Blood advances最新文献

Abstract: Real-world evidence (RWE) has been used to improve quality of care, accelerate innovation, and evaluate emerging therapies for drugs, devices, and biologics. The Coordinated Registry Network (CRN), aggregating and linking highly curated patient data, has emerged as a model for RWE generation that has guided the development of the American Society of Hematology Research Collaborative (ASH RC) Data Hub. With the aim of bolstering research, enhancing clinical care, and expediting evidence generation using RWE, the ASH RC and the Innovative Genomics Institute launched a joint initiative, "Accelerating Innovations for Sickle Cell Disease (SCD) with Real-World Evidence," to evaluate and make recommendations to the Data Hub. An expert panel used a "maturity model" to evaluate the following: (1) Data Hub standardization of RWE guidelines to ensure successful monitoring of new therapies' safety and effectiveness; and (2) the Data Hub's engagement with patients (including collection of data on patient experience) and collaboration among partners, including regulators, industry, and clinicians. The Data Hub gathers patient-level data from electronic health records, with plans to incorporate data from individuals receiving gene therapy. The program is currently curating and aggregating data on ∼27 000 individuals with SCD cared for across 22 hospitals in the United States. The SCD Data Hub program includes a total of 56 centers, some of which are not yet contributing data, which will increase the total cohort to ∼50 000 patients. The unique organizational structure of the CRN model facilitates acceleration of innovation through collaborative relationships between multiple clinical sites and partners with various evidentiary needs.

Abstract: Hematopoietic stem cell transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially fatal multisystem complication of hematopoietic cell transplantation for which there is no approved treatment. In a single-arm study (NCT02222545), narsoplimab treatment for TA-TMA demonstrated a median overall survival (OS) of 274 days from date of diagnosis. Here, we compare OS observed in 2 cohorts treated with narsoplimab to OS in a well-matched external control to test survival benefit in patients with high-risk TA-TMA. OS in patients (aged ≥16 years) with high-risk TA-TMA treated with narsoplimab in a single-arm, open-label study (NCT02222545) or in the narsoplimab expanded access program (EAP; NCT04247906) was compared with OS in a control group with high-risk TA-TMA from the Kyoto Stem Cell Transplantation Group (KSCTG) registry. Narsoplimab-treated patients in the single-arm study (N = 28) had a fourfold reduction in risk of mortality compared with patients from the KSCTG registry (N = 111; hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.19, 0.34; P < .0001). Similarly, in high-risk patients treated with narsoplimab in the EAP (N = 49), mortality risk was significantly lower than among high-risk patients from the KSCTG registry (N = 121; HR 0.38; 95% CI 0.28, 0.51; P < .0001). When narsoplimab-treated patients from the single-arm study and the EAP (N = 77) were compared with KSCTG patients, the HR for mortality was 0.28 (95% CI, 0.22, 0.37; P < .0001). In conclusion, in patients with high-risk TA-TMA, narsoplimab treatment significantly reduced mortality relative to a well-matched external control group who did not receive narsoplimab. These results support narsoplimab as a potential therapeutic option for TA-TMA.

Abstract: Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Abstract: Venous thromboembolism (VTE) is a frequent occurrence in patients with cancer. However, it is not known whether treatment with different classes of anticoagulants impacts the risk of subsequent arterial thromboembolism. We performed a retrospective, population-based cohort study using Surveillance, Epidemiology, and End Results data linked with Medicare claims. Patients were eligible for study inclusion if they had a diagnosis of primary brain, colorectal, gastric, pancreatic, lung, or ovarian cancer between 2007 and 2015, were diagnosed with VTE, and had a prescription claim for a direct oral anticoagulant (DOAC), low-molecular-weight heparin (LMWH), or warfarin. We matched patients by propensity score in a 1:1:1 ratio into anticoagulant treatment groups based on their baseline demographic information, cancer-specific characteristics, and cardiovascular comorbidities. The primary aim of the study was to determine and compare the 6-month cumulative incidence of ischemic stroke across anticoagulant classes. The study comprised 4875 total patients with 1625 in each treatment group. At 6 months, the cumulative incidence of ischemic stroke was 5.6% (95% confidence interval [CI], 5.0-6.3) overall and 6.8% (95% CI, 5.6-8.1) in the DOAC, 4.9% (95% CI, 3.9-6.0) in the LMWH, and 5.2% (95% CI, 4.1-6.2) in the warfarin treatment groups (P = .040). We identified hypertension (odds ratio [OR], 1.75), atrial fibrillation/flutter (OR, 1.37), DOAC use (OR, 1.36), and previous stroke (OR, 3.59) as statistically significant risk factors for ischemic stroke in the multivariable modeling. In conclusion, ischemic stroke is a common occurrence after cancer-associated VTE and may occur more frequently in patients treated with DOACs.

