Clinical trial NCT01404949
Conditions: Acute Promyelocytic Leukemia
Keywords: Tretinoin all-trans retinoic acid ATRA Vesanoid Arsenic Trioxide ATO Trisenox 11-040
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2011-07-01; Completion date: 2021-02-01
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find what effects, good and/or bad, treatment with two drugs has on leukemia. The first medicine is tretinoin (also called all-trans retinoic acid, ATRA, or Vesanoid). It is an approved medicine that causes the leukemia cells in APL to mature. It is related to vitamin A. The second is arsenic trioxide (Trisenox). It is an approved medicine for APL that comes back after earlier treatment.

APL is most often treated with tretinoin and standard chemotherapy drugs. These chemotherapy drugs can cause infection and bleeding. They can also damage the heart and normal bone marrow cells. This can lead to a second leukemia years later.

In this study, the investigators are using tretinoin and arsenic trioxide together. Both drugs work to treat APL. They have been used together in only a limited number of people. The investigators want to use these drugs together to reduce the amount of standard chemotherapy and decrease side effects. The patient will receive standard chemotherapy with a drug called idarubicin only if they have a higher chance of the leukemia coming back or a higher risk of side effects.

Detailed description:
Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in two divided doses (25 mg/m2 in patients \<20 years of age) for 35 days and ATO 0.15 mg/kg IV daily for 35 doses given 5-7 days per week. The drugs will then be discontinued, and the patient will be followed until a clinical complete remission is achieved. Idarubicin 12 mg/m2 IV for 4 doses will be added during induction on day 2 if the presenting WBC is \>10,000/μl, or if the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 15,000/μl on day 15, because of the increased risk of the APL differentiation syndrome and relapse in these patients. Dexamethasone 10 mg twice daily with be given on days 1-14 of induction as prophylaxis for the APL differentiation syndrome. All patients will then receive four courses of consolidation with tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) (25 mg/m2 in patients \<20 years of age) for 15 days and ATO 0.15 mg/kg IV for 25 doses.

Patients with high-risk disease or who received Idarubicin during Induction may receive intrathecal cytarabine as CNS prophylaxis given by the treating physician during consolidation, at the discretion of the site PI. High-risk patients will also receive maintenance therapy with additional courses of tretinoin and ATO every 3 months for 2 years. Each maintenance course will consist of tretinoin 45 mg/m2 po daily (25 mg/m2 in patients \<20 years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses. Disease status will be monitored with serial analyses of peripheral blood samples using RT-PCR for PML-RARα mRNA. Patients will be followed until relapse, death, loss to follow-up, or removal from study.

Induction therapy can be given as an inpatient or outpatient. Consolidation and maintenance treatments will be given as an outpatient. Consolidation may also be given at the patient's local institution. Intrathecal cytarabine treatments will be administered as an outpatient.

Arms: arm 1: This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of standard chemotherapy required for long-term remission.
Interventions: intervention 1: Tretinoin and Arsenic Trioxide
Intervention descriptions: intervention 1: See Detailed Description

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
1 
 
 
Approval date: 07-Mar-2018 
Phase II Study of Combined Tretinoin and Arse 
For Patients with Newly Diagnosed Acute Promyelocytic 
Risk-Adapted Postremission Therap 
MSKCC THERAPEUTIC/DIAGNOSTIC PROT 
Principal Investigator/Department: 
Jae Park, MD 
nic Trioxide 
Leukemia Followed by 
y 
OCOL 
Medicine 
Co-Principal  Investigator(s)/Department: 
Martin S. Tallman, MD 
Medicine 
Investigator(s)/Department: 
Omar I. Abdel-Wahab, MD 
Ellin Berman, MD 
Renier J. Brentjens, MD, PhD 
Virginia Klimek, MD 
Ross Levine, MD 
Peter G. Maslak, MD 
David A. Scheinberg, MD, PhD 
Katherine Panageas, PhD 
Stephen S. Chung, MD 
Raajit K. Rampal, MD, PhD 
Eytan M. Stein, MD 
Michael J. Mauro, MD 
Aaron Viny, MD 
Jacob Glass, MD, PhD 
Alan Shih, MD, PhD 
Anthony Daniyan, MD 
Mark Geyer, MD 
Aaron Goldberg, MD 
Bernadette Cuello, NP 
Coleen Ranaghan, NP 
Marisa Hine, NP 
Linda Ouyang, NP 
Emily Toulouse, RN 
Kelsey Alvarez, RN 
Katelyn Kelly-Johnson, RN 
Louise Ligresti, MD 
Paul Hamlin, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Neha Korde, MD 
Matthew J. Matasar, MD 
Sham Mailankody, MD 
Jahan Aghalar, MD 
Wanqing Iris Zhi, MD, PhD 
Avni Desai, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
Philip Caron, MD, PhD 
Hani Hassoun, MD 
Andrew Zelenetz, MD 
Neha Korde, MD 
Medicine 
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Epidemiology and Biostatistics 
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2 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
 
 
 
 
 
Jason Konner, MD 
Colette Owens, MD 
Marina Shcherba, DO 
Medicine 
Medicine 
Medicine 
Consenting  Professional(s)/Department: 
Jae Park, MD 
Medicine 
Martin S. Tallman, MD 
Medicine 
Omar I. Abdel-Wahab, MD 
Medicine 
Ellin Berman, MD 
Medicine 
Renier J. Brentjens, MD, PhD 
Medicine 
Virginia Klimek, MD 
Medicine 
Ross Levine, MD 
Medicine 
Peter G. Maslak, MDDavid A. 
Medicine 
Scheinberg, MD, PhD 
Medicine 
Stephen S. Chung, MD 
Medicine 
Raajit K. Rampal, MD, PhD 
Medicine 
Eytan M. Stein, MD 
Medicine 
Michael J. Mauro, MD 
Medicine 
Aaron Viny, MD 
Medicine 
Jacob Glass, MD 
Medicine 
Alan Shih, MD, PhD 
Medicine 
Anthony Daniyan, MD 
Medicine 
Mark Geyer, MD 
Medicine 
Aaron Goldberg, MD 
Medicine 
 
 
Collaborating Institutions 
PI's Name 
Site's Role 
Northwestern University 
Jessica Altman, MD 
Data Collection 
New York Presbyterian Hospital Cornell 
Medical Center 
Gail Roboz, MD 
Data Collection 
Ontario Cancer Institute/Princess 
Margaret Hospital 
Andre Schuh, MD 
Data Collection 
University of Southern California 
Vinod Pullarkat, MD 
Data Collection 
National Heart, Lung and Blood Institute 
(NIH) 
Neal S. Young, MD 
Data and/or Specimen 
Analysis 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Commack 
Rockville Centre 
Westchester 
Monmouth 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


3 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 6 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 12 
4.1 
Design................................................................................................................................. 12 
4.2 
Intervention .............................................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 14 
6.1 
Subject Inclusion Criteria ..................................................................................................... 14 
6.2 
Subject Exclusion Criteria ................................................................................................... 15 
7.0 
RECRUITMENT PLAN .................................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 17 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 22 
Table IV. Long Term Follow Up ............................................................................................. 27 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 28 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 29 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 29 
14.0 
BIOSTATISTICS ............................................................................................................... 30 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ................ 31 
15.1 
Research Participant Registration ....................................................................................... 31 
15.2 
Randomization .................................................................................................................... 31 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 32 
16.1 
Quality Assurance............................................................................................................... 34 
16.2 
Data and Safety Monitoring .................................................................................................... 34 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 37 
17.1 
Privacy ................................................................................................................................ 37 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................ 37 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 40 
19.0 
REFERENCES ....................................................................................................................... 41 
20.0 
APPENDICES ................................................................................................................... 45 


4 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
1.1 
Study Title:  Phase II study of combined tretinoin and arsenic trioxide for patients 
with newly diagnosed acute promyelocytic leukemia followed by risk adapted 
postremission therapy. 
1.2 
Objectives:  (1) To determine the rate of molecular remission after induction with 
combined tretinoin and ATO (along with idarubicin in patients with high-risk disease or 
who develop leukocytosis) in acute promyelocytic leukemia (APL); (2) to determine the 
rate of clinical complete remission (CR) and the time to remission after induction with 
tretinoin and ATO (with idarubicin in patients with high-risk disease or who develop 
leukocytosis); (3) to determine the proportion of patients in molecular remission after each 
course of postremission therapy; (4) to determine the disease-free and event-free survival 
of patients treated with this program; (5) to determine the toxicity of this treatment 
program, including the early death rate (within 30 days), the incidence of APL 
differentiation syndrome, the number and length of hospitalizations, the incidence of 
secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), and the 
effects of treatment on left ventricular ejection fraction (LVEF); (6) to characterize the 
differentiation of APL cells during treatment with combined tretinoin and ATO using serial 
immunophenotyping studies of peripheral blood, and (7) explore the in vivo induction of 
telomerase-dependent cell death by ATRA and ATO. 
1.3 
Patient Population:  Patients with untreated APL >18 years of age will be eligible. 
 
1.4 
Study Design:  Risk groups will be assigned according to established criteria at 
the time of diagnosis:  (1) low-risk patients have a presenting WBC ≤10,000/µL and 
platelet count >40,000/µL; (2) intermediate-risk patients have a presenting WBC 
≤10,000/µL and platelet count ≤40,000/µL, and (3) high-risk patients have a presenting 
WBC >10,000/µL.  Induction for all patients will consist of tretinoin 45 mg/m2 po daily 
(rounded to the nearest 10-mg increment) in two divided doses (25 mg/m
2  in patients <20 
years of age due to a higher incidence of pseudotumor cerebri) for 35 days and ATO 0.15 
mg/kg IV daily for 35 doses, given 5-7 days per week.  The drugs will then be 
discontinued, and the patient will be followed until a clinical complete remission is 
achieved.  Idarubicin 12 mg/m
2 IV for 4 doses will be added during induction for patients 
with high-risk disease or who develop leukocytosis during therapy, because of the 
increased risk of APL differentiation syndrome and relapse.  Dexamethasone 10 mg twice 
daily with be given on days 1-14 of induction as prophylaxis for the APL differentiation 
syndrome.  All patients will then receive four courses of consolidation with tretinoin for 15 
days and ATO for 25 doses.  During consolidation, high-risk patients or patients who have 
received Idarubicin during induction will receive central nervous system prophylaxis with 6 
doses of 70mg intrathecal cytarabine, at the discretion of the site PI.  Patients who have 
not achieved a molecular remission after the completion of Consolidation 4 will be 
removed from study.  Following consolidation, high-risk patients will receive 8 cycles of 
maintenance therapy consisting of tretinoin for 15 days and ATO for 10 doses every 3 
months.  Low- and intermediate-risk patients will not receive maintenance therapy.  The 
differentiating effects of therapy will be characterized by serial flow cytometric analyses of 
peripheral blood. Effects of combined ATRA and ATO on telomerase activity, telomere 
length, and TERT expression will be assessed by analyses of serial blood and bone 
marrow samples.  Disease status will be monitored with serial analyses of blood samples 
using RT-PCR for PML-RARα mRNA.  Patients will be followed until relapse, death, loss 
to follow-up, or removal from study. 


5 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
 
 
 
 
1.5 
Time to Completion:  Up to 39 patients will be entered on this study.  With an 
expected accrual of 10-15 patients per year, this study will take approximately 3-4 years to 
complete. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consolidation 4 
ATRA 45 mg/m2/day orally x 15 days (25 mg/m2/day in patients <20 years) 
ATO 0.15 mg/kg/day IV x 25 doses 
RT-P CR – 
RT-P CR + 
 
Low- and Intermediate-Risk 
High-Risk 
 
 
 
 
 
 
 
 
 
Fig. 1.  Treatment Schema.  See Section 1.4 for details.  Risk assessment will be performed at the 
time of diagnosis.  Idarubicin will be added during induction on day 2 if the presenting WBC is > 
10,000/μL or i f WBC is >5,000/μL on day 5, >10,000/ μL on day 10, or >15,000/μL on day 15.  Low- 
and intermediate-risk patients with a molecular remission after Consolidation 4 will go on to long- 
term follow-up, where as high-risk patients in molecular remission will receive maintenance therapy. 
Patients failing to achieve a molecular remission after Consolidation 4 will be removed from study. 
Patients with high-risk disease or patients that receive Idarubicin during Induction will also receive a 
Long-term Follow-up 
Maintenance 
ATRA 45 mg/m2/day orally x 15 days 
(25 mg/m
2/day in patients <20 years) 
ATO 0.15 mg/kg/day IV x 10 doses 
q 3 months x 8 cycles 
Long-term Follow-up 
Off Study 
Consolidation 3 
ATRA 45 mg/m2/day orally x 15 days (25 mg/m2/day in patients <20 years) 
ATO 0.15 mg/kg/day IV x 25 doses 
Consolidation 2 
ATRA 45 mg/m
2/day orally x 15 days (25 mg/m
2/day in patients <20 years) 
ATO 0.15 mg/kg/day IV x 25 doses 
Consolidation 1 
ATRA 45 mg/m2/day orally x 15 days (25 mg/m2/day in patients <20 years) 
ATO 0.15 mg/kg/day IV x 25 doses 
Induction 
ATRA 45 mg/m2/day orally x 35 days (25 mg/m2/day in patients <20 years) 
ATO 0.15 mg/kg/day IV x 35 doses 
± IDR 12 mg/m2 IV every other day x 4 doses (See below) 
Dexamethasone 10 mg bid (oral or IV), days 1-14 


6 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
 
 
 
 
 
total of 6 doses of cytarabine 70 mg intrathecally every 2 to 4 weeks during consolidation, at the 
discretion of the site PI. Abbrevi ations: ATRA, all-trans retinoic acid; ATO, arsenic trioxide; IDR, 
idarubicin; 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: 
 
• 
To determine the rate of molecular remission after induction with combined 
tretinoin and ATO (along with idarubicin in patients with high-risk disease or who 
develop leukocytosis) in APL. 
 
