Conditions: Acute Myeloid Leukemia AML, Childhood
Keywords: acute myeloid leukemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
The investigators propose to study an Aflac-AML chemotherapy backbone prospectively to validate its use in all pediatric AML and to further evaluate the cardiotoxicity with this approach for low risk AML.

Detailed description:
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). The investigators 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, they 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. The investigators propose to study an Aflac-AML chemotherapy backbone prospectively to validate its use in all pediatric AML and to further evaluate the cardiotoxicity with this approach for low risk AML.

Arms:
arm 1: Participants in this arm will receive the standard Aflac-AML Regimen with the following chemotherapy:

* Induction-1: patients on Induction-I will receive gemtuzumab + ADE therapy based on genotyping. Lasts a total of 28 days.
* Induction II - MA
* Intensification I - AE
* Intensification II - 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. arm 2: Participants in this arm will receive standard Aflac-AML Regimen with the following chemotherapy:

* Induction-1: patients will receive gemtuzumab in addition to ADE therapy based on genotyping. Induction I lasts a total of 28 days.
* Induction 1 for FLT3-ITD patients - ADE (10+3+5) with GO with Sorafenib
* Induction II - MA
* Induction II for FLT3-ITD patients - MA with Sorafenib
* Intensification I - AE
* Intensification I for FLT3-ITD patients - AE with sorafenib
* Intensification II - HD ARAC/LASP
* Intensification II for FLT3-ITD patients - HD ARAC/LASP with sorafenib
* Hematopoietic stem cell transplantation (HSCT)

If a patient is classified as High risk after Induction I, they may proceed to best allogenic donor SCT following Induction II. These patients may receive a third course of chemotherapy prior to HSCT. In cases where HSCT is not an option, patients can receive 4 cycles of chemotherapy. Only patients with FLT3-ITD mutation will receive sorafenib.

Interventions: intervention 1: Cytarabine intervention 2: Daunorubicin intervention 3: Erwinase intervention 4: Etoposide intervention 5: Gemtuzumab ozogamicin intervention 6: Stem cell transplantation (SCT) intervention 7: Sorafenib
Intervention descriptions: intervention 1: 100 mg/m²/dose every 12 hours IV Days 1-10 intervention 2: 50 mg/m²/dose IV Days 1, 3, 5 intervention 3: 25,000 International Units/m²/dose IM Days 2, 9 intervention 4: 150 mg/m²/dose IV Days 1-5 intervention 5: Administered as a single 3 mg/m2 dose of GO to be given between days 6-10 during Induction I for patients with CC genotype, in addition to ADE therapy. intervention 6: Transplantation of multipotent hematopoietic stem cells from bone marrow intervention 7: 200 mg/m2/dose daily, rounded to accommodate tablet size. The maximum dose will be 400 mg. Days 7 through 34.

Protocol document:
Prot_SAP_000.pdf: 
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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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REFERENCES 
 
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Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and 
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Aplenc R, Meshinchi S, Sung L, et al. The Addition of Bortezomib to Standard 
Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without 
Therapeutic Benefit: A Report from the Children's Oncology Group. Blood. 2016;128(22). 
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Gibson BE, Webb DK, Howman AJ, et al. Results of a randomized trial in children with 
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Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger 
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Loken MR, Alonzo TA, Pardo L, et al. Residual disease detected by multidimensional 
flow cytometry signifies high relapse risk in patients with de novo acute myeloid 
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Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among 
survivors of childhood cancer. JAMA : the journal of the American Medical Association. 
2010;304(2):172-179. 
7. 
Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year 
survivors of childhood cancer: childhood cancer survivor study. Journal of the National 
Cancer Institute. 2001;93(8):618-629. 
8. 
Mertens AC, Yasui Y, Neglia JP, et al. Late mortality experience in five-year survivors of 
childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol. 
2001;19(13):3163-3172. 
9. 
Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA. Anthracycline-induced 
clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol. 
2001;19(1):191-196. 
10. 
Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 
2018;392(10147):593-606. 
11. 
Bernstein ID. Monoclonal antibodies to the myeloid stem cells: therapeutic implications 
of CMA-676, a humanized anti-CD33 antibody calicheamicin conjugate. Leukemia. 
2000;14(3):474-475. 
12. 
van Der Velden VH, te Marvelde JG, Hoogeveen PG, et al. Targeting of the CD33- 
calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo 
and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood. 
2001;97(10):3197-3204. 
13. 
Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in 
relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490-1496. 
14. 
Drexler HG. Classification of acute myeloid leukemias--a comparison of FAB and 
immunophenotyping. Leukemia. 1987;1(10):697-705. 
15. 
Estey EH, Giles FJ, Beran M, et al. Experience with gemtuzumab ozogamycin 
("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood. 
2002;99(11):4222-4224. 
16. 
Kell WJ, Burnett AK, Chopra R, et al. A feasibility study of simultaneous administration of 
gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in 
younger patients with acute myeloid leukemia. Blood. 2003;102(13):4277-4283. 
17. 
Amadori S, Suciu S, Willemze R, et al. Sequential administration of gemtuzumab 
ozogamicin and conventional chemotherapy as first line therapy in elderly patients with 


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acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA 
leukemia groups. Haematologica. 2004;89(8):950-956. 
18. 
Eom KS, Kim HJ, Min WS, et al. Gemtuzumab ozogamicin in combination with 
attenuated doses of standard induction chemotherapy can successfully induce complete 
remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or 
older. Eur J Haematol. 2007;79(5):398-404. 
19. 
Sievers EL. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33- 
positive acute myeloid leukaemia in first relapse. Expert Opin Biol Ther. 2001;1(5):893- 
901. 
20. 
Giles FJ, Kantarjian HM, Kornblau SM, et al. Mylotarg (gemtuzumab ozogamicin) 
therapy is associated with hepatic venoocclusive disease in patients who have not 
received stem cell transplantation. Cancer. 2001;92(2):406-413. 
21. 
Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab 
ozogamicin during induction and postconsolidation therapy in younger patients with 
acute myeloid leukemia. Blood. 2013;121(24):4854-4860. 
22. 
Rowe JM, Lowenberg B. Gemtuzumab ozogamicin in acute myeloid leukemia: a 
remarkable saga about an active drug. Blood. 2013;121(24):4838-4841. 
23. 
Tarlock K, Alonzo TA, Gerbing RB, et al. Gemtuzumab Ozogamicin Reduces Relapse 
Risk in FLT3/ITD Acute Myeloid Leukemia: A Report from the Children's Oncology 
Group. Clin Cancer Res. 2015. 
24. 
Pollard JA, Loken M, Gerbing RB, et al. CD33 Expression and Its Association With 
Gemtuzumab Ozogamicin Response: Results From the Randomized Phase III 
Children's Oncology Group Trial AAML0531. J Clin Oncol. 2016;34(7):747-755. 
25. 
Lamba JK, Pounds S, Cao X, et al. Coding polymorphisms in CD33 and response to 
gemtuzumab ozogamicin in pediatric patients with AML: a pilot study. Leukemia. 
2009;23(2):402-404. 
26. 
Mortland L, Alonzo TA, Walter RB, et al. Clinical significance of CD33 nonsynonymous 
single-nucleotide polymorphisms in pediatric patients with acute myeloid leukemia 
treated with gemtuzumab-ozogamicin-containing chemotherapy. Clin Cancer Res. 
2013;19(6):1620-1627. 
27. 
Lamba JK, Chauhan L, Shin M, et al. CD33 Splicing Polymorphism Determines 
Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From 
Randomized Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol. 
2017;35(23):2674-2682. 
28. 
Mulrooney DA, Dover DC, Li S, et al. Twenty years of follow-up among survivors of 
childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer 
Survivor Study. Cancer. 2008;112(9):2071-2079. 
29. 
Chellapandian D, Pole JD, Nathan PC, Sung L. Congestive heart failure among children 
with acute leukemia: a population-based matched cohort study. Leuk Lymphoma. 
2018:1-10. 
30. 
Getz KD, Sung L, Ky B, et al. Occurrence of Treatment-Related Cardiotoxicity and Its 
Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report 
From the Children's Oncology Group. J Clin Oncol. 2019;37(1):12-21. 
31. 
Curran CF, Narang PK, Reynolds RD. Toxicity profile of dexrazoxane (Zinecard, ICRF- 
187, ADR-529, NSC-169780), a modulator of doxorubicin cardiotoxicity. Cancer Treat 
Rev. 1991;18(4):241-252. 
32. 
Hasinoff BB, Hellmann K, Herman EH, Ferrans VJ. Chemical, biological and clinical 
aspects of dexrazoxane and other bisdioxopiperazines. Curr Med Chem. 1998;5(1):1-28. 
33. 
Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. 
FASEB journal : official publication of the Federation of American Societies for 
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34. 
Asselin BL, Devidas M, Chen L, et al. Cardioprotection and Safety of Dexrazoxane in 
Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or 
Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's 
Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol. 
2016;34(8):854-862. 
35. 
Schwartz CL, Wexler LH, Krailo MD, et al. Intensified Chemotherapy With Dexrazoxane 
Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the 
Children's Oncology Group. Pediatr Blood Cancer. 2016;63(1):54-61. 
36. 
Kim H, Kang HJ, Park KD, et al. Risk Factor Analysis for Secondary Malignancy in 
Dexrazoxane-Treated Pediatric Cancer Patients. Cancer Res Treat. 2018. 
37. 
Meshinchi S, Woods WG, Stirewalt DL, et al. Prevalence and prognostic significance of 
Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 
2001;97(1):89-94. 
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Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in 
pediatric AML. Blood. 2006;108(12):3654-3661. 

