Mitoxantrone: 
Do not re-start anthracyclines if held for left ventricular shortening dysfunction that 
is not associated with a microbiologically proven bacteremia or sepsis. If the left 
ventricular shortening  dysfunction occurred  in  the setting  of  microbiologically 
proven bacteremia or sepsis, then anthracyclines may be reinstituted  at the 
treating clinician’s discretion once the shortening fraction has returned to ≥ 28% or 
EF ≥ 55%. 
 
6.3.3 Sorafenib in Combination with Chemotherapy: 
Sorafenib should be held for a shortening fraction of < 28% or EF < 55% regardless 
of attribution. Sorafenib should be restarted at a reduced dose (100 mg/m2) when 
the shortening fraction has returned to ≥ 28% or EF ≥ 55%. If SF decreases below 

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28% or EF decreases below 55% on 100 mg/m2, then sorafenib should be 
discontinued permanently. Sorafenib dose may not be re-escalated in combination 
with chemotherapy. 
 
6.3.4 Hypertension: 
The table below will be used to manage hypertension possibly, probably or 
definitely related to sorafenib. Management of hypertension not related to 
sorafenib is at the treating clinician’s discretion. Should initiation of anti- 
hypertensive (anti-HTN) therapy be required, single agent therapy (such as 
amlodipine or nifedipine) should be started. For patients greater than age 18, rely 
on CTCAE v.5.0 grading of hypertension for consideration of dose adjustment. 
 
GRADE 
MANAGEMENT 
For grade 1 
No anti-HTN therapy, no change in sorafenib dose 
For grade 2 
Initiate monotherapy with anti-HTN medication, no 
change in sorafenib dose 
For grade 3 
Add additional agent for anti-HTN therapy, hold 
sorafenib dose. Restart if blood pressure comes back in 
range for age, gender then dose reduce sorafenib to 
100 mg/m2/day 
For grade 4 
Permanently discontinue sorafenib 
 
6.4 
Coagulopathy 
If symptomatic, omit Day 9 asparaginase and consider factor replacement (FFP, 
cryoprecipitate, factor VIIa). Do not hold asparaginase (Erwinia) for abnormal laboratory 
findings without clinical symptoms. 
 
6.5 
Hepatic Toxicity 
6.5.1 Transaminases: 
If the ALT or AST are > 10 x ULN, attempts should be made to identify the cause 
and notify the Study Chair. In most cases, the therapy will proceed without 
modification. 
 
6.5.2 Hyperbilirubinemia: 
If the direct bilirubin is > 3 mg/dL, notify the Study Chair. In some cases, it may be 
necessary to proceed if the bilirubin elevation is a result of the leukemia itself. If 
the elevated direct bilirubin is not a result of the leukemia, modify the doses of 
daunorubicin, etoposide and mitoxantrone as follows below. For all cases in which 
the direct bilirubin is elevated at the point in time that the next course is to begin, 
consider delaying the course for 1 week to determine whether the direct bilirubin 
falls to an acceptable level. 
 
6.5.3 Asparaginase: 
L-asparaginase has been associated with hepatic toxicity but dosing guidelines for 
hepatic toxicity are not available. Thus, asparaginase administration in the setting 
of hepatic toxicity is at the clinician’s discretion. 
 
6.5.4 Daunorubicin, Etoposide and Mitoxantrone: 
In severe liver dysfunction, the half-life of mitoxantrone is prolonged and the AUC 
may be more than 3-fold that of patients with normal hepatic function. However, 

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there are no available dose adjustment guidelines in the literature. Therefore, 
similar dose reductions of mitoxantrone as outlined below for daunorubicin are 
utilized on this protocol. 
 
 
 
6.6 
Neurologic Toxicity 
6.6.1 Cytarabine: 
Patients with > Grade 3 CTCAE v 5.0 nervous system disorders from high dose 
cytarabine should not receive further high dose cytarabine. The most common 
nervous system disorder is an acute cerebellar syndrome that may manifest itself 
as ataxia, nystagmus, dysarthria, or dysmetria. However, seizures and 
encephalopathy have also occurred following therapy with high dose cytarabine. 
 
6.7 
Pancreatitis 
6.7.1 Asparaginase 
Discontinue asparaginase (Erwinia) in the presence of hemorrhagic pancreatitis or 
severe pancreatitis (abdominal pain > 72 hours and > Grade 3 amylase elevation 
(> 2.0 x ULN). In the case of mild pancreatitis after Day 2, Day 9 asparaginase 
may be given only if symptoms and signs subside, and amylase levels return to 
normal. Severe pancreatitis is a contraindication to additional asparaginase 
administration. 
 
6.8 
Renal Toxicity 
6.8.1 Cytarabine: 
Patients with nephrotoxicity secondary to antibiotics, or antifungals, may have 
prolonged excretion of cytarabine leading to more severe marrow and 
extramedullary toxicity. Patients with a serum creatinine > 2 mg/dL or > 2 x normal 
for age should be hydrated orally or intravenously. Following hydration, the patient 
must have a creatinine clearance ≥ 60 mL/min/1.73m² as measured preferably by 
a nuclear GFR Scan or timed urine collection for creatinine clearance before 
proceeding with high dose cytarabine therapy (doses of 1,000 mg/m2 or greater). 
If the CrCl is abnormal (< 60 mL/min/1.73m2) then high dose cytarabine should be 
reduced from twice daily to once daily dosing, at the same previously prescribed 
doses (e.g., 50% daily dose reduction). With this approach, previous research has 
shown the prevention of subsequent neurotoxicity in recipients of high dose 
cytarabine in the face of renal insufficiency. 
 
6.8.2 Etoposide: 
In patients with impaired renal function, the following initial dose modification of 
etoposide should be considered based on measured creatinine clearance: 
• 
for CrCl > 60 mL/min, give full dose, 
• 
for CrCl of 15 – 60 mL/min, give 75% of the dose (25% dose reduction). 

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• 
for CrCl < 15 mL/min, notify the Study Chair. 
 
(Please note: For dose adjustment in renal dysfunction for children, use the 
“corrected” value for creatinine clearance measured in mL/min/1.73 m2, which 
‘corrects’ that value for the standardized values of CrCl in adults is measured in 
mL/min. The “corrected” value is loosely interpreted as being equivalent to 
creatinine clearance measured in an adult patient). Subsequent doses should be 
based on patient tolerance and clinical effect. 
 
