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