Abstract Exposure of macrophages to iron has been implicated in sterile inflammation through reactive oxygen species (ROS)‐dependent cell pro‐inflammatory activation. Here, we compare the effect of the commonly used oral iron salt, iron sulfate (FeSO 4 ), with that of an innovative formulation, sucrosomial® iron (SI), on the iron status and inflammatory activation of tissue macrophages in mice with iron‐deficiency (ID) anemia. Despite similar recovery of anemia and tissue ID, FeSO 4 treatment, but not SI, elevated transferrin saturation, generated non‐transferrin bound iron (NTBI), and quickly corrected macrophage ID compared to SI, with a more pronounced cell transferrin receptor 1 (TfR1) suppression and labile iron pool expansion. In both ex vivo and in vitro ID macrophages, the rapid kinetic of ID correction by FeSO 4 was associated with increased ROS and inflammatory cytokine production, whereas these responses were minimally affected by the slower kinetic of SI uptake. Metabolome data suggest that FeSO 4 but not SI suppressed lipid metabolism in macrophages, indicating reduced fatty acid β‐oxidation and limited reliance on mitochondrial activity, metabolic hallmarks of cell inflammatory skewing. Ultimately, we demonstrate that FeSO 4 drives a higher autocrine production of hepcidin compared to SI, via inflammatory cytokine‐mediated activation of the STAT3 signaling pathway, further limiting macrophage iron recycling in ID. In conclusion, our data prove that the kinetic of macrophage ID correction by iron formulations determines cell inflammatory activation and modulates hepcidin production. Overall, SI appears a superior formulation than FeSO 4 due to its reduced pro‐oxidant potential, inflammatory action, and hepcidin induction, with relevance for ID treatment in individuals with pre‐existing inflammatory conditions.
Abstract The impact of venetoclax‐based therapies on autoimmune cytopenias (AIC) in patients with chronic lymphocytic leukemia (CLL) is largely unknown. This study aimed to evaluate preexisting and treatment‐emergent AIC in patients with CLL treated with venetoclax, focusing on the differential impact of venetoclax monotherapy versus venetoclax‐based combinations. In this retrospective multicenter study, data from 1720 patients were collected; 23.1% received venetoclax single agent and 76.9% venetoclax combinations (mostly containing anti‐CD20 monoclonal antibodies and/or BTK inhibitors). Combination regimens were used in 97.7% of treatment‐naïve (TN) patients and 65.8% of patients with relapsed/refractory (R/R) CLL. Preexisting AIC were reported in 11.7% of patients (8.7% in TN and 13.4% in R/R, P = 0.005). CLL‐related genetic risk factors and disease outcomes did not differ in patients with and without preexisting AIC. Irrespective of treatment type, venetoclax therapy resulted in AIC resolution or improvement in 63% of patients with active or controlled AIC. Treatment‐emergent AIC occurred in 2.6% of patients (2% in TN and 2.9% in R/R, not statistically significant). AIC episodes were reported in 4.3% of patients treated with venetoclax monotherapy and in 2.1% of those treated with venetoclax‐based combinations (P = 0.02). After standard management, AIC was considered resolved or controlled in 82% of the patients, with no substantial difference between treatment groups. Venetoclax‐based therapies have a beneficial impact on the outcome of CLL‐associated preexisting AIC. Treatment‐emergent AIC is a rare and generally manageable event. Although more frequent with venetoclax monotherapy in unadjusted analysis, this association was attenuated after adjustment for baseline prognostic factors.
Abstract Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are the most aggressive forms of cutaneous T‐cell lymphoma and remain associated with a poor prognosis and heterogeneous therapeutic approaches. Recent advances, including targeted therapies and improved transplant strategies, have substantially expanded treatment options, highlighting the need for updated international guidance integrating dermatologic, hematologic, and transplant perspectives. An international multidisciplinary panel convened by the European Hematology Association (EHA), the EORTC Cutaneous Lymphoma Tumours Group (EORTC‐CLTG), the International Society for Cutaneous Lymphoma (ISCL), and the EBMT Lymphoma Working Party reviewed the available evidence and developed consensus recommendations for the management of advanced MF and SS. Thirty international experts participated in the process. Recommendations address diagnostic work‐up, systemic therapies, treatment sequencing, combination strategies, and indications for allogeneic hematopoietic cell transplantation (allo‐HCT). The consensus supports a stage‐adapted and compartment‐oriented therapeutic approach. Immunomodulatory strategies remain central in advanced CTCL: extracorporeal photopheresis is commonly used as first‐line therapy in SS and in patients with significant blood involvement, while interferon‐α and retinoids are widely used in MF, often in combination with skin‐directed therapies. Mogamulizumab and brentuximab vedotin represent key options after prior systemic therapy, with differential activity across skin, blood, and nodal compartments. Combination approaches integrating systemic and skin‐directed treatments may improve response depth and durability. Practical treatment algorithms for advanced MF and SS are proposed to support therapeutic sequencing and multidisciplinary management. Allo‐HCT remains the only potentially curative treatment and should be considered early in selected patients with high‐risk disease features.
Abstract Lineage switch (LS) is a rare but aggressive immunophenotypic transformation of acute leukemia associated with limited therapeutic options and poor clinical outcome. Although LS has been increasingly recognized in the era of CD19‐directed immunotherapies, its biological basis remains incompletely understood. Most reported pediatric LS cases occur in KMT2A ‐rearranged ( KMT2A ‐r) leukemia, highlighting a link between developmental origin and lineage plasticity. In this review, we provide a comprehensive overview of the clinical, molecular, epigenetic, and cellular determinants of pediatric LS. We systematically reviewed the literature and identified 201 pediatric LS cases reported between 1994 and 2026. Among these, 70.1% involved B‐lymphoblastic leukemias switching to acute myeloid leukemias, with KMT2A ‐r (47.8%) and DUX4 ‐rearranged (14.9%) leukemias representing the most frequent genetic subtypes. Across the published cases, LS occurred earlier following blinatumomab exposure than after chimeric antigen receptor cells or chemotherapy alone. We discuss current mechanistic concepts underlying LS, including epigenetic remodeling, chromatin regulation, developmental programs, the cell‐of‐origin, and therapy‐associated selective pressures that promote lineage plasticity. By integrating clinical evidence with current insights into leukemia biology, this review provides a framework for understanding LS in pediatric leukemias and highlights priorities for future research, early detection, and development of preventive and/or therapeutic strategies.