6.9 
Thrombosis 
6.9.1 Asparaginase 
Discontinue asparaginase and treat with appropriate antithrombotic therapy, as 
indicated. Do not hold asparaginase for abnormal laboratory findings without 
clinical sequelae. For significant thrombosis, not line related, consider evaluation 
for inherited predisposition to thrombosis. 
 
6.10 
Sinusoidal Obstruction Syndrome (SOS, formerly VOD) of the Liver 
6.10.1 Gemtuzumab Oozagamicin (GO) 
SOS is a known toxicity of GO. No specific predisposing factor is known that may 
identify the patient at risk. 
 
Criteria for the diagnosis of SOS of the liver 
 
For the purposes of reporting toxicity, the following definition for SOS will be used: 
1) Weight gain of more than 10% baseline, and 
2) Right upper quadrant pain or tender hepatomegaly, and 
3) Total bilirubin 2 mg/dL or greater, and 
4) Edema or ascites. 
 
Reversal of portal venous blood flow by ultrasound or pathologic confirmation by 
liver biopsy are not required for the diagnosis but may be done in support of the 
clinical diagnosis and/or the evaluation of other diagnostic possibilities. Ultrasound 
may also be used to assess the severity and course of the patient’s SOS. 
 
6.11 
Palmar-Plantar Erythrodysesthesia Syndrome, Skin Pain that impacts ADLs or 
Rash Maculo-Papular 
6.11.1 Sorafenib 
Grade 1 – Continue sorafenib with topical therapy and supportive care* 
 
Grade 2 
- 
First occurrence – hold sorafenib, if rash improved to <grade 2 in 2 weeks, 
restart at same dose. If does not improve in 2 weeks, hold till rash improves 
then start drug at 100 mg/m2/day dose. 
- 
Second occurrence – hold sorafenib, if rash improved in 2 weeks, restart 
at 100 mg/m2/day dose. If does not improve to <grade 2 in 2 weeks, stop 
sorafenib 
- 
Third occurrence – stop sorafenib 

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Grade 3 
- 
First occurrence – hold sorafenib, if rash improved in 2 weeks, restart at 
100 mg/m2/day dose. If does not improve to <grade 2 in 2 weeks, stop 
sorafenib 
- 
Second occurrence – stop sorafenib 
 
*Treatment of sorafenib related Rash/Hand-foot syndrome 
▪ 
Patients who develop hand-foot syndrome may receive topical emollients 
(such as Aquaphor) as well as topical or oral steroids or antihistamines if 
appropriate. Hand foot syndrome may include skin pain without rash that 
impacts activities of daily living. 
▪ 
Oral administration of vitamin B 6 (pyridoxine) can also be used for these 
patients - BSA < 0.5m2: 50 mg per day; BSA 0.5 - 1.0 m2: 100 mg per day; 
BSA 1.1 - 1.5 m2: 200 mg per day, and BSA > 1.5m2: 300 mg per day. 
 
 
7.0 
SUPPORTIVE CARE 
 
7.1 
General Guidelines 
The following guidelines are intended to give general direction for optimal patient care and to 
encourage uniformity in the treatment of this study population. We will follow our institutional 
guidelines for management of hospitalization and discharge for these patients. 
 
Hospitalization/Hospital Environment 
Hospitalization following each course of chemotherapy is strongly recommended until the 
absolute phagocyte count (sum of the neutrophils, bands and monocytes) is rising for 2 
successive days, and the patient is afebrile and clinically stable. 
 
It is recommended that patients should be assigned to rooms with special air filtration systems 
such as high efficiency particulate air filters (HEPA) or clean-air rooms with constant positive 
pressure airflow if at all possible. 
 
Central Venous Access 
It is recommended that all patients have a double lumen central venous access line placed prior 
to the beginning of therapy. 
 
Hyperleukocytosis and Metabolic Derangement 
Patients with high peripheral blast counts (> 100,000/μL) may have increased problems related 
to metabolic abnormalities, bleeding, and hyperviscosity. Transfusion with packed red blood cells 
should be given very cautiously, since it may increase viscosity and increase the risk of 
leukostasis. In these patients, the platelet count should be maintained at least greater than 
20,000/μL 
Continuation of AML Therapy 
AML therapy can proceed when there is documented evidence of response to antimicrobial 
therapy for infections complications, absence of fever or other signs or symptoms of infection, 
and other starting criteria have been met. 
 
Nutrition 
Active measures should be used to prevent weight loss of greater than 10% of pre-illness body 
weight. If possible, enteral feedings are preferred to parenteral. 

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Mucosal Evaluation and Care 
Mucositis is expected and may be severe; liberal use of pain medications for this condition is 
encouraged. For patients with poor oral hygiene, consultation by dentistry is recommended prior 
to initiating therapy. 
 
Suppression of Menstruation 
Menstruating females may receive depo-injections or another suppressant during the entire 
course of this protocol per institutional standards. 
 
Irradiation 
Blood products should be irradiated following the current FDA guidelines found at:  
http://www.fda.gov/cber/gdlns/gamma.htm 
 
 
7.2 
Infection Prophylaxis 
Patients with AML are at a high risk for mortality and morbidity during therapy mainly due to 
infections. Therefore, patients require an aggressive approach to infection prevention and 
treatment as outlined below: 
 
• 
Hospitalization as mentioned in Section 7.1 
 
• 
Bacterial Prophylaxis 
It is required that all patients except those receiving sorafenib receive broad spectrum 
gram –positive and gram-negative anti-bacterial prophylaxis at the start of each cycle 
of therapy and until they have met criteria for discharge as mentioned in section 7.1. 
Antibiotic can be decided by the treating institution, although levofloxacin is 
recommended. 
 
• 
Pneumocystis jiroveci Prophylaxis 
It is required that all patients receive prophylaxis for Pneumocystis jiroveci pneumonia 
during each cycle. Trimethoprim-sulphamethoxazole, pentamidine isethionate and 
dapsone are acceptable though trimethoprim-sulphamethoxazole is preferred. 
 
• 
Fungal prophylaxis 
Prophylactic anti-fungal therapy with voriconazole (<13 yrs), posaconazole (≥13 yrs) 
or micafungin is required until they have met criteria for discharge as mentioned in 
section 7.1. 
 
 
 
Patients with an ANC < 500/μL (or < 1,000 /μL and falling) and an oral temperature > 38°C twice 
in 12 hours or ≥ 38.3°C once, should have empiric systemic antibiotics initiated immediately. 
Institutional guidelines as set forth for patients with AML which include guidelines for fever and 
neutropenia in AML patients, management of possible and documented fungal infections and 
pneumocystis prophylaxis will be followed. 

