A Simplified Patient Care Strategy to Decrease Early Deaths in Acute Promyelocytic Leukemia (APL)
Phase: NA
Conditions: Acute Promyelocytic Leukemia With PML-RARA, t(15;17)
Sponsor: ECOG-ACRIN Cancer Research Group

 
EA9131 
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A Simplified Patient Care Strategy to Decrease Early 
Deaths in Acute Promyelocytic Leukemia (APL) 
STUDY CHAIR: Anand P. Jillella, MD 
STUDY CO-CHAIR: Vamsi K. Kota, MD 
STUDY STATISTICIAN: Sandra Lee, ScD 
PREVENTION COMMITTEE CHAIR: Raymond Bergan, MD 
CANCER CARE DELIVERY RESEARCH 
COMMITTEE CHAIR: 
 
Ruth Carlos, MD 
CANCER CONTROL & SURVIVORSHIP 
COMMITTEE CHAIR: 
 
Lynne I. Wagner, PhD 
LEUKEMIA COMMITTEE CHAIR: Mark R. Litzow, MD 
  
 
Version Date:  May 25, 2018 
 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology, 
NCORP Sites Only 
 
August 16, 2017 
Addendum #1 – Prior to Activation 
ECOG-ACRIN / NCORP Sites Only 
 
Addendum #2 
NRG / NRG Oncology, NCORP Sites Only 
 
 
SWOG / SWOG, NCORP Sites Only 
 
 
COG / Children’s Oncology Group, NCORP Sites Only 
 
 
 
 
 
NCTN participation is limited to the following sites: 
 
 
FL080 / Mayo Clinic, Jacksonville (ECOG-ACRIN) 
 
 
MN026 / Mayo Clinic, Rochester (ECOG-ACRIN) 
 
 
NY016 / Memorial Sloan-Kettering Cancer Center 
(ECOG-ACRIN) 
 
 
IL036 / Northwestern University (ECOG-ACRIN) 
 
 
PA075 / University of Pennsylvania (ECOG-ACRIN) 
 
 
GA020 / Medical College of Georgia at August University
(ECOG-ACRIN) 
 
 
 
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STUDY CHAIR 
Anand P. Jillella, MD 
Georgia Cancer Center 
Medical College of Georgia at Augusta University 
1120 15th Street, BAA 5407 
Augusta, GA, 30912 
Office Phone: 706-721-2505 
Cell Phone: 706-951-5144 
Fax: 706-721-5566 
Email: ajillella@augusta.edu 
 
STUDY CO-CHAIR 
Vamsi K. Kota, MD 
Winship Cancer Institute of Emory University 
1365 Clifton Road NE, Room C1152 
Atlanta, GA 30322 
Office Phone: 404-778-1900 
Cell Phone: 706-825-4091 
Fax: 404-778-4755 
Email: vkota@emory.edu 
 
STUDY CHAIR LIAISON (SCL) 
Prachi Karkhanis 
Georgia Cancer Center 
Medical College of Georgia at Augusta University 
1120 15th Street, BAA 5407 
Augusta, GA 30912 
Office Phone: 706-721-9491 
Fax: 706-721-5566 
Email: pkarkhanis@augusta.edu 
 
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ECOG-ACRIN STUDY EXPERTS 
Anand P. Jillella, MD 
Georgia Cancer Center 
Medical College of Georgia at Augusta University 
1120 15th Street, BAA 5407 
Augusta, GA, 30912 
Office Phone: 706-721-2505 
Cell Phone: 706-951-5144 
Fax: 706-721-5566 
Email: ajillella@augusta.edu 
 
Jessica K. Altman, MD 
Northwestern University Feinberg School of 
Medicine 
Robert H. Lurie Comprehensive Cancer Center 
303 E. Superior Street, Chicago, IL 60611 
Office Phone: 312-503-1817 
Cell Phone: 773-575-2598 
Fax: 312-695-6189 
Email: j-altman@northwestern.edu 
 
Vamsi K. Kota, MD 
Winship Cancer Institute of Emory University 
1365 Clifton Road NE, Room C1152 
Atlanta, GA 30322 
Office Phone: 404-778-1900 
Cell Phone: 706-825-4091 
Fax: 404-778-4755 
Email: vkota@emory.edu 
 
Selina Luger, MD 
Abramson Cancer Center of the University of 
Pennsylvania 
2 West, Perelman Center for Advanced Medicine 
3400 Civic Center Road, Philadelphia, PA, 
19104 
Office Phone: 215-662-6348 
Cell Phone: 215-279-0657 
Fax: 215-662-4064 
Email: selina.luger@uphs.upenn.edu 
 
Martin S. Tallman, MD 
Memorial Sloan-Kettering Cancer Center 
Leukemia Service, Department of Medicine 
1275 York Avenue, New York, NY 10065 
Office Phone: 212-639-3842 
Cell Phone: 646-467-4670 
Fax: 212-639-3841 
Email: tallmanm@mskcc.org 
 
James M. Foran, MD, FRCPC 
Mayo Clinic Florida 
Division of Hematology & Medical Oncology 
4500 San Pablo Road, Jacksonville, FL 32224 
Office Phone: 904-953-7292 
Cell Phone: 904-955-3679 
Fax: 904-953-2315 
Email: foran.james@mayo.edu 
 
Mark R. Litzow, MD 
The Mayo Clinic 
Division of Hematology 
200 First Street, SW, Rochester, MN 55905 
Office Phone: 507-266-0523 
Cell Phone: 507-269-4848 
Fax: 507-266-4972 
Email: litzow.mark@mayo.edu 
 
 

