A Remission Induction Therapy and Risk-oriented Postremission Strategy for Adult Acute Myelogenous Leukemia (AML)
Condition: Acute Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 3

Summary: 
      The study was set up to assess:

        1. Standard-dose versus high-dose remission induction therapy. A standard ICE chemotherapy
           vs sequential high-dose cytarabine, with appropriate supportive/prophylactic measures,
           followed by morphological, cytogenetic and molecular monitoring of remission.

        2. A risk-oriented postremission therapy: HR patients will be electively submitted to
           allogeneic stem cell transplantation (allo-SCT), whenever possible (related/unrelated
           donor/cord blood; ablative/non-ablative conditioning according to national and local
           protocols and guidelines). Provided sufficient blood stem cells were previously
           collected (>2x10e6/kg Cluster of Differentiation 34 cells), SR patients and HR patients
           excluded from allo-SCT and aged 65 years or less will be randomized to: myeloablative
           autologous blood stem cell transplantation vs non-myeloablative, multicycle, autologous
           blood stem cell-supported high-dose cytarabine-based therapy.

             -  HR/SR patients unable to be randomized because of inadequate blood stem cell yield
                will receive intermediate-dose consolidation; patients aged >65 years will be
                treated with age-adapted therapy.
    

Detailed description: 
      Adult AML is a difficult-to-treat illness because of both biological and therapeutic reasons.
      Most patients are aged >50 years and/or present with comorbid conditions and/or display
      high-risk AML-related features (poor risk, cytogenetics, prior myelodysplasia, secondary
      AML). This results in unsatisfactory response to conventional first-line therapy and makes it
      difficult to apply the most effective post-remission consolidation options (allo-SCT in
      younger patients with HR features, autologous blood stem cell transplantation and high-dose
      cytarabine-based therapy in the remainder).

      In a prior, phase II uncontrolled NILG trial (registered NCT 00400637),a two-step increasing
      intensity induction was adopted in order to optimize induction results. 51% of ICE-refractory
      cases responded to the salvage regimen, irrespective of risk class. In the same study, all HR
      patients had to be sent to allografting whereas SR patients (by clinico-cytogenetics
      criteria) were to receive up to three high-dose cytarabine-based cycles, each one supported
      by a fixed amount of autologous blood-stem cells (1-2x10e6/kg Cluster of Differentiation 34
      cells cells), to minimize the risks of high-dose cytarabine-related myelosuppression and to
      increase treatment intensity by reducing intercycle delays. DFS was 41% at 5 years, 58% in SR
      patients aged <55 years, 47% in SR patients aged >55 years, and 47% in HR patients with an
      identifiable donor. No treatment-related death occurred during the pancytopenic phase in 118
      patients receiving 299 blood stem-cell supported high-dose cytarabine cycles.

      These facts led to the present trial, in which 1) high-dose induction formerly used as
      salvage is directly compared to standard ICE chemotherapy and 2) the blood-stem cell
      supported multicycle high-dose cytarabine program is directly compared to a standard
      autologous blood stem cell transplantation.

      RANDOM 1 CYCLE 1

        -  Standard ICE (all drugs by IV route): idarubicin 12 mg/m2/d on dd 1-3, cytarabine 100
           mg/m2/bd on dd 1-7, etoposide 100 mg/m2/d on dd 1-5, G-CSF from d 11.

        -  High-dose sequential (all drugs by IV route): cytarabine 2* g/m2/bd on dd 1-2 and 8-9,
           idarubicin 18 mg/m2/d on dd 3 and 10, G-Colony Stimulating Factory (G-CSF) from d 11. *1
           g/m2 in frail patients aged 60-65 and in all those aged >65 years.

      CYCLE 2 (if CR achieved after cycle 1): Standard IC: idarubicin 10 mg/m2/d on dd 1-3,
      cytarabine 100 mg/m2/bd on dd 1-7, G-CSF.

      CYCLE 3: Intermediate-dose cytarabine 1 g/m2/bd on dd 1-4 followed by G-CSF and by stem cell
      collection (1-2x10e6/kg CD34+ cells in three separate bags)

      ALLO-SCT (Allogeneic Stem Cells Transplantation): All HR patients are eligible to allo-SCT as
      first therapeutic option. Allo-SCT procedure: any type according to local
      protocols/guidelines.

      RANDOM 2

      All SR patients and HR ones excluded from allo-SCT:

        -  Autologous blood stem cell transplantation after BU-CY2 regimen (Busulfan 0.8 mg/kg IV
           on dd -8 to -5, Cy 60 mg/kg/d on dd -4 to -3, autograft on d 0 (2-6x10e6/kg CD34+ cells)
           and G-CSF from d +1.

        -  Autologous blood stem cell supported multicycle therapy (x3, monthly) with cytarabine 2
           g/m2/bd on dd 1-5, idarubicin 8 mg/m2/d on dd 1-2, autograft on d 6 (1-2x10e6/kg CD34+
           cells) and G-CSF from d 8.

      Patients excluded from Random 2 as well as from allo-SCT receive attenuated, unsupported
      consolidation with 1-2 intermediate-dose cytarabine cycles. Patients aged >65 years are
      excluded from Random 2.

      RISK CLASSIFICATION Cytogenetic risk classification is based on MRC/ECOG-SWOG/CALGB criteria
      (cytogenetic risk classes: favorable, normal/intermediate, unfavorable, other, unknown);
      clinical risk classification is based on selected diagnostic criteria and response to
      chemotherapy cycle 1. The final risk model integrates cytogenetic and clinical risk to
      encompass two broad risk classes (SR and HR).

        -  Standard risk (SR): favorable cytogenetics, CR achieved after cycle 1; or
           normal/intermediate cytogenetics, CR achieved after cycle 1, lack of high-risk
           characteristics.

        -  High risk (HR): unfavorable cytogenetics; or normal/intermediate cytogenetics with any
           high-risk characteristic (WBC >50x10e9/l,FAB M0,6,7 or corresponding WHO, secondary AML,
           Myelodysplastic Syndrome (MDS)-associated AML, hepatosplenomegaly, FLT3 mutation, CR)
           not achieved with cycle, persistent cytogenetic abnormality at CR), or other/unknown
           cytogenetics.
    

Intervention name(s): cytosine arabinoside
Intervention type(s): Drug
Intervention description(s): Arm A: use of standard-dose cytosine arabinoside (100 mg/m2/bd iv. on days 1-7) in association with idarubicin and etoposide.
Arm B: use of high-dose cytosine arabinoside (1000-2000 mg/m2/bd according to age +/-65 years iv. on days 1-2 and 8-9) in association with idarubicin.
Other intervention name(s): Aracytin; Cytarabine; Cytosar
Intervention MeSH terms: Cytarabine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute myelogenous leukemia; Adult patients; Cytogenetic risk class; Clinico-cytogenetic risk model; Risk-oriented therapy