Issue Archive

Systemic treatment of adult patients with acute lymphoblastic leukemia continues to evolve with the introduction of targeted and T-cell activating therapies, but central nervous system (CNS) disease remains a challenge. In this context, Kopmar and Cassaday illustrate their approaches to prevention and treatment of CNS leukemia with 4 clinical vignettes, summarizing current knowledge and laying out their preferred strategies in instances where high-quality evidence is lacking.

Acute lower gastrointestinal (GI) graft-versus-host disease (aGVHD) remains a leading cause of mortality and morbidity postallograft. Ponce et al report on the results of a multicenter single-arm, phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer in combination with systemic corticosteroids for newly diagnosed GI aGVHD. With no dose-limiting toxicity identified and a 70% day 28 response rate with associated expansion of healthy commensal GI flora, these data suggest acceptable safety and efficacy deserving of phase 3 evaluation.

The majority of children with sickle cell anemia (SCA) live in sub-Saharan Africa (SSA). Hydroxyurea remains the most effective and affordable option for disease-modifying therapy in resource-limited countries. In an open-label trial among children with SCA in 4 countries in SSA, Olupot-Olupot and colleagues report that hydroxyurea therapy at maximum-tolerated doses is associated with a lower malaria incidence, suggesting, but not proving, that there may be an additional benefit of this intervention in these circumstances.

Heightened expression of the proto-oncogene TCL1A is associated with aggressive biology in chronic lymphocytic leukemia (CLL). Using primary CLL cells and murine models, Stachelscheid and colleagues describe the pleiotropic effect of this proto-oncogene as a major factor in CLL pathogenesis through acceleration of premature and DNA damage-prone cell-cycle transition, causing aneuploidy, impaired DNA damage repair, increased cell-survival signaling, as well as apoptotic resistance. These data provide novel insights requiring further investigation.

Leukemic driver gene alterations that co-occur with FLT3 internal tandem duplication (FLT3^ITD) in acute myeloid leukemia (AML) vary with age; chromosomal rearrangements are more common in children and single-gene mutations, such as DNMT3A, and RUNX1 loss of function mutations are more common in adult AML. Li and colleagues explore the significance of those observations using murine models with complementary transcriptomic, epigenetic, and functional studies. The authors reveal that the functional consequences of FLT3^ITD signaling are dynamic, demonstrating age-, cell-type–, and comutation-specific dependencies, which help explain divergent clinical phenotypes.

A balance between intramolecular interactions and hemodynamic forces keeps the flexible multimeric protein von Willebrand factor (VWF) from binding circulating platelets while in the plasma. Upon immobilization, VWF unravels and elongates in response to fluid flow, activating specific monomers within the multimer to drive platelet adhesion. Using functional studies of wild type and mutated recombinant proteins, Tischer et al refine our understanding of how allostery contributes to these processes.

Notch signaling is critical to immune cell development and regulates mature T-cell activation, differentiation, and function during acute graft-versus-host disease (aGVHD). Previous attempts to directly target Notch signaling for aGVHD therapy have shown efficacy but also problematic toxicity. Taking a less direct path, Cheng and colleagues identify that targeting ovarian tumor deubiquitinase 1 (OTUD1) leads to inhibition of Notch2 signaling and abrogation of aGVHD in murine models, potentially reflecting a novel strategy for clinical exploration.