FLT3 inhibitors in acute myeloid leukemia: Choosing the best when the optimal does not exist

Abstract

Despite significant advances in deciphering the molecular and cytogenetic pathways governing acute myeloid leukemia, improvements in treatment strategies and clinical outcomes have been limited. The discovery of FLT3 pathway and its potential role in leukemogenesis has generated excitement in the field and has provided a potential target for drug development. Despite setbacks encountered with first-generation inhibitors, we are witnessing an outbreak of novel agents with potent activity and improved pharmacodynamics which continue to generate promising results. The disease, however, remains a challenge to both patients and physicians with rapid emergence of resistance and subsequent treatment failure. Multiple unanswered questions remain as to which are the optimal FLT3-inhibitors and which strategies and combinations are likely to overcome resistance. This review revisits the development of FLT3-inhibitors, the pathways incriminated in their failure and summarizes available molecularly-designed strategies to design better clinical trials.

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

“…Constitutive activation of FLT3 arising from ITD activates downstream signals including PI3K/AKT, STAT5, and Ras/MEK/ERK (Mizuki et al, 2000;Martelli et al, 2006;Zhang et al, 2016). FLT3 inhibitors have been shown to be effective in FLT3/ITD AML (Assi & Ravandi, 2018). However, tyrosine kinase domain (TKD) mutations in FLT3 confer drug resistance and are an important cause of treatment failure (Man et al, 2012;Smith et al, 2017).…”

The Time Has Come for Targeted Therapies for AML: Lights and Shadows

“…Immune checkpoint inhibitors have been widely studied in solid tumors, and their migration to hematological malignancies has become more prominent since the success in Hodgkin’s lymphoma. So far, clinical studies on immune checkpoint inhibitors (nivolumab, pembrolizumab, and ipilimumab) have provided limited results in AML [ 100 – 103 ]. However, immune checkpoint inhibitors given in association with HMAs could represent an interesting strategy to enhance the activity of immunotherapies.…”

The Progress of Next Generation Sequencing in the Assessment of Myeloid Malignancies

“…However, the prognostic effect of FLT3-TKD remains controversial (27). In 2017, the FDA approved treatment with midostaurin for newly diagnosed patients with FLT3-mutated AML due to the observation of a significant beneficial outcome (28,29). In MDS, FLT3 mutations are observed in high-risk subgroups and are associated with complex karyotype (30,31).…”