المؤلفون: Makiko Yamasaki-Morita, Yasuyuki Arai, Takashi Ishihara, Tomoko Onishi, Hanako Shimo, Kayoko Nakanishi, Yukiko Nishiyama, Tomoyasu Jo, Hidefumi Hiramatsu, Takaya Mitsuyoshi, Chisaki Mizumoto, Junya Kanda, Momoko Nishikori, Toshio Kitawaki, Keiji Nogami, Akifumi Takaori-Kondo, Miki Nagao, Souichi Adachi

المصدر: Blood Advances. 6(14):4216-4223

مصطلحات موضوعية: Adult, Receptors, Chimeric Antigen, Lymphoid Neoplasia, Immunobiology and Immunotherapy, Clinical Trials and Observations, Fibrinolysis, Lymphoma, Non-Hodgkin, Antigens, CD19, Receptors, Antigen, T-Cell, Hematology, Blood Coagulation Disorders, Plasminogen Activator Inhibitor 1, Humans, Thrombophilia, Lymphoma, Large B-Cell, Diffuse, Prospective Studies

الوصف: Anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy has facilitated progress in treatment of refractory/relapsed diffuse large B-cell lymphoma (DLBCL). A well-known adverse event after CAR-T therapy is cytokine release syndrome(CRS). However, the etiology and pathophysiology of CRS-related coagulopathy remain unknown. Therefore, we conducted a prospective cohort study to comprehensively analyze coagulation/ fibrinolysis parameters present in peripheral blood of adult DLBCL patients treated with tisagenlecleucel in a single institution. Samples were collected from 25 patients at 3 time points: before lymphocyte-depletion chemotherapy and on days 3 and 13 after CAR-T infusion. After infusion, all patients except 1 experienced CRS, and 13 required the administration of tocilizumab. A significant elevation in the plasma level of total plasminogen activator inhibitor 1 (PAI-1), which promotes the initial step of coagulopathy (mean, 22.5 ng/mL before lymphocyte-depletion and 41.0 on day 3, P = .02), was observed at the onset of CRS. Moreover, this suppressed fibrinolysis-induced relatively hypercoagulable state was gradually resolved after CRS remission with normalization of total PAI-1 to preinfusion levels without any organ damage (mean values of soluble fibrin: 3.16 µg/mL at baseline, 8.04 on day 3, and 9.16 on day 13, P < .01; and mean PAI-1: 25.1 ng/mL on day 13). In conclusion, a hypofibrinolytic and relatively hypercoagulable state concomitant with significant total PAI-1 elevation was observed at the onset of CRS even in DLBCL patients with mild CRS. Our results will facilitate understanding of CRS-related coagulopathy, and they emphasize the importance of monitoring sequential coagulation/fibrinolysis parameters during CAR-T therapy.
キメラ抗原受容体T細胞療法による血液凝固と線溶の変動を解析 --サイトカイン放出症候群に伴う凝固障害の病態解析にむけて--. 京都大学プレスリリース. 2022-06-20.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b7481c1000d98bb31e574178baf9d9c7Test
http://hdl.handle.net/2433/275429Test

المؤلفون: Yandan Yang, Sigrid Dubois, Takashi Ishio, Takanori Teshima, Shinya Tanaka, Emmanuel Bachy, Masao Nakagawa, Satoshi Hashino, Yibin Yang, Sarvesh Kumar, Yutaka Hatanaka, Anusara Daenthanasanmak, Joji Shimono, Tomoyuki Endo, Patrick L. Green, Bonita R. Bryant, Yoshihiro Matsuno, Michiyuki Maeda, Hiroo Hasegawa, Da-Wei Huang, Michael N. Petrus, Thomas A. Waldmann, Yuquan Lin, Takashi Yokota, Hideki Goto, Kanako C. Hatanaka, Louis M. Staudt

