Blood advances最新文献

Practice variation exists in the management of newly diagnosed pediatric immune thrombocytopenia (ITP) despite availability of evidence-based treatment guidelines. The American Society of Hematology (ASH) ITP guidelines recommend that initial treatment of children should be based on assessment of clinical symptoms rather than the degree of thrombocytopenia and that short courses of corticosteroids should be prescribed to children requiring initial medication treatment. Retrospective review evaluating treatment of newly diagnosed children with ITP has demonstrated that management continues to be based on the platelet count with high use of intravenous immunoglobulin, which results in overuse of medications and high rates of inpatient hospitalizations and medical visits for administration and management of side effects. To improve adherence to ASH guidelines, the ITP Consortium of North America implemented a clinical care pathway as a multicenter quality improvement initiative. Retrospective data (11 centers, n=284) were collected prior to implementation and compared to post-implementation data (12 centers, n=266). With implementation of the clinical pathway, documentation of a bleeding score for children at diagnosis increased from 1% (3/284) to 95% (253/266). At diagnosis, initial treatment with ITP-directed medications decreased in children with no or mild bleeding symptoms (62% (177/284) vs. 31% (83/266), p<0.0001). Intravenous immunoglobulin use reduced from 51% (145/284) to 15% (41/266), p<0.0001. With implementation of the pathway, clinical outcomes were comparable with no increase in inpatient hospitalizations or bleeding events. Implementation of a clinical care pathway for a rare condition increases adherence to evidence-based guidelines and is feasible to implement across multiple centers.

Chronic Graft versus Host Disease (cGVHD) remains a major hurdle to the success of hematopoietic stem cell transplantation (HSCT), directly impacting patient morbidity and mortality. Impaired Treg recovery in patients with cGVHD has led to clinical studies aiming to increase peripheral Treg numbers. We performed Phase I dose escalation clinical trials, testing the feasibility and safety of using freshly isolated donor-derived Treg infusions in steroid-refractory/dependent cGVHD. The Phase I was extended to a preliminary Phase II trial, resulting in a total of 33 treated patients. We report that Treg purification from donor leukapheresis using CliniMACS were feasible and that Treg infusions were safe. Importantly, Treg infusions resulted in improved symptoms, particularly at higher Treg doses. Global responses were observed in 71% of patients, and 52% of patients had at least a 2-point improvement in the cGVHD severity scale. Furthermore, improvement in cGVHD symptoms resulted in reductions in corticosteroids, ruxolitinib and mycophenolate (MMF) in 58%, 83% and 33% of patients, respectively, while calcineurin inhibitors were discontinued in 75% of patients. Exploratory analyses revealed the detection of infused Treg clonotypes up to 12 months post-infusion and suggest increased Treg numbers in circulation. We observed increases in serum levels of IL-7, IFN-g, and decreases in sCD13 and ST2 over time, which were not statistically significant following adjustment for multiple comparisons. Although these studies were not powered to assess efficacy, they suggest potential therapeutic benefits of donor-derived Treg in cGVHD treatment and highlight the need for larger Phase II clinical trials. NCT02385019 NCT03683498 (clinicaltrials.gov).

Newly diagnosed mantle cell lymphoma (MCL) is commonly treated with rituximab (R) combined with anthracycline-based chemotherapy, with or without autologous stem-cell transplantation (ASCT). While rituximab maintenance (RM) in clinical trials has been shown to prolong overall survival (OS), its impact at population level remains largely unknown. This study evaluates the effect of RM on outcome of patients with MCL. Patients aged ≥18 years diagnosed with MCL between 1989-2020 were identified using the Netherlands Cancer Registry, and categorized into periods reflecting R and RM implementation (1989-2000, 2001-2014, 2015-2020). Treatment strategies were categorized as R-CHOP, R-CHOP followed by high-dose cytarabine (intensive) and ASCT, and other. The primary endpoint was 5-year OS. Multivariable analysis (MVA) was performed using Cox regression. Among 4,751 patients, 5-year relative survival (RS) improved from 38% (1989-2000) to 47% (2001-2014) and 60% (2015-2020) (p<0.01), irrespective of age (≤65 years: 32% and >65 years: 20% increase over time. Patients with progression (POD) within 12 months had 2-year OS of 25%. Since 2014, RM implementation reached 80% in younger and 50% in older patients. RM was associated with improved OS especially for patients in partial remission (PR), after induction treatment with R-CHOP. In MVA patients with R-CHOP, RM was independently associated with reduced mortality (hazard ratio 0.69; 95% CI, 0.53 - 0.90). Relative survival in MCL improved by more than 20% over the past 30 years. Early disease progression remains associated with poor outcome. RM was associated with improved survival, especially for patients achieving PR following R-CHOP.

