Summary Although some patients with primary immune thrombocytopenia (ITP) benefit from current treatments, there are still some refractory patients. Our previous research showed that the imbalance of the intestinal microbiota is associated with ITP. Indole‐3‐lactic acid (ILA) may act as a communication channel between the gut microbiota and the immune system. This study aimed to assess the ILA metabolism and the role in ITP. Plasma metabolites were measured by liquid chromatography–tandem mass spectrometry. Flow cytometry was used to analyse T‐cell subsets and Fc gamma receptors on macrophages. Cytokine mRNA expression and plasma levels were detected by real‐time quantitative polymerase chain reaction (qPCR) and a multiplex assay kit. An ITP mouse model was used to explore the effect of ILA on immune homeostasis. Newly diagnosed and refractory ITP patients with a deficiency of ILA and an imbalance of T helper cell type 17 (Th17)/regulatory T cells (Tregs). ILA alleviated thrombocytopenia in ITP mice by inhibiting Th17 differentiation and the expression of interleukin (IL)‐1β, tumour necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and IL‐12/IL‐23p40, and by promoting Tregs differentiation. ILA reduced Th17 cells, increased the Treg/Th17 ratio, downregulated IL17A and TNFα mRNA, and upregulated IL10 mRNA in refractory ITP patients. ILA ameliorates thrombocytopenia in ITP by modulating Th17/Tregs differentiation and suppressing TNF‐α expression. Targeting ILA metabolism could be a promising therapeutic strategy for ITP.
Summary Rosai–Dorfman disease (RDD) is a rare histiocytic neoplasm with diverse clinical behaviour and immune abnormalities with unknown clinical significance. We performed a retrospective cohort study of 162 patients with RDD from 2003 to 2025 at five international referral centres. Median age was 48 years and 64.8% were female. Multisystem disease occurred in 87 patients (53.7%), commonly involving skin/subcutaneous tissue (49.4%), lymph nodes (39.5%) and bones (34%). Molecular testing was available for 102 patients; 40 (39.2%) were mitogen‐activated protein kinase/rat sarcoma virus oncogene homolog signaling pathway (MAPK/RAS)‐altered, commonly with kirsten rat sarcoma viral oncogene homolog ( KRAS ) or mitogen‐activated protein kinase 1 ( MAP2K/MEK ) alterations. MAPK/RAS alterations were associated with multisystem disease ( p = 0.0034). Autoimmune disease (AID) was documented in 29 patients (17.9%), usually preceding RDD, and 45/95 patients (47.4%) with available autoantibody status had at least one positive autoantibody. Among 153 patients with response data, objective response occurred in 94 (61.4%). Response distribution differed by disease extent; single‐system disease was associated with more complete responses and less progression than multisystem disease. At a median follow‐up of 2.49 years, eight deaths occurred; 5‐year overall survival was 93.4%. AID and autoantibody positivity were not associated with response or overall survival. These findings support disease extent and molecular status as clinically relevant dimensions of RDD assessment, while autoimmune and serological abnormalities should be interpreted in clinical context.
Summary Double‐expressor diffuse large B‐cell lymphoma (DE‐DLBCL) patients, defined by co‐expression of MYC proto‐oncogene protein (≥40%) and B‐cell lymphoma 2 protein (≥50%), typically have poor outcomes with the traditional first‐line R‐CHOP regimen. We conducted a multicentre, single‐arm, phase II study to evaluate the efficacy and safety of first‐line orelabrutinib plus R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), designated O‐RCHOP, in patients with non‐germinal centre B‐cell‐like (non‐GCB) DE‐DLBCL. From 19 November 2021 to 6 February 2025, 49 patients were enrolled. With a median follow‐up of 26.6 months, median event‐free survival (EFS), progression‐free survival (PFS) and overall survival (OS) were not reached, and the estimated 2‐year EFS, PFS and OS rates were 82.0% (95% confidence intervals [CIs]: 71.2%–94.3%), 82.0% (95% CI: 71.2%–94.3%) and 97.9% (95% CI: 94.0%–100.0%) respectively. At the end of treatment, the complete response rate was 89.8% (44/49; 95% CI: 77.8%–96.6%), and the objective response rate was 95.9% (47/49; 95% CI: 86.0%–99.5%). Grade ≥3 adverse events (AEs) occurred in 51.0% of patients, with neutropenia (38.8%) being the most common. No patients died because of AEs. Genetic alteration profiling revealed that the frequently mutated genes were Pim‐1 proto‐oncogene, serine/threonine kinase ( PIM1 ; 63.6%), MYD88 innate immune signal transduction adaptor ( MYD88 ; (51.5%) and CD79b molecule ( CD79B ; 48.5%). O‐RCHOP achieved encouraging efficacy with a manageable safety profile in newly diagnosed DE‐DLBCL, supporting its feasibility as a first‐line regimen.
Nucleophosmin 1 ( NPM1 ) mutations are found in around one third of all acute myeloid leukaemias (AMLs). However, little is known about the clinical role of the rare, non‐A NPM1 variants. Sangiorgio et al. showed that rare variants shared a similar molecular background and overall survival to the common type A, with FMS‐like tyrosine kinase 3 ( FLT3 ) status as the main determinant of outcome. Commentary on: Sangiorgio et al. Rare variants of NPM1 mutations share a similar molecular background to the common NPM1 type A variant and are associated with similar survival in adults with acute myeloid leukaemia. Br J Haematol 2026 (Online ahead of print). doi: 10.1182/blood‐2024‐202884 .
