Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative strategy for acute myeloid leukemia (AML), but the impact of HLA disparity in the era of posttransplant cyclophosphamide (PTCy) and reduced-toxicity conditioning remains unclear. We performed an EBMT registry study including 275 adult AML patients in first complete remission undergoing first allo-HSCT between 2012 and 2023 using a uniform platform of treosulfan-based conditioning and PTCy. Among them, 206 received haploidentical grafts and 69 underwent 9/10 mismatched unrelated donor (MMUD) transplantation. Median follow-up was 2.5 years. At 2 years, overall survival was 73.1% after haploidentical transplantation and 71.6% after MMUD transplantation (p = 0.96). Leukemia-free survival at 1 year was 66.3% and 65.2%, respectively (p = 0.76). Relapse incidence (17.1% vs. 18.7%, p = 0.84) and nonrelapse mortality (16.6% vs. 16.1%, p = 0.86) were comparable between groups. Rates of Grade II-IV and Grade III-IV acute GVHD were similar, whereas chronic GVHD was higher after haploidentical transplantation (36.4% vs. 12.7%, p = 0.001), without differences in extensive forms. In multivariable analyses, donor type was not associated with overall survival, leukemia-free survival, relapse incidence, or nonrelapse mortality. Increasing age adversely affected outcomes, while Karnofsky performance status >= 90 and reduced-intensity conditioning were associated with improved survival. These findings suggest that, within a treosulfan-PTCy platform, major transplant outcomes are comparable between donor types, although haploidentical transplantation was associated with a higher incidence of chronic GVHD.
Anbalcabtagene autoleucel (anbal-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy incorporating dual PD-1 and TIGIT knockdown to enhance antitumor function and durability. We report results from a phase 1 and 2 study in patients with relapsed or refractory large B-cell lymphoma. In phase 2, 79 patients received anbal-cel, and its efficacy was evaluated in 73 patients. The complete response (CR) and partial response rates were 67.1% and 8.2%, respectively. Median progression-free survival (PFS) was 6.04 months (95% confidence interval, 4.34-16.46), and the 6-, 12-, and 18-month PFS rates were 50.9%, 41.1%, and 35.2%, respectively. Median overall survival (OS) was not reached, with 12-and 18-month OS rates of 66.6% and 57.3%, respectively. CAR T-cell expansion (Cmax) was significantly greater in responders than in non-responders (median Cmax, 20 403 vs 8580 copies per mu g). Patients were categorized into long-term response (LR) group or non-LR group based on sustained CR at 6 months. Reduced PD-1 and TIGIT expression on CAR + T cells was observed in the LR group. Most patients (97.5%) experienced grade >= 3 adverse events, most commonly neutropenia (93.7%), followed by thrombocytopenia (41.8%) and anemia (30.4%). Cytokine release syndrome (CRS) and neurological events occurred in 57.0% and 13.9% of patients, respectively. Grade 3 CRS occurred in 8.9% of patients, with no grade 4 events reported, and grade >= 3 neurological events occurred in 3.8% of patients. Serious infections occurred in 25.3% of patients, including grade 5 infection reported in 3 patients. This trial was registered at www.clinicaltrials.gov as #NCT04836507.
Antiphospholipid syndrome (APS) is an immunothrombotic disorder, frequently attributed to autoantibodies that bind 2-glycoprotein I (2GPI). A study showed that the platelet-specific chemokine, platelet factor 4 (PF4), binds to 2GPI, enhancing recognition of 2GPI by APS antibodies. APS antibodies induce the release of neutrophil extracellular traps (NETs), webs of decondensed chromatin that bind both PF4 and 2GPI. We propose that PF4 bridges 2GPI to NETs (and other PF4-targeted polyanions), leading to the formation of prothrombotic PF4:2GPI:NET immunotargets in APS. Dynamic light-scattering studies of isolated immunoglobulin G from 4 patients with triple-positive APS show formation of PF4:2GPI:NET complexes that bind APS antibodies. NETs released in a microfluidic system bound 2GPI, but only in the presence of PF4, forming a multimolecular APS antigenic target. Whole blood infused through a photochemically injured, endothelium-lined microfluidic channel formed platelet-, fibrin-, and complement-rich thrombi that bound APS antibodies only in the presence of PF4. Thrombi were reduced in size if either ADAMTS13 or DNase I was infused. In a murine APS model, wild-type and transgenic mice expressing human PF4 (hPF4) +/- FcyRIIA developed more intense neutrophil rolling along veins and more extensive thrombus formation after laser injury to cremaster arterioles and venules, whereas mice lacking PF4 did not. Three antigenically distinct anti-hPF4 monoclonal antibodies blocked thrombosis in vitro and neutrophil rolling and thrombosis in vivo. Our studies provide new insights into the basis of APS that has mechanistic parallels to other known PF4 immunothrombotic disorders and offer potential diagnostic and nonanticoagulant therapeutic strategies for clinical management.
Purpose SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) provide cardiovascular (CV) benefits, but their first-line use among adults with severe mental illness (SMI) is not well characterized. We evaluated selective prescribing of SGLT2i, GLP-1 RA, and metformin among adults with SMI and type 2 diabetes (T2D).Methods Using 2017-2022 Medicare claims, we identified adults with SMI and T2D who initiated first-line SGLT2i, GLP-1 RA, or metformin during 1/1/2018-12/31/2021. By calendar year, standardized mean differences (SMD) assessed baseline characteristic differences, and propensity score overlap coefficients (OVL) assessed group comparability between SGLT2i or GLP-1 RA initiators and metformin initiators.Results We identified 1322 SGLT2i, 2306 GLP-1 RA, and 21 144 metformin initiators. From 2018 to 2021, SGLT2i initiators shifted from younger to older than metformin initiators (SMD, -0.11 to 0.19), while differences in CVD (0.10 to 0.50) and CKD (0.18 to 0.62) increased. GLP-1 RA initiators consistently had higher prevalence of obesity (SMD, 0.33 to 0.41) and CKD (0.42 to 0.28) than metformin initiators. Compared with metformin initiators, both SGLT2i and GLP-1 RA initiators had lower prevalence of schizophrenia, antipsychotic use, and recent psychiatrist visits but higher prevalence of major depressive disorder; these differences generally persisted over time. OVL increased from 42.7% to 50.7% for SGLT2i and from 42.3% to 50.0% for GLP-1 RA versus metformin.Conclusions First-line SGLT2i and GLP-1 RA prescribing among adults with SMI was selective according to cardiometabolic and mental health-related characteristics. Future comparative studies should account for these differences and temporal prescribing changes to mitigate confounding.
