Trial Information

Two-Step Remission Induction With Risk-Oriented Consolidation (High-Risk: Allogeneic Stem Cell Transplant; Standard-Risk: Multicycle High-Dose Cytarabine With Autologous Blood Stem Cell Support) for Adult Acute Myelogenous Leukemia

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).