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Table of Contents 
Schema ...................................................................................................................... 6 
1. Introduction ........................................................................................................ 7 
1.1 
Rationale for Proposed Study ................................................................... 7 
1.2 
Significance of the Study ........................................................................... 9 
1.3 
Study Overview ....................................................................................... 11 
2. Objectives ......................................................................................................... 12 
2.1 
Primary Objective .................................................................................... 12 
2.2 
Secondary Objectives .............................................................................. 12 
3. Selection of Patients ......................................................................................... 13 
3.1 
Eligibility Criteria ..................................................................................... 13 
4. Registration Procedures .................................................................................... 14 
4.1 
Protocol Number ..................................................................................... 17 
4.2 
Investigator Identification ....................................................................... 17 
4.3 
Patient Identification .............................................................................. 18 
4.4 
Eligibility Verification .............................................................................. 18 
4.5 
Additional Requirements ........................................................................ 18 
5. Methodology Plan ............................................................................................. 20 
5.1 
Lead Sites ................................................................................................ 20 
5.2 
Outlying NCORP Community Facility ...................................................... 21 
5.3 
Study Accrual and Timeline ..................................................................... 21 
5.4 
Adverse Event Reporting Requirements ................................................. 21 
5.5 
Completion of Induction ......................................................................... 23 
5.6 
Consolidation .......................................................................................... 23 
5.7 
Maintenance ........................................................................................... 23 
5.8 
Duration of Follow-up ............................................................................. 23 
6. Study Parameters .............................................................................................. 24 
7. Statistical Considerations .................................................................................. 25 
7.1 
Study Design and Objectives ................................................................... 25 
7.2 
Sample Size Considerations and Monitoring Plan .................................. 25 
7.3 
Statistical Analysis Plan ........................................................................... 26 
7.4 
Race, Gender, and Ethnicity Accrual Estimates ...................................... 27 
8. Electronic Data Capture .................................................................................... 28 
9. Patient Consent and Peer Judgment ................................................................ 28 
10. References ........................................................................................................ 28 
Appendix I  Acute Promyelocytic Leukemia Treatment Guidelines ........................ 29 
Appendix II  APL Expert and NCORP Provider Communication ............................... 32 
Appendix III  NCORP PROVIDER INFORMATION SHEET ........................................... 33 
Appendix IV  Patient Thank You Letter .................................................................... 34 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND 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 section of 
the protocol 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.  
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or 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 Web site is located at   https://www.ctsu.org 
 
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Schema 
All Patients 
with APL 
or 
Suspected
APL
Patient is at lead site1
Patient is at an NCORP 
community center2
Total Accrual Goal= 200
1.
Participation at lead sites will be limited to 30% of overall accrual. Lead sites are identified as: Medical College of George at Augusta University, MSKCC, Mayo Clinic - Rochester, MN, 
Northwestern, University of Pennsylvania, Mayo Clinic - Jacksonville, FL.
2.
It is preferred the APL expert for the catchment area is contacted first. It is suggested that the call be placed as soon as a diagnosis is suspected.
3.
Registration is done only if treating physician calls expert within 3 days of starting APL directed treatment.
4.
Follow treatment guidelines according to Appendix I. If necessary, deviations from guidelines may occur per discretion of treating physician and consulting physician.
5.
7 investigators at the lead sites have been identified as APL experts.
6.
Consent patient after APL diagnosis is confirmed.
Patient is treated locally 
at lead site4
Treating physician must 
call APL5 expert at any 
Lead Site to discuss 
algorithm and treatment 
plan2
Patient is treated locally 
at NCORP community 
center according to 
suggested treatment plan 
from APL expert4
Registration6
Registration/consent 
must not delay starting 
treatment
Registration3,6
Registration/consent 
must not delay starting 
treatment
S
I
T
E
E
D
U
C
A
T
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1. 
Introduction 
1.1 
Rationale for Proposed Study 
Acute Promyelocytic Leukemia (APL) is a highly curable malignancy with most 
large cooperative group trials showing a survival above 90%. Patients entered in 
cooperative group trials are a highly selected group of patients and may not be a 
representation of outcomes in the general population.  It is also likely that 
patients may not even be seen at a large treatment center due to the advanced 
nature of the disease and/or socioeconomic and distance constraints.  However 
in recent years, data from single institutions as well as large population data 
bases show that approximately 1 in 3 patients diagnosed with APL die within the 
first month of diagnosis.(1-5) The first group to systematically analyze this is a 
population-based study from Sweden.  All patients diagnosed with APL between 
1997 and 2006 in the Swedish Adult Leukemia Registry were included in the 
study.  A total of 105 patients with APL were diagnosed during that time and 
thirty (29%) of these patients died within 30 days of diagnosis with 23 of these 30 
patients dying within the first week of diagnosis. The major cause of death was 
reported as bleeding, with differentiation syndrome, sepsis and multi-organ 
failure being other causes contributing to early mortality.(1)  
While high early mortality was suspected in the US, definite evidence was 
established only recently by a well-designed epidemiologic study conducted by 
Park et al by utilizing the Surveillance, Epidemiology and End Results (SEER) 
program.(2) A total of 1,400 patients diagnosed with APL between 1992 and 2000 
were identified.  Data from 13 population based cancer registries that participate 
in the National Cancer Institute’s SEER program were analyzed.  The overall 
early death rate of all patients diagnosed with APL was 17.3% and 24% in 
patients aged > 55 years.  The authors from the SEER study also concluded that 
this might be an underestimate due to the flaws in the SEER reporting system 
and the actual death rate may be higher than what the study showed. MD 
Anderson Cancer Center also reported their data from various time periods and 
compared them with SEER data.(3) From 2002-2008, the 5 year relative survival 
in APL patients was 64% which is contrary to the reported outcomes in clinical 
trials. This data also suggests that the lower survival observed in the general 
population may not be due to deaths in only smaller treatment centers but may 
also be a problem in larger metropolitan areas (Figure 1).  Single institution 
experience from Stanford University showed an early death rate of 26%, 
suggesting that this problem might be pervasive even in larger treatment 
centers.(5) 