المصدر: Blood. 139:1541-1556

مصطلحات موضوعية: Adult, Cell cycle checkpoint, Lymphoma, Immunology, Apoptosis, mTORC1, Mechanistic Target of Rapamycin Complex 1, Palbociclib, Malignancy, Biochemistry, Adult T-cell leukemia/lymphoma, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Leukemia-Lymphoma, Adult T-Cell, biology, Cyclin-Dependent Kinase 6, Cell Biology, Hematology, medicine.disease, Leukemia, Cancer research, biology.protein, Cyclin-dependent kinase 6, Signal Transduction

الوصف: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d37d460096eecd745b9b386f3fc9c2f4Test
https://doi.org/10.1182/blood.2021012734Test

المؤلفون: Laurence Kraus-Berthier, Lucie Laplane, Véronique Saada, Céline Berthon, Maria E. Figueroa, Bouchra Badaoui, Margaux Sevin, Franck Debeurme, Eric Padron, Thorsten Braun, Qin Yang, Nathalie Droin, Raphael Itzykson, Guido Kroemer, Dorothée Selimoglu-Buet, Eric Solary, Oliver Kepp, Margot Morabito, Alix Derreal, Hannah Newman, Sylvain Thepot, Gabriel Etienne, Miguel Torres-Martin, Sébastien Banquet, Severine Badel, Orianne Wagner-Ballon, Pierre Fenaux

المساهمون: Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)

المصدر: Blood
Blood, American Society of Hematology, 2021, 137 (24), pp.3390-3402. ⟨10.1182/blood.2020008729⟩

مصطلحات موضوعية: Adult, Male, MAPK/ERK pathway, CCR2, Myeloid, Cell Survival, MAP Kinase Signaling System, [SDV]Life Sciences [q-bio], Immunology, Chronic myelomonocytic leukemia, Biochemistry, Monocytes, 03 medical and health sciences, Chemokine receptor, 0302 clinical medicine, hemic and lymphatic diseases, medicine, Humans, MCL1, Extracellular Signal-Regulated MAP Kinases, Autocrine signalling, Protein Kinase Inhibitors, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Kinase, Chemistry, [SHS.PHIL]Humanities and Social Sciences/Philosophy, Leukemia, Myelomonocytic, Chronic, Blood Proteins, Cell Biology, Hematology, Middle Aged, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Cytokines, Myeloid Cell Leukemia Sequence 1 Protein, Female

الوصف: Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a5a876fc49ce5e247d9cb91a3a300a22Test
https://doi.org/10.1182/blood.2020008729Test

المؤلفون: Vijaya Chaturvedi, Carl E. Allen, Hector R. Wong, Michelle L. Hermiston, Jay Greenberg, Stephan Ladisch, Jordana Goldman, Michael M. Henry, Trung C. Nguyen, Vandana Chaturvedi, Rebecca A. Marsh, Ahmed Naqvi, Erika Owsley, Michael Jeng, Michael B. Jordan, Adi Zoref-Lorenz

المصدر: Blood. 137:2337-2346

مصطلحات موضوعية: Adult, Male, endocrine system, Adolescent, T cell, Immunology, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Biochemistry, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, Sepsis, Young Adult, Immune system, hemic and lymphatic diseases, Immunopathology, medicine, Humans, Child, Hemophagocytic lymphohistiocytosis, Membrane Glycoproteins, business.industry, Infant, HLA-DR Antigens, Cell Biology, Hematology, medicine.disease, ADP-ribosyl Cyclase 1, Phenotype, medicine.anatomical_structure, Case-Control Studies, Child, Preschool, Female, Cytokine Release Syndrome, business, Cytokine storm, CD8

الوصف: Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation that has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. Although clinical similarities between these syndromes suggest similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T-cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T-cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38high/HLA-DR+ effector cells, with activation of CD8+ T cells being most pronounced. Activated T cells were type 1 polarized, proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue-infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38high/HLA-DR+ cells among CD8+ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T-cell activation whereas early sepsis is not, and that these 2 syndromes can be readily distinguished by T-cell phenotypes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dde66b5af7239cec550b4ec6de47b0d3Test
https://doi.org/10.1182/blood.2020009499Test