Secondary Objectives: 
 
• 
To determine the rate of clinical complete remission (CR) and the time to remission 
after induction with tretinoin and ATO (with idarubicin in patients with high-risk 
disease or who develop leukocytosis). 
 
• 
To determine the proportion of patients in molecular remission after each course of 
postremission therapy. 
 
• 
To determine the disease-free and event-free survival of patients treated with this 
program. 
 
• 
To determine the toxicity of this treatment program, including the early death rate 
(within 30 days), the incidence of APL differentiation syndrome, the number and 
length of hospitalizations, the incidence of secondary myelodysplastic syndrome 
(MDS)/acute myeloid leukemia (AML), and the effects of treatment on left 
ventricular ejection fraction (LVEF). 
 
• 
To characterize the differentiation of APL cells during treatment with combined 
tretinoin and ATO using serial immunophenotyping studies of peripheral blood. 
 
• 
Explore the in vivo induction of telomerase-dependent cell death by ATRA and 
ATO. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Disease Background.  APL is a subtype of AML with a distinct biology and clinical 
presentation marked by cytopenias and severe coagulopathy.  Although it accounts for 
only 10% of all cases of AML, it has become a model for therapies targeted to molecular 
abnormalities that produce a neoplastic phenotype.  The vast majority of APL is 
characterized by a specific translocation that fuses the promyelocytic leukemia gene 
(PML) located on chromosome 15 with a gene encoding a retinoic acid receptor (RAR) 
on chromosome 17 [1-4].  PML, which is predominantly localized within multi-protein 
nuclear body structures (PML bodies), normally exhibits growth suppressor and pro- 
apoptotic activity.  RAR at physiologic levels of its ligand, retinoic acid, acts as a 
transcriptional activator at retinoid response elements and is implicated in myeloid 
differentiation [5, 6].  The presence of the PML-RAR fusion protein disrupts these 
functions, leading to the development of leukemia. 
 
3.2 
Induction with ATRA.  Early studies showed that, as a single agent, ATRA 
produces complete remissions in up to 90% of patients by inducing terminal differentiation 
of APL cells [7-9].  Furthermore, the use of ATRA followed by consolidation chemotherapy 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
7 
 
 
 
 
significantly reduces relapse rates and improves survival [8, 10].  In studies conducted at 
Memorial Sloan Kettering Cancer Center (MSKCC), ATRA induction followed by three 
courses of idarubicin and cytarabine produced five-year disease-free and overall survival 
rates of 65% and 68%, respectively [11].  In the North American Intergroup study I0129, 
346 patients with APL were randomized to receive either ATRA or daunorubicin and 
cytarabine for remission induction followed by two courses of consolidation chemotherapy 
with or without ATRA maintenance.  While there was no difference in the remission rate 
between the ATRA and chemotherapy groups (72% vs. 69%, respectively), the three-year 
DFS was significantly improved in the ATRA-treated patients compared with those treated 
with standard chemotherapy (72% vs. 32%; p < 0.001) [12]. 
3.3 
Induction with Concomitant ATRA and Chemotherapy.  Fenaux et al. 
compared the use of concomitant ATRA and chemotherapy with ATRA alone for induction. 
Patients under age 65 years with presenting leukocyte counts below 5,000/μL were 
randomized to receive either ATRA alone (n = 109) or with daunorubicin and cytarabine (n 
= 99).  Chemotherapy was added in patients receiving ATRA alone if leukocytosis 
developed, and concomitant ATRA-chemotherapy was given to patients presenting with  
an elevated white blood count (WBC), since these patients were recognized to be at 
greater risk for the development of APL differentiation syndrome.  Patients then went on to 
receive two courses of consolidation therapy, followed by a second randomization to 
receive several different maintenance regimens or observation.  Relapse at two years was 
estimated at 6% in the ATRA-chemotherapy group compared with 16% in the group 
receiving ATRA alone (p = 0.04).  The two-year event-free survival was 84% in the ATRA- 
chemotherapy group and 77% in the ATRA alone group (p = 0.1) [13].  Exploiting the 
sensitivity of APL to anthracyclines when used as single agents for remission induction 
[14], Mandelli et al. similarly reported one- and two-year DFS rates of 83% and 79% for 
patients treated with ATRA and idarubicin followed by three cycles of consolidation  
therapy (the “AIDA” regimen) [15].  Moreover, combination ATRA and idarubicin produced 
molecular remissions in 60.5% of patients, whereas ATRA alone produces molecular 
remissions in only 5-15% of patients [16]. 
3.4 
Management and Prevention of APL Differentiation Syndrome.  Some APL 
patients treated with ATRA or ATO have experienced a syndrome characterized by fever, 
dyspnea, weight gain, leukocytosis, pulmonary infiltrates, and pleural or pericardial 
effusions.  This syndrome can be fatal.  Corticosteroids given at the first suspicion of the 
APL differentiation syndrome appear to mitigate signs and symptoms and reduce  
mortality.  If patients develop unexplained fever, dyspnea, weight gain, abnormal chest 
auscultatory findings, or chest radiographic abnormalities, treatment with dexamethasone 
10 mg intravenously q 12 hours should be initiated immediately.  Therapy should be 
continued for at least 3 days or longer until signs and symptoms have resolved [17, 18].  In 
uncontrolled trials, a very low mortality and morbidity rate was reported as a result of 
differentiation syndrome after ATRA treatment when corticosteroids were administered 
prophylactically in patients presenting with WBC counts >5,000/µL [19, 20]. 
3.5 
Consolidation with Anthracyclines Alone.  The administration of cytarabine 
during consolidation therapy is not required for long-term remissions in APL.  Estey et al. 
reported a one-year disease-free survival rate of 87% in patients initially treated with 
ATRA and idarubicin followed by two courses of idarubicin consolidation and maintenance 
therapy [21].  Similarly, Sanz et al. found that patients treated with a regimen identical to 
AIDA, except for the omission of cytarabine and etoposide during consolidation, had an 
overall estimated three-year relapse-free survival of 90% [22].  In this study, three risk 
groups were identified:  (1) low-risk patients have a presenting WBC ≤10,000/µL and 
platelet count >40,000/µL; (2) intermediate-risk patients have a presenting WBC 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
8 
 
 
 
 
≤10,000/µL and platelet count ≤40,000/µL, and (3) high-risk patients have a presenting 
WBC >10,000/µL.  Differences in relapse-free survival among these three groups were 
highly significant (P <0.0001).  In a subsequent trial, the addition of ATRA to idarubicin or 
mitoxantrone during consolidation significantly reduced the relapse rate (20.1% vs. 8.7%; 
p = 0.004) and improved disease-free and overall survival compared to consolidation 
chemotherapy without ATRA in patients with intermediate- or high-risk disease [20]. 
 
3.6 
Maintenance Therapy.  The role of maintenance therapy in APL remains 
controversial.  In the North American Intergroup trial I0129, of the 94 patients assigned to 
maintenance with ATRA, 29 relapsed, whereas 60 of the 105 patients assigned to 
observation relapsed.  The three-year DFS was 65% for patients receiving ATRA 
maintenance compared to 40% for those randomized to observation, regardless of 
induction regimen (p < 0.001) [12].  Fenaux et al. randomized patients to maintenance with 
intermittent ATRA (15 days every 3 months for two years), continuous low-dose 6- 
mercaptopurine and methotrexate, both ATRA and chemotherapy, or observation.  The 
two-year relapse rate was 11% in patients receiving maintenance chemotherapy  
compared to 27% in patients randomized to no chemotherapy (P = 0.0002) and 13% in 
patients receiving intermittent ATRA compared to 25% in patients not receiving ATRA (P = 
0.02).  Overall survival was improved in patients who received maintenance chemotherapy 
(P = 0.01), and there was a trend towards improved survival in patients treated with 
maintenance ATRA (P = 0.22) [13].  In contrast, two more recent reports included a 
Japanese [23] and Italian study [24] showed no benefit to maintenance therapy.  These 
discrepancies are likely attributable to the intensity of prior induction and consolidation. 
3.7 
RT-PCR Testing for PML-RARα.  Molecular detection of PML-RARα fusion  
mRNA by RT-PCR amplification has become an important tool in the management of APL. 
This assay is useful in the diagnosis of APL, in predicting response to ATRA, and in the 
detection of minimal residual disease after remission induction [25-28].  Additional studies 
also indicate that RT-PCR monitoring can predict relapse and identify patients who require 
further antileukemic therapy [29-31].  In studies conducted at Memorial Sloan Kettering 
Cancer Center (MSKCC), the bone marrow of 82 patients who received ATRA induction 
followed by postremission chemotherapy, RA, and other biologic agents was serially 
evaluated using RT-PCR.  Forty of 47 patients (85%) with newly diagnosed APL who were 
induced using ATRA alone had residual disease detectable by RT-PCR before additional 
therapy.  After three cycles of consolidation therapy, residual disease was found in only 
four of 40 evaluable patients (10%).  Among newly diagnosed patients who had two or 
more negative RT-PCR assays, only three of 41 (7%) relapsed, whereas all four patients 
(100%) who had two or more positive results relapsed.  These data indicate that two or 
more negative RT-PCR assays on bone marrow, performed at least one month apart after 
completing therapy, are strongly associated with long-term remissions. Conversely, a 
confirmed positive test is highly predictive of relapse [16]. 
 
Similar results were reported by Diverio et al., in which bone marrow samples of 163 
patients with APL in first remission were prospectively analyzed every three months using 
RT-PCR.  Of the 21 patients who converted to RT-PCR-positivity after the completion of 
therapy, 20 relapsed clinically at a median of 3 months (range, 1-14 months) after the first 
positive result.  The remaining patient subsequently tested negative and continued in 
clinical remission.  Among 142 patients who tested negative in two or more assays after 
consolidation therapy, only eight (6%) relapsed [32].  Quantitative real-time RT-PCR was 
also used retrospectively to assess PML-RAR mRNA before treatment and at various 
post-treatment time points in APL patients.  Results were reported as a normalized 
quotient (NQ), obtained by dividing the copy number of PML-RAR by that of the reference 
gene GAPDH.  NQs greater than 10-5  were found to be associated with a 17-fold 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
9 
 
 
 
 
increase in the relapse risk [33].  Based on these data, the goal of therapy in APL is 
molecular remission. 
3.8 
ATO for Relapsed APL.  The mechanism of action of ATO against APL is 
complex and remains poorly understood.  In vitro studies showed that NB4 cells 
expressing PML-RAR underwent apoptosis associated with down regulation of bcl-2 and 
modulation of PML-RAR [34].  These effects occurred in a dose-dependent manner with 
partial differentiation of leukemic promyelocytes at low concentrations (0.1-0.5 µmol/l) and 
apoptosis at higher concentrations (0.5-2 µmol/l) [35].  ATO also induced apoptosis in 
myeloid leukemia cell lines lacking the PML-RAR rearrangement, suggesting that the 
mechanism of action may be independent of PML-RAR expression [36]. 
 
