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Review
. 2018 Nov 9;10(11):429.
doi: 10.3390/cancers10110429.

Novel Agents for Acute Myeloid Leukemia

Mario Luppi  1 , Francesco Fabbiano  2 , Giuseppe Visani  3 , Giovanni Martinelli  4 , Adriano Venditti  5
Affiliations
Review

Novel Agents for Acute Myeloid Leukemia

Mario Luppi et al. Cancers (Basel). .

Abstract

Acute myeloid leukemia (AML) is a complex hematological disease characterized by genetic and clinical heterogeneity. Recent advances in the understanding of AML pathogenesis have paved the way for the development of new agents targeting specific molecules or mechanisms that contribute to finally move beyond the current standard of care, which is "3 + 7" regimen. In particular, new therapeutic options such as targeted therapies (midostaurin and enasidenib), monoclonal antibodies (gemtuzumab ozogamicin), and a novel liposomal formulation of cytarabine and daunorubicin (CPX-351) have been recently approved, and will be soon available for the treatment of adult patients with AML. In this review, we will present and describe these recently approved drugs as well as selected novel agents against AML that are currently under investigation, and show the most promising results as monotherapy or in combination with chemotherapy. The selection of these emerging treatments is based on the authors' opinion.

Keywords: CPX-351; FLT3; acute myeloid leukemia; enasidenib; gemtuzumab ozogamicin; midostaurin; palliative care; “7 + 3” regimen.

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Conflict of interest statement

M.L. has served on advisory boards for Novartis and Celgene. F.F. has served on advisory boards for Novartis. G.M. was a consultant for Amgen, Ariad, Incyte, Pfizer, Roche, Celgene, Janssen, Jazz Pharmaceuticals, Abbvie, and a speaker bureau for Pfizer and Celgene, and has received grant from Pfizer and Abbvie. A.V. was a consultant and served on advisory boards for Novartis.

Figures

Figure 1
Figure 1
Schematic representation and pharmacokinetics of CPX-351. (A) CPX-351 is a liposomal formulation of the cytotoxic drugs cytarabine and daunorubicin at a molar ratio of 1:5; (B) A comparison between the pharmacokinetic features of liposomal cytarabine and daunorubicin (on day 5 after infusion of CPX-351 (101 units/m2) [24]) versus non-liposomal forms [25,26,27].
Figure 2
Figure 2
Structure and signaling pathways of activated and mutated FMS-like tyrosine kinase 3 (FLT3). (A) Schematic representation of inactivated FLT3; (B) Ligand binding to the wild-type FLT3 receptor activates several signaling pathways, such as PI3K/Akt/mTOR and RAS/ mitogen-activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK), pathways, which are involved in cell survival, proliferation, and apoptosis; FLT3/ITD and FLT3/TKD constitutively stimulate RAS and PI3K downstream pathways, but FLT3/ITD activates STAT5 signaling and reduces the expression of SHP-1, while the mutant form FLT3-D835 activates SHP-1 phosphatase and negatively regulates STAT5 signaling. P: phosphorylation site; TM: transmembrane domain; JM: juxtamembrane domain; TKD: tyrosine kinase domain; ITD: internal tandem duplications; FL: FLT3 ligand.
See this image and copyright information in PMC

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