Blood最新文献

Multiple myeloma (MM)-induced bone disease affects not only patients' quality of life but also their overall survival. Our previous work demonstrated that the gut microbiome plays a crucial role in MM progression and drug resistance. However, the role of altered gut microbiota in MM bone disease remains unclear. In this study, we show that intestinal E. cloacae is significantly enriched in MM patients with osteolysis. Through fecal microbial transplantation and single bacterial colonization experiments in a 5TGM1 MM mouse model, we found that intestinal colonization of E. cloacae promotes osteolysis by increasing circulating ammonium levels. Elevated ammonium promotes osteoclastogenesis by increasing Trap protein levels in osteoclast precursors and by acetylating and stabilizing CCL3 protein in MM cells. Inhibition of ammonium synthesis, using E. cloacae with a deleted dcd gene, along with probiotic supplementation, alleviated osteolysis in MM. Overall, our work suggests that E. cloacae promotes osteolysis in MM by synthesizing ammonium. This establishes a novel mechanism and potential intervention strategy for managing MM with osteolysis.

Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF cases often require the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than from shock, and survivors are usually left with severe scarring and tissue loss. Despite these challenging features, PF is a pathophysiologically distinct, homogenous, and highly predictable form of sepsis-associated DIC for which poor outcomes are not a foregone conclusion. The fundamental pathologic lesion in PF is a failure of the anticoagulant protein C pathway, which leads to uncontrolled microvascular clotting and inadequate protein C-mediated cytoprotective effects, which are vital for survival in sepsis. Herein, we review the clinical features and diagnosis of PF. Drawing from the existing clinical literature and from recent advances in our understanding of the pathophysiology of PF, we describe rationally-designed treatment approaches for this disorder, including repletion of natural circulating anticoagulants, use of therapeutic anticoagulation, and ways to optimize transfusion support, and we outline specific interventions that we would recommend avoiding.

B-cell acute lymphoblastic leukemia (B-ALL) is a rare malignancy in adults with outcomes remaining poor, especially compared to children. Over the past two decades, extensive whole-genome studies have identified numerous genetic alterations driving leukemia, leading to the recognition of more than 20 distinct subtypes which are closely associated with treatment response and prognosis. In pediatric B-ALL, large correlation studies have made genetic classification a central component of risk-adapted treatment strategies. Notably, genetic subtypes are unevenly distributed according to age, and the spectrum of genetic alterations and their prognostic relevance in adult B-ALL have been less extensively studied, with treatment primarily based on the presence or absence of BCR::ABL1 fusion. This review provides an overview of genetic subtypes in adult B-ALL, including recent biological and clinical insights in well-established subtypes as well as data on newly recognized subtypes. Their relevance for risk classification, disease monitoring and therapeutic management, including in the context of B-cell-directed therapies, is discussed. This review advocates for continuing efforts to further improve our understanding of the biology of adult B-ALL to establish the foundation of future precision medicine in B-ALL.

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) progressing after chimeric antigen receptor T-cell therapy (CAR T) have dismal outcomes. The prespecified post-CAR T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR T. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary endpoint was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range 2-9), 71.7% were refractory to CAR T, and 48.3% relapsed within 90 days of CAR T. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR T products and time to relapse on CAR T. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 months and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no Grade ≥3 events). No cases of immune effector cell-associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), two of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for post-CAR T patients. This trial was registered at www.clinicaltrials.gov as #NCT02290951.