FLT3 inhibitors(Nanjing University of Chinese Medicine)

Addition of midostaurin to standard “7+3” (cytarabine and anthracycline) significantly prolongs overall and event-free survival. At University of Washington/Fred Hutchinson Cancer Center (UW/FHCC), the standard regimen for newly diagnosed (ND) and relapsed/refractory (R/R) AML is cladribine, high-dose cytarabine, GCSF, and mitoxantrone (CLAG-M); midostaurin is added if FLT3-mutated. There is limited data on the use of FLT3-inhibitors with high-dose cytarabine regimens in AML.

This study aimed to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M versus midostaurin plus 7+3 in FLT3-mutated AML patients.

This is a retrospective, multicenter review including FLT3-mutated AML patients undergoing (re)induction chemotherapy with either CLAG-M or 7+3 at UW/FHCC, Oregon Health & Science University, and Swedish Cancer Institute. The primary outcome was incidence of adverse events. Secondary outcomes included disease response per ELN2017 criteria and 28-day mortality. Excluded were patients on clinical trials or who started midostaurin 30 days after chemotherapy.

Eighty patients treated from September 2016 to December 2023 were included; 36 patients received CLAG-M, and 44 patients 7+3. Baseline characteristics were similar across all institutions. Adverse event rates were similar between the 2 cohorts, except diarrhea and bleeding which were more common in the 7+3 cohort. The rate of complete remission (CR) plus CR with incomplete blood count recovery did not significantly differ between the 2 cohorts: CLAG-M, 86% versus 7+3, 70% ( P = 0.11).

The toxicity profile of CLAG-M combined with midostaurin is comparable with the combination of 7+3 with midostaurin, and induces high remissions rates in adults with FLT3-mutated AML.

Acute Myeloid Leukemia (AML) is a hematological malignancy known for its aggressive nature, resistance to therapies, and high relapse rates. Approximately onethird of AML cases involve mutations in the FLT3 gene, making it a pivotal target for treatment strategies. Early FLT3 inhibitors demonstrated efficacy initially, yet subsequent issues with drug resistance and disease recurrence underscored the multifaceted challenges of AML management. Immunotherapy and combination therapies are effective strategies to overcome resistance, but there are limitations, such as toxic side effects. In contrast, FLT3 dual-target inhibitors exhibit excellent anti-tumor effects, while being safer and more controllable. Several of these inhibitors have progressed to clinical trials, underscoring their potential in advancing therapeutic options for AML. This review explores the synergistic potential of targeting FLT3 kinase in conjunction with other anti-cancer mechanisms and provides an overview of recent advancements in FLT3 dual-target inhibitors over the past decade.