Trial Information

A Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML)

Core binding factor (CBF) acute myeloid leukemias (AML) include AMLs carrying the t(8;21)
translocation as well as AMLs carrying either the inversion of chromosome 16 or
translocation t(16;16). CBF-AMLs are characterized by their high sensitivity to standard
chemotherapeutical agents, especially to cytarabine when administered as high-dose bolus
infusions, and thus by a relative good prognosis. However, relapse rates are still comprised
between 30 and 50% in these patients, even if overall survival may reach approximately 65%
due to the potential salvage of late relapses. Initial high white blood cell count,
activating mutations of cKit, Ras, and FLT3 genes, and persistence of high minimal residual
disease (MRD) levels (as evidenced by AML1-ETO or CBFb-MYH11 specific RQ-PCR tools) are the
main bad-prognostic factors in patients with CBF-AML.

This project includes a new single French protocol to treat patients with CBF-AML who
represent approximately 15% of all AML patients. This common protocol has been elaborated by
the two main French cooperative groups for adult AML (ALFA and GOELAMS). In addition to a
unique specific therapeutical strategy, this protocol includes the biological
characterization of the heterogeneity of these diseases (gene mutation and transcription
profiles), as well as a centralized MRD monitoring and centralized evaluation of
pharmacogenetic polymorphisms. This project which is well-positioned in the international
competition, will use many platforms of the POLECANCER with the following objectives : 1) to
improve the results of the treatment of CBF-AML patients; 2) to organize a French clinical
and biological network on CBF-AML with the aim to test new targeted therapeutical agents
(tyrosine kinase and/or farnesyl transferase inhibitors) in the next future.

TREATMENT DESIGN Induction course Systematic timed-sequential induction (arm A)
DAUNORUBICINE (DNR): 60 mg/m2/day IV (30 min), Day 1, 2, and 3 CYTARABINE (AraC): 500
mg/m2/day Continuous infusion, Day 1 to 3 DAUNORUBICINE (DNR): 35 mg/m2/day IV (30 min), Day
8 and 9 CYTARABINE (AraC): 1 gr/m2/12 h IV (2h), Day 8, 9, and 10 Response-adapted
timed-sequential induction (arm G) DAUNORUBICINE (DNR): 60 mg/m2/dayIV (30 min), Day 1, 2,
and 3 CYTARABINE (AraC): 200 mg/m2/dayContinuous infusion, Day 1 to 7

Peripheral blood and bone marrow evaluation at Day 15. The following second induction course
will be administered in patients with persistent marrow disease at Day 15 :

DAUNORUBICINE (DNR): 35 mg/m2/day IV (30 min), Day 16 and 17 CYTARABINE (AraC)1 gr/m2/12 h
IV (2h), Day 16, 17, and 18 Persistent marrow disease at Day 15 is defined by more than 10%
leukemic blasts in a non aplastic or non very hypoplastic bone marrow aspiration sample.

Salvage course In patients not reaching CR after the first induction course (either SI or
TSI), a salvage course will be administered. Salvage therapy should not be initiated before
Day 35 of arm A and Day 42 of arm G.

CYTARABINE (AraC) :3 gr/m2/12h IV (2h), Day 1, 3, 5, and 7 AMSACRINE : 100 mg/m2/day IV (30
min), Day 5 to 7 G-CSF lenograstim : from Day 8 until myeloid recovery (> 500 PMN/µL)

Consolidation cycles Three monthly cycles of consolidation will be administered in all
patients reaching hematological CR after induction or induction + salvage.

CYTARABINE (AraC): 3 g/m2/12h IV (2h), Day 1, 3, and 5 G-CSF lenograstim : from Day 8 until
myeloid recovery (> 500 PMN/µL)