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Figure 1: Early Deaths in APL (Day 1 to 30) 
Study 
Total 
patients 
Patients 
died 
Mortality 
rate 
Percentage of 
patients with 
hemorrhage in 
early death 
Brazil  
(2007)4 
134 
43 
32% 
66% 
Swedish registry 
(2011)1 
105 
30 
29% 
41% 
SEER data  
(2011)2 
1400 
238 
17% 
(24% in  
> 55yr) 
Not discussed 
Stanford  
(2012)5 
70 
19 
26% 
54% 
Ankara, Turkey, 
(2010)8 
49 
20 
40% 
65% 
AIIMS, India 
(2011)6 
33 
6 
18.8% 
Not discussed 
Germany > 60 years 
(2013)9 
91 
24 
26% 
Not discussed 
Hiroshima, Japan 
> 65 years 
(2013)7 
32 
7 
21.3% 
Not discussed 
GRU (our center) 
ASCO  
(2012)10 
19 
7 
37% 
57% 
Georgia Regents University Experience and Pilot Project: 
At Georgia Regents University (GRU), Augusta, GA, from July 2005 to June 
2009, 19 patients with APL were treated.  Seven of these 19 (37%) patients died 
during induction due to the following reasons; however the 11 surviving patients 
are in molecular remission and are presumed cured with a median follow up of 
2358 days. 
1. Delay in diagnosis and transfer to a treating center 
2. Bleeding from coagulopathy 
3. Differentiation syndrome 
4. Infections  
5. Inconsistency in the treatment algorithm and physician inexperience. 
After a thorough review, the investigators at GRU formulated a strategy to 
decrease early deaths and implemented it in 2010. This strategy aided 
physicians to rapidly diagnose the condition when suspected, and also follow a 
mechanism to rapidly transfer the patient from rural areas to GRU.  A 1.5 page 
concise treatment algorithm to simplify the treatment process was developed and 
implemented at GRU. The algorithm was made available to physicians at outlying 

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smaller treatment centers as well.  In addition, investigators at GRU 
communicated with treating physicians in the community and offered guidance.  
We treated or co-managed 143 patients thus far using this model, with 10 deaths 
(6.9%) Furthermore, after implementing the algorithm, data showed an 
encouraging decrease in induction mortality from an estimated 37% (N=19) to 
6.9% (N=143) (Figure 2).  Interestingly 40% of patients were treated in 
experienced leukemia centers and 60% were treated in outlying centers. Patients 
who survive the first 30 days have an excellent quality of life with a low chance of 
relapse and treatment related complications. 
Figure 2: Survival Pre and Post Algorithm 
 
Ongoing Study: 
Funding from the Leukemia & Lymphoma Society (LLS) supports the ongoing 
study efforts to follow the strategy developed at GRU as a model to implement it 
in the states of Georgia and South Carolina to cover a catchment population of 
15 million; the goal is to reduce the induction mortality from an estimated 30% to 
under 15%. 
1.2 
Significance of the Study 
As discussed earlier, the early mortality in APL continues to be high. The first 
large scale intervention to decrease early deaths in APL was undertaken by 
Rego et.al in Brazil, Mexico and Uruguay.  In a report published in 2007, it was 
noted that in Brazil the mortality rate during induction in a cohort of 134 patients 
was 32%.(4)  The cumulative mortality during induction and consolidation was 

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44.7%.  The overall survival in this group was 52% which is significantly lower 
than what is expected in developed countries (62 to 86%).  It was obvious that 
decreasing induction mortality would make the most impact in improving overall 
survival in this patient population. Analysis of the causes of early death showed 
that delayed diagnosis, hemorrhage, differentiation syndrome and infection were 
major causes of death.  This led to the development and implementation of a 
strategy that addressed all the above mentioned causes of early mortality.  This 
effort was supported by the International Members Committee of the American 
Society of Hematology (ASH) in 2005.  A simple and uniform protocol was 
developed and launched in Brazil, Mexico, Chile and Uruguay.  A standard 
program for rapid diagnosis, early initiation of treatment, aggressive management 
of coagulopathy, expedited transfer to a larger center, management of 
differentiation syndrome and effective treatment of infection was implemented.  
From 2006 to 2010, 183 patients were enrolled; 122 in Brazil, 30 in Mexico, 23 in 
Chile and 8 in Uruguay.  The cases were individually discussed by a core group 
of experts with the treating hematologists in outlying hospitals via Internet.  One 
third of the patients were high risk and 52% of the patients were intermediate 
risk. The induction mortality was 15% a decrease from 32% prior to the 
implementation of this study. The major cause of early deaths was still 
hemorrhage (48% of deaths). In addition, the overall survival (OS) improved from 
52% to 80% at 2 year follow-up.(11)  
APL is an uncommon disease; however excellent treatment modalities are 
available with cure rates of 90%. Current trials that are changing the treatment 
schedules, adding new drugs, or withholding maintenance might only have a 
minimal impact on survival in the general population. The intervention that will 
increase population wide survival is decreasing early deaths. Treating 
oncologists, who are not routinely involved in the care of acute leukemia patients 
in smaller centers as well as in larger treatment centers, may not be familiar with 
the treatment or expected complications. Addressing these issues by educating 
these physicians and co-managing patients will help improve survival in a 
condition that has a very high chance of cure. 
Patients that were managed using the simple algorithm (Appendix I) 
demonstrated remarkable improvement in the overall survival. More importantly, 
a network was established with other leukemia treatment centers in the 
catchment area and helped local oncologists manage patients and decreased the 
mortality to 6.9% in 143 patients managed thus far.  By replicating these results 
across a much wider population under the ECOG-ACRIN umbrella with additional 
sites, it is expected that adherence to the treatment guidelines and consultation 
with APL experts will reduce mortality rates even more than what previous trials 
have shown. 
Seven of the ten deaths in our experience was in elderly population and although 
this is significantly better than published literature that suggests non clinical trial 
deaths to be as high as 50-60% in the same age groups, it shows that patients 
above the age of 60 years need a different approach. In our approach which is 
similar to the published literature from Chinese experience, using lower doses or 
single agent ATRA might lead to better outcomes even in this high risk 
population. 
If the study is positive, efforts will be made to implement the concept nationally 
and manage APL patients with use of the streamlined guidelines and expert 

