Blood advances最新文献

Bemiltenase alfa, a factor X (FX) activator derived from Daboia russelii siamensis venom, was developed as a hemostatic agent for hemophilia A and B with inhibitors (HAwI and HBwI). We conducted two consecutives multicenter, open-label clinical trials. The phase Ib/IIa study assessed the safety, hemostatic efficacy, and pharmacokinetics/pharmacodynamics characteristics of bemiltenase alfa at a dose of 0.1U/kg. The phase IIb study further evaluated the safety and efficacy at a dose of 0.1U/kg. Primary efficacy endpoints encompassed the effective hemostasis rate, safety assessment and anti-drug antibodies (ADAs) development. There were six participants enrolled in phase Ib study, 20 in phase IIa and 25 in phase IIb study. Patients received bemiltenase alfa for bleeding episodes in phase IIa and IIb studies. In phase IIa, the effective hemostasis rates were 94.1% (95% CI: 88.7-97.4). Phase IIb showed an 81.9% rate (95% CI: 71.0-92.9). Most adverse events were mild with grade one in severity, with no serious events. ADA was detected in five patients, but no impact on efficacy and safety was found. Pharmacokinetics findings showed repeated doses of bemiltenase alfa resulted in progressive drug concentration, as indicated by the accumulation ratio index. Pharmacodynamics results indicated a reduction in activated partial thromboplastin time and an increase in thrombin generation peak. Additionally, a mild decline in FX activity was observed post-administration. The study demonstrates FX activation as a novel hemostatic strategy, with snake venom-derived bemiltenase alfa showing promising safety and efficacy for treating bleeding episodes in HAwI and HBwI patients. (clinicaltrials.gov: NCT05027230, NCT06289166).

Children with non-malignant hematological disorders (NMHD) often require numerous red blood cell transfusions prior to hematopoietic stem cell transplant (HSCT), leading to iron overload. Ferritin and liver iron concentration (LIC) are used to estimate the degree of iron overload to determine eligibility for HSCT, but neither marker has been definitively associated with poorer HSCT outcomes in pediatric cohorts. We conducted a multicenter retrospective cohort study using PEDSnet to examine the association between elevated pre-HSCT ferritin and LIC and HSCT outcomes, and to evaluate iron reduction therapy post-transplant. 580 patients with a pre-HSCT ferritin and 260 patients with a pre-HSCT LIC were studied. Patients with high pre-HSCT ferritin >2500 ng/mL had decreased 3-year overall survival (adjusted HR 2.31, 1.06-5.04). A sensitivity analysis demonstrated this trend only in patients with severe aplastic anemia (SAA). Elevated ferritin was associated with a markedly increased risk of bacteremia after HSCT in patients with SAA (HR 3.33, 1.72 - 6.44). Elevated pre-HSCT LIC >5 mg Fe/g dry weight was not associated with decreased survival, bacteremia, graft failure, or veno-occlusive disease (VOD). VOD was assessed only in patients undergoing busulfan-based transplant. Post-transplant, 63% of patients in the multicenter analysis had an elevated ferritin, while 68% had an elevated LIC. Chelation and phlebotomy were equally effective in reducing post-HSCT iron. These results challenge the use of LIC as the gold standard for iron-related risk stratification in HSCT. Further research into peri-HSCT iron management is necessary in an era of expanding availability of HSCT for NMHD.

Protease activated receptor 1 (PAR1) is expressed by numerous cell types, including endothelial. Thrombin cleaves PAR1 at Arg41 and activates pro-inflammatory and barrier disruptive signaling. Alternatively, PAR1 is cleaved at Arg46 by activated protein C (APC) bound to endothelial protein c receptor (ECPR), inducing anti-inflammatory and barrier protective signaling. In sickle cell disease (SCD), we showed that thrombin-PAR1 signaling contributes to vascular stasis, and more recently that PAR1-R41 biased signaling enhances inflammation, whereas PAR1-R46 signaling reduces thrombo-inflammation. We hypothesized that ECPR-PAR1-R46 biased signaling protects sickle mice from thrombo-inflammation. To test this hypothesis, Townes sickle mice were treated with parmodulin (parmodulin 2 (PM2, aka ML161), or NRD-21) to promote protective, anti-inflammatory PAR1-biased signaling. We found that PM2 significantly attenuated thrombin generation, inflammation, endothelial activation, and protected sickle mice from a model of lethal acute chest syndrome. These results suggest that utilizing PM2 to block thrombin-PAR1 signaling while inducing APC-like signaling can promote cytoprotective, anti-inflammatory effects in mouse models of SCD.