Abstract: Measurable residual disease (MRD) assessment by flow cytometry (FC) plays an essential role in prognosis and therapy escalation of B-cell acute lymphoblastic leukemia (B-ALL). However, the high degree of expertise and manual analysis time required limits the availability of this assay. To overcome this limitation, we developed a data-enhancing artificial intelligence (AI) pipeline that accelerates and simplifies MRD analysis. Unaltered FC files from 171 B-ALL MRD-positive and 89 MRD-negative cases were processed through an AI pipeline trained with 31 expert-gated negative controls. Cluster-informed downsampling reduced FC files from 1.2 million to 155 884 cells per case, on average, (87% cellularity reduction), whereas preserving small MRD populations (median, 100% retention for MRD of <1%) and allowing for true percentage MRD estimates using a correction factor. A deep neural network cell classifier automatically identified normal hematopoietic subsets (macro-averaged F1 score of 0.86); and an AI measure of anomaly discriminated B-ALL from benign mononuclear (area under the curve [AUC] of 0.98) or B-lymphoid cells (AUC of 0.94). Manual analysis of AI-enhanced files was completed in only 1.01 minutes per case, on average (standard deviation of ±0.57); with 100% positive agreement with conventional analysis (for MRD of ≥0.01%), 100% negative agreement, and excellent quantitative correlation (R2 = 0.92). Our cloud-based AI-enhancement solution accelerates B-ALL MRD identification without compromising test performance and has the potential of facilitating B-ALL MRD analysis by more clinical laboratories.

Inhibiting coagulation Factor XI (FXI) activity has emerged as a promising strategy to prevent intravascular thrombosis. Here, we describe the first-in-human trial with an N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA), RBD4059, targeting FXI. In this Phase 1 single ascending-dose study (NCT05653037), healthy volunteers were randomized to receive active drug or placebo (6+2), administered subcutaneously, in four consecutive dose cohorts from 50 mg to 600 mg. The primary endpoint was safety and tolerability up to Day 169 post dose. Secondary endpoints included pharmacokinetic and pharmacodynamic (PD) parameters. Single ascending doses of RBD4059 were well tolerated and no apparent safety concerns were identified. RBD4059 was associated with a dose-dependent and durable suppression of FXI activity up to greater than 90%. Modeling of the available PD data supports clinical dosing schemes of 3-6 months to achieve a robust antithrombotic effect. Altogether, these observations support the further clinical development of RBD4059 to provide an siRNA-based therapeutic option targeting FXI for patients inadequately treated with or contraindicated for thrombosis prophylaxis.

The phase 2 ALYCANTE trial aimed to evaluate the investigator-assessed complete metabolic response at 3 months from the axi-cel infusion as a primary endpoint in patients with high-risk relapsed/refractory large B-cell lymphoma who are ineligible for autologous stem cell transplantation (ASCT). This study showed a significant improvement in complete metabolic response rate at 3 months based on historical controls. The present study reports the health-related quality of life (HRQoL) results as a secondary endpoint. HRQoL was assessed using the EORTC QLQ-C30 cancer-specific questionnaire, the QLQ-NHL-HG29 high-grade non-Hodgkin lymphoma module, and the EQ-5D-5L generic questionnaire at baseline and 1, 3, 6, and 12 months post-axi-cel infusion. Among the 62 patients included, 60 (97%) completed a baseline and at least one post-baseline HRQoL assessment. At 1 month post-infusion, adjusted mean change in HRQoL scores from baseline showed a clinically significant deterioration (greater than the clinical threshold) in physical, role, social functioning and fatigue. However, all HRQoL dimensions recovered by 3 months post-infusion and remained stable or continued to improve by 12 months. In an exploratory analysis, adjusted mean change in HRQoL score from baseline in ALYCANTE was similar to or better than in ASCT-eligible patients who received axi-cel in the phase 3 ZUMA-7 trial. Finally, the global health status and fatigue scores of the ALYCANTE population improved to levels comparable to the general French population of similar age by 3 months post-infusion. These findings indicate that axi-cel improves HRQoL regardless of transplant eligibility, supporting its use across a broad patient population. NCT04531046.