المؤلفون: Dagmar Meyer zu Heringdorf, Corina Ratiu, Amro Elgheznawy, Voahanginirina Randriamboavonjy, Anastasia Kyselova, Ingrid Fleming, Mauro Siragusa, Alexander W. Mann, Beate Fisslthaler, Fredy Delgado Lagos

المصدر: Blood. 137:1641-1651

مصطلحات موضوعية: Adult, Blood Platelets, Male, 0301 basic medicine, Calcium-binding protein 1, Platelet Aggregation, Immunology, 030204 cardiovascular system & hematology, Biochemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Thrombin, Downregulation and upregulation, medicine, Animals, Humans, Osteonectin, Platelet, Platelet activation, biology, Chemistry, Matricellular protein, Cell Biology, Hematology, Middle Aged, Platelet Activation, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, Diabetes Mellitus, Type 2, biology.protein, Phosphorylation, Female, medicine.drug

الوصف: Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression is regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/− mice did not present detectable mature SMOC1 protein. Platelets from SMOC1+/− mice demonstrated attenuated responsiveness to thrombin (platelet neutrophil aggregate formation, aggregation, clot formation, Ca2+ increase, and β3 integrin phosphorylation), whereas responses to other platelet agonists were unaffected. SMOC1 has been implicated in transforming growth factor-β signaling, but no link to this pathway was detected in platelets. Rather, the SMOC1 Kazal domain directly bound thrombin to potentiate its activity in vitro, as well as its actions on isolated platelets. The latter effects were prevented by monoclonal antibodies against SMOC1. Platelets from miR-223–deficient mice expressed high levels of SMOC1 and exhibited hyperreactivity to thrombin that was also reversed by preincubation with monoclonal antibodies against SMOC1. Similarly, SMOC1 levels were markedly upregulated in platelets from individuals with type 2 diabetes, and the SMOC1 antibody abrogated platelet hyperresponsiveness to thrombin. Taken together, we have identified SMOC1 as a novel thrombin-activating protein that makes a significant contribution to the pathophysiological changes in platelet function associated with type 2 diabetes. Thus, strategies that target SMOC1 or its interaction with thrombin may be attractive therapeutic approaches to normalize platelet function in diabetes.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0bcf0b32aeb935a44038d5325894fca8Test
https://doi.org/10.1182/blood.2020009405Test

المؤلفون: Satoshi Yamashita, Naoko Hattori, Yuki Kurahashi, Toshikazu Ushijima, Naoko Sueoka-Aragane, Tatsuro Watanabe, Akemi Sato, Kensuke Kojima, Hideaki Nakamura, Atsushi Kawaguchi, Shinya Kimura, Eisaburo Sueoka, Nao Yoshida, Kazuharu Kamachi, Seiji Okada, Hiroshi Ureshino, Yuki Fukuda-Kurahashi

المصدر: Blood. 136:871-884

مصطلحات موضوعية: Adult, 0301 basic medicine, Pyridines, viruses, Immunology, Administration, Oral, Decitabine, Antineoplastic Agents, Biology, Biochemistry, Mice, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, medicine, Animals, Humans, Leukemia-Lymphoma, Adult T-Cell, Molecular Targeted Therapy, Cells, Cultured, Aged, Mice, Knockout, Regulation of gene expression, Human T-lymphotropic virus 1, Mice, Inbred BALB C, Gene Expression Regulation, Leukemic, Cell growth, T-cell receptor, Drugs, Investigational, Cell Biology, Hematology, DNA Methylation, Cell Transformation, Viral, HTLV-I Infections, Xenograft Model Antitumor Assays, Demethylation, Demethylating agent, 030104 developmental biology, chemistry, Cell culture, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, Female, medicine.drug, DNA hypomethylation

الوصف: Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1–infected individuals are asymptomatic, and only 3% to 5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1–infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV–infected T cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes downregulated because of promoter hypermethylation in HTLV-1–infected T cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1–infected cell lines but was normalized by reexpression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1–infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1–infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the 2 compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::30f0e7224c117c25f69a987a740a43e5Test
https://doi.org/10.1182/blood.2019003084Test

