A Risk-Oriented Therapeutic Strategy for Adult Acute Myelogenous Leukemia
Condition: Acute Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Study type: Interventional
Phase: Phase 2

Summary: 
      The study was set up to assess:

        1. A two-step, increasing-intensity remission induction phase. A conventional chemotherapy
           course (ICE, plus G-CSF) was followed, in unresponsive patients, by sequential high-dose
           cytarabine (plus G-CSF), aiming to provide an early effective rescue to as many
           refractory cases as possible.

        2. A risk-oriented postremission consolidation phase. The objective was to adopt allogeneic
           stem cell transplantation (alloSCT) in high-risk (HR) cases, while standard-risk (SR)
           ones were consolidated with a multicycle high-dose cytarabine-containing program, which
           included the use of autologous stem cells plus G-CSF to limit drug-related toxicity and
           intercycle treatment delays.
    

Detailed description: 
      Adult AML is a difficult-to-treat illness because of both biological and therapeutic reasons.

      As to the first point, many patients are aged >50 years and/or present with significant
      comorbidity and/or AML-related risk features (poor risk cytogenetics, prior myelodysplasia,
      secondary AML).

      As to the second point, standard-type remission induction therapy is ineffective in 20% or
      more of the patients, whereas the application of the more effective postremission
      consolidation options (alloSCT, high-dose cytarabine courses) is often flawed by high-grade
      toxicity which can offset expected benefits, particularly in older age groups (>50-55 years),
      where therapy-related death rates are seen in 5%-10% of the cases (chemotherapy) or more
      (transplants).

      Against this background an explorative study was developed in which:

        1. All patients aged 16-65 years were considered eligible (acute promyelocytic leukemia
           excluded), including those with an antecedent diagnosis of myelodysplasia/hematological
           disorder and/or secondary AML. Both age and disease subtype selection criteria are
           broader than in most studies on adult AML, adhering more closely to the reported
           epidemiology of the disease.

        2. Remission induction was attempted with a two-step regimen, consisting of conventional
           chemotherapy (ICE: idarubicin/cytarabine/etoposide +G-CSF) followed, only in the case of
           failure to respond, by a sequential high dose-cytarabine cycle (cytarabine 3 g/m2/bd on
           days 1,2,8,9; idarubicin on days 3 and 10; G-GSF; cytarabine dosing 2 g/m2 in patients
           aged >55 years). It was hoped that this choice would optimize salvage rates (hence
           overall response rates), by allowing more patients (and more fit, uncomplicated ones) to
           reach the salvage phase, compared to a policy where salvage is usually given after two
           failed induction courses.

        3. Remission consolidation was risk-oriented, the risk being defined through a mixed
           clinico-cytogenetic model. Thus all patients entering CR after one/two cycles were
           stratified as HR or SR according to what is reported below. Once defined the risk class,
           therapy consisted of an alloSCT for HR patients, and of 3 consecutive monthly
           cytarabine-based cycles (2 g/m2/bd on days 1-5; idarubicin on days 1,2) in SR patients,
           each cycle being followed by the reinfusion of a limited amount of autologous blood stem
           cells (1-2x10e6/kg CD34+ cells) and G-CSF. Blood stem cells were collected following an
           early consolidation cycle with intermediate-dose cytarabine plus G-CSF. HR patients
           unable/unfit to proceed to alloSCT were offered instead the SR-type multicycle
           cytarabine consolidation, whereas all patients unable to mobilize autologous stem cells
           were treated with one/two intermediate-dose cytarabine course(s).

      HR: high-risk cytogenetics or intermediate-risk/normal cytogenetics with FLT3 mutation and/or
      any one or more additional clinical risk factor(s), i.e. total WBC >50x10e9/l, FAB subtype
      M0, M6 or M7, prior myelodysplasia or secondary AML,hepatosplenomegaly, late CR (cycle 2), or
      favorable cytogenetics with late CR (cycle 2).

      SR: favorable cytogenetics (without associated high-risk abnormalities and in CR after cycle
      1) or intermediate-risk/normal cytogenetics without FLT3 mutation and/or without any one
      additional clinical risk factor(s), i.e. total WBC >50x10e9/l, FAB subtype M0, M6 or M7,
      prior myelodysplasia or secondary AML,hepatosplenomegaly, late CR (cycle 2).
    

Intervention name(s): Two-step remission induction and risk-oriented consolidation
Intervention type(s): Behavioral
Allocation: Non-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