ICF_001.pdf: 
IRB00111627 
IRB Approved 
7/27/2021 
Page 1 of 31 
IRB Form 06162020 
AflacLL1901 CHOAAML consent HIPAA 3-1-21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AflacLL1901 (CHOA-AML): A Pilot Study for Newly Diagnosed Pediatric Patients with Acute Myeloid 
Leukemia (AML) 
 
 
NCT04326439 
 
Date: 07/27/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB00111627 
IRB Approved 
7/27/2021 
Page 2 of 31 
IRB Form 06162020 
AflacLL1901 CHOAAML consent HIPAA 3-1-21 
 
 
 
You Are Being Asked to Be in a Research Study 
Concise presentation of key concepts 
 
 
You are being asked to be in a research study. A research study is designed to answer a scientific question. If 
you agree to be in the study, you will be one of 30 people who are being studied at Emory and Children’s 
Healthcare of Atlanta. 
 
Why is this study being done? 
This study is being done to answer the question: We want to study whether adjusting your treatment from 5 
cycles to 4 cycles will provide you with the same treatment results. We hope that fewer cycles will decrease 
the amount of side effects that you may experience during your treatment. We also want to test whether or 
not the addition of a drug used to treat AML, Gemtuzumab Ozogamicin (GO, MylotargTM), will reduce the 
chances of your type of AML from coming back after initial treatment. 
 
Do you have to be in the study? 
It is your decision to be part of this research study. You do not have to be in it. Your choice will not affect your 
access to medical care for your condition. Before you make your decision, you should take time to learn about 
the study. 
 
What do I have to do if I choose to participate in this study? 
If you are eligible and want to be part of the study, you are expected to receive treatment for about 6 to 
8 months. After treatment, you will have follow-up examinations and medical tests. 
 
We would like to continue to find out about your health every year for about 10 years after you enter this 
study. By keeping in touch with you for a while after you complete treatment, we can better understand the 
long-term effects of the study treatments. 
 
How is this study going to help you? 
If you are in the study, you will be helping the researchers answer the study question. There may be no direct 
benefit to you. This treatment may help prevent your AML from returning and reduce side effects. The 
researchers may learn things from your participation in this study that can help other transplant patients. 
 
What are the risks or discomforts I should know about before making a decision? 
The study will take time. The procedure that is being tested may not work any better than regular care and 
may even cause harm. All studies have some risks. Some risks are relatively small, like being bored or losing 
time. Some are more serious – for this study, these include infusion risks, risks associated with blood draws, 
loss of privacy, and breach of confidentiality. A full list of expected risks, their frequency and severity are in 
the “What are the possible risks and discomforts?” section of this document. 


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IRB Form 06162020 
AflacLL1901 CHOAAML consent HIPAA 3-1-21 
 
 
 
Alternatives to Joining This Study 
You can choose not to be in this study. You should know about your treatment options before you decide 
whether you will be in this study. You could be treated using standard medications and treatment cycles for 
AML. 
 
Costs 
You will have to pay for some of the study procedures, in particular those that are not covered by your 
medical insurance. 
 
The study team can help you work out how much you might have to pay. There is more information in the 
cost section below. 
 
What Should I Do Next? 
Read this form, or have it read to you. Make sure the study doctor or study staff explains the study to you. 
Ask questions (e.g., about exact time commitment, about unfamiliar words, more details on specific 
procedures, etc.) Make sure you understand which parts of the study are research and which are standard 
care that you would have even if you did not join the study. Take time to consider this and talk about it with 
your family and friends. 


IRB00111627 
IRB Approved 
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IRB Form 06162020 
AflacLL1901 CHOAAML consent HIPAA 3-1-21 
 
 
 
Emory University and Children’s Healthcare of Atlanta 
Consent to be a Research Subject / HIPAA Authorization 
 
 
Title: AflacLL1901 (CHOA-AML): A Pilot Study for Newly Diagnosed Pediatric Patients with Acute Myeloid 
Leukemia (AML) 
 
IRB#: 111627 
 
Principal Investigator: Himalee Sabnis, MD 
 
Study-Supporter: Aflac Cancer and Blood Disorders Center 
 
If you are the legal guardian of a child who is being asked to participate, the term “you” used in this consent 
refers to your child. 
 
Introduction 
You are being asked to be in a medical research study. This form is designed to tell you everything you need to 
think about before you decide if you want to be a part of the study. It is entirely your choice. If you decide to 
take part, you can change your mind later on and withdraw from the research study. The decision to join or 
not join the research study will not cause you to lose any medical benefits. If you decide not to take part in 
this study, your doctor will continue to treat you. 
 
Before making your decision: 
• Please carefully read this form or have it read to you 
• Please listen to the study doctor or study staff explain the study to you 
• Please ask questions about anything that is not clear 
 
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you 
would like to participate. You may wish to discuss your decision with family or friends. Do not sign this consent 
form unless you have had a chance to ask questions and get answers that make sense to you. By signing this 
form, you will not give up any legal rights. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This 
Web site will not include information that can identify you. At most the Web site will include a summary of the 
results. You can search this Web site at any time. 
 
What is the purpose of this study? 
You are being asked to take part in this research study because you have been newly diagnosed with Acute 
Myeloid Leukemia (AML). AML is a cancer of the bone marrow, the spongy tissue inside the large bones of the 
body where blood cells are made. In AML, the bone marrow makes large numbers of immature white blood 
cells called blasts. These blast cells crowd out the normal cells of the bone marrow. They may also invade body 
organs including the brain, testes, ovaries, or skin. These cancerous AML cells can sometimes form a solid 
tumor called a chloroma. 


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IRB Form 06162020 
AflacLL1901 CHOAAML consent HIPAA 3-1-21 
 
 
 
 
The current standard of care per cooperative pediatric oncology groups is to treat most patients with five 
cycles of chemotherapy. We have treated AML patients with four (similar but not exactly same) cycles of 
chemotherapy over the last five years and achieved similar cure rates like national studies. We now want to 
study prospectively in a larger group whether adjusting your treatment with 4 cycles of our treatment regimen 
will provide you with the same treatment results. We hope that fewer cycles will decrease the amount of side 
effects that you may experience during your treatment and especially reduce your risk of heart-related 
complications with therapy. With our 4-cycle regimen, we want to test whether or not the addition of a drug 
used to treat AML, Gemtuzumab Ozogamicin (GO, MylotargTM), will reduce the chances of your type of AML 
from coming back after initial treatment. We will compare the results of this study with previous studies. 
 
Another goal of the study is to understand the biology of AML better. Study doctors want to obtain and store 
blood or bone marrow for certain genetic changes (called genetic markers) in leukemia cells that will be 
studied in future. This would help them to learn more about AML and how to treat patients better. 
 
What will I be asked to do? 
This research study will be done at Children’s Healthcare of Atlanta, in the Aflac Cancer Center & Blood 
Disorders Center. The people that you will interact with on this research study will include bone marrow 
transplant doctors and nurses, research nurses, and other specialists, as needed. 
 
What is the Current Treatment for this Disease? 
The standard treatment for this disease is to use a combination of cancer-fighting drugs called chemotherapy 
given in different phases (also called courses). Chemotherapy destroys the leukemia cells in the blood and 
bone marrow. In the first phase, called Induction I, we try to remove all visible signs of leukemia and allow 
normal blood cells to be restored. This is called remission. The next phase of treatment is called Induction II 
which is another round of chemotherapy to kill the few remaining leukemia cells that may have survived 
Induction I. In the next phase of treatment, called Intensification I, more chemotherapy is used to kill any 
remaining blast cells. Then we do a Stem Cell Transplantation (SCT) or give additional high doses of 
chemotherapy (in a last phase called Intensification II) to try to maintain the remission. 
 
If you agree to participate in this study, you will undergo the following procedures: 
Screening and Pre-treatment Assessments 
No study procedures will be done until after you have agreed to participate by signing this Informed Consent. 
 
Standard Medical Tests 
Before treatment on this study begins, and while getting treatment, you will have a series of standard medical 
tests. These tests would be done even if you were not in this study: 
▪ Physical exam – including asking you some questions about your medical history and recording your height, 
weight, blood pressure, pulse, blood oxygen, and organ function. 
▪ Blood tests - we will take about a tablespoon of blood from your vein. We will look for infections, kidney 
function, liver function, and blood counts. Many blood samples will be taken during treatment to check 
blood counts and the balance of salts in the blood. 


