Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation

Abstract

IntroductionAcute myeloid leukemia (AML) refers to a genetically and biologically heterogeneous group of diseases characterized by an abnormal increase of myeloblasts in the bone marrow (BM) and peripheral blood (PB) circulation. Chemotherapy and hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment, but these modalities have reached an impasse with an overall cure rate of only 30%-40%. 1 An attractive strategy is to target specific genetic and biochemical alterations in AML, thereby providing an alternative treatment modality that may improve patient outcome. 2,3 FLT3 (fms-like tyrosine kinase-3) is a receptor tyrosine kinase (RTK) that is highly expressed in hematopoietic stem and progenitor cells. It includes an extracellular domain (ECD), a transmembrane domain (TMD), a juxtamembrane domain (JMD), and 2 tyrosine kinase domains (TKDs) separated by a kinase insert. 4 On binding with FLT3 ligand secreted by BM stromal cells, FLT3 undergoes dimerization, phosphorylation, and TKD activation. The FLT3 gene is mutated in approximately 30% of AMLs, particularly those with normal karyotypes, t(6;9), t(15;17), or trisomy 8. 5,6 The most common mutation is an internal tandem duplication (ITD) up to a few hundred base-pairs within the JMD. Single-base mutations have also been described, most commonly resulting in a substitution of aspartic acid with tyrosine or less commonly a histidine at residue 835 in the TKD. 7,8 At a molecular level, these mutations result in constitutive activation of the FLT3 receptor and hence downstream PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK/ STAT pathways. 9,10 The biologic consequences are enhanced proliferation and reduced apoptosis of the myeloblasts, which contribute to leukemogenesis. [11][12][13][14][15] Patients with FLT3-ITD respond poorly to conventional chemotherapy and have an inferior prognosis, 16,17 particularly in those with a high FLT3-ITD ϩ cell burden, 18 long ITD sequences, 19 and multiple FLT3-ITD ϩ subclones, 20 underscoring a pathogenetic role of FLT3-ITD in human AML. In mice, knock-in of a heterozygous FLT3-ITD resulted in a preleukemic model of a myeloproliferative disease, providing an in vivo demonstration of the important role of FLT3 in leukemia initiation. 21 We 22 and others 23,24 have shown that the FLT3-ITD allele can be found in leukemia initiating cells (LICs), as distinguished by their capability of regenerating leukemic progeny in transplanted immunodeficient mice. Therefore, targeting FLT3-ITD might provide a novel approach to therapeutic intervention.Several clinical trials on multi-TK inhibitors with different FLT3 specificities and in vitro efficacies have been reported, including the use of midostaurin, 25 lestautinib, 26 tandutinib, 27 sunitinib, 28 and sorafenib. 29 In most studies, clinical efficacy was restricted to FLT3-ITD ϩ AML and correlated with inactivation of FLT3 phosphorylation. 25,[30][31][32] Complete remission was rare and limited to anecdotal reports in relapsed AML after allogeneic HSCT. 33 Furthermore, after ...

Crenolanib is a selective type I pan-FLT3 inhibitor

“…All clinically active FLT3 TKIs [quizartinib (10,11), ponatinib (24), and sorafenib (15)] are multikinase inhibitors that also inhibit KIT. Because crenolanib has been reported to bind selectively to class III RTKs (18), we assessed its activity in a cell line that harbors an activating KIT D816 mutation (analogous to D835 in FLT3).…”

The Successful Complete Remission Induction by Sorafenib Monotherapy in a FLT3-D835Y-Positive Patient with Refractory Acute Monocytic Leukemia

“…Moreover, acquisition of secondary FLT3-TKD mutations, mainly at D835 (D835F/H/V/Y), are recognized as the major mechanisms of resistance of AML patients with FLT3-ITD to sorafenib. [10,11] It has been reported that sorafenib induced death of cells that expressed the FLT3-ITD or FLT3-D835G but not cells that expressed the FLT3-D835Y point mutant or wild-type FLT3 in vitro. [12] However, we report here the successful complete remission induction by sorafenib monotherapy in a FLT3-D835Y-positive patient with refractory AML-M5 followed by allogeneic stem cell transplantation.…”

“…[6][7][8][9] Most AML patients with FLT3-ITD show an initial clinical response to sorafenib, followed by the development of resistance within a few months to a year of treatment. [10,11] One of the most common mechanisms of resistance to FLT3 inhibitors is the acquisition of secondary FLT3-TKD mutations, especially amino acid exchanges at residue D835 (D835F/H/V/Y). [10,11] Up to now, the effect of sorafenib in AML patients with FLT3-TKD has never been widely investigated.…”

“…[10,11] One of the most common mechanisms of resistance to FLT3 inhibitors is the acquisition of secondary FLT3-TKD mutations, especially amino acid exchanges at residue D835 (D835F/H/V/Y). [10,11] Up to now, the effect of sorafenib in AML patients with FLT3-TKD has never been widely investigated. Here, we report the successful complete remission induction by sorafenib monotherapy in a FLT3-D835Y-positive patient with refractory AML prior to allogeneic stem cell transplantation ( Fig.…”

Primed for the kill: occupying Bcl-2 to target death in acute myeloid leukaemia

“…Gaining insights into the molecular basis of treatment failure will be a key objective for improving therapeutic outcomes of this aggressive blood cancer. For certain targeted therapies, such as FLT3 inhibitors, clinical resistance has been linked to emergence of "on-target" drug resistant mutations, which may be an important hurdle to the successful development of this drug class [4,5]. The biological basis for treatment failure with nontargeted therapies, such as chemotherapy, has been far more complex to decipher.…”