A Phase III Study for Patients With Newly Diagnosed Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide and All-Trans Retinoic Acid
Phase: PHASE3
Conditions: Acute Promyelocytic Leukemia With t(15;17)(q24.1;q21.2); PML-RARA
Sponsor: Children's Oncology Group

AAML1331 
Version Date: 03-16-2018 
1 
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
AAML1331 
 
 
A Phase III Study for Patients with Newly Diagnosed Acute Promyelocytic Leukemia (APL) using 
Arsenic Trioxide and All-Trans Retinoic Acid 
 
 
 
A COG Groupwide Phase III Study 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN 
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activated: 
06/29/2015 
Version Date: 
03-16-2018 
Closed: 
05/07/2019      
Amendment 
#3 

 
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AAML1331 
 
Version Date: 03-16-2018 
2 
 
CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact  the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
data submission schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and 
password. Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead Protocol 
Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 

 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
8 
ABSTRACT 
11 
EXPERIMENTAL DESIGN SCHEMA 
12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
13 
1.1 
Primary Aims 
13 
1.2 
Exploratory Aims 
13 
2.0 
BACKGROUND 
13 
2.1 
Historical Controls 
13 
2.2 
Arsenic Trioxide (ATO) in the Treatment of APL 
14 
2.3 
ATO and ATRA Regimen 
15 
2.4 
Cardiac Toxicity in APL Therapy 
16 
2.5 
Rationale for Elimination of Chemotherapy Maintenance Cycles 
16 
2.6 
Risk Stratification Based on WBC 
17 
2.7 
Differentiation Syndrome Prophylaxis and Treatment 
17 
2.8 
CNS Directed Therapy in APL 
18 
2.9 
PCR Monitoring of Bone Marrow 
18 
2.10 
Correlative Studies 
19 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
23 
3.1 
Study Enrollment 
23 
3.1.1 
Patient Registration 
23 
3.1.2 
IRB Approval 
24 
3.1.3 
Study Enrollment 
25 
3.1.4 
Timing 
25 
3.1.5 
Emergent Treatment 
26 
3.1.6 
Inclusion of Women and Minorities 
27 
3.2 
Patient Eligibility Criteria 
27 
3.2.1 
Age 
27 
3.2.2 
Diagnosis 
27 
3.2.3 
Prior Therapy 
28 
3.2.4 
Exclusion Criteria 
28 
3.2.5 
Regulatory Requirements 
29 
3.3 
Definitions 
29 
3.3.1 
Initial CBC 
29 
3.3.2 
Standard Risk 
29 
3.3.3 
High Risk 
30 
3.3.4 
CNS Disease and CNS Bleed 
30 
4.0 
TREATMENT PLAN 
31 
4.1 
Overview of Treatment Plan 
31 
4.1.1 
CNS Bleed and CNS Disease 
32 

 
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4.1.2 
Supportive Care 
33 
4.1.3 
Concomitant Therapy 
34 
4.2 
Induction – Standard Risk APL 
35 
4.2.1a Induction Therapy Delivery Map – Standard Risk APL 
35 
4.2.1b Induction Therapy Delivery Map Continued – Standard Risk APL 
36 
4.2.2 
Required Observations in Induction – Standard Risk APL 
37 
4.2.3 
Induction Treatment Details – Standard Risk APL 
38 
4.3 
Consolidation Cycle 1 – Standard Risk APL 
40 
4.3.1 
Consolidation Therapy Delivery Map Cycle 1 – Standard Risk APL 
40 
4.3.2 
Required Observations in Consolidation Cycle 1 – Standard Risk APL 
41 
4.3.3 
Consolidation Cycle 1 Treatment Details – Standard Risk APL 
42 
4.4 
Consolidation Cycle 2 – Standard Risk APL 
43 
4.4.1 
Consolidation Therapy Delivery Map Cycle 2 – Standard Risk APL 
43 
4.4.2 
Required Observations in Consolidation Cycle 2 – Standard Risk APL 
44 
4.4.3 
Consolidation Cycle 2 Treatment Details – Standard Risk APL 
45 
4.5 
MRD Positive Consolidation – Standard Risk APL 
47 
4.5.1 
MRD Positive Consolidation Therapy Delivery Map – Standard Risk APL 
47 
4.5.2 
Required Observations in MRD Positive Consolidation – Standard Risk APL 48 
4.5.3 
MRD Positive Consolidation Treatment Details – Standard Risk APL 
49 
4.6 
Consolidation Cycle 3 – Standard Risk APL 
50 
4.6.1 
Consolidation Therapy Delivery Map Cycle 3 – Standard Risk APL 
50 
4.6.2 
Required Observations in Consolidation Cycle 3 – Standard Risk APL 
51 
4.6.3 
Consolidation Cycle 3 Treatment Details – Standard Risk APL 
52 
4.7 
Consolidation Cycle 4 – Standard Risk APL 
53 
4.7.1 
Consolidation Therapy Delivery Map Cycle 4 – Standard Risk APL 
53 
4.7.2 
Required Observations in Consolidation Cycle 4 – Standard Risk APL 
54 
4.7.3 
Consolidation Cycle 4 Treatment Details – Standard Risk APL 
55 
4.8 
Induction – High Risk APL 
56 
4.8.1a Induction Therapy Delivery Map – High Risk APL 
56 
4.8.1b Induction Therapy Delivery Map Continued– High Risk APL 
57 
4.8.2 
Required Observations in Induction – High Risk APL 
58 
4.8.3 
Induction Treatment Details – High Risk APL 
59 
4.9 
Consolidation Cycle 1 – High Risk APL 
61 
4.9.1 
Consolidation Therapy Delivery Map Cycle 1 – High Risk APL 
61 
4.9.2 
Required Observations in Consolidation Cycle 1 – High Risk APL 
62 
4.9.3 
Consolidation Cycle 1 Treatment Details – High Risk APL 
63 
4.10 
Consolidation Cycle 2 – High Risk APL 
64 
4.10.1 Consolidation Therapy Delivery Map Cycle 2 – High Risk APL 
64 
4.10.2 Required Observations in Consolidation Cycle 2 – High Risk APL 
65 
4.10.3 Consolidation Cycle 2 Treatment Details – High Risk APL 
66 
4.11 
MRD Positive Consolidation – High Risk APL 
68 
4.11.1 MRD Positive Consolidation Therapy Delivery Map – High Risk APL 
68 
4.11.2 Required Observations in MRD Positive Consolidation – High Risk APL 
69 
4.11.3 MRD Positive Consolidation Treatment Details – High Risk APL 
70 

 
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4.12 
Consolidation Cycle 3 – High Risk APL 
71 
4.12.1 Consolidation Therapy Delivery Map Cycle 3 – High Risk APL 
71 
4.12.2 Required Observations in Consolidation Cycle 3 – High Risk APL 
72 
4.12.3 Consolidation Cycle 3 Treatment Details – High Risk APL 
73 
4.13 
Consolidation Cycle 4 – High Risk APL 
74 
4.13.1 Consolidation Therapy Delivery Map Cycle 4 – High Risk APL 
74 
4.13.2 Required Observations in Consolidation Cycle 4 – High Risk APL 
75 
4.13.3 Consolidation Cycle 4 Treatment Details – High Risk APL 
76 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
77 
5.1 
APL Differentiation Syndrome 
77 
5.2 
Tretinoin Dose Modifications (Including Modifications for Pseudotumor Cerebri) 
77 
5.2.1 
Pseudotumor Cerebri 
78 
5.3 
Arsenic Trioxide Dose Modifications 
79 
5.3.1 
Hepatotoxicity 
79 
5.3.2 
Hematological Toxicity 
79 
5.3.3 
Nausea/Vomiting 
80 
5.3.4 
Cardiac Toxicity 
80 
5.3.5 
Neurologic Toxicity 
81 
5.3.6 
Other Toxicities (Excludes hepatic, hematologic, nausea/vomiting, and cardiac 
toxicities which are described above) 
81 
5.4 
IDArubicin and MitoXANtrone Dose Modifications 
81 
5.4.1 
Hepatic Toxicity 
81 
5.4.2 
Renal Toxicity 
82 
5.4.3 
Left Ventricular Cardiac Function Toxicity 
82 
5.5 
Cytarabine Dose Modifications 
82 
5.5.1 
Neurological Toxicity 
82 
5.5.2 
Renal Toxicity 
82 
6.0 
DRUG INFORMATION 
83 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
83 
7.1 
Clinical Evaluation of RQ-PCR 
83 
7.2 
End of Therapy & Follow-up 
84 
7.3 
Research Studies for which Patient Participation is Optional 
86 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
87 
8.1 
Criteria for Removal from Protocol Therapy 
87 
8.2 
Off Study Criteria 
87 
9.0 
STATISTICAL CONSIDERATIONS 
87 
9.1 
Statistical Design 
87 
9.2 
Patient Accrual and Expected Duration of Trial 
88 
9.3 
Statistical Analysis Methods 
89 
9.4 
Correlative Biology Studies 
91 
9.5 
Gender and Minority Accrual Estimates 
93 
10.0 
EVALUATION CRITERIA 
94 

 
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10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
94 
10.2 
Response Criteria for Patients with Acute Promyelocytic Leukemia 
94 
10.2.1 Hematologic Complete Remission (hCR and hCRi) 
94 
10.2.2 Molecular Remission 
94 
10.2.3 Treatment Failure/Events 
94 
10.2.4 Relapse 
95 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
95 
11.1 
Purpose 
95 
11.2 
Determination of Reporting Requirements 
95 
11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS 
96 
11.4 
Routine Adverse Event Reporting 
97 
12.0 
RECORDS AND REPORTING 
97 
12.1 
CDUS 
97 
13.0 
PATHOLOGY GUIDELINES AND REQUIREMENTS 
98 
13.1 
Review of Diagnostic CSF for CNS Disease Patients 
98 
13.2 
Review of End Induction Bone Marrow 
98 
Optional Pathology Consultation 
98 
14.0 
CYTOGENETIC ANALYSIS GUIDELINES AND REQUIREMENTS 
98 
14.1 
Cytogenetic Analysis Overview 
98 
14.2 
Specimen Collection and Submission 
99 
14.2.1 Specimen Collection 
99 
14.2.2 Requirements for Data Submission 
99 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
101 
15.1 
FLT3 Mutations in Pediatric APL 
101 
15.1.1 Specimens 
101 
15.1.2 Preparation 
101 
15.1.3 Labeling 
102 
15.1.4 Shipping 
102 
15.1.5 Detection of FLT3 Mutations 
102 
15.2 
Bone Marrow and Peripheral Blood Minimal Residual Disease (MRD) Testing 
102 
15.2.1 Specimens 
103 
15.2.2 Preparation 
103 
15.2.3 Labeling and Shipping 
103 
15.2.4 Research MRD Testing 
103 
15.3 
Early Death and Coagulopathy Complications in Pediatric APL 
104 
15.3.1 Specimens 
104 
15.3.2 Preparation 
104 
15.3.3 Labeling 
105 
15.3.4 Shipping 
105 
15.3.5 Coagulation Studies 
105 
16.0 
NEUROCOGNITIVE OUTCOMES IN PEDIATRIC APL TREATMENT 
106 
16.1 
Study Design 
106 

 
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16.2 
Eligibility Criteria for the AAML1331 Neurocognitive Study 
107 
16.3 
Neurocognitive Study Consent 
108 
16.4 
Required Observations 
108 
16.4.1 Schedule of Observations 
108 
16.4.2 Procedure 
109 
16.5 
Measures 
109 
16.5.1 Behavior Rating Inventory of Executive Function (BRIEF) 
109 
16.5.2 CogState 
110 
16.5.3 Psychologist administered battery 
111 
16.6 
Feedback to Participants 
112 
17.0 
RADIATION THERAPY GUIDELINES 
113 
17.1 
General guidelines 
113 
17.2 
Eligibility 
113 
17.3 
Timing 
114 
17.4 
Equipment 
114 
17.4.1 Modality 
114 
17.4.2 Calibration 
114 
17.5 
Target Volume 
114 
17.5.1 Standard Tumor and Target Volume Definitions 
114 
17.6 
Target Dose 
114 
17.6.1 Prescription Point 
114 
17.6.2 Dose Definition 
114 
17.6.3 Tissue Heterogeneity 
115 
17.6.4 Dose and Fractionation 
115 
17.6.5 Dose Uniformity 
115 
17.7 
Normal Tissue Sparing 
115 
17.8 
Quality Assurance Review 
115 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
116 
APPENDIX II:  TRETINOIN (ALL-TRANS RETINOIC ACID, ATRA) DOSING TABLE 
119 
APPENDIX III: INFORMATION FOR PARENTS/CAREGIVERS FOR GIVING TRETINOIN 
(ATRA): 
120 
APPENDIX IV:  POSSIBLE DRUG INTERACTIONS 
121 
APPENDIX V:  PROCEDURES FOR CYTOGENETIC/FISH STUDIES 
124 
APPENDIX VI: ADMINISTRATION ORDER FOR PSYCHOLOGIST ADMINISTERED 
BATTERIES 
127 
APPENDIX VII:  YOUTH INFORMATION SHEETS 
128 
REFERENCES 
130 
 
 
 

  
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STUDY COMMITTEE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
      
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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AGENT 
NSC# 
IND# 
 
Arsenic Trioxide (ATO) 
706363 
Commerical 
 
Tretinoin (ATRA) 
122758 
Commercial 
 
Cytarabine 
63878 
Commercial 
 
Dexamethasone 
34521 
Commerical 
 
Hydrocortisone 
10483 
Commercial 
 
Idarubicin  
256439 
Commerical 
 
Leucovorin 
3590 
Commerical 
 
Methotrexate 
740 
Commerical 
 
Mitoxantrone 
301739 
Commerical 
 
 
 
 
 
 
SEE SECTIONS 13, 14 AND 15 FOR SPECIMEN SHIPPING ADDRESSES. 
 
 

  
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects. The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies. 
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act.  
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others. 
 
 
ABSTRACT 
The use of all-trans retinoic acid (ATRA) in combination with anthracyclines (AIDA regimen) has achieved 
remission rates over 90% and event free survival (EFS) greater than 70% for children with APL. The 
addition of arsenic trioxide (ATO) further decreases the risk of relapse for APL patients as evidenced by 
randomized data from patients ≥ 15 years old enrolled on the North American Leukemia Intergroup 
CALGB 9710 trial. In a previous Children’s Oncology Group (COG) APL trial (AAML0631), ATO 
Consolidation cycles were incorporated and total anthracycline dose reduced compared to prior AIDA 
based regimens. In a continuing evolution of APL treatment, a number of adult trials have utilized ATO in 
combination with ATRA and have successfully achieved excellent outcomes while significantly reducing, 
and even eliminating, anthracyclines and other conventional chemotherapy. This pediatric study will be 
based upon the MD Anderson Cancer Center (MDACC), GIMEMA-SAL-AMLSG APL0406, and 
Australasian APML4 studies utilizing ATRA and ATO. The Italian AIDA 0493 trial remains the most 
mature and has the best reported outcomes for a pediatric APL population, and thus will serve as the 
pediatric historical comparator. 
 
In this Phase III trial, patients will be stratified into risk groups based on their presenting white blood cell 
(WBC) count (< 10,000/L is standard risk and ≥ 10,000/L is high risk). All patients will receive daily 
ATRA and ATO during Induction. High risk patients will also receive 4 doses of idarubicin during 
Induction. Patients who are confirmed to have a hematologic complete remission at the end of Induction, 
will subsequently receive 28 weeks of Consolidation therapy with ATRA and ATO. Since there is no 
Maintenance therapy, the total duration of treatment will be reduced from approximately 30 months to 
approximately 8 months. Following 2 ATO cycles in Consolidation, patients will have a bone marrow 
evaluation to confirm molecular remission by real-time quantitative polymerase chain reaction (RQ-PCR) 
testing of PML-RARα. Based on the adult experience with this regimen, PCR positive disease at this 
Consolidation time point will be rare. The rare patients with PCR positive disease will receive an additional 
chemotherapy cycle (mitoxantrone, cytarabine and ATRA).  
 
Several important corollary studies, including assessment of FLT3 mutations, minimal residual disease 
(MRD) by RQ-PCR testing, and coagulopathy, as well as a quality of life study to determine the 
neurocognitive effects of this treatment, are important components of this clinical trial. 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Consolidation 
Cycles 3 and 4 
End of Protocol 
Therapy 
Repeat RQ-PCR 
Negative 
Repeat RQ-PCR Positive 
MRD Positive Consolidation 
Cycle with subsequent RQ- PCR 
on Day 29 of this cycle 
Subsequent RQ-PCR 
Negative 
Subsequent RQ-PCR Positive (with 
confirmation on second specimen 
1 - 2 weeks later), patient will go off 
protocol therapy. 
Risk Stratification 
Induction 
Standard Risk (WBC < 10,000/µL) 
Induction 
High Risk (WBC > 10,000/µL) 
Bone marrow on Induction Day 29 and every 2 weeks 
thereafter if needed (maximum 70 days) until 
hematologic complete remission (hCR/hCRi) achieved, 
then proceed to Consolidation Cycles 1 and 2 
If hematologic complete 
remission (hCR/hCRi) is not 
achieved by Day 70, patient 
will go off protocol therapy 
Consolidation Cycles 1 and 2; 
Perform bone marrow for RQ-PCR of PML-RARα 
on Day 43 of Consolidation Cycle 2 
RQ-PCR negative 
on Consolidation 
Cycle 2 Day 43 
RQ-PCR positive 
on Consolidation 
Cycle 2 Day 43 
Repeat bone marrow 
RQ-PCR in 1-2 weeks to 
confirm molecular status 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
1.1.1 To eliminate exposure to conventional chemotherapy (including anthracyclines), 
for patients with standard risk APL, through use of ATO and ATRA based therapy 
while achieving an event free survival (EFS) that is not inferior compared to 
historical controls. 
 
1.1.2 To significantly reduce exposure to conventional chemotherapy, and in particular, 
anthracycline exposure, for patients with high risk APL, through use of ATO and 
ATRA based therapy while achieving an event free survival that is not inferior 
compared to historical controls. 
 
1.2 
Exploratory Aims 
1.2.1 
To analyze the clinical impact of FLT3 mutations in pediatric APL. 
 
1.2.2 
To correlate clinical outcomes with the kinetics of reduction in PML/RARα 
transcript level by quantitative RT-PCR (RQ-PCR) in bone marrow and peripheral 
blood samples from diagnosis to time points during therapy. 
 
1.2.3 
To monitor incidence of coagulopathy complications, utilizing standardized 
conventional supportive care, and correlate with a battery of coagulation testing. 
 
1.2.4 
To evaluate the neurocognitive outcomes of patients treated on this protocol using 
patient-completed, 
performance-based 
measures 
of 
neuropsychological 
functioning and parent questionnaire report. 
 
 
2.0 
BACKGROUND 
The use of ATRA and ATO in the treatment of APL has greatly improved the outcome for patients 
with APL, such that it is now the most curable subtype of AML. Historically, AIDA (ATRA and 
anthracycline) based treatment regimens relied upon large cumulative doses of anthracyclines to 
achieve cure resulting in long term risk of cardiac toxicity, second malignancy and infertility, and 
more immediate risk of myelosuppression, with concomitant risk of infection. Recent trials, 
including the now closed COG trial AAML0631, have evaluated lower doses of anthracyclines in 
conjunction with ATO Consolidation cycles. Recently several large adult trials, which utilized little 
or no conventional chemotherapy, have demonstrated that APL may be cured with ATO and ATRA 
alone. Pediatric patients in particular may benefit from an anthracycline-reduced or free regimen 
given the expected duration of life following APL cure. Thus, this trial aims to study the efficacy 
of an ATO and ATRA regimen in pediatric patients with APL. 
 
2.1 
Historical Controls 
Outcomes in the treatment of both adult and pediatric APL improved greatly with the 
addition of ATRA to traditional cytotoxic chemotherapy.1-5 Children treated on the first 
North American intergroup trial (INT0129) had a significantly improved DFS if they 

  
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received ATRA during Induction and/or Maintenance compared to those who received 
only conventional chemotherapy (DFS 48% vs. 0%).5  
 
The Italian GIMEMA-AIEOP AIDA 0493 trial has one of the largest (n = 107) and most 
mature datasets in children with APL. The treatment regimen used in this trial included 
ATRA and idarubicin (Induction), cytarabine plus idarubicin/mitoxantrone/etoposide/6-
thioguanine (Consolidation) and ATRA, 6MP and methotrexate (Maintenance). The CR 
rate was 96%, 10-year overall survival (OS) was 89%, and 10-year EFS was 76%.6 On 
AIDA0493, patients with high risk disease (WBC count at diagnosis ≥ 10,000/µL) had a 
10-year EFS of 59% compared to 83% for patients with standard risk APL. The publication 
of this pediatric data included long term follow-up with EFS estimates at 10 years; 
molecular relapses were censored in that analysis. For the AIDA 0493 study, EFS estimates 
that include molecular relapses as an event were 91.3% at 2 years for standard risk patients 
and 71.1% at 3 years for high risk patients (personal communication, Anna Maria Testi, 
MD). 
 
The COG’s most recent clinical trial for patients with newly diagnosed APL was 
AAML0631. Treatment included Induction with idarubicin and ATRA, two Consolidation 
cycles with ATO and ATRA, a Consolidation cycle with mitoxantrone/high dose 
cytarabine/ATRA, a Consolidation cycle with idarubicin and ATRA, and for high risk 
patients an additional Consolidation cycle with idarubicin/high dose cytarabine/ATRA. All 
patients received Maintenance with mercaptopurine/methotrexate/ATRA. One hundred 
and one patients (66 SR and 35 HR) were evaluable for outcome. The 2-year event-free 
survival (EFS) was 97% for SR APL and 83% for HR APL.7  
 
The EFS for SR patients in AAML0631 was non-inferior to that of patients in the AIDA 
0493 historical control, which used a significantly higher anthracycline dose and did not 
include ATO consolidation. AAML0631 was not statistically designed to allow a formal 
comparison of outcome for HR APL patients treated on the AAML0631 and AIDA 0493 
regimens. However, the survival rate was higher on the AAML0631 trial and the 
incorporation of ATO with decreased anthracycline can be considered a new standard of 
care for these HR APL pediatric patients. Therefore while AAML1331 was initially 
designed to compare outcomes to ADIA 0493 during a time when the AAML0631 
outcomes were not yet known, amendment 2 of the protocol now includes a comparison of 
outcomes between AAML1331 and AAML0631. 
 
2.2 
Arsenic Trioxide (ATO) in the Treatment of APL 
ATO administered as a single agent has shown excellent efficacy for patients with relapsed 
APL, prompting further study of ATO in newly diagnosed patients. ATO appears to have 
even greater anti-tumor activity than ATRA in the treatment of APL since durable 
remissions have been achieved with ATO therapy alone.8-10 Two studies have shown CR 
rates of approximately 86% and a 5-year OS rates of 64% - 74% utilizing ATO as a single 
agent for newly diagnosed APL in adults and children.11,12 The North American APL 
intergroup study C9710 randomized patients ≥ 15 years old to two Consolidation cycles 
with ATO while all patients received a chemotherapy backbone including ATRA, 
daunorubicin and cytarabine (Induction), two cycles of ATRA and daunorubicin 
(Consolidation) and Maintenance with ATRA, 6MP and methotrexate. This study 
demonstrated an improved EFS and OS for patients who received ATO compared to those 
who did not (3-year EFS 80% vs. 63%, p < 0.0001, and 3-year OS 86% vs. 81%, p = 0.059, 
respectively).13 Supported by these results, the COG AAML0631 study incorporated two 

  
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ATO Consolidation cycles into a backbone of anthracycline and high dose cytarabine 
chemotherapy while reducing the total anthracycline dose by 38 - 45% compared to earlier 
AIDA regimens. The ATO containing cycles were well tolerated and there were fewer 
infectious related complications during those cycles compared to the cycles with 
anthracyclines and high dose cytarabine.7 
 
2.3 
ATO and ATRA Regimen 
There is evidence that combining ATRA with ATO produces results superior to ATO 
alone.14,15 Investigators at the University of Texas – MD Anderson Cancer Center 
(MDACC) developed a regimen for newly diagnosed APL combining ATO and ATRA 
without any traditional cytotoxic chemotherapy.16 Patients received ATO and ATRA daily 
for the first month of therapy as Induction, and subsequently received 28 weeks of 
Consolidation consisting of cycles of ATO (4 weeks every 8 weeks for 4 cycles) and ATRA 
(2 weeks every 4 weeks for 7 cycles). Patients with presenting WBC ≥ 10,000 also received 
a dose of gemtuzumab ozogamicin on Day 1 of Induction. Utilizing this regimen they 
achieved excellent outcomes with CR 98%, 5-year EFS 86% and 5-year OS 88%.16,17 WBC 
≥ 10,000 at diagnosis (high risk disease) continued to predict a worse outcome with this 
regimen. The Italian and German cooperative groups (GIMEMA-SAL-AMLSG) 
conducted a Phase III randomized trial (APL0406) of adult patients with standard risk APL 
comparing ATO/ATRA per the MDACC regimen to the Italian AIDA 2000 regimen. They 
demonstrated that ATO/ATRA was not inferior to AIDA therapy; patients in the 
ATO/ATRA arm vs. the AIDA arm achieving CR 97.4% vs. 95% (P = 0.12), 2-year EFS 
97% vs. 86.7% (P = 0.03) and 2-year OS 98.7% vs. 91.1% (P = 0.03), respectively.18,19 
This data was recently updated to include outcomes through September 2013 and the EFS 
for the ATO/ATRA arm remained excellent at 97.5% with 3 events including 1 death in 
CR and 2 relapses. With this longer follow-up, the relapse rate (RR) is only 2%, which is 
significantly lower than the RR of 9.5% for patients treated with AIDA chemotherapy 
(P = 0.048) (presentation by Giuseppi Avvisati, 6th International Symposium on Acute 
Promyelocytic Leukemia, Rome). 
 
In Australia and New Zealand (Australasian Leukaemia and Lymphoma Group), APL 
patients with both standard and high risk disease on study APML4 were treated with an 
Induction regimen including daily ATRA along with 4 doses of idarubicin given on 
Days 2, 4, 6, and 8 followed by daily ATO on Days 9 - 36. In Consolidation, Cycle 1 
included daily ATO and ATRA for 28 days and Cycle 2 included ATO 5 days weekly for 
5 weeks and ATRA 7 days on and 7 days off during the 5 weeks. This course was followed 
by 24 months of Maintenance with ATRA, mercaptopurine and methotrexate. This regimen 
achieved a 2-year OS of 93.2% and Failure Free Survival (FFS) of 88.1%.20 Recently 
updated data including 5-year survival estimates demonstrate continued excellent results 
with low relapse risk even among patients with high risk disease. For high risk disease, the 
5-year OS is 87% and 5-year EFS is 83%. Cumulative incidence of relapse at 5 years was 
similar between patients with standard risk disease and high risk disease (4.5% and 
5.3%, respectively). (Presentation by Harry Iland, 6th International Symposium on Acute 
Promyelocytic Leukemia, Rome) All survival endpoints were significantly superior in 
APML4 compared to the prior APML3 trial which did not include ATO (APML3 regimen 
included ATRA, idarubicin and 2 years of Maintenance chemotherapy). 
 
The therapy on the current study will include ATRA and ATO in Induction and 28 weeks 
of Consolidation per the same regimen that demonstrated excellent results in adult patients 
in the MDACC trial and APL0406. In place of gemtuzumab ozogamicin, as used on the 

  
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MDACC trial for high risk patients, AAML1331 will include four doses of idarubicin 
similar to the Induction regimen from APML4, which resulted in a low relapse risk for 
high risk patients. 
 
2.4 
Cardiac Toxicity in APL Therapy 
Many APL treatment regimens rely upon high cumulative doses of anthracyclines. It is 
well known that anthracycline exposure places patients at risk for significant cardiac 
toxicity.21,22 The risk increases with higher cumulative doses (especially over 300 mg/m2), 
and the risk is higher when children are exposed at a young age.23 On the European APL93 
and APL2000 trials a total of 26 children and 58 adolescents were treated. The treatment 
regimens included a total of 495 mg/m2 of daunorubicin. Three children experienced 
significant cardiac toxicity, including one patient with fatal heart failure during 
Consolidation, one patient who developed heart failure 6 years after completion of therapy 
and was managed with medical therapy, and one patient who relapsed and received 
additional mitoxantrone and auto-transplant prior to developing heart failure requiring a 
heart transplant.24 On the AML intergroup C9710 trial, there were 2 deaths attributed to 
cardiac toxicity among 56 children (personal communication, James Feusner, MD). 
 
A goal of AAML1331 is to further improve long-term outcomes and quality of life for 
survivors of childhood APL. For standard risk patients, no anthracyclines will be used in 
their treatment. For high risk patients, the cumulative dose of anthracycline will be reduced 
to 48 mg/m2 of idarubicin (approximately 192 mg/m2 daunorubicin equivalents). The 
current study will include repeated cycles of ATO, which is known to prolong the QTc 
during treatment. On the recently closed AAML0631, children received ten weeks of ATO 
(given as two courses of five weeks each) and QTc prolongation was monitored closely on 
the trial. Twenty four patients had prolonged QTc during their ATO cycles, but all were 
Grade 1 or 2, transient, and did not require dose adjustment.7 
 
2.5 
Rationale for Elimination of Chemotherapy Maintenance Cycles 
The role of Maintenance chemotherapy in APL has been tested in several studies with 
variable results. Two recent randomized studies failed to demonstrate a significant benefit 
for the addition of Maintenance. The AIDA 0493 trial initially randomized patients to 
4 Maintenance arms including mercaptopurine and methotrexate (6MP/MTX), ATRA 
alone, 6MP/MTX alternating with ATRA, or observation without Maintenance. Early 
results suggested a benefit to ATRA containing Maintenance prompting amendment of the 
trial. In long term follow-up, however, there was no difference in the Maintenance arms 
including the observation only group.25 Similarly, on the North American Intergroup 
C9710 study, initial Maintenance arms were ATRA versus observation until the study was 
amended to compare ATRA versus ATRA plus 6MP/MTX, based in part on the early 
immature results of AIDA 0493. Among the 50 patients enrolled prior to amendment, there 
was no difference in observation versus ATRA Maintenance. Long term follow-up has 
shown no difference in outcomes for ATRA versus ATRA plus 6MP/MTX for patients 
receiving ATO Consolidation.26 
 
The excellent results reported for adult patients in the MDACC trial and for standard risk 
patients on the APL0406 trial were attained using ATO/ATRA Induction followed by 
28 weeks of Consolidation without additional Maintenance cycles. The current study uses 
the same schedule without Maintenance. For high risk patients, the APML4 regimen 

  
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resulted in a low relapse risk using idarubicin in Induction, two Consolidation cycles with 
ATO and 24 months of low dose oral chemotherapy Maintenance. The data from 
AIDA 0493 and C9710 suggest that Maintenance chemotherapy may not improve survival, 
and the latter study indicates that this is particularly true when ATO Consolidation is 
included. The current study will use idarubicin in Induction similar to APML4. However, 
rather than  Maintenance chemotherapy, Consolidation will be extended to 28 weeks 
including a total of 16 weeks of post-Induction ATO versus 9 weeks of post-Induction 
ATO administrations in APML4. 
 
2.6 
Risk Stratification Based on WBC 
The risk criteria first published by Miguel Sanz based on WBC and platelet counts have 
proven to be predictive in pediatric patients.6 Standard risk disease (including both low and 
intermediate risk groups by Sanz criteria) includes patients with an initial WBC < 10,000 
at diagnosis. High risk disease includes patients with WBC ≥ 10,000. On the AIDA 0493 
study, pediatric patients with high risk disease had a worse EFS compared to those with 
standard risk disease. Early Induction deaths due to differentiation syndrome and 
coagulopathy occur more frequently in patients with high risk disease. The risk of relapse 
is also higher in patients with high risk disease. In this trial, therapy for high risk APL will 
differ from standard risk APL in that it will include 4 doses of idarubicin early in Induction. 
The goal of idarubicin for patients with high risk disease is to decrease risk of relapse as 
well as to decrease the white blood cell count (due to the associated early complications 
seen with uncontrolled leukocytosis). 
 
