Acute Promyelocytic Leukemia 2006 (APL)

Overview

To assess the role of Arsenic trioxide and/or ATRA during consolidation course in APL. It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen.

Full Title of Study: “A Randomized Trial Assessing the Role of Arsenic Trioxide and/or ATRA During Consolidation Course in Newly Diagnosed Acute Promyelocytic Leukemia (APL)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 2016

Detailed Description

Definition: Extended description of the protocol, including information not already contained in other fields, such as comparison(s) studied. APL is a specific type of acute myeloid leukemia (AML) characterized by its morphology (M3 or M3v in the FAB classification), t(15;17) translocation leading to PML-RARa fusion gene, and by a specific coagulopathy combining D.I.C., fibrinolysis and non specific proteolysis. ATRA can differentiate APL blasts in VITRO and in vivo. The combination of ATRA and anthracycline based chemotherapy yields CR rates greater than 90% in newly diagnosed APL. With early introduction of anthracycline AraC chemotherapy during induction treatment, and maintenance combining continuous 6MP and MTX to intermittent ATRA, the relapse risk in APL therefore now appears to be in the range of 10 to 15%. Nevertheless, 5 to 10% of the patients do not achieve CR and 10% to 15% still relapse. Another subset of patients (5 to 7% in APL 93 trial including 17% of patients aged greater than 65 years) die in CR, from complications of the consolidation treatment phase, mainly from infection during chemotherapy induced aplasia. Failure to achieve CR with current treatment approaches is almost exclusively due to early death during induction treatment. Causes of death are predominantly bleeding, ATRA syndrome and less often infection. Early deaths predominate in elderly patients and patients with high WBC counts. Reducing the amount of chemotherapy administered to newly diagnosed APL patients diminishes this toxicity. The Spanish PETHEMA group reported results of two successive phase II trials in newly diagnosed APL with ATRA and chemotherapy with intercalating agents (idarubicin and mitoxantrone) without AraC followed by maintenance combining ATRA and low dose chemotherapy (LPA96 and LPA99 trials). Results appeared similar to those of the best arm of APL 93 trial, but with less toxicity and only 2 to 3 % death in CR were seen, including in elderly patients. Arsenic trioxide (As2O3 or ATO) is an effective agent in relapsing or refractory APL, which induced 85% hematological and 79% molecular CR rates in a pivotal US study. The interest of ATO in the front-line therapy of newly-diagnosed APL has been strongly suggested in three studies which showed high complete remission rate, low incidence of relapse and limited toxicity. In this study, patients will be stratified based on age (≤ 70 years and > 70 years) and WBC count at diagnosis (WBC<10.000/mm3 and >10.000 /mm3). -Patients aged 70 years or less with WBC<10.000/mm3. In this population (about 70 % of APL) the best treatment group of APL2000 trial (ATRA with early introduction of anthracycline-AraC chemotherapy but where Idarubicin will be substituted for Daunorubicin, followed by 2 anthracycline-AraC consolidation courses and maintenance combining continuous chemotherapy and intermittent ATRA) will be compared to the same regimen, but without AraC during consolidation courses which will be replaced by: – either ATO – or ATRA It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen. – Patients aged 70 years or less with WBC>10.000/mm3 Patients ages 70 years or less with initial WBC counts > 10000/mm3 (ie very high counts for APL), which represent about 20% of APL, remain at relatively high risk of relapse even with the current reference treatment. The main objective of the study will be to test the addition of ATO during consolidation courses to our current standard ATRA and chemotherapy regimen. Patients will receive the best treatment group of APL 2000 trial (but where Idarubicin will be substituted for Daunorubicin) with or without ATO during the 2 consolidation cycles. – Patients older than 70 years with WBC<10.000 /mm3. Elderly patients with initial WBC ≤ 10000/m3 (about 8% of APL) and no contra indication to this treatment will receive a regimen with reduced cumulative dose of chemotherapy but addition of ATO during consolidation courses and during the first year of maintenance treatment. The main purpose of this non randomized part of the trial is to reduce the early death mortality and death in CR observed in elderly patients, without increasing the relapse rate. – Patients older than 70 years with WBC>10.000 /mm3. Elderly patients with initial WBC > 10000/m3 (about 2 to 3% of APL) and no contra indication to intensive regimen will receive the same regimen as those with low WBC but with moderate doses of Aracytine during the induction and during the first consolidation course. The main purpose of this non randomized part of the trial is to reduce the early death mortality and death in CR observed in elderly patients, without increasing the relapse rate.