المؤلفون: Bianca Rocca, Francesca Palandri, Giovanna Petrucci, Chiara Paoli, Cristina Bucelli, Benedetta Porro, Nicola Vianelli, Francesco Rodeghiero, Elena Rossi, Alessandra Iurlo, Carlo Patrono, Irene Bertozzi, Alessandro M. Vannucchi, Maria Luigia Randi, Andrea Timillero, Monica Carpenedo, Mauro Di Ianni, Giuseppe Carli, Alfredo Dragani, Silvia Betti, Denise Soldati, Elena Maria Elli, Eloise Beggiato, Valerio De Stefano, Daniele Cattaneo, Giuseppe Lanzarone, Alberto Tosetto, Viviana Cavalca, Marco Ruggeri, Giorgina Specchia, Alessandra Ricco, Paola Ranalli

المصدر: Blood. 136:171-182

مصطلحات موضوعية: Adult, medicine.medical_specialty, Randomization, Immunology, 030204 cardiovascular system & hematology, Biochemistry, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Internal medicine, Antithrombotic, medicine, Humans, Cyclooxygenase Inhibitors, Platelet, Platelet activation, Aged, Aspirin, Essential thrombocythemia, business.industry, Cell Biology, Hematology, Middle Aged, medicine.disease, Epoprostenol, Thromboxane B2, Regimen, chemistry, 030220 oncology & carcinogenesis, Cyclooxygenase 1, business, Platelet Aggregation Inhibitors, Thrombocythemia, Essential, medicine.drug

الوصف: Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a2745a074f0e9fb3a40b7e799bc767c0Test
https://doi.org/10.1182/blood.2019004596Test

المؤلفون: Yi Bin Chen, Edward D. Ball, Robert J. Soiffer, Vincent T. Ho, Pavan Bachireddy, Corey Cutler, David Avigan, Asad Bashey, Catherine J. Wu, Howard Streicher, Michael Mazzeo, Jerome Ritz, Alexandra Savell, Edwin P. Alyea, Frederick L. Locke, Haesook T. Kim, Philippe Armand, Caitlin Costello, Adrienne Anderson, Alex F. Herrera, Sarah Nikiforow, Rodrigo O. Maegawa, Alexander P. Boardman, Augustine Weber, Matthew S. Davids

المصدر: Blood

مصطلحات موضوعية: Adult, Male, Oncology, medicine.medical_specialty, Programmed Cell Death 1 Receptor, Immunology, Graft vs Host Disease, Kaplan-Meier Estimate, Biochemistry, Antineoplastic Agents, Immunological, Recurrence, Internal medicine, medicine, Humans, Prospective Studies, Treatment Failure, Adverse effect, Prospective cohort study, Aged, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Cell Biology, Hematology, Middle Aged, Allografts, medicine.disease, Clinical trial, Nivolumab, Graft-versus-host disease, Hematologic Neoplasms, Toxicity, Female, business

الوصف: Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti–PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patients was 32% (8/25). With a median follow-up of 11 months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti–PD-1 antibody for post–alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti–PD-1 therapy post–alloHCT may require specific toxicity mitigation strategies. This trial was registered at www.clinicaltrials.gov as #NCT 01822509.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7ccfee23c6c4a9f2f961a7899b967304Test
https://doi.org/10.1182/blood.2019004710Test

المؤلفون: Madan Jagasia, Karl Staser, Michael Pratta, Gary J. Schiller, Jaebok Choi, Yi-Bin Chen, Peter Langmuir, Gabrielle Meyers, Miguel-Angel Perales, Haris Ali, Leah Gehrs, Ying Yan, H. Jean Khoury, Nithya Srinivas, John F. DiPersio, Mark A. Schroeder, Michael C. Arbushites