2.7 
Differentiation Syndrome Prophylaxis and Treatment 
Steroid prophylaxis has been incorporated into APL trials to prevent the development of 
APL differentiation syndrome (DS), a potentially fatal complication of APL treatment. 
Both ATRA and ATO are differentiating agents in APL treatment, and when used together 
in Induction therapy there is potential for significant DS symptoms, especially in high risk 
patients. Therefore, prednisone was used as prophylaxis in all patients on the Australasian 
study, APML4, on Days 1 - 10 of Induction, as well as on the Italian-German study, 
APL0406, on Day 1 through the end of Induction. Patients on these studies who developed 
symptoms of DS were treated with dexamethasone. There were no deaths due to DS of 
124 patients treated on APML4 versus 4 deaths due to DS of 101 treated patients in 
APML3. On APL0406 there were no deaths due to DS on the ATO/ATRA arm and 2 DS 
related deaths on the AIDA chemotherapy arm (out of 156 treated patients all of whom 
were standard risk). In this trial, patients who developed symptoms of DS were switched 
to dexamethasone IV. While 47% of patients developed leukocytosis (WBC > 10,000) 
during Induction therapy, all these patients were successfully managed with protocol 
specified hydroxyurea for therapy-induced leukocytosis. On the Spanish PETHEMA 
study, LPA99, prednisone prophylaxis was also given to all patients on Days 1 - 15 of 
Induction. On the subsequent study LPA2005, dexamethasone was given Days 1 - 15 at 
2.5 mg/m2 twice daily to patients with WBC > 5,000/µL. This approach resulted in similar 
rates of severe and moderate DS (24% on LPA99 vs. 28% on LPA2005, P = 0.12) and 
similar low rates of death (1.4% on LPA99 vs. 1.0% on LPA2005, P = 0.55).27 
 
On the current study, high risk patients will receive DS prophylaxis with dexamethasone 
2.5 mg/m2/dose PO or IV, twice daily for 14 days. For patients with standard risk APL, if 
the WBC count rises above 10,000/µL during Induction, hydroxyurea and dexamethasone 
prophylaxis will be started to control the leukocytosis and reduce the risk of DS. Guidelines 

  
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for the management of DS are provided for those patients who develop symptoms of DS 
(see Section 5.1). 
 
2.8 
CNS Directed Therapy in APL 
The incidence of CNS relapse in APL is low. The PETHEMA trials LPA96 and LPA99 
did not include CNS prophylaxis and demonstrated a 1.1% 3-year incidence of CNS 
relapse.28 A literature review of pediatric APL patients found a < 1% incidence of isolated 
CNS relapse in pediatric patients with standard risk APL who were treated without CNS 
prophylaxis.29 Regimens with single agent ATO (including studies in India and Iran) and 
combined ATO and ATRA (including the MDACC trial, APML4 and APL0406) have all 
achieved low CNS relapse rates without use of prophylactic intrathecal chemotherapy. 
ATO is able to cross the blood brain barrier with CSF levels up to 50% of serum levels30. 
These data indicate that there is no role for prophylactic intrathecal chemotherapy in the 
majority of APL patients. However, a specific group of patients at risk for CNS relapse 
was identified on PETHEMA studies in Spain. CNS hemorrhage in Induction, which was 
a rare event with incidence of 2.7%, was a significant risk factor for CNS relapse (5-year 
cumulative incidence of CNS relapse of 18.7%).28 
 
Prophylactic intrathecal chemotherapy will not be used on the current study with the 
exception of patients with a documented CNS bleed. These rare patients will receive triple 
intrathecal chemotherapy at the end of Induction and every 4 weeks during Consolidation 
for 6 doses as prophylaxis against CNS relapse. Patients with CNS symptoms concerning 
for CNS disease will have a lumbar puncture performed once coagulopathy is resolved. If 
a patient has CNS disease, the recommended treatment will include twice-weekly triple 
intrathecal chemotherapy until the CSF is cleared plus two additional twice-weekly 
treatments. Following the twice-weekly treatments, these patients with documented CNS 
disease will have additional triple intrathecal chemotherapy every 4 weeks during 
Consolidation on the same schedule as for patients with a CNS bleed. 
 
Data from patients with CNS relapse APL suggests that triple intrathecal therapy (ITT) is 
effective for treatment of CNS disease.28,31,32 There is little data about the efficacy of IT 
cytarabine alone in the treatment of APL CNS disease. Thus the current study will utilize 
ITT with dosing similar to that used on the CCG 2961 study for AML patients. During 
Induction for patients with CNS disease receiving twice weekly treatments, a dose of 
leucovorin will be given 24 hours after each ITT treatment to prevent systemic 
myelosuppressive effects of repeated methotrexate dosing.  
 
2.9 
PCR Monitoring of Bone Marrow 
Quantitative RT-PCR (RQ-PCR) provides several advantages in the diagnosis of APL by 
providing a very sensitive and specific diagnostic test that establishes the breakpoint 
specific transcript for monitoring for persistent MRD or for surveillance to detect relapse. 
A panel of primers that covers the various breakpoints in the PML-RARα fusion gene 
transcript is used. An internal housekeeping gene, used to standardize the transcript level 
and determine the quality of the RNA, decreases false negative results.33 Thus, PCR testing 
has become the “gold standard” for confirmation of the diagnosis of APL.34 PCR testing 
can confirm the presence of the PML-RARα fusion gene and distinguishes this common 
type of APL from other rare variants (e.g., PLZF-RARα) that may not respond to ATRA 
treatment and should not be included on clinical trials utilizing ATRA as an essential 
component of therapy. The PCR testing is a very sensitive assay for detection of the 

  
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PML- RARα fusion gene transcript, which allows for detection of MRD and molecular 
relapse (the latter is recurrent disease detected by PCR prior to signs of full hematologic 
relapse). 
 
MRD may be detected as a persistently positive PCR result during therapy. With 
chemotherapy, persistent PCR positive disease at the end of Consolidation (prior to 
Maintenance therapy) has been correlated with high risk of relapse.33,35 On the COG study 
AAML0631, if a patient with standard risk disease was PCR positive at end of 
Consolidation Course 3, they received an additional course of Consolidation. However, no 
standard risk patient met this protocol specified criteria (personal communication, John 
Gregory, MD). Using an ATO/ATRA regimen that included 4 ATO Consolidation cycles, 
the MDACC trial included a recommendation for additional doses of gemtuzumab 
ozogamicin for patients with persistent PCR positive disease after 2 ATO Consolidation 
cycles. However, similar to the COG study, all patients were PCR negative at that time 
point on the trial.16 Thus we would expect it to be rare for a patient on the current study to 
have PCR positive disease at Day 43 of Consolidation Cycle 2. In the unlikely event a 
patient has persistent disease at this time point, the proposed protocol specifies a course of 
mitoxantrone and high dose cytarabine (MA). The MA course has been used on recent 
(MRC-based) COG studies for AML patients. In the current AAML1031 study, this cycle 
is used as a second Induction course for patients who remain MRD positive at the end of 
the first Induction. Patients who remain PCR positive after the MA course will be taken off 
protocol therapy. 
 
In the case of relapse, studies have demonstrated an advantage to detecting the disease at 
the molecular stage in bone marrow rather than at the later stage of overt hematologic 
relapse.36,37 Greater disease burden carries increased risk for the potentially fatal 
complications of coagulopathy and differentiation syndrome. The sensitivity of RQ-PCR 
allows early detection of relapse, and it has been demonstrated that PCR positive disease 
(that has been confirmed with at least two tests) will invariably present as hematologic 
relapse in the absence of a therapeutic intervention.38,39 Based on the sensitivity of RQ- PCR 
and the kinetics of the rise of PML-RARα transcripts during relapse, PCR testing on bone 
marrow samples is usually performed every 3 months.40,41 RQ-PCR testing detects disease 
at a sensitivity of 1 in 104 cells in bone marrow, and the kinetics of relapse disease 
progression showed a median of 1.1 log fold increase in RQ-PCR transcript per month.40 
Thus, an interval of 3 months between testing generally allows detection of molecular 
relapse without sufficient time for the disease to progress to hematologic relapse between 
testing time points. This monitoring is continued for 2 - 3 years following Consolidation 
therapy since most patients relapse during this period. However, these serial bone marrow 
evaluations usually require sedation for pediatric patients. The cost and risks of these 
sedated procedures must be balanced with the benefit of such monitoring. With the 
ATO/ATRA regimen the risk of relapse for standard risk patients is expected to be very 
low. Thus the benefit of such post-therapy monitoring is likely outweighed by the risk and 
costs of the procedure. However, the relapse risk is greater in high risk patients, therefore, 
monitoring with serial bone marrow RQ-PCR testing every 3 months until 3 years from 
diagnosis is strongly recommended in the high risk cohort. 
 
2.10 
Correlative Studies 
2.10.1 FLT3 Mutations in Pediatric APL 
The purpose of this study is to test the hypothesis that FLT3 mutations in pediatric 
APL are prognostic markers. 

  
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Analysis of an exploratory cohort of patients from prior COG studies has shown 
that 40% of pediatric APL patients have FLT3-ITD or FLT3-ALM.42 This analysis 
also demonstrated that patients with FLT3 mutations (either FLT3-ITD or FLT3-
ALM) were at increased risk of early death. In the current study, we will determine 
FLT3 mutation status and correlate this with patient characteristics (such as 
presenting WBC, coagulation study parameters, and APL M3v subtype), patient 
outcomes (including early death, EFS, DFS and OS), and in select cases 
assessments of pathway activation using phosphoflow. These analyses will provide 
important information for potential future trials examining FLT3 inhibitors in APL 
treatment. 
 
2.10.2 Bone marrow and Peripheral Blood Minimal Residual Disease Testing in 
Pediatric APL 
This study will test the hypothesis that RQ-PCR test results (either in bone marrow 
or peripheral blood) following an ATO based Induction can be prognostic for 
treatment outcome. 
 
RQ-PCR for PML-RARα is used to monitor response to therapy and for post 
therapy (molecular) relapse. At defined time points during treatment, bone marrow 
testing by RQ-PCR will determine if patients will receive an additional 
molecularly refractory treatment course. This study will investigate additional 
research time points for peripheral blood (PB) RQ-PCR and bone marrow (BM) 
RQ-PCR to analyze whether the rate of clearance of BM and/or PB RQ-PCR while 
on therapy can predict risk for relapse. 
 
In both pediatric ALL and AML, MRD at end of Induction therapy has proven to 
be one of the most important prognostic markers for outcome. In APL, PCR for 
the PML-RARα transcript is more sensitive than flow-based MRD. The 
PML- RARα PCR may remain positive at the end of Induction due to persistence 
of maturing myelocytes. A significant percentage of patients may have PCR 
detectable disease while at the same time having entered a morphologic remission. 
Therefore, this study will use hematologic complete remission as the criteria to 
move onto Consolidation therapy (the same as utilized in the model studies at 
MDACC and APL0406). Most patients who are PCR positive at end Induction 
will go onto achieve durable molecular remissions, and thus a positive test is not 
a specific marker of relapse risk. Earlier studies (not utilizing ATO therapy) 
suggested that the end Induction PCR was not prognostic for outcomes.40,41 
However, the use of ATO in Induction may change the kinetics of PML-RARα 
clearance as assessed by PCR. Indeed there is evidence that a negative or low 
normalized copy number (NCN) PCR result at end Induction may be a marker for 
low relapse risk when ATO is used in Induction. In a Chinese study, pediatric 
patients with high risk APL were treated with ATO and ATRA and those with 
standard risk disease were treated with ATRA alone or in combination with ATO. 
One third of patients (34.2%) had end Induction PCR of < 1 NCN. These patients 
who rapidly achieved molecular remission had a 100% DFS at 5 years compared 
to patients with end Induction PCR > 1 NCN who had DFS of 55.2% (P = 0.018).43 
A report of patients treated with ATO monotherapy in India also demonstrated 
that negative PCR testing at end Induction was associated with a lower relapse 
risk.44 The current study will analyze end Induction PML-RARα PCR values and 
correlate NCN values with outcomes. The log-fold reduction in NCN from 

  
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diagnosis to end Induction will also be correlated with outcomes. Validation of a 
low NCN for PCR (or a certain log fold reduction) as a marker of low relapse risk 
could allow use of this response criteria in future studies to identify patients who 
could benefit from further treatment reductions and decreased relapse monitoring. 
 
2.10.3 Early Death and Coagulopathy Complications in Pediatric APL 
This study will test the hypothesis that a biomarker (elevation in thrombomodulin 
level) used alone or in combination with a clinical predictive score (the 
International Society on Thrombosis and Haemostasis (ISTH) DIC score), will 
correlate with bleeding and clotting events during Induction therapy of APL. Our 
specific aim is to compare sensitivity and specificity of thrombomodulin levels 
along with the ISTH DIC score in predicting Grade 3 or higher episodes of 
hemorrhage or thrombosis from diagnosis through end of Induction. Additionally 
we will test the hypothesis that global coagulation test results (thrombin generation 
parameters, fibrinolytic parameters, microparticles levels) used alone or in a 
stepwise combination with the ISTH DIC score and thrombomodulin levels will 
improve identification of APL patients at risk for adverse events of hemorrhage or 
thrombosis. 
 
Early deaths and morbidity due to coagulopathy (both hemorrhage and thrombosis) 
remain a significant problem in APL.45,46 The coagulopathy of APL is unique as 
there is activation of the coagulation cascade (due to expression of tissue factor 
and other procoagulants) with concomitant increase in primary and secondary 
fibrinolysis due to expression of annexin II on the APL blasts. Additionally, due 
to the secretion of various cytokines, there is increased vascular fragility. The exact 
outcome depends on the net balance between these mechanisms. 
 
Some studies have shown that various clinical (low performance status) and 
laboratory parameters (elevated WBC count at presentation, low platelet count, or 
low fibrinogen level with elevation in PT) are able to predict those APL patients 
at higher risk for hemorrhagic complications.47 The ISTH DIC score was 
developed in order to offer a standard approach with objective criteria for the 
diagnosis and severity of DIC. A score of ≥ 5 is correlated with overt DIC48. In one 
retrospective study an ISTH DIC score of ≥ 6 independently correlated with an 
increased risk of hemorrhagic early death.49 We calculated the ISTH DIC score for 
patients enrolled in the AAML0631 study. Complete data for coagulation 
parameters (PT, fibrinogen level, D-Dimer levels) and clinically significant 
bleeding or thrombosis (Grade 3 or higher) during Induction were available for 
76 of 102 patients. Amongst the 31 patients with an ISTH DIC score ≥ 6 there were 
10 clinical adverse effects related to coagulopathy (including four early deaths) 
and amongst the 45 patients with an ISTH DIC score < 6, there were 4 clinical 
adverse effects related to coagulopathy (no deaths). The sensitivity of the ISTH 
DIC score in predicting coagulopathy events during Induction was only 66.7% and 
the specificity was 65.6% further underscoring the fact that although the ISTH DIC 
score may be valuable in predicting early hemorrhagic death, it has inherent 
limitations in identifying pediatric APL patients at risk for serious hemorrhage and 
thrombosis. 
 
Traditional coagulation tests such as PT, aPTT and fibrinogen levels (as are used 
to calculate the ISTH DIC score) are limited as they cannot measure the unique 
contribution of fibrinolysis or the balance between procoagulation and fibrinolysis. 

  
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To implement specific interventions that prevent these serious events improved 
biomarkers are needed to accurately predict patients at risk for coagulopathy and 
differentiate patients at risk for either bleeding or thrombosis. Recently, 
measurement of soluble thrombomodulin (sTM) levels has been used for risk 
stratification and prognostic evaluation of septic patients with coagulopathy.50,51 
Also, recent advances in global coagulation assays that assess thrombin generation 
and measure the fibrinolytic potential of blood may be of additional benefit in 
identifying patients at risk for coagulopathy. 
 
This study will determine the incidence of clinically significant bleeding and 
clotting events (defined as Grade 3 or higher) in pediatric and young adult patients 
receiving both ATRA and ATO in Induction. Data on APL related coagulopathy 
will be collected including results of local coagulation studies as well as central 
testing of soluble thrombomodulin levels, fibrinolytic parameters by the Clot 
Formation and Lysis (CloFAL assay), thrombin generation and APL associated 
microparticles. These data may provide a method to identify patients most at risk 
for lethal complications and also provide a framework on which to test novel 
interventions for control or prevention of coagulopathy (including investigational 
agents such as recombinant thrombomodulin) in future studies. 
 
2.10.4 Neurocognitive Outcomes in Pediatric APL Treatment 
The purpose of this correlative study, which is optional for subjects, is to 
longitudinally monitor cognitive side effects associated with this treatment.  
 
Arsenic can enter the brain and have toxic effects on the central nervous system 
(CNS).52 Chronic arsenic exposures via drinking water or industrial sources have 
been widely reported to be associated with impaired neurocognitive function in 
children.53-59 However, little is known about the CNS effects of arsenic 
administration when used at therapeutic doses for the treatment of APL. There are 
case reports in adults suggesting that short-term exposure to high concentrations 
of arsenic can alter the verbal learning and memory, cause confusion and visual 
sensations, and adversely affect learning, memory and concentration.60-63 Arsenic 
trioxide has been administered safely to children and adolescents with relapsed as 
well as newly diagnosed APL. Reports from studies in India, China and 
Australia/New Zealand have not noted any overt arsenic-related CNS toxicities in 
their pediatric populations.11,14,20,64,65 Also, no significant CNS toxicity has been 
attributed to the arsenic containing Consolidation cycles on COG AAML0631 
(personal communication John Gregory, MD). However, no research has been 
done using more sensitive and specific neurocognitive testing batteries to study the 
short-term and long-term neurocognitive impact in children with APL who are 
exposed to arsenic.  
 
In most epidemiological studies, arsenic concentrations in drinking water between 
100 µg – 300 µg/L will cause a significant neurocognitive delay in school aged 
children.59 This concentration is roughly correlated with a blood arsenic 
concentration of 10 µg/L.66 Since all the epidemiological studies published are 
cross sectional, the length of time required to develop neurocognitive delay at this 
concentration is unclear. In the Phase I pediatric clinical trial using arsenic at 
0.15 mg/kg per dose, daily, as single agent, the median plasma arsenic maximum 
concentration was 0.28 µM (56 µg/L).67 In the current study, all children with 
newly diagnosed APL will be treated with ATO at 0.15 mg/kg dose daily for a 

  
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23 
minimum of 20 weeks. This is comparable arsenic exposure to previous APL 
studies. Since > 95% children are expected to have long-term survival, it is 
important to study the neurocognitive impact of arsenic exposure on the 
developing brain in these children. 
 
To evaluate neurocognitive functioning in children receiving ATO treatment for 
APL, we will use a brief battery of computerized tasks (patient-completed) and 
behavioral ratings (parent-completed) administered at two time points during 
treatment and three times following treatment, as well as a short battery of 
traditional performance-based measures administered at three time points 
following treatment completion. 
 
The primary goal of this exploratory aim is to evaluate the neurocognitive 
outcomes of patients treated on this protocol using patient-completed, 
performance-based measures of neuropsychological functioning and parent 
questionnaire reports. Declines in neurocognitive functioning will be measured by 
CogState, BRIEF, and a psychologist-administered battery of tests in children with 
ATO-treated APL, as defined by a clinically meaningful decrease in mean scores 
apparent at 2 years off therapy in the following domains: working memory, 
executive function, visual motor, processing speed, visual attention, IQ, verbal 
learning, processing speed, and adaptive functioning.  
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every newly 
diagnosed patient needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study.  
At this time, however, enrollment onto APEC14B1 is NOT a prerequisite to 
enrollment on AAML1331. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 

  
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registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to:  
 
An active Federal Wide Assurance (FWA) number  
 
An active roster affiliation with the Lead Network or a participating 
organization 
 
A valid IRB approval 
 
Compliance with all protocol specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for 
this study are not required to submit IRB approval documentation to the CTSU 
Regulatory Office. For sites using the CIRB, IRB approval information is received 
from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. Other site registration 
requirements 
(i.e., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 

  
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3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
 
All eligibility criteria have been met within the protocol stated timeframes. 
 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.4 
Timing 
Study enrollment must take place within five (5) calendar days of beginning 
protocol therapy. If enrollment takes place before starting therapy, the date 
protocol therapy is projected to start must be no later than five (5) calendar days 
after enrollment. 
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 

  
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 CLINICAL RQ-PCR Testing 
Specimens for RQ-PCR of PML-RARα are required and must be obtained 
prior to Day 1 of protocol directed therapy (pre-treatment with ATRA 
allowed). These specimens must be sent to one of the approved labs for 
PML-RARα RQ-PCR testing but the cost is not covered by the study. It 
should 
be 
billed 
as 
a 
regular 
clinical 
lab 
through 
the 
institution/insurance/patient as appropriate. A list of approved labs is 
available on the protocol-specific web page of the COG website located at 
https://cogmembers.org/PROT/AAML1331/AAML1331ValidatedRQ-
PCRLabsList.pdf  
 
Results of the clinical RQ-PCR testing are not required to be 
completed prior to enrollment or initiation of therapy, but samples 
must be collected prior to the initiation of therapy or patient will be 
taken off study. (For Standard Risk patients see Section 4.2.2 and for 
High Risk patients see Section 4.8.2 for required studies to be obtained 
prior to starting protocol therapy.) Prior therapy, per Section 3.2.3, is 
allowed before drawing samples. 
 
NOTE: This CLINICAL testing is separate from RESEARCH samples 
submitted for the optional MRD study. Details on the CLINICAL 
specimens can be found in Section 7.1. Details on the RESEARCH 
specimens for the optional MRD biology study can be found in Section 
15.2. Results of that RESEARCH MRD testing are not returned to sites 
and do not take the place of the CLINICAL RQ-PCR testing that must 
occur at diagnosis. 
 
 Cytogenetics 
Specimens for cytogenetics analysis are required and must be obtained 
prior to therapy initiation. For COG treatment sites, it is strongly 
recommended that they be sent to a COG-approved institutional 
cytogenetics laboratory. A listing of these laboratories, as well as methods 
of attaining COG approval for local cytogenetics laboratories without 
current COG approval may be found on the COG website. 
 
Results of cytogenetics and FISH are not required to be completed 
prior to enrollment, but samples must be collected prior to the 
initiation of therapy. 
 
Cytogenetic and FISH results should be sent to the appropriate central 
reviewer within 2 weeks from start of therapy. See Section 14 for specimen 
collection and data submission details. 
 
3.1.5 
Emergent Treatment 
 
A diagnosis of APL is a hematologic emergency and treatment with ATRA 
should be initiated without waiting for confirmatory genetic testing if there is 
a clinical suspicion of the diagnosis. Up to 5 days of ATRA pre-treatment, 
prior to start of protocol directed therapy, is allowed. Of note, if the patient is 
later determined to have non-APL AML they could remain eligible for the 

  
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COG study of non-APL AML (AAML1031) since ATRA pre-treatment is also 
allowed on AAML1031. 
 
 
In patients with standard risk disease (WBC < 10,000/µL), ATRA should be 
started at time of first suspicion of APL diagnosis and then ATO given (when 
available) on Day 1 of protocol directed therapy. 
 
 
In patients with high risk disease (WBC ≥ 10,000/µL at diagnosis), ATRA 
should be started at time of first suspicion of APL diagnosis. Idarubicin and 
ATO should be given on Day 1 of protocol therapy. If an institution does not 
have ATO available on Day 1 when idarubicin is given, it will not be a protocol 
violation to start protocol directed therapy with idarubicin and ATRA as long 
as the ATO is started within 48 hours of the first idarubicin dose. 
 
3.1.6 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study.  
 
3.2 
Patient Eligibility Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived. All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record 
which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. 
 
For Standard Risk patients see Section 4.2.2 and for High Risk patients see Section 4.8.2 
for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Age 
Patient must be ≥ 12 months and < 22 years of age at first diagnosis of APL. 
 
3.2.2 
Diagnosis 
 
Patients must be newly diagnosed with a clinical diagnosis of APL (initially by 
morphology of bone marrow or peripheral blood). 
 
Bone marrow is highly preferred but in cases where marrow cannot be obtained 
at diagnosis, peripheral blood will be accepted. 
 

  
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 
If the RQ-PCR results are known at the time of study enrollment, the patient must 
demonstrate the PML-RARα transcript by RQ-PCR to be eligible. 
 
NOTE: A lumbar puncture is not required in order to be enrolled on study nor 
are lumbar punctures recommended at the time of diagnosis. If the diagnosis of 
APL is known or suspected, diagnostic lumbar punctures in patients with neurologic 
symptoms should be deferred until any coagulopathy is corrected. If CNS disease is 
suspected or proven, a CT or MRI should be considered to rule out the possibility of 
an associated chloroma. If CNS disease is documented, patients are still eligible and 
will receive protocol directed intrathecal treatments. 
 
3.2.3 
Prior Therapy 
 
Patients may receive up to a maximum of 5 days of pre-treatment with ATRA 
prior to administration of protocol therapy. 
 
 
Treatment with hydroxyurea, corticosteroids (any route) and intrathecal 
cytarabine prior to beginning protocol directed therapy is allowed. However, 
it should be noted that lumbar puncture and intrathecal therapy at initial 
diagnosis of APL is not recommended due to the possible complications of 
coagulopathy. 
 
Please see Section 4.1.3 for concomitant therapy restrictions for patients during 
treatment. 
 
3.2.4 
Exclusion Criteria 
 Secondary APL 
Patients with secondary APL are excluded. This includes all patients with 
APL that may have resulted from prior treatment (chemotherapy or 
radiation). 
 
 Isolated Myeloid Sarcoma 
Patients with isolated myeloid sarcoma (myeloblastoma, chloroma, 
including leukemia cutis) but without evidence of APL by bone marrow 
or peripheral blood morphology are excluded. 
 
 EKG Abnormalities 
 
Patients with a pre-existing diagnosis of a prolonged QT syndrome 
(even if QTc is normal at the time of APL diagnosis) are excluded due 
to the use of arsenic trioxide, which can prolong the QT interval. 
 
 
Patients with a baseline QTc of > 450 msec are excluded. Bazett’s 
formula is to be used for measurement of the corrected QT interval: 
the QT interval (msec) divided by the square root of the RR interval 
(msec). 
 
 
Patients with a history or presence of significant ventricular or atrial 
tachyarrhythmia are excluded. 

  
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 
Patients with right bundle branch block plus left anterior hemiblock, 
bifascicular block are excluded. 
 
 Renal Dysfunction 
Patients with serum creatinine > 3.0 mg/dL and patients on active dialysis 
for renal dysfunction are excluded. 
 
 Prior Chemotherapy 
Patients who have received treatment with any other cytotoxic 
chemotherapy prior to beginning protocol therapy (other than allowed in 
Section 3.2.3) are excluded. 
 
 Pregnancy and Breast Feeding  
3.2.4.6.1 Female patients who are pregnant are excluded. Treatment 
under this protocol would expose an unborn child to significant 
risks. Patients should not be pregnant or plan to become 
pregnant while on treatment. There is an extremely high risk 
of fetal malformation if pregnancy occurs while on ATRA in 
any amount, even for short periods. 
 
A pregnancy test prior to enrollment is required for female 
patients of childbearing potential. 
 
3.2.4.6.2 Lactating females who plan to breastfeed their infants are 
excluded. 
 
3.2.4.6.3 Sexually active patients of reproductive potential who have not 
agreed to be abstinent or use 2 forms of effective contraception 
during treatment through 1 month off therapy are excluded. 
 
3.2.5 
Regulatory Requirements  
 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
 All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
3.3 
Definitions 
3.3.1 
Initial CBC 
The first CBC from the COG treating institution. 
 
3.3.2 
Standard Risk 
Patients with a WBC < 10,000/µL on the initial CBC at diagnosis are defined as 
standard risk. 
 

  
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3.3.3 
High Risk 
Patients with a WBC ≥ 10,000/µL on the initial CBC at diagnosis are defined as 
high risk. 
 
3.3.4 
CNS Disease and CNS Bleed 
3.3.4.1 CNS disease 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 or 
hypothalamic syndrome).  Patients with retinal hemorrhage alone do 
not have CNS leukemia. Patients with documented CNS bleed and 
with neurologic symptoms that are fully attributable to the CNS bleed 
do not have CNS leukemia unless they meet one of the other criteria 
in this section (CSF or chloroma) but these patients do meet criteria 
for “CNS Bleed”. See Section 3.3.4.2 below. 
 
Radiographic evidence of an intracranial, intradural mass consistent 
with a chloroma. 
 
*NOTE: For patients who are diagnosed with CNS disease based on 
blasts in the CSF, we strongly recommend that you contact the COG 
APL investigator James “Jim” Feusner, MD to discuss central review 
of 
the 
CSF 
slides. 
Dr. 
Feusner 
can 
be 
contacted 
at 
jfeusner@mail.cho.org and he will provide shipping information upon 
contact. 
 
 CNS Bleed is defined as: 
 
Any radiographic evidence of hemorrhage into the brain 
parenchyma, spinal cord or subarachnoid, subdural or epidural 
spaces. 
 
Retinal hemorrhage alone is not a CNS bleed.  
 
 Method of Evaluating Initial 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 
 
 
 

  
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4.0 
TREATMENT PLAN 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Treatment on this study will consist of an Induction course to achieve an hCR/hCRi, 
followed by 28 weeks of Consolidation. There is no randomization in this study. Patients 
will be stratified into risk groups based on WBC at diagnosis. The standard risk group 
includes patients with WBC < 10,000/μL, and the high risk group includes patients with 
WBC ≥ 10,000/μL. 
 
Induction therapy consists of daily arsenic trioxide and twice daily tretinoin for all patients. 
Patients with high risk APL will also receive 4 doses of idarubicin and prophylaxis dosing 
of dexamethasone to help prevent differentiation syndrome. All doses of therapy on the 
protocol should be calculated using actual (not ideal or adjusted) body weight.  
 
Induction will last a minimum of 28 days. Beginning on Day 29 of Induction, patients will 
have bone marrow testing every 2 weeks as needed to confirm morphologic remission. 
Induction may last up to a maximum of 70 days. Once in morphologic remission, 
Consolidation therapy will start a minimum of 14 days after Induction and upon count 
recovery, whichever occurs later. 
 
Consolidation therapy will be the same for patients with standard risk and high risk APL. 
Consolidation consists of 28 weeks of therapy including 2 weeks of tretinoin every 4 weeks 
(7 cycles of tretinoin) and 4 weeks of arsenic trioxide every 8 weeks (4 cycles of arsenic 
trioxide). After Week 14 of Consolidation (on Day 43 of Cycle 2) there is a bone marrow 
assessment to determine if patients are in molecular remission (RQ-PCR for PML-RARα). 
A clinical sample for RQ-PCR must be sent at that time. Patients not in molecular remission 
will receive an additional cycle of Consolidation chemotherapy (mitoxantrone, cytarabine 
and tretinoin) and will again be tested for molecular remission. Those patients in molecular 
remission will proceed with Cycles 3 and 4 of Consolidation therapy. Those patients not in 
molecular remission will go off protocol therapy. 
 

  
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A schematic overview of the treatment plan follows: 
 
ATRA= tretinoin 
ATO= arsenic trioxide 
 
Induction: 
Standard Risk APL (WBC < 10,000/L at diagnosis) 
Day: 
1…………………………………………………28 
ATRA XXXXXXXXXXXXXXXXXXXXXXXXXXX   (further daily doses if not hCR/hCRi 
 
 
 on Day 29 bone marrow) 
ATO 
XXXXXXXXXXXXXXXXXXXXXXXXXXX   (further daily doses if not hCR/hCRi 
 
 
 on Day 29 bone marrow) 
(Hydroxyurea and dexamethasone will be used to control leukocytosis if WBC rises to 
> 10,000/µL during Induction) 
 
 
High Risk APL (WBC ≥ 10,000/L at diagnosis) 
Day: 
1………………………14………………………28 
ATRA XXXXXXXXXXXXXXXXXXXXXXXXXXX   (further daily doses if not hCR/hCRi 
 
 
 
 
 
 
 
    on Day 29 bone marrow) 
ATO 
XXXXXXXXXXXXXXXXXXXXXXXXXXX   (further daily doses if not hCR/hCRi 
 
 
 
 
 
 
 
    on Day 29 bone marrow) 
Dex 
 
Ida 
X X X X 
(Ida= Idarubicin given on Days 1, 3, 5, 7) 
 
 
Consolidation: 
Standard Risk and High Risk APL 
Week 
      2      4      6      8     10     12     14     16     18     20     22     24     26     28  
ATRA 
ATO 
RQ-PCR testing: 
 
 
            ↑    ↑*  
 
 
          ↑ 
(*Only if Week 14 RQ-PCR of PML-RARα positive, repeat testing in 1-2 weeks. If 
repeat test is confirmed positive continue to MRD Positive Consolidation) 
 
 
See the Chemotherapy Administration Guidelines (CAG) for children on the COG website 
at:  
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for special 
precautions and suggestions for patient monitoring. As applicable, also see the CAG for 
suggestions on hydration, or hydrate according to institutional guidelines. 
 
4.1.1 
CNS Bleed and CNS Disease 
CNS Bleed 
Patients with documented CNS bleed will receive CNS prophylaxis to include 
triple intrathecal chemotherapy on Day 29 of Induction and 6 additional doses 
during Consolidation. 
 
Note: routine (screening) imaging is not recommended, rather imaging should be 
performed for neurologic symptoms. 

