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

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Brief Title

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

Official Title

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

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 Phase

Phase 4

Study Type

Interventional


Primary Outcome

To evaluate the efficacy of AIDA with a dose reduction in patients older than 70 years of age in the remission induction of APL


Condition

Acute Promyelocytic Leukemia

Intervention

AIDA


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug


Start Date

March 1999

Completion Date

November 2007

Primary Completion Date

August 2007

Eligibility Criteria

        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.
      

Gender

All

Ages

N/A - 75 Years

Accepts Healthy Volunteers

No

Contacts

Sanz Miguel Angel, Dr, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT00465933

Organization ID

Pethema LPA-99 protocol



Study Sponsor

PETHEMA Foundation


Study Sponsor

Sanz Miguel Angel, Dr, Study Chair, HOSPITAL LA FE VALENCIA


Verification Date

March 2008