584 results match your criteria Bruton Agammaglobulinemia


Clinical and Genetic Study of X-linked Agammaglobulinemia Patients (The Benefit of Early Diagnosis).

Iran J Allergy Asthma Immunol 2020 Jun 23;19(3):305-309. Epub 2020 Jun 23.

Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by genetic defects in the Bruton tyrosine kinase (Btk) gene. XLA is characterized as an antibody deficiency by recurrent bacterial infections, the absence of peripheral B cells, and profound reductions in all immunoglobulin isotypes. This study aims to report the clinical and genetic features of five Iranian patients with XLA. Read More

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http://dx.doi.org/10.18502/ijaai.v19i3.3458DOI Listing

Hereditary Predisposition to Hematopoietic Neoplasms: When Bloodline Matters for Blood Cancers.

Mayo Clin Proc 2020 Jun 19. Epub 2020 Jun 19.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN. Electronic address:

With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms- collectively known as hereditary predisposition syndromes (HPS)-are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Read More

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http://dx.doi.org/10.1016/j.mayocp.2019.12.013DOI Listing

Inhibition of Bruton tyrosine kinase in patients with severe COVID-19.

Sci Immunol 2020 06 5;5(48). Epub 2020 Jun 5.

Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD; Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD; Willamette Valley Cancer Institute and Research Center, US Oncology, Eugene, OR; Hematology-Oncology Department, Walter Reed National Military Medical Center, Bethesda, MD; John Theurer Cancer Center, Hackensack Meridian and School of Medicine at Seton Hall, NJ; Rocky Mountain Cancer Center, US Oncology, Colorado Springs, CO; Department of Emergency Medicine, Penrose-St. Francis Health Services, Colorado Springs, CO; US Acute Care Solutions, Canton, OH; Department of Medicine, St. Peter's Hospital and US Oncology, Albany, NY; Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; Acerta Pharma, South San Francisco, CA; Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Bethesda, MD, USA AstraZeneca, One MedImmune Way, Gaithersburg, MD

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Read More

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http://dx.doi.org/10.1126/sciimmunol.abd0110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274761PMC

X-linked Agammaglobulinemia Presenting with Multiviral Pneumonia.

Cureus 2020 Apr 29;12(4):e7884. Epub 2020 Apr 29.

Internal Medicine, Smolensk State Medical University, Smolensk, RUS.

X-linked agammaglobulinemia (XLA) is a primary humoral immunodeficiency characterized by severe hypogammaglobulinemia and increased risk of infection. The genetic condition results from a mutation in the Bruton tyrosine kinase (BTK) gene located on the X chromosome leading to a near absence of B cells. Patients affected by XLA are most commonly predisposed to frequent and severe bacterial infections. Read More

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http://dx.doi.org/10.7759/cureus.7884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255535PMC

Pseudomonas aeruginosa sepsis presenting as oral ecthyma gangrenosum in identical twins with Bruton tyrosine kinase gene mutation: Two case reports and review of the literature.

J Microbiol Immunol Infect 2020 Apr 17. Epub 2020 Apr 17.

Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address:

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease. We reported two 7-month-old identical male twins with Pseudomonas aeruginosa sepsis who initially manifested as oral ecthyma gangrenosum and were finally diagnosed to have XLA. In both cases, we confirmed the c. Read More

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http://dx.doi.org/10.1016/j.jmii.2020.04.009DOI Listing

Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial.

Lancet 2020 04;395(10232):1278-1291

The Ohio State University Comprehensive Cancer Center and Division of Hematology, Columbus, OH, USA. Electronic address:

Background: Acalabrutinib is a selective, covalent Bruton tyrosine-kinase inhibitor with activity in chronic lymphocytic leukaemia. We compare the efficacy of acalabrutinib with or without obinutuzumab against chlorambucil with obinutuzumab in patients with treatment-naive chronic lymphocytic leukaemia.

Methods: ELEVATE TN is a global, phase 3, multicentre, open-label study in patients with treatment-naive chronic lymphocytic leukaemia done at 142 academic and community hospitals in 18 countries. Read More

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http://dx.doi.org/10.1016/S0140-6736(20)30262-2DOI Listing

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

J Allergy Clin Immunol 2020 Mar 10. Epub 2020 Mar 10.