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8.1 
EVALUATIONS/DATA TO BE ACCESSIONED 
 
STUDIES TO BE OBTAINED 
Baseline 
Each Course of 
chemotherapy 
End of 
therapy 
Relapse/ 
Refractory 
History 
X 
--- 
--- 
--- 
Physical Exam 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
Height, Weight, BSA 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
CBC with differential, platelets 
X 
X 
X 
X 
Liver Function – AST, ALT, Total and 
Direct Bilirubin, Total Protein, 
Albumin 
X 
X 
X 
X 
Kidney Function – BUN, Creatinine 
X 
X 
X 
X 
Electrolytes (Sodium, Potassium, 
Chloride, Calcium, Magnesium, 
Phosphorous) and Glucose 
X 
X 
X 
X 
Chest X-ray and Pulse oximetry 
X 
--- 
--- 
X 
ECHO and EKG 
X 
X 
Prior to each 
course 
X 
X 
Bone marrow aspirate (BMA) and/or 
biopsy for morphology and flow 
cytometry to include CD33 
expression 
X 
--- 
--- 
X 
BMA for FLT3 testing 
X 
--- 
--- 
X 
BMA for CD33 Genotype 
X 
--- 
--- 
--- 
BMA for genomic testing 
X 
--- 
--- 
X 
Lumbar Puncture with cell count and 
cytospin 
X 
--- 
--- 
X 
Imaging of chloroma –CT/MRI if 
applicable 
X 
--- 
--- 
X 
BMA for MRD testing 
-- 
X 
End of each 
course 
X 
-- 
Concomitant Medication Data 
X 
X 
X 
X 
Adverse Event/Toxicity Monitoring 
X 
X 
 
8.2 
Data Collection 
The REDCap™ system, a secure web application for building and managing online surveys and 
databases, will be used for data submission. Access to the system will be provided through 
CHOA, a REDCap™ consortium partner. REDCap will be used to capture data for enrollment, 
baseline patient, disease and treatment characteristics, and outcomes. 
 
8.3 
Data Confidentiality 
The confidentiality of each participant record will be rigorously maintained using existing 
institutional standards. HIPAA and state/federal government regulations for protecting participant 
privacy and security will be strictly observed. Printing study documents will be discouraged and 
avoided whenever possible. If it is necessary to print source documentation, it will be maintained 
and protected by clinical research personnel and kept in a locked file cabinet. All computers used 

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in the study will be encrypted according to institutional policies. Databases will be stored on the 
secured servers maintained by Emory University and CHOA 
 
No participant or subject-identifiable information will be given to third parties, including family 
members (except legal guardians of minors), unless that subject (or legal guardian of minors) has 
given written or witnessed consent to do so. The results of research studies may be published, 
but all data will be de-identified prior to publication and individual subjects will not be identified. 
 
If a participant contacts the study’s project personnel, he or she will be informed of the status of 
the research without revealing specific findings. 
 
 
8.4 
Data and Safety Monitoring 
This study will be centrally reviewed by the Data Safety and Monitoring Board (DSMB) of the Aflac 
Clinical Research Office. 
 
The DSMB meets quarterly to review all adverse events and deaths and determine whether any 
patient safety problems necessitate protocol modifications or discontinuation of the trial. 
 
The DSMB will also meet on an ad hoc basis if unexpected safety events occur that may 
necessitate study suspension or closure. The DSMB will discontinue the review of outcomes when 
this protocol is closed to accrual. 
 
Before each regularly scheduled DSMB meeting, the study coordinator will submit a report 
including tabular summaries of all reported SAEs, AEs, and deaths on study to date. The report 
will also include a brief summary of each previously unreported SAE and death, including an 
assessment of whether the event was unexpected or related to the study. 
 
If the DSMB recommends protocol or informed consent changes during the study, the 
recommendations will be reviewed by the Protocol Chair and incorporated into the protocol as 
deemed appropriate. The protocol with incorporated changes will be distributed to the 
participating PIs after approval by the Emory University IRB. 
 
8.3.1   Adverse Event Reporting Requirements 
 
The timely reporting of adverse drug reactions (including toxic deaths) is required by the 
US Food and Drug Administration. The reporting of adverse reactions is in addition to and 
does not supplant the reporting of toxicities as part of the data reporting for this study. The 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be utilized 
for adverse event reporting in this trial. 
 
Serious adverse event (SAE) or reaction is any untoward medical occurrence (including 
an abnormal laboratory finding) associated with the use of a drug in humans that at any 
dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, is a 
congenital anomaly/birth defect, or requires medical or surgical intervention in order to 
prevent one of the previous listed outcomes. Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other situations, such 
as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above. These should also usually be 

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considered serious. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; or development of drug dependency or drug 
abuse. 
 
Unexpected adverse drug experience means any adverse drug experience, the 
specificity or severity of which is not consistent with the current investigator brochure or if 
an investigator brochure is not required or available, the specificity or severity of which is 
not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. “Unexpected” as used in this definition, 
refers to an adverse drug experience that has not been previously observed (e.g., included 
in the investigator brochure) rather than from the perspective of such experience not being 
anticipated from the pharmacological properties of the pharmaceutical product. 
 
Attribution: The investigator will be asked to document his/her opinion of the relationship 
of the event to study medication as follows: 
 
The categories are: 
• 
Definite: The adverse event is clearly related to the study drug(s). 
• 
Probable: The adverse event is most likely related to the study drug(s). 
• 
Possible: The adverse event may be related to the study drug(s). 
• 
Unlikely: The adverse event is doubtfully related to the study drugs(s). 
• 
Unrelated: The adverse event is clearly not related to the study drug(s). 
 
For an SAE, the Primary Study Coordinator should be notified via phone or email within 
24 hours of the study personnel becoming aware of the event, and they will notify the 
DSMB. A copy of the completed Serious Adverse Event form must also be sent to study 
coordinator through REDCap within 5 calendar days after the incident. The investigator is 
responsible for reporting serious adverse events and unanticipated problems (UPs) to the 
IRB according to the guidelines mandated by the institutional IRB. The PI will report to 
FDA any serious unexpected adverse reactions (SUSARs) according to FDA regulations. 
Copies of all serious adverse event reports will be kept on file in the Clinical Research 
Office of the Cancer Center. 
 