Since the introduction of allogeneic bone marrow transplantation (BMT) for aplastic anemia, major advances have included refinements in conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, high-resolution human leukocyte antigen (HLA) typing, pre-transplant transfusion practices, and general supportive care. We present a comprehensive retrospective single-center cohort study of 607 children and adults who underwent allogeneic transplantation for aplastic anemia over six decades at a single BMT center. We highlight key temporal changes in conditioning for related donor transplants, GVHD prophylaxis, and HLA matching that correspond with improved non-relapse mortality, reduced GVHD rates, and better overall survival among HLA-matched related and unrelated donor transplants. This work provides a historical perspective on the evolution of BMT for aplastic anemia for HLA-matched related and unrelated donor recipients and identifies persistent barriers to curative therapy, including patient age and donor availability. Further studies are needed to clarify the role of anti-thymocyte globulin in conditioning regimens, improve GVHD prevention and management, and expand use of alternative donors.

Background: In patients with immune thrombocytopenia (ITP), a critical bleed such as intracranial hemorrhage or bleeding causing hemodynamic instability, requires urgent treatment to rapidly raise the platelet count and restore hemostasis. There is no standardized approach to this hematological emergency.

Objective: The McMaster ITP Emergency Management Guideline Group developed evidence-informed recommendations for the management of a critical bleed in adults and children with ITP.

Methods: The guideline panel included 5 clinical experts in adult ITP, 3 clinical experts in pediatric ITP, 2 emergency department physicians, 1 emergency department nurse, 2 methodologists, and 4 patient partners. To inform recommendations, the guideline team conducted a multicentre retrospective cohort study and systematic reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence and GRADE's evidence-to-decision framework to formulate recommendations.

Results: Given the life-threatening nature or significant morbidity associated with the condition, despite low or very low certainty evidence, the panel made strong recommendations for the combined use of high-dose corticosteroids, high-dose intravenous immunoglobulin (IVIG), platelet transfusions, tranexamic acid, and thrombopoietin receptor agonists (TPO-RAs) for the treatment of adults or children with a critical ITP bleed. The panel made a conditional recommendation for urgent splenectomy when other treatments have failed and, due to the risk of thrombosis, a conditional recommendation against the use of recombinant factor VIIa.

Conclusions: Motivated by the life-threatening nature of the condition, the panel made strong recommendations for the combined use of high-dose corticosteroids, high-dose IVIG, platelet transfusions, tranexamic acid, and TPO-RAs for the emergency management of adults and children with a critical ITP bleed.

Patients with large B-cell lymphoma (LBCL) are at increased risk of heart failure (HF) potentially due to anthracycline-based chemotherapy. However, associations with LBCL treatment intensity, HF subtype, and outcome remain under-characterized. We conducted a nationwide cohort study of 8,453 Swedish patients diagnosed with LBCL (median age 70 years) between 2007-2022 and 71,506 matched population comparators without a history of HF. The 5-year cumulative incidence of new-onset HF among patients was 8.1% overall, corresponding to a two-fold increased rate, driven mainly by non-ischemic HF (hazard ratio [HR]non-ischemic 2.33, 95% confidence interval [CI] 2.16-2.50), and less by ischemic HF (HRischemic 1.30, 95% CI 1.04-1.62). An increased rate of new-onset non-ischemic HF remained after 2 years of follow-up (HR 1.78, 95% CI 1.60-1.94). Few patients had reduced-intensity treatment (4 R-CHOP, n=84) of whom none developed HF. Patients selected for intensive treatment (e.g., R-CHOEP/R-DA-EPOCH) were not at higher risk of HF compared with standard R-CHOP (HR 0.73, 95% CI 0.58-0.92), although unmeasured differences in baseline fitness or frailty may have influenced treatment selection. After HF onset, LBCL patients had consistently higher all-cause (but not cardiovascular) mortality than comparators. Our findings indicate that LBCL patients face a sustained long-term risk of non-ischemic HF, highlighting the importance of survivorship care and vigilant HF symptom screening.

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.