Blood Advances

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In a Phase 1 study (NCT04000165), we established proof-of-concept for activating pyruvate kinase (PK) in sickle cell disease (SCD) as a viable anti-sickling therapy. AG-348 (mitapivat), a PK activator, increased adenosine triphosphate (ATP) and decreased 2,3- diphosphoglycerate levels while patients were on treatment in line with the mechanism of the drug. We noted that the increased hemoglobin persisted for 4 weeks after stopping AG-348 until the end of study (EOS). Here, we investigated the pathways modulated by activating PK that may contribute to the improved red blood cell (RBC) survival after AG-348 cessation...

Sickle cell trait (SCT) is a risk factor for venous thromboembolism (VTE). Prior studies investigating the association of SCT and VTE have been performed nearly exclusively in Black populations. However, race-based research can contribute to systemic racism in medicine. We leveraged data from the 23andMe Research cohort (4,184,082 participants) to calculate the ancestry-independent risk of VTE associated with SCT as well as comparative risk estimates for heterozygous factor V Leiden (FVL). Odds ratios (OR) were calculated using a meta-analysis of 3 genetic ancestry groups (European [n=3,183,142], Latine [n=597,539], and African [n=202,281]) and a secondary full-cohort analysis including 2 additional groups (East Asian [n=159,863] and South Asian [n=41,257])...

β-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit β (HBB) gene. In β-thalassemia intermedia (βTI), a non-transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin stabilizes the iron exporter ferroportin (FPN) on the basolateral membrane of enterocytes. High FPN activity may deplete intracellular iron and enhance expression of the predominant iron importer divalent metal-ion transporter 1 (DMT1)...

Myelofibrosis (MF) in the chronic phase is a challenging disease entity to treat, and conventional treatment options are geared towards symptom palliation. In this prospective, multicenter, phase II trial, 21 patients with myelofibrosis (18 chronic-phase, 2 accelerated-phase, 1 blast-phase) were treated with a 10-day schedule of subcutaneous decitabine at 0.3 mg/kg/day. The overall response rate was 33% (95% CI, 15-57), primarily manifested as an improvement in cytopenias. The median duration of response was 7 months (range, 3-44)...

Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after evaluation of plasma coagulation and platelet function. The underlying mechanisms are unclear, but increased fibrinolysis and abnormal clot formation may play a role. All BDUC patients (n=375) from the Vienna bleeding biobank were analyzed in comparison to healthy controls (HC, n=100) in this case-control study. Plasmin generation (PG) parameters were analyzed using calibrated fluorescence detection in citrated-plasma samples. Turbidimetric plasma clot formation/ lysis of 293 (78%) BDUC patients and confocal microscopy of clots from representative BDUC patients (n=6) and HC (n=9) were assessed...

Adeno-associated virus (AAV)-based gene therapy (valoctocogene roxaparvovec) is an attractive treatment for hemophilia A. Careful clinical management is required to minimize the risk of hepatotoxicity, including assessment of baseline liver condition to determine treatment eligibility and monitoring liver function after gene therapy. This article describes recommendations (developed by a group of hemophilia experts) on hepatic function monitoring before and after gene therapy. To prevent harmful liver-related effects, gene therapy is contraindicated in patients with uncontrolled liver infections, autoimmune hepatitis, liver stiffness ≥8 kPa or cirrhosis...

The multicenter, prospective phase II Australasian Leukaemia and Lymphoma Group (ALLG) NHL29 trial (ACTRN12615000551594) was conducted to assess the addition of ibrutinib to R-mini-CHOP (IRiC) in patients aged ≥75 years with newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib-R-mini-CHOP followed by two 21-day cycles of rituximab-ibrutinib. Co-primary endpoints were deliverability and 2-year overall survival (OS). All six cycles of R-mini-CHOP were completed in 63/79 patients (80%) with the median Average Relative Total Dose and Average Relative Dose Intensity for the entire regimen both 97% (IQR 82, 100; 88, 100)...

Platelets are crucial in thrombus formation during ST-elevation myocardial infarction (STEMI). In addition, they also play an important role in post-ischemic thromboinflammation which is determined by the interplay between activated platelets and neutrophils. The latter form neutrophil extracellular traps (NETs) which are detectable in plasma as citrullinated histone H3 - DNA complexes. Prediction of risk of recurrent events is important in precision medicine. Therefore, we investigated if circulating thromboinflammatory markers predict clinical outcome after STEMI...

Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, patient-derived xenografts and primary cells or their conditioned media can also trigger CAF formation...

There are limited data assessing the risk scores for primary treatment failure (PTF) classical Hodgkin lymphoma (cHL, PTF-cHL) undergoing autologous hematopoietic cell transplantation (auto-HCT). ECLIPSE is a multicenter retrospective cohort of patients with PTF- cHL (15 years or older) diagnosed on or after Jan 1, 2005, at 15 US medical centers. PTF was defined as one of the following patterns of failure: [1] progressive disease by imaging during or within 6 weeks of completion of frontline chemotherapy (primary progression [PP]); [2] partial response (PR) or stable disease (SD) by imaging after completion of frontline treatment (PR/SD); [3] progression of disease by imaging (and confirmed by biopsy) within 12 months of frontline therapy completion after prior documentation of complete response (CR, early relapse [ER])...

Although broadly employed, consolidative autologous hematopoietic stem cell transplantation (autoHCT) for relapsed/refractory (r/r) T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) has never been specifically investigated. Here we have analyzed outcomes of autoHCT for THRLBCL compared to diffuse large cell B-cell lymphoma not otherwise specified (DLBCL). Eligible for this retrospective registry study were adult patients with r/r THRLBCL and DLBCL, respectively, who underwent a first autoHCT in a salvage-sensitive disease status as assessed by PET-CT between 2016 and 2021 and were registered with the European Society for Blood and Marrow Transplantation (EBMT) database...

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy...

Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining the anti-cluster-of-differentiation (CD) 47 activity of magrolimab with the anti-CD20 activity of rituximab (M+R) has antitumor activity against R/R iNHL. Here, we report 3-year follow-up data from this phase 1b/2 study (NCT02953509) assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 groups of phase 1b M+R patients received 10-45 mg/kg magrolimab maintenance doses with 375 mg/m2 rituximab...

Hematopoietic stem cells (HSCs) readily recover from acute stress, but persistent stress can reduce their viability and long-term potential. Here we show that the nuclear factor of activated T cells 5 (NFAT5), a transcription modulator of inflammatory responses, protects the HSC pool under stress. NFAT5 restrains HSC differentiation to multipotent progenitors (MPPs) after bone marrow transplantation and bone marrow ablation with ionizing radiation or chemotherapy. Correspondingly, NFAT5-deficient HSCs fail to support long-term reconstitution of hematopoietic progenitors and mature blood cells after serial transplant...

The expression of thrombomodulin variant c.1611C>A (p.Cys537Stop) leads to the synthesis of a protein with no cytoplasmic tail and a transmembrane domain shortened by 3 amino acids (TM536). Little is known about the release mechanism and properties of TM536. Using umbilical vein endothelial cells and peripheral blood-derived endothelial colony-forming cells from a heterozygous carrier of TM536 variant as well as overexpression cell models, we demonstrate that TM536 is released from cells by an unusual mechanism...

The burden of iron-deficiency anemia remains significant during pregnancy. Oral iron is first-line medication, but there is uncertainty about a range of factors including adherence and side-effects of different doses. We conducted a pilot randomized trial to investigate the impact of different doses of oral iron supplementation started early in pregnancy, in non-anemic women, for four main outcomes; recruitment and protocol compliance, adherence, maintenance of maternal hemoglobin and side-effects. Participants at antenatal clinic visits were allocated to one of three trial arms, in a 1:1:1 ratio, as 200mg ferrous sulphate daily, alternate days or three-times per week, with follow-up to delivery...

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Clinical features in patients with the B-cell lymphoma, Waldenström Macroglobulinaemia (WM), include cytopenias, IgM-mediated hyperviscosity, fatigue, bleeding and bruising. Therapeutics such as Bruton's tyrosine kinase inhibitors (BTKis) exacerbate bleeding risk. Abnormal haemostasis arising from platelet dysfunction, altered coagulation or vascular impairment have not been investigated in WM patients. To evaluate haemostatic dysfunction in samples from WM patients. Whole blood (WB) samples were collected from 14 WM patients not receiving therapy, 5 patients receiving BTKis and 15 healthy donors (HDs)...

No abstract text is available yet for this article.