Issue Archive

Inborn errors of immunity can reveal nonredundant molecular requirements for the generation, maintenance, and function of human immune cells. In this Plenary Paper, Knox and colleagues report on a large functional complement of 134 variants in SPI1, the gene encoding the transcription factor PU.1, present in molecularly undiagnosed patients with agammaglobulinemia. The authors found 25 variants causing haploinsufficiency in 21 kindreds, each clinically manifested as severe B- and dendritic-cell deficiency with propensity for sinopulmonary bacterial infections. These data greatly expand our knowledge of the recently discovered PU.1-mutated agammaglobulinemia syndrome and provide a reminder that in silico prediction of novel variant pathogenicity is insufficient without functional studies.

Among myeloid neoplasms (MNs), there are a large number of rare disease entities, collectively “nonclassical” myeloproliferative and myelodysplastic/myeloproliferative disorders, defined by prominent clinical and/or genetic features, for which high quality data on definitive management, including allogeneic hematopoietic stem cell transplant (allo-HCT), are lacking. In this Special Report, Polverelli and colleagues from 2 international working groups synthesize the available data and provide guidance on the role of allo-HCT in 8 “nonclassical” entities. Where the evidence allows, the authors make recommendations about prognostication and timing of transplant, and they suggest alignment with preparatory regimens and transplant policies used routinely for more common “classical” MNs.

New molecular techniques and the use of sophisticated bioinformatic pipelines have uncovered many new fusion oncogenes driving acute myeloid leukemia (AML), especially in pediatric disease. Beyond allowing for better classification and understanding of biology, does this new knowledge change therapeutic options and improve outcomes? Egan and Tasian review the evidence, focusing on emerging new targeted therapies for 3 high-risk subtypes of AML with oncogenic gene fusions that pediatric physicians regularly encounter.

After CD19 chimeric antigen receptor (CAR) T-cell therapy, most relapses of B-cell acute lymphoblastic leukemia (B-ALL) still express CD19, suggesting exhaustion of the response rather than a loss of antigen as the mechanism of failure. Falgàs et al examined samples at diagnosis and relapse and identified parallel upregulation of the checkpoint receptor TIM-3 on CD8+ T cells and its ligand galectin-9 (Gal-9) on relapsed B-ALL. The authors show that incubating T cells with Gal-9 led to impaired CAR T-cell survival and cytotoxicity, and they describe a novel CAR T-cell armor strategy via secretion of a TIM-3–Fc decoy to overcome TIM-3-Gal-9–mediated CAR T-cell exhaustion. These promising preclinical data portend further evolution of clinical CAR T-cell products.

Cereblon (CRBN) is the molecular target of thalidomide and its analogs, and mutations in the protein can mediate resistance in this class of drug. Chrisochoidou et al systematically evaluated the structural and functional consequences of CRBN missense mutations observed in patients with immunomodulatory drug–resistant myeloma, identifying 3 categories that render cells resistant to all such drugs, or have no effect, or have selective effects depending on the specific drug tested. These data will help refine development of CRBN E3 ligase modulators.

Preliminary evidence suggests that venetoclax–hypomethylating agent regimens approved for older, unfit patients with acute myeloid leukemia (AML) may perform well in younger adults. Lu et al report results of the first randomized clinical trial comparing outcomes in newly diagnosed younger patients with AML treated with venetoclax-decitabine (VEN-DEC) vs idarubicin-cytarabine as induction, prior to conventional consolidation therapy for all. The study found similar rates of complete remission, measurable residual disease negativity, and event-free survival, while demonstrating superior safety with VEN-DEC. While overall survival data remain immature, the study potentially identifies differential efficacy according to AML subtype. This pioneering trial points one way forward as we wrestle with how to incorporate venetoclax-based regimens into the care for young, fit adults with AML.

Meta-analyses of epidemiological studies teach us that people with non-O blood groups (A, AB, and B) have a 2 to 3-fold higher risk of venous thromboembolism (VTE) than those from the O blood group. Onsaker and colleagues analyzed plasma proteome data from a large population-based case-control study of healthy people who develop VTE and provide evidence that links histo–blood group ABO system transferase (BGAT) with this elevated risk, especially for unprovoked VTE. The authors found that the effects of higher BGAT levels in non-O blood groups likely go beyond influencing von Willebrand factor and factor VIII levels, but future mechanistic studies are needed to define the precise biological explanation for the association.