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Oncotarget Jun 2024Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable... (Review)
Review
Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Protein Kinase Inhibitors; Cardiotoxicity; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Adenine; Risk Assessment; Pyrimidines; Pyrazoles; Biomarkers; Polymorphism, Single Nucleotide; KCNQ1 Potassium Channel; Tyrosine Kinase Inhibitors
PubMed: 38829647
DOI: 10.18632/oncotarget.28589 -
Medicina (Kaunas, Lithuania) May 2024: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset,...
: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. : 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and -mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to -mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. : We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). : Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.
Topics: Humans; Greece; Male; Female; Adult; CTLA-4 Antigen; Middle Aged; Child; Aged; Delayed Diagnosis; Adolescent; Common Variable Immunodeficiency; Young Adult; Immunologic Deficiency Syndromes; Agammaglobulinemia
PubMed: 38792965
DOI: 10.3390/medicina60050782 -
International Journal of Molecular... May 2024Patients with predominantly antibody deficiencies (PADs) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign...
Patients with predominantly antibody deficiencies (PADs) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes, display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for defects, in order to investigate the possible contribution to PAD clinical phenotype. Ten CVID patients carried heterozygous pathogenic defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474), which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend genetic analysis in PAD in order to identify patients with a higher risk for liver disease.
Topics: Humans; alpha 1-Antitrypsin; Male; Female; Common Variable Immunodeficiency; Adult; Heterozygote; Middle Aged; Phenotype; Alleles; