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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00465933
Recruitment Status : Completed
First Posted : April 27, 2007
Last Update Posted : March 31, 2008
Information provided by:
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.

Condition or disease Intervention/treatment Phase
Acute Promyelocytic Leukemia Drug: AIDA Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : March 1999
Actual Primary Completion Date : August 2007
Actual Study Completion Date : November 2007

Primary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. To evaluate the toxicity of the induction, consolidation, and maintenance chemotherapy [ Time Frame: 2 years ]
  4. 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. 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 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00465933

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Basurtuko Ospitalea
Basurto, Spain
Hospital La Fe de Valencia
Valencia, Spain
Sponsors and Collaborators
PETHEMA Foundation
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Study Chair: Sanz Miguel Angel, Dr HOSPITAL LA FE VALENCIA
Additional Information:
Slack JL: Recent advances in the biology and treatment of acute promyelocytic leukemia. Educational Book of the 34th Meeting of the American Society of Clinical Oncology, Los Angeles, CA 1998, p.54-65

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Responsible Party: pethema Identifier: NCT00465933    
Other Study ID Numbers: Pethema LPA-99 protocol
First Posted: April 27, 2007    Key Record Dates
Last Update Posted: March 31, 2008
Last Verified: March 2008
Keywords provided by PETHEMA Foundation:
Acute Promyelocytic Leukemia
Additional relevant MeSH terms:
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Leukemia, Promyelocytic, Acute
Neoplasms by Histologic Type
Leukemia, Myeloid, Acute
Leukemia, Myeloid