Interventions

  • Procedure: Arsenic trioxide
    • Arsenic trioxide
  • Procedure: ATRA
    • ATRA

Arms, Groups and Cohorts

  • Experimental: 1
    • Arsenic trioxide

Clinical Trial Outcome Measures

Primary Measures

  • For Patients aged 70 years or less with WBC<10.000/mm3, The primary end point will be event free survival at 2 years from CR achievement
    • Time Frame: during de study
    • For Patients aged 70 years or less with WBC<10.000/mm3, The primary end point
  • For patients older than 70 years with WBC>10.000 /mm3, The primary end point will be EFS at 2 years from diagnosis
    • Time Frame: during the study
    • For patients older than 70 years with WBC>10.000 /mm3, The primary end point will be EFS at 2 years from diagnosis

Secondary Measures

  • For Patients aged 70 years or less with WBC<10.000/mm3 :
    • Time Frame: during the study
    • For Patients aged 70 years or less with WBC<10.000/mm3 :
  • Relapse (molecular or hematological).
    • Time Frame: during the study
    • Relapse (molecular or hematological).
  • Kinetics of decrease of PML-RARA transcript level during and after consolidation course.
    • Time Frame: during the study
    • Kinetics of decrease of PML-RARA transcript level during and after consolidation course.
  • Survival at 2 years.
    • Time Frame: during the study
    • Survival at 2 years.
  • Side effects of the treatment, including treatment-related mortality and morbidity of consolidation treatment.
    • Time Frame: during th study
    • Side effects of the treatment, including treatment-related mortality and morbidity of consolidation treatment.
  • Days on antibiotics, transfusion requirement and nights spent in Hospital
    • Time Frame: during the study
    • Days on antibiotics, transfusion requirement and nights spent in Hospital
  • For Patients aged 70 years or less with WBC>10.000/mm3
    • Time Frame: during the study
    • For Patients aged 70 years or less with WBC>10.000/mm3
  • event free survival at 2 years from CR achievement
    • Time Frame: during the study
    • event free survival at 2 years from CR achievement
  • Side effects of the treatment, including treatment-related mortality and morbidity of consolidation treatment.
    • Time Frame: during the study
    • Side effects of the treatment, including treatment-related mortality and morbidity of consolidation treatment.
  • For Patients older than 70 years with WBC<10.000 /mm3
    • Time Frame: during the study
    • For Patients older than 70 years with WBC<10.000 /mm3
  • Kinetics of decrease of PML-RARA transcript level during and after consolidation course.
    • Time Frame: during the study
    • Kinetics of decrease of PML-RARA transcript level during and after
  • Relapse and survival at 2 years.
    • Time Frame: during the study
    • Relapse and survival at 2 years.
  • Side effects of the treatment, including mortality and morbidity of consolidation treatment.
    • Time Frame: during the study
    • Side effects of the treatment, including mortality and morbidity of
  • For patients older than 70 years with WBC>10.000 /mm3
    • Time Frame: during the study
    • For patients older than 70 years with WBC>10.000 /mm3

Participating in This Clinical Trial

Inclusion Criteria

  • Diagnosis of APL based on morphological grounds, which will have to be confirmed by the presence of t(15;17) and/or PML-RARA rearrangement with characterization of the bcr subtype (PML-RAR characterization). – Untreated patients. – No contraindication to intensive chemotherapy (especially well documented cardiac contraindication to idarubicin). – In female patients: absence of pregnancy and adequate contraceptive methods (due to teratogenetic effects of ATRA in early pregnancy). – Absence of Hypersensitivity to Arsenic derivatives. – No QT interval prolongation or complete atria-ventricular block. – Written informed consent. Exclusion Criteria:

  • Patients already treated. – Patients with contraindication to intensive chemotherapy, especially well documented cardiac contraindication to Idarubicin. – In female patients: pregnancy or absence of adequate contraceptive Methods – QT interval prolongation or complete atria-ventricular block. – Hypersensitivity to Arsenic derivatives.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Lionel ADES, MD,PhD, Principal Investigator, Assistance Publique – Hôpitaux de Paris
  • Overall Contact(s)
    • Lionel ADES, MD, +33(0)-148 95 70 55, Lionel.ades@avc.aphp.fr

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