Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Standard gilteritinib therapy for relapsed/refractory FLT3-mutated acute myeloid leukemia (AML) has limited efficacy.
• Preclinical studies suggest synergistic activity between gilteritinib and venetoclax in FLT3-mutated AML models.

Purpose of the Study:

• To evaluate the safety and efficacy of combining venetoclax and gilteritinib in relapsed/refractory AML patients.
• To determine the recommended Phase II dose (RP2D) for this combination therapy.
• To assess the modified composite complete response (mCRc) rate in FLT3-mutated AML patients.

Main Methods:

• A Phase Ib, open-label, dose-escalation/expansion study (NCT03625505) enrolled patients with relapsed/refractory AML.
• Patients received oral venetoclax (400 mg daily) plus oral gilteritinib (80 mg or 120 mg daily).
• Primary objectives included safety, RP2D identification, and mCRc rate using ADMIRAL criteria.

Main Results:

• The RP2D was determined to be 400 mg venetoclax and 120 mg gilteritinib daily.
• The mCRc rate in FLT3-mutated AML patients was 75%, with similar rates in those with or without prior FLT3 inhibitor therapy.
• Common adverse events included Grade 3/4 cytopenias (80%), necessitating dose interruptions in 51% for venetoclax and 48% for gilteritinib.

Conclusions:

• The combination of venetoclax and gilteritinib demonstrated high mCRc and FLT3 molecular response rates in relapsed/refractory AML.
• Efficacy was consistent regardless of prior FLT3 inhibitor exposure.
• Myelosuppression management required dose interruptions, highlighting the need for careful monitoring.