APL93: Timing of CxT and Role of Maintenance

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

Status and phase

Completed

Phase 3

Conditions

Leukemia, Promyelocytic, Acute

Treatments

Drug: ATRA

Drug: ATRA and or Chemo as maintenance

Study type

Interventional

Funder types

Other

Identifiers

NCT00599937

APL93

Details and patient eligibility

About

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

Full 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.

Enrollment

576 patients

Sex

All

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Diagnosis of APL, based on morphology criteria
Age 75 years or less; and
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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

576 participants in 7 patient groups

ATRA ->Chemo

No Intervention group

Description:

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.

ATRA+CT

Experimental group

Description:

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.

Treatment:

Drug: ATRA

High WBC

No Intervention group

Description:

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 maintenance

No Intervention group

Description:

No maintenance

maintenance ATRA

Experimental group

Description:

Intermitent ATRA as maintenance

Treatment:

Drug: ATRA and or Chemo as maintenance

maintenance Cxt

Experimental group