An initial report from Chinese investigators showed that among 10 patients with a 
molecularly confirmed diagnosis of relapsed APL, nine achieved complete remission after 
treatment with single-agent ATO [37].  This striking antileukemic activity was confirmed in 
a pilot study at MSKCC, in which low-dose ATO induced remissions in 11 of 12 patients 
with relapsed APL.  Clinical response was associated with incomplete differentiation and 
induction of apoptosis with caspase activation in leukemic cells [38].  In a larger, 
multicenter trial, ATO produced clinical complete remissions in 34 of 40 patients (85%)  
with relapsed APL.  Fourteen of the 29 patients (48%) evaluable for RT-PCR conversion 
became negative after an initial induction course, and 25 patients (86%) were RT-PCR- 
negative after subsequent consolidation courses.  Ten patients developed signs or 
symptoms of APL differentiation syndrome and were effectively treated with 
dexamethasone.  Electrocardiographic QT prolongation was seen in 63% of patients.  One 
patient with an absolute QT interval of over 500 msec developed asymptomatic torsades 
de pointe [39]. 
3.9 
Single-Agent ATO for Newly Diagnosed APL.  Mathews et al. treated 72  
patients with ATO 10 mg/day in adults and 0.15 mg/kg in pediatric patients for up to 60 
days in induction.  This was followed by a 28-day consolidation.  Patients then received 
ATO for 10 days/month for 6 months [40].  Sixty-two patients (86%) achieved hematologic 
remission.  There were seven early deaths.  With median follow-up of 58 months, the 
estimated 5-year overall, event-free, and disease-free survival rates for the entire group 
were 74%, 69%, and 80%, respectively.  Five-year overall and event-free survival for 
good-risk (presenting WBC <5,000/µL and platelets >20,000/µL) and high-risk groups (all 
others) were 100% vs. 63% and 90% vs. 60%, respectively [41].  This study demonstrates 
that single-agent ATO can produce durable remission in newly diagnosed APL, particularly 
for patients with low- or intermediate-risk disease. 
3.10 
Concomitant ATRA and ATO for Remission Induction.  Although some early 
reports suggested potential antagonistic effects of ATRA and ATO, based on  
differentiation parameters obtained from in vitro culture systems [42], more recent studies 
have shown additive or synergistic effects against NB4 cells in in vitro and in vivo systems 
[43, 44].  Using syngeneic grafts of leukemic blasts from PML-RAR transgenic mice, 
Lallemand-Breitenbach et al. demonstrated that concomitant ATRA-ATO accelerates 
tumor regression through enhanced differentiation and apoptosis.  While treatment with 
ATRA or ATO alone prolonged survival of these animals by two- to three-fold, combining 
these agents led to prolonged tumor-free survival [45].  Similarly, Rego et al. showed that 
combination ATRA and ATO prolonged survival in leukemic PML-RAR transgenic mice 
or nude mice transplanted with PML-RAR leukemia cells, compared with either drug 
alone [46]. 


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IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
10 
 
 
 
 
Induction with combination ATRA and ATO (n = 21) has been compared to single-agent 
ATRA (n = 20) and ATO (n = 20) in patients with newly diagnosed APL [47].  One of three 
different chemotherapy regimens was added in patients who had a WBC >10,000/μL.  All 
patients then received three cycles of consolidation followed by one of three maintenance 
regimens.  The complete remission rates for ATRA, ATO, and combined ATRA and ATO 
were 95%, 90%, and 95%, respectively.  The time to achieve complete remission, 
however, differed significantly among the three groups, with a median time of 40.5 days 
(range, 25-65) for ATRA, 31 days (range, 28-38) for ATO, and 25.5 days (range, 18-35) 
for the combination.  The decrease in PML-RARα transcripts determined by quantitative 
real-time RT-PCR was significantly greater for combination therapy as compared to ATRA 
or ATO monotherapy (P < 0.01).  All patients in the combination group remained in 
remission, whereas seven of the 37 patients treated with single-agent ATRA or ATO 
relapsed after a follow-up duration of 8-30 months (median, 18 months). 
 
Estey et al. have also studied combined ATRA and ATO for remission induction in APL. 
Patients began ATO on day 10 of therapy and continued both drugs until attaining a 
marrow remission.  This was followed by three courses of consolidation with ATRA and 
ATO.  Targeted chemotherapy with gemtuzumab ozogamicin (Mylotarg) was added if the 
initial WBC was over 10,000/µL or if patients had not achieved a molecular remission 
within 3 months of a documented clinical CR.  Thirty-nine of 44 patients (89%) achieved 
clinical complete remissions after a median of 28 days.  Although 35 of 37 patients (95%) 
remained RT-PCR-positive for PML/RAR at the time of clinical remission, all 29 
evaluable patients achieved molecular remission within three months of clinical remission. 
Three patients with high-risk disease have relapsed [48].   In a follow-up report, results 
from this trial were reported for 82 patients.  In the initial cohort of 65 patients, ATO was 
added to ATRA on day 10 of therapy.  A second cohort of 17 patients received ATRA and 
ATO concomitantly on day 1.  As above, GO was given to high-risk patients on day 1. 
There were seven early deaths, and 75 patients (92%) attained remission.  Molecular 
remission was documented at the time of CR in 5 of 13 patients (38%) and by three 
months in 47 of 50 patients (94%).  The estimated 3-year survival was 85% [49]. 
 
3.11 
Reducing Standard Postremission Chemotherapy.  While there has been 
dramatic improvement in long-term survival for patients with APL, the development of 
therapy-related MDS and AML is an emerging problem.  In one study, of 77 patients with 
APL treated with chemotherapy with or without ATRA during induction followed by 
consolidation chemotherapy, five (6.5%) developed secondary MDS or AML [50]. 
Moreover, multiple courses of anthracycline-based chemotherapy can lead to late cardiac 
toxicity [51].  Among 141 patients treated with doxorubicin-based therapy for lymphoma, 
39 patients (28%) developed subclinical cardiomyopathy [52].  The introduction of newer 
agents for the treatment of APL provides the basis for reducing the amount of standard 
chemotherapy required for long-term remission, thereby decreasing the morbidity and 
long-term complications of treatment. 
 
In a study conducted at MSKCC, 31 patients with newly diagnosed APL received an 
unconjugated humanized anti-CD33 monoclonal antibody HuM195 after achieving a 
clinical complete remission with ATRA-based induction followed by standard consolidation 
chemotherapy [53].  Twelve of the 24 patients (50%) who were evaluable for conversion of 
a positive RT-PCR assay for PML-RAR became negative after HuM195, without 
additional therapy.  All patients achieved a molecular remission after one cycle of 
consolidation chemotherapy.  In contrast, previous studies at MSKCC showed that ATRA 
induction followed by three cycles of intensive chemotherapy produced molecular 
remissions in 90% of patients [16].  After a median follow-up of 5 years, relapse-free 
survival was 93% [54]. 


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11 
 
 
 
 
Based on these data, a subsequent study tested a risk-adapted approach to postremission 
therapy based on molecular monitoring of residual disease [55].  Fifteen patients with  
newly diagnosed APL who achieved a clinical CR following ATRA-based induction were 
treated with HuM195 (3 mg/m
2 twice weekly for 3 weeks) followed by ATO (0.15 mg/kg 5 
times weekly for 5 weeks).  Patients in molecular remission after ATO received one 
consolidation course of idarubicin.  If patients remained RT-PCR-positive after ATO, up to 
three cycles of idarubicin could be given, with one cycle beyond documentation of 
molecular remission.  Minimal residual disease was detectable by RT-PCR analysis in 
seven patients prior to enrollment.  Four of these patients converted to RT-PCR negativity 
after treatment with HuM195, and three achieved molecular remission after ATO.  No 
patient required more than one course of consolidation with idarubicin.  Thirteen of the 15 
patients are alive after 15+ to 64+ months (median follow-up, 43 months).  Two patients 
relapsed with extramedullary disease (CNS and kidney) after 6 and 56 months.  One of 
these patients died in remission due to thrombotic stroke and encephalopathy resulting 
from treatment for isolated CNS relapse, and one died of relapsed leukemia.  One patient 
had a molecular relapse after 8 months but is now RT-PCR-negative following allogeneic 
bone marrow transplantation.  Using this risk-adapted approach, the mean number of 
hospital days during consolidation therapy was 16 (range, 0-52).  In the previous study,  
the mean number of hospital days was 55 (range, 24-82) (P < 0.001) for patients who 
received HuM195 and three cycles of idarubicin and cytarabine. 
 
Using a similar strategy, Estey et al. treated 19 patients with APL with combination ATRA 
and gemtuzumab ozogamicin (GO).  Idarubicin was added in three patients because of 
hyperleukocytosis.  Postremission therapy consisted of 8 courses of ATRA and GO. 
Idarubicin could be administered for persistent or recurrent RT-PCR-positivity.  Sixteen 
patients achieved clinical complete remission.  All 12 evaluable patients were RT-PCR- 
negative within 2 to 4 months of clinical remission.  After a median follow-up of 5 months 
(range 1-14+), all patients remained in molecular remission [56].  Taken together, these 
studies suggest that the use of newer agents along with RT-PCR monitoring of minimal 
residual disease can reduce or eliminate the need for standard anthracycline-based 
consolidation in APL while maintaining high durable remission rates. 
 
The Australasian Leukaemia and Lymphoma Group (ALLG) treated 124 patients with 
newly diagnosed APL with induction consisting of: (1) ATRA on days 1-36, (2) idarubicin 
(12 mg/m2) on days 2, 4, 6, and 8, (3) ATO on days 9-36, and (4) prophylactic prednisone 
(1 mg/kg) on days 1-10 for prevention of APL differentiation syndrome.  This was followed 
by two courses of consolidation with ATRA and ATO and two years of maintenance with 
ATRA, methotrexate and mercaptopurine.  With a median follow-up of 20 months, the 3- 
year overall survival and event-free survival rates were 93% and 87%, respectively.  There 
were 4 early deaths and 2 relapses.  This strategy maintained a high long-term remission 
rate with significant reduction in exposure to standard chemotherapy [57]. 
 
3.12 
Induction of Telomerase-Dependent Death by ATRA/ATO.  Telomerase is an 
enzyme that maintains the length of chromosomal ends or telomeres, which otherwise 
would progressively shorten after each cell division [58].  Loss-of-function mutations in the 
telomerase complex genes can cause bone marrow failure syndromes, presumably by 
limiting normal stem cell proliferation [59].  On the other hand, telomerase activity is often 
increased in advanced cancer cells and may be important for continuous cancer cell 
proliferation [60].  Indeed, shortened telomere length and elevated telomerase activity in 
APL patients have correlated with disease progression and relapse [61].  Early in vitro 
studies demonstrated that ATO inhibits transcription of the reverse transcriptase subunit of 
the human telomerase gene (hTERT) [62].  More recently, combination ATRA and ATO 
were shown in vitro to have a synergistic effect in triggering downregulation of telomerase 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
12 
 
 
 
 
in ATRA-resistant APL cell lines [63].  Ghaffari et al. reported decreased telomerase 
activity and increased telomere length over the course of treatment with ATO in patients 
with APL [61] 
 
 
3.13 
Summary.   This study seeks to minimize the morbidity and long-term 
complications of standard APL therapy by exploiting the antileukemic activity of ATRA and 
ATO.  The ability to monitor the effect of treatment using RT-PCR techniques can reduce 
and potentially eliminate the need for standard chemotherapy.  Previous studies indicate 
that combined ATRA and ATO produce high rates of clinical and molecular remission 
when used as induction [47, 48, 49, 57].  The true molecular remission rate of this 
combination after induction therapy, however, is unknown.  The 5% molecular remission 
rate reported by Estey et al. is surprisingly low, possibly due to delayed initiation of ATO 
[48].  We hypothesize that maximally exploiting the well-described synergism of ATRA and 
ATO by beginning both agents on day 1 of therapy may improve the molecular remission 
rate after induction.  In contrast to the recent study from the ALLG [57], in which idarubicin 
was given during induction to all patients, this study proposes to limit its use to patients 
with high-risk disease and those who develop leukocytosis during therapy.  This  
population is known to be at increased risk for the APL differentiation and syndrome and 
relapse [13].  We expect that approximately 20-25% of patients will present with high-risk 
disease [22], and an additional 30-35% of patient will develop hyperleukocytosis requiring 
treatment with idarubicin [13, 39].  This is in contrast to other standard regimens, where up 
to 15 doses of anthracyclines or anthracenediones are given [20].  The use of intravenous 
cytarabine will be eliminated since this agent is not required for long-term remission [21, 
22].  Several studies showed that ATO has activity against minimal residual disease in 
both patients with relapsed [38, 39] and newly diagnosed APL [48, 55].  ATRA is included 
during consolidation since its addition to standard anthracycline-based therapy improved 
disease-free survival in an earlier trial [20]. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a multicenter, phase II trial to study the efficacy of combined tretinoin and ATO in 
the treatment of newly diagnosed APL in an effort to reduce or eliminate the amount of 
standard chemotherapy required for long-term remission.  Patients will be treated at 
Memorial Sloan Kettering Cancer Center, Northwestern University, and the Ontario 
Cancer Institute/Princess Margaret Hospital.  The rates of molecular remission, as well as 
clinical CR and time to remission, will be determined after induction with combined 
tretinoin and ATO (along with idarubicin in patients who present with or develop 
leukocytosis).  Minimal residual disease will be monitored by serially analyzing peripheral 
blood samples using quantitative RT-PCR for PML-RAR after each course of 
postremission therapy in local laboratories.  The differentiating effects of combined 
tretinoin and ATO during induction will be characterized by serial flow cytometric analyses 
of peripheral blood in local laboratories.  Effects of combined ATRA and ATO on 
telomerase activity, telomere length, and TERT expression will be assessed by analyses 
of serial blood and bone marrow samples in the laboratory of Dr. Neal Young at the NIH. 
Patients will be followed for disease-free and event-free survival, as well as toxicity, 
including early death, the number and length of hospitalizations, the incidence of 
secondary MDS/AML, and the effects of treatment on LVEF. 
 
