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Abstract: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD., (© 2021 by The American Society of Hematology.)

B-cell receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B-cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B-cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy because NOTCH has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from hematopoietic stem cell transplantation patients with and without cGVHD. Consistent with a molecular link between pathways, we found that BCR-NOTCH activation significantly increased the proximal BCR adapter protein BLNK. BCR-NOTCH activation also enabled persistent NOTCH2 surface expression, suggesting a positive feedback loop. Specific NOTCH2 blockade eliminated NOTCH-BCR activation and significantly altered NOTCH downstream targets and B-cell maturation/effector molecules. Examination of the molecular underpinnings of this "NOTCH2-BCR axis" in cGVHD revealed imbalanced expression of the transcription factors IRF4 and IRF8 , each critical to B-cell differentiation and fate. All- trans retinoic acid (ATRA) increased IRF4 expression, restored the IRF4 -to- IRF8 ratio, abrogated BCR-NOTCH hyperactivation, and reduced NOTCH2 expression in cGVHD B cells without compromising viability. ATRA-treated cGVHD B cells had elevated TLR9 and PAX5 , but not BLIMP1 (a gene-expression pattern associated with mature follicular B cells) and also attained increased cytosine guanine dinucleotide responsiveness. Together, we reveal a mechanistic link between NOTCH2 activation and robust BCR responses to otherwise suboptimal amounts of surrogate antigen. Our findings suggest that peripheral B cells in cGVHD patients can be pharmacologically directed from hyperactivation toward maturity.

Background: Peripherally inserted central catheters (PICCs) are associated with an increased risk of venous thromboembolism. However, the size of this risk relative to that associated with other central venous catheters (CVCs) is unknown. We did a systematic review and meta-analysis to compare the risk of venous thromboembolism associated with PICCs versus that associated with other CVCs., Methods: We searched several databases, including Medline, Embase, Biosis, Cochrane Central Register of Controlled Trials, Conference Papers Index, and Scopus. Additional studies were identified through hand searches of bibliographies and internet searches, and we contacted study authors to obtain unpublished data. All human studies published in full text, abstract, or poster form were eligible for inclusion. All studies were of adult patients aged at least 18 years who underwent insertion of a PICC. Studies were assessed with the Newcastle-Ottawa risk of bias scale. In studies without a comparison group, the pooled frequency of venous thromboembolism was calculated for patients receiving PICCs. In studies comparing PICCs with other CVCs, summary odds ratios (ORs) were calculated with a random effects meta-analysis., Findings: Of the 533 citations identified, 64 studies (12 with a comparison group and 52 without) including 29 503 patients met the eligibility criteria. In the non-comparison studies, the weighted frequency of PICC-related deep vein thrombosis was highest in patients who were critically ill (13·91%, 95% CI 7·68-20·14) and those with cancer (6·67%, 4·69-8·64). Our meta-analysis of 11 studies comparing the risk of deep vein thrombosis related to PICCs with that related to CVCs showed that PICCs were associated with an increased risk of deep vein thrombosis (OR 2·55, 1·54-4·23, p<0·0001) but not pulmonary embolism (no events). With the baseline PICC-related deep vein thrombosis rate of 2·7% and pooled OR of 2·55, the number needed to harm relative to CVCs was 26 (95% CI 13-71)., Interpretation: PICCs are associated with a higher risk of deep vein thrombosis than are CVCs, especially in patients who are critically ill or those with a malignancy. The decision to insert PICCs should be guided by weighing of the risk of thrombosis against the benefit provided by these devices., Funding: None., (Copyright © 2013 Elsevier Ltd. All rights reserved.)