Venetoclax in Association With 3+7 and Midostaurin in FLT3-mutated Acute Myeloid Leukemia

Screening of 226 clinical trials on ClinTrial.gov showed 26 studies evaluating intensive chemotherapy (daunorubicin+cytarabine) and VEN but none in combination with MIDO even though 30% of patients eligible for intensive chemotherapy do receive such a regimen. Intensive chemotherapy and MIDO showed a significant median overall survival improvement but a moderate increase of patients still alive at 3 years, around an additional 10% 1. Moreover, MIDO does not allow an increase in proportion of patients in first complete remission (CR1) or CR with incomplete hematologic recovery (CRi1) after the 1st induction course. Another study with a second-generation tyrosine kinase inhibitor, quizartinib (QuANTUM-First) showed that among patients with CR1/CRi1, 42% had a measurable residual disease (MRD) <10-4 in quizartinib arm versus 38% in placebo arm, despite, here again, a significant median overall survival improvement 2. These data show that tyrosine kinase inhibitors do not increase the rate of complete remission (CR) without MRD, explaining probably the moderate improvement of definitive cure rate. The investigators hypothesize that adding VEN to this standard treatment will increase complete remission rate without MRD and improve OS of patients with FLT3-mutated AML. Two clinical trials evaluated VEN in AML patients eligible to intensive chemotherapy and showed high levels of complete remission without MRD and a manageable toxicity profile, related to VEN start date and duration of exposure 3,4. In the current study, the investigators propose the following schedule to find the best treatment sequence while preventing the risk of myelosuppression, based on available data from the two clinical trials previously presented: In schedule A, VEN will be used from D8 to D14 to harness the synergy between FLT3 and BCL2 inhibition; in schedule B, VEN will be used from D4 to D10 to harness the synergy between chemotherapy and BCL2 inhibition then between FLT3 and BCL2 inhibition. If previous schedules A and B are safe, the investigators propose to prolong VEN exposure to 10 days allowing longer association between MIDO and VEN with a schedule C with VEN from D8 to D17 and finally a schedule D with VEN from D4 to D13. Follow-up will include up to 3 consolidation courses with intermediate dose cytarabine and VEN according to previous French phase 2 clinical trial COVENIDAC 5 and MIDO in this label from D8 to D21. Finally, patients will receive 12 cycles maintenance by MIDO with VEN D1-D14 in 28-day cycles. Patients will undergo allogeneic stem cell transplantation (HSCT) according to standard indications and procedures.

Main inclusion criteria:

• 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%).

FLT3-TKD D835 or I836 is assessed by NGS. Positivity is defined as a VAF > 5%.

• Patient must be eligible for intensive chemotherapy.

Main exclusion criteria:

• 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
• Significant active cardiac disease within 6 months prior to the start of study treatment or QTc interval using Fridericia's formula (QTcF) ≥ 450 msec.
• Cardiac ejection fraction <45%