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support. A complement of experts is required to be made available permanently 
and the model should be followed for this project to be sustainable. 
1.3 
Study Overview 
This is a multi-center study with 7 lead investigators accruing at 6 lead sites: 
Medical College of Georgia at Augusta University, Augusta, GA; Memorial Sloan 
Kettering Cancer Center, New York, NY; Mayo Clinic, Rochester, MN; 
Northwestern University, Chicago, IL; University of Pennsylvania, Philadelphia, 
PA and Mayo Clinic, Jacksonville, FL. The study will be restricted to the above 
mentioned SIX NCTN SITES. All six sites will be referred to as lead sites. Other 
Academic sites will not participate in this trial. 
Physicians treating patients at NCORP community centers will call one of the 
lead investigators as early as possible but no later than 3 days after APL directed 
treatment is started. The algorithm will be made available and the contacted lead 
investigator will provide guidance during induction and follow up treatment. The 
providing physicians will be encouraged to call as and when there are problems. 
1.3.1 
Treatment guidelines: 
The treatment guidelines were developed after extensive review of the 
literature on standard treatment of APL. Physicians at the NCORP 
community centers will be provided this algorithm. The study does not 
exclude patients by age or comorbidities and complete adherence 
might not be feasible in certain clinical circumstances. This study is 
directed at co-managing patients by discussions between APL experts 
and treating physicians to improve the care. 
1.3.2 
Feasibility 
The incidence of APL in the US is approximately 1,500 per year. Our 
goal is to target an accrual of 200 patients over a 4 year period. As 
this will be a data collection study, we expect to enroll these patients 
in this time frame. We do not plan to change the treatment from 
present standard of care and therefore will not include any new 
interventions. As described earlier, decreasing early mortality in this 
curable malignancy will have the biggest impact in improving 
outcomes. APL is a rare disease and physicians in some centers may 
not see enough APL patients to be proficient enough.  Transferring 
these patients to larger academic centers is not always feasible for 
multiple reasons. As an increasing number of community hospitals are 
treating patients with acute leukemia, it is important to improve the 
survival in inexperienced centers as well.  This would also make it 
easier for the patient and family and help them remain closer to home.  
From our experience in rural Georgia and South Carolina, most 
leukemia treatment centers have adequate supportive care 
infrastructure such as pharmacy, blood bank, pathology and sub-
specialty services.  We believe that expert guidance will ensure better 
adherence to the guidelines and earlier recognition of impending 
complications and thereby improve survival. 
 
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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To evaluate if the proposed patient care strategy, that includes use of 
simplified Guidelines along with APL expert support, decreases the 
one-month induction mortality rate from 30% to under 15%.  
2.2 
Secondary Objectives 
2.2.1 
To assess the overall survival 1 year after accrual is completed. 
2.2.2 
To assess incidence and severity of differentiation syndrome 
2.2.3 
To correlate outcomes with time to initiation of ATRA from diagnosis 
or suspicion of diagnosis. 
2.2.4 
To evaluate outcomes in academic and community centers 
separately. 
2.2.5 
To evaluate factors associated with outcome. 
 

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3. 
Selection of Patients 
3.1 
Eligibility Criteria 
3.1.1 
All patients ≥ 18 years of age who are confirmed to have a diagnosis 
of APL, which is defined as: 
3.1.1.1 
Positive t(15:17) by FISH, OR 
3.1.1.2 
Positive t(15:17) by conventional karyotype, OR 
3.1.1.3 
Positive PML/RAR alpha by PCR  
3.1.2 
Patients must accept treatment and supportive care guidelines. 
3.1.3 
Referrals must be made as early as possible by treating physician 
(provider) but no later than 3 calendar days after ATRA or APL 
directed therapy is initiated. Consent can be obtained up until day 7 
after initiating APL Directed Therapy. 
3.1.4 
Co-management can be started as soon as referral is made including 
weekends. The Physician at the NCORP community facility should 
make every effort to call the APL expert at the first suspicion of APL. 
 
