Treatment of Acute Promyelocytic Leukemia With All-Trans Retinoic Acid (ATRA) and Idarubicin (AIDA)

Phase 4

Completed

• Conditions: Acute Promyelocytic Leukemia

• Registration Number: NCT00465933
• Lead Sponsor: PETHEMA Foundation

Brief Summary

The purpose of this study is to evaluate the efficacy of all-trans retinoic acid (ATRA) and idarubicin (AIDA) with a dose reduction in patients older than 70 years of age in the remission induction of acute promyelocytic leukemia (APL).

With regard to the induction, the excellent results obtained by the combination of ATRA and idarubicin (AIDA), especially in terms of antileukemic efficacy (1% of resistance), do not support the introduction of substantial changes in this combination. However, given that most of the induction failures were caused by complications, especially of a hemorrhagic nature, and that these had a major impact in the hyperleukocytic forms and in patients older than 70 years of age, the induction was modified as follows:

1. Reduction of idarubicin dose in patients older than 70 years of age (three days instead of four);

2. Early administration of corticosteroid therapy in all patients as ATRA syndrome prophylaxis. A preliminary analysis of the Italian Group for Adult Hematologic Diseases (Gruppo Italiano Malattie Ematologiche dell'Adulto, GIMEMA) has shown that low dose prednisone use in a prophylactic manner appears to reduce the incidence and severity of the ATRA syndrome, which could also have a favorable impact on the hemorrhagic mortality (non-published data); and

3. Treatment of the hyperfibrinolysis with an antifibrinolytic agent (tranexamic acid). It has been recently reported that APL cells present abnormally high levels of annexins (especially annexin II), and that these levels may provide the fundamental mechanism for the hemorrhagic complications in APL by increasing the production of t-PA dependent plasmin. These findings provide new reasons for the introduction of tranexamic acid in the hemorrhagic prophylaxis of APL.

Detailed Description

Induction chemotherapy:

All-trans retinoic acid, will be administered by mouth (PO) from the first day at a dose of 45 mg/m²/day, fractionated into 2 doses.

In patients aged \< 20 years, the ATRA dose will be reduced to 25 mg/m²/day fractionated into 2 doses.

The treatment with ATRA will continue until a CR is achieved or for a maximum of 90 days in the case of persistence of atypical promyelocytes in the bone marrow.

Idarubicin, 12 mg/m² on days 2, 4, 6 and 8 of treatment by slow intravenous infusion (20 minutes).

In patients older than 70 years of age only 3 doses of idarubicin will be given on days 2, 4, and 6.

Supporting measures:

Prednisone, 0.5 mg/kg/day days 1 to 15. Tranexamic acid, 100 mg/kg/day in continuous perfusion, if platelets \< 50 x 10\^9/L or evident clinical-biological signs of coagulopathy. This treatment will be discontinued if the platelet counts are \> 50 x 10\^9/L.

Transfusion of platelet concentrates to keep up counts above 30 x 10\^9/L during the first 10 days and PRC to maintain hemoglobin levels greater than 9 g/dL.

Prophylactic heparin should not be used.

Study Timeline

• Study Start: 1999-03
• Study First Submitted: 2007-04-25
• Study First Submitted QC: 2007-04-25
• Study First Posted: 2007-04-27
• Primary Completion: 2007-08
• Study Completion: 2007-11
• Status Verified: 2008-03
• Last Update Submitted: 2008-03-27
• Last Update Posted: 2008-03-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

• Age <= 75 years
• ECOG = 3.
• Morphological diagnosis of M3 or M3v. Those cases without typical morphology but with PML-RARa rearrangement may also be included.
• Genetic diagnosis: t(15;17), PML-RARa rearrangement, monoclonal anti-PML positive. Obviously, the result of these tests may become available after having initiated the treatment based on a tentative morphological diagnosis. The presence of secondary cytogenetic changes associated with t(15;17) is not a reason for exclusion nor do they require a different therapeutic approach.

Exclusion Criteria

• Age > 75 years (the treatment with this protocol can be considered on an individual basis but these patients will be analysed separately)
• Absence of PML-RARa rearrangement.
• Prior antileukemic chemotherapy.
• Presence of an associated neoplasm.
• Presence of a severe psychiatric disease.
• HIV seropositivity.
• Contraindication for intensive chemotherapy, especially to anthracyclines.
• Serum creatinine = 2.5 mg/dL.
• Bilirubin, alkaline phosphatase, or SGOT > 3 times the upper normal limit
• Positive pregnancy test.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
To evaluate the efficacy of AIDA with a dose reduction in patients older than 70 years of age in the remission induction of APL	6 months
To evaluate the impact on morbidity and mortality of the prophylactic measures included in induction therapy (low dose prednisone and tranexamic acid)	1 year
To evaluate the toxicity of the induction, consolidation, and maintenance chemotherapy	2 years
To evaluate the impact on the event free survival, disease free survival and global survival in each relapse risk group	5 years
To evaluate the rates of molecular remission (PML/RARa negative by RT-PCR) in the successive therapeutic phases with special emphasis on patients with a higher risk for relapse	2 years

Trial Locations

Locations (2)

Basurtuko Ospitalea; 🇪🇸 Basurto, Spain

Hospital La Fe de Valencia; 🇪🇸 Valencia, Spain