Issue Archive

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of CD19- and BCMA–positive hematologic malignancies, and emerging evidence highlights its potential in autoimmune diseases. This Perspective from Mougiakakos and coauthors explores the early successes and future prospects of B-cell–targeting CAR T-cell therapy in autoimmune disease, offering a balanced overview of current data and anticipated developments, including potential alternatives such as bispecific antibodies.

In recent years, several novel CD3×CD20 bispecific immunotherapies have received accelerated approval for the treatment of follicular lymphoma and diffuse large B-cell lymphoma. In this Blood Spotlight, Lewis and colleagues review the challenges in patient selection and discuss current prognostic and potentially predictive biomarkers to help guide therapy.

With therapeutic drug monitoring to guide leucovorin rescue, high-dose methotrexate (MTX) can be safely administered; however, a subset of patients may still develop life-threatening toxicities. Gupta et al report significant improvements in the recovery from renal failure and other less frequent MTX-related toxicities with the use of glucarpidase, a recombinant, bacterial-derived enzyme that cleaves the glutamate residue from folate analogues in patients receiving high-dose MTX who develop acute kidney injury. The authors’ study supports the use of glucarpidase in cases of delayed MTX elimination and acute renal failure following high-dose MTX therapy, although more precise threshold criteria for its use are still needed.

When combined with a hypomethylating agent, venetoclax has transformed the treatment landscape for newly diagnosed acute myeloid leukemia in older patients or those with significant comorbidities, and many studies are now exploring its role as part of initial therapy for fit patients. Mantzaris et al report on results from a phase 1b study evaluating venetoclax in combination with standard 7+3 induction chemotherapy, demonstrating that venetoclax can be safely administered alongside cytarabine and daunorubicin. An extension study and other ongoing trials will provide further efficacy data to help guide frontline treatment decisions.

Skeletal complications of multiple myeloma (MM) are common and contribute significantly to patient morbidity. Yang et al demonstrate that Enterobacter cloacae is significantly enriched in the intestines of patients with osteolytic lesions. In preclinical models, E cloacae promoted osteolysis by increasing circulating ammonium levels, which can be reversed by targeting E cloacae, thereby identifying a potential therapeutic avenue for preventing MM-associated bone disease.

In pediatric acute lymphoblastic leukemia (ALL), measurable residual disease (MRD) monitoring is a standard tool for identifying patients at higher risk of relapse who may benefit from more intensive therapy. In a large cohort of 7640 patients treated under the Chinese Children Cancer Group ALL 2015 protocol, Zhang et al demonstrated that treatment intensification for patients with B-cell ALL with MRD ≥1% on day 19 of induction significantly improved event-free survival, and patients who were MRD-negative at both day 19 and day 46 exhibited particularly favorable outcomes. These findings affirm the utility of MRD testing as a critical tool for risk stratification and treatment guidance in pediatric ALL.

Differentiation arrest and reliance on oxidative metabolism are shared features across genetically diverse acute myeloid leukemias (AMLs). In preclinical models, He et al identified that inhibition of phosphoseryl-transfer RNA kinase (PSTK), a key enzyme in selenoprotein synthesis, induced ferroptotic cell death and promoted differentiation in AML cells via a cGAS-STING–dependent mechanism and synergized with chemotherapy and venetoclax, while sparing normal hematopoietic cells. These findings support a strategy of timed metabolic intervention to enhance standard therapies and target residual leukemic cells.

Cardiovascular disease is a leading cause of morbidity and mortality in adults with sickle cell disease (SCD), yet the mechanisms underlying SCD-associated cardiomyopathy remain unclear. Using a humanized mouse model of SCD, Federti et al demonstrated that cardiomyocyte dysfunction is driven by unresolved inflammation due to hypoxia/reoxygenation stress. Treatment with 17(R)-resolvin D1 effectively mitigates this dysfunction, supporting development of novel anti-inflammatory therapies aimed at reducing cardiovascular disease in patients with SCD.

Thrombomodulin (TM) is a transmembrane glycoprotein primarily expressed on the surface of endothelial cells that inhibits the procoagulant activity of thrombin while significantly enhancing the activation of protein C, a key anticoagulant enzyme, as well as thrombin activatable fibrinolysis inhibitor. These critical functions suggest that both quantitative and qualitative alterations in TM may contribute to bleeding or thrombotic disorders. Van Laer et al expressed and characterized 8 TM gene variants of uncertain significance identified in patients with venous thromboembolism (VTE) or bleeding. Two variants, L433P and C175S, demonstrated defective anticoagulant activity, supporting their potential pathogenic role in VTE.

Apolipoprotein E (APOE) is a glycoprotein involved in metabolism, immune regulation, and neurodegenerative disease. In a retrospective analysis of 2 modern cohorts undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia, Ronnacker et al report that patients carrying at least 1 APOE2 allele have an increased risk of posttransplant mortality, driven by higher rates of severe chronic graft-versus-host disease (GVHD) and nonrelapse death, while transplantation of APOE2-positive allografts is associated with elevated incidence of both acute and chronic GVHD and reduced overall survival. Further validation in a prospective study is essential to confirm these results and elucidate the biological mechanisms linking APOE variants to posttransplant outcomes.