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia and ASST-Spedali Civili di Brescia, Brescia, Italy. Electronic address:

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.

Objective: Our aim was to describe the natural history of XLA. Read More

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http://dx.doi.org/10.1016/j.jaci.2020.03.001DOI Listing

[Laparoscopic Surgery for a Case of Double Digestive Cancers with X-Linked Agammaglobulinemia].

Gan To Kagaku Ryoho 2019 Dec;46(13):2571-2573

Dept. of Surgery, Japan Community Health care Organization(JCHO)Osaka Hospital.

A 65-year-old man was diagnosed with agammaglobulinemia at the age of 53 years. To investigate the cause of the increased CRP value, CT was performed and revealed thickening of the walls of the ascending colon and rectum. Colonoscopy revealed tumors and stenoses in the ascending colon and rectum. Read More

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December 2019

Uncovering Low-Level Maternal Gonosomal Mosaicism in X-Linked Agammaglobulinemia: Implications for Genetic Counseling.

Front Immunol 2020 12;11:46. Epub 2020 Feb 12.

Jeffrey Model Foundation Excellence Center, Barcelona, Spain.

X-linked agammaglobulinemia (XLA) is a clinically and genetically well-defined immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent bacterial infections, profound hypogammaglobulinemia, and few or no circulating B cells. XLA is caused by mutations in the gene, which encodes Bruton's tyrosine kinase (BTK). Read More

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http://dx.doi.org/10.3389/fimmu.2020.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028698PMC
February 2020

[Reaserch Advance on Bruton Tyrosine Kinase Inhibitors in the Treatment of B-Cell Tumors--Review].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2020 Feb;28(1):333-338

Department of Hematology, Huai'an First People's Hospital Affiliaed to Nanjing Medical University, Huai'an 223300, Jiangsu Province, China,Key laboratory of Hematology of Nanjing Medical University, Nanjing 210009, Jiangsu Province, China,E-mail:

Abstract  In recent years, development of the targeted drugs according to the biological characteristics of tumors have provided more treatment options for tumor patients. It was found that the overactivation or abnormality of B cell receptor (BCR) signal pathway closely related to the occurrence and development of various B cell tumors, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). As a key kinase in the BCR pathway, BTK inhibitors have obvious anti-tumor effect when its activity is being inhibitered. Read More

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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2020.01.056DOI Listing
February 2020

Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL.

Nat Commun 2020 Jan 29;11(1):577. Epub 2020 Jan 29.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. We identify a consistent regulatory program starting with a sharp decrease of NF-κB binding in CLL cells, which is followed by reduced activity of lineage-defining transcription factors, erosion of CLL cell identity, and acquisition of a quiescence-like gene signature. Read More

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http://dx.doi.org/10.1038/s41467-019-14081-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989523PMC
January 2020
10.742 Impact Factor

Bruton tyrosine kinase deficiency augments NLRP3 inflammasome activation and causes IL-1β-mediated colitis.

J Clin Invest 2020 Apr;130(4):1793-1807

Mucosal Immunity Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.

Bruton tyrosine kinase (BTK) is present in a wide variety of cells and may thus have important non-B cell functions. Here, we explored the function of this kinase in macrophages with studies of its regulation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. We found that bone marrow-derived macrophages (BMDMs) from BTK-deficient mice or monocytes from patients with X-linked agammaglobulinemia (XLA) exhibited increased NLRP3 inflammasome activity; this was also the case for BMDMs exposed to low doses of BTK inhibitors such as ibrutinib and for monocytes from patients with chronic lymphocytic leukemia being treated with ibrutinib. Read More

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http://dx.doi.org/10.1172/JCI128322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108929PMC

Bruton tyrosine-kinase inhibitor on the rise: acalabrutinib in Waldenström macroglobulinemia.

Authors:
Christian Buske

Lancet Haematol 2020 Feb 19;7(2):e85-e86. Epub 2019 Dec 19.

Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, 89081 Ulm, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(19)30214-5DOI Listing
February 2020

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study.

Lancet Haematol 2020 Feb 19;7(2):e112-e121. Epub 2019 Dec 19.

Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.

