APL93: Timing of CxT and Role of Maintenance

This study has been completed.
Sponsor:
Collaborator:
DRC lille, France
Information provided by:
Groupe d'etude et de travail sur les leucemies aigues promyelocytaires
ClinicalTrials.gov Identifier:
NCT00599937
First received: December 27, 2007
Last updated: January 23, 2008
Last verified: December 2007
  Purpose

Objectives of the trial were to assess the optimal timing of chemotherapy with or after ATRA and the role of maintenance therapy.


Condition Intervention Phase
Leukemia, Promyelocytic, Acute
Drug: ATRA
Drug: ATRA and or Chemo as maintenance
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Assessment of the Optimal Timing of Chemotherapy With or After ATRA and the Role of Maintenance

Resource links provided by NLM:


Further study details as provided by Groupe d'etude et de travail sur les leucemies aigues promyelocytaires:

Primary Outcome Measures:
  • For induction treatment event-free survival (EFS), calculated from the date of randomization, was the major endpoint. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Enrollment: 576
Study Start Date: January 1993
Study Completion Date: December 1998
Primary Completion Date: December 1998 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: ATRA ->Chemo
Patients 65 years of age with a WBC count less than 5,000 were randomized to receive the reference ATRA treatment of our previous trial (APL91 trial), ie, 45 mg/m2/d ATRA followed by CT or ATRA plus CT (ATRA+CT). In the ATRA followed byCT group, patients received 45 mg/m2/d ATRA orally until CR, with a maximum of 90 days. After CR achievement, they received a course of 60 mg/m2/d daunorubicin (DNR) for 3 days and 200 mg/m2/d AraC for 7 days (course I). However, course I was added to ATRA if the WBC count was increased to greater than 6,000, 10,000, or 15,000 by day 5, 10, and 15 of ATRA treatment, respectively, because, from our experience, patients were at risk of ATRA syndrome above those thresholds.
Experimental: ATRA+CT
Patients randomized to the ATRA+CT group received the same combination of ATRA and CT, with course I of CT starting on day 3 of ATRA treatment. This 48-hour interval before onset of CT was based on our previous report, because it allowed correction of coagulopathy.
Drug: ATRA
early introduction of ATRA
Other Name: ATRA
No Intervention: High WBC
Patients with a WBC count greater than 5,000 at presentation (irrespective of their age) and patients 66 to 75 years of age with a WBC count 5,000 were not randomized but received ATRA plus CT course I from day 1 (high WBC group) and the same schedule as in the ATRA->CT group (elderly group), respectively.
No Intervention: no maintenance
No maintenance
Experimental: maintenance ATRA
Intermitent ATRA as maintenance
Drug: ATRA and or Chemo as maintenance
patients were randomized both to receive or not receive intermittent ATRA (45 mg/m2/d, 15 days every 3 months) and to receive or not receive continuous CT with 6 mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, orally), according to a 2-by-2 factorial design stratified on the initial induction treatment group
Other Name: ATRA
Experimental: maintenance Cxt
continuous CT with 6 mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, orally) as maintenance
Drug: ATRA and or Chemo as maintenance
patients were randomized both to receive or not receive intermittent ATRA (45 mg/m2/d, 15 days every 3 months) and to receive or not receive continuous CT with 6 mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, orally), according to a 2-by-2 factorial design stratified on the initial induction treatment group
Other Name: ATRA
Experimental: maintenance both
continuous CT with 6 mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, orally) AND ATRA as maintenance
Drug: ATRA and or Chemo as maintenance
patients were randomized both to receive or not receive intermittent ATRA (45 mg/m2/d, 15 days every 3 months) and to receive or not receive continuous CT with 6 mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, orally), according to a 2-by-2 factorial design stratified on the initial induction treatment group
Other Name: ATRA

Detailed Description:

Induction treatment was stratified by age and initial WBC count. Patients ≤65 years of age with a WBC count less than 5,000/µL were randomized to receive the reference ATRA treatment of our previous trial (APL91 trial) {Fenaux, 1993 #2088}, ie, 45 mg/m2/d ATRA followed by CT (ATRA→CT group) or ATRA plus CT (ATRA+CT). In the ATRA→CT group, patients received 45 mg/m2/d ATRA orally until CR, with a maximum of 90 days. After CR achievement, they received a course of 60 mg/m2/d daunorubicin (DNR) for 3 days and 200 mg/m2/d AraC for 7 days (course I). However, course I was added to ATRA if the WBC count was increased to greater than 6,000/µL, 10,000/µL, or 15,000/µL by day 5, 10, and 15 of ATRA treatment, respectively, be-cause, from our experience, patients were at risk of ATRA syndrome above those thresholds{de Botton, 2003 #1127; De Botton, 1998 #1604}. Patients randomized to the ATRA+CT group received the same combination of ATRA and CT, with course I of CT starting on day 3 of ATRA treatment.

Patients with a WBC count greater than 5,000/µL at presentation (irrespective of their age) and patients 66 to 75 years of age with a WBC count ≤ 5,000/µL were not ran-domized but received ATRA plus CT course I from day 1 (high WBC group) and the same schedule as in the ATRA→CT group (elderly group), respectively.

Treatment of coagulopathy during the induction phase was based on platelet support to maintain the platelet count at a level greater than 50,000 /µL until the disappea-rance of coagulopathy. The use of heparin, tranexamic acid, fresh frozen plasma, and fibrinogen transfusions was optional.

CR patients received 2 CT consolidation courses, including course II (identical to course I) and course III, consisting of 45 mg/m2/d DNR for 3 days and 1 g/m2 AraC every 12 hours for 4 days. The elderly group only received course II.

Three to 4 weeks after hematological recovery from this consolidation CT, patients who were still in CR were randomized both to receive or not receive intermittent ATRA (45 mg/m2/d, 15 days every 3 months) and to receive or not receive continuous CT with 6 mercaptopurine (90 mg/m2/d, orally) and methotrexate (15 mg/m2/wk, oral-ly), according to a 2-by-2 factorial design stratified on the initial induction treatment group. Maintenance treatment was scheduled for 2 years. Randomizations for induc-tion and maintenance, stratified on center, were performed through a centralized tele-phone assignment procedure.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diagnosis of APL, based on morphology criteria
  2. Age 75 years or less; and
  3. Written informed consent. Diagnosis had to be subsequently confirmed by presence of t(15;17) or PML-RAR gene rearrangement. In the absence of t(15;17) and if no analysis of the rearrangement could be made, review of initial marrow slides by an independent morphologist was mandatory.
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00599937

Sponsors and Collaborators
Groupe d'etude et de travail sur les leucemies aigues promyelocytaires
DRC lille, France
Investigators
Principal Investigator: pierre fenaux, mD Assistance Publique - Hôpitaux de Paris
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: DRC Lille, CHU Lille
ClinicalTrials.gov Identifier: NCT00599937     History of Changes
Other Study ID Numbers: APL93
Study First Received: December 27, 2007
Last Updated: January 23, 2008
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Groupe d'etude et de travail sur les leucemies aigues promyelocytaires:
APL

Additional relevant MeSH terms:
Leukemia
Leukemia, Promyelocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid, Acute
Leukemia, Myeloid
6-Mercaptopurine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014