 
 
9.1 
AGENT INFORMATION 
 
9.2 
CYTARABINE - ALL ROUTES 
(Cytosine arabinoside, Ara-C, Cytosar®) NSC #63878 
 
Source and Pharmacology: 
Cytarabine appears to act through the inhibition of DNA polymerase. A limited, but significant, 
incorporation of cytarabine into both DNA and RNA has also been reported. It exhibits cell phase 
specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain 
conditions blocking the progression of cells from the G1 phase to the S-phase. Cytarabine is 
metabolized by deoxycytidine kinase and other nucleotide kinases to the nucleotide triphosphate 
(Ara-CTP), an effective inhibitor of DNA polymerase. Ara- CTP is inactivated by a pyrimidine 
nucleoside deaminase, which converts it to the nontoxic uracil derivative (Ara-U). It appears that 
the balance of kinase and deaminase levels may be an important factor in determining sensitivity 
or resistance of the cell to cytarabine. It has an initial distributive phase t½ of about 10 minutes, 
with a secondary elimination phase t½ of about 1 to 3 hours. Peak levels after intramuscular or 

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subcutaneous administration of cytarabine occur about 20 to 60 minutes after injection and are 
lower than IV administration. Intrathecally administered doses are metabolized and eliminated 
more slowly with a t½ of about 2 hours. 
 
 
Formulation: 
Cytarabine for Injection is available in vials of 100 mg, 500 mg, 1 g, and 2 g containing a sterile 
powder for reconstitution. It is also available at a 20 mg/mL concentration with benzyl alcohol (25 
mL per vial) or as a preservative free solution (5 mL, 50 mL per vial), and at a 100 mg/mL 
concentration with benzyl alcohol (20 mL vial) or as preservative free solution (20 mL vial). 

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Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. Store at 25°C (77°F); 
excursions permitted to 15°-30°C (59°-86°F). Cytarabine solutions should be protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
 
IV Infusion: 
Reconstitute the lyophilized powder with Bacteriostatic Water for Injection or NS injection. 
Solution containing bacteriostatic agent should not be used for the preparation of doses > 200 
mg/m2. May be further diluted with dextrose or sodium chloride containing solutions. May give by 
IV push injection, by IV infusion, or by continuous infusion. 
 
Low Dose (≤ 200 mg/m²/dose): For administration by IV push, reconstitute to a concentration of 
20- 100 mg/mL. 
 
High Dose (≥ 1000 mg/m²/dose): Administer steroid eye drops (dexamethasone or 
prednisolone), 2 drops each eye q6h beginning immediately before the first dose and continuing 
24 hours after the last dose. If patient does not tolerate steroid eye drops, administer artificial 
tears on a q2-4 hour schedule. 
 
Stability: When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 
hours at room temperature. Solutions reconstituted without a preservative should be used 
immediately. Discard if solution appears hazy. Diluted solutions in D5W or NS are stable for 8 
days at room temperature; however, the diluted cytarabine should be used within 24 hours for 
sterility concerns. 
 
Intrathecal: 
For intrathecal administration, dilute with 5-10 mL (or volume per institutional practice) 
preservative free 0.9% sodium chloride injection, lactated Ringer’s injection, Elliot’s B solution. 
The volume of CSF removed should be equal to at least ½ the volume delivered. 
 
*Rieselbach, R.E. et.al. Subarachnoid distribution of drugs after lumbar injection; N Engl J Med. 
1962 Dec 20; 267:1273-8 
 
Of Note: Larger volumes approximating at least 10% of the CSF volume, isovolumetric delivery, 
with the patient remaining prone after the procedure may facilitate drug distribution. These 
procedures have not been validated in clinical trials. They are allowed but not mandated for 
patients on COG studies. 
 
Stability: Intrathecal cytarabine mixed in NS, lactated Ringer’s injection, or Elliot’s B solution is 
stable for 24 hours at 25ºC but contains no preservative and should be administered as soon as 
possible after preparation. 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 

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9.3 
DAUNORUBICIN 
(Daunomycin, rubidomycin, Cerubidine®) NSC #82151 
 
Source and Pharmacology: 
Daunorubicin is an anthracycline antibiotic isolated from cultures of Streptomyces 
coeruleorubidus. Daunorubicin is closely related structurally to doxorubicin only differing in that 
the side chain of daunorubicin terminates in a methyl group rather than an alcohol. The cytotoxic 
effect of daunorubicin on malignant cells and its toxic effects on various organs are similar to 
those of doxorubicin and are thought to be related to nucleotide base intercalation and cell 
membrane lipid binding activities. Intercalation inhibits nucleotide replication and action of DNA 
and RNA polymerases. The interaction of daunorubicin with topoisomerase II to form DNA- 
cleavable complexes appears to be an important mechanism of cytocidal activity. Daunorubicin 
cellular membrane binding may affect a variety of cellular functions. Enzymatic electron reduction 
of daunorubicin by a variety of oxidases, reductases, and dehydrogenases generate highly 
reactive species including the hydroxyl free radical (OH•) which may lead to DNA damage or lipid 
peroxidation. Daunorubicin is metabolized more rapidly by aldoketoreductases to the active 
metabolite, daunorubicinol, than is doxorubicin. Daunorubicin hydrochloride is rapidly and widely 
distributed in tissues, with the highest levels in the spleen, kidneys, liver, lungs, and heart. 
Daunorubicin serum decay pattern is multiphasic. The initial t½ is approximately 45 minutes 
followed by a terminal t½ of 18.5 hours. By 1 hour after drug administration, the predominant 
plasma species is daunorubicinol, which disappears with a half-life of 26.7 hours. Twenty five 
percent of an administered dose of daunorubicin is eliminated in an active form by urinary 
excretion and an estimated 40% by biliary excretion. 
 

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Formulation and Stability: 
Daunorubicin is available as red-orange lyophilized powder1 for injection in 20 mg single dose 
vials and a preservative free 5mg/mL solution2 in 20 mg (4 mL) and 50 mg (10 mL) vials. 
¹ Each vial contains 21.4mg of daunorubicin hydrochloride (equivalent to 20 mg of daunorubicin) 
and 100 mg mannitol. 
² Each mL contains 5.3mg daunorubicin hydrochloride (equivalent to 5 mg of daunorubicin), 9 mg 
of sodium chloride, sodium hydroxide or hydrochloric acid to adjust pH, and Sterile Water for 
Injection. 
 
Powder for Injection: 
Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). Protect from light. Retain in 
carton until contents are used. Reconstitute a 20 mg vial with 4 mL SWFI to a final concentration 
of 5mg/mL. After adding the diluent, the vial should be shaken gently, and the contents allowed 
to dissolve. The reconstituted solution is stable for 24 hours at room temperature and 48 hours 
refrigerated. Protect from exposure to sunlight. 
 