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▪ HLA typing - we will take blood samples from you and your family for this genetic typing test. The results of 
this test will determine if any of your family members can be your bone marrow donor. 
▪ Urine tests - we will take a small sample of your urine to check for damage, bleeding, or infection in the 
kidneys or bladder. 
▪ Pregnancy tests – given to females of childbearing age prior to treatment 
▪ Magnetic Resonance Imaging (MRI) – Only for patients who have a chloroma. MRI uses magnetic waves to 
look at soft tissues of the body. Sometimes MRI requires an injection of contrast to see other areas of the 
body. MRI contrast (gadolinium) is administered through a small needle placed into a vein. During the 
administration of MRI contrast (gadolinium), you may experience the sensation of the contrast being 
injected. MRIs will be done throughout your treatment on this study. 
▪ Computed Tomography (CT) Scan – Only for patients who have a chloroma. CT scans use a computer to put 
multiple x-rays (pictures of the inside of your body taken with energy beams) together to create a complete 
picture of the inside of your body. 
▪ Biopsy - Only for patients who have a chloroma. A surgical procedure will be done to take a piece of the 
chloroma for testing. You will be given other consents that cover the risks of the biopsy and the anesthesia. 
▪ Hearing test - audiograms will be done throughout your therapy to monitor for changes in your hearing. 
▪ Spinal Tap – we will use a needle to take a small sample of the fluid surrounding your spinal column. This 
sample will be used to see if the tumor has spread to the spinal fluid. You will get pain medication during 
this procedure. You will be presented with a separate consent that explains the risks of this procedure. This 
is a not a research test and is considered standard of care. 
▪ Eye exam – an eye exam will be done at the time you are diagnosed to make sure your vision is okay. 
▪ Bone marrow tests - we will take a small amount of the soft part (marrow) of the center of your hip bone. 
This sample will be used to determine if the tumor has spread to your bone marrow. You will get pain 
medication during this procedure. You will be presented with a separate consent that explains the risks of 
this procedure. Testing of bone marrow includes estimation of disease by a technique called flow cytometry. 
A special kind of flow cytometry is called Minimal Residual Disease (MRD) testing and will be done as 
standard of care at the end of each therapy cycle. 
▪ Chest x-rays – we will use energy beams to take a picture of your chest to check for infection. 
▪ Tests of heart function– you will have an EKG (electrocardiogram, a recording of the electrical activity of the 
heart) and echocardiogram (ultrasound of the heart) to test how the heart works. 
▪ Tests of lung function – Only for transplant patients. We will check how your lungs are working by having 
you breathe into a machine. This is called a Pulmonary Function Test. 
▪ Tests of kidney function – we will check how your kidneys are working by checking blood levels of creatinine 
or by doing a Glomerular Filtration Rate (GFR) or a Creatinine Clearance. To do a GFR, you are injected with 
a special dye and then have several imaging studies of your kidneys. The imaging studies will take about 20 
minutes each and will be done 1 to 2 hours apart. You will get a separate consent from that covers the risks 
of a GFR scan. To do a Creatinine Clearance we will have to collect a 24-hour urine sample and then take 
one blood sample at the end of the 24-hour period. 
 
Treatment Plan 
The treatment plan involves cancer fighting medicine called chemotherapy. The treatment on this clinical trial 
takes about 6 to 8 months. It is divided into 4 stages: Induction I, Induction II, Intensification I, and 
Intensification II. Chemotherapy will also be given in the spinal fluid during Induction I, Induction II and 


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Intensification I. Depending on your disease risk group, you may receive a stem cell transplant instead of 
Intensification I and II. 
 
Chemotherapy will be given in the following stages: 
• 
Induction I: chemotherapy given for 10 days followed by 3 weeks of rest (28 days total). 
• 
Induction II: chemotherapy is given for 6 days followed by 3 weeks of rest (28 days total). 
• 
Intensification I: chemotherapy is given over 5 days followed by 3 weeks of rest (28 days total). 
• 
Intensification II: chemotherapy is given over 9 days followed by 3 weeks of rest (28 days total). 
 
During first course of chemotherapy (Induction I), genetic markers in your blood will be used to determine 
whether or not you receive gemtuzumab ozogamicin (GO). After completion of first course of chemotherapy 
(Induction I), patients will be classified into low or high-risk groups. 
 
Both groups will receive the treatment described in Induction II. 
 
The study doctor will then decide whether you get a stem cell transplant or more chemotherapy. This will be 
decided based on 2 factors: 1) whether your leukemia is considered high or low risk for relapse and 2) whether 
there is an appropriate stem cell donor for you. In all cases, the study doctor will discuss the pros and cons of 
each treatment option. 
 
In this study, subjects who are considered to be Low risk for relapse will not have a stem cell transplant even if 
they have a matched family donor. Researchers want to know if this group of subjects can have the same or 
better cure rate without the risk of side effects from a stem cell transplant. Subjects who are High risk will  
have a stem cell transplant with either a matched family donor or an alternative donor (matched non-family 
donor). 
 
If you are low risk, you will be given more chemotherapy, then you will proceed to: 
• Intensification I: chemotherapy is given over 5 days followed by 3 weeks of rest (28 days total) 
followed by 
Intensification II: chemotherapy is given over 9 days followed by 3 weeks of rest (28 days total). 
 
If you are high risk and given a stem cell transplant, then you will proceed to: 
• 
5 days of treatment to kill all of your bone marrow cells. The stem cell transplant will then replace 
these cells with stem cells from a matched donor. The donor may be a family member, an unrelated 
person, or donated cord blood. A separate consent with additional information about SCT will be 
provided to subjects proceeding to SCT. 
If you are high risk and there is a delay in receiving stem cell transplant, then you will proceed to: 
• Intensification I: Your physician will decide the best chemotherapy option for you during this cycle 
After this, you will proceed to stem cell transplant 
 
Patients who have a mutation in their leukemia called FLT3-ITD will be deemed high-risk. These subjects will 
take a FLT3-ITD inhibitor called sorafenib by mouth until Day 28 of each stage. Subjects will also be given a 
stem cell transplant if there is an appropriate donor following Induction II or Intensification I. As a final course, 


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these patients will receive 1 year of treatment with sorafenib alone, called Maintenance after stem cell 
transplant. 
 
Bone marrow tests are done at the end of Induction I, Induction II, Intensification I and at the end of 
treatment. If you are not responding to treatment, your doctor will remove you from the study and 
recommend a different treatment. 
 
Treatment Plan Tables 
Treatment that is standard for AML is described in Attachment #1. This includes the commonly used 
chemotherapy that all subjects will receive during Induction I, Induction II, and Intensification I, and also the 
radiation therapy that you may receive on this study if you have a chloroma (a greenish solid tumor mass that 
some people with AML have. It is made up of abnormal white blood cells and occurs anywhere in the body). 
 
The following tests will be done as standard of care. 
The results of these tests will be used to identify what risk group subjects belong to and will be used to make 
treatment decisions on this study. For these samples, we will label them with your name and the results will 
be part of your medical record. 
 
Cytogenetic Testing: 
The study doctors want to know about changes in the genetic material in your leukemia cells. This will help 
study doctors to identify abnormalities in the genes that might affect the development of AML and its 
treatment. This information will be sent to a reference laboratory to define the risk classification for relapse. 
Although cytogenetic testing is usually part of standard care, this study recommends that cytogenetic testing 
be done by an approved laboratory. If your institution does not have an approved laboratory, then it is 
possible that your blood/bone marrow samples will be shipped to a laboratory outside of your institution for 
cytogenetic testing. For this study, samples will be sent to FoundationOne® Heme. Additionally, once the 
testing has been done, a copy of the cytogenetics information will be sent to a cytogenetics specialist who will 
make sure that the diagnosis is correct. Having a specialist check the diagnosis is not part of standard care. For 
this testing we will collect about ½ teaspoonful to ¾ teaspoonful of bone marrow. If we cannot collect enough 
bone marrow, we may also collect some blood (about 1 teaspoonful). 
 
FLT3 Testing: 
The study doctors also want to know if there are molecular changes in the FLT3 gene of your leukemia cells. 
This will allow study doctors to identify FLT3 mutations (molecular changes) that may affect your treatment. 
Samples will be sent to an approved laboratory for this testing. FLT3 test results will define the risk classification 
in this study. If you have certain mutations in your FLT3 gene which have been shown to predict a higher risk of 
relapse, you will be assigned a high-risk classification. 
 
