Abstract
The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.
Highlights
Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, United States
An next generation sequencing (NGS)-based Fms-like tyrosine kinase 3 (FLT3) assay is commercially available and is currently used in in an ongoing trial of gilteritinib maintenance therapy following hematopoietic cell transplantation (HCT) (NCT02997202). Both polymerase chain reaction (PCR) and NGS-based assays are supported by the current National Comprehensive Cancer Network (NCCN) guidelines [8]; European LeukemiaNet (ELN) risk stratification is dependent upon FLT3 allele ratio (AR), which can only be determined by PCR
Multiple questions remain, including: How can we identify the patients for which FLT3 inhibitor maintenance is most beneficial? In SORMAIN, the strongest benefit from sorafenib maintenance was in patients with undetectable minimal residual disease (MRD) pre-HCT and detectable MRD post-HCT [133]
Summary
Given the prognostic and treatment implications, testing for FLT3-ITD in patients with newly diagnosed AML is recommended by both ELN and National Comprehensive Cancer Network (NCCN) guidelines [8, 11]. Due to competition from the FLT3-WT allele, the sensitivity of standard PCR-based assays may be lower than NGS-based methods, this can be overcome using patient-specific PCR primers [13]. An NGS-based FLT3 assay is commercially available and is currently used in in an ongoing trial of gilteritinib maintenance therapy following hematopoietic cell transplantation (HCT) (NCT02997202). Both PCR and NGS-based assays are supported by the current NCCN guidelines [8]; ELN risk stratification is dependent upon FLT3 AR, which can only be determined by PCR. Current usage and ongoing trials of established FLT3 inhibitors in newly diagnosed and relapsed/refractor (R/R) AML are summarized in Tables 2 and 3, respectively. The antileukemic effects of these non-specific inhibitors likely derive from
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