  
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CNS Disease 
Patients with CNS disease will receive twice weekly triple intrathecal 
chemotherapy until the CSF is cleared plus two additional twice weekly treatments 
during Induction (minimum of 4 and maximum of 6) and 6 additional doses during 
Consolidation. 
 
Note: Evaluations of CSF for CNS disease at initial APL diagnosis are only to be 
performed in patients with neurologic symptoms at diagnosis consistent with CNS 
disease, and the lumbar puncture to investigate this is not to be performed in these 
patients until APL associated coagulopathy has resolved. 
 
4.1.2 
Supportive Care 
Hospitalization is strongly recommended for at least the first 2 weeks of Induction 
(and until all coagulopathy or differentiation syndrome symptoms resolve). 
 
 Differentiation Syndrome: 
For any patient with symptoms of differentiation syndrome, treatment will 
include dexamethasone. For more details on the diagnosis and 
management of differentiation syndrome including treatment dosing of 
dexamethasone, see dose modifications Section 5.1. 
 
 Coagulopathy 
Patients with APL are at risk for life-threatening bleeding and thrombosis. 
Patients may experience these events despite only mild coagulation lab 
abnormalities. During at least the first 7 days of therapy (or longer if 
needed until coagulopathy resolves), aggressive blood product support 
should be employed as follows:  
 
Maintain platelet count above 50,000/µL. For patients with CNS 
hemorrhage maintain the platelet count above 100,000/µL until 
bleeding stable, coagulopathy improved and a minimum of 7 days 
from diagnosis of the bleed. 
 
Obtain stat CT scan of the head for any patient with neurologic 
symptoms consistent with possible intracranial bleed. If CNS 
bleed present, consider neurosurgery consultation for help in 
management. 
 
Transfuse 
cryoprecipitate 
to 
maintain 
fibrinogen 
above 
150 mg/dL  
 
Transfuse fresh frozen plasma to maintain PT and PTT within 
normal range. 
 
Routine use of heparin or anti-fibrinolytics is not recommended. 
 
 Other Recommendations 
i. 
Leukopheresis should be avoided, if possible, due to the concern of 
worsening of bleeding secondary to release of procoagulant 
substances during cell trauma of the procedure. Pre-treatment with 
hydroxyurea is allowed on this protocol (see Section 3.2.3). 
 

  
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ii. 
Routine use of prophylaxis against pneumocystis pneumonia is not 
necessary with this regimen.  
 
iii. 
Growth factors such as GCSF, GMCSF and erythropoietin are not to 
be used routinely. 
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines 
under Standard Sections for Protocols. 
 
4.1.3 
Concomitant Therapy 
An extensive number of medications have been reported to prolong the QTc 
interval that could potentially exacerbate the effect of ATO on the QTc interval. 
Caution should be taken when using any medications concomitantly with 
ATO. Since this list of medications can potentially change during the time this 
protocol is active, please refer to the following reference website for a current and 
complete list: 
https://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ 
 
These medications should be avoided during ATO therapy if other options exist. 
If these agents are used, they should be discontinued in any patient with normal 
serum electrolytes, calcium and magnesium who is found to have a 
QTc > 500 msec. Forty-eight hours after discontinuation of the agent, if the QTc 
remains > 500 msec or the patient is unable to discontinue these medications, the 
ATO must be discontinued. 
 
Azole antifungal medications may increase ATRA toxicity due to inhibition of 
cytochrome P-450 metabolism of ATRA, and thus toxicities (including 
pseudotumor cerebri and renal dysfunction) should be monitored closely during 
concomitant use. 
 
 
 

  
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Induction – Standard Risk 
4.2 
Induction – Standard Risk APL 
4.2.1a Induction Therapy Delivery Map – Standard Risk APL 
Standard Risk APL is defined as WBC < 10,000/µL at diagnosis.  
_________________________ 
_______________ 
 
Patient COG ID number 
DOB  
 
Induction lasts a minimum of 28 days and a maximum of 70 days See Section 4.2.3 for treatment details. This TDM is on 3 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 28 minimum.  
Continue up to Day 70 if not in 
hCR/hCRi. 
Total Dose: 25 mg/m2/day divided 
twice daily 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide (ATO) 
IV daily 
over 
2 hours* 
0.15 mg/kg/day 
1 - 28 minimum.  
Continue up to Day 70 if not in 
hCR/hCRi. 
*May lengthen infusion to 4 hours if 
active vasomotor symptoms occur. 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥ 3 yrs 
12 mg 
35 mg 
70 mg 
 
If CNS Disease: Twice weekly 
until CSF cleared plus 2 
additional twice weekly 
treatments (minimum of 4 and 
maximum of 6 treatments) 
 
If CNS Bleed: Day 29 only 
Only patients with CNS disease or 
CNS bleed will require intrathecal 
treatments (see Sections 3.3.4 and 
4.2.3 for details). 
 
Leucovorin (LCV) 
PO/IV 
10 mg/m2/dose 
CNS Disease ONLY: 
Leucovorin should be given 
24 hours after IT methotrexate. 
 
 
                                        
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations. 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
____mg 
ITT 
______mg (MTX) ______mg (HC) ______mg (ARAC) 
LCV 
_____mg  
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
____mg 
Only for patients with CNS disease (not CNS Bleed) give ITT twice weekly 
as directed (see Section 4.2.3 for details). 
Caution: Most patients will not need intrathecal treatment. Lumbar 
puncture is recommended only for patients with neurologic symptoms 
consistent with CNS disease and should not be performed until 
coagulopathy resolves. 
a-r*, s*, t* 
 
 
2 
_______mg 
_______mg 
____mg 
f, h, l 
 
 
3 
_______mg 
_______mg 
____mg 
f, h, l 
 
 
4 
_______mg 
_______mg 
____mg 
f, h, l 
 
 
5 
_______mg 
_______mg 
____mg 
f, h, l 
 
 
6 
_______mg 
_______mg 
____mg 
f, h, l 
 
 
7 
_______mg 
_______mg 
____mg 
Date CNS disease diagnosed:  _____________ 
 Date Given: __________  
______mg (MTX)  ______mg (HC)  ______mg (ARAC) 
 
 Date Given: __________ 
______mg (MTX)  ______mg (HC)  ______mg (ARAC) 
 
 
 Date Given: __________ 
______mg (MTX)  ______mg (HC)  ______mg (ARAC) 
 
 Date Given: __________ 
______mg (MTX)  ______mg (HC)  ______mg (ARAC) 
 
 
 Date Given: __________ 
______mg (MTX)  ______mg (HC)  ______mg (ARAC) 
 
 Date Given: __________ 
______mg (MTX)  ______mg (HC)  ______mg (ARAC) 
 
 
 
 
_____mg 
 
 
 
_____mg 
 
 
 
 
_____mg 
 
 
 
_____mg 
 
 
 
_____mg 
 
 
_____mg 
f, h, l 
 
 
8 
_______mg 
_______mg 
____mg 
b, f, h, j, l, m, t* 
 
 
9 
_______mg 
_______mg 
____mg 
 
 
 
10 
_______mg 
_______mg 
____mg 
 
 
 
11 
_______mg 
_______mg 
____mg 
 
 
 
12 
_______mg 
_______mg 
____mg 
 
 
 
13 
_______mg 
_______mg 
____mg 
 
 
 
14 
_______mg 
_______mg 
____mg 
 
 
 
15 
_______mg 
_______mg 
____mg 
b, f, h, j, l, m, t* 
 
 
16 
_______mg 
_______mg 
____mg 
 
 
 
17 
_______mg 
_______mg 
____mg 
 
 
 
18 
_______mg 
_______mg 
____mg 
 
 
 
19 
_______mg 
_______mg 
____mg 
 
 
 
20 
_______mg 
_______mg 
____mg 
 
 
 
21 
_______mg 
_______mg 
____mg 
 
 
 
22 
_______mg _______mg 
____mg 
b, f, h, j m 
 
 
23 
_______mg _______mg 
____mg 
 
 
 
24 
_______mg 
_______mg 
____mg 
 
 
 
25 
_______mg 
_______mg 
____mg 
 
 
 
26 
_______mg 
_______mg 
____mg 
 
 
 
27 
_______mg 
_______mg 
____mg 
 
 
 
28 
_______mg 
_______mg 
____mg 
 
 
 
29 
A bone marrow evaluation is performed on Day 29. If hCR/hCRi is achieved, proceed to Consolidation (see Section 4.3). 
If hCR/hCRi is not achieved on Day 29, continue with Induction (see Page 2 of this TDM). A bone marrow evaluation is 
done every 2 weeks until hCR/hCRi is achieved. When hCR/hCRi is achieved, proceed to Consolidation (see Section 4.3). b, c, f, h, j, l, m, 
o, s*, t* 
_______mg 
_______mg ____mg 
Day 29: Only for Patients with CNS Bleed 
(not CNS Disease): 
_____mg (MTX) _____mg (HC) _____mg (ARAC) 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
Page 1 of 3 

  
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AAML1331 
Version Date: 03-16-2018 
36 
Induction – Standard Risk 
4.2.1b Induction Therapy Delivery Map Continued – Standard Risk APL 
Standard Risk APL is defined as WBC < 10,000/µL at diagnosis. 
___________________ 
_____________ 
 
Patient COG ID number 
DOB 
 
Induction lasts a minimum of 28 days and a maximum of 70 days See Section 4.2.3 for treatment details. This TDM is on 3 pages 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
1 - 28 minimum.  
Continue up to Day 70 if not in 
hCR/hCRi. 
Total 
Dose: 
25 mg/m2/day 
divided, twice daily 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide 
(ATO) 
IV daily 
over 
2 hours* 
0.15 mg/kg/day 
1 - 28 minimum.  
Continue up to Day 70 if not in 
hCR/hCRi. 
*May lengthen infusion to 
4 hours if active vasomotor 
symptoms occur. 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥ 3 yrs 
12 mg 
35 mg 
70 mg 
 
If CNS Disease: Twice weekly until CSF 
cleared plus 2 additional twice weekly 
treatments (minimum of 4 and maximum 
of 6 treatments). 
 
If CNS Bleed: Day 29 only 
Only patients with CNS 
disease or CNS bleed will 
require intrathecal treatments 
(see Sections 3.3.4 and 4.2.3 
for details). 
Leucovorin (LCV) 
PO/IV 
10 mg/m2/dose 
CNS Disease ONLY: Leucovorin should 
be given 24 hours after IT methotrexate. 
 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations. 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
______mg 
ITT 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
LCV 
____mg  
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
30 
_______mg 
_______mg 
______mg 
Only for patients with CNS disease (not CNS Bleed) 
give ITT twice weekly as directed (see Section 4.2.3 for 
details). 
 
 
Caution: Most patients will not need intrathecal 
treatment. Lumbar puncture is recommended only for 
patients with neurologic symptoms consistent with CNS 
disease and should not be performed until 
coagulopathy resolves. 
 
 
 
 
 
 
NOTE: A MAXIMUM OF 6 TREATMENTS OF 
INTRATHECAL THERAPY SHOULD BE 
ADMINISTERED DURING INDUCTION 
 
ALL DOSES WILL BE RECORDED ON PAGE 1 
OF THIS TDM. 
 
 
 
 
31 
_______mg 
_______mg 
______mg 
 
 
 
32 
_______mg 
_______mg 
______mg 
 
 
 
33 
_______mg 
_______mg 
______mg 
 
 
 
34 
_______mg 
_______mg 
______mg 
 
 
 
35 
_______mg 
_______mg 
______mg 
 
 
 
36 
_______mg 
_______mg 
______mg 
b, f, h, j, m 
 
 
37 
_______mg 
_______mg 
______mg 
 
 
 
38 
_______mg 
_______mg 
______mg 
 
 
 
39 
_______mg 
_______mg 
______mg 
 
 
 
40 
_______mg _______mg 
______mg 
 
 
 
41 
_______mg _______mg 
______mg 
 
 
 
42 
_______mg 
_______mg 
______mg 
 
 
 
43 
_______mg 
_______mg 
______mg 
b, f, h, j, m, o 
 
 
44 
_______mg 
_______mg 
______mg 
 
 
 
45 
_______mg 
_______mg 
______mg 
 
 
 
46 
_______mg 
_______mg 
______mg 
 
 
 
47 
_______mg 
_______mg 
______mg 
 
 
 
48 
_______mg 
_______mg 
______mg 
 
 
 
49 
_______mg 
_______mg 
______mg 
 
 
 
50 
_______mg 
_______mg 
______mg 
b, f, h, j, m 
 
 
51 
_______mg 
_______mg 
______mg 
 
 
 
52 
_______mg 
_______mg 
______mg 
 
 
 
53 
_______mg 
_______mg 
______mg 
 
 
 
54 
_______mg 
_______mg 
______mg 
 
 
 
55 
_______mg 
_______mg 
______mg 
 
 
 
56 
_______mg 
_______mg 
______mg 
 
 
 
57 
_______mg 
_______mg 
______mg 
b, c, f, h, j, m, o 
 
 
58 
_______mg 
_______mg 
______mg 
 
 
 
59 
_______mg 
_______mg 
______mg 
 
 
 
60 
_______mg 
_______mg 
______mg 
 
 
 
61 
_______mg 
_______mg 
______mg 
 
 
 
62 
_______mg 
_______mg 
______mg 
 
 
 
63 
_______mg 
_______mg 
______mg 
 
 
 
64 
_______mg 
_______mg 
______mg 
b, f, h, j, m 
 
 
65 
_______mg 
_______mg 
______mg 
 
 
 
66 
_______mg 
_______mg 
______mg 
 
 
 
67 
_______mg 
_______mg 
______mg 
 
 
 
68 
_______mg 
_______mg 
______mg 
 
 
 
69 
_______mg 
_______mg 
______mg 
 
 
 
70 
_______mg 
_______mg 
______mg 
o 
 
 
 
A bone marrow evaluation is done every 2 weeks until hCR/hCRi is achieved. When hCR/hCRi is achieved, proceed to 
Consolidation (see Section 4.3). If hCR/hCRi is not achieved by Day 70, patient will go off protocol therapy. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  
Page 2 of 3 

  
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AAML1331 
Version Date: 03-16-2018 
37 
Induction – Standard Risk 
 
4.2.2 
Required Observations in Induction – Standard Risk APL 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below. Obtain other studies during Induction as 
indicated.  
 
a. 
History 
b. Physical Exam with VS: weekly 
c. 
Ht, Wt, BSA: Days 1, 29 and 57 
d. Performance status 
e. 
Pregnancy test: Female patients of childbearing potential require a negative pregnancy test 
prior to starting treatment; sexually active patients must use an acceptable method of birth 
control. 
f. 
CBC, differential, platelets: daily during Week 1, then at least once weekly 
g. Urinalysis 
h. Electrolytes including Ca++, Mg++, K+ and creatinine: daily during Week 1, then at least 
once weekly 
i. 
Uric Acid 
j. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): Once 
weekly 
k. Cholesterol triglycerides 
l. 
PT, PTT, fibrinogen, D-Dimer: daily during Week 1, then on Days 8, 15 and 29 (more 
frequently if needed for active coagulopathy) 
m. ECG for QTc monitoring: Weekly 
n. Echocardiogram or MUGA 
o. BMA for morphology: At diagnosis and Day 29 and every 2 weeks thereafter as needed 
until hCR/hCRi 
p. BMA for flow cytometry, cytogenetics & FISH: At diagnosis 
q. BMA for clinical RQ-PCR of PML-RARα: At diagnosis. This clinical testing is separate 
from research samples submitted for the optional MRD study; this mandatory clinical 
testing is not free of charge (cost is not covered by the study), but the specimen must be 
sent to one of the approved labs for PML-RARα RQ-PCR testing; a list of approved labs 
is available on the protocol-specific web page of the COG website. 
r. 
FLT3 (optional)*: bone marrow (or peripheral blood if bone marrow is unavailable) at 
diagnosis. See Section 15.1 for details. 
s. 
Research MRD (optional)*: bone marrow and peripheral blood at diagnosis and Day 29 
of Induction. See Section 15.2 for details. Results of this research testing will not be 
returned to sites. This research testing does not take the place of the mandatory RQ-PCR 
clinical testing that must be done at the time of initial diagnosis (see observation “q” 
above). 
t. 
Coagulopathy (optional)*: peripheral blood at diagnosis (if available), Day 1, Day 8, Day 
15 and Day 29 of Induction. See Section 15.3 for details. 
 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
Comments 
 
 
 
 
 
 
 
Page 3 of 3 

  
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AAML1331 
Version Date: 03-16-2018 
38 
Induction – Standard Risk 
4.2.3 
Induction Treatment Details – Standard Risk APL 
ATRA should be started at the time of first suspicion of APL diagnosis and ATO 
given (when available) on Day 1 of protocol directed therapy. 
 
Induction for standard risk APL consists of daily ATO and twice daily ATRA. 
Induction lasts at least 28 days (ATRA pre-treatment without ATO is not included 
in the 28 days). A bone marrow evaluation is performed on Day 29. Patients should 
remain on daily ATO/ATRA therapy while awaiting results of the Day 29 bone 
marrow hCR/hCRi assessment.  
 
If hCR/hCRi is achieved per the Day 29 bone marrow, patients stop daily induction 
therapy and proceed to Consolidation. If hCR/hCRi is not achieved, patients 
continue with Induction up to a maximum of 70 days, and a bone marrow 
evaluation is done every 2 weeks until hCR/hCRi is achieved. This end Induction 
determination of hematologic complete response is not dependent on results of 
genetic testing (such as cytogenetics, FISH or RQ-PCR testing). Patients who 
appear not to have achieved hematological complete remission after Day 43 of 
Induction may benefit from consultation for a rapid pathology review beginning 
with the Day 57 marrow sample (See Section 13 for details). 
 
Induction ends with the confirmation of an hCR/hCRi and after a minimum of 
28 days of induction. When hCR/hCRi is achieved the patient proceeds to 
Consolidation Cycle 1 (see Section 4.3). Following completion of Induction, 
Consolidation starts a minimum of 14 days from the end of Induction or when 
blood counts have recovered (ANC ≥ 1,000/μL and platelets ≥ 100,000/μL), 
whichever occurs later. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 28 minimum. Continue beyond Day 28 if not in hCR/hCRi up to a 
maximum of 70 days (See Section 10.2 for response criteria and definition of 
hCR/hCRi). 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). Guidance for administration of 
tretinoin by parents/caregivers can be found in Appendix III. 
Note: If the patient received pre-treatment with ATRA prior to starting Day 1 of 
protocol directed therapy (see Section 3.2.3), these pre-treatment doses are not 
considered part of the required 28 days minimum of induction protocol therapy.  
 
Arsenic Trioxide (ATO): IV daily over 2 hours (may lengthen infusion to 
4 hours if active vasomotor symptoms occur) 
Days: 1 - 28 minimum. Continue beyond Day 28 if not in hCR/hCRi up to a 
maximum of 70 days (See Section 10.2 for response criteria and definition of 
hCR/hCRi). 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
 
 
 

  
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AAML1331 
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39 
Induction – Standard Risk 
Indications for intrathecal therapy 
 
CNS Bleed 
Patients with documented CNS bleed will receive CNS prophylaxis to include 
triple intrathecal chemotherapy at Day 29 of Induction. See table below for 
age- based dosing. 
 
CNS Disease 
Patients with CNS disease (see Section 3.3.4 for definition) will receive twice 
weekly triple intrathecal chemotherapy (with a minimum interval of 48 hours 
between treatments) until the CSF is cleared plus two additional twice weekly 
treatments (minimum of 4 and maximum of 6 treatments). During Induction, 
patients with CNS disease will also receive a 10 mg/m2 dose of leucovorin, 24 
hours after each of the twice weekly triple intrathecal therapies. 
 
Age-based dosing of triple intrathecal therapy: 
 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3years 
12 mg 
35 mg 
70 mg 
 
4.2.3.1 Management of Leukocytosis during Induction  
 
If the WBC rises above 10,000/L during the first 28 days of Induction, 
hydroxyurea and dexamethasone should be started to control the 
leukocytosis and reduce the risk of differentiation syndrome symptoms. If 
the patient develops actual symptoms of differentiation syndrome, refer to 
Section 5.1 for recommendations on diagnosis and management of 
differentiation syndrome including treatment dosing of dexamethasone. 
Dosing is as follows: 
 
Dexamethasone:  
Days: As needed only if WBC rises above 10,000/L; discontinue when 
WBC falls below 10,000/L.  
Dose: 2.5 mg/m2/dose twice daily PO/IV 
Note: This is prophylaxis dosing of dexamethasone.  
 
Hydroxyurea: 
Days: As needed only if WBC rises above 10,000/L; discontinue when 
WBC falls below 10,000/L.  
Dose: 
For WBC ≥ 10,000/L: 30 mg/kg/dose (maximum, 1,000 mg/dose) PO 
four times daily. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 

  
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AAML1331 
Version Date: 03-16-2018 
40 
Consolidation Cycle 1 – Standard Risk 
Page 1 of 2 
 
4.3 
Consolidation Cycle 1 – Standard Risk APL 
4.3.1 
Consolidation Therapy Delivery Map Cycle 1 – Standard Risk APL 
Consolidation Cycle 1 starts a minimum of 14 days after end of Induction therapy or when blood 
counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
________________ 
________ 
 Patient COG ID number 
DOB  
 
Consolidation Cycle 1 lasts 8 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 and 
29 - 42 
Total Dose: 25 mg/m2/day divided twice 
daily. 
 
Administer with food. Refer to Appendix II 
for dosing table 
Arsenic Trioxide (ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.3.3 for additional details 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥3 yrs 
12 mg 
35 mg 
70 mg 
 
15 and 43 
Only patients with documented CNS 
disease or CNS bleed will require 
intrathecal treatments (see Sections 3.3.4 
and 4.3.3 for details). 
 
Ht _________cm  
Wt _________kg  
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
_______mg 
ITT 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
_______mg 
Only patients with CNS disease or CNS bleed will 
require intrathecal treatments (see Sections 3.3.4 and 
4.3.3 for details) 
a – g, h* 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
 
c, d, e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
 
15 
 
_______mg 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
 
17 
 
_______mg 
 
 
 
 
18 
 
_______mg 
 
 
 
 
19 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
22 
 
_______mg 
 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
 
24 
 
_______mg 
 
 
 
 
25 
 
_______mg 
 
 
 
 
26 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
29 
_______mg 
_______mg 
 
 
a, c, e 
 
 
--- 
 
 
 
 
 
 
42 
_______mg 
_______mg 
 
 
 
 
 
43 
 
 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
 
 
 
--- 
--- 
--- 
 
 
 
 
56 
 
 
 
 
 
 
57 
Proceed to Consolidation Cycle 2 (see Section 4.4) on Day 57 or when blood counts recover (ANC ≥ 1,000/L 
and platelet count ≥ 100,000/L), whichever occurs later 
 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 

  
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41 
Consolidation Cycle 1 – Standard Risk 
Page 2 of 2 
 
4.3.2 
Required Observations in Consolidation Cycle 1 – Standard Risk APL 
 
 
a. 
Physical Exam with VS: Every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly while receiving ATO and on Day 29. 
d. Electrolytes including Ca++, Mg++, K+ and Creatinine: Weekly while receiving ATO. 
e. 
Total bilirubin (and direct bilirubin if total is > 2 mg/dL), AST, ALT: Weekly while 
receiving ATO and on Day 29. 
f. 
ECG for QTc monitoring: Weekly while receiving ATO. 
g. Cholesterol, triglycerides 
h. Neurocognitive Testing (optional)*: CogState and BRIEF on Day 1 of Consolidation 
Cycle 1 (+/- 2 weeks). See Section 16 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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AAML1331 
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42 
Consolidation Cycle 1 – Standard Risk 
 
4.3.3 
Consolidation Cycle 1 Treatment Details – Standard Risk APL 
Consolidation Cycle 1 lasts 56 days.  
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 and 29 - 42 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
 
Indications for intrathecal therapy 
 
Intrathecal Triple Therapy (ITT): Only for patients with documented history of 
CNS bleed or CNS positive disease. 
 
Days: 15 and 43 
Dose: Age based dosing as follows: 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3 years 
12 mg 
35 mg 
70 mg 
 
Proceed to Consolidation Cycle 2 on Day 57 or when blood counts recover (ANC ≥ 
1,000/L and platelet count ≥ 100,000/L), whichever occurs later. See 
Section 4.4 for details. 
 

  
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43 
Consolidation Cycle 2 – Standard Risk 
Page 1 of 2 
4.4 
Consolidation Cycle 2 – Standard Risk APL 
4.4.1 
Consolidation Therapy Delivery Map Cycle 2 – Standard Risk APL 
Consolidation Cycle 2 starts on Day 57 of Cycle1 or when blood counts recover (ANC 
≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
_____________________ ___________ 
 Patient COG ID number 
DOB  
 
Consolidation Cycle 2 lasts 8 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 and 29 - 42 
Total Dose: 25 mg/m2/day divided 
twice daily. 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide (ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.4.3 for additional details 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥ 3 yrs 
12 mg 
35 mg 
70 mg 
 
15 and 43 
Only patients with documented 
CNS disease or CNS bleed will 
require intrathecal treatments (see 
Sections 3.3.4 and 4.4.3 for 
details). 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
_______mg 
ITT 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
_______mg 
Only patients with CNS disease or CNS bleed will 
require intrathecal treatments (see Sections 3.3.4 and 
4.4.3 for details) 
a – g 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
 
c, d, e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
 
15 
 
_______mg 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
 
17 
 
_______mg 
 
 
 
 
18 
 
_______mg 
 
 
 
 
19 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
22 
 
_______mg 
 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
 
24 
 
_______mg 
 
 
 
 
25 
 
_______mg 
 
 
 
 
26 
 
_______mg 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
_______mg 
_______mg 
 
 
a, c, e 
 
 
--- 
 
 
 
 
 
 
42 
_______mg 
_______mg 
 
 
 
 
 
43 
 
 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
h, i*, j* 
 
 
44 
 
 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
56 
 
 
 
 
 
 
57 
A bone marrow evaluation is performed for clinical RQ-PCR of PML-RARα  on Day 43. If negative continue to 
Consolidation Cycle 3 (Section 4.6) on Day 57 of this cycle. If positive, repeat 1-2 weeks later. If repeat test is 
negative continue to Consolidation Cycle 3 (see Section 4.6) on Day 57 of this cycle. If repeat test is confirmed 
positive continue to MRD Positive Consolidation Cycle (see Section 4.5) on Day 57 of this cycle. 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  

  
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44 
Consolidation Cycle 2 – Standard Risk 
Page 2 of 2 
 
4.4.2 
Required Observations in Consolidation Cycle 2 – Standard Risk APL 
 
 
a. 
Physical Exam with VS: Every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly while receiving ATO and on Day 29. 
d. Electrolytes including Ca++, Mg++, K+ and creatinine: Weekly while receiving ATO 
e. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): 
Weekly while receiving ATO and on Day 29. 
f. 
ECG for QTc monitoring: Weekly while receiving ATO 
g. Cholesterol, triglycerides 
h. BMA for clinical RQ-PCR of PML-RARα: Obtain on Day 43 of Consolidation Cycle 2. 
This testing is separate from research samples submitted for the optional MRD study; 
this mandatory clinical testing is not free of charge and the cost is not covered by the 
study, but the specimen must be sent to one of the approved labs for PML-RARα RQ-
PCR testing; a list of approved labs is available on the protocol-specific web page of the 
COG website. If the initial test is positive, contact the study chair and a repeat sample 
must be sent 1-2 weeks later. This testing is not paid for by the study, but it is 
recommended that this confirmation sample be sent to either Hematologics, Inc, Seattle, 
WA, USA or the Molecular Haematology Lab, Royal Prince Alfred Hospital, NSW, 
Australia due to their experience with these samples. 
i. 
FLT3 (optional)*: bone marrow on Day 43 of Consolidation Cycle 2. See Section 15.1 
for details. 
j. 
Research MRD (optional)*: bone marrow and peripheral blood on Day 43 of 
Consolidation Cycle 2. See Section 15.2 for details. Results of this research testing will 
not be returned to the sites. 
*Only obtain in patients who have consented to participation in this component of the trial. 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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45 
Consolidation Cycle 2 – Standard Risk 
4.4.3 
Consolidation Cycle 2 Treatment Details – Standard Risk APL 
Consolidation Cycle 2 lasts 56 days. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 and 29 - 42 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if active 
vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to arrange home 
infusion) and holidays may result in intermittent clinic closure. Therefore it is permissible 
for patients to miss doses of ATO on those days at the discretion of the treating physician. 
It is suggested that patients not miss more than 2 doses in a 4 week period (10% of doses). 
If more than 2 doses are missed in a 4 week period due to holidays, then make-up doses 
(following Day 26) may be administered at the discretion of the treating physician. 
 
Indications for intrathecal therapy 
Intrathecal Triple Therapy (ITT): Only for patients with documented history of CNS bleed 
or CNS positive disease. 
 
Days: 15 and 43 
Dose: Age based dosing as follows 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3 years 
12 mg 
35 mg 
70 mg 
 
Disease Evaluation: 
A clinical bone marrow evaluation is performed for RQ-PCR of PML-RARα on Day 43. 
This testing is separate from research samples submitted for the optional MRD study; this 
mandatory clinical testing is not free of charge (cost is not covered by the study), but the 
specimen must be sent to one of the approved labs for PML-RARα RQ-PCR testing. A list 
of approved labs is available on the protocol-specific web page of the COG website. If 
initial clinical RQ-PCR testing is negative continue to Consolidation Cycle 3 (Section 4.6) 
on Day 57 of this cycle or when blood counts recover (ANC ≥ 1,000/L and platelet count 
≥ 100,000/L), whichever occurs later.  If the initial clinical RQ-PCR test is positive, 
contact the study chair and a repeat sample must be sent 1-2 weeks later. This testing is not 
paid for by the study, but it is recommended that this confirmation sample be sent to either 
Hematologics, Inc, Seattle, WA, USA or the Molecular Haematology Lab, Royal Prince 
Alfred Hospital, NSW, Australia due to their experience with these samples. If repeat test 
is negative continue to Consolidation Cycle 3 (see Section 4.6) on Day 57 of this cycle. If 
repeat test is confirmed positive continue to MRD Positive Consolidation (Section 4.5) on 
Day 57 of this cycle. 
 

  
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46 
MRD Positive Consolidation – Standard Risk 
 
 
 
 
 
 
 
 
 
MRD Positive Consolidation is only for those patients 
with RQ-PCR of PML-RARα confirmed positive after 
Consolidation Cycle 2.  
 
 
 
 
 
If the RQ-PCR of PML-RARα is negative after 
Consolidation Cycle 2, proceed to Consolidation 
Cycle 3 (see Section 4.6) 
 
 
 
 

  
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MRD Positive Consolidation – Standard Risk 
Page 1 of 2 
4.5 
MRD Positive Consolidation – Standard Risk APL 
4.5.1 
MRD Positive Consolidation Therapy Delivery Map – Standard Risk APL  
MRD Positive Consolidation is only for those patients with RQ-PCR of PML-RARα 
confirmed positive after Consolidation Cycle 2. Start on Day 57 of Cycle 2 or when blood 
counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
 
_______________________ 
 Patient COG ID number 
____________ 
DOB  
This course lasts 28 days. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
High Dose Cytarabine 
(HD ARAC) 
IV over 1-3 hours every 
12 hours 
1000 mg/m2/dose, twice daily 
 
if BSA < 0.6m2, 33.3 mg/kg/dose, 
twice daily 
1 - 4 
Total dose: 2000 mg/m2/day, divided twice 
daily or 66.6 mg/kg/day, divided twice daily 
if BSA < 0.6 m2.  
Use eye drops as described in Section 4.5.3. 
MitoXANtrone 
(MITOX) 
IV daily over 15-30 minutes 
12 mg/m2/dose 
 
If BSA < 0.6 m2, 0.4 mg/kg/dose daily 
3 – 6 
On Days 3 and 4, administer 8 hours after the 
5th and 7th cytarabine infusions are 
completed. See Section 4.5.3 for details. 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14  
Total Dose: 25 mg/m2/day divided twice 
daily. 
 