Minimal Residual Disease at Diagnosis and End of Induction I: 
The study doctors want to look for minimal residual disease (MRD) in bone marrow and blood. MRD is a test 
to look for very small amounts of leukemia cells and is performed by a special test called flow cytometry. Flow 
cytometry is routinely done at the time of diagnosis to confirm the diagnosis of AML. MRD is a special kind of 
flow cytometry. MRD levels may be used to predict the risk of leukemia coming back. The results of the first 
MRD test at the end of Induction I (the first course of chemotherapy) will be used to evaluate how effective 


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treatment is for you and determine risk assignment and subsequent treatment. If you are MRD “positive” after 
Induction I, you will be assigned a high-risk classification. If you are MRD “negative” after Induction I, you will 
be assigned a low risk classification. Subjects that are classified as high risk will receive different treatment  
than subjects that are classified as low risk. Therefore, the MRD results may determine the type of treatment 
you receive. MRD testing is required for study participation and is not investigational. The amount of extra 
bone marrow taken at each time will be about ½ teaspoonful to 1 teaspoonful. If we cannot collect enough 
bone marrow, we may also collect some blood (about 1 teaspoonful). This study will provide more information 
about the use of MRD tests to determine the risk of leukemia relapse. 
 
Research Study Tests and Procedures 
Optional Research Tests 
There are biology research tests. These tests are not part of standard care and will only be done if you agree 
to give extra blood or bone marrow samples. At the end of this consent, there are questions for you to 
indicate if you want to take part in these optional research tests. 
 
Future Studies: 
If you agree, as part of future genetic studies we would like to take about 1 teaspoonful of blood before the 
beginning of treatment on this study and again at the end of Induction Course 1 therapy. The extra blood for 
this optional test can usually be obtained through the same needle stick as the samples for the routine tests. 
However, sometimes a second needle stick may be required. There may be additional pain associated with 
obtaining the blood. 
 
If you agree, we would like to keep any extra bone marrow or blood to bank for future studies. The research 
that may be done with the samples is not designed to help you during your present treatment. It might help 
people who have cancer and other diseases in the future. 
 
You will receive no payment or money for taking part in this study. If you provide specimens to the researcher, 
there are no plans for you to profit from any new products developed from research done on your specimens. 
 
Parts of your transplant care that will not be affected by being in this study 
Other parts of your AML care are not affected by being in this study. Participating in this study does not 
prevent your doctor from starting or stopping any medicines or doing any tests that they think are needed. 
 
How long will I be in the study? 
Participants in this clinical trial are expected to receive treatment on this study for 6 to 8 months. After 
treatment, subjects will have follow-up examinations. We will continue to collect some medical information 
about how you are doing for 10 years after the last subject starts the study. 
 
Your doctor or the study doctor may decide to take someone off this study under the following circumstances: 
• if he/she believes that it is in the person’s best interest 
• if the subject’s disease comes back during treatment 
• if the subject experiences side effects from the treatment that are considered too severe 
• if new information becomes available that shows that another treatment would be better for the person 


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You can stop participating at any time. However, if you decide to stop participating in the study, we 
encourage you to talk to the study doctor and your regular doctor first. Your study doctor or regular doctor 
will be able to help you stop treatment in way that is safe for you. 
 
Who owns my study information and samples? 
If you join this study, you will be donating your samples and study information. You will not receive any 
compensation if your samples or information are used to make a new product. If you withdraw from the 
study, data and samples that were already collected may be still be used for this study. If you withdraw and 
want your leftover samples destroyed, please write to Dr. Himalee Sabnis, 2015 Uppergate Drive, Atlanta, GA 
30322. 
 
What are the possible risks and discomforts? 
There are risks involved in this study, and there may be side effects from the treatment. The side effects we 
know about are described below. They may vary from person to person. With any drug, there may be 
complications or side effects that we do not know about. Please talk with your doctor about this. If you want 
to read more about AML, please ask the doctor for more information. 
 
Treatment Risks 
All people who receive cancer treatment are at risks of having side effects. In addition to killing tumor cells, 
cancer chemotherapy can damage normal tissue and produce side effects. Side effects are usually reversible 
when the medication is stopped but occasionally persist and cause serious complications. A person can die 
from these and other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be given to prevent or 
decrease nausea and vomiting. Hair loss is usually temporary but on very rare occasions it may be permanent. 
Some chemotherapy may lead to sterility. Sterility is the inability to have children. There is also the possibility 
that a second cancer may develop years later as a result of the chemotherapy. The risks of the individual 
drugs given as standard treatment and risks of radiation therapy are listed on the tables in Attachment #2. 
Side effects can be increased when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of blood cells resulting 
in anemia, increased chance of infection, and bleeding tendency. 
 
There is a risk that the treatment will not cure the cancer or that the cancer can go away after the treatment 
and then come back at a later date. 
 
For Women: 
The treatment on this study can affect an unborn child. You should not become pregnant or breast feed your 
baby while being treated on this study. If you are sexually active and are at risk of getting pregnant, you and 
your male partner(s) must use an effective method to avoid pregnancy or you must not have sex. The study 
doctor will talk to you about acceptable methods to avoid pregnancy while you are being treated on this study.  
You will have to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse)               
the whole time you are being treated on this study. Since chemotherapy may alter/disrupt normal menstrual 
cycles, resulting in missed or absent periods, natural methods of family planning should not be used. If you 


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have questions about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor. If you become pregnant during the research study, please tell the study doctor and your doctor 
immediately. 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You should not nurse 
your baby for the whole time you are getting the study medicines. You may need to continue this for a while, 
even after you finish the cancer treatment, so talk to your doctor about the length of time you need to avoid 
nursing. 
For Men: 
The treatment on this study can damage sperm. You should not father a child while on this study as the 
treatment may indirectly affect an unborn child. If you are sexually active and are at risk of causing a 
pregnancy, you and your female partner(s) must use an effective method to avoid pregnancy that works well, 
or you must not have sex. The study doctor will talk to you about the acceptable methods to avoid pregnancy 
while you are being treated on this study. You will have to use the chosen method to avoid pregnancy or 
abstain (not have sexual intercourse) the whole time you are being treated on this study. Natural family 
planning and the rhythm method will not be permissible means of avoiding pregnancy during study 
participation. If you have questions about this or want to change your method to avoid pregnancy during 
therapy, please ask your doctor. If your partner becomes pregnant during the research study, please tell the 
study doctor and your doctor immediately. 
The most serious side effect from cancer treatment is the depression of the number of blood cells. This can 
result in anemia, increased chance of infection and bleeding tendency. These complications can sometimes be 
fatal. Bone marrow tests, blood work, scans, spinal taps and laboratory tests will be done to monitor your 
progress. Blood transfusions may be necessary if the number of blood cells becomes too low. Transfusions of 
platelets (clotting cells) may also be necessary. 
Side effects can be increased with chemotherapy drugs are combined. Side effects are usually reversible when 
the medication is stopped, but occasionally can persist and cause serious complications. 
 
Risks of Study 
If you are being treated with gemtuzumab: 
The use of gemtuzumab may cause more complications when combined with the use of standard chemotherapy 
treatment for AML. The combination of standard therapy with gemtuzumab may result in possible side effects, 
including a serious liver ailment called Veno-occlusive Disease (VOD). VOD is characterized by an increased 
bilirubin in the blood and possible jaundice (temporary yellowing of the skin), an enlarged and painful liver, and 
fluid retention with associated weight gain. In severe cases, VOD can be fatal.  The risk of VOD may be greater 
if you get gemtuzumab and a stem cell transplant. 
 
The risks and side effects related to gemtuzumab are listed in the table below. In addition to the risks described 
here, there may be unknown risks, or risks that we did not anticipate, associated with being in this study. 


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Risks and side effects related to gemtuzumab 
Likely 
Less Likely 
Rare but serious 
• Nausea and vomiting 
• Headache 
• Mouth Sores 
• Loss of desire to eat 
• Constipation 
• Fever and chills including shaking 
chills. These reactions are more 
common with the first dose. 
• Feeling short of breath 
• Pain in the abdomen 
• A feeling of tiredness or weakness 
• Fewer white blood cells, red blood 
cells and platelets in the blood 
o a low number of white blood 
cells can make it easier to get 
infections 
o a low number of red blood cells 
can make you feel tired and weak 
o a low number of platelets causes 
you to bruise and bleed more 
easily 
• Low levels of potassium in the blood 
which may make you feel weak or 
your heartbeat irregularly 
• Increase in the blood of certain 
enzymes or bilirubin (a substance 
that comes from the liver breaking 
down waste products) which could 
indicate liver irritation or damage 
• A decrease or an 
increase in blood 
pressure 
• Rash, hives or 
itchiness during 
the infusion 
• Irregular 
heartbeat during 
the infusion 
• Pain in the back 
• Upset stomach 
• Diarrhea 
• Dizziness or 
fainting 
• Cough 
• Abnormally low 
levels of certain 
salts in the body 
like magnesium, 
calcium, and 
phosphate which 
may require that 
you take 
replacement 
doses 
• Increase in the 
sugar in the 
blood 
• Anxiety or 
depression 
• Difficulty sleeping 
• 
Allergic reactions during the infusion 
that can be severe and life-threatening 
and may lead to difficulty in breathing, 
a drop-in blood pressure, irregular 
heartbeat, fluid in the lungs or damage 
to the lungs and shock. 
• 
The rapid death of large numbers of 
tumor cells which can cause the 
potassium and phosphate salts and the 
uric acid in the blood to rise quickly and 
this could lead to a life-threatening 
irregular heartbeat or damage to the 
kidneys. 
• 
Damage to the lungs that can lead to 
fluid in the lungs and affect your ability 
to breath and the levels of oxygen in 
your blood. 
• 
Bleeding which can occur in the head, 
the stools, the nose, and urine and 
other places in the body. 
• 
Infections including those caused by 
bacteria, virus and fungus 
• 
Damage to the liver which can be 
severe and life-threatening and is more 
common if you have had a bone 
marrow transplant or plan to have one 
in the future. 
 
