Blood advances最新文献

Secondary acute myeloid leukemia (AML) comprises heterogeneous entities, unified by poor prognosis, defined by patients' previous history. We evaluated the associations of genetic profiles with blast counts and patients' history in a cohort of 924 patients with MDS/AML or AML, classified according to the International Consensus Classification (ICC). The cohort included 109 cases with "mutated TP53", 497 with "myelodysplasia-related (MDR) gene mutation" and 93 with "MDR-cytogenetic abnormality", 77 therapy-related and 136 "not otherwise specified" (NOS) AML as controls. Exploring the ICC hierarchy, "mutated TP53" and "MDR-cytogenetic abnormality" AML and MDS/AML categories presented similar biology and prognosis, irrespective of blast counts. Conversely, in MDS/AML with "MDR gene mutation" and NOS, profiles significantly differed from AML and characterized by a higher number of mutations in STAG2, SRSF2, ASXL1 and TET2. This corresponded to improved survival in MDS/AML vs AML (MDR-gene mutation: median OS 24.8 vs. 13.6 months, p<0.0001, and NOS: 49.9 vs. 19.2 months, p=0.028). Within each ICC-defined AML category, a prior MDS history versus de novo onset did not impact on patients' prognosis. We then analyzed secondary AML, defined by "prior MDS or MDS/MPN" or "therapy-related" (t-AML), as diagnostic qualifiers. According to ELN 2022, AML post-MDS mostly clustered in the adverse-risk group (84.1%), while t-AML showed more heterogeneous ELN profiles (12.9% favorable, 33.8% intermediate, and 53.3% adverse risk) reflecting diverse overall survival. Our findings underscore that genetic features and the ICC classification reliably capture disease biology, refine risk stratification, and ultimately guide treatment decisions in most secondary AML and MDS/AML.

Mantle cell lymphoma (MCL) predominantly affects older adults, and treatment options for relapsed/refractory (R/R) disease remain limited. Brexucabtagene autoleucel (brexu-cel) has demonstrated high efficacy in R/R MCL, but data in elderly populations are scarce. This retrospective, real‑world analysis evaluated patients aged ≥70 years with R/R MCL treated with brexu‑cel and reported to the EBMT registry between 2020 and 2024. A total of 233 patients from 96 centers across 13 countries were included (median age at infusion, 74.6 years; 44% >75 years). Most had ECOG 0-1 (89%) and were heavily pretreated; 62% had prior BTK inhibitor exposure. At day +100, the best overall response was complete remission in 78% and partial remission in 13%. At 30 days, the cumulative incidence of any-grade cytokine release syndrome (CRS) was 80% (grade ≥3, 9%) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) was 57% (grade ≥3, 22%). At 1 year, overall survival (OS) was 74%, progression-free survival (PFS) 62%, relapse/progression incidence (R-PI) 25%, and non-relapse mortality (NRM) 13%. Patients aged >75 years had outcomes comparable to those aged 70-75 years. In multivariable analysis, ECOG ≥2 remained the strongest predictor of inferior OS (HR 4.50; p<0.001) and PFS (HR 3.10; p<0.001), while age was not independently associated with outcomes. Brexu-cel is effective in patients aged ≥70 years with R/R MCL, achieving high remission rates and meaningful survival, despite relative high incidence of NRM. Functional status, rather than age, should guide eligibility.

Survival from diffuse large B-cell lymphoma (DLBCL) has improved, raising interest in mortality from non-lymphoma causes in DLBCL patients, which is known to be increased compared with the general population. This study investigates excess mortality after DLBCL, quantifying both the absolute magnitude of the total non-lymphoma excess and the contributions of major disease groups. 58,221 patients aged 18-79 diagnosed with DLBCL as their first lymphoma in England during 1997-2020 were identified from the National Cancer Registration and Analysis Service and followed for up to 25 years (median 10.2 years). Absolute excess mortality rates (AERs) and standardized mortality ratios (SMRs) were estimated. A total of 30,596 patients died, 35.6% from lymphoma and 17.0% from other causes. The non-lymphoma mortality rate was 58% higher than that of the general population (SMR=1.58, 95% confidence interval 1.55-1.61), with over 100 excess non-lymphoma deaths per 10,000 person-years (AER=103.8, 98.2-109.4). The non-lymphoma AER was substantial during the first year after diagnosis (AER=369.1, 349.1-389.7). It subsequently fell, but remained significantly elevated throughout follow-up, even beyond 10 years (AER=93.7, 80.5-107.3). Disease groups with the biggest contributions to the AER were: infection <1 year after diagnosis, constituting 29%; hematological causes excluding lymphoma (e.g., leukemia) during years 1-4, 38%; and solid tumors thereafter, 31% in years 5-9 and 34% in years 10-25. Deaths from circulatory disease were elevated overall, but the SMR diminished in more recent calendar years of diagnosis. These insights may help guide treatment developments, interventions, and screening strategies towards reducing excess non-lymphoma deaths in the future.