Background: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. Read More

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http://dx.doi.org/10.1016/S2352-3026(19)30210-8DOI Listing
February 2020

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL.

Int J Mol Sci 2019 Dec 20;21(1). Epub 2019 Dec 20.

Laboratory of Lymphoid Malignancies, Hematology Branch, NHLBI, NIH, Bethesda, MD 20892, USA.

B-cell receptor (BCR) signaling and tumor-microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Read More

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http://dx.doi.org/10.3390/ijms21010068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981459PMC
December 2019

Delayed diagnosis of X-linked agammaglobulinaemia in a boy with recurrent meningitis.

BMC Neurol 2019 Dec 12;19(1):320. Epub 2019 Dec 12.

Department of Neurology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 9# Jin Sui Road, 510623, Guangzhou City, Guangdong Province, People's Republic of China.

Background: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. Read More

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http://dx.doi.org/10.1186/s12883-019-1536-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907138PMC
December 2019

Treosulfan-based reduced toxicity hematopoietic stem cell transplantation in X-linked agammaglobulinemia: A cost-effective alternative to long-term immunoglobulin replacement in developing countries.

Pediatr Transplant 2020 02 10;24(1):e13625. Epub 2019 Dec 10.

Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Chennai, India.

X-linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. Read More

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http://dx.doi.org/10.1111/petr.13625DOI Listing
February 2020
5 Reads
1.630 Impact Factor

Acute primary purulent pericarditis in an adult patient with unknown X-linked agammaglobulinemia.

Immunobiology 2020 01 4;225(1):151861. Epub 2019 Nov 4.

Polo Cardio-Toraco-Vascolare, Policlinico S.Orsola-Malpighi, University of Bologna, Bologna, Italy.

X-linked agammaglobulinemia (XLA) is a rare form of inherited immunodeficiency due to an impairment in B-lymphocyte differentiation and maturation. In the majority of cases XLA is diagnosed in childhood, particularly among males affected by recurrent infections and with a family history of immunodeficiency. Infections of respiratory tract, gastrointestinal apparatus, eyes, nose and ears are frequent in XLA patients; on the contrary, infections of myocardium, cardiac valves and pericardium are rarely described in XLA. Read More

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http://dx.doi.org/10.1016/j.imbio.2019.10.010DOI Listing
January 2020

An in-depth evaluation of acalabrutinib for the treatment of mantle-cell lymphoma.

Expert Opin Pharmacother 2020 Jan 18;21(1):29-38. Epub 2019 Nov 18.

Hematology and Oncology Department, Biotechnology Research Unit, Cosenza, Italy.

: Regimens involving intensive immuno-chemotherapy, followed by high-dose therapy and autologous stem cell transplant represent the standard treatment for younger fit patients with mantle cell lymphoma (MCL). Targeted approaches (i.e. Read More

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http://dx.doi.org/10.1080/14656566.2019.1689959DOI Listing
January 2020

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on.

Hematol Oncol 2020 Apr 10;38(2):129-136. Epub 2019 Dec 10.

Department of Hematology, Hadassah-Hebrew-University Medical Center, Jerusalem, Israel.

A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib-resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. Read More

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http://dx.doi.org/10.1002/hon.2695DOI Listing
April 2020
3.084 Impact Factor

Effect and Mechanism of the Bruton Tyrosine Kinase (Btk) Inhibitor Ibrutinib on Rat Model of Diabetic Foot Ulcers.

Med Sci Monit 2019 Oct 23;25:7951-7957. Epub 2019 Oct 23.

Department of Hand and Foot Orthopedic Surgery, Weifang People's Hospital, Weifang, Shandong, China (mainland).

BACKGROUND Diabetes causes damage to the soft tissue and bone structure of the foot, referred to as "diabetic foot". Ibrutinib is a Bruton tyrosine kinase (Btk) inhibitor, and the role and mechanism of ibrutinib on the diabetic foot have not been elucidated. MATERIAL AND METHODS Male Wister rats were randomly divided into 3 groups: control group, model group, and ibrutinib group. Read More

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http://dx.doi.org/10.12659/MSM.916950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822560PMC
October 2019
2 Reads

Cutting Edge: ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor-BTK Signaling Pathway.