Administer with food. Refer to Appendix II 
for dosing table. 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
HD ARAC 
_______mg 
_______mg 
MITOX 
_______mg 
ATRA 
_______mg 
_______mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
 
_______mg 
_______mg 
 a – g 
 
 
2 
_______mg 
_______mg 
 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
_______mg 
_______mg 
 
 
 
5 
 
_______mg 
_______mg 
_______mg 
 
 
 
6 
 
_______mg 
_______mg 
_______mg 
 
 
 
7 
 
 
_______mg 
_______mg 
 
 
 
8 
 
 
_______mg 
_______mg 
c, d, e 
 
 
9 
 
 
_______mg 
_______mg 
 
 
 
10 
 
 
_______mg 
_______mg 
 
 
 
11 
 
 
_______mg 
_______mg 
 
 
 
12 
 
 
_______mg 
_______mg 
 
 
 
13 
 
 
_______mg 
_______mg 
 
 
 
14 
 
 
_______mg 
_______mg 
 
 
 
15 
 
 
 
c, d, e 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
c, d, e 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
A bone marrow evaluation will be done for clinical RQ-PCR of PML-RARα. If negative, continue to Consolidation 
Cycle 3 (see Section 4.6). If positive in 2 successive specimens, patient will go off protocol therapy. 
a, c, h 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  
 

  
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MRD Positive Consolidation – Standard Risk 
Page 2 of 2 
4.5.2 
Required Observations in MRD Positive Consolidation – Standard Risk APL 
 
 
a. Physical Exam with VS: every 4 weeks 
b. Ht, Wt, BSA 
c. CBC, differential, platelets: Weekly  
d. Electrolytes and creatinine: Weekly 
e. AST, ALT, Total Bilirubin (and prior to Mitoxantrone a Direct Bilirubin if 
Total Bilirubin is >3.3 mg/dL): Weekly 
f. Cholesterol, triglycerides 
g. Echocardiogram or MUGA 
h. BMA for mandatory clinical RQ-PCR of PML-RARα: Obtain on Day 29. If 
sample is positive, repeat 1 - 2 weeks later. This testing is not paid for by the 
study. It is recommended that this testing be sent to either Hematologics, Inc, 
Seattle, WA, USA or the Molecular Haematology Lab, Royal Prince Alfred 
Hospital, NSW, Australia due to their experience with these samples. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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49 
MRD Positive Consolidation – Standard Risk 
 
4.5.3 
MRD Positive Consolidation Treatment Details – Standard Risk APL 
MRD Positive Consolidation consists of a combination of high dose cytarabine, 
mitoxantrone and twice daily ATRA. This cycle lasts for 28 days. It is strongly 
recommended that the patients remain inpatient for the duration of this cycle of 
Consolidation and until count recovery.  
 
Antifungal prophylaxis should be strongly considered (dependent on institutional 
practice) during this cycle due to an expected prolonged period of neutropenia. 
However, treating physicians should be aware that azole antifungal medications 
may increase ATRA toxicity due to inhibition of cytochrome P - 450 metabolism 
of ATRA. Thus patients should be monitored closely for adverse events such as, 
pseudotumor cerebri or renal dysfunction, during periods of concomitant use. For 
prophylactic antifungal use, initiation of an azole antifungal could be delayed until 
after completion of ATRA on Day 14 of this cycle or an alternate non-azole 
antifungal should be considered. 
 
High Dose Cytarabine: IV over 1 - 3 hours every 12 hours 
Days: 1 - 4 (8 total doses) 
Dose: 1,000 mg/m2/dose every 12 hours. If BSA < 0.6 m2, 33.3 mg/kg/dose. 
 
NOTE: 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 final dose. If patient does 
not tolerate steroid eye drops, may administer artificial tears on an every 2 - 4 hour 
schedule. 
 
MitoXANtrone: IV daily over 15 - 30 minutes 
Days: 3 - 6 
Dose: 12 mg/m2/dose once daily. If BSA < 0.6 m2 0.4 mg/kg/dose. 
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 Days 3 and 4, 
mitoxantrone should be given 8 hours after the 5th and 7th high dose cytarabine 
infusions are complete. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
A bone marrow evaluation will be done for clinical RQ-PCR of PML-RARα on 
Day 29. This testing is not paid for by the study, but it is recommended that this 
testing be sent to either Hematologics, Inc, Seattle, WA, USA or the Molecular 
Haematology Lab, Royal Prince Alfred Hosptial, NSW, Australia due to their 
experience with these samples. If negative, continue to Consolidation Cycle 3 (see 
Section 4.6) on Day 29 or when blood counts recover (ANC ≥ 1,000/L and 
platelet count ≥ 100,000/L), whichever occurs later. If positive, repeat 1 - 2 weeks 
later and if second test is positive then patient will go off protocol therapy. 
 

  
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50 
Consolidation – Cycle 3 – Standard Risk 
Page 1 of 2 
4.6 
Consolidation Cycle 3 – Standard Risk APL 
4.6.1 
Consolidation Therapy Delivery Map Cycle 3 – Standard Risk APL 
Start Consolidation Cycle 3 only if RQ-PCR of PML-RARα is negative. Cycle 3 starts on Day 
57 of Cycle 2 or when blood counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), 
whichever occurs later. OR Consolidation Cycle 3 starts on Day 29 of MRD Positive 
Consolidation cycle if needed or when blood counts recover (ANC ≥ 1,000/L and platelet 
count ≥ 100,000/L), whichever occurs later. 
__________________ _________ 
 Patient COG ID number 
DOB  
 
Consolidation Cycle 3 lasts 8 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 and 29 - 42 
Total Dose: 25 mg/m2/day divided 
twice daily. 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide (ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.6.3 for additional details 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥3 yrs 
12 mg 
35 mg 
70 mg 
 
15 and 43 
Only patients with documented 
CNS disease or CNS bleed will 
require intrathecal treatments (see 
Sections 3.3.4 and 4.6.3 for 
details). 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
1 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
____mg 
ITT 
_____mg (MTX) _____mg (HC) _____mg (ARAC)  
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
_______mg 
Only patients with CNS disease or CNS bleed 
will require intrathecal treatments (see 
Sections 3.3.4 and 4.6.3 for details) 
a – g, h* 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
 
c, d. e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
 
15 
 
_______mg 
_____mg (MTX) _____mg (HC) _____mg (ARAC)  
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
 
17 
 
_______mg 
 
 
 
 
18 
 
_______mg 
 
 
 
 
19 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
22 
 
_______mg 
 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
 
24 
 
_______mg 
 
 
 
 
25 
 
_______mg 
 
 
 
 
26 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
29 
_______mg 
_______mg 
 
 
a, c, e 
 
 
--- 
 
 
 
 
 
 
42 
_______mg 
_______mg 
 
 
 
 
 
43 
 
 
_____mg (MTX) _____mg (HC) _____mg (ARAC) 
 
 
 
--- 
--- 
--- 
 
 
 
 
56 
 
 
 
 
 
 
57 
Proceed to Consolidation Cycle 4 (see Section 4.7) on Day 57 or when blood counts recover (ANC 
≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 

  
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Consolidation – Cycle 3 – Standard Risk 
Page 2 of 2 
4.6.2 
Required Observations in Consolidation Cycle 3 – Standard Risk APL 
 
 
a. 
Physical Exam with VS: every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly while receiving ATO and on Day 29. 
d. Electrolytes including Ca++, Mg++, K+ and creatinine: Weekly while receiving ATO 
e. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): 
Weekly while receiving ATO and on Day 29. 
f. 
ECG for QTc monitoring: Weekly while receiving ATO 
g. Cholesterol, triglycerides 
h. Neurocognitive Testing (optional)*: CogState and BRIEF on Day 1 of Consolidation 
Cycle 3 (+/-2 weeks). See Section 16 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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52 
Consolidation – Cycle 3 – Standard Risk 
 
4.6.3 
Consolidation Cycle 3 Treatment Details – Standard Risk APL 
Consolidation Cycle 3 lasts 56 days. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 and 29 - 42 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
Indications for intrathecal therapy 
 
Intrathecal Triple Therapy (ITT): Only for patients with documented history of 
CNS bleed or CNS positive disease. 
 
Days: 15 and 43 
Dose: Age based dosing as follows 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3years 
12 mg 
35 mg 
70 mg 
 
Proceed to Consolidation Cycle 4 on Day 57 or when blood counts recover 
(ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. See 
Section 4.7 for details. 
 
 

  
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Consolidation – Cycle 4 – Standard Risk 
Page 1 of 2 
4.7 
Consolidation Cycle 4 – Standard Risk APL 
4.7.1 
Consolidation Therapy Delivery Map Cycle 4 – 
Standard Risk APL 
Consolidation Cycle 4 starts on Day 57 of Cycle 3 or when blood 
counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), 
whichever occurs later. 
______________________ 
_____________ 
 
Patient COG ID number 
DOB  
 
Consolidation Cycle 4 lasts 4 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 
Total Dose: 25 mg/m2/day divided 
twice daily 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide 
(ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.7.3 for additional details 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations. 
 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
_______mg 
Studies 
Comments (Include any 
held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
_______mg 
_______mg 
_______mg 
a – g 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
c, d, e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
15 
 
_______mg 
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
17 
 
_______mg 
 
 
 
18 
 
_______mg 
 
 
 
19 
 
_______mg 
 
 
 
--- 
--- 
--- 
 
 
 
22 
 
_______mg 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
24 
 
_______mg 
 
 
 
25 
 
_______mg  
 
 
 
26 
 
_______mg 
 
 
 
27 
--- 
--- 
 
 
 
28 
 
 
a, c, h, i, j*,k* 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 

  
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54 
Consolidation – Cycle 4 – Standard Risk 
Page 2 of 2 
4.7.2 
Required Observations in Consolidation Cycle 4 – Standard Risk APL 
 
a. 
Physical Exam with VS: Days 1 and 28 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly 
d. Electrolytes including Ca++, Mg++, K+ and creatinine: Weekly while receiving ATO 
e. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): 
Weekly while receiving ATO 
f. 
ECG for QTc monitoring: Weekly while receiving ATO 
g. Cholesterol, triglycerides 
h. Echocardiogram or MUGA: at the end of protocol therapy 
i. 
BMA for clinical RQ-PCR of PML-RARα: at the end of protocol therapy. This 
clinical testing is separate from research samples submitted for the optional MRD 
study; this mandatory clinical testing is not free of charge and the cost is not 
covered by the study, but the specimen must be sent to one of the approved labs for 
PML-RARα RQ-PCR testing; a list of approved labs is available on the protocol-
specific web page of the COG website. 
j. 
Research MRD (optional)*: bone marrow and peripheral blood at the end of protocol 
therapy. See Section 15.2 for details. 
k. Neurocognitive Testing (optional)*: CogState, BRIEF and the psychologist 
administered battery at the end of protocol therapy (up to 3 months after the end of 
protocol therapy). See Section 16 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Consolidation – Cycle 4 – Standard Risk 
 
4.7.3 
Consolidation Cycle 4 Treatment Details – Standard Risk APL 
Consolidation Cycle 4 lasts 28 days. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
A bone marrow evaluation is performed for clinical RQ-PCR of PML-RARα on 
Day 28. This testing is separate from research samples submitted for the optional 
MRD study; this mandatory clinical testing is not free of charge (cost is not 
covered by the study), but the specimen must be sent to one of the approved labs 
for PML-RARα RQ-PCR testing; a list of approved labs is available on the 
protocol-specific web page of the COG website. 
 
 
 
 

  
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56 
Induction – High Risk 
Page 1 of 3 
 
4.8 
Induction – High Risk APL 
4.8.1a Induction Therapy Delivery Map – High Risk APL 
High Risk APL is defined as WBC ≥ 10,000/µL at diagnosis. 
___________________________ 
______________ 
 
Patient COG ID number 
DOB 
This course lasts 28 days (beyond Day 28 up to 70 days if not in hCR/hCRi) See Section 4.8.3 for treatment details. This TDM is on 3 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
1 - 28 minimum.  
Continue up to Day 70 if not in 
hCR/hCRi. 
Total Dose: 25 mg/m2/day divided 
twice daily 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide (ATO) 
IV daily over 
2 hours* 
0.15 mg/kg/day 
1 - 28 minimum.  
Continue up to Day 70 if not in 
hCR/hCRi. 
*May lengthen infusion to 4 hours 
if active vasomotor symptoms 
occur. 
IDArubicin 
(IDA) 
IV bolus over 
15 minutes 
12 mg/m2/dose 
(NOTE: if BSA < 0.6 m2, 0.4 mg/kg/dose) 
1, 3, 5, 7 
 
Dexamethasone (DEX) 
PO/IV 
2.5 mg/m2/dose, twice daily 
1 - 14 
Total Dose: 5 mg/m2/day divided 
twice daily 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥3 yrs 
12 mg 
35 mg 
70 mg 
 
If CNS Disease: Twice weekly 
until CSF cleared plus 2 
additional twice weekly 
treatments (minimum of 4 and 
maximum of 6 treatments). 
 
If CNS Bleed: Day 29 only 
Only patients with CNS disease or 
CNS bleed will require intrathecal 
treatments (see Sections 3.3.4 and 
4.8.3 for details). 
 
Leucovorin (LCV) 
PO/IV 
10 mg/m2/dose 
CNS Disease ONLY: 
Leucovorin should be given 
24 hours after IT methotrexate. 
 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
____mg ____mg 
ATO 
____mg 
IDA 
___mg 
DEX 
___mg 
ITT 
____mg (MTX) ____mg (HC) ____mg (ARAC)  
LCV 
___mg  
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
____mg ____mg 
____mg 
___mg 
___mg Only for patients with CNS disease (not CNS Bleed) give ITT 
twice weekly as directed (see Section 4.8.3 for details). 
Caution: Most patients will not need intrathecal treatment. 
Lumbar puncture is recommended only for patients with 
neurologic symptoms consistent with CNS disease and should 
not be performed until coagulopathy resolves. 
a-r*, s*, t* 
 
 
2 
____mg ____mg 
____mg 
 
___mg 
f, h, l  
 
 
3 
____mg ____mg 
____mg 
___mg 
___mg 
f, h, l 
 
 
4 
____mg ____mg 
____mg 
 
___mg 
f, h, l 
 
 
5 
____mg ____mg 
____mg 
___mg 
___mg 
f, h, l 
 
 
6 
____mg ____mg 
____mg 
 
___mg 
f, h, l 
 
 
7 
____mg ____mg 
____mg 
___mg 
___mg  
Date CNS disease diagnosed:  _____________ 
 Date Given: __________  
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 Date Given: __________ 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 
 Date Given: __________ 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 Date Given: __________ 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 
 Date Given: __________ 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 Date Given: __________ 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 
 
 
 
___mg 
 
 
 
___mg 
 
 
 
 
___mg 
 
 
 
___mg 
 
 
 
___mg 
 
 
 
___mg 
f, h, l 
 
 
8 
____mg ____mg 
____mg  
___mg 
b, f, h, j, l, m, t* 
 
 
9 
____mg ____mg 
____mg  
___mg 
 
 
 
10 
____mg ____mg 
____mg  
___mg 
 
 
 
11 
____mg ____mg 
____mg  
___mg 
 
 
 
12 
____mg ____mg 
____mg  
___mg 
 
 
 
13 
____mg ____mg 
____mg  
___mg 
 
 
 
14 
____mg ____mg 
____mg  
___mg 
 
 
 
15 
____mg ____mg 
____mg  
 
b, f, h, j, l, m, t* 
 
 
16 
____mg ____mg 
____mg  
 
 
 
 
17 
____mg ____mg 
____mg  
 
 
 
 
18 
____mg ____mg 
____mg  
 
 
 
 
19 
____mg ____mg 
____mg  
 
 
 
 
20 
____mg ____mg 
____mg  
 
 
 
 
21 
____mg ____mg 
____mg  
 
 
 
 
22 
____mg ____mg 
____mg  
 
b, f, h, j, m 
 
 
23 
____mg ____mg 
____mg  
 
 
 
 
24 
____mg ____mg 
____mg  
 
 
 
 
25 
____mg ____mg 
____mg  
 
 
 
 
26 
____mg ____mg 
____mg  
 
 
 
 
27 
____mg ____mg 
____mg  
 
 
 
 
28 
____mg ____mg 
____mg  
 
 
 
 
29 
A bone marrow evaluation is performed on Day 29. If hCR/hCRi is achieved, proceed to Consolidation (see Section 4.9). 
If hCR/hCRi is not achieved on Day 29, continue with Induction (see Page 2 of this TDM). A bone marrow evaluation is 
done every 2 weeks until hCR/hCRi is achieved. When hCR/hCRi is achieved, proceed to Consolidation (see Section 4.9). b, c, f, h, j, l, m, 
o, s*, t* 
____mg ____mg 
____mg 
 
 
Day 29: Only for Patients with CNS Bleed  
(not CNS Disease): 
____mg (MTX) ____mg (HC) ____mg (ARAC) 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 

  
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57 
Induction – High Risk 
 
4.8.1b Induction Therapy Delivery Map Continued– High Risk APL 
High Risk APL is defined as WBC ≥ 10,000/µL at diagnosis. 
_______________________ ______________ 
Patient COG ID number 
DOB  
This course lasts 28 days (beyond Day 28 up to 70 days if not in hCR/hCRi) See Section 4.8.3 for treatment details. This TDM is on 3 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 28 minimum. 
Continue up to Day 70 if not in 
hCR/hCRi. 
Total 
Dose: 
25 mg/m2/day 
divided twice daily 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide 
(ATO) 
IV daily over 
2 hours* 
0.15 mg/kg/day 
1 - 28 minimum. 
Continue up to Day 70 if not in 
hCR/hCRi. 
*May lengthen infusion to 
4 hours if active vasomotor 
symptoms occur. 
IDArubicin 
(IDA) 
IV bolus over 
15 minutes 
12 mg/m2/dose 
NOTE: if BSA < 0.6 m2, 0.4 mg/kg/dose 
1, 3, 5, 7 
 
Dexamethasone 
(DEX) 
PO/IV 
2.5 mg/m2/dose, twice daily 
1 - 14 
Total Dose: 5 mg/m2/day 
divided twice daily 
Triple Intrathecal 
Therapy (ITT) 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥3 yrs 
12 mg 
35 mg 
70 mg 
 
If CNS Disease: Twice weekly until 
CSF cleared plus 2 additional twice 
weekly treatments (minimum of 4 
and maximum of 6 treatments). 
If CNS Bleed: Day 29 only 
Only patients with CNS 
disease or CNS bleed will 
require intrathecal treatments 
(see Section 3.3.4 and 4.8.3 for 
details). 
Leucovorin (LCV) 
PO/IV 
10 mg/m2/dose 
CNS Disease ONLY: Leucovorin 
should be given 24 hours after IT 
methotrexate. 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations  
Date 
Due 
Date 
Given 
Day 
ATRA 
______mg 
______mg 
ATO 
_____mg 
ITT 
____mg (MTX) ____mg (HC) _____mg (ARAC) 
LCV 
_______mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
30 
______mg 
______mg 
_____mg 
Only for patients with CNS disease (not CNS Bleed) 
give ITT twice weekly as directed (see Section 4.8.3 for 
details). 
 
 
Caution: Most patients will not need intrathecal 
treatment. Lumbar puncture is recommended only for 
patients with neurologic symptoms consistent with CNS 
disease and should not be performed until coagulopathy 
resolves. 
 
 
 
 
 
 
NOTE: A MAXIMUM OF 6 TREATMENTS OF 
INTRATHECAL THERAPY SHOULD BE 
ADMINISTERED DURING INDUCTION 
 
ALL DOSES WILL BE RECORDED ON PAGE 1 OF 
THIS TDM. 
 
 
 
31 
______mg 
______mg 
_____mg 
 
 
 
32 
______mg 
______mg 
_____mg 
 
 
 
33 
______mg 
______mg 
_____mg 
 
 
 
34 
______mg 
______mg 
_____mg 
 
 
 
35 
______mg 
______mg 
_____mg 
 
 
 
36 
______mg 
______mg 
_____mg 
b, f, h, j, m 
 
 
37 
______mg 
______mg 
_____mg 
 
 
 
38 
______mg 
______mg 
_____mg 
 
 
 
39 
______mg 
______mg 
_____mg 
 
 
 
40 
______mg 
______mg 
_____mg 
 
 
 
41 
______mg 
______mg 
_____mg 
j 
 
 
42 
______mg 
______mg 
_____mg 
 
 
 
43 
______mg 
______mg 
_____mg 
b, f, h, j, m, o 
 
 
44 
______mg 
______mg 
_____mg 
 
 
 
45 
______mg 
______mg 
_____mg 
 
 
 
46 
______mg 
______mg 
_____mg 
 
 
 
47 
______mg 
______mg 
_____mg 
 
 
 
48 
______mg 
______mg 
_____mg 
 
 
 
49 
______mg 
______mg 
_____mg 
 
 
 
50 
______mg 
______mg 
_____mg 
b, f, h, j, m 
 
 
51 
______mg 
______mg 
_____mg 
 
 
 
52 
______mg 
______mg 
_____mg 
 
 
 
53 
______mg 
______mg 
_____mg 
 
 
 
54 
______mg 
______mg 
_____mg 
 
 
 
55 
______mg 
______mg 
_____mg 
 
 
 
56 
______mg 
______mg 
_____mg 
 
 
 
57 
______mg 
______mg 
_____mg 
b, c, f, h, j, m, o 
 
 
58 
______mg 
______mg 
_____mg 
 
 
 
59 
______mg 
______mg 
_____mg 
 
 
 
60 
______mg 
______mg 
_____mg 
 
 
 
61 
______mg 
______mg 
_____mg 
 
 
 
62 
______mg 
______mg 
_____mg 
 
 
 
63 
______mg 
______mg 
_____mg 
 
 
 
64 
______mg 
______mg 
_____mg 
b, f, h, j m 
 
 
65 
______mg 
______mg 
_____mg 
 
 
 
66 
______mg 
______mg 
_____mg 
 
 
 
67 
______mg 
______mg 
_____mg 
 
 
 
68 
______mg 
______mg 
_____mg 
 
 
 
69 
______mg 
______mg 
_____mg 
 
 
 
70 
______mg 
______mg 
_____mg 
o 
 
 
 
A bone marrow evaluation is done every 2 weeks until hCR/hCRi is achieved. When hCR/hCRi is achieved, proceed to 
Consolidation (see Section 4.9). If hCR/hCRi is not achieved by Day 70, patient will go off protocol therapy. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  
Page 2 of 3 

  
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58 
Induction – High Risk 
 
4.8.2 
Required Observations in Induction – High Risk APL 
All baseline studies must be performed prior to starting protocol therapy 
unless otherwise indicated below. Obtain other studies during Induction as 
indicated.  
 
a. 
History 
b. Physical Exam with VS: weekly 
c. 
Ht, Wt, BSA: Days 1, 29 and 57 
d. Performance status 
e. 
Pregnancy test: Female patients of childbearing potential require a negative pregnancy 
test prior to starting treatment; sexually active patients must use an acceptable method of 
birth control. 
f. 
CBC, differential, platelets: daily during Week 1, then at least once weekly 
g. Urinalysis 
h. Electrolytes including Ca++, Mg++, K+ and creatinine: daily during Week 1, then at least 
once weekly 
i. 
Uric Acid 
j. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): Once 
weekly 
k. Cholesterol triglycerides 
l. 
PT, PTT, fibrinogen, D-Dimer: daily during Week 1, then on Days 8, 15 and 29 (more 
frequently if needed for active coagulopathy) 
m. ECG for QTc monitoring: Weekly 
n. Echocardiogram or MUGA 
o. BMA for morphology: At diagnosis and Day 29 and every 2 weeks thereafter as 
needed until hCR/hCRi 
p. BMA for flow cytometry, cytogenetics & FISH: At diagnosis 
q. BMA for clinical RQ-PCR of PML-RARα: At diagnosis. This clinical testing is 
separate from research samples submitted for the optional MRD RQ-PCR study; this 
mandatory clinical testing is not free of charge and the cost is not covered by the 
study, but the specimen must be sent to one of the approved labs for PML-RARα RQ-
PCR testing; a list of approved labs is available on the protocol-specific web page of 
the COG website. 
r. 
FLT3 (optional)*: bone marrow (or peripheral blood if bone marrow is unavailable) at 
diagnosis. See Section 15.1 for details. 
s. 
Research MRD (optional)*: bone marrow and peripheral blood at diagnosis and Day 29 
of Induction. See Section 15.2 for details. Results of this research testing will not be 
returned to sites. This research testing does not take the place of the mandatory RQ-PCR 
clinical testing that must be done at the time of initial diagnosis (see observation “q” 
above). 
t. 
Coagulopathy (optional)*: peripheral blood at diagnosis (if available), Day 1, Day 8, 
Day 15 and Day 29 of Induction. See Section 15.3 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
Comments 
 
 
 
 
 
 
Page 3 of 3 

  
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59 
Induction – High Risk 
 
 
4.8.3 
Induction Treatment Details – High Risk APL 
ATRA should be started at the time of first suspicion of APL diagnosis and then 
idarubicin and ATO should be given on Day 1 of protocol therapy. If an institution 
does not have ATO available on Day 1 when idarubicin is given, it will not be a 
protocol violation to start protocol directed therapy with idarubicin and ATRA as 
long as the ATO is started within 48 hours of the first idarubicin dose. 
 
Induction for high risk APL consists of daily ATO, twice daily ATRA, IDArubicin, 
and prophylaxis dosing of dexamethasone. Induction lasts at least 28 days (ATRA 
pre-treatment without ATO is not included in the 28 days). A bone marrow 
evaluation is performed on Day 29. Patients should remain on daily ATO/ATRA 
therapy while awaiting results of Day 29 bone marrow hCR/hCRi assessment.  
 
If hCR/hCRi is achieved, patients should stop daily induction therapy and proceed 
to Consolidation. If hCR/hCRi is not achieved, patients continue with Induction 
up to a maximum of 70 days, and a bone marrow evaluation is done every 2 weeks 
until hCR/hCRi is achieved. This end Induction determination of hematologic 
complete response is not dependent on results of genetic testing (such as 
cytogenetics, FISH or RQ-PCR testing). Patients who appear not to have achieved 
hematological complete remission after Day 43 of Induction may benefit from 
consultation for a rapid pathology review beginning with the Day 57 marrow 
sample (See Section 13 for details). 
 
Induction ends with the confirmation of an hCR/hCRi and after a minimum of 
28 days of induction. Then patient proceeds to Consolidation Cycle 1 (see 
Section 4.9). Following completion of Induction, Consolidation starts a minimum 
of 14 days from the end of Induction or when blood counts have recovered (ANC 
≥ 1,000/μL and platelets ≥ 100,000/μL), whichever occurs later. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 28 minimum. Continue beyond Day 28 if not in hCR/hCRi up to a 
maximum of 70 days (See Section 10.2 for response criteria and definition of 
hCR/hCRi) 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). Guidance for administration of 
tretinoin by parents/caregivers can be found in Appendix III. 
Note: If the patient received pre-treatment with ATRA prior to starting Day 1 of 
protocol directed therapy (see Section 3.2.3), these pre-treatment doses are NOT 
considered part of the required 28 days minimum of induction protocol therapy. 
 
Arsenic Trioxide (ATO): IV daily over 2 hours (may lengthen infusion to 
4 hours if active vasomotor symptoms occur) 
Days: 1 - 28 minimum. Continue beyond day 28 if not in hCR/hCRi up to a 
maximum of 70 days (See Section 10.2 for response criteria and definition of 
hCR/hCRi) 
Dose: 0.15 mg/kg/day (no maximum dose) 
 

  
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Induction – High Risk 
IDArubicin: IV bolus over 15 minutes 
Days: 1, 3, 5, 7 
Dose: 12 mg/m2/dose, once a day 
 NOTE: if BSA < 0.6 m2, 0.4 mg/kg/dose 
 
Dexamethasone: PO/IV BID 
Days: 1 - 14  
Dose: 2.5 mg/m2/dose twice daily. The total daily dose is 5 mg/m2/day. 
Note: This is prophylaxis dosing of dexamethasone. If the patient develops actual 
symptoms of differentiation syndrome, refer to Section 5.1 for recommendations 
on diagnosis and management of differentiation syndrome including treatment 
dosing of dexamethasone. 
 
 
Indications for intrathecal therapy 
 
CNS Bleed 
Patients with documented CNS bleed will receive CNS prophylaxis to include 
triple intrathecal chemotherapy at Day 29 of Induction. See table below for age-
based dosing. 
 
CNS Disease 
Patients with CNS disease (see Section 3.3.4 for definition) will receive twice 
weekly triple intrathecal chemotherapy (with a minimum interval of 48 hours 
between treatments) until the CSF is cleared plus two additional twice weekly 
treatments (minimum of 4 and maximum of 6 treatments). During Induction, 
patients with CNS disease will also receive a 10 mg/m2 dose of leucovorin, 24 
hours after each of the twice weekly triple intrathecal therapies.  
 
Age-based dosing of triple intrathecal therapy: 
 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3 years 
12 mg 
35 mg 
70 mg 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 
 

  
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61 
Consolidation – Cycle 1 - High Risk 
Page 1 of 2 
 
4.9 
Consolidation Cycle 1 – High Risk APL 
4.9.1 
Consolidation Therapy Delivery Map Cycle 1 – High Risk APL 
Consolidation Cycle 1 starts a minimum of 14 days after end of Induction therapy or when blood 
counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
________________ 
________ 
 Patient COG ID number 
DOB  
 
Consolidation Cycle 1 lasts 8 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 and 
29 - 42 
Total Dose: 25 mg/m2/day divided twice 
daily. 
 
Administer with food. Refer to Appendix II 
for dosing table 
Arsenic Trioxide (ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.9.3 for additional details 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥3 yrs 
12 mg 
35 mg 
70 mg 
 
15 and 43 
Only patients with documented CNS 
disease or CNS bleed will require 
intrathecal treatments (see Sections 3.3.4 
and 4.9.3 for details). 
 
Ht _________cm 
 
Wt _________kg  
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
_______mg 
ITT 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
_______mg 
Only patients with CNS disease or CNS bleed will 
require intrathecal treatments (see Sections 3.3.4 and 
4.9.3 for details) 
a – g, h* 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
 
c, d, e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
 
15 
 
_______mg 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
 
17 
 
_______mg 
 
 
 
 
18 
 
_______mg 
 
 
 
 
19 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
22 
 
_______mg 
 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
 
24 
 
_______mg 
 
 
 
 
25 
 
_______mg 
 
 
 
 
26 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
29 
_______mg 
_______mg 
 
 
a, c, e 
 
 
--- 
 
 
 
 
 
 
42 
_______mg 
_______mg 
 
 
 
 
 
43 
 
 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
 
 
 
--- 
--- 
--- 
 
 
 
 
56 
 
 
 
 
 
 
57 
Proceed to Consolidation Cycle 2 (see Section 4.10) on Day 57 or when blood counts recover (ANC ≥ 1,000/L 
and platelet count ≥ 100,000/L), whichever occurs later 
 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 

  
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Consolidation – Cycle 1 - High Risk 
Page 2 of 2 
 
4.9.2 
Required Observations in Consolidation Cycle 1 – High Risk APL 
 
 
a. 
Physical Exam with VS: Every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly while receiving ATO and on Day 29. 
d. Electrolytes including Ca++, Mg++, K+ and Creatinine: Weekly while receiving ATO. 
e. 
Total bilirubin (and direct bilirubin if total is > 2mg/dL), AST, ALT: Weekly while 
receiving ATO and on Day 29. 
f. 
ECG for QTc monitoring: Weekly while receiving ATO. 
g. Cholesterol, triglycerides 
h. Neurocognitive Testing (optional)*: CogState and BRIEF on Day 1 of Consolidation 
Cycle 1 (+/- 2 weeks). See Section 16 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Consolidation – Cycle 1 - High Risk 
 
4.9.3 
Consolidation Cycle 1 Treatment Details – High Risk APL 
Consolidation Cycle 1 lasts 56 days.  
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 and 29 - 42 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
 
Indications for intrathecal therapy 
 
Intrathecal Triple Therapy (ITT): Only for patients with documented history of 
CNS bleed or CNS positive disease. 
 
Days: 15 and 43 
Dose: Age based dosing as follows: 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3 years 
12 mg 
35 mg 
70 mg 
 
Proceed to Consolidation Cycle 2 on Day 57 or when blood counts recover (ANC ≥ 
1,000/L and platelet count ≥ 100,000/L), whichever occurs later. See 
Section 4.10 for details. 
 

