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 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.