J Immunol 2019 10 18;203(8):2043-2048. Epub 2019 Sep 18.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;

Inhibitors of Bruton tyrosine kinase (BTK), a kinase downstream of BCR, display remarkable activity in a subset of mantle cell lymphoma (MCL) patients, but the drug resistance remains a considerable challenge. In this study, we demonstrate that aberrant expression of ROR1 (receptor tyrosine kinase-like orphan receptor 1), seen in a large subset of MCL, results in BCR/BTK-independent signaling and growth of MCL cells. ROR1 forms a functional complex with CD19 to persistently activate the key cell signaling pathways PI3K-AKT and MEK-ERK in the BCR/BTK-independent manner. Read More

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http://dx.doi.org/10.4049/jimmunol.1801327DOI Listing
October 2019
9 Reads

Metastatic colorectal cancer and severe hypocalcemia following irinotecan administration in a patient with X-linked agammaglobulinemia: a case report.

BMC Med Genet 2019 09 12;20(1):157. Epub 2019 Sep 12.

Department of Pharmacy, Changzheng Hospital, Secondary Military Medical University, Shanghai, China.

Background: X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by germline mutations in the Bruton tyrosine kinase (BTK) gene on X chromosome. These mutations disturb B-cell development, decrease immunoglobulin levels, increase susceptibility to infection or neoplasms, and increase the risk of developing colorectal cancer (CRC). For occasional cases of CRC have been reported in XLA patients, low levels of B lymphocytes and immunoglobulins induced by congenital immune disorder make them more susceptible to drug-related toxicities (DRT). Read More

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http://dx.doi.org/10.1186/s12881-019-0880-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739925PMC
September 2019
3 Reads

A Novel Gene Mutation in a Child With Atypical X-Linked Agammaglobulinemia and Recurrent Hemophagocytosis: A Case Report.

Front Immunol 2019 20;10:1953. Epub 2019 Aug 20.

Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan.

X-linked agammaglobulinemia (XLA), caused by a mutation in the Bruton's tyrosine kinase () gene, is rarely reported in patients with recurrent hemophagocytic lymphohistiocytosis (HLH). This mutation leads to significantly reduced numbers of circulatory B cells and serum immunoglobulins in patients. Therefore, they exhibit repetitive bacterial infections since infancy, and immunoglobulin (Ig) replacement therapy is the primary treatment. Read More

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http://dx.doi.org/10.3389/fimmu.2019.01953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711359PMC
August 2019
2 Reads

Role of the Btk-PLC2 Signaling Pathway in the Bone Destruction of Apical Periodontitis.

Mediators Inflamm 2019 25;2019:8767529. Epub 2019 Jul 25.

Department of Endodontics and Periodontics, College of Stomatology, Dalian Medical University, Dalian, Liaoning Province, China.

Chronic apical periodontitis is characterized by alveolar bone absorption in the apical region and is the result of the participation of various inflammatory mediators. Studies have shown that the Bruton tyrosine kinase- (Btk-) phospholipase C2 (PLC2) signaling pathway plays an important role in bone absorption, but it is unknown whether it plays a role in apical periodontitis bone destruction. Therefore, this study verified the role of Btk and PLC2 in bone resorption of apical periodontitis by and experiments. Read More

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http://dx.doi.org/10.1155/2019/8767529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683780PMC
January 2020

Impaired polysaccharide responsiveness without agammaglobulinaemia in three patients with hypomorphic mutations in Bruton Tyrosine Kinase-No detection by newborn screening for primary immunodeficiencies.

Scand J Immunol 2020 Jan 30;91(1):e12811. Epub 2019 Oct 30.

Department of Pediatric Pneumology, Immunology and Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. Read More

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http://dx.doi.org/10.1111/sji.12811DOI Listing
January 2020
5 Reads

Single and combined BTK and PI3Kδ inhibition with acalabrutinib and ACP-319 in pre-clinical models of aggressive lymphomas.

Br J Haematol 2019 12 29;187(5):595-601. Epub 2019 Jul 29.

Institute of Oncology Research, Università della Svizzera italiana, Bellinzona, Switzerland.