  
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Consolidation – Cycle 2 – High Risk 
Page 1 of 2 
4.10 
Consolidation Cycle 2 – High Risk APL 
4.10.1 Consolidation Therapy Delivery Map Cycle 2 – High Risk APL 
Consolidation Cycle 2 starts on Day 57 of Cycle1 or when blood counts recover 
(ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
_____________________ 
___________ 
 
Patient COG ID number 
DOB  
 
Consolidation Cycle 2 lasts 8 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 and 29 - 42 
Total Dose: 25 mg/m2/day divided 
twice daily. 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide (ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.10.3 for additional details 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥ 3 yrs 
12 mg 
35 mg 
70 mg 
 
15 and 43 
Only patients with documented 
CNS disease or CNS bleed will 
require intrathecal treatments (see 
Sections 3.3.4 and 4.10.3 for 
details). 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
_______mg 
ITT 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
_______mg 
Only patients with CNS disease or CNS bleed will 
require intrathecal treatments (see Sections 3.3.4 and 
4.10.3 for details) 
a – g 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
 
c, d, e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
 
15 
 
_______mg 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
 
17 
 
_______mg 
 
 
 
 
18 
 
_______mg 
 
 
 
 
19 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
22 
 
_______mg 
 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
 
24 
 
_______mg 
 
 
 
 
25 
 
_______mg 
 
 
 
 
26 
 
_______mg 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
_______mg 
_______mg 
 
 
a, c, e 
 
 
--- 
 
 
 
 
 
 
42 
_______mg 
_______mg 
 
 
 
 
 
43 
 
 
_______mg (MTX) _______mg (HC) _______mg (ARAC) 
h, i*, j* 
 
 
44 
 
 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
56 
 
 
 
 
 
 
57 
A bone marrow evaluation is performed for clinical RQ-PCR of PML-RARα on Day 43. If negative continue to 
Consolidation Cycle 3 (Section 4.12) on Day 57 of this cycle. If positive, repeat 1-2 weeks later. If repeat test is 
negative continue to Consolidation Cycle 3 (see Section 4.12) on Day 57 of this cycle. If repeat test is confirmed 
positive continue to MRD Positive Consolidation Cycle (see Section 4.11) on Day 57 of this cycle. 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  

  
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Consolidation – Cycle 2 – High Risk 
Page 2 of 2 
 
4.10.2 Required Observations in Consolidation Cycle 2 – High Risk APL 
 
 
a. 
Physical Exam with VS: Every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly while receiving ATO and on Day 29. 
d. Electrolytes including Ca++, Mg++, K+ and creatinine: Weekly while receiving ATO 
e. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): 
Weekly while receiving ATO and on Day 29. 
f. 
ECG for QTc monitoring: Weekly while receiving ATO 
g. Cholesterol, triglycerides 
h. BMA for clinical RQ-PCR of PML-RARα: Obtain on Day 43 of Consolidation Cycle 2. 
This clinical testing is separate from research samples submitted for the optional MRD 
RQ-PCR study; this mandatory clinical testing is not free of charge and the cost is not 
covered by the study, but the specimen must be sent to one of the approved labs for 
PML-RARα RQ-PCR testing; a list of approved labs is available on the protocol-specific 
web page of the COG website. If the initial test is positive, contact the study chair and a 
repeat sample must be sent 1-2 weeks later. This testing is not paid for by the study, but 
it is recommended that this confirmation sample be sent to either Hematologics, Inc, 
Seattle, WA, USA or the Molecular Haematology Lab, Royal Prince Alfred Hospital, 
NSW, Australia due to their experience with these samples. 
i. 
FLT3 (optional)*: bone marrow on Day 43 of Consolidation Cycle 2. See Section 15.1 
for details. 
j. 
Research MRD (optional)*: bone marrow and peripheral blood on Day 43 of 
Consolidation Cycle 2. See Section 15.2 for details. Results of this research testing will 
not be returned to sites.  
*Only obtain in patients who have consented to participation in this component of the trial. 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Consolidation – Cycle 2 – High Risk 
4.10.3 Consolidation Cycle 2 Treatment Details – High Risk APL 
Consolidation Cycle 2 lasts 56 days. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 and 29 - 42 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
Indications for intrathecal therapy 
Intrathecal Triple Therapy (ITT): Only for patients with documented history of 
CNS bleed or CNS positive disease. 
Days: 15 and 43 
Dose: Age based dosing as follows 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3 years 
12 mg 
35 mg 
70 mg 
 
A bone marrow evaluation is performed for clinical RQ-PCR of PML-RARα on 
Day 43. This testing is separate from research samples submitted for the optional 
MRD study; this mandatory clinical testing is not free of charge (cost is not 
covered by the study), but the specimen must be sent to one of the approved labs 
for PML-RARα RQ-PCR testing; a list of approved labs is available on the 
protocol-specific web page of the COG website. If the initial RQ-PCR is negative 
continue to Consolidation Cycle 3 (Section 4.12) on Day 57 of this cycle or when 
blood counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), 
whichever occurs later. If the initial RQ-PCR test is positive, contact the study 
chair and a repeat sample must be sent 1-2 weeks later. This testing is not paid for 
by the study, but it is recommended that this confirmation sample be sent to either 
Hematologics, Inc, Seattle, WA, USA or the Molecular Haematology Lab, Royal 
Prince Alfred Hospital, NSW, Australia due to their experience with these samples. 
If repeat test is negative continue to Consolidation Cycle 3 (see Section 4.12) on 
Day 57 of this cycle. If repeat test is confirmed positive continue to MRD Positive 
Consolidation (Section 4.11) on Day 57 of this cycle. 
 

  
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MRD Positive Consolidation – High Risk 
 
 
 
 
 
 
 
 
 
MRD Positive Consolidation is only for those patients 
with RQ-PCR of PML-RARα confirmed positive after 
Consolidation Cycle 2.  
 
 
 
 
 
If the RQ-PCR of PML-RARα is negative after 
Consolidation Cycle 2, proceed to Consolidation 
Cycle 3 (see Section 4.12) 
 
 
 
 

  
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MRD Positive Consolidation – High Risk 
Page 1 of 2 
4.11 
MRD Positive Consolidation – High Risk APL 
4.11.1 MRD Positive Consolidation Therapy Delivery Map – High Risk APL 
MRD Positive Consolidation is only for those patients with RQ-PCR confirmed positive 
after Consolidation Cycle 2. Start on Day 57 of Cycle 2 or when blood counts recover 
(ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
 
_______________________ 
 Patient COG ID number 
 
____________ 
DOB  
This course lasts 28 days. This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
High Dose Cytarabine 
(HD ARAC) 
IV over 1-3 hours every 
12 hours 
1000 mg/m2/dose, twice daily 
 
if BSA < 0.6m2, 33.3 mg/kg/dose, 
twice daily 
1 - 4 
Total dose: 2000 mg/m2/day, divided twice 
daily or 66.6 mg/kg/day, divided twice daily 
if BSA < 0.6 m2.  
Use eye drops as described in Section 4.11.3. 
MitoXANtrone 
(MITOX) 
IV daily over 15-30 minutes 
12 mg/m2/dose 
 
If BSA < 0.6 m2, 0.4 mg/kg/dose daily 
3 – 6 
On Days 3 and 4, administer 8 hours after the 
5th and 7th cytarabine infusions are 
completed. See Section 4.11.3 for details. 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14  
Total Dose: 25 mg/m2/day divided twice 
daily. 
 
Administer with food. Refer to Appendix II 
for dosing table. 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
 
Date 
Due 
Date 
Given 
Day 
HD ARAC 
_______mg 
_______mg 
MITOX 
_______mg 
ATRA 
_______mg 
_______mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
 
_______mg 
_______mg 
 a – g 
 
 
2 
_______mg 
_______mg 
 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
_______mg 
_______mg 
 
 
 
5 
 
_______mg 
_______mg 
_______mg 
 
 
 
6 
 
_______mg 
_______mg 
_______mg 
 
 
 
7 
 
 
_______mg 
_______mg 
 
 
 
8 
 
 
_______mg 
_______mg 
c, d, e 
 
 
9 
 
 
_______mg 
_______mg 
 
 
 
10 
 
 
_______mg 
_______mg 
 
 
 
11 
 
 
_______mg 
_______mg 
 
 
 
12 
 
 
_______mg 
_______mg 
 
 
 
13 
 
 
_______mg 
_______mg 
 
 
 
14 
 
 
_______mg 
_______mg 
 
 
 
15 
 
 
 
c, d, e 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
c, d, e 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
A bone marrow evaluation will be done for RQ-PCR of PML-RARα. If negative, continue to Consolidation 
Cycle 3 (see Section 4.12). If positive in 2 successive specimens, patient will go off protocol therapy. 
a, h 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  

  
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MRD Positive Consolidation – High Risk 
Page 2 of 2 
4.11.2 Required Observations in MRD Positive Consolidation – High Risk APL 
 
 
a. 
Physical Exam with VS: every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly  
d. Electrolytes and creatinine: Weekly 
e. 
AST, ALT, Total Bilirubin (and prior to Mitoxantrone a Direct Bilirubin if Total 
Bilirubin is >3.3 mg/dL): Weekly 
f. 
Cholesterol, triglycerides 
g. Echocardiogram or MUGA 
h. BMA for clinical RQ-PCR of PML-RARα: Obtain on Day 29, if positive, repeat 1 - 2 
weeks later. This mandatory testing is not paid for by the study. It is recommended that 
this testing be sent to either Hematologics, Inc, Seattle, WA, USA or the Molecular 
Haematology Lab, Royal Prince Alfred Hospital, NSW, Australia due to their experience 
with these samples. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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MRD Positive Consolidation – High Risk 
 
4.11.3 MRD Positive Consolidation Treatment Details – High Risk APL 
MRD Positive Consolidation consists of a combination of high dose cytarabine, 
mitoxantrone and twice daily ATRA. This cycle lasts for 28 days. It is strongly 
recommended that the patients remain inpatient for the duration of this cycle of 
Consolidation and until count recovery.  
 
Antifungal prophylaxis should be strongly considered (dependent on institutional 
practice) during this cycle due to an expected prolonged period of neutropenia. 
However, treating physicians should be aware that azole antifungal medications 
may increase ATRA toxicity due to inhibition of cytochrome P - 450 metabolism 
of ATRA. Thus patients should be monitored closely for adverse events such as, 
pseudotumor cerebri or renal dysfunction, during periods of concomitant use. For 
prophylactic antifungal use, initiation of an azole antifungal could be delayed until 
after completion of ATRA on Day 14 of this cycle or an alternate non-azole 
antifungal should be considered. 
 
High Dose Cytarabine: IV over 1 - 3 hours every 12 hours 
Days: 1 - 4 (8 total doses) 
Dose: 1,000 mg/m2/dose every 12 hours. If BSA < 0.6 m2, 33.3 mg/kg/dose. 
 
NOTE: 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 final dose. If patient does 
not tolerate steroid eye drops, may administer artificial tears on an every 2 - 4 hour 
schedule. 
 
MitoXANtrone: IV daily over 15 - 30 minutes 
Days: 3 - 6 
Dose: 12 mg/m2/dose once daily. If BSA < 0.6 m2 0.4 mg/kg/dose. 
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 Days 3 and 4, 
mitoxantrone should be given 8 hours after the 5th and 7th high dose cytarabine 
infusions are complete. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
A bone marrow evaluation will be done for clinical RQ-PCR of PML-RARα on 
Day 29. This testing is not paid for by the study, but it is recommended that this 
testing be sent to either Hematologics, Inc, Seattle, WA, USA or the Molecular 
Haematology Lab, Royal Prince Alfred Hosptial, NSW, Australia due to their 
experience with these samples. If negative, continue to Consolidation Cycle 3 (see 
Section 4.12) on Day 29 or when blood counts recover (ANC ≥ 1,000/L and 
platelet count ≥ 100,000/L), whichever occurs later. If positive, repeat 1 - 2 weeks 
later and if second test is positive then patient will go off protocol therapy. 
 

  
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Consolidation – Cycle 3 – High Risk 
Page 1 of 2 
4.12 
Consolidation Cycle 3 – High Risk APL 
4.12.1 Consolidation Therapy Delivery Map Cycle 3 – High Risk APL 
Start Consolidation Cycle 3 only if RQ-PCR of PML-RARα is negative. Cycle 3 starts on 
Day 57 of Cycle 2 or when blood counts recover (ANC ≥ 1,000/L and platelet count ≥ 
100,000/L), whichever occurs later. OR Consolidation Cycle 3 starts on Day 29 of MRD 
Positive Consolidation cycle if needed or when blood counts recover (ANC ≥ 1,000/L and 
platelet count ≥ 100,000/L), whichever occurs later. 
__________________ _________ 
 Patient COG ID number 
DOB  
 
Consolidation Cycle 3 lasts 8 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 and 29 - 42 
Total Dose: 25 mg/m2/day divided 
twice daily. 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide (ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.12.3 for additional details 
Triple Intrathecal 
Therapy (ITT) 
 
Methotrexate (MTX) 
Hydrocortisone (HC) 
Cytarabine (ARAC) 
IT 
Age 
MTX 
HC 
ARAC 
1-1.99 yrs 
8 mg 
15 mg 
30 mg 
2-2.99 yrs 
10 mg 
25 mg 
50 mg 
≥3 yrs 
12 mg 
35 mg 
70 mg 
 
15 and 43 
Only patients with documented CNS 
disease or CNS bleed will require 
intrathecal treatments (see 
Sections 3.3.4 and 4.12.3 for 
details). 
 
Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations 
1 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
____mg 
ITT 
_____mg (MTX) _____mg (HC) _____mg (ARAC)  
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_______mg 
_______mg 
_______mg 
Only patients with CNS disease or CNS bleed 
will require intrathecal treatments (see 
Sections 3.3.4 and 4.12.3 for details) 
a – g, h* 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
 
c, d. e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
 
15 
 
_______mg 
_____mg (MTX) _____mg (HC) _____mg (ARAC)  
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
 
17 
 
_______mg 
 
 
 
 
18 
 
_______mg 
 
 
 
 
19 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
22 
 
_______mg 
 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
 
24 
 
_______mg 
 
 
 
 
25 
 
_______mg 
 
 
 
 
26 
 
_______mg 
 
 
 
 
--- 
--- 
--- 
 
 
 
 
29 
_______mg 
_______mg 
 
 
a, c, e 
 
 
--- 
 
 
 
 
 
 
42 
_______mg 
_______mg 
 
 
 
 
 
43 
 
 
_____mg (MTX) _____mg (HC) _____mg (ARAC) 
 
 
 
--- 
--- 
--- 
 
 
 
 
56 
 
 
 
 
 
 
57 
Proceed to Consolidation Cycle 4 (see Section 4.13) on Day 57 or when blood counts recover (ANC 
≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. 
 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 

  
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Consolidation – Cycle 3 – High Risk 
Page 2 of 2 
4.12.2 Required Observations in Consolidation Cycle 3 – High Risk APL 
 
 
a. 
Physical Exam with VS: every 4 weeks 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly while receiving ATO and on Day 29. 
d. Electrolytes including Ca++, Mg++, K+ and creatinine: Weekly while receiving ATO 
e. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): 
Weekly while receiving ATO and on Day 29. 
f. 
ECG for QTc monitoring: Weekly while receiving ATO 
g. Cholesterol, triglycerides 
h. Neurocognitive Testing (optional)*: CogState and BRIEF on Day 1 of Consolidation 
Cycle 3 (+/-2 weeks). See Section 16 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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Consolidation – Cycle 3 – High Risk 
 
4.12.3 Consolidation Cycle 3 Treatment Details – High Risk APL 
Consolidation Cycle 3 lasts 56 days. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 and 29 - 42 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
Indications for intrathecal therapy 
 
Intrathecal Triple Therapy (ITT): Only for patients with documented history of 
CNS bleed or CNS positive disease. 
 
Days: 15 and 43 
Dose: Age based dosing as follows 
 
Triple Intrathecal Therapy (ITT) 
Age 
Methotrexate Hydrocortisone 
Cytarabine 
1 - 1.99 years 
8 mg 
15 mg 
30 mg 
2 - 2.99 years 
10 mg 
25 mg 
50 mg 
≥ 3years 
12 mg 
35 mg 
70 mg 
 
Proceed to Consolidation Cycle 4 on Day 57 or when blood counts recover 
(ANC ≥ 1,000/L and platelet count ≥ 100,000/L), whichever occurs later. See 
Section 4.13 for details. 
 
 

  
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Consolidation – Cycle 4 – High Risk 
Page 1 of 2 
4.13 
Consolidation Cycle 4 – High Risk APL 
4.13.1 Consolidation Therapy Delivery Map Cycle 4 – High 
Risk APL 
Consolidation Cycle 4 starts on Day 57 of Cycle 3 or when blood 
counts recover (ANC ≥ 1,000/L and platelet count ≥ 100,000/L), 
whichever occurs later. 
______________________ 
_____________ 
 
Patient COG ID number 
DOB  
 
Consolidation Cycle 4 lasts 4 weeks. This TDM is on 2 pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Tretinoin (ATRA) 
PO 
12.5 mg/m2/dose, twice daily 
 
1 - 14 
Total Dose: 25 mg/m2/day divided 
twice daily 
 
Administer with food. Refer to 
Appendix II for dosing table 
Arsenic Trioxide 
(ATO) 
IV over 
2 hours* 
0.15 mg/kg/day 
1 - 5, 8 - 12,  
15 - 19, 22 - 26  
*May be extended to 4 hours see 
Section 4.13.3 for additional 
details 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
Actual body weight (not ideal or adjusted weight) should be used for all dose calculations. 
 
 
Date 
Due 
Date 
Given 
Day 
ATRA 
_______mg 
_______mg 
ATO 
_______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below  
 
 
 
1 
_______mg 
_______mg 
_______mg 
a – g 
 
 
2 
_______mg 
_______mg 
_______mg 
 
 
 
3 
_______mg 
_______mg 
_______mg 
 
 
 
4 
_______mg 
_______mg 
_______mg 
 
 
 
5 
_______mg 
_______mg 
_______mg 
 
 
 
6 
_______mg 
_______mg 
 
 
 
 
7 
_______mg 
_______mg 
 
 
 
 
8 
_______mg 
_______mg 
_______mg 
c, d, e, f 
 
 
9 
_______mg 
_______mg 
_______mg 
 
 
 
10 
_______mg 
_______mg 
_______mg 
 
 
 
11 
_______mg 
_______mg 
_______mg 
 
 
 
12 
_______mg 
_______mg 
_______mg 
 
 
 
13 
_______mg 
_______mg 
 
 
 
 
14 
_______mg 
_______mg 
 
 
 
 
15 
 
_______mg 
c, d, e, f 
 
 
16 
 
_______mg 
 
 
 
17 
 
_______mg 
 
 
 
18 
 
_______mg 
 
 
 
19 
 
_______mg 
 
 
 
--- 
--- 
--- 
 
 
 
22 
 
_______mg 
c, d, e, f 
 
 
23 
 
_______mg 
 
 
 
24 
 
_______mg 
 
 
 
25 
 
_______mg   
 
 
26 
 
_______mg 
 
 
 
27 
--- 
--- 
 
 
 
28 
 
 
a, c, h, i, j*, k* 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 

 
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Consolidation – Cycle 4 – High Risk 
Page 2 of 2 
4.13.2 Required Observations in Consolidation Cycle 4 – High Risk APL 
 
a. 
Physical Exam with VS: Day 1 and 28 
b. Ht, Wt, BSA 
c. 
CBC, differential, platelets: Weekly 
d. Electrolytes including Ca++, Mg++, K+ and creatinine: Weekly while receiving ATO 
e. 
AST, ALT, Total Bilirubin (and Direct Bilirubin if Total Bilirubin is >2 mg/dL): 
Weekly while receiving ATO 
f. 
ECG for QTc monitoring: Weekly while receiving ATO 
g. Cholesterol, triglycerides 
h. Echocardiogram or MUGA: at the end of protocol therapy 
i. 
BMA for clinical RQ-PCR of PML-RARα: at the end of protocol therapy. This 
testing is separate from research samples submitted for the optional MRD RQ-PCR 
study; this mandatory clinical testing is not free of charge (cost is not covered by 
the study), but the specimen must be sent to one of the approved labs for PML-
RARα RQ-PCR testing; a list of approved labs is available on the protocol-specific 
web page of the COG website. 
j. 
Research MRD (Optional)*: bone marrow and peripheral blood at the end of protocol 
therapy. See Section 15.2 for details. 
k. Neurocognitive Testing (Optional)*: CogState, BRIEF and the psychologist 
administered battery at the end of protocol therapy (up to 3 months after the end of 
protocol therapy). See Section 16 for details. 
*Only obtain in patients who have consented to participation in this component of the trial. 
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Consolidation – Cycle 4 – High Risk 
 
4.13.3 Consolidation Cycle 4 Treatment Details – High Risk APL 
Consolidation Cycle 4 lasts 28 days. 
 
Tretinoin (ATRA): PO divided BID 
Days: 1 - 14 
Dose: 12.5 mg/m2/dose, twice daily. The total dose is 25 mg/m2/day divided twice 
daily. 
Administer with food. Refer to Appendix II for dosing table (includes dose 
recommendations for very young patients). 
 
Arsenic Trioxide (ATO): IV over 2 hours (may lengthen infusion to 4 hours if 
active vasomotor symptoms occur) 
Days: 1 - 5, 8 - 12, 15 - 19 and 22 - 26 
Dose: 0.15 mg/kg/day (no maximum dose) 
 
NOTE: Some patients may require infusion in a clinic setting (i.e. unable to 
arrange home infusion) and holidays may result in intermittent clinic closure. 
Therefore it is permissible for patients to miss doses of ATO on those days at the 
discretion of the treating physician. It is suggested that patients not miss more than 
2 doses in a 4 week period (10% of doses). If more than 2 doses are missed in a 
4 week period due to holidays, then make-up doses (following Day 26) may be 
administered at the discretion of the treating physician. 
 
A bone marrow evaluation is performed for RQ-PCR of PML-RARα on Day 28. 
This testing is separate from research samples submitted for the optional MRD 
study; this mandatory clinical testing is not free of charge (cost is not covered by 
the study), but the specimen must be sent to one of the approved labs for PML-
RARα RQ-PCR testing; a list of approved labs is available on the protocol-specific 
web page of the COG website. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
5.1 
APL Differentiation Syndrome 
The APL differentiation syndrome (described below) is a life-threatening complication of 
APL generally seen during Induction therapy after starting tretinoin and arsenic trioxide 
and prior to the patient achieving remission. Patients with high risk APL will receive 
dexamethasone at prophylaxis dosing to help prevent this syndrome. Also patients with 
standard risk APL who have their WBC count rise to > 10,000/L without symptoms of 
APL differentiation syndrome should begin prophylactic dosing of dexamethasone. If a 
patient develops symptoms of APL differentiation syndrome, follow guidelines for 
treatment dosing of dexamethasone (see below). 
 
APL differentiation syndrome: a spectrum of clinical manifestations of a 
cardiorespiratory distress syndrome that include at least three of the following: respiratory 
distress, hypoxemia, fever, erythematous rash, pulmonary infiltrates, pleural or pericardial 
effusions, weight gain, peripheral edema, acute renal failure, congestive heart failure and 
hypotension. Patients with this syndrome may develop progressive cardiopulmonary 
failure. 
 
If this syndrome is suspected:  
 
Promptly start treatment dose dexamethasone 5.8 mg/m2/dose IV BID (max 
10 mg/dose BID) for a minimum of 3 days and continue until resolution of 
symptoms, at which point dexamethasone should be continued at a prophylactic 
dose through Day 14. 
 
Hold tretinoin and arsenic trioxide. Once the symptoms and the patient’s clinical 
condition improve, restart both medications at 50% of the previous dose (for 
tretinoin 6.25 mg/kg/dose twice daily (12.5 mg/m2/day), for arsenic trioxide, 0.075 
mg/kg/day) during the first 7 days. After 7 days, increase back to the full dose as 
prescribed in the protocol. Do not make-up missed doses during the cycle. If 
patients experience recurrent symptoms of APL differentiation syndrome, follow 
the same dose reduction directions above again and ensure the patient is on 
dexamethasone at treatment doses.  
NOTE: In patients with high risk APL, Induction doses of IDArubicin should not 
be held or dose adjusted due to APL differentiation syndrome unless the clinician 
feels that cardiac function is impaired to a degree that would make idarubicin 
dosing contraindicated. If IDArubicin doses are held for this reason, the doses 
should be restarted when tolerable (do not skip idarubicin doses). 
 
Furosemide may be used as clinically indicated to treat fluid overload. 
 
Notify the study chair of any patient with persistent signs/symptoms of the APL 
differentiation syndrome that requires holding tretinoin and arsenic trioxide for 
more than 3 days. 
 
5.2 
Tretinoin Dose Modifications (Including Modifications for Pseudotumor Cerebri) 
Commonly observed toxicities with tretinoin include hepatotoxicity (increased AST and 
ALT), neurologic changes including headache or pseudotumor cerebri (see below), 
dermatology/skin changes and others including chelitis, epistaxis, fatigue, musculoskeletal 
pain, and conjunctivitis. If a patient experiences a Grade ≥ 3 toxicity that is felt to be related 
to tretinoin, then tretinoin will be held until the toxicity has resolved to the Grade 1 level. 

 
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At that time restart tretinoin at 25% dose reduction (19 mg/m2/day divided twice daily). 
Dosing of tretinoin should be as close as possible to 19 mg/m2/day divided twice daily, i.e., 
round to the nearest 10 mg (round < 5 mg down and ≥ 5 mg up). If necessary, the AM dose 
may differ from the PM dose to deliver a total daily dose as close as possible to 
19 mg/m2/day divided twice daily. Recurrent episodes of Grade ≥ 3 toxicity will result in 
discontinuation of the tretinoin until the toxicity resolves to Grade ≤ 1; tretinoin will then 
be resumed with an additional 25% reduction (50% total dose reduction) in the tretinoin 
dose (12.5 mg/m2/day divided twice daily). Dosing of tretinoin should be as close as 
possible to 12.5 mg/m2/day divided twice daily; i.e., round to the nearest 10 mg (round < 
5 mg down and ≥ 5 mg up). If necessary, the AM dose may differ from the PM dose to 
deliver a total daily dose closest to 12.5 mg/m2/day divided twice daily. Patients 
experiencing Grade ≥ 3 toxicity attributable to tretinoin while on 12.5 mg/m2/day of 
tretinoin should have tretinoin held until the toxicity resolves to Grade ≤ 1. tretinoin will 
then be resumed at the same 50% dose reduction (12.5 mg/m2/day divided twice daily) 
while continuing to monitor for toxicity and holding doses as needed for Grade ≥ 3 toxicity. 
Please notify the study chair about patients experiencing Grade ≥ 3 toxicity while on 50% 
dose reduction. 
 
If patients whose doses are reduced by 25% (19 mg/m2/day divided twice daily) or 50% 
(12.5 mg/m2/day divided twice daily) tolerate the lower dose for 7 days without recurrence 
of the toxicity that led to dose adjustment, a dose escalation may be attempted. If the patient 
had been decreased to 50% dosing (12.5 mg/m2/day divided twice daily) and tolerates an 
escalation to 75% dosing (19 mg/m2/day divided twice daily) for an additional 7 days, 
another escalation back to 100% dosing (25 mg/m2/day divided twice daily) may be 
attempted. 
 
The APL Differentiation Syndrome should be treated as outlined in Section 5.1. 
5.2.1 
Pseudotumor Cerebri 
Pseudotumor cerebri (PTC) must be confirmed by proper history, exam and other 
clinically relevant studies. Symptoms/signs of PTC include headache, 
papilledema, visual field defects (ocular/visual), and absence of focal neurological 
symptoms, except for occasional cranial nerve (CN) VI palsy (neuropathy: cranial 
CN VI). Cerebrospinal fluid should be evaluated and should be negative for signs 
of infection. However, lumbar puncture should be avoided while active 
coagulopathy is present. An opening pressure should be obtained; a pressure 
> 200 mm water helps to establish the diagnosis of PTC. A CT or MRI of the brain 
(to evaluate for meningitis, intracranial bleed, intracranial thrombosis, etc.) should 
be performed and should be compatible with PTC. Neurological and 
ophthalmologic consultations should be obtained in order to assist in making the 
proper diagnosis. Carefully follow the visual field status of the patient. One should 
also strongly consider obtaining a MRI/MRV to exclude the possibility of a sagittal 
sinus thrombosis. Consider acetazolamide (Diamox) therapy and periodic lumbar 
puncture with therapeutic removal of cerebrospinal fluid as appropriate for 
age/size. 
 
If PTC develops:  
 
Hold tretinoin until this toxicity improves to Grade 0 or 1 (“mild” headache). 

 
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 
Restart tretinoin at 75% of the original dose (19 mg/m2/day divided twice 
daily). If PTC reoccurs, hold tretinoin as above and then resume at 50% of 
original dose (12.5 mg/m2/day divided twice daily).  
 
If the patient tolerates reduced dosing for more than 7 days, dose re-escalation can 
be attempted. Dose escalation from 50% (12.5 mg/m2/day divided twice daily) to 
75% (19 mg/m2/day divided twice daily) to 100% (25 mg/m2/day divided twice 
daily) at 7 day intervals may be attempted if clinically appropriate. 
 
5.3 
Arsenic Trioxide Dose Modifications 
Missed doses due to holidays or dose modifications do not need to be made up. However, 
if more than 2 doses are missed in a 4 week period due to holidays (not dose modifications), 
then make-up doses (following Day 26 of Consolidation Cycles 1 - 4) may be administered 
at the discretion of the treating physician. 
 
 
5.3.1 
Hepatotoxicity 
At initial diagnosis, patients may have abnormal liver function tests due to their 
malignancy and no dose adjustment of arsenic trioxide is needed at initiation of 
therapy. Hepatotoxicity that occurs during arsenic trioxide treatment should 
prompt dose modifications as noted below. 
 
If during arsenic trioxide administration, the patient has either: 
 
 
AST > 5 fold increase over the upper limit of normal (ULN)  
 
or direct bilirubin > 2 mg/dL 
 
then hold arsenic trioxide until AST ≤ 3x ULN and direct bilirubin ≤ 0.5 mg/dL, 
after which resume arsenic trioxide treatment with a 50% dose reduction (0.075 
mg/kg/day) during the first 7 days. 
 
After 7 days of the reduced dose, and in the absence of worsening of the previous 
toxicity, arsenic trioxide should be resumed at full dose. 
 
If a patient meets hepatotoxicity criteria for holding arsenic trioxide a second time, 
again hold arsenic trioxide until AST ≤ 3x ULN and direct bilirubin ≤ 0.5 mg/dL, 
then resume treatment with a 50% dose reduction (0.075 mg/kg/day) for all further 
doses of arsenic trioxide (no re-escalation of dose). If hepatotoxicity recurs while 
on 50% dosing, hold arsenic trioxide again until AST ≤ 3x ULN and direct 
bilirubin ≤ 0.5 mg/dL prior to restarting again at the 50% dose reduction (0.075 
mg/kg/day). Please notify the study chair of cases in which hepatotoxicity occurs 
while on 50% dosing. 
 
5.3.2 
Hematological Toxicity 
During Induction: No dose adjustment is required for anemia, decreased neutrophil 
count or decreased platelet count. 
 
During Consolidation: If the patient has absolute neutrophil count < 1,000/uL or 
platelets < 50,000/uL lasting more than 5 weeks, then during the next cycle arsenic 

 
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trioxide should be dosed at 75% (0.11 mg/kg/day). If the patient again has absolute 
neutrophil count < 1,000/uL or platelets < 50,000/uL lasting more than 5 weeks, 
then during the next cycle arsenic trioxide should be dosed at 50% (0.075 
mg/kg/day). 
 
 
5.3.3 
Nausea/Vomiting 
Nausea/vomiting of any grade should be handled with symptomatic treatment with 
anti-emetics. If > 6 - 8 episodes occur daily, despite adequate trial of anti-emetics, 
then hold treatment until clinical improvement before resuming treatment at full 
dose. If treatment-refractory nausea/vomiting recurs, then hold treatment until 
improvement to Grade ≤ 1 and then resume treatment with a 50% dose reduction 
(0.075 mg/kg/dose). The dose may be escalated back to 100% (0.15 mg/kg/dose) 
at the next cycle. 
 
When selecting anti-emetics, investigators should consider the potential for QTc 
prolongation when used in conjunction with arsenic trioxide. 
 
 
5.3.4 
Cardiac Toxicity 
Guidelines for the management of prolongation of the corrected QT (QTc) interval 
are as follows: 
 
Measure the QT interval (from the start of the Q wave to the end of the T wave) 
and the preceding RR interval. The QTc interval will be calculated using Bazett’s 
formula: the QT interval (msec) divided by the square root of the RR interval 
(msec).  
 
 
QTc interval 450 - 500 msec: Continue arsenic. Serum K+, Mg++, and Ca++ 
should be monitored and repleted only if low.  
 
QTc interval 501 - 600 msec: Hold arsenic temporarily and replete serum 
K+, Mg++, and Ca++ with IV and/or oral supplements immediately.  Serum 
K+ and Mg++ should be repleted to minimum target levels of 4.0 and 
1.8 mg/dL, respectively. Discontinue any medications that prolong the QT 
interval. Resume arsenic on same day if target levels are achieved; re-
check serum electrolytes prior to the next dose. 
 
QTc interval > 600 msec: Hold arsenic. Aggressive IV K+ and Mg++ 
repletion. If the QTc interval falls below 600 msec, outpatient 
management may be considered with additional oral supplements and an 
ECG should be repeated the following day and/or prior to further arsenic 
treatment. Serum K+ and Mg++ should be repleted to minimum target levels 
of 4.0 and 1.8 mg/dL, respectively. Discontinue any medications that 
prolong the QT interval. Resume arsenic on same day if target levels are 
achieved; re-check serum electrolytes prior to the next dose. If the QTc 
interval does not fall below 600 msec with this level of repletion, the 
patient should undergo ECG monitoring by telemetry, preferably in the 
hospital, along with continued IV K+ and Mg++.  
 