Vaso-occlusion is a signature pathology of sickle cell disease (SCD). However, the lack of in vivo methods to observe individual blood cell dynamics in humans limits our understanding of occlusion formation mechanisms. We present a novel in vivo, non-invasive, label-free, and high-resolution imaging technique to study blood flow and sickled cell behavior in affected individuals. We used oblique back-illumination microscopy (OBM) to capture videos of 91.0 ± 42.3 sublingual capillaries in each of ten subjects with SCD before and after red cell transfusions and compared measurements to ten unaffected controls. With direct observation of blood cell activity, we identified microvascular occlusions initiated by red blood cells (RBCs) that adhered to the endothelium and caused mechanical vessel obstruction. Often, the RBCs were sickled. Then, in each observed vessel, we classified blood flow as fast, slow, or no flow, and counted adhered RBCs. Compared to controls, SCD subjects before transfusion had fewer fast-flowing vessels (48.7% vs. 77.7%, p=5.8x10-4), more no flow vessels (16.1% vs. 2.4%, p=0.0010), and more adhered RBCs (1.37 vs. 0.01 cells per vessel, p=0.0025). From before to after transfusion, SCD subjects' microvasculature had increased fast-flowing (48.7% vs. 65.8%, p=0.0098) and decreased no flow vessels (16.1% vs. 6.0%, p=0.0039); adhered RBCs decreased (1.37 vs. 0.71 cells per vessel, p=0.043). These hemorheological indices captured transfusion-induced changes to vascular dynamics and events leading to microvascular dysfunction and occlusion in SCD. Our findings demonstrate the potential of OBM to study vaso-occlusion pathobiology, accelerate therapeutic evaluation, and personalize treatment strategies in people with SCD.

Platelet integrin αIIbβ3 plays a pivotal role in hemostasis and thrombosis. Protein disulfide isomerase (PDI) binds to αIIbβ3 and mediates its activation. The binding region(s) on αIIbβ3 for PDI remains to be established. We identified a new anti-αIIbβ3 murine monoclonal antibody, R21C11, that inhibits PDI binding to platelets, ligand binding to αIIbβ3, and platelet aggregation. R21C11 inhibited recombinant PDI binding to platelets activated with the PAR1 thrombin receptor activating peptide SFLLRN (T6). Reciprocally, PDI partially reduced R21C11 binding to platelets. PDI was translocated to the platelet surface after activation and activated platelets showed higher PDI reductase activity. R211C11 decreased both the amount of PDI and the reductase activity. R21C11 partially inhibited both fibrinogen and PAC-1 binding to αIIbβ3 and platelet aggregation induced by ADP and T6. R21C11 bound slowly to unactivated platelets and more rapidly after T6 activation; eptifibatide, which induces the αIIbβ3 extended-open conformation, also increased the speed of R21C11 binding. Activation also increased total R21C11 binding. Cryogenic electron microscopy single particle analysis of the R21C11 Fab-αIIbβ3 complex revealed that R21C11 binds to the β3 β-tail domain in both nearly bent and semi-extended-closed conformations of αIIbβ3. R21C11 Fab clashed with the β3 β-I domain in the fully bent conformation, accounting for the slow binding rate of R21C11. These data are consistent with R21C11 inhibiting PDI binding by steric hindrance and the activation-dependence of PDI binding. Taken together, these data suggest that the β-tail domain and/or neighboring area is the binding site for PDI on integrin αIIbβ3.

Myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a diverse group of hematopoietic stem cell neoplasms associated with an increased risk of hematologic progression to secondary MF or leukemia and cardiovascular disease (CVD). Elevated total cholesterol levels are traditional CVD risk factors. Patients with MPNs may have reduced cholesterol levels, potentially reflecting an underlying hypermetabolic state. The impact of serum total cholesterol on clinical outcomes in patients with MPNs has not yet been evaluated. We performed a multicenter retrospective cohort study of patients with MPNs who had undergone transthoracic echocardiography (TTE) with available serum lipid levels at time of TTE not on statin therapy. Patients were categorized by total cholesterol level (≥ 150, 120 - 149, and < 120 mg/dL). Outcomes evaluated were MPN disease progression to secondary MF or acute leukemia, major adverse cardiovascular events (MACE), and death. Multivariable competing-risk regression modeling was performed. A total of 305 patients were included of whom 54.4% had total cholesterol ≥ 150, 21.3% 120 - 149, and 24.3% < 120 mg/dL. After a median follow-up of 50.8 months, total cholesterol < 120 was associated with increased risk of MPN disease progression (aSHR 3.00, 95% CI 1.36 - 6.63), heart failure hospitalization (aSHR 3.76, 95% CI 1.77 - 7.96), and all-cause death (aHR 1.87, 95% CI 1.06 - 3.30) vs ≥ 150 mg/dL. Among patients with MPN, low total cholesterol levels were associated with increased risk of MPN disease progression.

The optimal busulfan exposure window in pediatric patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation remains to be defined. We identify this window for patients receiving busulfan within the prospective international, randomized controlled phase III ALLSCTped 2012 FORUM trial (NCT01949129). We included prospectively recruited participants receiving fludarabine-busulfan-thiotepa conditioning, with available busulfan plasma levels. Busulfan exposure was estimated using a validated pediatric population pharmacokinetic model. Primary outcomes were event-free survival (EFS) and graft-versus-host disease-free relapse-free survival (GRFS). Data from 145 patients aged between 0.5 and 19.5 years (treated from 2014 to 2022), with a median follow-up of 5.0 years (IQR 4.8-5.4) were analyzed. The optimal busulfan exposure was defined as cAUC 73.3-98.0 mg·h/L based on EFS and GRFS. Patients with non-optimal exposure had lower EFS (hazard ratio of event [HR] 1.93, 95% confidence interval [CI] 1.19-3.14, p=0.008) and GRFS (HR 2.01, 95%CI 1.29-3.13, p=0.002). Underexposure (cAUC <73.3 mg.h/L) was associated with higher relapse rates (HR 1.93, 95%CI 1.11-3.35, p=0.026), and overexposure (cAUC >98.0 mg.h/L) with an increased risk of treatment-related toxicities and GvHD. Patients with optimal busulfan exposure showed no differences in EFS, GRFS, overall survival or relapse with post-hoc matched total-body irradiation recipients (N=51 in each group). This study identifies a favorable busulfan exposure window for pediatric ALL patients undergoing HSCT from an HLA-matched donor. Therapeutic drug monitoring for optimized personalized busulfan dosing improves HSCT outcomes and might be validated for use as an alternative to irradiation.

Extranodal natural killer/T-cell lymphoma is an aggressive Epstein-Barr virus-associated lymphoma with poor outcomes in advanced-stage disease. High-dose methotrexate-containing, asparaginase-based regimens induce responses but are limited by toxicity, and lower-intensity alternatives show suboptimal durability. We conducted a prospective, multicenter, single-arm phase II trial of the LEAP regimen in newly diagnosed stage IV disease. Eligible patients had ECOG 0-3 and were >65 years or ≤65 years with contraindications to high-dose methotrexate. Treatment comprised up to eight 21-day cycles of sintilimab 200 mg (day 1), pegaspargase 2500 IU/m2 (day 1), and anlotinib 8 mg (days 1-14), with autologous hematopoietic stem cell transplantation (auto-HSCT) allowed for complete responders at the investigator's discretion and patient's preference. Thirty-seven patients were enrolled (median age 64; range, 32-78). At week 24, the complete remission (CR) was 72.9% (27/37), surpassing the prespecified 55% threshold. With a median follow-up of 48 months, estimated 4-year progression-free survival (PFS) and overall survival (OS) were 56.6% and 75.2%, respectively. Seventeen patients underwent auto-HSCT after achieving CR and had lower relapse (17.6% vs 60.0%) and improved PFS (Hazard Ratio=0.23; p<0.05) versus observation. Grade ≥3 adverse events were limited to neutropenia (10.8%) and hyperbilirubinemia (10.8%), with no treatment discontinuations for toxicity or treatment-related deaths. LEAP regimen produced high CR rates and durable survival with manageable toxicity in advanced-stage disease unsuitable for HD-MTX induction and may enable curative-intent therapy; randomized validation is warranted. The study was registered at ClinicalTrials.gov (NCT04004572).