Aqueous Solution: 
Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in carton until contents are used. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Administer by IV side arm into a rapidly flowing infusion solution. Alternately, daunorubicin may 
be further diluted in saline or dextrose containing solutions and administered by infusion. Protect 
final preparation from light. To avoid extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for further 
information. 
 
9.4 
ETOPOSIDE INJECTION 
(VePesid®, Etopophos®,VP-16) NSC #141540 
 
Source and Pharmacology: 
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase II and 
DNA which results in single and double strand DNA breaks. Its main effect appears to be in the 
S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal half-life is 4 to 
11 hours. It is primarily excreted in the urine. In children, approximately 55% of the dose is 
excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 
mL/min/m² or about 35% of the total body clearance over a dose range of 80 to 600 mg/m². 
Etoposide, therefore, is cleared by both renal and non-renal processes, i.e., metabolism and 
biliary excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary 
excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous 
dose is recovered in the bile as etoposide. Metabolism accounts for most of the non renal 
clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) exhibit 
a high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily 
serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is 
related to toxicity. Preliminary data suggests that systemic exposure for unbound etoposide 
correlates better than total (bound and unbound) etoposide. There is poor diffusion into the CSF 
< 5%. 

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Etoposide phosphate is a water-soluble ester of etoposide which is rapidly and completely 
converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that 
etoposide phosphate is bioequivalent to etoposide when it is administered in molar equivalent 
doses. 
 
 
Formulation and Stability: 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials (5 mL, 25 
mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL 
contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg modified polysorbate 
80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace 
contains nitrogen. Unopened vials of etoposide are stable until expiration date on package at 
controlled room temperature (20˚-25˚C or 68˚- 77˚F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized 
powder in single-dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 
mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under 
refrigeration (2°-8°C or 36°-46°F). Unopened vials of etoposide phosphate are stable until the 
expiration date on the package. 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
Etoposide: 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions are 
stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; stability is 
24 hours at room temperature with concentrations of 0.4 mg/mL. The time to precipitation is highly 
unpredictable at concentrations > 0.4 mg/mL. Use in-line filter during infusion secondary to the 
risk of precipitate formation. However, the use of an in-line filter is not mandatory since etoposide 
precipitation is unlikely at concentrations of 0.1-0.4 mg/mL. Do not administer etoposide by 
rapid intravenous injection. Slow rate of administration if hypotension occurs. 

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Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred with 
etoposide 0.4mg/mL in NS. To avoid leaching, prepare the etoposide solution as close as 
possible, preferably within 4 hours, to the time of administration or alternatively as per institutional 
policy; glass or polyethylene-lined (non-PVC) containers and polyethylene-lined tubing may be 
used to minimize exposure to DEHP. 
 
Etoposide Phosphate: 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS, Bacteriostatic 
Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride for Injection with Benzyl 
Alcohol for a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide equivalent (22.7 
mg/mL or 11.4 mg/mL etoposide phosphate), respectively. Use diluents without benzyl alcohol 
for neonates and infants < 2 years of age or patients with hypersensitivity to benzyl 
alcohol. 
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or plastic 
containers under refrigeration for 7 days. When reconstituted with a diluent containing a 
bacteriostat, store at controlled room temperature for up to 48 hours. Following reconstitution with 
SWFI, D5W, or NS store at controlled room temperature for up to 24 hours. 
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as low as 
0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under refrigeration 
or at controlled room temperature for 24 hours. 
 
Supplier: 
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
9.4 
GEMTUZUMAB OZOGAMICIN 
(Mylotarg®, CDP-771, CMA-676, hP67.6-calicheamicin) NSC # 720568 
 
Source and Pharmacology: Gemtuzumab ozogamicin is a combination of recombinant 
humanized anti-CD33 monoclonal antibody, conjugated with the cytotoxic antibiotic 
calicheamicin, isolated from fermentation of a bacterium, Micromonospora echinospora subsp. 
calichensis. The antibody portion of Gemtuzumab binds specifically to the CD33 antigen 
expressed on the surface of leukemic blasts and immature normal cells of myelomonocytic 
lineage, but not on normal hematopoietic stem cells. This antigen is expressed on the surface of 
leukemic blasts in more than 80% of patients with acute myeloid leukemia (AML). The binding of 
anti-CD33 antibody with the CD33 antigen results in the formation of a complex that is 
internalized, releasing the calicheamicin inside the lysosomes of the myeloid cell. The 
calicheamicin derivative binds to DNA in the minor growth groove, causing DNA double-strand 
breaks and cell death. 
 
The first administration of a 9 mg/m2 dose of gemtuzumab ozogamicin, given as a 2 hour infusion, 
results in elimination half-lives of total and unconjugated calicheamicin of about 41 and 143 hours, 
respectively. After the second 9 mg/m2 dose, the half-life of total calicheamicin was increased to 
about 64 hours and the area under the concentration-time curve (AUC) was about twice that in 
the first dose period. The AUC for the unconjugated calicheamicin increased 30% after the second 
dose. 

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Formulation and Stability: Available as single dose 5 mg amber vials of lyophilized powder. 
Store in the refrigerator at 2º to 8ºC (36º-46º F), protected from light. Bring the vials to room 
temperature before diluting. Reconstitute vial contents with 5 mL of sterile water, and gently swirl 
the solution. Inspect the final solution for particulates. The reconstituted solution has a 
concentration of 1 mg/mL and is stable ≤ 8 hours if refrigerated and protected from light or ≤ 2 
hours at room temperature prior to a 2-hour infusion. 
 
Note: The product is very light sensitive. The vials should be diluted, and solution 
prepared, in a biologic safety cabinet with the fluorescent lights turned off. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
Add appropriate  dose  to  100  mL of normal saline in either a  polyvinyl  chloride  (PVC)  or 
ethylene/polypropylene copolymer (non-PVC) IV bag covered by an ultraviolet (UV) light 
protector. 
 
Gemtuzumab should only be diluted with 0.9% sodium chloride solution. 
The diluted solution is stable ≤ 16 hours at room temperature prior to a 2-hour infusion. 
 
Infuse over a 2-hour period in a peripheral or central line. Do not give IV push or bolus. Give 
through a separate IV line, using a 0.22 micron or 1.2-micron low protein-binding in-line filter. 
 
Premedicate with acetaminophen and diphenhydramine and repeat every 4 hours as needed to 
prevent post-infusion symptom complex. Handle as with other cytotoxic agents. Protect solution 
from light at all times. Monitor vital signs during infusion and for 4 hours following infusion. 
 
Supplier: Commercially available in the U.S. See package insert for further information. 