Consider cardiology consultation if QTc is found to be prolonged. 
 
If syncope or rapid or irregular heartbeat develops, the patient should be 
hospitalized for monitoring and serum electrolytes should be assessed. 
Treatment with arsenic trioxide should be temporarily discontinued until 

 
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the QTc interval regresses to below 450 msec, electrolyte abnormalities 
are corrected, and the syncope and irregular heartbeat cease. 
 
5.3.5 
Neurologic Toxicity 
Arsenic trioxide may cause neuropathy which most commonly involves painful 
peripheral neuropathy. This should be managed with medications appropriate for 
neuropathy (such as gabapentin or pregabalin) and pain medication (including 
narcotics as needed). Arsenic trioxide dosing should be modified for Grade ≥3 
neuropathy by following the guidelines in Section 5.3.6 below.  
 
5.3.6 
Other Toxicities (Excludes hepatic, hematologic, nausea/vomiting, and cardiac 
toxicities which are described above) 
If a patient has active vasomotor symptoms during the infusion (including 
dizziness, hypotension, tachycardia, or flushing) the infusion time may be 
extended to 4 hours. 
 
If a patient experiences a Grade ≥ 3 toxicity that is felt to be related to arsenic 
trioxide, arsenic trioxide will be held until the toxicity has resolved to Grade ≤ 1. 
At that time restart arsenic trioxide at a 75% dose (0.11 mg/kg/day). Recurrent 
episodes of Grade ≥ 3 toxicity will result in holding of arsenic trioxide until the 
toxicity resolves to Grade ≤ 1; arsenic trioxide will then be resumed with an 
additional 25% reduction in the arsenic trioxide dose (0.075 mg/kg/day). Patients 
experiencing Grade ≥ 3 toxicity attributable to arsenic trioxide while on 0.075 
mg/kg/day of arsenic trioxide should be discussed with the study chair. 
 
5.4 
IDArubicin and MitoXANtrone Dose Modifications  
5.4.1 
Hepatic Toxicity 
IDArubicin 
 
Dose Adjustments for IDArubicin 
Direct Bilirubin 
BSA ≥ 0.6m2 
BSA < 0.6m2 
< 2.6 mg/dL 
100% dosing (12 mg/m2/dose) 
100% dosing (0.4 mg/kg/dose) 
2.6-5 mg/dL 
50% dosing (6 mg/m2/dose) 
50% dosing (0.2 mg/kg/dose) 
> 5 mg/dL 
Hold until direct bilirubin < 5 
mg/dL 
Hold until direct bilirubin < 5 
mg/dL 
 
If held for direct bilirubin > 5 mg/dL, start (or restart) IDArubicin doses once the 
direct bilirubin falls below 5 mg/dL (give at 50% dose if the direct bilirubin is 2.6 
- 5 mg/dL or give at full dose if direct bilirubin is < 2.6 mg/dL). Although the doses 
may be delayed, all high risk patients should still receive a total of 4 
IDArubicin doses (each dose may be either full dose or reduced dose) spaced at 
least 48 hours apart during Induction.  Please notify the study chair of patients who 
require delays in IDArubicin doses due to direct hyperbilirubinemia in Induction 
 
 
 
 
 

 
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MitoXANtrone 
 
Dose Adjustments for MitoXANtrone 
Direct Bilirubin 
BSA ≥ 0.6m2 
BSA < 0.6m2 
< 3.4 mg/dL 
100% dosing (12 mg/m2/dose) 
100% dosing (0.4 mg/kg/dose) 
3.4-5 mg/dL 
25% dosing (3 mg/m2/dose) 
25% dosing (0.1 mg/kg/dose) 
> 5 mg/dL 
Hold until direct bilirubin < 5 
mg/dL 
Hold until direct bilirubin < 5 
mg/dL 
 
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. If the 
direct bilirubin is > 5 mg/dL, hold the mitoXANtrone dose. If the direct bilirubin 
is between 3.4 and 5 mg/dL, give 25% of the mitoXANtrone dose. Monitor the 
direct bilirubin closely and if it decreases to < 3.4 mg/dL, further doses of 
mitoXANtrone may be given at full dose. 
 
5.4.2 
Renal Toxicity 
If creatinine clearance (CrCl) < 50 mL/minute, administer 75% of the IDArubicin 
dose (if BSA < 0.6 m2, 0.3 mg/kg/dose, if BSA ≥ 0.6 m2, 9 mg/m2/dose). 
 
5.4.3 
Left Ventricular Cardiac Function Toxicity 
IDArubicin and mitoXANtrone will be withheld if there is significant evidence of 
cardiac disease by echocardiogram or MUGA (shortening fraction < 27%). Do not 
re-start these drugs if withheld for this reason.  
 
5.5 
Cytarabine Dose Modifications 
5.5.1 
Neurological Toxicity 
Patients with Grade > 3 neurotoxicity from high dose cytarabine should not receive 
further high dose cytarabine. The most common neurotoxicity is an acute 
cerebellar syndrome that may manifest itself as ataxia, nystagmus, or dysarthria. 
However, seizures and encephalopathy have also occurred following therapy with 
high dose cytarabine.  
 
5.5.2 
Renal Toxicity 
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 upper 
limit of 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, timed urine collection for creatinine 
clearance, or calculated by the IDMS-traceable Schwartz equation for children68 
or the IDMS-traceable MDRD study equation for adults69 (see equations below) 
before proceeding with HD cytarabine therapy (doses of 1 g/m2). 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 (i.e., 
50% daily dose reduction if BSA < 0.6 m2, 33.3 mg/kg/day, if BSA ≥ 0.6 m2, 
1,000 mg/m2/day). With this approach, previous research has shown the prevention 

 
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of subsequent neurotoxicity in recipients of high dose cytarabine in the face of 
renal insufficiency.70 
 
For patients < 18 years old: 
GFR (in mL/min/1.73 m2) = (0.41 x Height in cm)/(serum creatinine in mg/dL) 
 
Online calculator for patients < 18 years old available at: 
http://nkdep.nih.gov/lab-evaluation/gfr-calculators/children-conventional-
unit.asp 
 
For patients ≥ 18 years old: 
GFR (in mL/min/1.73 m2) = 175 x (serum creatinine in mg/dL)-1.154 x (Age in 
years)-0.203 x (0.742 if female) x (1.212 if African American) 
 
Online calculator for patients ≥ 18 years old available at: 
http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-conventional-unit.asp 
 
 
 
6.0 
DRUG INFORMATION 
See the consent document for toxicities. All other information is available on the COG website in 
the commercial agent monographs manual titled “Drug Information for Commercial Agents used 
by the Children’s Oncology Group.” On the COG website, this manual is provided under 
Standard Sections for Protocols 
at:  https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials  
 
Please see Appendix IV for drug interactions associated with the drugs used in this study. 
 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
7.1 
Clinical Evaluation of RQ-PCR 
Patients on AAML1331 require bone marrow samples for RQ-PCR of PML-RARα 
testing for clinical reasons. These specimens must be sent to one of the approved labs for 
PML-RARα RQ-PCR testing and the cost is not covered by the study. It should be billed 
as a regular clinical lab through the institution/insurance/patient as appropriate. A list of 
approved labs is available on the protocol-specific web page of the COG website located 
at https://cogmembers.org/PROT/AAML1331/AAML1331ValidatedRQ-
PCRLabsList.pdf  
 

 
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7.1.1 Time Points for Clinical Evaluation of RQ-PCR of PML-RARα 
 
At diagnosis prior to initiating therapy. (See Section 3.1.4.1)  
 
Day 43 of Consolidation Cycle 2  
o If the initial Day 43 clinical RQ-PCR test is positive, contact the study 
chair and a repeat sample must be sent 1-2 weeks later. It is recommended 
that this confirmation sample be sent to either Hematologics, Inc, Seattle, 
WA, USA or the Molecular Haematology Lab, Royal Prince Alfred 
Hospital, NSW, Australia due to their experience with these samples. 
(These are billed to the patient) If repeat test is negative continue to 
Consolidation Cycle 3. If repeat test is confirmed positive continue to 
MRD Positive Consolidation. 
 
Day 29 of MRD Positive Consolidation if applicable 
 
End of protocol therapy 
 
Relapse 
 
 
7.1.2 Required Specimens 
Site should always confirm with the selected RQ-PCR laboratory with regard to 
what quantity of specimen and tube is appropriate for testing at their lab.  
In general specimens can be drawn as follows: 
 
3 mL of bone marrow in a purple top. 
 
 
7.2 
End of Therapy & Follow-up 
 
STUDIES TO BE OBTAINED 
End of Therapy 
Follow-Up 
Relapse 
History 
 
 
X 
Physical Exam with VS 
X 
Monthly to 12 months, 
q3 months to 36 months,  
q6 months to 48 months, 
then yearly to 10 years 
X 
Ht, Wt, BSA 
 
 
X 
Performance Status 
X 
 
X 
CBC, differential, platelets 
X 
Monthly to 12 months,  
q3 months to 36 months,  
q6 months to 48 months 
then yearly to 10 years 
X 
Electrolytes (Ca++, Mg++, K+), 
and Creatinine 
 
 
X 
Uric Acid 
 
 
X 
Echocardiogram or MUGA, and 
ECG 
X 
Yearly to 10 years 
 
BMA for morphology 
 
 
X 
BMA for flow cytometry, 
cytogenetics & FISH 
 
 
X 
BMA for clinical RQ-PCR of 
PML-RARα 
X 
Strongly recommended 
for all patients with high 
risk APL and those 
patients with standard 
X 

 
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risk APL who required 
the MRD positive 
Consolidation Cycle:  
q3 months until 3 years 
from diagnosis. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up at:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 

 
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7.3 
Research Studies for which Patient Participation is Optional 
Optional Study 
Specimen 
Diagnosis Day 
1 
Day 
8 
Day 
15 
Day 
29 
Consolidation 
Cycle 1 
Day 1 
Consolidation 
Cycle 2 
Day 43 
Consolidation 
Cycle 3 
Day 1 
End of 
therapy 
2 years post 
therapy 
4 years 
post 
therapy 
Relapse (either 
molecular or 
morphologic) 
FLT3 
Bone 
Marrow  
X1, 3 
 
 
 
 
 
X 
 
 
 
 
X 
MRD 
Bone 
Marrow 
AND  
Peripheral 
Blood 
X1 
 
 
 
X 
 
X 
 
X 
 
 
X 
Coagulopathy 
Peripheral 
Blood in 
Citrate tube 
AND 
Peripheral 
Blood 
in CTI tube 
X2 
X 
X 
X 
X 
 
 
 
 
 
 
 
Neurocognitive 
Testing4 
CogState 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
BRIEF 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
Psychologist 
administered 
battery 
 
 
 
 
 
 
 
 
X 
X 
X 
 
1 If bone marrow is not obtained at diagnosis, may submit peripheral blood only. 
2 Requested if available. 
3 Diagnostic specimens collected on Project Every Child (APEC14B1). 
4 See Section 16.4.1 for evaluation time point details. 
 

 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Failure to achieve an hCR/hCRi by Day 70 of Induction. 
b) Refractory CNS leukemia following 6 doses of intrathecal therapy. 
c) Failure to achieve molecular remission following the MRD Positive Consolidation cycle 
(mitoxantrone/cytarabine/ATRA) 
d) Relapse (hematologic, molecular or extramedullary) during Consolidation therapy. 
e) Repeat eligibility studies (if required) prior to initiation of protocol therapy are outside the 
parameters required for eligibility (see Section 3.2). 
f) Refusal of further protocol therapy by patient/parent/guardian. 
g) Completion of planned therapy.  
h) Unacceptable toxicity due to protocol therapy (see Section 5.0) 
i) Physician determines it is in patient’s best interest. 
j) Development of a second malignancy. 
k) Pregnancy 
 
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 patient is taken Off Study.  
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Tenth anniversary of the date the patient was enrolled on this study. 
f) RQ-PCR determines patient to be PML-RARα negative at diagnosis or RQ-PCR 
inevaluable (including patients determined to have a variant RARA translocation such as 
PLZF-RARα, NPM1-RARα, NUMA-RARα). 
g) RQ-PCR sample not collected prior to initiation of protocol therapy. 
 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Design 
This is a non-randomized study of pediatric patients with APL stratified by risk group 
based on presenting WBC. Patients with standard risk disease (WBC < 10,000/µL at 
diagnosis) and high risk disease (WBC ≥ 10,000/µL at diagnosis) will be assessed 
independently for outcome measures. The primary endpoint will be event-free survival 
(EFS). EFS is defined as the time from on study to failure to achieve hematological CR 
prior to start of Consolidation, persistence of molecular positive disease after MRD 
Positive Consolidation course (mitoxantrone/cytarabine/ATRA chemotherapy course 
following Consolidation Cycle 2), relapse (molecular, morphologic or extramedullary), or 
death. 

 
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Other outcome measures will include the hematological, molecular, and cytogenetic 
remission rates after each phase of therapy, early death rates, overall survival from on 
study, treatment related mortality, relapse risk, percentage of patients experiencing Grade 3 
or higher toxicity or any grade of cardiac toxicity, time to count recovery, and duration of 
hospitalization. 
 
When AAML1331 was developed and opened, outcome data from the most recent prior 
COG APL study AAML0631 was not mature. Thus, similar to AAML0631, the statistical 
plan of AAML1331 initially used the historical comparator AIDA 0493 (the most mature 
and best outcomes published for pediatric APL). During the course of AAML1331 accrual, 
AAML0631 outcome data became available and demonstrated that the addition of arsenic 
trioxide (ATO) consolidation therapy resulted in higher survival estimates compared to 
AIDA0493. Therefore the statistical plan of AAML1331 was amended to include a primary 
outcome comparison to AAML0631. 
AAML0631 included 2 cycles of ATO consolidation and has excellent survival results. 
Thus, we would not expect AAML1331 to be significantly superior to AAML0631, but 
rather the goal of the study should be to show non-inferiority to AAML0631. This design 
is clinically appropriate because the AAML1331 treatment regimen represents a significant 
reduction in cytotoxic chemotherapy treatments which should result in decreased toxicities 
(both in the short and long term). To demonstrate that AAML1331 therapy is non-inferior 
to AAML0631 would be a major step forward in reducing treatment morbidity and 
mortality. 
Standard risk APL treatment on AAML0631 included 335 mg/m2 of doxorubicin 
equivalents whereas AAML1331 includes no anthracycline for standard risk APL patients. 
Historical data suggests that patients with >300 mg/m2 of anthracycline have a 
cardiomyopathy odds ratio of 27 compared to patients not exposed to anthracycline.71 A 
large cohort of children treated with anthracycline and with long term follow-up has 
showed a clinical heart failure rate of 9.8% at 20 years when the cumulative anthracycline 
dose was >300 mg/m2. Among patients who developed clinical heart failure (and did not 
die from their malignancy) the rate of death due to their heart failure was approximately 
40%.72 Therefore we believe it is appropriate to consider powering our analysis of standard 
risk APL outcomes on AAML1331 in a comparison that allows a very modest decrease in 
EFS from the 97% observed on AAML0631.  
Our non-inferiority (NI) margin of 10% for the standard risk APL comparison is designed 
to allow sufficient power (80%) to demonstrate non-inferiority for an observed EFS of 
95%. This allows a modest decrease of 2% from the 97% EFS observed on AAML0631 to 
account for the benefit of elimination of anthracycline chemotherapy (also knowing that 
most APL relapses are successfully treated with further therapy and autologous transplant 
consolidation). We also feel that the NI margin for the high risk group is clinically relevant 
given the degree of uncertainty in the AAML0631 survival estimates. The high risk group 
includes a NI margin of 14.5%, but the AAML0631 24 month EFS estimate has a similarly 
large confidence interval of +/-13%. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
The Children’s Oncology Group recently completed a Phase III study of children with 
newly diagnosed APL (COG AAML0631). On AAML0631, the actual accrual rate was 
31.5 patients per year (20 standard risk, 11.5 high risk). Allowing for up to 5% of patients 

 
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to be ineligible for study enrollment, enrollment of up to 158 patients will be required to 
assure that a total of 96 eligible patients with standard risk APL and 54 eligible patients 
with high risk APL are enrolled. It is estimated that accrual goals will be met in 5 years for 
both standard and high risk APL.  
 
9.3 
Statistical Analysis Methods 
9.3.1 
Analysis Plan 
Primary Objective 1 
EFS for patients with SR APL on this study will be compared against a fixed EFS 
of 97% at 24 months, which was observed for patients with SR APL treated on 
AAML0631. 
 
The non-inferiority null hypothesis is that the 2-year EFS for SR patients on this 
study is not non-inferior to 97% with a non-inferiority (NI) margin of 10%. The 
alternative hypothesis is that the 2-year EFS for SR patients is non-inferior to 97% 
with a NI margin of 10%. The Kaplan-Meier method will be used to estimate 2-
year EFS along with 90% log-minus-log transformed confidence limits for SR 
patients. If the lower confidence limit for the 2 year EFS exceeds 97% - 10% = 
87%, non-inferiority will be concluded. The final analysis of EFS will occur after 
a minimum of 2-years following the enrollment of the last eligible SR patient. 
 
Primary Objective 2 
EFS for patients with HR APL on this study will be compared against a fixed EFS 
of 83% at 24 months, which was observed for patients with HR APL treated on 
AAML0631. The non-inferiority null hypothesis is that the 2-year EFS for HR 
patients on this study is not non-inferior to 83% with a NI margin of 14.5%. The 
alternative hypothesis is that the 2-year EFS for HR patients is non-inferior to 83% 
with a NI margin of 14.5%. The Kaplan-Meier method will be used to estimate 2-
year EFS along with 90% log-minus-log transformed confidence limits for SR 
patients. If the lower confidence limit for the 3-year EFS exceeds 83% - 14.5% = 
68.5%, non-inferiority will be concluded. The final analysis of EFS will occur after 
a minimum of 2 years following the enrollment of the last eligible HR patient. 
 
9.3.2 
Power Calculations 
Primary Objective 1 
A study of 96 evaluable SR patients using a one-sided type I error rate of 0.05 and 
10% NI margin will have 80%, 91% and 97% power to reject the null hypothesis 
that the 2-year EFS is not non-inferior to 97% for a 2-year EFS of 95%, 96% and 
97% respectively. Power calculations were performed using PASS 14. 
 
Primary Objective 2 
A study of 54 evaluable HR patients using a one-sided type I error rate of 0.05 and 
14.5% NI margin will have 80% power to reject the null hypothesis that the 2-year 
EFS is not non-inferior to 83% for a 2-year EFS of 83%. Power calculations were 
performed using PASS 14. 
 
9.3.3 
Interim Monitoring 
Interim analysis of the incidence of adverse events mainly due to arsenic trioxide 
will be performed for each cycle of therapy. If excessive toxicity is observed, then 

 
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treatment modification or study termination will be considered. 
 
Futility monitoring – Standard Risk patients 
The SR arm will be monitored for futility when approximately 50% of the expected 
number of EFS events have been observed (at least 4 of the 71 total events). The 
interim analysis is anticipated to occur after 80% of the patients are enrolled. We 
will calculate the conditional probability that the 90% log-minus-log transformed 
confidence limits for 2-year EFS exceeds 87%. For those who have not 
experienced an EFS event by the time of analysis, EFS time will be simulated 
under the alternative hypothesis using cure models consistent with 2-year EFS of 
96%. If the conditional probability of rejecting the null hypothesis is less than 5%, 
the treatment arm will be identified for possible closure of accrual. 
 
Simulations of the operating characteristics of this futility monitoring plan were 
performed 500 times assuming that EFS for SR patients enrolled up to the time of 
the interim monitoring would follow a cure model, S(t), consistent with a 2-year 
EFS of 87%. That is, S(t) = [S0631 (t)]3.41, where   
S0631(t) = 0.906 + 0.094 exp(-0.0238*t), t measured in months, is the cure model 
corresponding to the AAML0631 EFS results for SR patients. For those who have 
not experienced an EFS event by the time of analysis (including those who have 
not enrolled yet), EFS was simulated 500 times using a cure model, S(t), consistent 
with a 2-year EFS of 97%. That is, S(t) = [S0631 (t)]0.746. 60.4% of the time the 
conditional probability of rejecting the null hypothesis was less than 5%.  
 
Simulations of the impact of this futility monitoring plan on overall power were 
performed 500 times assuming that EFS for SR patients enrolled up to the time of 
the interim monitoring would follow a cure model, S(t), consistent with a 2-year 
EFS of 97%. That is, S(t) = [SAIDA (t)]0.746, where   
S0631(t) = 0.906 + 0.094 exp(-0.0238*t), t measured in months, is the cure model 
corresponding to the AAML0631 EFS results for SR patients. For those who have 
not experienced an EFS event by the time of analysis (including those who have 
not enrolled yet), EFS was simulated 500 times using the same cure model S(t). 
The overall power accounting for stopping due to futility monitoring is 95%. 
 
Futility monitoring – High Risk patients 
The HR arm will be monitored for futility when approximately 50% of the 
expected number of EFS events have been observed (at least 6 of the 12 total 
events). The interim analysis is anticipated to occur after 80% of the patients are 
enrolled. We will calculate the conditional probability that the 90% log-minus-log 
transformed confidence limits for 2-year EFS exceeds 68.5%. For those who have 
not experienced an EFS event by the time of analysis, EFS time will be simulated 
under the alternative hypothesis using cure models consistent with 2-year EFS of 
82%. If the conditional probability of rejecting the null hypothesis is less than 5%, 
the treatment arm will be identified for possible closure of accrual. 
 
Simulations of the operating characteristics of this futility monitoring plan were 
performed 500 times assuming that EFS for HR patients enrolled up to the time of 
the interim monitoring would follow a cure model, S(t), consistent with a 3-year 
EFS of 71%. That is, S(t) = [S0631 (t)]1.73, where   

 
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S0631(t) = 0.7973 + 0.2027 exp(-0.0976*t), t measured in months, is the cure model 
corresponding to the AAML0631 EFS results for HR patients. For those who have 
not experienced an EFS event by the time of analysis (including those who have 
not enrolled yet), EFS was simulated 500 times using a cure model, S(t), consistent 
with a 2-year EFS of 82%. That is, S(t) = [S0631 (t)]1. 58.4% of the time the 
conditional probability of rejecting the null hypothesis was less than 5%. 
 
Simulations of the impact of this futility monitoring plan on overall power were 
performed 500 times assuming that EFS for HR patients enrolled up to the time of 
the interim monitoring would follow a cure model, S(t), consistent with a 2-year 
EFS of 82%. That is, S(t) = [S0631 (t)]1, where   
S0631(t) = 0.7973 + 0.2027 exp(-0.0976*t), t measured in months, is the cure model 
corresponding to the AIDA 0493 EFS results for HR patients. For those who have 
not experienced an EFS event by the time of analysis (including those who have 
not enrolled yet), EFS was simulated 500 times using this cure model S(t). The 
overall power accounting for stopping due to futility monitoring is 78%. 
 
9.4 
Correlative Biology Studies 
9.4.1 
Study design for Study Objective 1.2.1 (FLT3 Mutations) 
A Fisher’s exact test will be used to compare the Induction death rate for patients 
with FLT3 mutations to patients with wild type FLT3. Assuming 140 patients have 
FLT3 results available and a FLT3 mutation prevalence of 40% (based on prior 
pediatric APL data), this study will have 80% power with two-sided 0.05 type I 
error to detect differences of 19.5% and 15.5% in Induction death rates for 
Induction death rates of 30% and 20%, respectively, for FLT3 mutant patients.42 
The mutational analysis will be performed on diagnostic samples with an expected 
sample size of 140 and average accrual of 2.3 patients/month. 
 
9.4.2 Study design for Study Objective 1.2.2 (Bone Marrow and Peripheral Blood MRD 
Testing) 
For patients in remission at the end of Induction, the log-rank test will be used to 
test for differences in disease free survival (DFS) for those with end of Induction 
RQ-PCR of < 1 normalized copy number (NCN) compared with those with end of 
Induction RQ-PCR ≥ 1 NCN. Assuming 90% of patients are in remission at the 
end of Induction and 65% of these have specimens available to be analyzed by 
PCR, there will be at least 85 patients in remission at the end of Induction with 
PCR results. This corresponds to an average accrual rate of 1.4 patients/month. 
This study will have 80% power with two-sided 0.05 type I error to detect a 
difference of 32% in 5-year DFS (90% vs. 58%, 5.2 hazard ratio). 
 
9.4.3 Study design for Study Objective 1.2.3 (Early Death and Coagulopathy 
Complications) 
Adverse event reporting will be used to estimate the rate of serious early 
coagulopathy events (Grade 3 or higher hemorrhage or thrombosis from diagnosis 
through end of Induction). We will calculate the ISTH DIC score as has been 
previously described49 and compare the sensitivity and specificity (to accurately 
predict patients who will experience a serious early coagulopathy event) of ISTH 
with that of thrombomodulin using McNemar's test for paired data. Based on a 

 
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target accrual of 150 patients for AAML1331, if all patients participate in this 
biology study with submission of specimens and the clinical data required to 
calculate ITSH, then the average accrual rate will be 2.5 patients/month. 
Estimating that serious early coagulopathy events occur in 20% of the patients 
(based on the rate seen in AAML0631), then there will be 30 AAML1331 patients 
with these events. AAML1331 will have 81% power to detect a difference in 
sensitivities of 22% (68% vs. 90%) using a 1 sided test with 0.05 significance level 
assuming 23% proportion discordant. There will also be at least 90% power to 
detect a difference in specificities of 20% (66% vs. 86%) using a 1 sided test with 
0.05 significance level. To improve the predictive ability of the ISTH DIC score, 
we will use a stepwise combination of biomarkers (elevation in thrombomodulin 
levels, thrombin generation, fibrinolytic parameters and microparticles). Receiver 
operating characteristic (ROC) curve will be used to assess the accuracy in 
prediction of bleeding events during Induction and the areas under the ROC curve 
(AUC) will be compared. 
 
9.4.4 
Study design for Study Objective 1.2.4 (Neurocognitive Outcomes) 
The primary objective of this study is to use CogState testing to evaluate change 
in neurocognitive function from end of Induction to 2 years off therapy. The three 
secondary objectives include first, use of parent-reporting on the BRIEF 
questionnaire to assess change in neurocognitive function from end of Induction 
to 2 years off therapy, and for the other secondary aims, use of a psychologist 
administered battery to assess change in neurocognitive function from end of 
therapy to 4 years off therapy. 
 
Actual CogState scores for each domain at each time point will be summarized and 
examined by descriptive statistics and scatter plots. Change in score for a domain 
from end of Induction will be calculated and similarly summarized by descriptive 
statistics. For the CogState scores, the mean change of score from end of Induction 
to a later time point will be estimated along with its 95% CI. One sample t-test on 
the change of score will be used to examine if there is significant decline in 
neurocognitive function from end of Induction to 2 years off therapy. Thus our 
analysis of CogState outcome data will be restricted to participants who have 
completed CogState testing following Induction (i.e., we will include data from 
patients who are 5 years of age or older by Day 1 of Consolidation Cycle 1). 
Outcomes for younger patients not completing the initial Induction assessment will 
be reported in a descriptive manner. Linear mixed models using scores from all 
time points as outcome will also be used to estimate the change in scores between 
time points with adjustment for within-patient correlation of the score by random 
effects for individual patients. If the change in score over time appears 
approximately linear in time, linear mixed models assuming time as a continuous 
covariate will be used to estimate the rate of decline over time and determine 
whether the rate of decline is significantly higher than zero. 
 
Since each domain will be analyzed separately, the alpha level for each analysis is 
set to 0.01 for CogState and the psychologist administered battery and 0.017 for 
BRIEF according to Bonferroni adjustment to maintain an overall alpha of 0.05. 
For the primary objective utilizing CogState testing, assuming that there are 120 
patients 5 - 18 years old who consent to participate in neurocognitive testing and 
receive all protocol therapy, there will be 80% power to detect the unit change 

 
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provided in the table below in the mean change score between end of Induction 
and 2 years off therapy using a one-sample t-test at two-sided alpha level for the 
SD of the change of score between two time points provided in the table below. 
For the secondary objectives, mean change score will be compared from end of 
Induction to 2 years off therapy for the BRIEF and from end of therapy to 4 years 
off therapy for the psychologist administered battery, BASC-2 Anxiety, 
Depression, and Social Skills scores, and the PedsQL Total and Physical Health 
scores. 
 
Outcome 
Unit Change 
Change SD 
CogState (each of five tasks) 
4.3 
13.6 
BRIEF (each of three tasks) 
4.3 
14.5 
Estimated IQ 
6.7 
20.4 
CVLT Total Score 
4.3 
13.6 
Processing Speed Index 
6.5 
20.4 
CMS Stories and Faces Immediate Memory 
1.3 
4.1 
ABAS-II General Adaptive Composite 
6.5 
20.4 
BASC-2 (each of three scales) 
8.2 
26.0 
PedsQL (each of two scales) 
10.3 
32.4 
 
In AAML0631, 91.7% of participants were between the ages of 5 and 18 and the 
upper age of enrollment was 21 years of age. Therefore, we would anticipate 
91.7% or 138 of the 150 subjects in the proposed sample to be 5 - 18 years old. 
Based on the accrual to date to this optional embedded study, we project that up to 
120 patients 5 - 18 years old will participate in neurocognitive testing and receive 
all protocol therapy.  
 
 
9.5 
Gender and Minority Accrual Estimates 
The gender and minority distribution of the study population is expected to be: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
0 
3 
0 
0 
3 
Asian 
5 
0 
0 
0 
5 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
11 
9 
0 
0 
20 
White 
57 
38 
21 
14 
130 
More Than One Race 
0 
0 
0 
0 
0 
Total 
73 
50 
21 
14 
158 
 
This distribution was derived from AAML0631. 

 
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10.0 
EVALUATION CRITERIA  
10.1 
Common Terminology Criteria for Adverse Events (CTCAE)  
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE 
v4.0 as referenced on the CTEP website (i.e., v4.02 and all subsequent iterations prior to 
version 5.0). 
 
10.2 
Response Criteria for Patients with Acute Promyelocytic Leukemia 
10.2.1 Hematologic Complete Remission (hCR and hCRi) 
 
In a bone marrow sample, hematologic complete remission (hCR) is defined 
as a differential count of at least 200 nucleated cells with less than 
5% promyeloblasts/abnormal promyelocytes. There must be signs of 
recovering marrow with an absolute neutrophil count > 1,000/μL and platelets 
> 100,000/μL. Extramedullary disease must have resolved including clearance 
of the CNS (CSF negative for blasts) and resolution of chloromas. 
 
Hematologic complete remission with incomplete blood count recovery 
(hCRi): all the above criteria for hCR except for residual neutropenia 
(< 1,000/μL) or thrombocytopenia (< 100,000/μL). 
 
Patients who appear not to have achieved hematological complete remission after 
Day 43 of Induction may benefit from consultation for a rapid pathology review 
(see Section 13). 
 
 
10.2.2 Molecular Remission 
 
Molecular remission is the absence of PML-RARα fusion transcript by 
RQ- PCR (with an assay sensitivity of at least 10-4) in a bone marrow specimen 
obtained after at least 14 weeks of Consolidation therapy. A positive test 
(detectable PML-RARα fusion transcripts) must be confirmed by a repeat test 
on a separate bone marrow specimen obtained at least 1 to 2 weeks later. 
 
10.2.3 Treatment Failure/Events 
 
Resistant Disease: failure to achieve hCR/hCRi by Day 70 of Induction. 
 
 
Molecular Resistant Disease: persistence of PML-RARα fusion transcript by 
RQ-PCR in two consecutive marrow samples taken 1 - 2 weeks apart following 
the MRD Positive Consolidation cycle (mitoxantrone/cytarabine/ATRA). 
 

 
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 
Induction Death: all deaths during Induction phase prior to achievement of 
hCR/hCRi. 
 
10.2.4 Relapse 
 
Hematologic 
Relapse: 
reappearance 
of 
promyeloblasts/abnormal 
promyelocytes (> 5%) in the bone marrow with genetic confirmation of 
t(15;17) PML/RARα by cytogenetics, FISH or RQ-PCR in a patient who had 
previously achieved hCR/hCRi. 
 
 
Molecular Relapse: persistence of hematologic CR but reappearance of the 
PML-RARα transcript by PCR testing in two successive bone marrow samples 
in a patient who had previously achieved molecular remission. 
 
 
Extramedullary 
Relapse: 
reappearance 
or 
development 
of 
promyeloblasts/abnormal promyelocytes found in the CSF or on biopsy of any 
tissue with features suspicious for extramedullary disease. Genetic 
confirmation of PML-RARα with FISH or RT-PCR testing is required. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents.  
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of 
the adverse event including the grade (severity); 2) the relationship to the study therapy 
(attribution); and 3) the prior experience (expectedness) of the adverse event. 
  