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4. 
Registration Procedures 
CTEP 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 
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. 
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
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An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU members’ 
website. 
Additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, 
please contact the CTEP Associate Registration Help Desk by email at 
<ctepreghelp@ctep.nci.nih.gov>. 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
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 the following: 
• 
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. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
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 IRB Manager 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. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the EA9131protocol page located on 
the CTSU members’ website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EA9131 
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• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Requirements for EA9131 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 via the Regulatory 
Submission Portal, 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. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE: 
At the main sites, the PI and other designated investigators will obtain the 
consent. 
If a patient is being treated at an NCORP community site, the local PI or 
Co/Sub-PI will consent the patient. The treating physician at the NCORP 
community site will contact an APL expert as soon as the diagnosis is 
suspected but no later than 3 days after ATRA has been initiated. 
NOTE: 
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
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• 
Date of review. 
• 
Signature of IRB official 
Checking Your Site’s Registration Status: 
You can verify your site registration status on the members’ section of the CTSU 
website. 
• 
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 
• 
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 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. 
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 LPO or 
participating organization roster. Registrars must hold a minimum of an AP registration 
type. 
The Study Chair Liaison 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 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. 
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. The Study Chair Liaison will print this 
confirmation and provide it to the site for records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org.  For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Protocol Number  
4.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
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4.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
• 
Gender 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3. 
4.5 
Additional Requirements  
4.5.1 
Patients must provide a signed and dated, written informed consent 
form. This document may be signed patient’s next of kin or person 
with power of attorney, if necessary. 
NOTE: 
Copies of the consent are not collected by the ECOG-ACRIN 
Operations Office 
NOTE: 
Patients should be consented only after APL diagnosis is confirmed. 
4.5.1.1 
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 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. 
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 
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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 
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5. 
Methodology Plan 
There will be 7 investigators accruing at 6 different centers (LEAD SITES) who will serve 
as the APL experts for this proposal. The patients treated at these 6 centers will be 
enrolled at their particular institution. The study will not be open at other academic 
centers. The APL expert at each site will either manage the patient or provide 
consultative oversight to the treating team. The sub-investigators at lead sites can consent 
patients but it is expected that the local PI will provide oversight. We expect to enroll a 
maximum of 30% of the patients at these lead sites. Induction mortality is a problem in 
larger centers as well from extensive data that has been published. We postulate that 
using the guidelines along with expert input will improve outcome in lead sites. This will 
give us the opportunity to assess the problem as well as outcome in academic centers 
and compare the results to community centers. Since the accrual goal is 200 patients 
over a 4 year period, the accrual at lead centers will be limited to 60 patients over a 4-
year period (30%). The Study Chair and ECOG-ACRIN office will monitor this closely 
and once the target is achieved, enrollment at lead sites will be put on hold.  
Investigators from the LEAD sites will meet or have a conference call twice a year to 
discuss the progress and results. 
Prior to enrolling patients, while the study is being reviewed by the IRBs at the 
respective sites, the study investigators will contact NCORP community centers that are 
likely to treat APL in their catchment area. These visits will also be a part of publicizing 
the trial to ensure other treating physicians are aware of the study and also the risk of 
early deaths in this disease. In addition to physician visits, flyers and regular emails will 
also be sent out to ensure that there are frequent reminders about the study. At sites 
that open the trial there will also be a webinar to raise awareness for the trial and provide 
training on the treatment guidelines prior to study activation. 
The trial will be conducted at NCORP community sites in addition to the Lead Sites. We 
conducted a survey of NCORP sites to assess their interest in participating in the study. 
The survey had 3 questions. a. Does your center treat patients with APL?  b. Are you 
aware the induction mortality in APL is approximately 30%? c. Will your Center 
participate in a trial focused on decreasing induction mortality? Eleven sites responded 
and expressed interest. The PI and Co-PI will make personal contact with the other 
NCORP sites and present the goals of the trial and get other sites to open. We have also 
asked the NCORP leadership to give us an opportunity to participate in their annual 
meeting and conference calls and publicize the study to get more sites to participate. 
5.1 
Lead Sites 
5.1.1 
Lead Sites 
• 
Medical College of Georgia at Augusta University. 
• 
Memorial Sloan-Kettering Cancer Center, New York, NY 
• 
The Mayo Clinic, Rochester, MN 
• 
Northwestern University Feinberg School of Medicine, Chicago, IL 
• 
Abramson Cancer Center of the University of Pennsylvania, 
Philadelphia, PA 
• 
The Mayo Clinic, Jacksonville, FL 
5.1.2 
Patients treated at Lead Sites will be treated locally at the Lead Site 
using treatment guidelines. The local PI will provide expert support to 
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the treating team.  The presentation of APL can be highly variable; 
hence adherence to the guidelines is not always feasible. Deviations 
that are made from the guidelines based on particular clinical 
situations will be documented in the medical record. 
5.2 
Outlying NCORP Community Facility 
5.2.1 
The study will be opened only at the NCORP community sites. It will 
not be open at academic NCORP centers. The treating physician 
from the NCORP community Facility should call the APL Expert in 
their catchment area for treatment guidance. Seeking advice from an 
APL expert is a key component of our model.  The call should be 
made as soon as APL is suspected but no later than 3 days after 
starting ATRA and communication should be ongoing based on the 
clinical developments until a hematologic remission is achieved. The 
presentation in APL can be highly variable; hence complete 
adherence to the guidelines is not always feasible. Deviations that are 
made from the guidelines based on particular clinical situations will be 
documented in the medical record. 
5.2.1.1 
The provider at NCORP community centers will be the 
Hematologist/Oncologist attending caring for the patient. 
Initial contact has to be made by a 
Hematologist/Oncologist.  
5.2.1.2 
It is expected that the initial contacting 
Hematologist/Oncologist will continue the communication; 
alternatively, other members of the practice can 
communicate with the APL expert on an ongoing basis. 
5.2.1.3 
Trainees or advanced level practice providers (physician 
assistants or nurse practitioners) and trainees can be in 
communication subsequently with APL experts to continue 
the care. 
5.2.2 
A log will be maintained by the APL expert (Please see Appendix II). 
This will include information on Date admitted, date APL suspected, 
date APL confirmed, date APL therapy started and date APL expert 
was contacted. Subsequent calls and decisions made will be 
documented on the log sheet.  
5.2.3 
It will be suggested that the treating physician will also document the 
communication on an ongoing basis. 
5.3 
Study Accrual and Timeline 
The study will accrue from years one to 4. Follow up will be for one year after last 
patient is accrued and accrual is completed. The total study duration is 5 years. 
5.4 
Adverse Event Reporting Requirements 
The adverse events to treatment will be collected from the hospital records 
obtained from the patients induction period and also follow up at the treating 
physician’s office. An AE log need not be maintained since this study will not 
include any new drugs. The complications from treatment will be noted in the 
database and will be used for analysis of outcomes.  The only SAE that has to be 
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5.4.1 
Reporting Procedure 
This study requires that expedited serious adverse event reporting 
use CTEP’s Adverse Event Reporting System (CTEP-AERS). The 
CTEP’s guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov.  A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the SAE Team at ECOG-ACRIN (857-504-2900) 
• 
the NCI (301-897-7497)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-0159) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.4.2 
Expedited Reporting Requirements for EA9131 
Grade 5a 
Unexpected 
Expected 
24-Hour 5 Calendar Days 
24-Hour 5 Calendar Days 
24-Hour; 5 Calendar Days – The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the AE, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
a This includes all deaths within one year of registration, regardless of 
cause.  Thereafter, deaths must only be reported on the protocol specific 
case report forms. 
NOTE: A death due to progressive disease should be reported as a Grade 
5 “Disease progression” under the System Organ Class (SOC) 
“General disorder and administration site conditions”.  Evidence 
that the death was a manifestation of underlying disease (e.g. 
radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) should be 
submitted. 
5.4.3 
Other recipients of adverse event reports and supplemental data 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable. 
Serious Adverse events determined to be reportable via CTEP-AERS 
must also be reported by the institution, according to the local policy 
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and procedures, to the Institutional Review Board responsible for 
oversight of the patient. 
5.5 
Completion of Induction 
Induction will be continued until the patient achieves hematologic remission (as 
per guidelines). 
5.6 
Consolidation 
Consolidation will be at the treating physician’s discretion. 
5.7 
Maintenance 
Maintenance will be per treating physician’s discretion. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue treatment early, 
will be followed for survival for 1 year after the accrual is completed. 
 

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6. 
Study Parameters 
NOTE: 
Please refer to Appendix I for all recommended tests and procedures 
 
Baseline 
Confirmed APL Dianosis1 
X 
Referral to APL Expert2 
X 
Informed Consent3 
X 
Subject Registration4 
X 
1. Positive t(15:17) by FISH OR conventional karyotype OR PML/RARα by PCR, Rare variants 
can also be included if confirmed. 
2. It is preferred that the APL expert for the catchment area is contacted, however, any APL 
Expert at any Lead Site may be contacted.  Referrals must be made within 3 calendar days 
after ATRA or APL directed therapy is initiated. 
3. Written informed consent must be obtained within 7 days of initiating APL directed therapy. 
4. Registration can be done after initiating treatment. 
 
