AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

Abstract

Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of their safer profile and fewer side effects. However, the resistance phenomenon of leukemic cells necessitates the search for drugs that would help to overcome the resistance and improve treatment outcomes. One of the resistance mechanisms takes place through the upregulation of MCL-1 and BCL-XL, preventing BAX/BAK-driven MOMP (mitochondrial outer membrane permeabilization), thus stopping the apoptosis process. Possible partners for BCL-2 inhibitors may include inhibitors from the FLT3i (FMS-like tyrosine kinase-3 inhibitor) group. They resensitize cancer cells through the downregulation of MCL-1 expression in the FLT3 mutated cells, resulting in the stronger efficacy of BCL-2 inhibitors. Also, they provide an additional pathway for targeting the clonal cell. Both preclinical and clinical data suggest that the combination might show a synergistic effect and improve patients’ outcomes. The aim of this review is to determine whether the combination of venetoclax and FLT3 inhibitors can impact the therapeutic approaches and what other agents they can be combined with.

Targeting BMAL1 reverse drug resistance of acute myeloid leukemia cells and promoting ferroptosis through HMGB1-GPX4 signaling pathway

“…The combination of venetoclax with other drugs, such as azacitidine and decitabine, has been shown to signi cantly improve the rate of complete remission and patient survival. However, when used as a monotherapy, its e cacy is limited (Milnerowicz et al 2023). In addition, a signi cant proportion of patients exhibit primary or acquired resistance to venetoclax (Dhakal et al 2023).…”

Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway

“…The combination of venetoclax with other drugs, such as azacitidine and decitabine, has been shown to significantly improve the rate of complete remission and patient survival. However, when used as a monotherapy, its efficacy is limited (Milnerowicz et al 2023 ). In addition, a significant proportion of patients exhibit primary or acquired resistance to venetoclax (Dhakal et al 2023 ).…”

CXCR4-Mediated Codelivery of FLT3 and BCL-2 Inhibitors for Enhanced Targeted Combination Therapy of FLT3-ITD Acute Myeloid Leukemia

“…BCL-2 is an antiapoptotic protein that is overexpressed in AML cells and promotes leukemic blast survival through regulation of the mitochondrial apoptotic pathway . Venetoclax (VEN), a highly selective BCL-2 inhibitor, in combination with hypomethylating agents or low-dose cytarabine has been approved as a standard option for newly diagnosed AML patients who are unfit for intensive chemotherapy. − Recent studies have indicated the synergistic effect of VEN in combination with FLT3 inhibitors in FLT3-ITD AML models, , likely due to the simultaneous downregulation of MCL-1 and BCL-XL antiapoptotic proteins, which can facilitate VEN resistance. , Moreover, early phase clinical trials have shown encouraging response rates and survival benefits in FLT3 mutant AML patients after combination therapy with VEN and FLT3 inhibitors. − Nevertheless, this combination is associated with poor bioavailability, dose-dependent myelosuppression, overlapping systemic toxicity, and drug resistance, limiting its clinical benefits.…”