We will be checking you closely to see if any side effects are happening. Side effects of drugs like gemtuzumab 
usually get better if the treatment is stopped, but in some cases the side effects can be serious or long lasting. 
If you do have side effects, we may recommend medicine or treatments to try to control them and make you 
more comfortable. 
 
A risk for subjects randomized to standard Arm A is that you will not receive a new treatment for AML that may 
have some benefits. 


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Surgery Risks 
Risks associated with any surgery will be presented in a separate consent form by the surgical staff. 
Sedation Risks 
If you require anesthesia for any procedure, you will be presented with a separate consent from that explains 
the risks associated with anesthesia. 
 
Blood Transfusion Risks 
This treatment and/or your disease may cause low blood counts. If your blood count gets low enough, you may 
need to have a blood transfusion. Blood products come from voluntary donors who are carefully selected and 
tested. However, there are still some risks to blood transfusion. Occasional risks include fever; allergic reactions 
and formation of antibodies. Less frequent risks include infections with viruses such as hepatitis (risk is 1 in 
2,000,000 transfusions) and fluid overload. These complications are uncommon and are usually mild but may 
be severe or life threatening. Very rare risks are serious incompatibility reactions and infections other than 
hepatitis. This could include the virus that causes AIDS (risk is 1 in 2,000,000 transfusions). The alternative to 
volunteer donor blood is directed donor blood, if appropriate for your disease. 
 
Bone Marrow Aspirate/Biopsy Risks 
The test is painful and has some small risk of infection or bleeding. The pain normally lessens within seconds to 
hours. Many patients may get some form of sedation or anesthesia during this procedure. A small area over 
the hipbone on the back will be cleaned and numbed with lidocaine and/or with an anesthetic cream. You will 
be given another consent form that covers the risks associated with this procedure. 
 
Spinal Taps Risks (Lumbar Punctures, “LPs”) 
Spinal taps are painful and may cause headaches. The skin at the site of needle insertion is usually numbed with 
an anesthetic cream or lidocaine. You will be given another consent form that covers the risks associated with 
this procedure. 
 
Blood Draw Risks 
Risks associated with needle sticks for drawing blood are slight, but some possible risks include excessive 
bleeding, fainting or feeling lightheaded, bruising, infection (a slight risk any time the skin is broken), and 
multiple punctures to locate veins. 
Echocardiogram/EKG Risks 
The echocardiogram and EKG tests are non-invasive. They do not require needles, blood samples, or tissue 
samples. 
 
Scan Risks 
Some scans require injections of substances (contrast) to make body parts more visible. There is a slight risk of 
an allergic reaction from the MRI contrast (gadolinium). You could also have pain or bruising at the injection 
site. Some types of scans (i.e., CT scans, x-rays, nuclear medicine scans), expose the patient to small doses of 
radiation. The principal risk associated with this radiation dose is the possibility of developing a radiation- 
induced cancer sometime later in life. The risk for radiation-induced cancer from this study is minimal. Everyone 
in the world is exposed to some level of “background radiation” or naturally occurring radiation from sources 
such as cosmic rays, buildings and soil. The level of background radiation everyone gets each year is about 300 


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millirems. In comparison, the exposure allowed to radiation workers is 5000 millirems per year. By participating 
in this study, you will be exposed to approximately 1865 millirems of radiation. However, all the scans done for 
this study are standard care and would be done even if you were not in this study. 
 
Transplant Risks 
Severe nausea and vomiting can be expected during the stage of BMT therapy when high dose 
Cyclophosphamide is given. Bladder soreness and bleeding may also occur during this period, producing blood 
in the urine. A condition called SIADH may also occur. This is characterized by a fluid imbalance that causes the 
body to retain water and not be able to excrete urine. The water retention may result in a fluid build-up in the 
body resulting in weight gain. We will take measures to less the side effects during Cyclophosphamide 
administration. 
Bone Marrow Infusion 
The donor cells are given through the central line, like a blood transfusion. Most patients do not have any side 
effects during the infusion. Rarely, patients can have blockage of blood vessels causing damage to organs (lungs, 
kidneys, brain). Occasionally, patients have nausea and temporary trouble breathing. Just like any blood 
transfusion, in rare cases patients have allergic reactions (may be life-threatening) or fever and infections from 
the infusion. 
 
Graft Failure 
It is possible that the donor cells will not grow in your bone marrow. You would either grow your own cells in the 
marrow again, or you would be without working bone marrow cells. We think that this problem, called graft failure, 
may happen in less than about 1 of every 20 patients treated on this research study. If you are not able to make 
new bone marrow cells, you could die. If you have graft failure, it may be necessary for you to receive additional 
medications and another collection of marrow cells from the same or another donor. 
 
Graft Versus Host Disease 
A transplant can cause a side effect called graft-versus-host disease or GVHD. This happens when certain white 
blood cells, called T-cells, in the donor cells (the graft) attack the patient's body. GVHD commonly causes skin, 
liver, stomach and intestinal problems, and may damage other parts of the body as well (including lungs, mouth 
and eyes). However, GVHD can be severe (blistering skin rash, severe or bloody diarrhea and severe jaundice) 
or even fatal. GVHD can happen any time after new cells start to grow and it can happen weeks or months later. 
It may go away but then come back again. 
 
When GVHD happens in the first 3 months after transplant, it is called acute GVHD. When it does not go away, or 
starts after the 3 months after transplant, it is called chronic GVHD. Chronic GVHD can make you very sick and 
can even cause death. It causes a discolored skin rash that can become tight and make it hard to move. It can 
also cause dry mouth, dry eyes, chronic nausea and diarrhea, weight loss, and liver problems, and can increase the 
risk of severe or fatal infections. 
 
We will try and prevent GVHD by giving Cyclosporine and Methotrexate. These drugs do not always work. If 
GVHD occurs, other medicines may be needed to suppress the immune system. GVHD is a main reason that you 
must take all medicines as instructed and must come to all clinic visits so that we can look for signs of GVHD. 


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Veno-Occlusive Disease (VOD) of the Liver 
Some bone marrow transplant patients develop veno-occlusive disease of the liver or VOD, which can be fatal. 
This happens when the normal blood flow through the liver is blocked, causing jaundice and swelling in the body. 
In some studies, VOD happens in 1 to 6 of every 10 patients transplanted. VOD can range from mild, which causes 
mild jaundice and swelling, to severe, which may cause death. Your risk for VOD following transplant may be 
increased due to the use of gemtuzumab earlier in therapy. 
 
Infections 
Transplant patients can develop serious infections when numbers of infection-fighting cells are low around the 
time of the transplant. This can also happen later when infection-fighting cells from the donor are not yet present. 
Infections can come from any kind of germ, including bacteria, funguses and viruses. Most of these infections can 
be treated with medicines such as antibiotics. Sometimes an infection cannot be treated, and patients can die of 
infection. 
 
Relapse 
It is possible that your original disease may come back even if the transplant is successful. 
 
Interstitial Pneumonitis 
Some patients suffer severe lung problems from either a viral infection (CMV) or a reaction to the chemotherapy 
and/or radiation given in the preparative regimen. Treatments are available, but this complication can be fatal. 
 
Immunodeficiency 
Full and complete recovery of your immune system may take several months following successful marrow 
engraftment. During this time, there is an increased susceptibility to infections. You will be prescribed certain 
medications to reduce the chance of those infections, and you will be told how to take safety measures to 
reduce your risk. Preventive treatment is not always effective. If you have signs of an infection, you may have 
to be re-hospitalized after transplant. Some of these infections may be fatal (cause death). 
 
Late Effects 
Some side effects from the BMT preparative regimen and complications may not happen right away. In fact, 
they can happen many years after transplant. These include sterility, hormone problems, growth problems and 
body appearance changes, and organ damage (especially heart, lung and kidney). A second malignancy (cancer) 
different from the original disease may happen following chemotherapy and irradiation. This is a rare 
complication. 
 
It is possible that the researchers will learn something new during the study about the risks of being in it. If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not. You may be 
asked to sign a new consent form that includes the new information if you decide to stay in the study. 
 