Effective transition programs are essential for adolescents and young adults with sickle cell disease (SCD), yet their long-term impact remains unexplored. The St. Jude SCD Transition Program provides structured transition interventions, including disease education, personal health record (PHR) communication training, transition skills-building, academic guidance, and early adult care introduction for patients aged 12-25 . This 13-year retrospective cohort study evaluated program effectiveness on first adult visit attendance, successful adult care transfer, adult ambulatory and acute care utilization, and health-related quality of life (HRQOL). Among 638 patients, 74.5% attended their first adult visit and 40.0% successfully transferred to adult care (2 visits within the first-year post-transfer). Increased participation in nearly all transition interventions was associated with first adult visit attendance, and all interventions were associated with successful transfer. In-person SCD education and early introduction to adult care were independently associated with first adult visit attendance, while in-person SCD education and PHR training were independently associated with successful transfer. A predictive model incorporating intervention exposure and demographics yielded an area under the curve of 0.81 for attendance at the first adult visit (95% CI: 0.75-0.88; sensitivity 0.76, specificity 0.70). PHR training was associated with adult ambulatory utilization up to 3 years post-transfer and improved early adulthood HRQOL. No interventions were associated with acute care utilization. Transition interventions improving disease literacy, communication, and care transfer processes are linked to better transition outcomes and HRQOL, though sustained adult care engagement remains low. Future research is needed to promote adult care engagement.

Despite decades of research, the precise cellular origins of coagulation factor VIII (FVIII), deficient in the inherited bleeding disorder hemophilia A (HA), have remained controversial. Early studies proposed that FVIII comes from hepatocytes, similar to most other coagulation factors. More recent data pointed to liver sinusoidal endothelial cells (LSECs) as the primary source of FVIII, but conflicting reports and methodological limitations have obscured a clear understanding of hepatic and extrahepatic FVIII expression. Discordance between natural FVIII biosynthesis sites and cellular targets of adeno-associated viral (AAV) vectors has been implicated in efficacy limitations of current gene therapies for hemophilia A. Here, we developed and employed a novel gene-edited F8 promoter-reporter mouse model, humanized mice, and human tissue samples to definitively map FVIII-producing cells. We found that FVIII originates primarily from LSECs, not hepatocytes, corroborating most recent reports. Additionally, we detected the F8 reporter in renal endothelial cells. Further, we identified a striking microanatomical variation in FVIII expression between LSECs situated in different hepatic lobular zones, revealing that FVIII synthesis is predominantly localized to LSECs in Zones 2 and 3 of hepatic lobules in both mice and humans, with minimal expression in Zone 1. This zonal pattern was maintained even in the context of steatohepatitis. Our work clarifies the primary cellular source of FVIII and unravels the microheterogeneity of FVIII expression within the liver, providing insights for optimizing gene therapy strategies for hemophilia A that aim to induce FVIII production in its natural endogenous expression sites.