Recently characterised mutations Phe2561Tyr, Pro2555Arg in the Von Willebrand Factor (VWF) C4 domain and Gly2705Arg in the C6 domain reportedly confer gain-of-function-like activity on the molecule, increasing responsiveness to shear stress, resulting in enhanced platelet capture. This implies that the C-terminal stem, comprised of the D4-C6 domains, plays a crucial role in modulating VWF function. To further investigate this, we used site-directed mutagenesis to generate a panel of uncharacterised C-domain variants. VWF expression and function were analysed under static and shear stress conditions, and the biophysical properties of the variants were characterised by single-molecule optical tweezers (OT), and atomic force microscopy (AFM) imaging. All the expressed variants exhibited normal function in static assays, except the C1 domain Arg2287Trp variant that demonstrated increased binding to GPIbα. Under flow conditions at 1500s-1, all the variants had normal VWF-mediated platelet capture to collagen, however at 5000s-1 Arg2287Trp demonstrated enhanced platelet capture, while Asn2636Tyr (C5 domain), Thr2647Met (C6 domain) and Gly2705Arg showed reduced activity. Further analysis of the formation of rolling VWF-platelet aggregates over a VWF surface demonstrated an enhanced response to shear stress for the Arg2287Trp and Arg2384Trp (C2 domain) variants. OT analysis identified novel extension events exclusive to the C-terminal domains and more frequent unfolding events and longer unfolding extensions for Arg2287Trp and Arg2384Trp, consistent with increased flexibility and stem opening. AFM imaging confirmed that both variants favoured the open stem conformation. Together, we demonstrate that mutations in the C1 and C2 domains alter stem dynamics, rendering VWF more responsive to shear stress.

Graft failure post-allogeneic haematopoietic stem cell transplant (HSCT) is life threatening complication. The Inborn Errors Working Party (IEWP) conducted a retrospective study to examine outcome of second HSCT for children with non-SCID inborn errors of immunity (IEI). 159 children from 37 centres who received a second transplant between 2009-2020 were included in this analysis. The median interval between first and second HSCT was 6.9 months (0.7-155.2 months). The 5-year OS and EFS were 78% and 69%, respectively. Second HSCT for primary graft failure had a significantly lower OS (69%,55-83% versus secondary graft failure, 81%,73-89%; p=0.044) and EFS (52%,37-68% versus secondary graft failure, 75%,67-84%; p<0.001). Viral infections at second HSCT resulted in significantly lower EFS (p=0.030), but not OS (p=0.089). Improved EFS was observed in patients who received MAC/RTC (74%,66-81%) compared to NMA (50%,29-71%, p=0.003), but this association was not observed in OS. Upon multivariable analysis, cord blood was the only independent negative predictor for EFS (HR 4.9,1.3-18.7, p=0.020). The 1-year cumulative incidence (CIN) of all graft failure post-second HSCT was 13% (95% confidence intervals (CI),8-19%). The Day-100 CIN of grade II and grade III-IV aGvHD was 19% (13-25%) and 8% (4-13%), respectively. Whole blood chimerism >90% was reported in 84.3% at last follow-up. We report the first international experience with the largest cohort of second conditioned HSCT in non-SCID IEI to date. This study provides valuable insights into the clinical outcomes following second transplant, identifying key predictors of survival.