What Will Be Done to Minimize the Risks? 
The study doctor and/or staff will be checking you closely for side effects during the study. You will be checked 
with complete blood counts (CBC) including differential and studies of liver and kidney functions. You will also 
have scans (x-rays, CT scans, ultrasounds, etc.) to make sure the tumor is not growing back. 


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Most side effects disappear after the treatment is stopped. In the meantime, the study doctor may prescribe 
drugs to keep side effects under control. Your treatment will be changed, whenever needed, to prevent 
permanent damage.  The study doctor will do everything possible to prevent any serious complications.  If 
serious complications do occur, the study  doctor will provide appropriate measures (blood transfusions, 
antibiotics, anti-vomiting medications, etc.). 
 
Although you will be treated according to a specific plan (protocol), individual circumstances may arise. In such 
cases, your health will always be considered more important than strictly following the protocol. Changes will 
be discussed before they are made whenever possible. 
 
Will I benefit directly from the study? 
There may be no direct benefit to you from taking part in this study. We hope (but are not certain) that adding 
gemtuzumab will improve the effectiveness of this treatment. In addition, we hope that information learned 
from this study will benefit other patients with AML the future. 
 
What are my other options? 
If you choose not to be on this study, you may choose one of the following options: 
▪ Another experimental treatment (if available) 
▪ The standard therapy used for AML - the therapy as given on this study without gemtuzumab 
▪ You may choose no therapy at this time. However, if you choose not to receive specific therapy for the 
disease, the cancer is extremely likely to progress and cause death. You will receive supportive therapy 
(such as narcotics for pain or transfusions for anemia). 
 
The study doctor can give you detailed information about the disease and the benefits of the various treatments 
available. Please feel free to discuss the disease and future outlook with the study doctor. You can still be 
treated at our centers, even if you do not take part in this study. 
 
Please talk to your regular doctor about these and other options. 
 
Compensation 
You will not receive any money or other gifts or rewards for being in this study. You will not get anything for free 
(for example, medications) because you are in this study. 
 
How will you protect my private information that you collect in this study? 
Whenever possible, a study number, rather than your name, will be used on study records. Your name and 
other identifying information will not appear when we present or publish the study results. 
 
Study records can be opened by court order. They also may be provided in response to a subpoena or a 
request for the production of documents. 
 
Medical Record 
If you have been an Emory and Children’s Healthcare of Atlanta patient before, then you already have an 
Emory and Children’s Healthcare of Atlanta medical record. If you have never been an Emory and Children’s 
Healthcare of Atlanta patient, you do not have one.  An Emory and Children’s Healthcare of Atlanta medical 


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record will be made for you if an Emory and Children’s Healthcare of Atlanta provider or facility gives you any 
services or procedures for this study. Copies of the consent form/HIPAA authorization that you sign will be put 
in any Emory and Children’s Healthcare of Atlanta medical record you have now or any time during the study. 
 
Emory and Children’s Healthcare of Atlanta may create study information about you that can help with your 
care. For example, the results of study tests or procedures. These study results will be put in your Emory and 
Children’s Healthcare of Atlanta medical record. Anyone who has access to your medical records will be able 
to have access to all the study information placed there. The confidentiality of the study information in your 
medical record will be protected by laws like the HIPAA privacy rule. State and federal laws may not protect 
the research information from disclosure. 
 
Emory and Children’s Healthcare do not control results from tests and procedures done at other places, so 
these results will not be placed in your Emory or Children’s Healthcare medical record. They will likely not be 
available to Emory or Children’s Healthcare to help take care of you. Emory and Children’s do not have control 
over any other medical records that you may have with other healthcare providers. Emory and Children’s 
Healthcare will not send any test or procedure results from the study to these providers. If you decide to be in 
this study, it is up to you to let your health providers know. 
 
The researchers will review the results of certain study tests and procedures only for the research. The 
researchers will not be looking at the results of these tests and procedures to make decisions about your 
personal health or treatment. For this study, those things include research blood tests. 
 
In Case of Injury 
If you get ill or injured from being in the study, Emory and Children’s Healthcare of Atlanta will help you get 
medical treatment.  Emory and Children’s Healthcare of Atlanta have not, however, set aside any money to 
pay you or to pay for this medical treatment. The only exception is if it is proven that your injury or illness is 
directly caused by the negligence of an Emory and Children’s Healthcare of Atlanta employee. “Negligence” is 
the failure to follow a standard duty of care. 
 
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs. If you 
do not have insurance, or if your insurer does not pay, then you will have to pay these costs. 
 
If you believe you have become ill or injured from this research, you should contact Dr. Himalee Sabnis at
 
 You should also let any health care provider who treats you know that you are in a research study. 
 
Costs 
Most of the costs on this study are from tests and treatments that are part of regular medical care for a 
patient with AML. We will not bill you for any tests that are only for research, or for any testing required 
before the infusion that is not considered standard of care. 
You will have to pay for the items or services that are not paid for by the study. We will not pay for your 
regular medical care. If you have insurance, Emory and Children’s Healthcare of Atlanta will submit claims to 
your insurance for items and services that are part of this study. Emory and Children’s Healthcare of Atlanta 
will send in only those claims for items and services that it reasonably believes your insurance will pay and 
that the study has not paid. 


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The actual amount that you have to pay depends on whether or not you have health insurance and whether  
or not that insurance will pay for any research study costs. Generally, insurance companies will not pay for 
items and services that are required just for a research study. Some insurance companies will not pay for 
regular medical treatment or treatment for complications if you are in a study. How much you will have to  
pay for any co-payments, deductibles or co-insurance depends on your plan. Emory and Children’s Healthcare 
of Atlanta will not pay for these costs. 
 
It is a good idea to contact your insurance provider and tell them you want to be in this research study. Ask 
them what they will pay for and what they will not pay for. You can also ask the study team for help in 
figuring out what you will have to pay. 
 
If you do not have insurance, Emory and Children’s Healthcare of Atlanta will review your case as part of its 
program for low-income patient care. The standard policies of that program will apply. The program will 
figure out if you have to pay any costs for taking part in the study and what those costs will be. 
 
Withdrawal from the Study 
You have the right to leave a study at any time without penalty. 
 
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment. If you leave the study before the final planned study visit, the researchers may ask you to have 
some of the final steps done. 
 
Taking part in this study is your choice. You have the right to refuse to be in this study. You can still be treated 
here, even if you decide not to be in the study. You can stop being in the research at any time after giving  
your consent, by telling your transplant doctor. This decision will not affect your current or future medical care 
or any other benefits that you are otherwise entitled to. It will not affect your relationship with this institution 
and your doctors. Once you have had the transplant, you will continue to get the special medical care needed 
for any transplant patient, even if you decide to leave the study. 
 
Study doctors have the right to end your participation in this study without your consent for any of these 
reasons: 
• You do not qualify to be in the study because you do not meet the study requirements. Ask your doctor if 
you would like more information about this. 
• The investigator decides that continuing in the study would be harmful to you 
• The study treatments have a bad effect on you 
• You become pregnant 
• You were to object to any future changes that may be made in the study plan 
• For any other reason 
 
If you stop being in the study or your doctor takes you out of the study, all study information about you that has 
already been collected will be part of the study. We would like to continue to learn about your progress from 
your doctor. You may, of course, say “no” to having your doctor give us your follow-up information 


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Authorization to Use and Disclose Protected Health Information 
 
The privacy of your health information is important to us. We call your health information that identifies you, your 
“protected health information” or “PHI.” To protect your PHI, we will follow federal and state privacy laws, including the 
Health Insurance Portability and Accountability Act and regulations (HIPAA). We refer to all of these laws as the “Privacy 
Rules.” Here we let you know how we will use and disclose your PHI for the main study and for any optional studies in 
which you may choose to participate. 
 
Main Study 
 
PHI that Will be Used/Disclosed: 
The PHI that we will use or share for the research study includes: 
• Medical information about you including your medical history and present/past medications. 
• Results of exams, procedures and tests you have before and during the study. 
• Laboratory test results. 
 
Purposes for Which Your PHI Will be Used/Disclosed: 
We will use and share your PHI for the conduct and oversight of the research study. We will use and 
share your PHI to provide you with study related treatment and for payment for such treatment. We 
will also use and share your PHI to conduct normal business operations. We may share your PHI with 
other people and places that help us conduct or carry out the study, such as laboratories, data 
management centers, data monitors, contract research organizations, Institutional Review Boards 
(IRBs) and other study sites. If you leave the study, we may use your PHI to determine your health, vital 
status or contact information. 
 
Use and Disclosure of Your Information That is Required by Law: 
We will use and disclose your PHI when we are required to do so by law. This includes laws that require 
us to report child abuse or abuse of elderly or disabled adults. We will also comply with legal requests 
or orders that require us to disclose your PHI. These include subpoenas or court orders. 
 
