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

Study Overview
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Brief Summary
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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.

Detailed Description
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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still fail to achieve mCR, together with high-risk group who fail to achieve mCR after consolidation therapy will be withdrawn from the study and proceed to salvage treatment.

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

Conditions
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Acute Promyelocytic Leukemia

Intervention / Treatment
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* Drug: ATRA+Arsenic
* Drug: ATRA+Chemo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATRA+Arsenic<br>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<br>* 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.<br>* Other names: retinoic acid + arsenic trioxide;|
| Active Comparator: ATRA+chemo<br>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<br>* 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.<br>* Other names: retinoic acid + idarubicin or daunorubicin +/- Cytarabine;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute promyelocytic leukemia, ATRA, arsenic