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7. 
Statistical Considerations 
7.1 
Study Design and Objectives 
This study will accrue 200 APL patients over a 4-year period. The primary 
hypothesis is that the proposed process will lower the one-month mortality rate 
from 30% to < 15%. The primary endpoint is the one-month mortality rate 
Secondary endpoints include: i) overall survival, one-year survival rate, ii) safety, 
iii) initiation of treatment from diagnosis, iv) survival in academic and community 
centers v) compliance with treatment guidelines and vi) evaluation of factors 
associated with outcome. 
7.2 
Sample Size Considerations and Monitoring Plan 
Of the 200 patients accrued, it is expected to have 180 eligible patients after 
adjusting for ineligible and/or lost-to-follow up cases. We allowed 10% for 
ineligible and/or lost-to-follow-up cases. We often allow additional cases (up to 
10%) to account for ineligible cases in ECOG studies. We do not expect any lost-
to-fu cases at 1 month. However, we used 10% ineligibility and/or lost-to-follow-
up to be conservative and general in this study.   
After 100 patients (for 90 eligible) are enrolled and have followed for one-month 
mortality endpoint, one interim analysis will be conducted. Using the critical value 
corresponding to the O’Brien and Fleming boundary at 50% information time, 
95% Repeated Confidence Interval (RCI) for the one-month mortality rate will be 
constructed. The result will be discussed with the ECOG-ACRIN DSMC 
members. If deemed efficacious, accrual will continue to 200 (for 180 eligible) 
patients. This design will have at least 90% power with a two-sided type I error 
rate of < 0.05. Another rationale for the sample size of 200 is that we would like 
to build a 95% RCI with a tight interval. For the expected one-month mortality 
rate, if the observed rate is 10% (18/180) the 95% RCI will be 6-15.4%.If the 
observed one-month mortality rate is 15%, the 95% RCI will be 10.1-21.1%. 
We plan to limit the accrual from the large academic centers to a maximum of 
30% of the total patients. Thus 60 patients (54 eligible) from major academic 
centers and 140 (126 eligible) from NCORP community sites are anticipated. The 
primary analysis and monitoring will be based on all patients regardless of 
enrollment site. After the study is completed, one-month mortality rate will be 
estimated for patients enrolled from NCORP and academic sites separately as a 
secondary analysis.  With 126 eligible patients from NCORP sites, there will be at 
least 90% power for the hypothesis testing of reducing mortality rate from 30% to 
15%, with a two-sided error rate of 0.05. There is sufficient power to test if one-
month mortality rate for NCORP sites can be reduced from 30% to < 15% 
For NCORP sites, 95% CI is 5.6-17% for the observed one-month mortality rate 
of 10.3% (13/126) and 95% CI is 9.3-22.5% for the observed one-month mortality 
rate of 15.1%. (19/126). With 54 eligible patients from academic sites, there will 
be less than 80% power for the hypothesis testing of reducing mortality rate from 
30% to 15%, with a two-sided error rate of 0.05.  For academic sites, 95% CI is 
3-20.3%% for the observed one-month mortality rate of 9.3% (5/54) and 95% CI 
is 6.6-27.1% for the observed one-month mortality rate of 14.8%. (8/54). 
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At 50% information time (i.e. 90 eligible patients have one-month mortality 
assessed), 95% Repeated Confidence Interval will be built for the one-month 
mortality estimate using the O’Brien-Fleming boundary for 50% information time. 
This analysis will be presented to the ECOG-ACRIN DSMC and discussed 
further.  
We do not expect major safety issues in this study.  However adverse events 
data will be monitored in ongoing basis and will be brought to ECOG-ACRIN 
DSMC attention. 
7.3 
Statistical Analysis Plan 
7.3.1 
Primary Objective 
One-month mortality rate will be estimated by dividing total number of 
deaths within one month of study entry by total number of cases with 
at least one-month follow up data. 95% RCI will be provided for this 
endpoint. We will also evaluate the OS data using the Kaplan-Meier 
plot. 
7.3.2 
Secondary Objectives 
Using the method of Kaplan-Meier, overall survival (OS) data will be 
described.  The median OS and one-year OS rate will be estimated 
and 95% CI will be provided. 
We confirm that the primary objective is to assess one-month 
mortality rate among all cases. Secondary analysis will involve 
evaluating outcome data in NCORP and academic sites separately. 
We clarified this further in Section 7.2.  Overall the expected one-
month mortality rate is in the range of 10-15% across all patients as 
well as in two subgroups of NCORP and academic sites.    
With 200 (180 eligible) patients, we expect to build a confidence 
interval not wider than 11% for the expected one-month mortality rate 
of 10-15%.  With 140 (126 eligible) cases from NCORP sites, the 
confidence interval for the one-month mortality rate will be not be 
wider than 13%. 
For the safety endpoints, the severity and duration of coagulopathy, 
bleeding, infections and differentiation syndrome will be measured 
based on the CTC version 4.0. Analysis of the safety data will be 
mostly descriptive. The proportion of patients with the worst degree 
toxicity of grade 3 or higher will be assessed and presented with 95% 
CI. The length of hospital stay is defined as a period between the 
discharge and admission dates for the first hospitalization. For 
patients with no hospitalization, this will be defined as 0. To assess 
the associations between the length of hospital stay and toxicity 
measures (bleeding, infections, differentiation syndrome), each 
toxicity measures will be dichotomized as “mild” vs. “severe” and the 
length of hospital stay will be compared using the two-sample t-test. 
The time from diagnosis and initiation of treatment will be assessed 
and dichotomized as “short’ vs. “long” using the median value. One-
month mortality rate will be compared in these two groups (short vs. 
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compared in these two groups using the logrank test. In this analysis, 
the time of diagnosis will be determined by both: i) confirmed 
diagnosis date and ii) date of suspicious APL. The dichotomized value 
of long vs. short based on the both times will be evaluated. Similarly 
the one-month morality rate and overall survival between the lead 
institutions and NCORP community centers will be compared. For all 
comparisons, two-sided p-values will be reported. 
Compliance with treatment guidelines will be assessed as binary 
outcome and the successful compliance rate will be described with 
95% confidence interval. A regression model will be developed to 
evaluate the factors associated with outcome.  Data items such as 
age, risk status, comorbidity will be collected and evaluated. 
7.4 
Race, Gender, and Ethnicity Accrual Estimates 
Racial Categories 
Ethnic Categories 
Total 
Hispanic or Latino 
Not Hispanic or 
Latino 
Females 
Males 
Females 
Males 
American Indian or Alaskan Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
2 
2 
Native Hawaiian or other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African American 
0 
0 
12 
4 
16 
White 
0 
0 
84 
98 
182 
Total 
0 
0 
96 
104 
200 
 
