Inhibition of FLT3 in AML: a focus on sorafenib

Abstract

FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma. Sorafenib monotherapy or in combination with conventional chemotherapy, has been evaluated in various settings in AML, including front-line, relapsed or refractory disease including post-allograft failures and, more recently, as post-transplant maintenance therapy. Encouraging data have emerged with several other agents like lestaurtinib, midostaurin, crenolanib, gilteritinib and quizartinib. Although transient responses to FLT3 inhibitors are often observed in case of disease relapse, the most promising approach is the use of FLT3 inhibitors either in combination with induction chemotherapy or as consolidation/maintenance therapy after allogeneic hematopoietic cell transplantation. In this review, we summarize the clinical data on sorafenib and other FLT3 inhibitors in AML.

Sequential Conditioning with Thiotepa in T Cell- Replete Hematopoietic Stem Cell Transplantation for the Treatment of Refractory Hematologic Malignancies: Comparison with Matched Related, Haplo-Mismatched, and Unrelated Donors

“…This approach in association with pDLI could enhance the graftversus-leukemia effect and is also being evaluated in a prospective trial (NCT 01541280) in high-risk AML patients. Preliminary data and a recent report case report suggest that FLT3 TKIs also could be effective for patients with FLT3 internal tandem duplication in the post-transplantation setting [46][47][48]. Because of the retrospective nature of this study, immunomodulation combining pDLI with early administration of preventive azacytidine or sorafenib was not proposed for all patients.…”

Sorafenib improves survival of FLT3-mutated acute myeloid leukemia in relapse after allogeneic stem cell transplantation: a report of the EBMT Acute Leukemia Working Party

“…FLT3 tyrosine kinase inhibitors (TKI) were tested in FLT3-ITD AML. 3 Midostaurin improves overall survival (OS) when combined with chemotherapy, which led to its approval. 4 Because of its availability, sorafenib has been studied in various settings in FLT3-ITD AML, including first-line therapy, post-transplant maintenance therapy, or treatment of relapse, either alone or combined with chemotherapy or hypomethylating agents.…”

“…4 Because of its availability, sorafenib has been studied in various settings in FLT3-ITD AML, including first-line therapy, post-transplant maintenance therapy, or treatment of relapse, either alone or combined with chemotherapy or hypomethylating agents. 3,[5][6][7][8][9][10] Gilteritinib was recently approved for relapsed/refractory FLT3-ITD AML and is currently being tested (BMT-CTN 1506; clinicaltrials.gov identifer: 02997202) as post-transplant maintenance. Conflicting results were reported on the use of sorafenib or other FLT3 inhibitors, either alone or combined with donor lymphocyte infusion (DLI), chemotherapy, or azacytidine, for patients in relapse after allo-SCT.…”

An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies

“…For instance, patients harboring a long insertion in the FLT3 gene were found to have decreased overall survival . Several small‐molecule FLT3 tyrosine kinase inhibitors are being evaluated for this mutation . Patients with MET exon 14 skipping (a form of long deletion) can potentially benefit from MET inhibitor treatment , and thus its successful detection becomes a critical step in clinical practice.…”