Autoimmune neutropenia (AiN) in adults is rare when compared to children. It occurs predominantly in female patients and in individuals with other autoimmune conditions. Anti‑neutrophil antibodies are detected in ~50% of patients with AiN, and it is not clear whether this reflects testing limitations or cell-mediated (rather than antibody-mediated) mechanisms of neutrophil destruction. Unlike the commonly self‑limited pediatric disease, adult AiN is generally chronic. The degree of neutropenia and the clinical severity is highly variable, and most patients remain asymptomatic and free of infection despite absolute neutrophil counts (ANC) persistently lower than 500 /uL. As most patients do well despite their neutropenia, observation and supportive care are generally preferred over active treatment. Where necessary, empiric treatment recommendations have stemmed from small numbers of cases. Therapy focuses on boosting endogenous neutrophil production, reducing immune-mediated destruction, or eliminating pathogenic autoantibodies. Clinical response is highly variable, and second-line therapies, including T‑cell-directed approaches, can be effective, supporting a role for cell-mediated mechanisms of neutrophil destruction in a subset of patients. Emerging strategies, such as plasma cell-targeted therapies, modulation of cytokine signaling pathways, and complement blockade also show promise. Collaboration and discussion around this rare condition is critical to enhance treatment algorithms.

Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.

Talquetamab is the first and only approved bispecific antibody targeting G protein-coupled receptor class C group 5 member D (GPRC5D) for treatment of relapsed/refractory multiple myeloma based on results from the phase 1/2 MonumenTAL-1 study. Here, we report efficacy and ongoing safety from MonumenTAL-1 with 3 years of follow-up. Patients naïve to T-cell redirection therapy (TCR) received talquetamab 0.4 mg/kg weekly (n=143) or 0.8 mg/kg every other week (n=154); a separate cohort received prior TCR (n=78, either talquetamab dose). Median follow-up was 38, 31, and 30 months in the 3 cohorts, respectively, as of September 2024. Overall response rate was 67-74% and complete response or better rate was 33-42%. Median progression-free survival was 7.5, 11.2, and 7.7 months, and median overall survival (OS) was 34.0 months, not reached, and 28.3 months (36-month OS rates 49.3%, 60.8%, and 44.6%), in the 3 cohorts, respectively. The most common adverse events (AEs) were cytokine release syndrome (73-79%; grade 3/4, 0.6-2.1%), taste changes (72-76%), and infections (61-78%; grade 3/4, 21-26%). Ataxia/balance disorders occurred in 5.3% of patients (no grade 4/5 events). Dose reduction and discontinuation rates due to AEs remained low; no patients died due to talquetamab-related AEs. With 3 years of follow-up, talquetamab continued to demonstrate high rates of deep and durable responses. The long-term safety profile was comparable to previous results and continued to show lower risk of high-grade infections relative to approved BCMA-targeting bispecific antibodies. NCT03399799 (phase 1) and NCT04634552 (phase 2).

Ex vivo expansion of human hematopoietic stem cells (HSCs) holds promise for overcoming their limited availability, a major barrier to broader clinical application. Although recent advances in culture systems can increase HSC numbers, these conditions frequently impair self-renewal and induce myeloid bias, and the underlying molecular mechanisms remain poorly understood. Here, we performed single-cell multiome sequencing (scMultiome-seq) on human umbilical cord blood-derived CD34⁺ hematopoietic stem and progenitor cells to co-profile transcriptional and epigenetic adaptations within the same cells during ex vivo culture. Our analyses revealed reduced transcriptional and epigenetic HSC signatures, accompanied by markedly increased activity of myeloid-associated transcription factor motifs, providing molecular insight into the functional decline and myeloid bias of cultured HSCs. We further observed substantial functional heterogeneity among phenotypically defined HSCs following culture. To address these limitations, we established a niche-mimetic culture system that integrates intrinsic and extrinsic bone marrow regulatory cues, including pharmacologic inhibition of the m6A reader YTHDF2 using the small molecule Y13-27, a three-dimensional microenvironment, and N-cadherin-mediated adhesion. This condition (3D-NcadP-Y) robustly preserved long-term repopulating capacity. When combined with the self-renewal agonist UM729, the resulting platform (3D-NcadP-Y-UM) uniquely enabled the expansion of serially transplantable long-term HSCs with balanced multilineage potential. scMultiome-seq and cellular analyses demonstrated that this condition preserves transcriptional and epigenetic long-term HSC signatures, maintains multilineage-associated transcription factor motifs, and limits excessive cell-cycle activation. Together, these findings elucidate molecular mechanisms underlying culture-induced HSC dysfunction and establish a niche-mimetic strategy for expanding functional human long-term HSCs while preserving key features of stemness.