The B-cell receptor and the phosphatidylinositol 3-kinase (PI3K) signalling pathways, together with their downstream partners, represent important therapeutic targets for B-cell lymphomas. Here, we evaluated the activity of acalabrutinib (ACP-196) and ACP-319 (AMG-319), second generation inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ inhibitor, respectively, in lymphoma pre-clinical models. The two compounds showed activity in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), mantle cell lymphoma and marginal zone lymphoma. Read More

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http://dx.doi.org/10.1111/bjh.16118DOI Listing
December 2019
2 Reads

Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL.

Blood 2019 09 24;134(11):851-859. Epub 2019 Jul 24.

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Read More

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http://dx.doi.org/10.1182/blood.2019001160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742923PMC
September 2019
20 Reads
10.452 Impact Factor

Kawasaki disease and immunodeficiencies in children: case reports and literature review.

Rheumatol Int 2019 Oct 16;39(10):1829-1838. Epub 2019 Jul 16.

Clinical Immunology Department, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, 04530, Mexico City, Mexico.

Kawasaki disease (KD) has features that appear supporting an infectious cause with a secondary deranged inflammatory/autoimmune response. The association of KD in adults with human immunodeficiency virus infection and the presence of KD in patients with immunodeficiency disorders support the infectious theory. We present four KD patients associated with immunodeficiencies: one with X-linked agammaglobulinemia, one with HIV infection, and two with leukemia; one of these patients also had Down syndrome. Read More

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http://dx.doi.org/10.1007/s00296-019-04382-wDOI Listing
October 2019
5 Reads

Abivertinib, a novel BTK inhibitor: Anti-Leukemia effects and synergistic efficacy with homoharringtonine in acute myeloid leukemia.

Cancer Lett 2019 Oct 13;461:132-143. Epub 2019 Jul 13.

Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, People's Republic of China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, People's Republic of China. Electronic address:

Ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), has shown promising pharmacologic effects in acute myeloid leukemia (AML). In this study, we report that abivertinib or AC0010, a novel BTK inhibitor, inhibits cell proliferation, reduces colony-forming capacity, and induces apoptosis and cell cycle arrest in AML cells, especially those harboring FLT3-ITD mutations. Abivertinib was also found to be more sensitive than ibrutinib in treating AML. Read More

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http://dx.doi.org/10.1016/j.canlet.2019.07.008DOI Listing
October 2019
6 Reads

Prevalence of and mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study.

Blood 2019 08 26;134(7):641-644. Epub 2019 Jun 26.

Groupe de Hôpitaux Universitaires Paris Seine-Saint-Denis (GHUPSSD), Assistance Publique-Hôpitaux de Paris (AP-HP), Bobigny, France.

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase () and/or phospholipase Cγ2 () genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Read More

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http://dx.doi.org/10.1182/blood.2019000854DOI Listing
August 2019
13 Reads
10.452 Impact Factor

A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors.

Oncology 2019 21;97(2):102-111. Epub 2019 Jun 21.

Department of Clinical Translational Research, HonorHealth/TGen, Scottsdale, Arizona, USA.

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. Read More

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http://dx.doi.org/10.1159/000500571DOI Listing
August 2019
35 Reads

p65BTK is a novel potential actionable target in KRAS-mutated/EGFR-wild type lung adenocarcinoma.

J Exp Clin Cancer Res 2019 Jun 14;38(1):260. Epub 2019 Jun 14.

Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Background: Lung cancer is still the main cause of cancer death worldwide despite the availability of targeted therapies and immune-checkpoint inhibitors combined with chemotherapy. Cancer cell heterogeneity and primary or acquired resistance mechanisms cause the elusive behaviour of this cancer and new biomarkers and active drugs are urgently needed to overcome these limitations. p65BTK, a novel isoform of the Bruton Tyrosine Kinase may represent a new actionable target in non-small cell lung cancer (NSCLC). Read More

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http://dx.doi.org/10.1186/s13046-019-1199-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570906PMC
June 2019
16 Reads
5.646 Impact Factor

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton's tyrosine kinase.

Proc Natl Acad Sci U S A 2019 06 12;116(26):12952-12957. Epub 2019 Jun 12.

School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, 08826 Seoul, Korea;

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Read More

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http://dx.doi.org/10.1073/pnas.1821552116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600927PMC
June 2019
7 Reads

Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions.