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. In some cases an agent obtained commercially may be used for 
indications not included in the package label. In addition, NCI may on some occasions 
distribute commercial supplies for a trial. Even in these cases, the agent is still considered 
to be a commercial agent and the procedures described below should be followed. 
 
Determine the prior experience Expected events are those that have been previously 
identified as resulting from administration of the agent. An adverse event is considered 
unexpected, for reporting purposes only, when either the type of event or the severity of 
the event is not listed in:  
 
 
the current known toxicities for each commercial agent as provided in the Drug 
Information for Commercial Agents Used by the Children’s Oncology Group 
posted on the COG website; or 
 
the drug package insert. 
 

 
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Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A metastasis 
of the initial neoplasm is not considered a secondary malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP- AERS. Three options are available to describe the event:  
 
Leukemia secondary to oncology chemotherapy   
 
Myelodysplastic syndrome  
 
Treatment related secondary malignancy 
 
11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS 
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited Reporting 
System), accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B. The commercial agent(s) used 
in this study are listed in the front of this protocol immediately following the Study 
Committee roster.  
 
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event. 
 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
 
CTCAE term (AE description) and grade: 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 at: http://ctep.cancer.gov/protocolDevelopment/electronic_
applications/ctc.htm.  
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy With a Commercial Agent or Within 30 Days1 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution. Any death that occurs more than 
30 days after the last dose of treatment with a commercial agent that can be 
attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence must be reported via CTEP-AERS. 

 
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11.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
The NCI defines both routine and expedited AE reporting. Routine reporting is 
accomplished via the Adverse Event (AE) Case Report Form (CRF) within the study 
database. For this study, routine reporting while on protocol therapy will include all 
toxicities reported via CTEP-AERS and all Grade 3 and higher non-hematological Adverse 
Events and all grades of the following cardiac adverse events: prolonged QTc interval, 
ventricular arrhythmia, and left ventricular systolic dysfunction. Routine reporting while 
in follow-up (off protocol therapy) will include all toxicities reported via CTEP-AERS and 
all grades of the following cardiac adverse events: prolonged QTc interval, ventricular 
arrhythmia, and left ventricular systolic dysfunction. 
 
NOTE: Adverse events related to coagulopathy including hemorrhage/bleeding and 
thrombosis/clotting events are NOT considered hematologic toxicities for this study. 
Coagulopathy in APL is a targeted event in this study and therefore it is important to report 
all Grade 3 or higher hemorrhage/bleeding and thrombosis/clotting events included in the 
CTCAE catalog as follows: 
 
Hemorrhage (all sites) 
 
Bleeding (all sites) 
 
Disseminated Intravascular Coagulation 
 
Hematosalpinx 
 
Menorrhagia 
 
Epistaxis 
 
Purpura 
 
Hematoma 
 
Vascular Access Complication (if related to thrombosis) 
 
Ischemia cerebrovascular 
 
Superior Vena Cava syndrome 
 
Thromboembolic event 
 
Superficial Thrombophlebitis 
 
Portal Vein Thrombosis 
 
 
12.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 

 
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13.0 
PATHOLOGY GUIDELINES AND REQUIREMENTS 
13.1 
Review of Diagnostic CSF for CNS Disease Patients 
For patients who are diagnosed with CNS disease based on blasts in the CSF, we strongly 
recommend that you contact the COG APL investigator James “Jim” Feusner, MD to 
discuss central review of the CSF slides. Dr. Feusner can be contacted at 
jfeusner@mail.cho.org and he will provide shipping information upon contact. 
 
13.2 
Review of End Induction Bone Marrow 
 
Optional Pathology Consultation 
In some cases the local pathologist may have difficulty or need a second opinion 
interpreting the marrow status at the end of Induction.  If a consultation for a difficult case 
is desired then this would be arranged on a consultation basis only and a fee may be 
charged. If a consultation is desired, the institution may send pathology materials (stained 
and unstained slides from bone marrow and peripheral blood and pathology, bone marrow, 
flow cytometry reports including copies of blast gate and dot plots of markers) and pertinent 
cytogenetics data to the study pathologist.  Please contact the study pathologist to request a 
consult and verify what is needed for the consultation prior to submitting pathology 
materials. 
Copies of consult reports will be sent to contributing institution and study chair, in order 
to include them in study data files.  
 
Materials sent for consultation must be shipped using the institution’s courier account to:  
 
AAML1331 Study Review Pathologist 
Samir Kahwash, MD 
Department of Pathology 
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, OH 43205 
Phone: (614) 722-5450 
Fax: 
(614) 722-2899 
Email:  Samir.Kahwash@nationwidechildrens.org 
 
 
14.0 
CYTOGENETIC ANALYSIS GUIDELINES AND REQUIREMENTS 
14.1 
Cytogenetic Analysis Overview 
It is strongly recommended that all patients enrolled on AAML1331 have a 
cytogenetics/FISH PML-RARα study performed by a COG approved laboratory at the time 
of initial diagnosis and relapse.  
 
The institutional CRA must inform the cytogenetics laboratory that the patient has been 
enrolled in a COG APL study and that the cytogenetics/FISH data must be submitted 
within 2 weeks of enrollment on the AAML1331 protocol. See Appendix V for 
cytogenetics procedures and for the Study Authorization Form for reflexive FISH testing.  

 
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14.2 
Specimen Collection and Submission 
It is strongly recommended that specimens for cytogenetic/FISH PML-RARα analysis be 
sent to a COG approved institutional cytogenetics laboratory. If a COG institution does not 
have a COG approved laboratory, the institution may send the samples for 
karyotyping/FISH studies to any COG approved cytogenetics laboratory on a fee-for-
service basis. Prior arrangements for performing cytogenetics and/or FISH studies should 
be made with the laboratory. An authorization form for the reflexive FISH testing signed 
and dated (by the physician or designees just as with any order) and sent to the cytogenetics 
laboratory with the sample will simplify and enhance the ability to obtain FISH testing and 
results. 
 
14.2.1 Specimen Collection 
A minimum of 2 mL (optimal volume is 3 mL) of fresh whole bone marrow 
aspirated through a needle into a syringe containing sodium heparin (preservative-
free is preferable) is recommended in all cases. A first or second draw, or a draw 
from a repositioned needle, is best to ensure a sufficient number of leukemic cells 
in the aspirate. The specimens should be kept at room temperature and 
transported to the institutional cytogenetics laboratory as quickly as possible 
(always within 24 hours of collection). If shipping is done by overnight courier 
to an approved laboratory, that laboratory should be contacted to obtain 
instructions on transport. Some laboratories request that specimens be transferred 
in a 15 mL conical tube filled with RPMI - 1640 and 15% heat inactivated fetal 
calf serum. Specimens should be kept at ambient temperature. 
 
 If bone marrow cannot be aspirated, a trephine biopsy should be 
submitted. Also if available, 1 - 2 unstained bone marrow aspirate slide(s) 
can be used for FISH with PML-RARα probes to confirm the diagnosis. 
 
 Peripheral blood (3 - 5 mL) collected in sodium heparin should be 
submitted as a back-up to the bone marrow when the marrow sample is 
suboptimal or unobtainable, if more than 20% circulating blasts are 
identified, or when a constitutional abnormality (e.g., trisomy 21) is a 
possibility. 
 
Please note: Results of these studies should be submitted to the corresponding 
coordinator of the COG Myeloid Cytogenetics Committee for central review (see 
below). 
 
14.2.2 Requirements for Data Submission 
The following are required for each case: a completed COG Cytogenetics/FISH 
PML-RARα Reporting Form (found on the COG member website) and two 
original karyotypes (different cells), with corresponding full size metaphase 
spreads of each abnormal clone or two karyotypes of normal cells with 
corresponding full size metaphase spreads in the case of normal cytogenetic 
analysis. A normal karyotype in the leukemic cells of a patient with APL could be 

 
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due to a cryptic insertion/rearrangement that would be detected by FISH with 
PML-RARα probes. In such cases a sequential G-banded metaphase to FISH, or 
reverse DAPI on a metaphase should be performed to aid the localization of the 
probes. In very rare instances an evaluation of the case using a RARα break apart 
probe may be required. This information must be sent to the appropriate 
coordinating cytogeneticist within 2 weeks of enrollment on the AAML1331 
protocol (see Appendix V) and within one month of disease relapse, if applicable. 
Reports must be sent electronically. Reporting Cytogenetics forms must be filled 
out for all cases, whether or not the cytogenetic analyses were successful. A 
separate form is required for each specimen (i.e., bone marrow and blood) 
analyzed. FISH form, using the PML-RARα probe, should also be completed and 
sent to the coordinating cytogeneticist with images documenting the abnormal or 
normal (in rare instances) FISH patterns. If the laboratory is not able to perform 
FISH, contact the COG cytogenetic coordinators for advice. Any discrepancies in 
interpretation between cytogenetics/FISH results from the laboratory and the 
coordinator will be discussed between the coordinators, with consult of additional 
cytogenetics committee members as necessary. The COG cytogenetics committee 
decision will be used for data analysis of trial results related to cytogenetic 
classification. 
 
 
Cytogenetic Coordinators 
Please send above materials by e-mail to the following COG Cytogenetics 
Laboratories:  
 
WEST OF MISSISSIPPI RIVER 
(INCLUDE MINNESOTA AND 
WISCONSIN), AUSTRALIA, NEW 
ZEALAND, WESTERN CANADA 
EAST OF MISSISSIPPI RIVER 
(EXCLUDE MINNESOTA AND 
WISCONSIN), EUROPE, EAST 
CANADA 
SEND TO:  
SEND TO: 
Betsy Hirsch, PhD 
Susana C. Raimondi, PhD, FACMG 
Director of Cytogenetics Laboratory 
Director of Cytogenetics Laboratory 
Department of Laboratory Medicine and 
Pathology 
Department of Pathology  
(Room 4023A) 
University of Minnesota 
St. Jude Children's Research Hospital 
Mayo Mail Code 609 
262 Danny Thomas Place, Mail Stop 250 
420 Delaware St. SE 
Memphis, Tennessee 38105-3678 
Minneapolis, MN 55455 
USA 
USA 
Telephone: 901-595-3537 
Telephone: 612-273-4952/3171 
Fax: 901-595-3100 
Fax: 612-273-4689 
E-mail: susana.raimondi@stjude.org 
E-mail: hirsc003@umn.edu 
 
 
Recommendations for Case Analysis by Institutional, COG Approved 
Cytogenetics Laboratories. See Appendix V. 
 
 
 

 
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15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
The exploratory studies detailed in this section are for research purposes only, and results will not 
be used to make clinical treatment decisions. Thus, results will not be obtained in real-time (but 
rather batched for retrospective review) and results will not be returned to the treating physician. 
 
Please note, if there is an inadequate amount of bone marrow or blood for all optional studies, the 
studies should be prioritized in the following order: 
1. Bone Marrow and Peripheral Blood Minimal Residual Disease Testing (see Section 15.2) 
2. Early Death and Coagulopathy Complications in Pediatric APL (see Section 15.3) 
3. Specimen Banking and FLT3 Mutations in Pediatric APL (see Section 15.1) 
 
Additionally, if patient/parent/responsible party consents, any specimens left over on this study 
after required tests are performed will be banked for future research studies. 
 
Optional Biology 
Specimens 
Diagnosis 
Induction 
Consolidation 
Cycle 2 
End of 
Therapy 
Relapse 
FLT3 Study 
(Section 15.1) 
X 
 
X (Day 43) 
 
X 
MRD Study 
(Section 15.2) 
X 
X (Day 29) 
X 
X 
X 
Coagulopathy Study 
(Section 15.3) 
X 
X (Days 1, 
8, 15, 29) 
 
 
 
 
 
15.1 
FLT3 Mutations in Pediatric APL 
15.1.1 Specimens 
From consenting patients, 1 mL to 3 mL of bone marrow specimen will be 
collected at the following time points: 
 
At diagnosis. If bone marrow is not obtained at diagnosis, may submit 3 
to 10 mL of peripheral blood instead. When APEC14B1 opens to AML 
patients, this diagnostic specimen will be collected through enrollment on 
APEC14B1. 
 
Day 43 of Consolidation Cycle 2 
 
At the time of either a molecular or morphologic relapse, if applicable.  
 
15.1.2 Preparation 
Bone marrow (1 - 3mL) must be obtained in purple top tube (EDTA tube). If unable 
to obtain bone marrow, may send peripheral blood (3 - 10 mL) in purple top tubes 
(EDTA tube). Samples may be stored at room temperature if shipped on the day 
of collection. If stored for longer, please refrigerate. If the sample is stored for 
longer than 24 hours, please add equal volume of RPMI medium (1 mL RPMI for 
1 mL of specimen). 
 
Utilize AML Specimen Transmittal forms specific for AAML1331. Specimens 
should be placed inside a leak proof biohazard envelope with absorbent material 
and then a pressure resistance Tyvek envelope as per IATA regulations. Blood  and 

 
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marrow should be shipped in a shipping container with an Exempt Human 
Specimen label. 
 
15.1.3 Labeling 
Label the tubes with COG patient ID number, patient name and date of birth, date 
and time of collection, time point (include treatment cycle and day of cycle), and 
source of material (i.e., bone marrow or blood).  
 
15.1.4 Shipping 
COG Leukemia Biospecimen Bank 
Nationwide Children’s Hospital  
575 Children’s Crossroads, Room WB2255 
Columbus, OH 43215 
Phone: (614)722-2866 
Fax: 
(614)722-2887 
Email: MGLab@nationwidechildrens.org 
 
Call or email the Leukemia Bank only when shipping a sample to be delivered on 
Saturday. 
 
Samples should be mailed by FEDERAL EXPRESS Priority Overnight. COG sites 
may use the COG Federal Express account number available at:  
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf 
 
Samples should be sent as soon as possible and preferably less than 24 hours from 
sample collection; except samples collected on weekends or holidays should be 
shipped the first working day following collection.  
 
15.1.5 Detection of FLT3 Mutations 
FLT3 mutation testing will be performed in the laboratory of Dr. Soheil Meshinchi 
(Seattle, WA). Dr. Meshinchi has an NIH R01 grant to study the role of FLT3 
mutations in myeloid disease. 
 
Genomic DNA is used to amplify exon 14/15 and exon 20 of the FLT3 gene using 
duplex PCR with specifically designed primers. The amplified products will be 
subjected to EcoRV digestion, capillary electrophoresis and GenScan analysis for 
identification of FLT3-ITD as well as FLT3 activation loop mutations (FLT3-
ALM)73. FLT3-ITD allelic ratio (ITD-AR) is determined as a ratio of mutant to 
normal product. Presence of FLT3-ALM and FLT3-ITD at various ITD-ARs will 
be correlated with clinical characteristics and outcome (on a retrospective research 
basis). 
 
15.2 
Bone Marrow and Peripheral Blood Minimal Residual Disease (MRD) Testing 
Note: This optional research sample is different than the required RQ-PCR of PML-RARal 
research saclinical reasons which should be sent to an approved CLIA certified lab at time 
points indicated in the protocol. See Section 7.1 for details.  

 
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15.2.1 Specimens 
From consenting patients, 1 to 3 mL of bone marrow and 5 mL of peripheral blood 
will be obtained at the following timepoints to perform research evaluation of 
MRD.  These samples are for research only and results will not be returned to the 
institution.  
 
At diagnosis (If bone marrow is not obtained at diagnosis, may submit 
peripheral blood only.) 
 
Induction Day 29 
 
Consolidation Cycle 2 Day 43 (and repeated 1-2 weeks later if positive) 
 
At the end of therapy 
 
At the time of either a molecular or morphologic relapse, if applicable  
 
15.2.2 Preparation 
Bone marrow (1 - 3mL) and peripheral blood (5 mL) must be obtained in purple 
top tubes (EDTA tubes). Samples may be stored at room temperature. Utilize AML 
Specimen Transmittal forms specific for AAML1331. Specimens should be placed 
inside a leak proof biohazard envelope with absorbent material and then a pressure 
resistance Tyvek envelope. Blood and marrow should be shipped in a shipping 
container with an Exempt Human Specimen label. 
 
15.2.3 Labeling and Shipping 
MRD specimens should be sent to the COG Leukemia Biospecimen Bank at 
Nationwide Children’s Hospital. Please see Sections 15.1.3 and 15.1.4 for labeling 
and shipping information. 
 
15.2.4 Research MRD Testing 
The requested specimens for this biology study (including paired peripheral blood 
and bone marrow samples) are additional research-only specimens and results will 
not be reported back to the treating institution. This research testing will be batched 
(not performed in real-time) and performed at Hematologics, Inc. (Seattle, WA) or 
a similar qualified laboratory. RQ-PCR testing for the PML-RARα transcripts will 
be performed following EAC standards or per methods with similar or better 
reliability should new techniques be developed in the future.74 The EAC standard 
testing includes use of 3 separate forward primers to cover the PML breakpoints 
along with a single reverse primer and probe for the RARα gene. NCN is calculated 
as copies PML- RARα divided by copies control gene ABL. Reportable NCN 
values will be within a range of 2.000 – 0.001. NCN values outside of this range 
will be reported as HIGH POSITIVE or LOW POSITIVE. For NCN < 0.0001 
results will be reported as NEGATIVE within the quantitative range of this assay. 
If the specimen failed to amplify the ABL control gene with Ct values > 35 after 
repeat testing, RNA quality will be deemed inadequate. NB4 cell line cDNA will 
be used for positive control. 
 

 
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15.3 
Early Death and Coagulopathy Complications in Pediatric APL 
15.3.1 Specimens 
Patients consenting to this biology study will have 5.4 mL of blood collected 
(2.7 mL into a citrate tube and 2.7 mL into a Corn Trypsin inhibitor tube) on 
Days 1, 8, 15 and 29 of Induction.  
 
If any frozen citrated plasma sample is available from the day of presentation 
(diagnosis), it will also be analyzed for thrombomodulin levels and the CloFAL 
assay. 
 
Corn Trypsin Inhibitor (CTI) tubes will be sent to each center by the central 
coordinating center (Children’s Hospital of Michigan) upon study approval and 
will be replaced every 6 months (prior to the tube expiry) or if CTI tubes were used 
for a previous subject.  
 
Blood will be drawn at each time point for measurement of thrombomodulin levels 
& for assessment of fibrinolysis by the CloFAL assay (2.7 mL citrate tube) and for 
thrombin generation and microparticle assay (2.7 mL Corn Trypsin inhibitor, CTI 
tube). 
 
15.3.2 Preparation 
Samples are to be drawn via atraumatic venipuncture. Please do not attach the CTI 
tube directly to the needle as it is not sterile. The tubes should be filled to ensure 
proper anticoagulant to blood ratio. All specimen processing should occur within 
30 minutes after blood draw. 
 
Citrate tube: 
 
Centrifuge at room temperature at 2500 xg for 15 minutes. 
 
Using a plastic disposable pipette, remove plasma, avoiding the buffy coat, 
and place into a plastic tube for the second spin. 
 
Centrifuge again using the same temperature and speed for another 
15 minutes. 
 
Remove plasma using a clean plastic pipette, taking care to not disturb the 
cell button. 
 
Aliquot the plasma into at least 4 polypropylene tubes, 2 tubes with 500 µL 
and 2 tubes with 300 µL. 
 
Please clearly label with “Citrate tube” date of collection and type of 
sample (see Section 15.3.3). 
 
Please send any left over plasma in a separate tube (clearly label with 
“citrated plasma” and day of sample). 
 
Freeze samples at -80º C immediately after aliquoted into polypropylene 
tubes. 
 
Corn Trypsin Inhibitor (CTI tube): 
 
Centrifuge at room temperature at 2400 xg for 20 minutes. 
 
Using a plastic disposable pipette, remove plasma, avoiding the buffy coat, 
and place into a plastic tube for the second spin. 
 
Centrifuge again at 2500 xg at room temp for another 20 minutes. 

 
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 
Remove plasma using a clean plastic pipette, taking care to not disturb the 
cell button. 
 
Aliquot the plasma into at least 2 polypropylene tubes, with 1.0 mL in each 
tube. 
 
Please clearly label with “CTI tube” date of collection and type of sample 
(see Section 15.3.3). 
 
Please send any left over plasma in an additional separate polypropylene 
tube.  
 
Please clearly label with “CTI plasma” and day of sample. 
 
Freeze samples at -80º C immediately after aliquoted into polypropylene 
tubes. 
 
15.3.3 Labeling 
In addition to the study number, COG patient ID number and BPC number, clearly 
label “citrate” tube or “CTI” tube, date of collection and type of sample (diagnosis, 
Days 1, 8, 15 or 29). 
 
15.3.4 Shipping 
Samples should be sent to: 
 
 
Children’s Hospital of Michigan 
3901 Beaubien St. 
Detroit, MI 48201 
Phone: (313) 993-8805 
Fax: 
(313) 745-5237 
 
Contact Person: Wendy Hollon 
E-mail: whollo@med.wayne.edu  
Phone: (313) 745-5529 
Fax: 
(313) 745-5237 
Lab PI: Madvhi Rajpurkar, MD 
 
Samples should be sent frozen, on dry ice, using overnight delivery. Deliveries are 
accepted Tuesday – Friday. Please contact Wendy Hollon prior to shipping to 
obtain a FedEx account number and provide her the FedEx tracking number so that 
the samples can be tracked. Include a COG Generic Specimen Transmittal Form 
with each shipment. 
 
Samples can be stored frozen at -80º C and shipped once all 4 or 5 (if additional 
frozen citrated sample from day of presentation is available) samples are collected 
for each subject. 
 
15.3.5 Coagulation Studies 
All patients will have local coagulation studies (including platelet count, PT, PTT, 
D-Dimer and fibrinogen levels) checked regularly during the first week of therapy 
as part of standard care to help manage any coagulopathy complications. The 
results of this testing will be collected on the Coagulation CRF. The study PI will 

 
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assign a score as per the International Society on Thrombosis and Haemostasis 
(ISTH) disseminated intravascular coagulation (DIC) score criteria.49 
 
 
16.0 
NEUROCOGNITIVE OUTCOMES IN PEDIATRIC APL TREATMENT 
16.1 
Study Design 
The purpose of this optional embedded study is to longitudinally monitor cognitive side 
effects from this treatment, as defined by the following endpoints: 
 
 
Primary outcome:  
o To evaluate the change in CogState scores over time, defined as a decline of 
5 units in mean scores apparent at 2 years off therapy, as measured by the five 
tasks of the computerized CogState battery (i.e., processing speed, visual 
attention, visual learning, working memory, executive functioning). 
 
Secondary outcomes: 
o To evaluate change in parent-reported executive functioning over time, 
defined as a decline of 5 units in mean scores apparent at 2 years off therapy, 
as measured by the Behavioral Regulation, Working Memory and 
Metacognition Indices of the parent-completed BRIEF.  
o To evaluate change in intellectual, memory, verbal learning, and adaptive 
functioning over time, defined by declines on the Wechsler-derived estimated 
IQ and Processing Speed scores, CMS Faces and Stories memory scores, 
CVLT Total score, and ABAS-II General Adaptive Behavior Composite score 
at 4 years off-therapy. 
o To evaluate change in parent-reported psychosocial functioning and quality of 
life over time, defined by declines on the BASC-2 Anxiety, Depression, and 
Social Skills scores, and the PedsQL Total and Physical Health scores at 
4 years off-therapy. 
 
For this study, we have chosen to maximize our ability to examine neurocognitive 
functioning across a wide age range with minimal institutional and participant burden. 
Towards this aim, a combination of computerized and traditional neurocognitive measures, 
using two batteries that are already widely used within COG member institutions will be 
utilized. Specifically, we will use a brief computerized assessment system (CogState; see 
below) that targets the neurocognitive processes known to be most affected in leukemia 
survivors (i.e., attention, processing speed, and memory), and a widely used rating scale 
(the BRIEF, see below) to evaluate real world behaviors related to these processes.75 In 
addition, participants will also complete a short neurocognitive battery that has been used 
in COG ALTE07C1. Specifically, participants will complete a one hour screening battery 
of traditional neurocognitive tests, administered by a psychologist, evaluating intellectual 
functioning, immediate and learning memory, processing speed, and working memory. 
 
Both the CogState battery and the psychologist administered screening battery are being 
used in COG protocols. The proportion of patients who consent to the neurocognitive 
ancillary study embedded within COG AALL1131 is currently 71.5%. We anticipate a 
similar participation rate on this trial, particularly given that the neurocognitive tests used 
on psychologist administered battery provide a clinical screening service to the patients at 
no cost. The results from the screening battery can be used clinically to either establish a 

 
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need for further testing that is more likely to be covered by insurance, or shared with the 
child’s school to help establish the need for any accommodations or other services. 
 
The batteries have some overlap in content, but are very different in terms of their ability 
to detect small changes in cognitive functioning over time, and to highlight clinical 
meaningfulness of any demonstrated deficits. Computerized batteries allow for a larger 
number of responses compared with traditional measures. When tasks have a small number 
of items, they become susceptible to skewed distributions as well as floor and ceiling 
effects. With CogState, however, data from a large number of short trials is obtained, 
resulting in data on a true interval scale. Computerized batteries thus have the potential to 
be more sensitive to subtle changes in performance across time, making this an ideal tool 
for use in the current protocol. Finally, test-retest scores for CogState in a large sample of 
healthy individuals differed by approximately 2% on average, compared with between 
7 - 19% for traditional measures. The absence of practice effects is of particular benefit to 
the current study, as it will allow us to evaluate participants across shorter intervals than 
are typically suggested when using traditional neurocognitive measures. 
 
Although CogState has highly desirable psychometric properties that make it ideal for use 
in longitudinal studies with assessment intervals shorter than one year, traditional 
neuropsychological measures have well described associations with real-world 
functioning. Thus, in combination, the CogState and traditional task batteries will provide 
the ability to detect any changes in cognition over time, as well as to determine the clinical 
and functional significance of those changes. 
 
CogState may be administered by bachelor’s level clinical or research staff who have 
completed online training. These measures are already being used in 120 institutions within 
COG in association with an embedded, ancillary study to COG AALL1131. The test 
battery used in that trial is identical to the current study, and has been associated with a 
96% data collection rate (aggregated across time points). The ALTE07C1 battery is 
currently open at 131 institutions and is associated with 90% data collection rate at time 1. 
Thus, there is a well-established infrastructure within COG for successfully collecting 
neurocognitive data in this manner. 
 
In sum, data for this ancillary study will be obtained from two sources: 
 
1. During treatment, data will be obtained from testing with the CogState 
computerized battery and the Behavior Rating Inventory of Executive Function 
(BRIEF) from participants aged 5 - 18 years who enroll on the ancillary 
neurocognitive study embedded within AAML1331. 
2. At approximately the end of treatment, data will also be obtained from testing with 
a brief, psychologist administered battery of performance-based measures and 
parent questionnaires. 
 
16.2 
Eligibility Criteria for the AAML1331 Neurocognitive Study 
 
Enrolled on AAML1331 
 
≤ 18 years at diagnosis 
 
English-, French- or Spanish-speaking  
 
No known history of neurodevelopmental disorder prior to diagnosis of APL (e.g., 
Down syndrome, Fragile X, William syndrome, mental retardation) 

 
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 
No significant visual or motor impairment that would prevent computer use or 
recognition of visual test stimuli 
 
Note: Children who are younger than age 5 years at diagnosis may enroll on the 
neurocognitive study, but will not be evaluated with the CogState battery until the next 
assessment point following their 5th birthday. Similarly, children who are younger than 
30 months of age at diagnosis may enroll on the neurocognitive study but will not be 
evaluated with the psychologist administered battery until they reach 30 months of age. 
 
16.3 
Neurocognitive Study Consent 
This correlative study is embedded within the larger therapeutic study. Consent for this 
study is incorporated into the consent for enrollment of eligible patients onto the parent 
study. Patients who enroll in AAML1331 and meet the eligibility requirements listed above 
may elect to enroll on this ancillary study as an option, not a requirement. 
 
Note: Patients enrolling on this embedded study will complete assessments similar to those 
used on ALTE07C1 and thus patients on this study should not need to co-enroll on 
ALTE07C1. 
 
16.4 
Required Observations 
The required observations for participants in the neurocognitive study are included in the 
therapy delivery maps (see Section 4.0). To reduce participant burden, all study 
assessments coincide with regularly scheduled clinic visits when possible.  
 
16.4.1 Schedule of Observations 
In previous literature describing neurocognitive effects in both pediatric cancer 
populations and in children who have been exposed to heavy metals, some changes 
may appear acutely (and later resolve), whereas other cognitive changes may take 
years to fully emerge. The assessment intervals are designed to be able to detect 
both acute neurocognitive changes as well as more subtle changes that would 
emerge over time, according to the schedule listed below. 
 
Observation 
Number 
Treatment Phase 
CogState 
battery 
BRIEF 
Psychologist 
battery 
1 
Day 1 of 
Consolidation Cycle 1 
(+/- 2 weeks) 
 
 
 
2 
Day 1 of 
Consolidation Cycle 3 
(+/- 2 weeks) 
 
 
 
3 
End of therapy 
(+ 3 months) 
 
 
 
4 
2 years Off-therapy 
(+/- 3 months) 
 
 
 
5 
4 years Off-therapy 
(+/- 3 months) 
 
 
 
 

 
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It is important to note that the CogState battery has not been validated in children 
less than 5 years of age, which means that we will be unable to capture data from 
computerized testing from children who are less than 5 year at diagnosis. In 
AAML0631, only 6 eligible participants (5%) were enrolled who were less than 
5 years, so it is likely that we will have similarly few children enrolled on this trial 
in this age range. However, in an effort to capture information about cognitive 
changes in this vulnerable age group, we will attempt to collect computerized 
neurocognitive data (i.e., CogState) for children who are under age 5 at enrollment 
as soon as they turn 5 years of age. In addition, we will collect data from the 
performance-based measures for patients once they turn 30 months of age. Of note, 
the psychologist administered battery also includes standardized measurement of 
adaptive functioning, including developmental milestones for young patients, 
which may be particularly relevant in describing outcomes of interest for this age 
group. 
 
16.4.2 Procedure 
For each computerized assessment, participants will complete a 20 - 30 minute 
computerized cognitive evaluation, administered by a clinical research assistant, 
nurse, psychologist, or any other professional available in the pediatric oncology 
clinic who completes our online training in administration of CogState. While 
patients are completing the computerized assessment, their parent/guardian will be 
asked to complete a paper-and-pencil measure of executive functioning (the 
BRIEF, see below).76 Completion of the BRIEF takes approximately 10 - 12 
minutes. 
 
Psychologist administered evaluations based on the ALTE07C1 battery will 
include abbreviated testing for intellectual functioning, memory, working 
memory, and verbal learning. Parents or caregivers will also be asked to complete 
questionnaire measures of the child’s social, emotional, and behavioral 
functioning. 
 
16.5 
Measures 
16.5.1 Behavior Rating Inventory of Executive Function (BRIEF) 
The BRIEF is a widely used assessment of executive functioning for children aged 
4 - 18 years.76 The parent report version consists of 86 items, which map onto 
2 broad areas: behavioral regulation and metacognition, as well as 2 validity scales. 
The Behavioral Regulation domain is further divided into 3 clinical subscales: 
Inhibit, Shift, and Emotional Control, whereas the Metacognition domain is 
divided into 5 clinical subscales: Initiate (i.e., beginning a task), Working Memory 
(i.e., holding information), Plan/Organize (i.e., anticipating future events and 
developing appropriate strategies), Organization of Materials (i.e., maintaining 
order in memory), and Monitor. Parents are asked to consider the frequency with 
which each item has been a problem over the last 6 months, responding on a 3 point 
Likert scale consisting of “never,” “sometimes,” and “often.” Items were 
developed to be ecologically valid behavioral correlates to presumed 
neurocognitive difficulties with executive functioning; thus, this measure was 
selected to provide parent and patient reported outcomes of problems related to 
attention, memory, and executive function that occur in everyday life. 

 
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Psychometric properties of this measure are strong using normative samples 
(1,419 parents) weighted to match ethnic and gender proportions in the US 
population. Internal consistency is high (alpha range = 0.73 to 0.90) and test-retest 
reliability exceeds 0.80 for both measures over intervals from 2 to 4 weeks. Scores 
are linear transformations of raw scores into T scores (mean = 50, SD = 10); higher 
scores indicate greater difficulties. 
 
