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

Phase 3
Not Enrolling
Leukemia, Promyelocytic, Acute

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Trial Information

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

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.

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.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

For induction treatment event-free survival (EFS), calculated from the date of randomization, was the major endpoint.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

pierre fenaux, mD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

January 1993

Completion Date:

December 1998

Related Keywords:

  • Leukemia, Promyelocytic, Acute
  • APL
  • Leukemia
  • Leukemia, Promyelocytic, Acute