Enasidenib in the treatment of relapsed/refractory acute myeloid leukemia: an evidence-based review of its place in therapy.

Introduction: Acute myeloid leukemia (AML) remains a disease with high mortality, especially for older patients and those with relapsed/refractory (R/R) disease. With recent advances in molecular testing, targeting particular leukemogenic mutations such as those occurring in isocitrate dehydrogenase (IDH) became possible. Enasidenib is a new small-molecule inhibitor of mutant isocitrate dehydrogenase-2 (IDH2). Aim: The objective of this article is to review the evidence for the use of enasidenib in R/R AML, as well as to outline future directions of enasidenib therapy. Evidence Review: Enasidenib was approved in August 2017, after a successful Phase I/II trial showing an overall response rate (ORR) of 40.3% in R/R disease, with 19.3% of patients achieving complete remission (CR). Enrollees in the trial were mostly older adults. The most prominent toxicities were hyperbilirubinemia and IDH-differentiation syndrome (IDH-DS), though the drug was generally well tolerated and the maximum tolerated dose was not reached. A Phase III trial is currently ongoing. Conclusion: Enasidenib provides a new therapeutic option for patients with R/R AML. Further studies are ongoing to ascertain its role in combination with other agents and newly diagnosed disease

Acquired Elliptocytosis as a Manifestation of Myelodysplastic Syndrome with Ring Sideroblasts and Multilineage Dysplasia.

Acquired elliptocytosis is a known but rarely described abnormality in the myelodysplastic syndromes (MDS). Here we report the case of an elderly male who was admitted to the hospital with chest pain, dyspnea, and fatigue and was found to be anemic with an elliptocytosis that had only recently been noted on peripheral smears of his blood. After bone marrow biopsy he was diagnosed with MDS with ring sideroblasts and multilineage dysplasia and acquired elliptocytosis. Here we report a rare case of acquired elliptocytosis cooccurring with MDS with ring sideroblasts and multilineage dysplasia

Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia.

Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with acute myeloid leukemia (AML). Monitoring patients for measurable residual disease (MRD) is helpful to identify those at risk for relapse. Hypomethylating agents are being investigated as post-remission therapy. Identification of recurrent genetic alterations that drive disease progression has enabled the design of new, personalized approaches to therapy for patients with AML. Emerging data suggest that targeted post-remission therapy, alone or in combination with chemotherapy, may improve outcomes. Results of ongoing clinical trials will further define potential clinical benefits

Neutrino-heated winds from millisecond protomagnetars as sources of the weak r-process

We explore heavy element nucleosynthesis in neutrino-driven winds from rapidly rotating, stronglymagnetized protoneutron stars (‘millisecond protomagnetars’) forwhich themagnetic dipole is aligned with the rotation axis, and the field is assumed to be a static force-free configuration. We process the protomagnetar wind trajectories calculated by Vlasov, Metzger & Thompson through the r-process nuclear reaction network SkyNet using contemporary models for the evolution of the wind electron fraction during the protoneutron star cooling phase. Although we do not find a successful second or third-peak r-process for any rotation period P, we show that protomagnetars with P ∼ 1–5 ms produce heavy element abundance distributions that extend to higher nuclear mass number than from otherwise equivalent spherical winds (with the mass fractions of some elements enhanced by factors of �100–1000). The heaviest elements are synthesized by outflows emerging along flux tubes that graze the closed zone and pass near the equatorial plane outside the light cylinder. Due to dependence of the nucleosynthesis pattern on the magnetic field strength and rotation rate of the protoneutron star, natural variations in these quantities between core collapse events could contribute to the observed diversity of the abundances of weak r-process nuclei in metal-poor stars. Further diversity, including possibly even a successful third-peak r-process, could be achieved for misaligned rotators with non-zero magnetic inclination with respect to the rotation axis. If protomagnetars are central engines for GRBs, their relativistic jets should contain a high-mass fraction of heavy nuclei of characteristic mass number ¯A ≈ 100, providing a possible source for ultrahigh energy cosmic rays comprised of heavy nuclei with an energy spectrum that extends beyond the nominal Grezin–Zatsepin–Kuzmin cut-off for protons or iron nuclei

Oxy-functionalization of nucleophilic rhenium(I) metal carbon bonds catalyzed by selenium(IV)

We report that SeO_2 catalyzes the facile oxy-functionalization of (CO)_5Re(I)-Me^(δ−) with IO_4− to generate methanol. Mechanistic studies and DFT calculations reveal that catalysis involves methyl group transfer from Re to the electrophilic Se center followed by oxidation and subsequent reductive functionalization of the resulting CH_3Se(VI) species. Furthermore, (CO)_3Re(I)(Bpy)-R (R = ethyl, n-propyl, and aryl) complexes show analogous transfer to SeO_2 to generate the primary alcohols. This represents a new strategy for the oxy-functionalization of M−R^(δ−) polarized bonds

Mechanism of efficient anti-Markovnikov olefin hydroarylation catalyzed by homogeneous Ir(III) complexes

The mechanism of the hydroarylation reaction between unactivated olefins (ethylene, propylene, and styrene) and benzene catalyzed by [(R)Ir(μ-acac-O,O,C^3)-(acac-O,O)_2]_2 and [R-Ir(acac-O,O)_2(L)] (R = acetylacetonato, CH_3, CH_2CH_3, Ph, or CH_2CH_2Ph, and L = H_2O or pyridine) Ir(III) complexes was studied by experimental methods. The system is selective for generating the anti-Markovnikov product of linear alkylarenes (61 : 39 for benzene + propylene and 98 : 2 for benzene + styrene). The reaction mechanism was found to follow a rate law with first-order dependence on benzene and catalyst, but a non-linear dependence on olefin. ^(13)C-labelling studies with CH_3^(13)CH_2-Ir-Py showed that reversible β-hydride elimination is facile, but unproductive, giving exclusively saturated alkylarene products. The migration of the ^(13)C-label from the α to β-positions was found to be slower than the C–H activation of benzene (and thus formation of ethane and Ph-d_5-Ir-Py). Kinetic analysis under steady state conditions gave a ratio of the rate constants for CH activation and β-hydride elimination (k_(CH): k_β) of 0.5. The comparable magnitude of these rates suggests a common rate determining transition state/intermediate, which has been shown previously with B3LYP density functional theory (DFT) calculations. Overall, the mechanism of hydroarylation proceeds through a series of pre-equilibrium dissociative steps involving rupture of the dinuclear species or the loss of L from Ph-Ir-L to the solvento, 16-electron species, Ph-Ir(acac-O,O)_2-Sol (where Sol refers to coordinated solvent). This species then undergoes trans to cis isomerization of the acetylacetonato ligand to yield the pseudo octahedral species cis-Ph-Ir-Sol, which is followed by olefin insertion (the regioselective and rate determining step), and then activation of the C–H bond of an incoming benzene to generate the product and regenerate the catalyst

Acquired Elliptocytosis as a Manifestation of Myelodysplastic Syndrome with Ring Sideroblasts and Multilineage Dysplasia

Acquired elliptocytosis is a known but rarely described abnormality in the myelodysplastic syndromes (MDS). Here we report the case of an elderly male who was admitted to the hospital with chest pain, dyspnea, and fatigue and was found to be anemic with an elliptocytosis that had only recently been noted on peripheral smears of his blood. After bone marrow biopsy he was diagnosed with MDS with ring sideroblasts and multilineage dysplasia and acquired elliptocytosis. Here we report a rare case of acquired elliptocytosis cooccurring with MDS with ring sideroblasts and multilineage dysplasia