Authorization to Use PHI is Required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this document. 
You do not have to sign this form to authorize the use and disclosure of your PHI. If you do not sign 
this form, then you may not participate in the research study or receive research-related treatment. 
You may still receive non-research related treatment. 
 
People Who will Use/Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the research study: 
 
• The Principal Investigator and the research staff will use and disclose your PHI to conduct the 
study and give you study related treatment. 
• Emory and Children’s Healthcare of Atlanta may use and disclose your PHI to get payment for 
study related treatment and to run normal business operations. 


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• The Principal Investigator and research staff will share your PHI with other people and groups 
to help conduct the study or to provide oversight for the study. 
• The following people and groups will use your PHI to make sure the research is done correctly 
and safely: 
o Emory and Children’s Healthcare of Atlanta offices that are part of the Human Research 
Participant Protection Program and those that are involved in study administration and 
billing. These include the Emory and Children’s Healthcare of Atlanta IRBs, the Emory 
Research and Healthcare Compliance Offices, and the Emory Office for Clinical Research. 
o Government agencies that regulate the research including the Food and Drug 
Administration. (The Food and Drug Administration will be involved in overseeing this 
research.) 
o Public health agencies. 
o Research monitors and reviewers 
o Accreditation agencies 
• Sometimes a Principal Investigator or other researcher moves to a different institution. If this 
happens, your PHI may be shared with that new institution and their oversight offices. PHI will 
be shared securely and under a legal agreement to ensure it continues to be used under the 
terms of this consent and HIPAA authorization. 
 
Optional Study: Biology research tests (blood and bone marrow banking) 
 
Authorization for This Use of PHI is Required to Participate in Optional Study, but Not in Main Study: 
You do not have to authorize the use and disclosure of your PHI for the optional study(ies). If you do not 
authorize the use and disclosure of your PHI for the optional study(ies), then you may not participate in the 
optional research study, but you can still be in the main research study. 
 
Expiration of Your Authorization 
This authorization will not expire because it is a research study. 
 
Revoking Your Authorization 
If you sign this form, at any time later you may revoke (take back) your permission to use your information. If 
you want to do this, you must write to Dr. Himalee Sabnis, 2015 Uppergate Dr., Atlanta, GA 30322. 
 
At that point, the researchers would not collect any more of your PHI. But they may use or disclose the 
information you already gave them so they can follow the law, protect your safety, or make sure that the 
study was done properly, and the data is correct. If you revoke your authorization you will not be able to stay 
in the study. 
 
Other Items You Should Know about Your Privacy 
Not all people and entities are covered by the Privacy Rules. HIPAA only applies to health care providers, 
health care payers, and health care clearinghouses. If we disclose your information to people who are not 
covered by the Privacy Rules, including HIPAA, then your information won’t be protected by the Privacy Rules. 
People who do not have to follow the Privacy rules can use or disclose your information with others without 
your permission if they are allowed to do so by the laws that cover them. 


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To maintain the integrity of this research study, you generally will not have access to your PHI related to this 
research until the study is complete. When the study ends, and at your request, you generally will have access 
to your PHI that we maintain in a designated record set. A designated record set is data that includes medical 
information or billing records that your health care providers use to make decisions about you. If it is  
necessary for your health care, your health information will be provided to your doctor. 
 
We may remove identifying information from your PHI. Once we do this, the remaining information will not 
be subject to the Privacy Rules. Information without identifiers may be used or disclosed with other people or 
organizations for purposes besides this study. 
 
Contact Information 
Contact Dr. Himalee Sabnis at 
: 
• if you have any questions about this study or your part in it, 
• if you feel you have had a research-related injury or a bad reaction to the study drug, or 
• if you have questions, concerns or complaints about the research 
 
Contact the Emory Institutional Review Board at 
: 
• if you have questions about your rights as a research participant. 
• if you have questions, concerns or complaints about the research. 
• You may also let the IRB know about your experience as a research participant through our Research 
Participant Survey at 
 
If you are a patient receiving care at Children’s Healthcare of Atlanta of Atlanta and have a question about 
your rights, please contact Sarah Marie Huban, Director of Research Administration at 
. 


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Consent and Authorization 
 
 
TO BE FILLED OUT BY SUBJECT ONLY 
Please print your name, sign, and date below if you agree to be in the study. By signing this consent and 
authorization form, you will not give up any of your legal rights. We will give you a copy of the signed form to 
keep. 
 
 
 
Name of Subject 
 
 
 
 
 
Signature of Subject (18 or older and able to consent) 
Date 
Time 
 
 
 
 
Signature of Legally Authorized Representative with authority for 
Date 
Time 
research decisions 
 
 
 
Authority of Legally Authorized Representative or Relationship to Subject 
 
 
TO BE FILLED OUT BY STUDY TEAM ONLY 
 
 
 
Name of Person Conducting Informed Consent Discussion 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
Date 
Time 


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ADDITIONAL CONSENT POSSIBILITIES 
 
Please read each sentence below and think about your choice. After reading each sentence, check "Yes" or "No" 
then add your initials and date after your answer. 
 
1. My bone marrow and/or blood may be kept (banked) for future use in research to learn about, prevent, or 
treat cancer or to learn why some people have complications from therapy and others do not (including 
genetic studies on leukemia cells). 
 
#1: 
Yes  
 
No  
 
  /   
  Initials 
 
Date 
 
2. My bone marrow and/or blood may be kept (banked) for use in research to learn about, prevent or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart disease). 
 
#2: 
Yes  
 
No  
 
  
/   
 
 
Initials 
Date 


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Attachment #1 
 
 
Treatment and Procedures Common to all Subjects with de novo AML 
 
Methods for Giving Drugs 
Various methods will be used to give drugs. 
• IV – Drug is given using a needle or tubing inserted into a vein. It can be given over a few minutes 
(“push “) or slowly over minutes or hours (“infusion”). 
• IT – Drug used to treat the brain and spinal cord is given using a needle inserted into the spinal fluid 
(intrathecally, IT). 
• IM – Drug is given by inserting a needle injected into the muscle (IM shot). 
 
Central Line 
Your doctor may recommend that you get a special kind of IV called a “central line.” This is a kind of IV placed 
into a big vein in your chest that can stay in for a long time. The risks connected with central lines will be 
explained to you and all your questions will be answered. If you are to have a central line inserted, you will be 
given a separate informed consent document to read and sign for this procedure. 
 
Standard Treatment Tables 
The treatment described below is standard treatment for patients with de novo AML. 
 
The chemotherapy treatment plan described below for low risk subjects has been used in past COG AML 
studies. 
 
Induction I - Standard therapy (28 Days) 
Chemotherapy is given for 10 days followed by 3 weeks of rest (28 days total). 
Drug 
How the drug will be given 
Day(s) 
Intrathecal 
Cytarabine (IT ARAC) 
Intrathecal (IT) 
given at diagnostic lumbar 
puncture or Day 1 
Cytarabine 
IV over 1-2 minutes given every 12 
hours 
1-10 
Daunorubicin 
IV over 15 minutes 
1, 3, and 5 
Etoposide 
IV over 60-120 minutes 
1-5 
 
If you have a chloroma at the time you begin this study, your doctor may treat it with radiation therapy at the 
beginning of Induction. The risks of radiation therapy for chloroma are found in Attachment #2. 
 
Induction II – Standard Therapy (28 Days) 
Chemotherapy is given for 6 days followed by 3 weeks of rest (28 days total) 
Drug 
How the drug will be given 
Day(s) 
Intrathecal 
Cytarabine (IT ARAC) 
Intrathecal (IT) 
given on Day 1 of Induction II or 
with bone marrow evaluation 


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diagnostic lumbar puncture or 
Day 1 
Cytarabine 
IV over 1-3 hours given every 12 
hours 
1-4 
Mitoxantrone 
IV over 15-30 minutes 
3-6 
 
 
Intensification I – Standard Therapy (28 Days) 
Chemotherapy is given over 5 days followed by 3 weeks of rest (28 days total) 
Drug 
How the drug will be given 
Days 
Cytarabine 
IV over 1-3 hours given every 12 
hours 
1-5 
Etoposide 
IV over 60-120 minutes 
1-5 
You will receive eye drops during and for 24 hours after you receive this drug to help with the side effects of the 
drug. 
 
Intensification II – Standard Therapy (28 Days) 
Chemotherapy is given over 9 days followed by 3 weeks of rest (28 days total). 
Drug 
How the drug will be given 
Days 
Cytarabine 
IV over 3 hours, every 12 hours 
1, 2 and 8, 9 
Erwinia L-Asparaginase 
IM (may be given IV over 1 hour 
2, 9 
You will receive eye drops during and for 24 hours after you receive this drug to help with the side effects of 
the drug. 
 