 
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8. 
Electronic Data Capture 
Please refer to the EA9131 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. In case of 
withdrawal from the study, data will be collected to the point of withdrawal. 
9. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
10. 
References 
1. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Mollgard L, et al. 
Continuing high early death rate in acute promyelocytic leukemia: a population-
based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 
2011;25(7):1128-34.  
2. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early 
death rate in acute promyelocytic leukemia remains high despite all-trans retinoic 
acid. Blood. 2011;118(5):1248-54.  
3. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F. Acute promyelocytic leukemia: 
a population-based study on incidence and survival in the United States, 1975-2008. 
Cancer. 2012;118(23):5811-8.  
4. Jacomo RH, Melo RA, Souto FR, de Mattos ER, de Oliveira CT, Fagundes EM, et al. 
Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia 
who received ATRA and anthracyclines. Haematologica. 2007;92(10):1431-2.  
5. McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, , et al.Treatment advances 
have not improved the early death rate in acute promyelocytic leukemia. 
Haematologica.2012;97(1):133-6.  
6. Bajpai J1, Sharma A, Kumar L, Dabkara D, Raina V, Kochupillai V, Kumar R. Acute 
promyelocytic leukemia: an experience from a tertiary care centre in north India. 
Indian J Cancer. 2011 Jul-Sep;48(3):316-22.  
7. Imagawa J, Harada Y, Shimomura T, Tanaka H, Okikawa Y, Harada H. High early 
death rate in elderly patients with acute promyelocyticleukemia treated with all-trans 
retinoic acid combined chemotherapy. Int J Hematol. 2013 Aug;98(2):264-6.  
8. Serefhanoglu, S., et al. (2010). "Clinical features and outcomes of 49 Turkish 
patients with acute promyelocytic leukemia who received ATRA and anthracyclines 
(PETHEMA protocol) therapy." Leuk Res 34(12): e317-319 
9. Lengfelder, E., et al. (2013). "Outcome of elderly patients with acute promyelocytic 
leukemia: results of the German Acute Myeloid Leukemia Cooperative Group." Ann 
Hematol 92(1): 41-52 
10. Anand P. Jillella, Ibrahim Sadek, Devi Morrison, Kavita Natrajan, Farrukh Tauseef 
Awan, Ravindra Kolhe, Vamsi Kota. A simple but effective model to decrease early 
deaths in acute promyelocytic leukemia (APL). J Clin Oncol 30, 2012 (suppl; abstr 
6573) 
11. Rego EM, Kim HT, Ruiz-Arguelles GJ, Undurraga MS, Uriarte Mdel R, Jacomo RH, 
et al. Improving acute promyelocytic leukemia (APL) outcome in developing 
countries through networking, results of the International Consortium on APL. Blood. 
2013;121(11):1935-43.  

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Leukemia (APL) 
Appendix I 
 
Acute Promyelocytic Leukemia Treatment Guidelines 
Developed at Georgia Regents University, August 2013 Revised May 2017 
AUTHORS: 
Dr. Anand P. Jillella 
Mobile: 706 -951- 5144   
Office: 706-721-2505 
Dr. Vamsi K. Kota 
Mobile: 706- 825- 4091  
Office: 404-778-1900 
WORK-UP 
BASELINE 
• 
Chest X-ray  
• 
Echocardiogram and EKG 
• 
PICC line placement – NO central lines in chest or neck or invasive procedures 
(bronchoscopy, spinal tap, endoscopy) 
• 
Bone marrow examination (aspirate, biopsy, flow, cytogenetics, FISH for t15:17, PCR for 
PML-RARa). Day 14 marrow is NOT necessary. 
DAILY 
• 
CBC, CMP, PT, PTT, fibrinogen TWICE DAILY until lab & clinical coagulopathy is resolved. 
CMP daily and twice a day as dictated by clinical condition. 
• 
D-dimer ONCE DAILY for ENTIRE hospitalization. 
PREVENTION/TREATMENT OF COAGULOPATHY 
• 
Intracranial, pulmonary and GI hemorrhages are frequent   
• 
Risk of hemorrhage is ↑ with the presence of any of the following - active sites of bleeding,  
↓ fibrinogen, ↑ D-dimers, ↑ PT & PTT, ↑ WBC, ↑peripheral blasts, renal failure and poor 
performance status; 
• 
Keep platelets above 50,000 (until resolution of DIC) 
• 
If there are any active sites of bleeding on presentation (e.g., needle sticks, bone marrow 
biopsy sites,), and prolonged PT/PTT), give 4 units of fresh frozen plasma (FFP) at the start 
of ATRA and chemotherapy.  CONTINUE FFP support TWICE A DAY until clinical bleeding 
resolves. 
• 
Keep fibrinogen above 150.  Use 10 units of cryoprecipitate if < 150 (until DIC resolves). 
• 
When clinical & lab coagulopathy is resolved, blood product support is per standard 
guidelines. 
→ APL IS A MEDICAL EMERGENCY - START ATRA ASAP ← 
PREVENTION/TREATMENT OF APL DIFFERENTIATION SYNDROME 
Differentiation Syndrome-symptoms are – dyspnea, unexplained fever, ↑ weight, peripheral 
edema, unexplained hypotension, acute renal failure, CHF, pleuro-pericardial effusions, and 
interstitial pulmonary infiltrates. 
• 
Daily weights - BEDSIDE SCALES ONLY 
• 
Keep I/O matched – METICULOUSLY 
Rev. Add2 
Rev. Add2 