Clin Adv Hematol Oncol 2019 Apr;17(4):223-233

Arthur G. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Read More

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April 2019
5 Reads

Plasma therapy leads to an increase in functional IgA and IgM concentration in the blood and saliva of a patient with X-linked agammaglobulinemia.

J Transl Med 2019 05 23;17(1):174. Epub 2019 May 23.

Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, The Netherlands.

Background: Patients with X-linked agammaglobulinemia (XLA) are protected against invasive bacterial infections due to IgG replacement therapy, but are still at higher risk for mucosal infections of the gut and respiratory tract. This might be explained by to the lack of IgA and IgM, as these antibodies are especially important for protection against invading bacterial pathogens on the mucosal surface.

Methods: In an attempt to eliminate a chronic norovirus infection in a patient with X-linked agammaglobulinemia, fresh frozen plasma (FFP) was given two times a week for 3 weeks. Read More

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http://dx.doi.org/10.1186/s12967-019-1928-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533670PMC
May 2019
4 Reads

A novel Bruton tyrosine kinase gene variation was found in an adult with X-linked agammaglobulinemia during blood cross-matching prior to surgical operation.

Transfus Med 2019 Oct 22;29(5):364-368. Epub 2019 May 22.

Department of Hematology, First Affiliated Hospital of Dalian Medical University, Dalian, China.

Aims/objectives: To investigate the underlying molecular mechanism of the patient's ABO typing discrepancy.

Background: ABO typing discrepancy was frequently seen in patients due to different causes. In this study, ABO typing discrepancy was found in a 24-year-old man with arthralgia, whose forward ABO grouping was O and reverse ABO grouping was AB. Read More

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http://dx.doi.org/10.1111/tme.12601DOI Listing
October 2019
7 Reads

Achromobacter xylosoxidans Sepsis Unveiling X-linked Agammaglobulinemia Masquerading as Systemic-onset Juvenile Idiopathic Arthritis.

Indian Pediatr 2019 05;56(5):423-425

Department of Pediatrics, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.

Background: X-linked agammaglobulinemia, a primary immunodeficiency, can present with musculoskeletal manifestations.

Case Characteristics: A 4-year-old boy, diagnosed as systemic juvenile idiopathic arthritis at the age of 3 years and treated with biological agents, presented with fever, dyspnea and chest pain. Blood culture and pericardial fluid culture revealed Achromobacter xylosoxidans. Read More

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May 2019
8 Reads

Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib.

Blood Adv 2019 05;3(9):1553-1562

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Read More

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http://dx.doi.org/10.1182/bloodadvances.2018030007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517672PMC
May 2019
10 Reads

Btk Inhibitors as First Oral Atherothrombosis-Selective Antiplatelet Drugs?

Thromb Haemost 2019 Aug 14;119(8):1212-1221. Epub 2019 May 14.

Institute for Prevention of Cardiovascular Diseases, LMU (Ludwig-Maximilians University Munich), Munich, Germany.

Bruton's tyrosine kinase (Btk) is essential for B cell differentiation and proliferation, but also platelets express Btk. Patients with X-linked agammaglobulinemia due to hereditary Btk deficiency do not show bleeding, but a mild bleeding tendency is observed in high dose therapy of B-cell malignancies with ibrutinib and novel second-generation irreversible Btk inhibitors (acalabrutinib and ONO/GS-4059). This review discusses recent studies that may explain this apparent paradox and gives mechanistic insights that suggest a unique potential of low dose irreversible Btk inhibitors as atherothrombosis-focused antiplatelet drugs. Read More

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http://dx.doi.org/10.1055/s-0039-1687877DOI Listing
August 2019
4 Reads
4.984 Impact Factor

Accelerated Immunodeficiency-associated Vaccine-derived Poliovirus Serotype 3 Sequence Evolution Rate in an 11-week-old Boy With X-linked Agammaglobulinemia and Perinatal Human Immunodeficiency Virus Exposure.

Clin Infect Dis 2020 01;70(1):132-135

Centre for Vaccines and Immunology, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg.

Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child's perinatal exposure to human immunodeficiency virus. Read More

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http://dx.doi.org/10.1093/cid/ciz361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912151PMC
January 2020
12 Reads

Comparison of clinical and immunological features and mortality in common variable immunodeficiency and agammaglobulinemia patients.

