Combined Retinoic Acid,Arsenic Trioxide and Chemo for Newly-diagnosed APL

Combined Retinoic Acid,Arsenic Trioxide and Chemotherapy for Newly-diagnosed Acute Promyelocytic Leukemia: Chinese National Multi-center Randomized Study

In this prospective randomized study for patients with newly diagnosed acute promyelocytic leukemia, patients will be randomized (1:1) into two groups which receive retinoic acid and arsenic trioxide based treatment versus retinoic acid and chemotherapy based regimen.

Study Overview

• Status: Unknown
• Conditions: Acute Promyelocytic Leukemia
• Intervention / Treatment: Drug: ATRA+Arsenic; Drug: ATRA+Chemo

Detailed Description

The study is carried out based on Sanz risk stratification of newly-diagnosed APL patients into low-, intermediate- and high-risk groups, and all of them will receive ATRA and ATO as induction therapy (ATRA 25 mg/m2 per day orally + ATO 0.16mg/kg intravenously daily). Anthracycline is added to both high-risk groups or intermediate-risk group with hyperleukocytosis developed during induction therapy but not in low-risk groups.

After achieving CR, patients enter into consolidation therapy. Low-risk patients receive either 2 courses of ATRA plus ATO (Experimental group) or 2 courses of ATRA plus anthracycline chemotherapy (Control group). Intermediate-risk patients receive either 3 courses of ATRA plus ATO (Experimental group) or 2 courses of ATRA plus anthracycline chemotherapy (Control group). Patients of high-risk disease receive 2 courses of ATRA plus ATO and anthracycline and 1 course of ATRA plus ATO treatment (Experimental group) or 2 courses of ATRA plus anthracycline and cytarabine and 1 course of ATRA plus mid-dose cytarabine (Control group).

After consolidation therapy, patients with molecular complete remission (mCR) enter into maintenance therapy. Low- and intermediate-risk patients receive 3 cycles of ATRA and ATO sequential treatment, while those of high-risk receive 5 cycles of ATRA, ATO and methotrexate (MTX) treatment.

For low- and intermediate-risk patients who fail to achieve mCR after consolidation therapy, 3 courses of consolidation therapy of high-risk group will be given with cross-over (i.e. patients in Experimental group received the therapy of Control group, and patients in Control group received the therapy of Experimental group). If patients still fail to achieve mCR, together with high-risk group who fail to achieve mCR after consolidation therapy will be withdrawn from the study and proceed to salvage treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 738
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Shanghai, China, 200025
    • Department of Hematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Newly-diagnosed patients with acute promyelocytic leukemia via cytogenetics and molecular assay
• Age: 18-65
• Hepatic/renal function: Bil≤35μmol/L，AST/ALT less than 2Xnormal range, Cr 150μmol/L
• Normal cardial function
• ECOG：0-4
• Informed consent

Exclusion Criteria:

• QTC interval >450ms
• Pregnant or breast feeding patients
• Patients with drug addiction or mental illness
• Patients documented of CNS infiltration at diagnosis
• Patients with severe heart disease (acute myocardial infarction or heart failure)
• Patients with concurrent active malignancy, tuberculosis or HIV infection
• Patients with contraindication or allergy to anthracyclines or other agent in the protocol
• Patients enrolled in other clinical trials
• Patients not apply to the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ATRA+Arsenic; All low- and intermediate-risk patients receive retinoic acid and arsenic trioxide based consolidation. High-risk patients receive ATRA+Arsenic+Anthracycline consolidation.	Drug: ATRA+Arsenic; ATRA: 25mg/m2 daily；Induction: D1 to CR; Consolidation: D1-14 each course; Maintenance: D1-14 each course. Arsenic: 0.16mg/kg daily. Induction: D1 to CR; Consolidation: low/intermediate-risk patients 28 days each course; high-risk: 14 days each course; Maintenance: 14 days on and off each course. Idarubicin 8mg/m2 or Daunorubicin 45mg/m2 daily. Induction: 3-4 days in high-risk patients or intermediated-risk patients with leukocytosis developed during induction therapy. Consolidation: 3 days in high-risk patients in first 2 courses. MTX: 15mg/m2 qw Maintenance: qw x 4 in each course for high-risk patients.; Other Names: retinoic acid + arsenic trioxide
Active Comparator: ATRA+chemo; All low-risk and intermediate-risk patients receive retinoic acid and chemotherapy with idarubicin or daunorubicin as consolidation. High-risk patients receive ATRA+anthracycline and cytarabine as consolidation.	Drug: ATRA+Chemo; ATRA: 25mg/m2 daily；Induction: D1 to CR; Consolidation: D1-14 each course; Maintenance: D1-14 each course. Arsenic: 0.16mg/kg daily. Induction: D1 to CR; Maintenance: 14 days on and off each course. Idarubicin 8mg/m2 or Daunorubicin 45mg/m2 daily. Induction: 3-4 days in high-risk patients or intermediated-risk patients with leukocytosis developed during induction therapy. Consolidation: 3 days in all patients in 2 courses. Cytarabine: 150mg/m2 or 1g/m2. Consolidation: 150mg/m2 daily x 7 days in high risk patients in first 2 courses; 1g/m2 q12 x 6 doses in third course. MTX: 15mg/m2 qw Maintenance: qw x4 in each course for high-risk patients.; Other Names: retinoic acid + idarubicin or daunorubicin +/- Cytarabine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival (DFS)	DFS is defined for patients having achieve CR as time to relapse either in bone marrow or extra medullary site, or fail to achieve molecular remission, or death of all causes.	3 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission (CR) rate	Blast and promyelocytic leukemia less than 5% in bone marrow	after induction therapy
Molecular CR (mCR)	mCR is defined the absence of detectable PML-RARα transcripts by nested RT-PCR or RQ-PCR in two successive bone marrow samples	after consolidation therapy
Early death (ED) rate	Early death is referred to death within 30 days from the entry into the treatment.	30 days
Overall survival (OS)	OS is defined for patients entering the study as time to death of all causes.	3 years
Cumulated incidence of relapse (CIR)	CIR is defined for patients having achieved CR as time to any relapse or persistence of PCR positivity after consolidation therapy	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematological or non hematological toxicitytoxicitie	Assessed according to the Common Terminology Criteria for Adverse Events Version 4.0 (National Cancer Institute)	3 years

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital of Anhui Medical University; Peking University People's Hospital; First Affiliated Hospital, Sun Yat-Sen University; Southwest Hospital, China; West China Hospital; Tongji Hospital; Qilu Hospital of Shandong University; Nanfang Hospital of Southern Medical University; First Affiliated Hospital of Zhejiang University; Shandong Provincial Hospital; Institute of Hematology & Blood Diseases Hospital; The First Affiliated Hospital of Soochow University; Guangdong Provincial People's Hospital; Wuhan Union Hospital, China; Tang-Du Hospital; First Hospital of China Medical University; Ningbo No. 1 Hospital; The Second Affiliated Hospital of Dalian Medical University; First Affiliated Hospital of Guangxi Medical University; Union hospital of Fujian Medical University
• Investigators: Principal Investigator: Jun-min Li, M.D, Department of Hematology, Rui Jin Hospital, Shanghai JiaoTong University School of Medicine

Publications and helpful links

General Publications

• Chen L, Zhu HM, Li Y, Liu QF, Hu Y, Zhou JF, Jin J, Hu JD, Liu T, Wu DP, Chen JP, Lai YR, Wang JX, Li J, Li JY, Du X, Wang X, Yang MZ, Yan JS, Ouyang GF, Liu L, Hou M, Huang XJ, Yan XJ, Xu D, Li WM, Li DJ, Lou YJ, Wu ZJ, Niu T, Wang Y, Li XY, You JH, Zhao HJ, Chen Y, Shen Y, Chen QS, Chen Y, Li J, Wang BS, Zhao WL, Mi JQ, Wang KK, Hu J, Chen Z, Chen SJ, Li JM. Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial). Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):e2020382118. doi: 10.1073/pnas.2020382118.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2012
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: December 6, 2012
• First Submitted That Met QC Criteria: November 12, 2013
• First Posted (Estimate): November 19, 2013

Study Record Updates

• Last Update Posted (Actual): August 19, 2019
• Last Update Submitted That Met QC Criteria: August 15, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: ATRA; arsenic; acute promyelocytic leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Leukemia, Promyelocytic, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Antibiotics, Antineoplastic; Keratolytic Agents; Arsenic Trioxide; Cytarabine; Daunorubicin; Idarubicin; Tretinoin
• Other Study ID Numbers: APL2012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No