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9.5 
ASPARAGINASE (ERWINIA CHRYSANTHEMI) 
(Erwinia chrysanthemi, Erwinase®, ErwinazeTM, Crisantaspase) 
 
Source and Pharmacology: 
L-asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid 
by a reaction catalyzed by the enzyme L-asparagine synthetase. Neoplastic cells associated with 
acute lymphoblastic leukemia, acute myeloid leukemia and lymphoblastic lymphosarcoma are 
asparagine-dependent but lack asparagine synthetase activity. The administration of L- 
asparaginase produces an anti-neoplastic effect by catalyzing asparagine into aspartic acid and 
ammonia. As a result, these cells lack the ability to produce the asparagine necessary for protein 
metabolism and survival. Deamination of glutamine may also play a role in the antineoplastic 
activity of asparaginase. 
 
Asparaginase Erwinia chrysanthemi (Erwinaze®) is asparaginase derived from cultures of 
Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four identical subunits 
has a molecular weight of approximately 35 kDa. Asparaginase Erwinia chrysanthemi is 
immunologically distinct from E. coli L-asparaginase and may allow continued asparaginase 
therapy when a hypersensitivity reaction occurs to Escherichia coli-derived asparaginase. The 
package labeling states that there is insufficient information to characterize the incidence of 
antibodies to asparaginase Erwinia chrysanthemi. Several factors are involved in immunogenicity 
assay results and the assessment of antibodies, including assay methodology, assay sensitivity 
and specificity, sample handling, timing of sample collection, concomitant medications, and the 
underlying disease state. The following data have been reported on each of the three preparations 
of asparaginase: 
 
Effective asparaginase levels have been defined as activity of ≥ 0.1 International Units per mL. 
Clinical trials with asparaginase Erwinia chrysanthemi demonstrated that 100% of patients 
achieved effective asparaginase levels at 48 and 72 hours (n=35 and n=13, respectively) following 
the third total dose when given on a Monday, Wednesday, Friday schedule using the IM route of 
administration. In a multicenter study characterizing the pharmacokinetic profile of 25,000 
International Units/m2 Erwinaze® given intravenously over one hour on the same dosing schedule 
of Monday, Wednesday, Friday for 2 consecutive weeks, 83% (20/24) and 43% (9/21) of 
evaluable patients achieved an asparaginase activity level of ≥ 0.1 International Units/mL at 48 
post-dose 5 and 72 hours post-dose 6, respectively. No formal drug interaction studies have been 
performed with asparaginase Erwinia chrysanthemi. 

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Formulation and Stability: 
Asparaginase Erwinia chrysanthemi is supplied as a sterile, white lyophilized powder for 
reconstitution in a clear glass vial with a 3 mL capacity. Each vial contains 10,000 International 
Units of asparaginase Erwinia chrysanthemi and the following inactive ingredients: glucose 
monohydrate (5.0 mg), sodium chloride (0.5 mg). Store intact vials between 2°C and 8°C (36° to 
46ºF). Protect from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
Erwinia asparaginase can be administered by intramuscular injection or by intravenous infusion. 
Use appropriate precautions for preparation of a hazardous agent. Visually inspect the powder in 
vial for foreign particles or discoloration prior to reconstitution. 
 
For intramuscular administration, the contents of each vial should be reconstituted by slowly 
adding 1 mL or 2 mL of sterile, preservative-free NS to the inner vial wall. The final concentration 
is 10,000 International Units per mL when using 1 mL for reconstitution or 5,000 International 
Units per mL when using 2 mL for reconstitution. Gently mix or swirl the contents to dissolve the 
contents of the vial. Do not shake or invert the vial. The resulting solution should be clear and 
colorless. Discard if any particulate matter or protein aggregates are visible. Withdraw the 
appropriate dosing volume into a polypropylene syringe within 15 minutes of 
reconstitution. Polycarbonate luer-lok syringes from B-D (1 mL) are also acceptable (personal 
communication, EUSA Pharma). Discard any unused drug; do not save or use any unused drug 
remaining the in the vial. No more than 2mL should be given at any one injection site. Doses 
larger than 2 mL should be divided and given in separate administration sites. 
For intravenous use, slowly inject the appropriate volume of reconstituted solution into a Normal 
Saline 100 mL infusion bag; do not shake or squeeze the bag. Infuse Erwinia asparaginase over 
1 hour. Do not infuse other intravenous drugs through the same intravenous line while infusing 
Erwinia asparaginase. 

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Administer the dose within a 4 hour time period from reconstitution. If the dose is not used 
within this time period, discard the dose. Do not freeze or refrigerate the reconstituted solution. 
Have  available  during  and  after  the  infusion:  antihistamine,  epinephrine,  oxygen,  and  IV 
corticosteroids. Observe patient for ONE hour after administration for signs of hypersensitivity 
reactions. 
 
9.6 
SORAFENIB TOSYLATE 
(BAY 43-9006 tosylate, BAY 54-9085 Nexavar®) 
 
Source and Pharmacology: Sorafenib tosylate has the chemical name: 
4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl] ureido} phenoxy) N2-methylpyridine-2-carboxamide 
4-methylbenzenesulfonate. Sorafenib is a kinase inhibitor that decreases tumor cell proliferation 
in vitro. Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and 
cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß). Several 
of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. 
Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma, human 
renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice. 
 
The mean relative bioavailability of sorafenib administered as an oral tablet was 38–49% when 
compared to an oral solution. Pharmacokinetics studies in adults who received oral sorafenib 
showed that sorafenib reaches peak plasma levels in approximately 3 hours. When given with a 
moderate-fat meal (30% fat; 700 calories), the bioavailability was similar to that in the fasted state, 
however, with a high-fat meal (50% fat; 900 calories), sorafenib bioavailability was reduced by 
29% compared to administration in the fasted state. Therefore, it is recommended that sorafenib 
be administered without food. 
 
The mean maximum plasma concentration (Cmax) and area under the concentration curve (AUC) 
increased less than proportionally when doses greater than 400 mg are given orally twice daily. 
In vitro binding of sorafenib to human plasma proteins is 99.5%. Sorafenib is metabolized mainly 
in the liver through oxidation by cytochrome P-450 (CYP) isoenzyme 3A4, and glucuronidation by 
uridine diphosphate-glucuronosyltransferase (UGT) 1A9. Sorafenib accounted for approximately 
70–85% of the circulating analytes in plasma at steady state. Eight metabolites of sorafenib have 
been identified. The primary metabolite, a pyridine N-oxide derivative, is pharmacologically active, 
shows in vitro potency similar to that of sorafenib, and accounts for approximately 9-16% of total 
plasma concentrations of the drug. Approximately 77% of an oral dose of sorafenib is excreted in 
feces; 19% is eliminated in urine as glucuronidated metabolites. Unchanged sorafenib is 
recovered in feces and accounts for 51% of a single dose. No unchanged sorafenib is recovered 
in the urine. 
 