المصدر: Blood advances, vol 4, iss 8

مصطلحات موضوعية: Adult, medicine.medical_specialty, Adolescent, Anemia, medicine.medical_treatment, Clinical Trials and Supportive Activities, Graft vs Host Disease, Hematopoietic stem cell transplantation, Gastroenterology, law.invention, Rare Diseases, Randomized controlled trial, Adrenal Cortex Hormones, Stem Cell Research - Nonembryonic - Human, Clinical Research, law, hemic and lymphatic diseases, Internal medicine, Clinical endpoint, Humans, Medicine, Adverse effect, Protein Kinase Inhibitors, 6.2 Cellular and gene therapies, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Evaluation of treatments and therapeutic interventions, Janus Kinase 1, Hematology, Stem Cell Research, medicine.disease, Clinical trial, Orphan Drug, surgical procedures, operative, Tolerability, 6.1 Pharmaceuticals, Steroids, business

الوصف: Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1–selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4387f96205dd71cf94603607ea441257Test
https://doi.org/10.1182/bloodadvances.2019001043Test

المؤلفون: David A. Jacobsohn, Christine Duncan, Giorgos Bakoyannis, Francis Pike, Jamie L. Renbarger, Robert A. Krance, Kenneth R. Cooke, Conrad Russell Y. Cruz, Paul A. Carpenter, Courtney M. Rowan, Sherif S. Farag, Samir M. Hanash, Hao Liu, Sophie Paczesny, Catherine M. Bollard, Abhijeet Malatpure

المصدر: Blood. 135:1428-1437

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Adolescent, Immunology, Graft vs Host Disease, Biochemistry, Adult age, Young Adult, Risk Factors, Internal medicine, Biomarkers, Tumor, medicine, Humans, Prospective Studies, Child, Prospective cohort study, Aged, business.industry, Hazard ratio, Age Factors, Hematopoietic Stem Cell Transplantation, Infant, Newborn, Infant, Cell Biology, Hematology, Middle Aged, Prognosis, medicine.disease, Interleukin-1 Receptor-Like 1 Protein, Confidence interval, Survival Rate, Transplantation, Graft-versus-host disease, Child, Preschool, Hematologic Neoplasms, Cohort, Biomarker (medicine), Female, Neoplasm Recurrence, Local, business, Follow-Up Studies

الوصف: Assessment of prognostic biomarkers of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group is lacking. To address this need, we conducted a prospective cohort study with 415 patients at 6 centers: 170 were children age 10 years or younger and 245 were patients older than age 10 years (both children and adults were accrued from 2013 to 2018). The following 4 plasma biomarkers were assessed pre-HCT and at days +7, +14, and +21 post-HCT: stimulation-2 (ST2), tumor necrosis factor receptor 1 (TNFR1), regenerating islet–derived protein 3α (REG3α), and interleukin-6 (IL-6). We performed landmark analyses for NRM, dichotomizing the cohort at age 10 years or younger and using each biomarker median as a cutoff for high- and low-risk groups. Post-HCT biomarker analysis showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in children age 10 years or younger (ST2: hazard ratio [HR], 9.13; 95% confidence interval [CI], 2.74-30.38; P = .0003; TNFR1: HR, 4.29; 95% CI, 1.48-12.48; P = .0073; REG3α: HR, 7.28; 95% CI, 2.05-25.93; P = .0022); and in children and adults older than age 10 years (ST2: HR, 2.60; 95% CI, 1.15-5.86; P = .021; TNFR1: HR, 2.09; 95% CI, 0.96-4.58; P = .06; and REG3α: HR, 2.57; 95% CI, 1.19-5.55; P = .016). When pre-HCT biomarkers were included, only ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, and graft-versus-host-disease prophylaxis), ST2 remained associated with NRM only in recipients age 10 years or younger (HR, 4.82; 95% CI, 1.89-14.66; P = .0056). Assays of ST2, TNFR1, and REG3α in the first 3 weeks after HCT have prognostic value for NRM in both children and adults. The presence of ST2 before HCT is a prognostic biomarker for NRM in children age 10 years or younger allowing for additional stratification. This trial was registered at www.clinicaltrials.gov as #NCT02194439.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7737622ba67c6716c0751fb431b8532cTest
https://doi.org/10.1182/blood.2019002334Test