4.3 
Intervention 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
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13 
 
 
 
 
Induction will consist of tretinoin 45 mg/m2 po daily (rounded up to the nearest 10mg) in 
two divided doses (25 mg/m
2 in patients <20 years of age) for 35 days and ATO 0.15 
mg/kg IV daily for 35 doses given 5-7 days per week.  The drugs will then be discontinued, 
and the patient will be followed until a clinical complete remission is achieved.  Idarubicin 
12 mg/m2 IV for 4 doses will be added during induction on day 2 if the presenting WBC is 
>10,000/μl, or if the WBC increases to 5,000/μl on day 5, 10,000/μl on day 10, or 
15,000/μl on day 15, because of the increased risk of the APL differentiation syndrome 
and relapse in these patients.  Dexamethasone 10 mg twice daily with be given on days 1- 
14 of induction as prophylaxis for the APL differentiation syndrome.  All patients will then 
receive four courses of consolidation with tretinoin 45 mg/m2  po daily (rounded up to the 
nearest 10mg) (25 mg/m2 in patients <20 years of age) for 15 days and ATO 0.15 mg/kg  
IV for 25 doses.  Patients with high-risk disease or who received Idarubicin during 
Induction may receive intrathecal cytarabine as CNS prophylaxis given by the treating 
physician during consolidation at the discretion of the site PI.  High-risk patients will also 
receive maintenance therapy with additional courses of tretinoin and ATO every 3 months 
for 2 years. Each maintenance course will consist of tretinoin 45 mg/m 2 po daily (25 mg/m2 
in patients <20 years of age) for 15 days and ATO 0.15 mg/kg IV for 10 doses.  Disease 
status will be monitored with serial analyses of peripheral blood samples using RT-PCR  
for PML-RARα mRNA.  Patients will be followed until relapse, death, loss to follow-up, or 
removal from study. 
 
Induction therapy can be given as an inpatient or outpatient.  Consolidation and 
maintenance treatments will be given as an outpatient. Consolidation may also be given at 
the patient’s local institution.  Intrathecal cytarabine treatments will be administered as an 
outpatient. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Tretinoin (all-trans retinoic acid, ATRA, Vesanoid).  Tretinoin (Roche 
Pharmaceuticals, Nutley, NJ) is a retinoid that induces maturation of APL cells.  It is 
available in a 10-mg soft gelatin-filled capsule for oral administration.  Chemically, tretinoin 
is related to retinol (vitamin A).  It is a yellow to light orange crystalline powder with a 
molecular weight of 300.44 g.  Tretinoin should be stored at 15-30oC and protected from 
light. 
 
5.2 
Arsenic Trioxide (ATO, Trisenox ).  ATO (Cephalon, Frazer, PA) is a trivalent 
inorganic arsenical.  The molecular formula for the drug substance in solid state is As2O3, 
with a molecular weight, 197.8 g.  The raw material is a white crystalline powder that is 
poorly soluble in water.  The finished product, ATO, is formulated as a sterile, 
nonpyrogenic, clear solution in water-for-injection using sodium hydroxide and dilute 
hydrochloric acid to adjust to pH 8.  The drug product is preservative-free.  Arsenic 
trioxide, the active ingredient, is present at a concentration of 1.0 mg/ml.  Inactive 
ingredients and their respective approximate concentrations are sodium hydroxide (1.2 
mg/ml) and hydrochloric acid, which is used to adjust the pH to 7.0-9.0.  ATO is supplied 
as a sterile, clear, colorless solution in 10 ml glass, single-use ampules containing 10 mg 
of drug.  ATO should be stored at 25
oC.  Excursions are permitted from 15-30
oC. 
Ampules must not be frozen. 
 
ATO should be diluted with 100-250 ml 5% dextrose injection, USP or 0.9% sodium 
chloride injection, USP, using proper aseptic technique, immediately after withdrawal from 
the ampule.  Unused portions of each ampule should be discarded properly and not be 
saved for later dilution and administration.  ATO should not be mixed with any other 
medications.  After dilution, ATO is chemically and physically stable for up to 24 hours 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
14 
 
 
 
 
when stored at room temperature and up to 48 hours when refrigerated.  ATO should be 
administered intravenously over 1-2 hours.  The infusion duration may be extended up to 
4 hours if acute vasomotor reactions are observed.  A central venous catheter is not 
required. 
5.3 
Idarubicin (Idamycin).  Idarubicin (Pharmacia & Upjohn, New York, NY) is 
supplied as a sterile, semi-synthetic, preservative-free solution antineoplastic 
anthracycline for intravenous use.  Chemically, idarubicin hydrochloride is 5,12- 
Napthacenedione,   9-acetyl-7-[(3-amino-2,3,6-trideoxy--L-lyxo-hexopyranosyl)osyl]- 
7,8,9,10-tetrahydro-6,9,11-trihydroxyhydrochloride, (7S-cis).  Idarubicin is a sterile, red- 
orange, isotonic parenteral preservative-free solution, available in 5 ml (5 mg), 10 ml (10 
mg), and 20 ml (20 mg) single-use-only vials.  Caution in handling the solution must be 
exercised as skin reactions associated with idarubicin may occur.  The drug should be 
administered slowly over 10-15 minutes through the side arm of a freely flowing 
intravenous infusion of 0.9% sodium chloride injection, USP or 5% dextrose injection, 
USP.  Unless specific compatibility data are available, idarubicin should not be mixed with 
other drugs.  Precipitation occurs with heparin.  If extravasation occurs during intravenous 
administration, ice packs should be placed over the area intermittently (½ hour 
immediately, then ½ hour 4 times daily for 3 days). 
5.4 
Dexamethasone (Decadron
®).  Dexamethasone is corticosteroid that decreases 
inflammation by suppression of neutrophil migration, decreases production of 
inflammatory mediators, and reverses increased capillary permeability.  It is available for 
oral administration in 0.5 mg, 1 mg, 2 mg, and 4 mg, tablets and should be taken with 
food.  It is also supplied as dexamethasone sodium phosphate for intravenous injection as 
4 mg/mL (1 mL, 5 mL vials) and 10 mg/mL (10 mL vial).  It is diluted in 25-50 mL D5W or 
NS and administered IV piggyback. 
5.5 
Cytarabine (Ara-C, Cytosine Arabinoside, Cytosar-U®).  Cytarabine is a 
pyrimidine analog supplied as powder for reconstitution in 100 mg, 500 mg, 1 gm, and 2 
gm vials.  It is prepared for intrathecal administration using preservative-free powder and 
preservative-free normal saline for injection.  Five ml of preservative free NS is added to 
100 mg vial to yield a 20 mg/ml solution. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Patients with newly diagnosed APL will be eligible for this trial. 
 
6.2 
Subject Inclusion Criteria 
 
• 
Previously untreated patients with a morphologic diagnosis of APL, confirmed by 
demonstration of t(15;17) using conventional cytogenetics OR florescence in situ 
hybridization (FISH), OR a positive RT-PCR assay for PML-RAR at the subject’s 
local institution. 
 
• 
Age ≥18 years. 
 
• 
Karnofsky performance status of ≥ 60%. 
 
• 
Adequate renal function as demonstrated by a serum creatinine ≤ 2.0 mg/dl or a 
creatinine clearance of > 60 ml/min. 


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IRB Number: 11-040 A(13) 
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15 
 
 
 
 
• 
Adequate hepatic function as demonstrated by a bilirubin < 2.0 mg/dl (unless 
attributable to Gilbert’s disease) and an alkaline phosphatase, AST, and ALT ≤ 2.5 
times the upper limit of normal. 
 
• 
Normal cardiac function as demonstrated by a left ventricular ejection fraction ≥ 
50% on echocardiogram or MUGA scan. 
 
• 
QTc ≤ 500 msec on baseline ECG. 
 
• 
Negative serum pregnancy test in women of childbearing potential. 
 
• 
Ability to swallow oral medication. 
 
• 
Men and women of child-bearing potential must be willing to practice an effective 
method of birth control during treatment and at least 4 months after treatment is 
finished. 
 
• 
Patients with central nervous system involvement by APL are eligible and may 
receive concomitant treatment with radiation therapy and/or intrathecal 
chemotherapy in accordance with standard medical practice. 
 
6.3 
Subject Exclusion Criteria 
 
• 
Previous treatment for APL, except tretinoin, which may be given for up to 7 
days prior to study entry. 
 
• 
Active serious infections not controlled by antibiotics. 
 
• 
Pregnant women or women who are breast-feeding. 
 
• 
Concurrent active malignancy requiring immediate therapy. 
 
• 
Clinically significant cardiac disease (NY Heart Association Class III or IV), 
including chronic arrhythmias, or pulmonary disease. 
 
• 
Other serious or life-threatening conditions deemed unacceptable by the principal 
investigator. 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s treatment team, 
the protocol investigator, or research team at Memorial Sloan Kettering Cancer Center 
(MSKCC).  Patient recruitment will occur in medical oncology clinics or the inpatient 
service of the Leukemia Service at MSKCC.  Investigators will screen the patient’s medical 
records for suitable research study participants and discuss the study and their potential  
for enrolling in the research study. 
 
Similar recruitment procedures will be followed at collaborating institutions.  It is expected 
that each of the four participating sites will enroll 10-20 patients each over a 3-year period. 
 
Participating site recruitment will be conducted as outlined within the protocol. Any 
participating sites that require a limited waiver must obtain it from their site IRB/PB via a 
separate protocol addendum or request.  It is the responsibility of the MSK staff to confirm 
participating data collection sites have a limited waiver approved by their local IRB(s)/PBs. 


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16 
 
 
 
 
As of August 19th 2016 this protocol has been closed to new patient accruals. Patients 
were enrolled at MSK and Northwestern University only. Treatment and/or follow up of 
existing patients continues. 
 
 
 
 
8.1 
PRETREATMENT EVALUATION 
 
The following tests should be performed within one week of entry on study: 
 
• 
Complete medical history and physical examination. 
 
• 
Complete blood count with leukocyte differential. 
 
• 
Comprehensive biochemistry profile (including BUN, creatinine, serum electrolytes, 
calcium, glucose, total bilirubin, total protein, albumin, alkaline phosphatase, AST, and 
ALT), 
 
• 
Phosphorous 
 
• 
Magnesium 
 
• 
LDH 
 
• 
Uric Acid 
 
• 
Coagulation profile, including PT, PTT, fibrinogen, and D-dimer levels. 
 
• 
Chest radiograph or Chest CT Scan. 
 
• 
Electrocardiogram. 
 
• 
Serum pregnancy test in women of child-bearing potential. 
 
• 
Echocardiogram or MUGA scan. 
 
• 
Bone marrow aspiration, including immunophenotyping, cytogenetics/FISH analysis for 
t(15;17), RT-PCR for PML-RAR, telomerase activity, telomere length and TERT 
expression.  A biopsy may be done if clinically indicated.  Alternatively, FISH and PCR 
studies may be sent on peripheral blood. 
 
• 
Peripheral blood immunophenotyping (MSKCC patients only). 
 
• 
Peripheral blood for telomerase activity, telomere length and TERT expression. 
 
Immunophenotyping Studies (MSKCC patients only).  Two lavender top tubes of 
peripheral blood and two ml of bone marrow in EDTA will be sent for immunophenotyping 
studies.  Surface-membrane antigens will be detected by direct immunofluorescence 
staining with the use of fluorescein isothiocyanate (FITC)-conjugated or phycoerythrin 
(PE)-conjugated monoclonal antibodies against CD16, CD11b, CD33, HLA-DR, CD45, 
CD14, and CD117 (Beckton Dickinson, Mountain View, CA; Immunotech Immunology, 
Marseilles, France).  Dual-color staining will be performed by incubating cells 


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17 
 
 
 
 
simultaneously with two monoclonal antibodies, including CD33-PE and CD11b-FITC or 
CD33-PE and CD16-FITC.  Apoptosis will be assayed by dual staining for Annexin V and 
7-AAD.  The expression of surface antigens, including CD33 and CD11b, on peripheral 
blood and bone marrow mononuclear cells will be plotted over time to characterize the 
differentiating effect of combined therapy with ATRA and ATO on APL cells during 
induction. 
 