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• 
Diuretics if increase in fluid retention or weight. 
• 
Prednisone 0.5 to 1 mg/Kg in all patients for 2 weeks as prophylaxis starting on day 1 
followed by a taper. 
• 
Increase Dexamethasone to 10 mg IV BID from the prophylactic dose above, if onset of DS 
symptoms. 
• 
If WBC > 10,000, dexamethasone 10 mg IV bid could be started on day 1 before initiating 
ATRA. 
• 
Temporary discontinuation of ATRA or Arsenic Trioxide (ATO) is indicated only in case of 
severe cases of DS. 
• 
Continue dexamethasone until 3 days after all symptoms are resolved. ATRA and/or arsenic 
can be resumed. 
SUPPORTIVE CARE 
• 
Allopurinol 300 mg daily. 
• 
Antibiotic prophylaxis - levofloxacin 500 mg po daily or similar antibiotic. 
• 
Antifungal prophylaxis - posaconazole 200 mg po 3 x3x daily, voriconazole 200 mg po 2 x2x 
daily, Micafungin 50 mg daily or a similar drug as per institutional standard. 
• 
Anti-viral prophylaxis  - acyclovir 400 mg po 2 x2x daily or valacyclovir 1000 mg PO daily. 
• 
RBC transfusion recommended when HGB ↓ 8. 
INDUCTION OF LOW AND INTERMEDIATE RISK PATIENTS WBC < 10,000 and PLTS < 
40,000 -  
• 
ATRA 45mg/m2 in divided doses twice a day plus ATO 0.15 kg daily until complete 
hematologic remission (no anthracycline). Prednisone 0.5 mg/kg for 14 days followed by a 
gradual taper if no evidence of DS. 
OR 
• 
ATRA on Day 1 at 45 mg/m2 DAILY in divided doses twice a day until complete hematologic 
remission. 
• 
Idarubicin 12 mg/m2 on Days 2, 4, 6 and 8. Prednisone 0.5 mg/kg for 14 days followed by a 
gradual taper if no evidence of DS. 
INDUCTION OF HIGH RISK PATIENTS WBC > 10,000 
• 
ATRA to be started as soon as diagnosis is suspected at 45 mg/m2 in divided doses twice a 
day until complete hematologic remission. 
• 
Idarubicin to be started on the SAME DAY OR AS SOON AS POSSIBLE WHEN THE 
DIAGNOSIS IS CONFIRMED at 12 mg/M2 on days 1, 3, 5 and 7. 
• 
Dexamethasone 10 mg IV bid on days 1 to 14 followed by a taper. 
• 
Arsenic at 0.15 mg/Kg can be started on day 10. 
• 
Even if the genetic results are not available, it is reasonable to start Idarubicin if the 
diagnosis is otherwise strongly suggested. 
ARSENIC ADMINISTRATION 
• 
Prednisone 0.5 mg/Kg from days 1-14 days followed by a taper. If high risk, dexamethasone 
10 mg IV bid on days 1 to 14 followed by a taper. 
• 
Watch for differentiation syndrome. 
Rev. Add2 
Rev. Add2 
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• 
Watch for prolonged QTc interval. 
• 
Keep Mg above 2.0 and K above 4.0. 
• 
Follow LFTs for grade 2 - 4 liver dysfunction. If this occurs HOLD arsenic. 
SUGGESTED MANAGEMENT OF ATRA/ARSENIC-INDUCED LEUKOCYTOSIS 
• 
WBC 5 - 50 K- Hydroxyurea 500 mg qid 
• 
WBC > 50K- Hydroxyurea 1000 mg qid 
• 
If leukocytosis does not resolve one or two doses of Idarubicin or Cytarabine could be 
considered. 
• 
NO LEUKOPHERESIS. 
ELDERLY PATIENTS / ≥ 60 years AND PATIENTS WITH SEVERE COMORBID 
CONDITIONS 
• 
May not be candidates for cytotoxic chemotherapy. 
• 
Consider dose reduction of ATRA. Single agent and consider 25 mg/M2 for 14 days. 
• 
Consider dose reduction of ATO and consider 0.075 mg/M2 and add on day 15. 
 

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Leukemia (APL) 
Appendix II 
 
APL Expert and NCORP Provider Communication 
 
1. Date patient admitted 
- 
2. Date APL suspected 
- 
3. Date APL confirmed 
- 
4. Date APL therapy started 
- 
5. Date APL expert contacted 
- 
6. Subsequent communications - 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 

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A Simplified Patient Care Strategy to Decrease Early Deaths in Acute Promyelocytic 
Leukemia (APL) 
Appendix III 
 
NCORP PROVIDER INFORMATION SHEET 
This is a research study focused on decreasing induction mortality in Acute Promyelocytic 
Leukemia (APL).  Historical data shows an induction mortality of 30% in the general population 
and the purpose of this study is to decrease it to < 15%. NCORP providers will be given this 
information sheet along with the treatment guidelines in Appendix I. 
A. The study will consist of using the simplified APL treatment algorithm that is attached. 
B. Equally important is for the provider at NCORP sites to call an APL expert listed in the 
protocol or the PI/Co-PI.  Cell phone numbers of APL experts are in the Protocol. 
C. The APL expert will function as a resource during induction to prevent and manage 
complications.  It is suggested that the provider at NCORP sites call the APL expert as 
frequently as needed during the first 4 weeks.  The experts are available 24/7. 
D. NCORP providers will document discussion with the APL expert and clinical decisions in the 
Medical Record. APL experts will fill the Expert/NCORP Provider communication sheet. 
E. There are no obvious discomforts to the patient since the patient will be treated on the 
accepted standard of care.  Expert support may help in preventing and managing 
complications and improving outcome. 
F We will retain all patient records and signed informed consent forms filed in a secure 
location.  Database is maintained using web-based database system.  Only research 
members are granted access to web-based database system with user ID and password. 
G. Participation is voluntary and the patient may choose not to participate in the trial.  In that 
case the patient will be treated per usual treatment guidelines. Participants may discontinue 
at any time without penalty or loss of benefits. 
 

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A Simplified Patient Care Strategy to Decrease Early Deaths in Acute Promyelocytic 
Leukemia (APL) 
Appendix IV 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME]                                                                                                     [DATE] 
[PATIENT ADDRESS] 
 
 
Dear Mr. / Mrs. / Ms. ___________, 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of ___________________ and ECOG-ACRIN, we thank you again and look 
forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME]