Issue Archive

Marques and colleagues review the state of our understanding of the role of iron in the pathophysiology of the anemia of inflammation and discuss novel therapeutic strategies for its treatment.

The FDA approved axicabtagene ciloleucel (axi-cel) for second-line treatment of diffuse large B-cell lymphoma (DLBCL) based on the ZUMA-7 study demonstrating that axi-cel improved event-free survival compared to salvage chemotherapy and autologous transplantation. In modeling using a willingness-to-pay threshold of $150 000/quality-adjusted life year, Kambhampati and colleagues demonstrate axi-cel to be cost-effective in about 73% of iterations; however, cost-effectiveness is dependent on favorable long-term outcomes transpiring, and routine use would add >$1 billion to US healthcare expenditures. Further cost reductions are needed to make the therapy widely affordable.

Cunningham and colleagues report that AML blasts and leukemic stem cells (LSCs) uniquely depend on methionine for both protein translation and as a source of methyl groups to histones. Methionine depletion induces increased apoptosis and cell-cycle blockade in AML cells and LSCs but not in normal hematopoietic stem cells, suggesting a novel metabolic pathway that can be targeted therapeutically.

Xu et al report results of a phase 1 trial of mitapivat, an activator of pyruvate kinase, in 17 patients with sickle cell disease. Mitapivat decreases the concentration of 2,3-DPG, increasing hemoglobin oxygen affinity and decreasing hemoglobin S polymerization. Treatment was associated with decreases in hemolysis and increased hemoglobin in over half the patients. Further study is needed to see if it has a clinical impact on vaso-occlusive crises.

Thrombotic events have been reported to increase at high altitudes. Li et al link these cases to enhanced coagulation potentiated by serum transferrin. They report that hypoxia and low temperatures lead to increased expression of hypoxia-inducible factor (HIF)-1α levels. HIF-1α induces transferrin expression, leading to elevated transferrin levels. Transferrin binds to thrombin and factor XIIa, enhancing their activity. Inhibition of transferrin may be a novel target to reduce pathologic coagulation at high altitudes.

Wang et al report that leukemia inhibitory factor (LIF) unexpectedly protects against the development of graft-versus-host disease (GVHD). Recombinant LIF protects mice from GVHD, especially in the gut, without a loss of graft-versus-leukemia (GVL) activity. LIF downregulates IL12-p40 expression in dendritic cells, with effects on MHC-II expression on gut epithelial cells and modulatory effects on T-cell activation. Modulation of LIF may provide a novel clinical strategy to limit GVHD while preserving GVL.