Anti-malaria benefit of hydroxyurea in SCA, IL-22 in the treatment in lower GI acute GVHD, and FLT3ITD changes depend on context in AML
In this week’s episode we will review a study in sub-Saharan Africa where treatment of sickle cell anemia with hydroxyurea is associated with a lower incidence of malaria. New research suggests mild myelosuppression associated with hydroxyurea treatment may actually have a salutary effect. Next, a potential new treatment approach in lower GI acute GVHD. Adding an interleukin-22 therapy to corticosteroid treatment was well tolerated with a high rate of response in this very challenging patient population. Finally, common AML driver mutations such as FLT3ITD (or internal tandem duplications) orchestrate distinct transcriptional and epigenetic programs based on different genetic contexts. In the context of a common pediatric AML mutation, FLT3ITD selectively activated type I interferon signaling, suggesting a distinct therapeutic vulnerability.
How I prevent and treat central nervous system disease in adults with acute lymphoblastic leukemia
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.
Hydroxyurea treatment is associated with lower malaria incidence in children with sickle cell anemia in sub-Saharan Africa
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.
A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract
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.
FLT3ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation
Leukemic driver gene alterations that co-occur with FLT3 internal tandem duplication (FLT3ITD) 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 FLT3ITD signaling are dynamic, demonstrating age-, cell-type–, and comutation-specific dependencies, which help explain divergent clinical phenotypes.
Removal of the vicinal disulfide enhances the platelet-capturing function of von Willebrand factor
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.
