Acute myeloid leukemia (AML) with FLT3 mutation accounts for 30% of patients and is associated with a poor prognosis. Because of the FLT3 mutation, a tyrosine kinase inhibitor, midostaurin (MIDO), is added to the standard treatment with daunorubicin and cytarabine, from D8 to D21 of induction and of each consolidation cycle, followed by one year of maintenance. Venetoclax (VEN), a BCL2 inhibitor, has revolutionized the management of AML patients ineligible for intensive chemotherapy, in combination with azacitidine or cytarabine. The investigators hypothesize that a four-drug induction regimen (daunorubicin+cytarabine+MIDO+VEN) will increase complete remission (CR) rate without measurable residual disease (MRD) and improve event free survival (EFS), relapse free survival (RFS) and overall survival (OS) of this subgroup of patients with unmet medical need.
Age ≥18 years and ≤70 years
Newly diagnosed AML according to World Health Organization (WHO) 2022 classification
Documented FLT3 gene mutation (-TKD D835 or I836 or -ITD or both) FLT3-ITD is assessed by DNA fragment analysis. Positivity is defined as an ITD/wt ratio of ≥ 0.05 (5%).
Patient must be eligible for intensive chemotherapy.
Prior treatment for AML or myelodysplastic (MDS) phase.
Prior exposure to VEN or other BCL2 inhibitors
AML secondary to prior hematological disorders, including myelodysplastic syndrome, myeloproliferative disorders and/or therapy-related AML.
Acute promyelocytic leukemia, CBF-AML, Phi+ AML
Single group
Venetoclax in association with 3+7 and midostaurin
Drug(1) induction with daunorubicin 60 mg/m²/day for 3 days, cytarabine 200 mg/m²/day for 7 days and MIDO 50 mg x 2/day from D8 to D21, (2) consolidation with 3 courses of intermediate dose cytarabine 1-1.5 gr/m² x 2/day at D1, D2 and D3 and MIDO 50 mg x 2/day from D8 to D21 in 35-day cycles, and (3) a maintenance with MIDO 50 mg x 2/day from D1 to D28 in 28-day cycles for 12 cycles. VEN is a highly potent BCL-2 inhibitor, synergistic with cytarabine, anthracyclines, and tyrosine kinase inhibitors. In the current study we aim at harnessing this synergistic effect with standard chemotherapy (cytarabine, anthracyclines) and tyrosine kinase inhibitor (MIDO) during induction, consolidation and maintenance. Our strategy aims at determining the best schedule of combination during induction chemotherapy whereas we do not foresee specific safety issues during consolidation and maintenance strategy
Phase 1: Maximum tolerated schedule (MTS) of VEN in combination with 3+7+MIDO to define the recommended phase 2 schedule (RP2S).
Phase 2: Proportion of participants with complete remission (CR)/CR with incomplete hematologic recovery (CRi) without measurable residual disease (MRD)
Measured by multiparameter flow cytometry (MFC) according to European Leukemia Net (ELN) 2022
Phase 1:Number of participants with Dose Limiting Toxicities (DLTs), Serious Adverse Events (SAEs), and Adverse Events (AEs) leading to treatment discontinuation
Number of participants with Dose Limiting Toxicities (DLTs), Serious Adverse Events (SAEs), and Adverse Events (AEs) leading to treatment discontinuation, defined according to the NCI CTCAE v5
Phase 1-2: Area under the concentration-time curve over a 12-hour dosing interval (- AUC 0-12h)
Phase 1-2: Peak concentration (Cmax)
Phase 1-2: Time to reach peak concentration (Tmax)
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