The mean elimination half-life of sorafenib is approximately 25 to 48 hours. Multiple dosing of 
sorafenib for 7 days resulted in a 2.5 to 7-fold accumulation compared to single dose 
administration. Steady-state plasma sorafenib concentrations are achieved within 7 days, with a 
peak-to-trough ratio of mean concentrations of less than 2. A study of the pharmacokinetics of 
sorafenib indicated that the mean AUC of sorafenib in Asians (N=78) was 30% lower than the 
mean AUC in Caucasians (N=40). In adult patients, gender and age do not appear to have a 
clinically meaningful effect on the pharmacokinetics of sorafenib. In children with refractory solid 
tumors or leukemias, single agent sorafenib pharmacokinetics were similar to adults. Significant 
interpatient variability was observed both on Day 1 and at steady state. Drug exposure increased 
only marginally with dose escalation from 150 to 200 mg/m2 for day 1 pharmacokinetics. The 
terminal half-life in children appeared to be prolonged (≥24 hours) but could not be estimated. 
Sorafenib accumulated after multiple doses and steady state appeared to be achieved after 5 to 

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7 days. Steady-state sorafenib concentrations (AUC0–12h/12) were 4.1 ± 2.1 μg/mL at the 150 
mg/m2 and 5.4 ± 1.8 μg/mL at 200 mg/m2 dose levels, respectively. The median apparent 
sorafenib clearance at the MTD was 56.0 mL/min/m2. The apparent sorafenib clearance 
increased with patient age. The observed single agent sorafenib MTD in pediatric patients was 
200 mg/m2/dose twice daily for solid tumors and 150 mg/m2/dose twice daily for leukemias. The 
pharmacokinetics of sorafenib in patients with varying degrees of renal and hepatic impairment 
have been studied. No dose adjustment is necessary in patients with renal impairment or with 
mild to moderate hepatic impairment. 
 
Studies in human liver microsomes demonstrated that sorafenib competitively inhibited CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. However, sorafenib 400 mg twice daily 
for 28 days with substrates of CYP3A4, CYP2D6 and CYP2C19 did not increase the systemic 
exposure of these substrates. Studies with cultured human hepatocytes demonstrated that 
sorafenib did not increase CYP1A2 and CYP3A4 activities, suggesting that sorafenib is unlikely 
to induce CYP1A2 or CYP3A4 in humans. Drug interaction studies with the CYP3A4 inhibitor 
ketoconazole did not demonstrate a clinically important decrease in sorafenib exposure, however, 
the concentration of the active N-oxide metabolite decreased. Therefore, the use of strong or 
clinically relevant moderate CYP3A4 inhibitors should be avoided or used with caution. 
Continuous concomitant administration of sorafenib and rifampicin resulted in an average 37% 
reduction of sorafenib AUC. Other inducers of CYP3A4 activity (e.g., St. John’s wort, phenytoin, 
carbamazepine, phenobarbital, and dexamethasone) may also increase the metabolism of 
sorafenib and thus decrease sorafenib concentrations. Please see Appendix II. 
 
In vitro studies indicate that sorafenib inhibits glucuronidation by the uridine diphosphate- 
glucuronosyltransferase (UGT) 1A1 and 1A9 pathways. Systemic exposure to UGT 1A1 or 1A9 
substrates may increase when co-administered with sorafenib. Caution is recommended when 
sorafenib is used concomitantly with drugs predominantly metabolized by the UGT 1A1 pathway 
such as irinotecan, whose active metabolite SN-38 is metabolized by UGT 1A1. 
Sorafenib also inhibited P-glycoprotein in vitro and could increase the concentrations of 
concomitantly administered drugs that are P-glycoprotein substrates. 
Concomitant use of docetaxel or doxorubicin with continuous sorafenib administration resulted in 
an increase in the AUC of both docetaxel and doxorubicin. With fluorouracil, both increases and 
decreases in AUC were seen. Therefore, caution is recommended when administering sorafenib 
with these chemotherapeutic drugs. Sorafenib does not appear to affect the metabolism of 
warfarin (a CYP2C9 substrate) in vivo; however, infrequent bleeding events or elevations of the 
International Normalized Ratio (INR) have been reported in some patients receiving concomitant 
therapy with warfarin. Patients taking concomitant warfarin should be monitored regularly for 
changes in prothrombin time, INR or clinical bleeding episodes. 
Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the 
femoral growth plate at daily doses ≥ 600 mg/m2 (approximately 0.3 times the AUC at the 
recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 
mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and alterations 
of the dentin composition at 600 mg/m2/day. Similar effects were not observed in adult dogs when 
dosed for 4 weeks or less. 

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Toxicity 
 

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-- 
Adwrse  Ewnts  nith  Possil:ie 
Relationship  to Sorafenih (BAY 43-9006;    exa\:lr) 
(CTCAE  4 .0 Term) 
[n= 2 571] 
Likely (=·20 % ) 
Less Likely «20%) 
Rare but Serious (<c3%) 
Lymphocytecotmt  decreased 
Neutrophi1coun:t  decreased 
Platelet cotmt decreased 
Serum amylase increased 
Weight loss 
\Vhite blood cell decreased 
MErABOilSM AND NUTRITION DISORDERS 
Anore.xia 
Hypercalcemia 
Hyperglycemia 
Hyperkalemia 
Hypernatremia 
Hypoalblllllinemia 
Hypocalcemia 
Hypoglycemia 
Hypokalemia 
Hyponatremia 
Hypophosphatemia 
MUSCULOSKELErAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
Back pain 
Bonepain 
Musculoskeletal and cowiective 
tissue disorder - Other (muscle 
spasm) 
Mya!gia 
Pain in extremity 
NEOPIASMS BENICN,  MAUCNANT AND UNSPECIFIED  (INCL CYSTS AND 
POLYPS) 
Treatment related secondary 
malicy 
NERVOUS  SYSTEM  DISORDERS 
Dizziness 
Headache 
Intracranial  hen1orrhage 
Reversible posterior 
leukoencephalopathy 
syndrome 
PSYCHIATRIC   DISORDERS 
Insomnia 
RENAL AND URINARY DISORDERS 
Acute kidney injury 
RESPIRATORY, THORAOC AND MEDIA STINAL DISORDERS 
Coug)l 
Dyspnea 
Respiratory henuorrhage> 
Voice alteration 
SKlN AND SUBCUTANEO US TISSUE DISORDERS 

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Formulation and Stability: 
Sorafenib is supplied as a yellow-orange 50 mg and a red-colored 200 mg, round, immediate- 
release filmcoated tablet containing the excipients croscarmellose sodium, microcrystalline 
cellulose, hydroxypropylmethylcellulose, sodium lauryl sulfate, and magnesium stearate. The 200 
mg film-coat consists of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and 
red iron oxide. The 50 mg film- coat consists of hypromellose, PEG 3350, titanium dioxide, and 
yellow ferric oxide. The film coating has no effect on active BAY 43-9006 tosylate release rate. 
 