Allogeneic hematopoietic stem cell transplantation is used for consolidation in children and adolescents with refractory or early relapsed ALK-positive anaplastic large cell lymphoma (ALCL). The immune system plays a major role in the sustained control of the disease. We therefore retrospectively analyzed whether the type of conditioning, donor type, and in-vivo T-cell depletion correlate with outcome in a large population-based cohort of 57 children with CNS-negative ALCL relapse transplanted between 2005-2022. Progression-free (PFS) and overall survival from transplantation were 84±10% and 91±8% at 3 years, respectively. Conditioning was based on total body irradiation (TBI) in 30 patients and on chemotherapy in 27 patients, mainly with reduced-toxicity conditioning (RTC; Treosulfan, Fludarabine, and Thiotepa). PFS and graft-vs.-host disease-and event-free survival (GEFS) were comparable between TBI and chemotherapy, 87±6% versus 81±8%, (p=0.62) and 67±9 versus 74±8 (p=0.63), respectively. Patients with transplantation from unrelated donors with rabbit anti-human T lymphocyte globulin (ATLG) had superior PFS and GEFS compared to those receiving grafts from matched sibling donors without ATLG:94±7% versus 67±22% (p=0.0007), and 82±13% versus 44±24% (p=0.011), respectively. Progression during frontline chemotherapy, minimal residual disease, and remission status at allogeneic SCT were not associated with outcome. PFS and survival of eight additional patients with CNS-positive disease were 50% and 62%, respectively. Non-relapse mortality was 5.6% for all 65 patients and cumulative incidence of grade II-IV acute GvHD was 25%. Our data support the use of TBI-free conditioning and suggest improved outcomes with unrelated donors receiving ATLG prophylaxis. NCT00317408.

We conducted a phase 1-2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tildrakizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft versus host disease (GVHD) prophylaxis. Fifty patients were enrolled between March 2020 and June 2023 with a median age of 56 (range 19-64). All patients received myeloablative busulfan-based conditioning and were transplanted with HLA-matched related or unrelated peripheral blood stem cell grafts. Patients were treated with tildrakizumab on an extended subcutaneous administration schedule for five doses which was well tolerated. The cumulative incidences of grades II-IV and III-IV acute graft versus host disease were 14% (95% CI 7-28) and 4% (95% CI 1-16) at day 100, respectively. The incidence of chronic GVHD requiring systemic immune suppression was 52.7% (95% CI 40.4-68.9) at twelve months. The one-year probabilities of overall, disease-free, and GVHD-free relapse-free survival were 80% (95% CI 70-92), 78% (95% CI 67-90), and 19.3% (90% CI 11.8-31.4), respectively. Pharmacokinetic analysis revealed that the half-life of tildrakizumab approximated 28 days without formation of detectable anti-tildrakizumab neutralizing antibodies. Comparative examination of fecal microbial composition in tildrakizumab and a similarly transplanted cohort treated with tocilizumab prophylaxis demonstrated that both cytokine blockade strategies had a low frequency of enterococcal dominance. We conclude that tildrakizumab resulted in a low incidence of acute GVHD and attenuation of microbiome dominance with potentially pathogenic organisms but did not mitigate the emergence of chronic GVHD as administered on this dosing schedule. NCT04112810.

The hallmark of ERCC6L2 disease (ED) is a highly penetrant progression from bone marrow failure (BMF) to erythroid-predominant, TP53-mutated myeloid malignancy with a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option, but concerns exist regarding transplant-related toxicities due to the underlying DNA repair defect. This is the first study to report a systematic analysis of HSCT in ED. We conducted a retrospective multicenter study involving 45 patients with ED who underwent HSCT in 2004-2024. The primary outcomes were overall survival (OS), transplant-related toxicity, and non-relapse mortality (NRM). The 1-year and 3-year OS were 79% (95% confidence interval [CI], 66-91) and 54% (95% CI, 35-73), respectively. Prior history of excess blasts significantly predicted inferior survival (hazard ratio [HR], 6.8; 95% CI, 2.2-20.3; P<0.001), with a median survival of 12 months (95% CI, 0-24). Grade 3-5 endothelial toxicities occurred in 27% of patients and were associated with higher NRM (HR, 7.7; 95% CI, 1.5-38.8; P=0.016). The use of non-treosulfan-based myeloablative conditioning (MAC) regimens increased the risk of endothelial complications compared to reduced-intensity conditioning (RIC) (HR, 4.9; 95% CI, 1.1-22.0; P=0.040), whereas outcomes with treosulfan-based MAC were comparable to RIC. In summary, allogeneic HSCT is a viable curative strategy for ED when performed before transformation to an aggressive malignancy i.e. myelodysplasia with excess blasts or acute myeloid leukemia. However, the elevated incidence of endothelial toxicity highlights the importance of optimizing conditioning intensity and enhancing peritransplant monitoring in this population.