Trial Information

Phase III Trial in AML Comparing Standard-dose vs High-dose Remission Induction and, Within a Risk-oriented Postremission Strategy, Autologous Blood Stem Cell Transplantation vs Blood Stem Cell-supported Multicycle High-dose Program

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 stenm 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
CD34+ 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-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: 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, MDS-associated AML, hepatosplenomegaly, FLT3 mutation, CR) not achieved with
cycle, persistent cytogenetic abnormality at CR), or other/unknown cytogenetics.