Immunol Lett 2019 06 3;210:55-62. Epub 2019 May 3.

Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. Read More

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http://dx.doi.org/10.1016/j.imlet.2019.05.001DOI Listing
June 2019
7 Reads
2.512 Impact Factor

Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma.

Curr Oncol 2019 04 1;26(2):e233-e240. Epub 2019 Apr 1.

BC Cancer, Centre for Lymphoid Cancer, and University of British Columbia, Vancouver, BC.

Mantle cell lymphoma (mcl) is a rare subtype of aggressive B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Patients typically require multiple lines of therapy, and those with relapsed or refractory (r/r) disease have a very poor prognosis. The Bruton tyrosine kinase (btk) inhibitor ibrutinib has proven to be an effective agent for patients with r/r mcl. Read More

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http://dx.doi.org/10.3747/co.26.4345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476444PMC
April 2019
3 Reads

Pseudomonas aeruginosa severe skin infection in a toddler with X-linked agammaglobulinemia due to a novel BTK mutation.

Infez Med 2019 Mar;27(1):73-76

Infectious Disease Unit, Istituto Giannina Gaslini, University of Genoa, Italy.

Agammaglobulinemia is a congenital deficit of humoral immunity characterized by a decreased level or complete absence of immunoglobulins and profound reduction of B-lymphocytes associated with an increased risk of life-threatening bacterial infection. We report a case of invasive Pseudomonas aeruginosa severe skin and soft tissue infection treated with vacuum-assisted closure and antibiotics in a toddler with a previously unreported mutation of the Bruton tyrosin kinase gene. Read More

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March 2019
9 Reads

Management of adverse effects/toxicity of ibrutinib.

Authors:
Semra Paydas

Crit Rev Oncol Hematol 2019 Apr 10;136:56-63. Epub 2019 Feb 10.

Cukurova University Faculty of Medicine Dept of Medical Oncology, Adana, Turkey. Electronic address:

Bruton tyrosine kinase signaling (BTK) is critical step for B-cell development and immunoglobulin synthesis. Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib has been approved by FDA for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft-versus-host disease in allogeneic stem cell transplantation. Read More

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http://dx.doi.org/10.1016/j.critrevonc.2019.02.001DOI Listing
April 2019
8 Reads

Toll-Like Receptor Signaling Drives Btk-Mediated Autoimmune Disease.

Front Immunol 2019 30;10:95. Epub 2019 Jan 30.

Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, Netherlands.

Bruton's tyrosine kinase (Btk) is a signaling molecule involved in development and activation of B cells through B-cell receptor (BCR) and Toll-like receptor (TLR) signaling. We have previously shown that transgenic mice that overexpress human Btk under the control of the CD19 promoter (CD19-hBtk) display spontaneous germinal center formation, increased cytokine production, anti-nuclear autoantibodies (ANAs), and systemic autoimsmune disease upon aging. As TLR and BCR signaling are both implicated in autoimmunity, we studied their impact on splenic B cells. Read More

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http://dx.doi.org/10.3389/fimmu.2019.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363707PMC
December 2019
1 Read

The stable rower: identifying a rare disease.

Authors:
Tim Badcock

Br J Gen Pract 2019 Feb;69(679):86

Woodland Road Surgery, 57 Woodland Road, Northfield, Birmingham B31 2HZ, UK. Email:

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http://dx.doi.org/10.3399/bjgp19X701117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355259PMC
February 2019

Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA).

Eur Cytokine Netw 2018 Nov;29(4):153-158

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are two major humoral immunodeficiencies, causing a high rate of early age mortality in children. In order to identifiy the possible factors involved in the pathogenesis of CVID and XLA, recent studies have focused on Toll-like receptors (TLRs) and demonstrate the defects in different TLR pathways in immune cells of CVID and XLA patients. Herein, we measured TLR-4 and TLR-9 RNA levels and consequently TNF-α and IFN-α production in peripheral blood mononuclear cells (PBMCs) of patients with CVID and XLA. Read More

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http://dx.doi.org/10.1684/ecn.2018.0420DOI Listing
November 2018
25 Reads
1.960 Impact Factor