Neutrophil-mediated persistent inflammation and neutrophil extracellular trap formation (NETosis) are critical in the pathogenesis of deep vein thrombosis (DVT). Identifying the mechanisms controlling these pro-inflammatory and pro-thrombotic functions is critical for designing and developing new therapeutics for DVT. However, how neutrophils acquire these phenotypes during the early stages of DVT remains poorly understood. Here, multiomic analyses (RNA-sequencing, proteomics, flow cytometry) of bone-marrow neutrophils 3 hours after DVT revealed consistent overexpression of CD14. Concurrently, mice with DVT exhibited significantly elevated plasma granulocyte colony-stimulating factor (G-CSF) and neutrophil hyperactivation. Mechanistic studies using a geometric deep learning model (DeepPBS) and chromatin immunoprecipitation (ChIP) revealed that elevated G-CSF drives CD14 overexpression by upregulating the transcription factor C/EBPα (leucine zipper CCAAT-enhancer binding protein α). Importantly, neutrophil-specific CD14 knockdown using a novel lentiviral shRNA approach significantly improved DVT outcomes by lowering thrombus burden, thrombosis incidence, and intra-thrombus neutrophil and citrullinated histone H3 accumulation. Studies in G-CSF stimulated primary human neutrophils revealed that CD14 inhibition reduces markers of inflammation and NETosis (activated gasdermin D, citrullinated histone H3, and S100A8/A9), while increasing apoptosis, thus demonstrating translational relevance. Collectively, our study uncovers an essential role of neutrophil CD14 in DVT pathogenesis and establishes it as a promising therapeutic target for DVT.

Platelets must balance hemostatic function with pathological thrombosis, particularly under metabolic stress conditions. Mitogen-activated protein kinases (MAPKs) are central to platelet responses, but how these platelet signals differentially regulate hemostasis remains poorly understood. To investigate the role of Traf2/Nck-interacting kinase (TNIK), we generated megakaryocyte/platelet-specific TNIK-knockout mice (Tnikf/f PF4-Cre+) and evaluated platelet function, hemostasis, and thrombosis under normal and hyperlipidemic conditions using chimeric Tnikf/f PF4-Cre+ Apoe-/-mice fed high-fat diets. TNIK-deficient mice exhibited prolonged bleeding times, delayed arterial thrombosis and platelet activation under normal conditions, primarily due to impaired dense granule secretion. Mechanistically, TNIK interacted with JNK-interacting protein 1 (JIP1) to promote MLK3/MKK4/JNK pathway activation during hemostatic responses. Surprisingly, under hyperlipidemic conditions, TNIK deficiency accelerated thrombosis and enhanced platelet responses to oxidized low-density lipoprotein (ox-LDL). In this context, TNIK specifically bound to protein kinase C epsilon (PKCε) and suppressed the NOX2/ROS/ERK5 pathway, thereby inhibiting excessive platelet activation. We conclude that TNIK functions as a molecular switch in platelets, promoting normal hemostasis while simultaneously preventing hyperlipidemia-associated thrombosis through distinct signaling pathways. This dual regulatory mechanism provides insight into how platelets balance hemostatic function with pathological thrombosis risk and identifies TNIK as a potential therapeutic target in metabolic thrombotic disorders.

Hereditary hemorrhagic telangiectasia (HHT) causes severe recurrent epistaxis, chronic gastrointestinal bleeding, solid organ arteriovenous malformations, and a profound anemia burden. It is the second most common inherited bleeding disorder worldwide yet remains without approved therapies. The multicenter U.S. randomized, controlled PATH-HHT trial demonstrated efficacy of short-term pomalidomide treatment of epistaxis in HHT. However, many critical questions regarding long-term safety, effectiveness, and utility for HHT-associated gastrointestinal bleeding remain. The PATH-HHT After Trial Longitudinal Assessment Study (NCT07018401) was a multicenter U.S. longitudinal observational study evaluating patients enrolled in PATH-HHT who continued pomalidomide post-PATH-HHT through a post-study drug access program, with ongoing close monitoring per PATH-HHT protocol and as mandated by FDA. Sixty-two patients treated with pomalidomide for HHT for up to 4.4 years were included. Significant, durable improvements in mean Epistaxis Severity Score (5.55 points [baseline] to 2.80 points [month 12], p<0.0001) and mean Hematologic Support Score (9.11 red-cell unit equivalents [RUEs] during 6 months pretreatment to 5.73 RUEs [months 7-12], p=0.0056) were observed. Pomalidomide was less effective for gastrointestinal bleeding than epistaxis, particularly in patients with high RBC transfusion requirements. Thirty-one patients (50%) dose-reduced from 4-mg daily, primarily due to neutropenia, but most maintained effectiveness at 2- or 3-mg daily. Over 105.2 patient-years of pomalidomide treatment, 0 patients developed peripheral neuropathy, 1 developed venous thromboembolism, and 5 developed serious infections. In conclusion, pomalidomide was highly and durably effective for HHT-associated epistaxis, albeit with nontrivial potential toxicities, and may be considered a routine long-term antiangiogenic therapeutic option for certain patients with HHT. NCT07018401.