APL93: Timing of CxT and Role of Maintenance

January 23, 2008 updated by: Groupe d'etude et de travail sur les leucemies aigues promyelocytaires

Assessment of the Optimal Timing of Chemotherapy With or After ATRA and the Role of Maintenance

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

576

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
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 Names:
  • 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 Names:
  • 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 Names:
  • ATRA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
For induction treatment event-free survival (EFS), calculated from the date of randomization, was the major endpoint.
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Groupe d'etude et de travail sur les leucemies aigues promyelocytaires

Collaborators

DRC lille, France

Investigators

  • Principal Investigator: pierre fenaux, mD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 1993

Primary Completion (Actual)

December 1, 1998

Study Completion (Actual)

December 1, 1998

Study Registration Dates

First Submitted

December 27, 2007

First Submitted That Met QC Criteria

January 23, 2008

First Posted (Estimate)

January 24, 2008

Study Record Updates

Last Update Posted (Estimate)

January 24, 2008

Last Update Submitted That Met QC Criteria

January 23, 2008

Last Verified

December 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • APL93

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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