16.5.2 CogState 
CogState is a computerized testing software package that offers a range of semi-
automated assessment modules for individuals aged 5 - 90 years.75 The software 
can be installed on most computer systems and can be proctored by a research 
assistant after completing minimal training. For this study, we use 5 tasks, 
described in the table below, in the following domains: (1) visual learning; (2) 
processing speed; (3) visual attention; (4) executive function, and (5) working 
memory. These tasks were selected because they measure the neurocognitive 
functions identified in previous research as being susceptible to decline in children 
exposed to environmental heavy metals. The entire battery is estimated to take 
approximately 20 to 30 minutes. For CogState, reliability (intra-class correlation) 
is 0.77 with very good stability (i.e., low within-subjects standard deviations) and 
negligible practice effects when testing intervals are greater than one week.77 For 
healthy individuals (n = 867), stability of performance is robust, particularly 
compared with that of traditional, paper and pencil neuropsychological measures. 
Specifically, test-retest scores in a large sample of healthy individuals differed by 
approximately 2% on average, compared with between 7 - 19% for traditional 
measures.78 
 
The table below lists descriptions and other information about the CogState tasks. 
 
Neurocognitive 
Function 
Name of 
Task 
Task 
Duration 
Task Description 
Interpretation 
Visual learning 
One-card 
learning 
5 - 7 mins 
Subject must indicate 
whether or not a card has 
been shown previously in 
the battery 
Higher scores 
reflect better 
performance 
Executive 
function 
Groton Maze-
Learning 
Task 
6 - 10 
mins 
Subject must complete a 
hidden maze by following 
clues on the computer 
Lower scores 
reflect better 
performance 
Visual attention 
Identification 
Task 
3 - 4 mins 
Subject must indicate 
whether or not a card is 
red 
Lower scores 
reflect better 
performance 
Processing speed 
Detection 
Task 
2 - 3 mins 
Subject must quickly 
indicate when a card has 
flipped over on the screen 
Lower scores 
reflect better 
performance 
Working 
memory 
One-back test 
 
4 - 6 mins 
Subject must indicate 
when a stimuli is the same 
as the one that preceded it 
(one-back); or is the same 
as the one two items 
previously (two-back test) 
Higher scores 
reflect better 
performance 
 
 
 

 
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Demographic and symptom information: 
CogState can be programmed to allow input of customized patient data at the time 
of testing. For this study, the CRA (or other individual administering the 
computerized testing) should enter each participant’s COG identification number, 
gender, and age into the computer program. At the first evaluation, the CRA should 
also ask the parent or guardian accompanying the child to provide information 
about their highest level of education attained to estimate socioeconomic status 
(SES), given recent recommendations that this data be collected and included as a 
potential moderator of outcomes in studies of this kind. Finally, because prior 
longitudinal work suggests that children experiencing physical complaints at the 
time of testing perform more poorly on assessments both then and at subsequent 
evaluations, we also ask participants to report on their current experience of fatigue 
and nausea on a 4 point Likert scale anchored by (none/not at all and very much). 
 
16.5.3 Psychologist administered battery 
The screening battery of established neuropsychological measures as described in 
the ALTE07C1 protocol is being utilized. Specifically, that battery consists of an 
abbreviated intellectual test Block Design and Vocabulary subtests from the 
Wechsler Preschool and Primary Scale of Intelligence – Fourth Edition 
(WPPSI- IV79; ages 30 months through 5 years), the Wechsler Intelligence Scale 
for Children – Fifth Edition80 (WISC-V; ages 6 years through 16 years), or the 
Wechsler Adult Intelligence Scale – Fourth Edition81 (WAIS-IV; ages 17 and up). 
In addition, participants complete two measures of immediate visual memory 
(Children’s Memory Scale82 (CMS; ages 5 through 17 years) Dot Locations and 
Faces, a measure of immediate verbal memory (CMS Stories subtest), and a 
measure of verbal learning (California Verbal Learning Test – Children’s 
Version83 for 5 years through 17 years, or California Verbal Learning Test – 
Second Edition84 for 17 and up). Finally, participants complete measures of 
working memory (WISC-V or WAIS-IV Digit Span subtest) and processing speed 
(WISC-V or WAIS-IV processing speed index tasks). 
 
The measures vary by age group and should be completed in the order presented 
in Appendix VI. 
 
Patient-Completed Measures 
 
Wechsler Intelligence Scales (WPPSI-IV79; WISC-V80; WAIS-IV81). The 
Wechsler batteries measure intellectual functioning in children aged 2½ - 7 
(WPPSI-IV), 6 - 16 (WISC-V), and 16+ (WAIS-IV). For this project, the 
Vocabulary and Block Design subtests from the version appropriate for each 
child’s age will be used at baseline only to estimate IQ. Additionally, one working 
memory subtest (Digit Span) for participants age 6 years and up will be 
administered. 
 
Children’s Memory Scale (CMS82). The CMS is a test to assess verbal and visual 
memory in individuals 5 - 16 years of age. 
 
Wechsler Memory Scale, 4th edition (WMS-IV85). The WMS-IV is a test to assess 
verbal and visual memory in individuals greater than 16 years of age. 

 
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California Verbal Learning Tests (CVLT-C83; CVLT-II84). The CVLT-C and 
CVLT-II involve verbally presenting a list learning task over the course of 5 trials. 
The test measures multiple aspects of how verbal learning occurs, or fails to occur, 
as well as the amount of verbal material learned. The CVLT-C is for individuals 
5 - 16 years of age while the CVLT-II is for individuals older than 16 years of age. 
 
Parent-Completed Measures 
Behavior Assessment System for Children, 2nd edition (BASC-II86). The BASC-
II describes the behaviors, thoughts, and emotions of children and adolescents. The 
parent rating scale will be utilized for individuals older than 2 years and less than 
18 years of age. The questionnaire yields composite and scale scores in the 
domains of externalizing, internalizing, school, and other problems as well as 
adaptive skills and behavioral symptoms. 
 
Behavior Rating Inventory of Executive Functioning (BRIEF; BRIEF-P87) is a 
parent-completed measure of behavioral executive functioning. There are two 
versions available: one for preschoolers (BRIEF-P) and one for older children and 
adolescents (BRIEF). For this study, items from the Metacognition subscales will 
be used. The BRIEF will be administered at all time points as an additional 
outcome measure. 
 
Adaptive Behavior Assessment System, 2nd edition (ABAS-II88). The ABAS-II 
will be used for the assessment of adaptive skills in individuals older than 2 years 
and less than 18 years of age. Separate scale scores are available for 10 areas of 
adaptive skills. 
 
Pediatric Quality of Life Inventory Version 4 (PedsQL 4.0). The PedsQL 4.0 is a 
modular approach to measuring health-related quality of life in healthy children 
and adolescents as well as in those with acute and chronic health conditions. The 
Generic Version consists of 23 items, with separate parent-report forms for ages 
2 - 4, 5 - 7, 8 - 12, and 13 - 18. Patients who are > 18 years of age will complete a 
self-report form. The questionnaire yields domain scores for Physical, Emotional, 
Social, and School Functioning as well as summary scores for Total Quality of 
Life, Physical Health, and Psychosocial Health. Reliability and validity have been 
established for this measure. Questions regarding the PedsQL 4.0, including 
question regarding access, should be sent to Dr. Kristina Hardy at: 
AAML1331_neurocog@childrensoncologygroup.org 
 
COG Language Preference Questionnaire. The 8 item COG Language 
Preference Questionnaire was developed to determine the primary language of 
study participants. Parents will complete this questionnaire for patients who are 
between 2 - 18 years of age. This questionnaire is available on the COG website at 
https://members.childrensoncologygroup.org/Prot/AAML1331/AAML1331COG
LangPrefQuest.pdf. 
 
16.6 
Feedback to Participants 
Real-time scoring is available for the CogState measure; thus, scores for each participant 
may be generated immediately. CogState is not designed to be a comprehensive measure 

 
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of neurocognitive functioning; however, problems identified by CogState may indicate that 
the patient may require a more complete neuropsychological evaluation. Consistent with 
the existing protocol developed for AALL1131, we plan to inform the health care providers 
of participants who have scored in the bottom 7% (i.e., 1.5 SD below the mean) relative to 
the standardization sample for CogState, or in the most extreme 7% of scores on the 
BRIEF, given that extreme scores on either of these measures may reflect significant 
difficulties that can interfere with learning. Score reports for the BRIEF and CogState are 
generated automatically by the scoring programs for each measure. When children receive 
scores at or more extreme than 1.5 SD from the mean, their health care team will be 
informed of the results in the form of a letter listing the scores of concern, provided by the 
correlative study research team. There will not be recommendations for dose modification 
based on the CogState score alone, as this battery has not been validated in this manner. 
The health care team can follow up with families to determine if further assessment is 
warranted based on whether or not families are observing difficulties in their child’s 
functioning at home or in school, and make a referral as they would normally do when 
families report concerns of this kind. 
 
With regard to the psychologist administered battery, the first administration of traditional 
tests will be at the end of therapy and thus results will not impact individual patient 
treatment decisions or dose modification.  
 
 
17.0 
RADIATION THERAPY GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved 
COG RT facilities.  
 
17.1 
General guidelines 
Radiation therapy is not routinely used in the curative treatment of APL and is reserved in 
this study for emergent situations with threat to neurologic or other function. Treatment is 
at the discretion of the treating physician. Submission of treatment data is not required. 
 
17.2 
Eligibility 
No patient is required to receive radiation therapy. Radiation therapy may be considered 
for patients who present with a chloroma that is producing or threatens to produce an 
irreversible neurologic deficit.  
 
 

 
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17.3 
Timing  
If the patient presents with a chloroma that is producing or threatens to produce an 
irreversible neurologic deficit (e.g., visual impairment or myelopathy), radiation therapy 
may be given at the beginning of Induction therapy. However, radiation therapy is not 
required in this circumstance. 
 
17.4 
Equipment 
17.4.1 Modality 
Standard photon conformal arrangements or electron beam RT may be sufficient 
for most cases. Treatment modality is at the discretion of the treating radiation 
oncologist.  
 
17.4.2 Calibration 
All therapy units used for this protocol shall have their calibrations verified by the 
IROC Houston QA Center (RPC). 
 
17.5 
Target Volume 
17.5.1 Standard Tumor and Target Volume Definitions 
International Commission of Radiation Units and Measurements (ICRU) reports 
50, 62, and 78 (www.icru.com) define prescription methods and nomenclature that 
will be utilized for this study. Treatment planning will be based on the following 
definitions: 
 
 Gross tumor volume (GTV) is the volume occupied by disease visible on 
diagnostic or planning imaging. For this study the GTV is the initial, pre-
chemotherapy chloroma visible on 3D imaging. 
 
 Clinical target volume (CTV) includes the GTV and sites with potential 
occult tumor involvement. In this protocol this will include only 
microscopic disease just beyond the GTV. CTV is defined as GTV plus 
a uniform 0.5 cm expansion. 
 
 Planning target volume (PTV) is defined as CTV plus an institutional 
margin for day-to-day set up variation related to patient immobilization 
and physiological motion of the CTV. A minimum margin of 0.5 cm is 
recommended for photon and electron plans (total of 1 cm from GTV).  
17.6 
Target Dose 
17.6.1 Prescription Point 
Dose should be prescribed to an isodose surface that encompasses the PTV and allows 
the dose uniformity requirements to be satisfied. 
 
17.6.2 Dose Definition 
The absorbed dose is specified as cGy-to-muscle. 

 
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17.6.3 Tissue Heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed 
with CT based treatment planning to generate dose distributions and treatment 
calculations from CT densities. 
 
17.6.4 Dose and Fractionation 
A dose of 1,800 cGy will be delivered to the PTV in 10 fractions of 180 cGy each 
delivered once daily. 
 
17.6.5 Dose Uniformity 
The dose variations in the target volume will be within ±10% of the prescription 
dose. 
 
17.7 
Normal Tissue Sparing 
An effort should be made to limit the radiation dose to the lens of each eye to less than 
600 cGy, if this can be done without compromising the dose to the target. 
 
17.8 
Quality Assurance Review 
Submission of RT treatment data on this study is not required for review. 
 

 
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
 
Added to a site roster 
 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 
Act as the site-protocol PI on the IRB approval 
 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for AAML1331 Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab 
Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website.  (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 

 
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enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 

 
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APPENDIX II:  TRETINOIN (ALL-TRANS RETINOIC ACID, ATRA) DOSING TABLE 
 
Dose: 25 mg/m2/day 
BSA (m2) 
Dose 
≤ 0.59 
10 mg every day 
0.6 - 0.99 
10 mg twice daily 
1 - 1.39 
20 mg every AM, 10 mg every PM 
1.4 - 1.79 
20 mg twice daily 
1.8 - 2.19 
30 mg every AM, 20 mg every PM 
2.2 - 2.59 
30 mg twice daily 
2.6 - 2.99 
40 mg every AM, 30 mg every PM 
3 - 3.39 
40 mg twice daily 
 
 
For additional administration guidelines for administering tretinoin (ATRA) to patients unable to swallow 
whole capsules either due to young age or level of consciousness (including intubated patients) please see 
Appendix III. Further details about tretinoin (ATRA) can also be found in the commercial agent monographs 
manual titled “Drug Information for Commercial Agents used by the Children’s Oncology Group.” This 
manual is provided under Standard Sections for Protocols at:  
https://www.cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials .  
  
 

 
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APPENDIX III: INFORMATION FOR PARENTS/CAREGIVERS FOR GIVING TRETINOIN 
(ATRA): 
 
Tretinoin gel capsules should be swallowed whole when possible. There is minimal data on the absorption 
of tretinoin when it is given by other methods. In addition, tretinoin is sensitive to heat, light and air, so 
avoid exposure to those as much as possible. Alternative methods of delivery should only be used when it 
is not possible to swallow the gel capsules (i.e., intubated patients, neurologically impaired patients, very 
young patients).  
 
Note: Gloves must be worn when handling tretinoin capsules unless the capsules are intact.  
 
For children unable to swallow the capsules whole, the following options may be used:  
 
1. Capsules can be chewed then swallowed if the child is able. A small hole can be poked in the 
capsules before the child chews them to make this easier.  
2. Capsules can be softened in water and the softened capsule can be chewed/swallowed and/or mixed 
with pudding or a fatty food and swallowed.  
3. Contents of the capsules can be squeezed out and mixed with a fatty food. If at all possible, have 
the child suck on the empty capsule in hopes of getting more of the intended dose.  
 
If the contents are withdrawn from the capsules and mixed with food, give the dose as soon as possible 
(within ONE hour). 
 
 
 

 
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APPENDIX IV:  POSSIBLE DRUG INTERACTIONS 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Arsenic Trioxide (ATO) 
Drugs that may interact with arsenic trioxide 
 Antibiotics  
o Azithromycin, ciprofloxacin, clarithromycin, erythromycin, levofloxacin, moxifloxacin, 
telithromycin 
 Antidepressants and antipsychotics  
o Citalopram, clozapine, escitalopram, paliperidone, quetiapine, risperidone, thioridazine, 
trazodone 
 Heart medications  
o Amiodarone, dronedenarone, dofetilide, flecainide, ibutilide, procainamide, propafenone, 
sotalol 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Many other drugs, including the following: 
o Chloroquine, chlorpromazine, foscarnet, granisetron, haloperidol, ivabradine, methadone, 
mifepristone, ondansetron, pentamidine, pimozide, saquinavir, voriconazole 
Food and supplements that may interact with arsenic trioxide** 
 
Unknown 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
 
Tretinoin (ATRA) 
Drugs that may interact with tretinoin 
 Anti-seizure medications such as carbamazepine, phenobarbital, phenytoin, primidone 
 Arthritis medications such as leflunomide, tofacitinib 
 Some oral contraceptives 
 Some antibiotics, like doxycycline, tetracycline, and tigecycline 
 Other medications such as aminolevulinic acid, amiodarone, clopidogrel, deferasirox, gemfibrozil, 
irbesartan, losartan, mifepristone, natalizumab, pioglitazone, rabeprazole, rifampin, ritonavir, 
rosiglitazone, tranexamic acid 
Food and supplements that may interact with tretinoin** 
 Echinacea 
 St. John’s Wort 
 Vitamin A supplements or multivitamins that contain vitamin A 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. 
All forms should be avoided.  
 
Cytarabine (IV) 
Drugs that may interact with cytarabine 
 Clozapine, digoxin, flucytosine, leflunomide 

 
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Food and supplements that may interact with cytarabine** 
 Echinacea 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
Dexamethasone 
Drugs that may interact with dexamethasone 
 Antibiotics  
o Ciprofloxacin, levofloxacin, moxifloxacin, clarithromycin, erythromycin, nafcillin, 
rifabutin, rifampin, telithromycin 
 Antidepressants and antipsychotics  
o Aripiprazole, buproprion, citalopram, clozapine, escitalopram, fluvoxamine, lurasidone, 
nefazodone, quetiapine 
 Antifungals  
o Caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
 Arthritis medications  
o Leflunomide, tofacitinib 
 Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
 Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, rilpivirine, ritonavir, saquinavir, Stribild, 
telaprevir, tipranavir 
 Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
 Heart medications  
o Amiodarone, amlodipine, dronedenarone, verapamil 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Some oral contraceptives or birth control medications 
 Many other drugs, including the following: 
o Aprepitant, artemether/lumefantine, aspirin, deferasirox, ibuprofen, ivacaftor, lomitapide, 
mifepristone, natalizumab, nimodipine, praziquantel, warfarin 
 
Food and supplements that may interact with dexamethasone** 
 Echinacea 
 St. John’s Wort 
 Grapefruit, grapefruit juice, Seville oranges, star fruit 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
Idarubicin 
Drugs that may interact with idarubicin 
 Antibiotics and antifungals  
o Clarithromycin, erythromycin, itraconazole, ketoconazole, rifampin 
 Antivirals and antiretrovirals  
o Darunavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir, tenofovir, tipranavir 

 
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 Anti-rejection medications 
o Cyclosporine, tacrolimus 
 Anti-seizure medications  
o Carbamazepine, phenobarbital, phenytoin 
 Arthritis medications  
o Leflunomide, tofacitinib 
 Some heart medications  
o Amiodarone, carvedilol, digoxin, dronedarone, nicardipine, propranolol, verapamil 
 Some chemotherapy (be sure to talk to your doctor about this) 
 Other medications such as atorvastatin, clozapine, ivacaftor, natalizumab, trazodone 
 
Food and supplements that may interact with idarubicin** 
 
Echinacea 
 
Grapefruit, grapefruit juice 
 
St. John’s Wort 
 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
Leucovorin 
Drugs that may interact with leucovorin 
o Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone) 
 
Food and supplements that may interact with leucovorin** 
 Folic acid 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
 
Mitoxantrone 
Drugs that may interact with mitoxantrone 
 Aripiprazole 
 Clozapine 
 Cyclosporine 
 Dofetilide 
 Leflunomide  
 Natalizumab 
 Pimozide 
 Tofacitinib  
 
Food and supplements that may interact with mitoxantrone** 
 Echinacea 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
 

 
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APPENDIX V:  PROCEDURES FOR CYTOGENETIC/FISH STUDIES 
(A COPY OF THIS SECTION MUST BE SENT TO THE RECOMMENDED INSTITUTIONAL COG-
APPROVED CYTOGENETICS LABORATORY) 
 
CHROMOSOME ANALYSIS 
 
Bone marrow should be studied by cytogenetics methods in all cases of APL. 
 
 
A back-up blood specimen should be studied when the bone marrow aspirate or trephine biopsy is 
inadequate or unobtainable (in which case short-term unstimulated cultures are established to 
examine spontaneously dividing [presumably leukemic] cells) or when a constitutional 
chromosomal abnormality is a possibility (phytohemagglutinin-stimulated cultures should be 
established to examine presumably nonleukemic [constitutional] lymphocytes). 
 
 
If no bone marrow sample is available to send to the cytogenetics laboratory, 1 - 2 unstained bone 
marrow slides could be sent for FISH PML-RARα to confirm APL. 
 
 
Short-term (15 - 48 hours) unstimulated cultures are recommended for each bone marrow sample. 
Analysis of direct preparations is successful in some laboratories. Mitogen-stimulated cultures of 
bone marrow samples should not be initiated. 
 
 
All preparations must be G-banded. (Q- or R-banding will not be accepted as a stand-alone banding 
method.) 
 
 
Complete analysis of 20 G-banded metaphases is required for each case, except as noted below. 
Complete analysis is defined as follows: the chromosomes in each metaphase cell have been 
counted; each chromosome has been examined to determine whether the banding pattern is normal, 
and all abnormalities present in the cell have been defined. Analysis may be accomplished by 
examining metaphase spreads under the microscope or by imaging. Sometimes analysis of 
20 metaphases is not possible because of poor in vitro growth or a very limited quantity of 
specimen. However, limited characterization of the abnormal clone can still be informative. Such 
informative cases will be considered acceptable. A minimum analysis of 20 metaphases is required 
for a normal case. 
 
 
Identification of clones will follow the criteria of the Second International Workshop on 
Chromosomes in Leukemia, as stated in the General Report (Cancer Genet. Cytogenet 2:93-96, 
1980): at least two metaphases with identical structural abnormalities or extra chromosomes, or at 
least three metaphases with identical missing chromosomes will constitute a clone. Nonclonal 
abnormalities (excluding random loss) should also be recorded. 
 
 
Karyotypes are to be designated according to the guidelines described in ISCN 2013, An 
International System for Human Cytogenetic Nomenclature (2013), Shaffer, McGowan-Jordan, 
Schmid (eds); S. Karger, Basel, 2013. 
 
FLUORESCENCE IN SITU HYBRIDIZATION (FISH) 
 
FISH using commercially available probes for PML-RARα is required for all APL cases. If a case 
has the t(15;17)(q22;q21) by G-banding, FISH testing will confirm the PML-RARα fusion. Also 
FISH with PML-RARα, preferentially on metaphases, will allow the evaluation of missing deleted 
3’ or 5’ regions of the participating genes. In cases with a t(15;17) present or normal chromosomes, 
if FISH with PML-RARα is not informative, the RARα break apart probe should be used to improve 
the detection of cryptic insertions. The laboratory is expected to follow the standards and guidelines 

 
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for FISH put forth by the American College of Medical Genetics. If the laboratory is unable to 
perform FISH tests, contact cytogenetics coordinators for advice. 
 
CYTOGENETIC STUDY/FISH SUBMISSION 
Steps to obtain the FORMS by the COG institution’s CRA 
1. www.childrensoncologygroup.org 
2. COG members 
3. Protocols ►Protocol Reference Materials ►Generic Forms 
4. Under COG ►Cytogenetics Reporting/FISH Forms 
 
The COG Forms should be completed by the designated individual in the Cytogenetics Laboratory and 
signed by the Cytogenetics Director. It is required to scan the Forms and e-mail with the appropriate 
documentation to COG reviewers for the Myeloid Committee.  
 
The case must be sent to the appropriate reviewer within 2 weeks of enrollment. 
 
Cytogenetic Coordinators 
Please send above materials by e-mail to the following COG Cytogenetics Laboratories:  
 
WEST OF MISSISSIPPI RIVER 
(INCLUDE MINNESOTA AND 
WISCONSIN), AUSTRALIA, NEW 
ZEALAND, WESTERN CANADA 
EAST OF MISSISSIPPI RIVER 
(EXCLUDE MINNESOTA AND 
WISCONSIN), EUROPE, EAST CANADA 
SEND TO:  
SEND TO: 
Betsy Hirsch, PhD 
Susana C. Raimondi, PhD 
Director of Cytogenetics Laboratory 
Director of Cytogenetics Laboratory 
Department of Laboratory Medicine and 
Pathology 
Department of Pathology (Room 4023A) 
University of Minnesota 
St. Jude Children's Research Hospital 
Mayo Mail Code 609 
262 Danny Thomas Place, Mail Stop 250 
420 Delaware St. SE 
Memphis, Tennessee 38105-3678 
Minneapolis, MN 55455 
USA 
USA 
 
Telephone: 612-273-4952/3171 
Telephone: 901-595-3537 
Fax: 612-273-4689 
Fax: 901-595-3100 
E-mail: hirsc003@umn.edu 
E-mail: susana.raimondi@stjude.org 
 
CYTOGENETICS REVIEW 
 
The region’s cytogenetics coordinator will review each case when it is submitted. She/he will determine 
whether each case is adequate in terms of the numbers of metaphase cells analyzed, quality of banding, and 
interpretation of the karyotypes. If the coordinator agrees with the submitting laboratory, the results of the 
study will be entered into the appropriate Rave. If the coordinator does not agree, she/he will send the case 
to another member of the COG Cytogenetics Review Committee for rapid review. If the case is determined 
as not adequate it will be registered as unknown cytogenetics.  
 
 
 

 
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(A SIGNED AND DATED COPY OF THIS AUTHORIZATION FORM FOR REFLEXIVE FISH 
TESTING MUST BE SENT TO THE CYTOGENETICS LABORATORY, TOGETHER WITH 
THE BONE MARROW SAMPLE) 
 
 
AUTHORIZATION FORM FOR REFLEXIVE FISH TESTS 
Patients enrolled in AAML1331 are required to have cytogenetic/FISH PML-RARα testing.  
 
It is authorized to perform reflexive FISH testing to rule-out cryptic aberrations and/or to evaluate 
molecular deletions. 
 
 
Patient Registration #  __________________________________________ 
 
 
___________________________________________________________ 
Print Name of Attending Physician 
 
 
_____________________________________________________________ 
Print Name of Institution and City, State 
 
 
Signature of attending physician or designee: ________________________  
 
 
 
Date: ______________________ 
 
  
 

 
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APPENDIX VI: ADMINISTRATION ORDER FOR PSYCHOLOGIST ADMINISTERED 
BATTERIES 
 
The measures vary by age group and should be completed in the order presented below. 
 
Parent Report 
Patient report 
2 years 
6 months 
through 
3 Years 
11 Months 
1. COG Language Preference 
Questionnaire* 
2. PedsQL 4.0 Generic Version 
3. BASC-2 
4. BRIEF-Preschool Version 
5. ABAS-II 
1. WPPSI-IV (Receptive Vocabulary, Block Design, Picture 
Memory) 
4 years 
0 months 
through 
4 years 
11 months 
1. COG Language Preference 
Questionnaire* 
2. PedsQL 4.0 Generic Version 
3. BASC-2 
4. BRIEF-Preschool Version 
5. ABAS-II 
1. WPPSI-IV (Vocabulary, Block Design, Picture Memory, 
Bug Search, and Cancellation) 
5 years 
0 months 
through 
5 years 
11 months 
1. COG Language Preference 
Questionnaire* 
2. PedsQL 4.0 Generic Version 
3. BASC-2 
4. BRIEF-Preschool Version 
5. ABAS-II 
1. CVLT-C 
2. WPPSI-IV (Vocabulary, Block Design, Picture Memory) 
3. CVLT-C Recall 
4. CMS (Story Memory, Faces, and Dot Location) 
5. WPPSI-IV (Bug Search and Cancellation) 
6. CMS Recall (Story Memory, Faces, and Dot Location) 
6 years 
0 months 
through 
16 years 
11 months 
1. COG Language Preference 
Questionnaire* 
2. PedsQL 4.0 Generic Version 
3. BASC-2 
4. BRIEF 
5. ABAS-II 
1. CVLT-C 
2. WISC-V (Vocabulary and Block Design) 
3. CVLT-C Recall 
4. CMS (Story Memory, Faces and Dot Location) 
5. WISC – V (Symbol Search, Coding and Digit Span) 
6. CMS Recall (Story Memory, Faces, and Dot Location) 
17 years 
0 months 
through 
17 years 
11 months 
1. COG Language Preference 
Questionnaire* 
2. PedsQL 4.0 Generic Version 
3. BASC-2 
4. BRIEF 
5. ABAS-II 
1. CVLT-II 
2. WAIS-IV (Vocabulary and Block Design) 
3. CVLT-II Recall 
4. WMS-IV (Logical Memory I and Symbol Span) 
5. WAIS-IV(Symbol Search, Coding, and Digit Span) 
6. WMS-IV Recall (Logical Memory II and Spatial Addition) 
18 years 
0 months 
and Older 
No Parent Report 
1. PedsQL 4.0 Generic Version (self report) 
2. BASC-2 (self report) 
3. ABAS-II (self report) 
4. BRIEF-A (self report) 
5. CVLT-II 
6. WAIS-IV (Vocabulary and Block Design) 
7. CVLT-II Recall 
8. WMS-IV (Logical Memory I and Symbol Span) 
9. WAIS-IV (Symbol Search, Coding, and Digit Span) 
10. WMS-IV Recall (Logical Memory II and Spatial Addition) 
* 
COG Language Preference Questionnaire will only be completed at the first psychologist administered battery time point. 
 
 

 
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APPENDIX VII:  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
A Treatment Study of Children with Newly Diagnosed Leukemia Called APL 
 
1. We have been talking with you about your acute promyelocytic leukemia (APL). Leukemia is a 
type of cancer that grows in the bone marrow. Bone marrow is the spongy tissue inside the bones 
of your body that make blood cells. After doing tests, we have found that you have this type of 
cancer. 
 
2. We are asking you to take part in a research study because you have APL. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are trying 
to learn more about how to treat the type of leukemia you have. This kind of leukemia is usually 
treated with anti-cancer medicines. Some of these anti-cancer medicines may cause heart problems 
later in life. This research study will use a new way to treat leukemia. We do not know if the new 
treatment will be better than the usual treatment. That is why we are doing this study.  
 
3. Children who are part of this study will be treated with anti-cancer medicines. Doctors want to see 
if this new treatment will make more children with leukemia get better, with fewer heart problems 
later in life. These medicines have been used together to treat leukemia in adults. They also have 
been used together to treat a small group of children. We don’t know if the new treatment will work 
well in children. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is a better chance at 
getting rid of the leukemia for as long as possible. We also hope that the study treatment will help 
keep more children from having heart problems later in life. However, we don’t know for sure if 
there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are receiving treatment that does not work as 
well as usual treatment at getting rid of the cancer for as long as possible. Another risk may be 
more problems, or side effects, from the study treatment. Other things may happen to you that we 
don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect extra blood and bone marrow. We want to see if there are 
ways to tell how the cancer will respond to treatment. You can still take part in this study even if 
you don't allow us to collect the extra blood and bone marrow samples for research.  
 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
A Treatment Study of Children with Newly Diagnosed Leukemia Called APL 
 
1. We have been talking with you about your acute promyelocytic leukemia (APL). Leukemia is a 
type of cancer that grows in the bone marrow. Bone marrow is the spongy tissue inside the bones 
of your body that make blood cells. After doing tests, we have found that you have this type of 
cancer. 
 
2. We are asking you to take part in a research study because you have APL. A research study is when 
doctors work together to try out new ways to help people who are sick. In this study, we are trying 
to learn more about how to treat the type of leukemia you have. Standard treatment for the kind of 
leukemia you have is chemotherapy (anti-cancer drugs). Some of the drugs used may cause bad 
effects that show up a long time after treatment is finished. These are called “late effects”. A 
common late effect from standard treatment is heart problems. This research study will use a new 
way to treat leukemia. We do not know if the new treatment will be better than the usual treatment. 
That is why we are doing this study.  
 
3. Children and teens who are part of this study will be treated with chemotherapy. Doctors want to 
see if this new treatment will make children with leukemia get better with fewer late effects. These 
medicines have been used to treat leukemia in adults and a small group of children. We don’t know 
if the new treatment will work well in children.  
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is a better chance at 
getting rid of the leukemia for as long as possible. We also hope that fewer late effects and heart 
problems will occur. However, we don’t know for sure if there is any benefit of being part of this 
study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are receiving treatment that does not work as 
well as standard treatment at getting rid of the cancer for as long as possible. Another risk may be 
more problems, or side effects, from the study treatment. Other things may happen to you that we 
don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood and bone marrow. We want to see if 
there are ways to tell how the cancer will respond to treatment. The bone marrow samples will be 
taken when other standard tests are being performed, so there would be no extra procedures. Some 
blood is requested when you would not usually need to have a blood sample taken. You can still 
take part in this study even if you don't allow us to collect the extra blood and bone marrow samples 
for research. 
  
 

 
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REFERENCES 
1. 
Mandelli F, Diverio D, Avvisati G, et al: Molecular remission in PML/RAR alpha-positive acute 
promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. 
Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di 
Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90:1014-21, 1997 
2. 
Tallman MS, Andersen JW, Schiffer CA, et al: All-trans-retinoic acid in acute promyelocytic 
leukemia. N Engl J Med 337:1021-8, 1997 
3. 
Sanz MA, Martin G, Rayon C, et al: A modified AIDA protocol with anthracycline-based 
consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed 
PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 94:3015-21, 
1999 
4. 
Burnett AK, Grimwade D, Solomon E, et al: Presenting white blood cell count and kinetics of 
molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans 
retinoic acid: result of the Randomized MRC Trial. Blood 93:4131-43, 1999 
5. 
Gregory J, Kim H, Alonzo T, et al: Treatment of children with acute promyelocytic leukemia: 
results of the first North American Intergroup trial INT0129. Pediatr Blood Cancer 53:1005-10, 
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