Sorafenib 200 mg tablets are supplied in high-density polyethylene (HDPE) bottles of 140 tablets 
and the 50 mg tablets are supplied in HDPE bottles of 100 tablets. The bottles should be stored 
at controlled room temperature (15-25ºC; 59-77°F) and storage temperature should not exceed 
25ºC (77°F). Stability testing is ongoing. 
 
 
10.1 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
10.2 
Criteria for Removal from Protocol Therapy 
1. Failure to attain or maintain remission following Induction II (≥ 5% malignant blasts or 
extramedullary disease). 
2. Relapse after Induction II of any site following remission. 
3. Refractory CNS leukemia following 6 doses of IT cytarabine therapy in Induction I or Induction 
II. 
4. CNS leukemia at start of Induction II after treatment for CNS leukemia in Induction I. 
5. Grade 3 or greater neurotoxicity from HD cytarabine or, 

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6. Other intolerable or unacceptable toxicity secondary to the standard chemotherapy backbone. 
7. Refusal of further protocol therapy by patient/parent/guardian. 
8. Completion of planned therapy. 
9. Physician determines it is in patient’s best interest. 
10. Development of a second malignancy. 
11. Graft failure 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study 
(see below). Follow-up data will be required unless consent was withdrawn. 
 
10.3 
Off Study Criteria 
1. Death. 
2. Lost to follow-up. 
3. Patient enrollment onto another study with tumor therapeutic intent (e.g., at recurrence).* 
4. Withdrawal of consent for any further data submission. 
5. Tenth anniversary of study entry. 
6. Excluded constitutional condition or oncologic diagnosis is indicated following enrollment 
7. FLT3/ITD status is unknown at End of Induction I. 
 
 
11.1 
STATISTICAL CONSIDERATIONS 
 
Sample size: This is a pilot study aimed at utilizing a risk-stratified approach along with 
pharmacogenomics to treat newly diagnosed patients with AML. Annually we expect to have 10- 
20 de novo AML patients to be diagnosed and treated at our institution. This two-year study would 
be expected to enroll approximately 30 patients (both low and high risk) during that time period. 
As a pilot study, this trial is not hypothesis-driven but rather estimation-driven, and the sample 
size is based on a feasible two-year target for our institution. 
 
Descriptive statistics will be conducted for demographic and patient characteristic variables, 
including toxicity related variables. Mean and standard deviation will be used for continuous 
variables and frequency and percent will be used for categorical variables. 
 
Primary Endpoints: 
1. Event-free survival: Event-free survival (EFS) is defined as the time from on study to 
death, failure to achieve remission or relapse, where those patients who do not 
experience these events will be censored at last follow-up date. EFS will be estimated 
using the Kaplan-Meier method for newly diagnosed patients with pediatric acute myeloid 
leukemia using a risk stratified approach. 
 
 
Secondary Endpoints: 
1. Disease-free survival: Disease-free survival (DFS) from end of first course of therapy is 
defined as time from end of first course of therapy to death or relapse, where those 
patients who do not experience these events will be censored at last follow-up date. DFS 
will be estimated using the Kaplan-Meier method for newly diagnosed patients with 
pediatric acute myeloid leukemia using a risk stratified approach. 
 
2. Overall survival: Overall survival (OS) is defined as (1) time from study entry and (2) from 
end of first course of therapy to death, where those who do not die will be censored at 

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last follow-up date. OS will be estimated using the Kaplan-Meier method for newly 
diagnosed patients with pediatric acute myeloid leukemia using a risk stratified approach. 
 
3. Minimal residual disease: Minimal residual disease (MRD) is the proportion of patients 
that are in remission (MRD negative) after one cycle of induction chemotherapy in both 
the GO and non-GO groups. Descriptive statistics (frequency and percent) will be used 
to estimate the frequency of MRD. 
 
4. Disease-free-survival MRD negative: Disease-free-survival, defined as time from end of 
first course of therapy to death or relapse, will be estimated for MRD negative patients 
who lack high or low risk molecular and cytogenetic features using the Kaplan-Meier 
method. 
 
5. Cardiac ejection fraction: Descriptive statistics (frequency and percent) will be used to 
estimate the frequency of patients that develop cardiac ejection fraction <50% (CTCAE 
V5.0 grade 2 or greater dysfunction) either during therapy (early cardiotoxicity) or after 
completion of therapy (late cardiotoxicity). 
 
Exploratory Endpoints: 
1. Molecular abnormalities: Descriptive statistics will be used to describe the molecular 
abnormalities seen in de-novo AML samples using comprehensive genomic testing. 
 
Analysis Datasets: 
All eligible patients who receive at least one dose of protocol therapy will be included in the 
primary efficacy analysis. Safety analysis will be conducted using the Safety Population, defined 
as any participant receiving at least one dose of study treatment. 
 
Interim Analysis: 
The rates of infectious and hematologic toxicities with each chemotherapy course are well 
established from prior COG study AAML0531 (refer to table below). These toxicity rates will be 
monitored after enrollment of the first 10 patients and subsequently after the next 10 patients are 
enrolled. While this is highly unlikely to happen, if toxicity rates are exceeding those expected for 
each course, the study will be stopped. 
 
AAML0531 
ADE 
ADE +GO 
MA 
AE 
Capizzi 
Infection incidence 
Documented infection 
35 % 
36 % 
69% 
49 % 
67% 
Neutropenic fever 
31 % 
32 % 
23% 
23 % 
18% 
Hematologic Recovery (days) 
Median time to platelets 
>50K 
26 
28 
38 
25 
42 
Median time to ANC 
>500 
30 
30 
37 
27 
40 

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APPENDIX I – SORAFENIB DOSING NOMOGRAM 

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APPENDIX II – CYP3A4 INDUCERS AND INHIBITORS 
 
 

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