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Recent advances in acute myeloid leukemia (AML) come from studies investigating younger (age<60 years) adults or older (age≥75 years) or less fit adults. Uncertainty exists for the management of otherwise healthy adults with AML in their 60s and 70s, which also represents a significant proportion of AML cases. We discuss current considerations in older, fit adults with AML including determination of fitness, what factors beyond fitness should be assessed, and finally what challenges and innovations lie ahead to improve outcomes for these patients., (Copyright © 2025 American Society of Hematology.)

Introduction: Allogeneic transplantation represents a potentially curative procedure for various lethal conditions; however, it is associated with serious immune mediated complications. The most serious complication is graft-versus-host disease (GVHD). Acute GVHD (aGVHD) is unresponsive to initial corticosteroid therapy in ~40% of cases. Corticosteroid-refractory aGVHD (CR-aGVHD) represents a significant unmet need with nearly 60% mortality in patients developing this state., Areas Covered: We review landmark trials which led to the US FDA approval of Ruxolitinb for the treatment of CR-aGVHD. Ruxolitinib phosphate is a Janus Kinase 1 and 2 inhibitor which inhibits pro-inflammatory signaling, and modulates T-cell subsets to an anti-inflammatory phenotype. Ruxolitinib was recently prospectively studied for the treatment of CR-aGVHD in the REACH1 trial, which added Ruxolitinib to corticosteroid therapy. This trial demonstrated favorable results with 73% of patients ultimately responding. Among responders, over 70% remained alive at 6 months. These results led to the US FDA to approve ruxolitinib as treatment for CR-aGVHD, the first approval of its kind., Expert Opinion: Ruxolitinib represents the standard option for CR-aGVHD. Future studies should identify patients less likely to respond to ruxolitinib and/or focus on a more targeted approaches to reduce infectious complications and cytopenias seen with this drug.

Aberrant activation of mTOR signaling in acute myeloid leukemia (AML) results in a survival advantage that promotes the malignant phenotype. To improve our understanding of factors that contribute to mammalian target of rapamycin (mTOR) signaling activation and identify novel therapeutic targets, we searched for unique interactors of mTOR complexes through proteomics analyses. We identify cyclin dependent kinase 9 (CDK9) as a novel binding partner of the mTOR complex scaffold protein, mLST8. Our studies demonstrate that CDK9 is present in distinct mTOR-like (CTOR) complexes in the cytoplasm and nucleus. In the nucleus, CDK9 binds to RAPTOR and mLST8, forming CTORC1, to promote transcription of genes important for leukemogenesis. In the cytoplasm, CDK9 binds to RICTOR, SIN1, and mLST8, forming CTORC2, and controls messenger RNA (mRNA) translation through phosphorylation of LARP1 and rpS6. Pharmacological targeting of CTORC complexes results in suppression of growth of primitive human AML progenitors in vitro and elicits strong antileukemic responses in AML xenografts in vivo.

Prognosis for patients with AML remains dismal. Despite multiple clinical trials across several decades, little improvement for the therapy of non-APL AML was noted. However, over the last couple of years, several new therapies have demonstrated efficacy in the therapy of patients with AML. Several of those have been approved by the FDA for AML therapy. These include CPX-351, midostaurin, gemtuzumab ozogamicin, enasidenib and ivosidenib. Our goal in this review is to summarize currently available data on these new therapies and discuss the rapidly evolving treatment landscape of AML., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Mitogen-activated protein kinase interacting protein kinases (Mnks) play important roles in the development and progression of acute myeloid leukemia (AML) by regulating eukaryotic translation initiation factor 4E (eIF4E) activation. Inhibiting Mnk1/2-induced phosphorylation of eIF4E may represent a unique approach for the treatment of AML. We provide evidence for antileukemic effects of merestinib, an orally bioavailable multikinase inhibitor with suppressive effects on Mnk activity. Our studies show that merestinib effectively blocks eIF4E phosphorylation in AML cells and suppresses primitive leukemic progenitors from AML patients in vitro and in an AML xenograft model in vivo. Our findings provide evidence for potent preclinical antileukemic properties of merestinib and support its clinical development for the treatment of patients with AML.

Flat, quantum dot like arrays of closely spaced, electron rich metal centres are seen as attractive subunits for device capability at the molecular level. Mn(II)9 grids, formed by self-assembly processes using 'tritopic' pyridine-2,6-dihydrazone ligands, provide easy and pre-programmable routes to such systems, and have been shown to exhibit a number of potentially useful physical properties, which could be utilized to generate bi-stable molecular based states. Their ability to form surface monolayers, which can be mapped by STM techniques, bodes well for their possible integration into nanometer scale electronic components of the future. This report highlights some new Mn(II)9 grids, with functionalized ligand sites, that may provide suitable anchor points to surfaces and also be potential donor sites capable of further grid elaboration. Structures, magnetic properties, electrochemical properties, surface studies on HOPG (highly ordered pyrolytic graphite), including the imaging of individual metal ion sites in the grid using CITS (current imaging tunneling spectroscopy) are discussed, in addition to an analysis of the photophysics of a stable mixed oxidation state [Mn(III)4Mn(II)5] grid. The grid physical properties as a whole are assessed in the light of reasonable approaches to the use of such molecules as nanometer scale devices.