Telomerase Activity, Telomere Length and TERT Expression.  Telomerase activity will 
be determined by the florescent telomerase repeat amplification protocol (TRAPeze XL, 
Chemicon).  Telomerase length will be determined by qPCRs performed in a 7500 Real 
Time PCR System (Applied Biosystems, Foster City, CA).  Each sample’s telomere length 
(x) will be based on the telomere to single copy gene ratio (T/S ratio) and on the 
calculation of the ΔCt [Ct(telomeres)/Ct(single gene)]. Telomere length will be expressed 
as relative T/S ratio, which is normalized to the average T/S ratio of reference sample [2- 
(ΔCtx – ΔCtr) = 2-ΔΔCt], used for the standard curve, as reference sample, and as 
validation sample.  In order to make comparable the results from different plate runs, the 
results of each plate will be approved only if the relative T/S ratio of the validation 
reference sample falls within 3% variation [64,65].  Expression of TERT will be assayed by 
RT-PCR (TaqMan Gene Expression Assays, Applied Biosystems) using a primer and 
probe premix.  Two-five ml of bone marrow in EDTA will be collected at baseline and at  
the time of clinical CR.  Two green top tubes of peripheral blood (approximately 10 ml in 
heparin) will be collected at baseline and weekly during induction until clinical CR is 
achieved.  Specimens from each center will be shipped under ambient conditions  
overnight directly to: 
Neal S. Young, MD 
Hematology Branch, NHLBI 
10 Center Dr., Building 10-CRC 
3-5140, MSC-1202 
Bethesda, MD  20892 
Email: YoungNS@mail.nih.gov 
Phone: 301-496-5093 
 
Participating sites will notify the Multicenter Trial Research Staff at MSKCC when marrow 
and/or blood samples are shipped by using a sample requisition form.  The Research Staff 
will contact Dr. Young’s laboratory to confirm receipt of the specimens.  The SKIFI system 
will be used to log and track samples from participating sites.  The following information  
will be recorded:  (1) MSKCC CRDB protocol participant number, (2) patient initials, (3) 
sample type (blood or bone marrow), (4) date specimen was obtained, (5) shipping date, 
and (6) date specimen was received. 
 
Differences in telomerase activity, telomere length, and TERT expression pre- and post- 
induction will be compared using the Wilcoxon rank-sum test. 
 
9.1 TREATMENT/INTERVENTION PLAN 
 
At initial presentation, risk groups will be assigned as follows [22]: 
• 
Low-risk:  Presenting WBC ≤10,000/µL and platelet count >40,000/µL 
• 
Intermediate-risk:  Presenting WBC ≤10,000/µL and platelet count ≤40,000/µL 
• 
High-risk:  Presenting WBC >10,000/µL. 
 
In an effort to minimize early death due to hemorrhagic events, treatment with tretinoin 
should be started at the first suspicion of the diagnosis of APL.  For this reason, up to 7 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
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18 
 
 
 
 
days of tretinoin at any dose and schedule is allowed before entry onto study.  This will not 
affect protocol therapy or the analysis of outcomes.  The diagnosis should be confirmed as 
quickly as possible by cytogenetic and/or molecular testing prior to initiation of protocol 
therapy. 
 
Treatment consists of induction with tretinoin and ATO (along with idarubicin in patients 
who present with a WBC >10,000/µL or who develop leukocytosis) followed by four cycles 
of consolidation with tretinoin and ATO.  High-risk patients or patients who have received 
Idarubicin during Induction will receive CNS prophylaxis with intrathecal cytarabine during 
consolidation because of increased risk of extramedullary relapse [66], at the discretion of 
the site PI.  High-risk patients will also receive maintenance therapy with additional 
courses of ATRA and ATO every 3 months for 8 cycles.  Maintenance will not be given to 
patients with low- or intermediate-risk disease (Fig. 1). 
 
9.2 
Induction.  All patients will begin induction therapy as an inpatient.  If they are 
clinically stable (e.g., no evidence of coagulopathy or APL differentiation syndrome), 
therapy may be continued in the outpatient department at the discretion of the treating 
physician.  Induction will consist of: 
 
Tretinoin 45 mg/m2/day (25 mg/m2/day in patients <20 years of age) orally in 2 
divided doses on days 1-35 and 
 
Arsenic trioxide 0.15 mg/kg/day intravenously for a total of 35 doses. 
 
The dose of tretinoin is reduced in patients younger than 20 years due to a higher 
incidence of pseudotumor cerebri [67].  Tretinoin doses will be rounded to the nearest 10- 
mg increment.  If the total calculated dose ends in a numeral <5, the administered dose 
will be rounded down; if the calculated dose ends in a numeral >5, the dose will be 
rounded up.  If the total daily dose of tretinoin is not equally divisible by 2, the larger of the 
two doses will be given in the morning.  For example, if the total daily dose is 90 mg, the 
drug will be given as 50 mg every morning and 40 mg every evening.  If tretinoin is given 
as an outpatient, patients will be given a medication log to document compliance with the 
drug. 
 
ATO may be given on consecutive days, weekdays only, or some combination thereof. 
Generally, the drug will be administered daily while patients are hospitalized and 5-7 days 
per week if it is given as an outpatient.  The maximum interval between doses may not 
exceed 2 days. 
 
Tretinoin will be discontinued after 35 days and ATO after 35 doses.  The patients will be 
followed until recovery of peripheral blood counts and a clinical CR (Section 12.1) is 
achieved. 
 
Because of the increased risk of APL differentiation syndrome and relapse in high-risk 
patients, cytotoxic chemotherapy will be added on day 2 if the presenting WBC is 
>10,000/μL.  Similarly, cytotoxic therapy will be added in patients who develop 
leukocytosis on treatment with a WBC >5,000/µL by day 5, > 10,000/µL by day 10, or 
>15,000/µL by day 15) [13].  These patients with receive: 
 
Idarubicin 12 mg/m2 by IV push every other day for 4 doses. 
Even if the leukocytosis resolves before completion of the entire course of idarubicin, all 
four doses will be administered. 


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19 
 
 
 
 
9.1.1 
Prevention and Management of APL Differentiation Syndrome.  In order to 
prevent development of the APL differentiation syndrome (see Section 3.4) when the risk 
is greatest, all patients with receive: 
 
Dexamethasone 10 mg twice daily (either oral or IV) on days 1-14. 
 
Beginning on day 15, dexamethasone may be tapered over 7-10 days, at the discretion of 
the treating physician. 
 
If there is suspicion of the APL differentiation syndrome during the first 14 days of therapy, 
and the patient is receiving dexamethasone orally, treatment should be changed to the 
intravenous preparation at a dose of 10 mg intravenously q 12 hours.  If suspicion of the 
differentiation syndrome occurs later, therapy with dexamethasone should be reinstituted 
at a dose of 10 mg intravenously q 12 hours.  Therapy should be continued for at least 3 
days or longer until signs and symptoms have resolved. 
9.1.2 
Management of Coagulopathy.  Intracerebral and pulmonary hemorrhages are 
relatively common life-threatening complications while the characteristic coagulopathy of 
APL is active.  CBC’s and coagulation parameters (PT/PTT, fibrinogen) should be 
monitored 2-4 times daily as clinically necessary.  Platelets should be transfused to 
maintain a count of >50,000/µL.  Fresh frozen plasma or cryoprecipitate should be 
transfused to maintain a fibrinogen level >150 mg/dL. 
 
9.1.3 
ECG Monitoring and Electrolyte Management.  ATO can cause QT interval 
prolongation and complete atrioventricular block.  QT prolongation can lead to torsade de 
pointes, a polymorphic ventricular arrhythmia that can be fatal.  The risk of torsade de 
pointes may be related to the extent of QT prolongation, concomitant administration of QT- 
prolonging drugs, a history of torsade de pointes, preexisting QT interval prolongation, 
congestive heart failure, administration of potassium-wasting diuretics, or other conditions 
that result in hypokalemia or hypomagnesemia. 
 
During therapy with ATO, patients may receive potassium and magnesium 
supplementation either orally or intravenously to keep the concentrations above 4 mEq/l 
and 2.0 mg/dl, respectively.  ECG’s will be obtained at least once per week and more 
frequently in patients whose routine ECG shows prolongation of the QT interval.  In 
patients who develop an absolute QT > 500 msec, actions should be taken to correct any 
concomitant risk factors, and ATO will be held until the QT is < 500 msec [68].  If syncope, 
rapid or irregular heartbeat develops, the patient will be hospitalized for monitoring, serum 
electrolytes will be assessed, and ATO will be discontinued until the QTc regresses to 
<460 msec, electrolyte abnormalities are corrected, and the syncope and irregular 
heartbeat cease. 
 
9.1.4 
Toxicity and Dose Modifications for Tretinoin. 
 
Management of Headache.  One of the most common adverse effects of tretinoin is 
headache of mild-to-moderate severity.  Pediatric patients appear to be more sensitive to 
this particular effect, and pseudotumor cerebri has been reported.  During induction 
therapy, intracranial hemorrhage should also be considered as a possible cause. 
Acetaminophen or oxycodone may be administered if headache develops.  If grade 3 
headache persists, the dose of tretinoin will be reduced by 50%.  Once symptoms resolve, 
the dose may be escalated to 45 mg/m2/day as tolerated. 
Interruption of Therapy and Dose Attenuation.  Treatment should be interrupted in the 
case of significant hepatotoxicity (defined as an increase in serum bilirubin, AST, ALT, or 


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20 
 
 
 
 
alkaline phosphatase to > 5 times baseline values) for up to two weeks.  Treatment may 
resume at 50% of the previous dose after these values recover to ≤ 4 times baseline 
values.  If values ≤ 4 times baseline persist for more than two weeks, tretinoin will be 
discontinued, but patients may remain on study and continue to receive ATO. 
9.1.5 
Toxicity and Dose Modifications for ATO. 
 
Management of Vasomotor Reactions.  Patients who experience acute vasomotor 
reactions, such as hypotension (≥ 25% decrease in systolic blood pressure from baseline) 
or dizziness, that are temporally related to infusion of the drug will receive additional 
intravenous fluids as appropriate until these signs and symptoms resolve.  Both the 
immediate and future drug infusion rates may be extended to 4 hours.  Generally, 
however, the infusion time should be reduced as tolerated to a minimum time of 1 hour. 
Treatment will be discontinued in patients with persistent or recurrent episodes of 
hypotension that are unresponsive to these maneuvers, and they will be removed from 
study. 
 
Interruption of Therapy and Dose Attenuation.  Treatment should be interrupted in the 
case of significant hepatotoxicity (defined as an increase in serum bilirubin, AST, ALT, or 
alkaline phosphatase to > 5 times baseline values), nephrotoxicity (defined as serum 
creatinine > 3.5 times the upper limit of normal), neurological impairment (defined as 
somnolence, seizures, or impaired mentation), ≥ grade 3 peripheral neuropathy, or any 
non-hematologic grade 4 adverse event (NCI CTCAE, Version 4.0).  Patients who 
experience such reactions that are considered drug-related should resume treatment only 
after resolution of the toxic event or after recovery to baseline status of the abnormality 
that prompted the interruption.  In such cases, treatment should resume at 50% of the 
preceding daily dose.  If the toxic event does not recur within 3 days of restarting 
treatment at the reduce dose, the daily dose can be escalated to 100% of the original 
dose.  Patients who experience a recurrence of toxicity or in whom toxicity does not 
resolve to baseline will be removed from study.  Patients with therapy interrupted for 
conditions that were not considered probably related to ATO could resume treatment at 
the full dose at the discretion of the investigator. 
 
Management of Overdose.  If symptoms suggestive of serious acute arsenic toxicity (e.g., 
convulsions, muscle weakness, and confusion that cannot be attributed to other causes) 
appear, ATO should be discontinued immediately, and the patient removed from study. 
Chelation therapy should be considered.  A conventional protocol for acute arsenic 
intoxication includes dimercaprol administered at a dose of 3 mg/kg intramuscularly every 
4 hours until immediate life-threatening toxicity has subsided.  Thereafter, penicillamine at 
a dose of 250 mg orally, up to a maximum frequency of four times daily, may be given for 
up to 3 months. 
9.2 
Consolidation Therapy.  All patients will receive four consolidation courses.  In 
general, this treatment will be given as an outpatient, or at the patient’s local institution; 
however, administration of this therapy as an inpatient is allowed at the discretion of the 
treating physician.  Consolidation 1 will begin 2-6 weeks after documentation of clinical 
CR.  Consolidations 2, 3, and 4 will begin 2-4 weeks after completion of the prior 
consolidation course.  Each consolidation course will be given over approximately 5 weeks 
and will consist of: 
Tretinoin 45 mg/m
2/day (25 mg/m
2/day in patients <20 years of age) orally in 2 
divided doses for 15 days and 
 
Arsenic trioxide 0.15 mg/kg/day intravenously for a total of 25 doses. 


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Approval date: 07-Mar-2018 
21 
 
 
 
 
ATO may be given on consecutive days, weekdays only, or some combination thereof. 
Generally, the drug will be administered 5 days per week for 5 weeks.  Although the 
schedule may omit holidays, the maximum interval between doses in a course of therapy 
may not exceed 4 days.  Since tretinoin will be administered as an outpatient, patients will 
be given a medication log to document compliance with the drug. 
 
The APL differentiation syndrome has not been described in patients receiving tretinoin or 
ATO while in clinical remission. ECG’s will be monitored and electrolytes will be managed 
as described in Section 9.1.3. Toxicities and dose modifications for tretinoin and ATO are 
described in Sections 9.1.4 and 9.1.5, respectively. 
9.2.1 
Consolidation Therapy at Local Institution 
 
Patient’s may receive consolidation therapy at their local institutions. Treatment decisions 
based on labs received at local institutions will be made by the treating physician at the 
local institution. Treating physicians at the local institution will monitor these labs 
according to parameters listed in Appendix A. The MSK or participating site treating 
physician will review these lab values weekly to ensure protocol adherence and patient 
management. 
 
