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

March 27, 2008 updated by: PETHEMA Foundation

Treatment of Acute Promyelocytic Leukemia: Remission Induction With ATRA + Idarubicin (AIDA) Risk Adapted Intensity of Consolidation and Addition of ATRA Maintenance With ATRA + Methotrexate + Mercaptopurine Salvage Therapy for Molecular and Haematological Relapses

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Basurto, Spain
        • Basurtuko Ospitalea
      • Valencia, Spain
        • Hospital La Fe de Valencia

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

No older than 75 years (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 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: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To evaluate the efficacy of AIDA with a dose reduction in patients older than 70 years of age in the remission induction of APL
Time Frame: 6 months
6 months
To evaluate the impact on morbidity and mortality of the prophylactic measures included in induction therapy (low dose prednisone and tranexamic acid)
Time Frame: 1 year
1 year
To evaluate the toxicity of the induction, consolidation, and maintenance chemotherapy
Time Frame: 2 years
2 years
To evaluate the impact on the event free survival, disease free survival and global survival in each relapse risk group
Time Frame: 5 years
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
Time Frame: 2 years
2 years

Collaborators and Investigators

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

Sponsor

PETHEMA Foundation

Investigators

  • Study Chair: Sanz Miguel Angel, Dr, Hospital La Fe Valencia

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

Helpful Links

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

March 1, 1999

Primary Completion (ACTUAL)

August 1, 2007

Study Completion (ACTUAL)

November 1, 2007

Study Registration Dates

First Submitted

April 25, 2007

First Submitted That Met QC Criteria

April 25, 2007

First Posted (ESTIMATE)

April 27, 2007

Study Record Updates

Last Update Posted (ESTIMATE)

March 31, 2008

Last Update Submitted That Met QC Criteria

March 27, 2008

Last Verified

March 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pethema LPA-99 protocol

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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