The evolving landscape in the therapy of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of myeloid precursors arrested in their maturation, creating a diverse disease entity with a wide range of responses to historically standard treatment approaches. While signifi cant progress has been made in characterizing and individualizing the disease at diagnosis to optimally inform those affected, progress in treatment to reduce relapse and induce remission has been limited thus far. In addition to a brief summary of the factors that shape prognostication at diagnosis, this review attempts to expand on the current therapies under investigation that have shown promise in treating AML, including hypomethylating agents, gemtuzumab ozogamicin, FLT3 tyrosine kinase inhibitors, antisense oligonucleotides, and other novel therapies, including aurora kinases, mTOR and PI3 kinase inhibitors, PIM kinase inhibitors, HDAC inhibitors, and IDH targeted therapies. With these, and undoubtedly many others in the future, it is the hope that by combining more accurate prognostication with more effective therapies, patients will begin to have a different, and more complete, outlook on their disease that allows for safer and more successful treatment strategies.

Targeting of FLT3-ITD kinase contributes to high selectivity of imidazoacridinone C-1311 against FLT3-activated leukemia cells

“…RTKs inhibitors that target constitutively active FLT3 mutant kinase are of particular interest since FLT3-ITD alterations occur in approximately 30% of patients with AML and are linked to an extremely bad prognosis [1,10]. Preliminary studies performed by Chau et al [27], revealed that anticancer imidazoacridinone C-1311, next to its DNA-damaging and topoisomerase II inhibitory properties, potently blocked wild-type FLT3 activity at nanomolar concentrations, when tested in a cell-free system.…”

“…Acute myeloid leukemia (AML) is a group of diverse hematopoietic neoplasms characterized by clonal proliferation of myeloid progenitors with a reduced capacity to differentiate into mature blood elements [1]. While AML is the most common myeloid malignancy in adults [2], the internal tandem duplication (ITD) mutations of FMS-like tyrosine kinase 3 (FLT3) represents one of the most frequent genetic alterations in AML, occurring in nearly 30% of cases, and being associated with poor disease outcome [3].…”

“…FLT3 is a member of the type III receptor tyrosine kinase family that acts as a key mediator during early hematopoiesis (for review see [4]). Gain-of-function FLT3-ITD mutations within the juxtamembrane domain drive constitutive autophosphorylation of the FLT3 receptor in the absence of FLT3 ligand, which results in the induction of downstream prosurvival pathways including the Ras/ MAPK, PK3K/Akt, and STAT5, and causes increased cell proliferation with suppression of apoptosis [1,5]. Although single base mutations at the FLT3 tyrosine kinase and at the juxtamembrane domains also lead to persistent activation of FLT3 receptor and altered signaling, the clinical benefits of FLT3 inhibition are generally limited to AML with FLT3-ITD [3].…”

“…However, there is now compelling evidence that: (1) despite promising in vitro results, none of the tested inhibitors sustained its activity in a single agent therapy for a prolonged time [6]; (2) clinical responses in AML FLT3-ITD + patients are moderate with rare complete remission cases [7]; and (3) although inhibition of FLT3 mutants rapidly eliminates circulating leukemic blasts, those from the bone marrow remain unaffected and may be responsible for high rate of relapse [8,9]. As a consequence, intensive research are undertaken to discover the novel agents with increased potency of FLT3 inhibition [10], as well as to develop new multikinase inhibitors targeting simultaneously FLT3 and alternative pathways [3].…”

Increased optical pathlength through aqueous media for the infrared microanalysis of live cells

“…Meanwhile, poor response rates to conventional chemotherapy and low overall survival rates [46] make AML a focus for new and redeployed therapies [47], especially due to the high toxicity of conventional chemotherapy to older, frailer patients, who make up a significant proportion of sufferers [48]. …”