9.3 
Central Nervous System Prophylaxis.  Patients presenting with WBC > 
10,000/µL have been noted to be at increased risk for the development of extramedullary 
relapse, particularly CNS disease [66].  Patients, who are high-risk or have received 
idarubicin during induction, will receive prophylactic intrathecal chemotherapy, at the 
discretion of the site PI.  Treatment will consist of: 
 
Cytarabine 70 mg intrathecally for a total of 6 doses. 
 
The first dose of intrathecal therapy will be given within 2 weeks of the documentation of 
clinical complete remission upon recovery from induction.  Subsequent doses will each be 
given approximately 2-4 weeks apart during consolidation.  These treatments will be given 
in the outpatient clinic or in the Neuroradiology Department under fluoroscopic guidance, if 
necessary. 
 
9.4 
Maintenance Therapy (High-Risk Patients Only).  Because of the increase risk 
of relapse in patients presenting with WBC > 10,000/µL, maintenance therapy will be 
administered to these patients.  Maintenance therapy should begin 4-6 weeks after the 
completion of Consolidation 4.  Each course of maintenance therapy will be given over 15 
days and will consist of: 
 
Tretinoin 45 mg/m
2/day (25 mg/m
2/day in patients <20 years of age) orally in 2 
divided doses for 15 days and 
 
Arsenic trioxide 0.15 mg/kg/day intravenously for a total of 10 doses. 
 
Treatment will be repeated every 3 months for 2 years, for a total of 8 cycles.  ATO may  
be given on consecutive days, weekdays only, or some combination thereof.  Generally, 
the drug will be administered 5 days per week for 2 weeks.  Although the schedule may 
omit holidays, the maximum interval between doses in a course of therapy may not  
exceed 4 days.  Since tretinoin will be administered as an outpatient, patients will be given 
a medication log to document compliance with the drug.  ECG’s will be monitored and 
electrolytes will be managed as described in Section 9.1.3.  Toxicities and dose 
modifications for tretinoin and ATO are described in Sections 9.1.4 and 9.1.5, respectively. 


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IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
22 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Listed below are the schedules for follow-up evaluations during Induction (Table I), 
Consolidations 1 – 4 (Table II), Maintenance (Table III) and Long-term Follow-up (Table 
IV). 


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Table I.  Evaluation on Study:  Induction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Only if presenting WBC is >10,000/µL. Alternativel y, if WBC is 5,000/µL by day 5, 10,000/µL by day 10, or 15,000/µL by day 15, therapy with idauricin w ill be initiated on the 
same dose and schedule. 
Week: 
Pre-treatment 
(within 7 days of 
study entry) 
1 
2 
3 
4 
5 
6-10 
Day: 
1-7 
8-14 
15-21 
22-28 
29-35 
36-70 
Tretinoin (ATRA) 
Daily 
Daily 
Daily 
Daily 
Daily 
Arsenic Trioxide (ATO) 
Daily 
Daily 
Daily 
Daily 
Daily 
Idarubicin (for patients with 
leukocytosis only)1 
Days 2, 4, 6, and 8 
Physical exam 
X 
Daily 
Daily 
Twice2 
Twice2 
Twice2 
Weekly until 
count recovery3 
CBC 
X 
Daily4 
Daily4 
Daily 
Daily 
Daily 
Weekly until 
count recovery3 
Electrolytes, BUN, creatinine, Mg 
4 times 5 
4 times 5 
4 times 5 
4 times 5 
4 times 5 
Comprehensive biochemistry profile,6 
PO4, Mg, LDH, uric acid 
X 
3 times 7 
3 times 7 
3 times 7 
3 times 7 
3 times 7 
PT, PTT, fibrinogen, D-dimer 
X 
Daily4 
Daily4 
Chest radiograph or Chest CT Scan 
X 
ECG 
X 
Once 
Once8 
Once8 
Once8 
Once8 
Seum pregnancy test (in women of 
child-bearing potential) 
X 
Echocardiogram or MUGA scan 
X 
Bone marrow aspiration9 
X 
At count 
recovery3 
Peripheral blood immunophenotyping 
(MSKCC patients only)10 
X 
Once8 
Once8 
Once8 
Once8 
At count 
recovery3 
Peripheral blood RT-PCR for 
PML/RARα 
At count 
recovery3 
Peripheral blood for telomerase 
activity, telomere length, and TERT 
expression10 
X 
Once8 
Once8 
Once8 
Once8 
At count 
recovery3 


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23-5 days apart, e.g., Monday-Thursday or Tuesday-Friday. 
3ANC ≥1,500/µL, platelet count ≥100,000/µL (see Section 12.1). 
42-4 times daily as clinically indicated until coagulopaty resolves. 
5On days when comprehensive biochemical panel is not obtained. 
6Includes BUN, creatinine, serum electrolytes, calcium, glucose, total bilirubin, total protein, albumin, alkaline phosphatase, AST, and ALT. 
72-3 days apart, e.g., Monday, Wednesday, and Friday. 
85-8 days apart. 
9Including morphology, cytogenetics OR FISH for t(15;17) OR RT-PCR for PML-RARα, immunophenotyping, telomerase activity10, telomere length10, TERT expression10,and 
biopsy (if clinically indicated). 
10Research non-billable test (RNB): Blood and bone marrow specimens for telomerase activity, telomere length and TERT expression will be collected, stored and shipped 
according to procedures given in Section 8.0. 


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IRB Number: 11-040 A(13) 
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Table II.  Evaluation on Study: Consolidations 1 – 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Within 14 days of beginning therapy of week 1 Consolidation 1. 
2ATO may be given on consecutive days, weekdays only, or some combination thereof. Generally, the drug will be administered 5 days per week for 5 weeks (see Section 
9.2). 
3A total of 6 doses of intrathecal cytarabine will be given to high-risk patients or patients that have received Idarubicin, at the discretion of the site PI. The first dose of 
intrathecal therapy will be given within 2 weeks of the documentation of clinical complete remission upon recovery from induc tion. Subsequent doses will each be given 
approximately 2-4 weeks apart during consolidation (see Section 9.3). 
45-8 days apart. 
53-5 days apart, e.g., Monday-Thursday or Tuesday-Friday.. 
6On days when ATO is administered but comprehensive biochemical profile is not done. 
7Includes BUN, creatinine, serum electrolytes, calcium, glucose, total bilirubin, total protein, albumin, alkaline phosphatase , AST, and ALT. 
8Prior to receiving treatment on consolidations 2, 3, and 4 only. 
Week: 
Pretreatment1 
1 
2 
3 
4 
5 
6 
Day: 
1-7 
8-14 
15-21 
22-28 
29-35 
36-42 
Tretinoin (ATRA) 
Daily 
Daily 
Day 15 
Arsenic Trioxide (ATO)
2
 
5 times 
5 times 
5 times 
5 times 
5 times 
IT Cytarabine 
(high-risk patients   or patients 
that have received Idarubicin 
during Induction) 
First dose3 
Physical exam 
X 
Once 
CBC 
X 
Twice5 
Twice5 
Twice5 
Twice5 
Twice5 
Once 
Electrolytes, BUN, creatinine, Mg 
4 times6 
4 times6 
4 times6 
4 times6 
4 times6 
Comprehensi ve  biochemistry 
profile,7 PO4, Mg, LDH, uric acid 
X 
Once 
Once4 
Once4 
Once4 
Once4 
Once4 
ECG 
Once 
Once4 
Once4 
Once4 
Once4 
Peripheral blood RT-PCR for 
PML/RARα 
X8 


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IRB Number: 11-040 A(13) 
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26 
 
 
 
 
Table III.  Evaluation on Study:  Maintenance (High-Risk Patients Only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1ATO may be given on consecutive days, weekdays only, or some combination thereof. Generally, the drug will be administered 5 days per week for 5 weeks (see Section 
9.4). 
25-8 days apart. 
3On days when ATO is administered but comprehensive biochemical profile is not done. 
4Includes BUN, creatinine, serum electrolytes, calcium, glucose, total bilirubin, total protein, albumin, alkaline phosphatase , AST, and ALT. 
5To be completed at the discretion of the treating physician. 
6To be completed during Week 1 of each cycle. 
Cycle 1 
Cycle s 2-8 
Month: 
1 
2 
3 
Week: 
1 
2 
3 
4 
Day: 
1-7 
8-14 
15-21 
22-28 
Tretinoin (ATRA) 
Daily 
Daily 
Day 15 
As in cycle 1 
Arsenic Trioxide (ATO)1 
5 times 
5 times 
Physical exam 
Once 
CBC 
Once 
Once2 
Electrolytes, BUN, creatinine, Mg 
4 times3 
4 times3 
Comprehensi ve  biochemistry 
profile4, Mg, LDH 
Once 
Once2 
ECG 
Once 
Once2 
Echocardiogram or MUGA scan 
(whichever was done during pre- 
treatment evaluation)5 
Once 
Once during 
cycle 5 only 
Peripheral blood RT-PCR for 
PML/RARα 
Once 
Once per 
cycle6 


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Table IV.  Long Term Follow Up 
 
 
 
 
 
 
 
 
 
 
 
1Only in patients who have received idarubicin during induction, at the discretion of the treating investigator 
2 To be performed 11-13 months apart. 
3Omit in high-risk patients. 
4To be completed within 4-6 weeks of Consolidation or Maintenance (for high risk patients only) 
5A +/- 7 day window will be allowed for completion of these assessments. 
6A +/- 14 day window will be allowed for completion of these assessments. 
7At least 2.5 years must be completed. 
Year7 
1 
2 
3 
4 
5 
Physical exam 
Monthly x 65, 
then q 3 months6 
q 3 months6 
q 3 months6 
q 6 months6 
q 6 months6 
CBC 
Monthly x 65, 
then q 3 months6 
q 3 months
6
 
q 3 months
6
 
q 6 months
6
 
q 6 months
6
 
Echocardiogram or MUGA scan (whichever 
was done during pre-treatment evaluation)1 
Once 
Once2 
Once2 
Once2,3 
Once2,3 
Peripheral blood RT-PCR 
q 3 months4, 6 
q 3 months6 
q 3 months6 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 
Toxicities of Tretinoin.  The most frequently reported adverse events associated 
with tretinoin are similar to those described in patients taking high doses of vitamin A and 
include headache (86%), fever (83%), skin/mucous membrane dryness (77%), nausea or 
vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), visual changes (17%), and 
bone pain (3%).  Approximately 25% of patients undergoing induction therapy with tretinoin 
can experience APL differentiation syndrome characterized by fever, dyspnea, weight gain, 
pulmonary infiltrates, and pleural or pericardial effusions.  Section 9.1.1 describes the APL 
differentiation syndrome and its treatment in detail.  Hyperleukocytosis has been frequently 
observed (75%), sometimes associated with the APL differentiation syndrome.  Arrhythmias 
have been reported in 23% of patients.  Central nervous system effects include dizziness 
(20%) and paresthesia (17%).  Children are more sensitive to the CNS effects of tretinoin, 
and there have been reports of pseudotumor cerebri in this population.   
Hypercholesterolemia and/or hypertriglyceridemia have been seen in up to 60% of patients. 
Elevated liver function tests occur in 50-60% of patients while taking tretinoin.  Guidelines for 
management of toxicity are given in Sections 9.1.1 and 9.1.4. 
11.2 
Toxicities of ATO.  The most common (≥ 5% of patients) severe and life-threatening 
(grade 3 and 4) adverse events attributed in ATO in previous clinical studies included APL 
differentiation syndrome, febrile neutropenia, leukocytosis, prolonged QT interval, torsade de 
pointe, hyperglycemia, peripheral neuropathy, atrial fibrillation, complete atrioventricular 
block, spontaneous abortion, hemorrhage, infections, pain, diarrhea, and nausea.  Prolonged 
QT as determined by ECG analyses occurred in 70% of patients.  Guidelines for ECG 
monitoring and electrolyte management are given in Section 9.1.2.  Leukocytosis occurred in 
50% of patients with APL.  The most common adverse events (occurring in ≥ 25% of 
patients) related to treatment with ATO were hyperglycemia, hypokalemia, headache, 
nausea, and fatigue.  Signs of arsenic overdose include convulsions, muscle weakness, and 
confusion.  Guidelines for management of toxicity are given in Sections 9.1.1, 9.1.3, and 
9.1.5. 
11.3 
Toxicities of Idarubicin.  Severe myelosuppression is the most frequent adverse 
effect associated with idarubicin.  This can lead to infection (95%) and hemorrhagic 
complications (63%).  Cardiotoxicities include decreased left ventricular function, congestive 
heart failure, arrhythmias, and myocardial infarction.  Gastrointestinal side effects include 
nausea/vomiting (82%), stomatitis (50%), abdominal cramps and diarrhea (73%).  Elevations 
in creatinine have been reported in 1% of patients receiving idarubicin.  Elevation of liver 
function tests have been described in < 5% of patients.  Alopecia is common (77%).  The 
drug is a vesicant; guidelines for management of extravasation are given in Section 5.3. 
 