If after Induction I, your AML has been classified as high risk, you may receive a Stem Cell Transplant. More 
information will be given to you with a separate consent. 
• If there is no stem cell donor available, you will receive treatment with more chemotherapy similar to 
low risk patients, during Induction II, Intensification I and Intensification II. 
• If you have high amounts of FLT3-ITD gene mutations you are classified as high risk and will receive 
therapy with a drug called sorafenib and you may receive a stem cell transplant. If you do not have an 
appropriate donor, you will receive treatment with more chemotherapy similar to low risk patients, 
during Induction II, Intensification I and Intensification II and in addition you will receive sorafenib in 
each chemotherapy cycle. 
 
Standard Tests and Procedures 
The following tests and procedures are part of regular cancer care and may be done even if you do not join the 
study: 
• 
Frequent  labs to monitor your blood counts and blood chemistries 
• 
Urine tests to measure how your kidneys are functioning 
• 
Pregnancy test for females of childbearing age before treatment begins 
• 
X-rays and scans to monitor your response to treatment 
• 
Tests to monitor your heart and lung functioning 
• 
Bone Marrow Aspirations to see if the leukemia is responding to treatment. 
• 
Spinal Taps to check for leukemia cells in the spinal fluid and to give chemotherapy into the spinal fluid. 


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Attachment #2 
Risks of Chemotherapy Drugs and X-Ray Therapy Used to Treat de novo AML 
 
 
Possible Side Effects of Erwinia Asparaginase 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Erwinia Asparaginase, more than 20 and up to 100 may have: 
• None 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Erwinia Asparaginase, from 4 to 20 may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat 
RARE, AND SERIOUS 
In 100 people receiving Erwinia Asparaginase, 3 or fewer may have: 
• Blood clot 
• Nausea 
• Diabetes 
• Pain in belly 
• Vomiting 
• Mini stroke 
• Bleeding 
• Increased blood level of liver tests which may mean there has been damage to the liver 
• Increased blood sugar levels which could lead to diabetes 


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Possible Side Effects of Cytarabine (Ara-C) IV 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine (Ara-C), more than 20 may have: 
• Blood clot 
• Rash 
• Swelling in the rectum which may cause rectal pain 
• Diarrhea, loss of appetite, nausea, vomiting 
• Sores in mouth which may cause difficulty swallowing 
• Anemia which may cause tiredness, or may require blood transfusions 
• Fever 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cytarabine (Ara-C), from 4 to 20 may have: 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat 
• Numbness and tingling of the arms and legs 
• Severe blood infection 
• Kidney damage which may cause swelling, may require dialysis 
• Headache 
• Chest pain 
• Hair loss 
• Liver damage which may cause yellowing of skin or eyes 
• Swelling and redness of the eye 
RARE, AND SERIOUS 
In 100 people receiving Cytarabine (Ara-C), 3 or fewer may have: 
• None 
 
Some drugs, food, and supplements may interact with cytarabine. Examples include: 
 
 
 
*Sometimes these drugs are used with cytarabine on purpose. Discuss all drugs with your doctor. 
Food and supplements that may interact with cytarabine** 
• Echinacea 
Drugs that may interact with cytarabine* 
• Clozapine 
• Digoxin 
• Flucytosine 
• Leflunomide 


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**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. Talk to your doctor before starting any new medications or herbal 
supplements and before making a significant change in your diet. 
 
 
Possible Side Effects of Daunorubicin 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Daunorubicin, more than 20 and up to 100 may have: 
• Hair loss 
• Nausea, vomiting 
• Pink or red colored urine, sweat, or saliva 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Daunorubicin, from 4 to 20 may have: 
• Damage to the heart which may cause shortness of breath, tiredness 
• Infection, especially when white blood cell count is low 
• Anemia which may require transfusion 
• Bruising, bleeding 
• Pain and sores in mouth and throat 
• Dark discoloration of the nail, skin 
• Loss of nails 
• Redness and pain at the site of previous radiation 
• Swelling and redness at the site of injection 
• Diarrhea 
RARE, AND SERIOUS 
In 100 people receiving Daunorubicin, 3 or fewer may have: 
• Cancer of the bone marrow (leukemia) cause by chemotherapy 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat 
 
Some drugs, food, and supplements may interact with daunorubicin. Examples include: 
 
Drugs that may interact with daunorubicin* 
• Some antibiotics and antifungals (clarithromycin, erythromycin, itraconazole, ketoconazole) 
• Some antiepileptics (carbamazepine, phenobarbital, phenytoin, fosphenytoin) 
• Some antiretrovirals (darunavir, lopinavir; nelfinavir, ritonavir, saquinavir, telaprevir, tenofovir, 
tipranavir) 
• Some heart medications (amiodarone, carvedilol, digoxin, dronedarone, nicardipine, propranolol, 
verapamil) 
• Other agents, such as atorvastatin, clozapine, cyclosporine, dexamethasone, ivacaftor, leflunomide, 
natalizumab, nefazodone, progesterone, rifampin, tacrolimus, tofacitinib, and trazodone 


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*Sometimes these drugs are used with daunorubicin on purpose. Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. Talk to your doctor before starting any new medications or herbal 
supplements and before making a significant change in your diet. 
 
 
Possible Side Effects of Etoposide 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Etoposide, more than 20 may have: 
• Hair loss 
• Chills 
• Sores in mouth which may cause difficulty swallowing 
• Diarrhea, loss of appetite, nausea, vomiting 
• Infection, especially when white blood cell count is low 
• Anemia which may require transfusion 
• Bruising, bleeding 
• Tiredness 
• Fever 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Etoposide, from 4 to 20 may have: 
• Heart failure or heart attack which may cause chest pain, shortness of breath, swelling of ankles, and 
tiredness 
• Severe skin rash with blisters and peeling which can involve inside of mouth and other parts of the 
body 
• Liver damage which may cause yellowing of eyes and skin, swelling 
RARE, AND SERIOUS 
In 100 people receiving Etoposide, 3 or fewer may have: 
• Cancer of bone marrow caused by chemotherapy 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of 
the face or throat 
Food and supplements that may interact with daunorubicin** 
• Echinacea 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• St. John’s Wort 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 


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Some drugs, food, and supplements may interact with etoposide. Examples include: 
Drugs that may interact with etoposide* 
• Antibiotics 
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics 
• Aripiprazole, clozapine, nefazodone 
• Antifungals 
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications 
• Leflunomide, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals 
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• Anti-seizure medications 
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications 
• Amiodarone, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Atovaquone, bosentan, sitaxentan, aprepitant, dexamethasone, mifepristone, natalizumab, 
pimozide, ivacaftor, deferasirox, lomitapide 
 
 
*Sometimes these drugs are used with etoposide on purpose. Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. Talk to your doctor before starting any new medications or herbal 
supplements and before making a significant change in your diet. 
Food and supplements that may interact with etoposide** 
• Echinacea 
• Glucosamine 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 


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Possible Side Effects of Mitoxantrone Hydrochloride 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Mitoxantrone hydrochloride, more than 20 and up to 100 may have: 
• Diarrhea, nausea, vomiting 
• Infection, especially when white blood cell count is low 
• Headache 
• Hair loss 
• Sores in mouth and throat which may cause difficulty swallowing 
• Pain 
• Hives, rash 
• Abnormal or absence of menstrual period 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Mitoxantrone hydrochloride, from 4 to 20 may have: 
• Damage to the heart or heart failure which may cause shortness of breath, tiredness and swelling 
• Anemia which may cause tiredness, or may require transfusion 
• Bruising, bleeding 
• Darkening of the skin and nails 
• Loss of nails 
• Swelling and redness at the site of the injection 
• Liver damage which may cause yellowing of the eyes and skin 
• Bluish/greenish discoloration of the urine, skin, eyes and saliva 
 
 
RARE, AND SERIOUS 
In 100 people receiving Mitoxantrone hydrochloride, 3 or fewer may have: 
• Cancer of the bone marrow (leukemia) caused by chemotherapy 


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Some drugs, food, and supplements may interact with mitoxantrone. Examples include: 
 
 
 
 
 
*Sometimes these drugs are used with mitoxantrone on purpose. Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. Talk to your doctor before starting any new medications or herbal 
supplements and before making a significant change in your diet. 
 
 
Radiation Risks from X-Ray Therapy for Chloroma 
X-ray therapy for chloromas may cause temporary or permanent side effects from the radiation. Subjects may 
experience changes in normal tissues in the area of the chloroma(s) being treated. The skin overlying the 
chloroma may become temporarily darkened, dry, and itchy. Additionally, a bone close to the chloroma being 
treated may not grow to a normal size. If subjects are receiving X-ray therapy near the brain, permanent losses 
may develop in thinking abilities and hormone production. Radiation may also increase the risk of having a 
second cancer. The risk, severity, and type of side effects will vary based upon your age, other treatment, and 
the normal tissues that are in or near the area that gets radiation. 
Food and supplements that may interact with mitoxantrone** 
• Echinacea 
Drugs that may interact with mitoxantrone* 
• Aripiprazole 
• Clozapine 
• Cyclosporine 
• Dofetilide 
• Leflunomide 
• Natalizumab 
• Pimozide 
• Tofacitinib