FLAG/IDA/Venetoclax Induction in Patients with FLT3+ Acute Myeloid Leukemia

Introduction

Induction chemotherapy (IC) in acute myeloid leukemia (AML) in younger and fit patients has combined an anthracycline (i.e., daunorubicin or idarubicin) with the antimetabolite, cytarabine. This is termed the 7 + 3 regimen. Response rates with this standard regimen approach 70-80%, but 30-40% of patients eventually relapse. Patients with FLT3 mutations have had poorer outcomes, however, the RATIFY trial, and more recently the QuANTUM-FIRST study, have shown that adding a targeted FLT3 inhibitor to the standard back bone of the 7+ 3 regimen improved response rates and overall survival. MD Anderson published a phase II study in which venetoclax was added to the standard anthracycline/cytarabine induction regimen of fludarabine, cytarabine, G-CSF, and idarubicin (FLAG-IDA/venetoclax). Results from this study showed an impressive 96% response rate for newly diagnosed (ND) AML patients. Based on these results, Fox Chase Cancer Center adopted this approach. Although this phase II study did include patients with FLT3, no studies have looked at outcomes with this protocol in patients with FLT3 mutations.

Methods

Patients between 2020 and 2024 who were treated with induction FLAG-IDA/venetoclax for AML, based on ELN 2022 criteria, were retrospective reviewed. Patients that had FLT3-ITD or TKD mutations were included in this review. All patients after induction either proceeded directly to allogenic stem cell transplant or proceeded to receive consolidation that included a FLT3 inhibitor.

Results

Overall, 9 patients were included in this study. Induction with FLAG-IDA/venetoclax lead to a 100% (N = 9/9) complete response rate on recovery marrow results per IWG criteria and FLT3 PCR negativity. MRD testing was not performed. There were no patient deaths during induction. Twenty-two percent (N=2/9) of patients relapsed despite receiving FLT3 directed therapy during the consolidation phase of their treatment. Data on long-term survival will require longer followup however thus far only 2 patients have had relapse. All patients were able to complete their induction course with no grade 3 or 4 cardiac events.

Conclusions

Based on our small review, FLAG-IDA/venetoclax appears to be an effective induction therapy for FLT3+ AML. Although the current standard of care for FLT3+ AML should include targeted therapy with FLT3 directed agents, this review shows it is not necessarily needed with induction. This is not surprising considering the combination of hypomethylating agents and venetoclax also showed excellent response rates. Adding FLT3+ inhibition to FLAG-IDA/venetoclax would be a promising study to explore in a phase I setting.

Abdelmessieh:Abbive: Consultancy; Sobi: Consultancy. Varshavsky-Yanovsky:Janssen: Consultancy, Other: Board of Directors/Advisory Committee; Pfizer: Consultancy; BMS: Consultancy. Fung:sobi: Consultancy, Speakers Bureau; Astra-Zeneca: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bioline: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Johnson and Johnson: Consultancy, Speakers Bureau.