11.4 
Toxicities of Dexamethasone.  The most common toxicities of dexamethasone are: 
weight gain and fluid retention, gastritis, development of peptic ulcers, insomnia, and mood 
changes.  Less likely toxicities include: glucose intolerance, diabetes mellitus, hypertension, 
osteoporosis, alopecia, decreased muscle mass, and myopathy.  Rare side effects include: 
development of cataracts, skin changes, aseptic necrosis of the hip, and impaired immunity. 
 
11.5 
Toxicities of Intrathecal Cytarabine.  Administration of cytarabine intrathecal has 
commonly been associated with fever, headache, nausea, and vomiting.  Rare but serious 
side effects include accessory nerve paralysis, necrotizing leukoencephalopathy (particularly 
when given concurrently with cranial irradiation and other intrathecal chemotherapy), and 
paraplegia. 


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29 
 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 
Clinical Complete Remission.  All three criteria defined by Cheson et al. [69] must 
be met for clinical complete remission: 
 
• 
Peripheral Blood Counts.  The peripheral blood neutrophil count should be ≥1,500/µl 
(sustained without growth factor support), and the platelet count should be 
≥100,000/µl (without transfusion).  No circulating blasts or abnormal promyelocytes 
should be detected. 
 
• 
Bone Marrow Aspirate.  The cellularity of the bone marrow should approximate 
normal.  There must be evidence of maturation of all cell lines.  The bone marrow 
aspirate should contain <5% blasts and no abnormal promyelocytes.  Auer rods 
should not be detected. 
 
• 
Extramedullary Leukemia.  Extramedullary leukemia, such as CNS or soft tissue 
involvement, must not be present. 
 
12.2 
Molecular Remission.  A molecular remission is defined as a clinical CR with a 
negative RT-PCR assay for PML-RAR performed on bone marrow. 
 
12.3 
Clinical Relapse.  Clinical relapse is defined as the reappearance of blasts or 
abnormal promyelocytes in the peripheral blood or the finding of more than 5% blasts and/or 
abnormal promyelocytes in the bone marrow aspirate.  These findings should not be 
attributable to another cause (e.g., myeloid growth factor administration, bone marrow 
regeneration). 
 
12.4 
Molecular Relapse.  Molecular relapse is defined as the conversion of RT-PCR for 
PML-RAR from negative to positive on two consecutive tests performed on bone marrow at 
least one week apart, while still meeting criteria for clinical CR. 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
• 
If the patient fails to achieve a clinical complete remission after Induction, he/she will be 
taken off study. 
 
• 
If the patient fails to achieve a molecular remission following completion of Consolidation 4 
or has a clinical or molecular relapse at any time, he/she will be taken off study and 
referred for alternative therapy. 
 
• 
If at any time the patient develops unacceptable toxicity as defined in Sections 9.1.3, 
9.1.4, and 9.1.5, he/she will be removed from study. 
 
• 
If at any time the patient is found to be ineligible for the protocol as designated in the 
section on Criteria for Patient/Subject Eligibility ( i.e., a change in diagnosis), the patient 
will be removed from study. 
 
• 
If the patient fails to comply with the defined treatment plan and follow-up evaluations, the 
patient will be removed from the study. 
 
• 
If the patient withdraws consent for continued participation, he/she will be removed from 
study. 


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14.1 
BIOSTATISTICS 
 
The major objective of this phase II trial is to determine the molecular remission rate after 
induction therapy combined with ATRA and ATO.  (Patients with high-risk disease at 
presentation or who develop leukocytosis will also receive idarubicin.)  The standard of care 
for patients with APL is induction with ATRA plus chemotherapy [13, 15, 20].  Based on 
previous studies the molecular remission rate after induction with ATRA and idarubicin is 
approximately 60% [15].  In this trial, we will utilize a Simon Minimax two-stage design in 
which a 50% molecular remission rate is considered not promising, a 70% molecular 
remission rate is considered promising, and the probabilities of a type I error (falsely 
accepting a non-promising therapy) and type II error (falsely rejecting a promising therapy) 
are set at 0.10 and 0.10, respectively.  In this scenario, the maximum trial size will be 39 
patients.  In the first stage of this design, 23 patients will be accrued.  If at least 12 patients 
achieve molecular remission after induction among these 23 patients, then an additional 16 
patients will be accrued to the second stage.  If 11 or less molecular remissions are seen 
after induction, the study will be terminated and declared negative.  This design yields at 
least a 0.90 probability of a positive result if the true molecular response rate is at least 70% 
and yields a 0.90 probability of a negative result if the true response rate is 50%. 
 
Any patient receiving any part of therapy on study will be considered evaluable, even if 
removed from study for toxicity.  Patients who attain a clinical CR but not a molecular 
remission after induction will remain on study and be followed for secondary endpoints as 
described below.  Patients who have not achieved at least a clinical CR after induction and a 
molecular remission after consolidation 4 will be considered treatment failures and removed 
from study. 
 
A number of secondary endpoints will be studied.  The clinical CR rate will be estimated after 
induction.  The proportion of RT-PCR-negative patients and the 95% confidence interval will 
be estimated at: (1) study entry, (2) after induction therapy, (3) after each course of 
consolidation with ATRA and ATO, and (4) every 3 months thereafter for 3 years. 
Proportions will be calculated at the conclusion of the trial by taking the number of RT-PCR- 
negative patients at a particular time point divided by the total number of patients who 
received any part of induction therapy.  The median time to clinical and molecular remissions 
will be estimated by standard life-table methods. 
 
Disease-free and event-free survival will be estimated using actuarial methods.  Disease-free 
survival analysis will include only those patients who achieve at least a clinical CR after 
induction and will be calculated from the time of clinical CR (or better) to relapse (molecular  
or clinical) or last follow-up.  Event-free survival will be calculated from the start of induction 
therapy to relapse (molecular or clinical), death, or last follow-up.   Event-free survival 
analyses will include all patients who receive any part of induction therapy. 
 
Frequencies of toxicities based on the NCI Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0 will be tabulated.  The incidence of APL differentiation syndrome and 
death within 30 days of beginning induction will be calculated.  The number of  
hospitalizations and number of hospital days will be tabulated for each patient.  The  
incidence of secondary MDS/AML will be calculated.  Immunophenotyping of peripheral  
blood will be performed weekly during induction, and the expression of surface antigens, 
including CD33 and CD11b, will be plotted over time to characterize the differentiating effect 
of combined therapy with ATRA and ATO on APL cells during induction.  Expected accrual at 
all sites is approximately 10-15 patients per year. This trial will take approximately 3-4 years 
to complete.  Bone marrow samples will be analyzed at baseline and at the time of clinical 
CR for telomerase activity, telomere length and TERT expression.  Peripheral blood samples 
will be analyzed at baseline and weekly during induction until clinical CR is achieved. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
31 
 
 
 
 
Differences in telomerase activity, telomere length, and TERT expression pre- and post- 
induction will be compared using the Wilcoxon rank-sum test. 
14.2 
Stopping Rule for Treatment-Related Mortality.  Treatment-related mortality during 
induction in excess of 15% would be unacceptably high.  If at any time, five patients die from 
treatment-related causes, the trial will be terminated.  The probability of stopping the trial is 
72% if the true rate of mortality is 15%, 35% if the true mortality rate is 10%, and 4% if the 
true mortality rate is 5%. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Central registration for this study will take place at MSK. 
 
To complete registration and enroll a participant from another institution, the participating site 
must contact the MSK study coordinator to notify him/her of the participant registration. 
 
The following documents must be sent to the MSK study coordinator for each enrollment 
within 24 hours of the informed consent form being signed: 
 
• The completed or partially completed MSK eligibility checklist 
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (e.g. laboratory results, 
pathology report, radiology reports, MD notes, physical exam sheets, medical history, 
prior treatment records, and EKG report). 
 
Upon receipt, the MSK study coordinator will conduct an interim review of all documents. If 
the eligibility checklist is not complete or source documentation is missing, the participant will 
be registered PENDING and the participating site will be responsible for sending the 
completed registration documents within 30 days of the consent. 
 
If the external registration submission is complete, the participating site IRB has granted 
approval for the protocol, and the participating site is in good standing, the MSK study 
coordinator will send the completed registration documents to the MSK Protocol Participant 
Registration Office for participant enrollment as stated in the protocol. 
 
Once the participant is registered, the participant will be assigned a protocol participant 
number in the MSK Clinical Research Database (CRDB).  This number will be relayed back 
to study staff at the registering participating site via e-mail and will serve as the enrollment 
confirmation.  The number is unique to the participant and must be written on all data and 
correspondence for the participant. 
15.3 
Randomization 
 
There is no randomization in this trial. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
32 
 
 
 
 
16.1 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team.  The data collected for this study will be entered into a secure 
database, the MSKCC Clinical Research Database (CRDB).  Source documentation will be 
available to support the computerized patient record. 
 
16.1.1 Data and Source Documentation for Participating Sites 
 
Data:  Standardized Case Report Forms (CRFs), directions for use and sign off requirements 
have been generated for this study.  Blank case report forms will be sent to the study staff at 
each participating site for use.  The participating Site PI is responsible for ensuring these 
forms are completed accurately, legibly and in a timely manner. 
Source Documentation:  Source documentation refers to original records of observations, 
clinical findings and evaluations that are subsequently recorded as data. Source 
documentation should be consistent with data entered into CRFs. Relevant source 
documentation to be submitted throughout the study includes: 
 
• 
Baseline measures to assess pre-protocol disease status (ex. CT results, bone 
marrow) 
• 
Treatment records 
• 
Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
• 
Response designation 
• 
Any other forms of source documentation requried per protocol 
 
Source documentation should include a minimum of two identifiers to allow for data 
verification. MSK will maintain the confidentiality of any subject-identifiable information it may 
encounter. 
 
16.1.2 Data and Source Documentation Submission for Participating Sites 
 
Participating sites should e-mail CRFs and source documentation to MSKCC research staff. 
Submissions should include a cover page listing all CRFs enclosed per participant. 
 
16.1.3 Data and Source Documentation Submission Timelines for Participating Sites 
 
Data and source documentation to support data should be transmitted to MSKCC according 
to Table V below: 


 
Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
 
 
Table V.  Data and Source Submission Requirements and Timelines 
 
 
Baseline 
Induction 
Consolidations 
1, 2, 3, & 4 
Maintenance 
Long-term 
Follow-up 
SAE 
Off 
Study 
SUBMISSION  SCHEDULE 
Source  Documentation 
Within 24 hours (see 
Section 15.1.1) 
Within 14 
days of the 
end of each 
week 
Within 14 days 
of the end of 
each cycle 
Within 14 
days of the 
end of each 
cycle 
Within 14 
days after 
each visit 
Within 3 days of 
event (see section 
17.2.1); updates to 
be submitted as 
available 
Within 14 
days of 
visit 
CRFs 
Within 7 days of 
initial evaluation 
Required Forms 
Demographics Form 
X 
Medical History Form 
X 
Concomitant  Medications 
Form 
X 
X 
X 
X 
X 
X 
Physical Exam Form 
X 
X 
X 
X 
X 
X 
Treatment Form 
X 
X 
X 
X 
Laboratory Form 
X 
X 
X 
X 
X 
X 
Disease Status Form 
X 
X 
X 
X 
X 
Adverse Event Form 
X 
X 
X 
X 
X 
X 
Serious Adverse Event 
Form 
X 
Off Study Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
33 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
34 
 
 
 
 
16.1.4 Data Review and Queries for Participating Site Data 
 
Research staff at MSKCC will review data and source documentation as it is submitted. Data 
will be monitored against source documentation and discrepancies will be sent as queries to 
the participating sites. Queries will be sent by MSKCC Research staff twice a month. 
 
Participating sites should respond to data queries within 14 days of receipt. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data.  Routine data quality reports will be generated to assess missing data 
and inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action.  Random-sample data quality 
and protocol compliance audits will be conducted by the study team, at a minimum of two 
times per year, more frequently if indicated.  Additionally, monthly teleconferences including 
principal investigators and/or their designees from all sites will be held to expedite the review 
of toxicity and efficacy data. 
 
16.2.1 Quality Assurance for Participating Sites 
 
Quality Assurance will be conducted according to MSK guidelines and Multicenter SOPs. 
 
Research staff at MSK will conduct periodic reviews of regulatory documentation, protocol 
compliance and data, and issue queries as appropriate. The level and frequency of 
monitoring or auditing may be adjusted based on ongoing site performance. 
 
16.2.2 Response Review 
 
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC). 
Radiology, additional lab reports and possibly bone marrow biopsies and/or aspirates will 
need to be obtained from the participating sites for MSKCC TRRC review and confirmation of 
response assessment.  These materials must be sent to MSKCC promptly upon request. 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found 
at:  http://www.cancer.gov/clinicaltrials/conducting/dsm -guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research.  The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Monitoring%   
20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control. 
Additionally, two institutional committees are responsible for monitoring the activities of our 
clinical trials programs.  The committees, Data and Safety Monitoring Committee (DSMC) for 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
35 
 
 
 
 
Phase I and II clinical trials and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
Patients treated collaborating institutions will also be included in these reviews. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed, 
and the monitoring procedures will be established at the time of protocol activation. 
16.3 
Regulatory Documentation 
 
Site Activation 
 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
 
The following documents must be provided to MSK before the participating site can be 
initiated and begin enrolling participants: 
 
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• 
Participating Site IRB approved informed consent form and HIPAA authorization 
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
• 
Curriculum vitae and medical licenses for each investigator and consenting 
professional 
• 
Documentation of Human Subject Research Certification training for investigators, 
consenting professionals and key study personnel at the participating site 
• 
Documentation of Good Clinical Practice training for the participating site PI and co-PI 
• 
Participating site laboratory certifications and normals 
 
Upon receipt of the required documents, MSK will formally contact each participating site and 
grant permission to proceed with enrollment. 
 
16.3.1 Amendments 
 
Each change to the protocol document must be organized and documented by MSK and 
approved first by the MSK IRB/PB. Protocol amendments that affect MSK only (e.g. change 
in MSK Co-Investigator, MSK translation, etc.) do not require IRB review at the participating 
site(s). All other protocol amendments will be immediately distributed to each participating 
site upon receipt of MSK IRB/PB approval. 
Each participating site must obtain IRB approval for all amendments within 90 calendar days 
of MSK IRB/PB approval. If the amendment is the result of a safety issue or makes eligibility 
criteria more restrictive, participating sites will not be permitted to continuing enrolling new 
participants until site IRB approval of the revised protocol documents is granted and 
submitted to MSK. 
16.3.2.1  Additional IRB Correspondence 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
36 
 
 
 
 
Continuing Review Approval 
The Continuing Review Approval letter from each participating site’s IRB and the most current 
approved version of the informed consent form must be submitted to MSK within 7 days of 
expiration. Failure to submit the re-approval in the stated timeline will result in suspension of 
new participant enrollment. 
 
Deviations 
A protocol deviation on this study is defined as any incident involving non-adherence to an 
IRB approved protocol. Deviations typically do not have a significant effect on the rights, 
safety, or welfare of research participants or on the integrity of the resultant data. Deviations 
that represent unanticipated problems involving risks to participants or others, or serious 
adverse events should be reported according to sections 17.3 and 17.5. 
 
Deviations that do not adversely affect the rights and/or welfare of the participant or the 
scientific validity of the study and are related to protocol scheduling changes outside of the 
allowed window due to a holiday (e.g., New Year’s, Thanksgiving, etc.) and/or inclement 
weather or other natural event do not require reporting to the MSK IRB/PB.  However, they 
must be clearly documented in the patient’s medical record. 
 
Prospective Deviations 
Deviations to the research protocol that involve patient eligibility, an informed consent 
procedure change, and/or treatment/pharmacy alterations that are not allowed by the protocol 
require prospective approval from the MSK IRB/PB prior to the change being carried out. 
Participating sites should contact the MSK PI who will in turn seek approval from the MSK 
IRB/PB. 
 
Retrospective Deviations 
Deviations that include a change or departure from the research protocol without prior 
approval from the MSK IRB/PB are considered retrospective deviations. Retrospective 
deviations should be reported to the MSK PI as soon as possible, who will in turn report the 
deviation to the MSK IRB/PB as per MSK guidelines. 
Participating Site IRB Reporting 
Participating sites should report all deviations to their institution’s IRB per local guidelines. 
Approvals/acknowledgments from the participating site IRB for protocol deviations should be 
submitted to MSK upon receipt. 
 
Other Correspondence 
Participating sites should submit all other correspondence to their institution’s IRB according 
to local guidelines, and submit copies of official site IRB correspondence, including approvals 
and acknowledgements, to MSK. 
 
 
16.3.3 Document Maintenance 
 
The MSK PI and participating site PI will maintain adequate and accurate records to fully 
document protocol implementation and allow data to be subsequently verified. 
 
The participating sites will ensure that all regulatory documents and participating site IRB 
correspondence are maintained in an on-site regulatory binder and sent to MSK. The on-site 
regulatory binder will be reviewed by the designated study monitor at monitoring visits. A 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
37 
 
 
 
 
regulatory binder for each participating site will also be maintained at MSK within the 
institution’s Protocol Information Management System (PIMS). 
 
After study closure, the participating sites must maintain all source documents, study related 
documents and CRFs for 3 years. 
 
16.4 Noncompliance 
 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments may be withheld, if applicable, until the outstanding 
issues have been resolved. 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org containing the following information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
17.4 Serious Adverse Event (SAE) Reporting for Participating Sites 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
38 
 
 
 
 
Responsibilities of Participating Sites 
• 
Participating sites are responsible for reporting all SAEs to their site IRB per local 
guidelines. Site IRB approvals/acknowledgments must be sent to MSK upon receipt. 
• 
Participating sites are responsible for submitting the SAE Report form to MSK within 3 
calendar days of learning of the event. 
• 
When a life threatening event or death is unforeseen and indicates participants or 
others are at increased risk of harm, participating sites should notify the MSK PI as 
soon as possible but within 24 hours of the time the site becomes aware of the event. 
 
Responsibilities of MSK 
• 
MSK is responsible for submitting all SAEs to the MSK IRB/PB and funding entities (if 
applicable) as described in the protocol. 
• 
MSK is responsible for informing all participating sites about all unexpected SAEs that 
are either possibly, probably, or definitely related to the study intervention within 15 
days of receiving the stamped SAE report from the MSK IRB/PB. 
• 
MSK is responsible for informing all participating sites within 24 hours or on the next 
business day about a life threatening event or death that is unforeseen and indicates 
participants or others are at increased risk of harm. 
 
17.5 Safety Reports 
 
MSK must submit outside safety reports to the MSK IRB/PB according to institutional 
guidelines. All outside safety reports will be made available to the participating sites. Outside 
safety reports that are reportable to the MSK IRB/PB will be distributed to the participating 
sites immediately upon receiving a stamped copy from the MSK IRB/PB. Participating sites 
will receive a special alert for any outside safety reports that warrant a significant change to 
the conduct of the study. Outside safety reports that are not reportable to the MSK IRB/PB, 
will be sent to the participating sites monthly. 
 
Participating sites are responsible for submitting safety reports to their site IRB per their local 
guidelines. All site IRB approvals/acknowledgments of safety reports must be sent to MSK 
upon receipt. 
17.6 Unanticipated Problems 
 
Unanticipated problems involving risks to participants or others (UPs) are defined as any 
incident, experience or outcome that meets all of the following criteria: 
 
• 
Unanticipated (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB- 
approved research protocol and informed consent document; and (b) the characteristics 
of the subject population being studied; and 
• 
Related or possibly related to participating in the research (possibly related means there 
is a reasonable probability that the incident, experience or outcome may have been 
caused by procedures involved in the research); and 
• 
Suggests that the research place participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
39 
 
 
 
 
Participating sites are responsible for reporting all UPs to MSK as soon as possible but within 
3 calendar days of learning of the event. UPs that are SAEs should be reported to MSK via 
SAE Report form. All other UPs should be reported to MSK in a memo signed by the site PI. 
 
MSK is responsible for submitting UPs to the MSK IRB/PB according to institutional 
guidelines. In addition, MSK is responsible for notifying participating sites of all non-SAE UPs 
that may affect the sites. 
 
17.7 
Potential Benefits. 
 
While current therapeutic approaches for APL produce long-term remissions in 75- 
90% of patients, short-term complications include prolonged hospitali zations and 
morbidity due to multiple courses of intensi ve anthracycline-based chemotherapy. 
This therapy can produce late cardiotoxicity and secondary MDS/AML in up to 6.5% 
of patients. A treatment regimen that combines highly acti ve agents for APL in a 
strategy that minimizes exposure to anthracycli ne-based chemotherapy using 
molecular monitoring of response may reduce hospitali zations, morbidity, and 
delayed complications of therapy while still maintaining high long -term remission 
rates. 
 
17.8 Risks in Relation to Anticipated Benefits. 
 
This is a phase II trial to study the efficacy of combined ATRA and ATO in the 
treatment of newly diagnosed APL and the use of molecular monitoring of minimal 
residual disease to reduce or eliminate the amount of standard chemotherapy 
required for long-term remission.  The risks of this investigational approach may 
include increased risk of relapse in exchange for the benefit of decreased courses of 
chemotherapy with less exposure to the toxic side effects of such treatment.  If 
results from the study show an equivalent probability of long-term remission to those 
found in previous trials (80% ± 7% at three years) with less short-term morbidity and 
late complications, a randomized study would be needed to verify these findings and 
determine the risk-benefit ratio. 
 
17.9 Procedures for Protecting Against and Minimizing Risks. 
 
Guidelines for the management of APL syndrome are given in Section 9.1.1. ECG 
monitoring and electrolyte management guidelines in order to avoid complications 
caused by a prolonged QT interval are described in Section 9.1.3.  Management of 
toxicities and dose modifications for ATRA are given in Section 9.1.4.  Management 
of toxicities and dose modifications for ATO are given in Section 9.1.5. Left 
ventricular function will be assessed with serial echocardiograms or MUGA scans, at 
the discretion of the treating physician, to detect changes from baseli ne cardiac 
function. Pack red blood cell transfusions will be given as cli nically indicated. 
Disseminated intravascular coagulation will be treated with transfusions of platelets 
and fresh frozen plasma or cryoprecipitate acco rding to guidelines given in Section 
9.1.2.  Infections will be treated with intravenous antibiotics as clinically indicated. 
Treatment-related mortality during induction in excess of 15% would be unacceptably 
high.  If at any time, four patients die from treatment-related causes, the trial will be 
terminated. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
40 
 
 
 
 
 
 
17.10 Alternative Treatments 
 
Alternative therapy would include a standard regimen consisting of induction with ATRA and 
an anthracycline with or without cytarabine followed by 2-3 courses of anthracycline-based 
consolidation with or without maintenance therapy, consisting of ATRA ± oral mercaptopurine 
and methotrexate. 
 
17.11 Incentives/Costs 
 
No incentives will be offered to patients/subjects for participation in the study.  Participation is 
voluntary.  The patient/subject will be responsible for the costs of standard medical care, 
including ATRA, ATO, idarubicin, all other standard medications, blood and platelet 
transfusions, radiographic studies, laboratory tests, and all hospitalizations, even for 
complications of treatment.  Weekly peripheral blood immunophenotyping during induction as 
well as peripheral blood and bone marrow analyses for telomerase activity, telomere length, 
and TERT expression are research non-billable studies. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
18.2 For Participating Sites 
 
The investigators listed on the Consenting Professionals Lists at each participating site may 
obtain informed consent and care for the participants according to Good Clinical Practice and 
protocol guidelines. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
41 
 
 
 
 
A note will be placed in the participant’s medical record documenting that informed consent 
was obtained for this study, and that the participant acknowledges the risk of participation. 
 
19.0 
REFERENCES 
 
1. 
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promyelocytic leukaemia fuses the retinoic acid receptor  gene to a novel transcribed 
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Miller WH Jr, Warrell RP Jr, Frankel SR, et al: Novel retinoic acid receptor- transcripts 
in acute promyelocytic leukemia responsive to all-trans retinoic acid. J Natl Cancer Inst 
1990; 82:1932-1933. 
 
3. 
Kakizuka A, Miller WH Jr, Umesono K, et al: Chromosomal translocation t(15;17) in 
human acute promyelocytic leukemia fuses RAR- with a novel putative transcription 
factor, PML. Cell 1991; 66:663-674. 
 
4. 
de Thé H, Lavau C, Marcio A, et al. The PML-RAR- fusion mRNA generated by the 
t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered 
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5. 
Salomoni P, Pandolfi PP. The role of PML in tumor suppression. Cell 2002; 108:165- 
170. 
 
6. 
Kastner P, Chan S. Function of RAR during the maturation of neutrophils. Oncogene 
2001; 20:7216-7222. 
 
7. 
Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute 
promyelocytic leukemia. Blood 1988; 72:567-572. 
 
8. 
Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation 
therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990; 76:1704-1709. 
 
9. 
Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute 
promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1991; 
324:1385-1393. 
 
10. Warrell RP Jr, Maslak PG, Eardley A, et al. Treatment of acute promyelocytic leukemia 
with all-trans retinoic acid: an update of the New York experience. Leukemia 1994; 
8:929-933. 
 
11. Soignet S, Fleischauer A, Polyak T, et al.  All-trans retinoic acid significantly increases 5- 
year survival in patients with acute promyelocytic leukemia:  Long-term follow-up of the 
New York study. Cancer Chemother Pharmacol 1997; 40(Suppl):S25-S29. 
 
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20.0 
APPENDICES 


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IRB Number: 11-040 A(13) 
Approval date: 07-Mar-2018 
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Appendix A: Local Institution Guidelines (Local Institution Consolidation Therapy 
Guidelines 
 
Appendix B: Consolidation/Maintenance Pill Diary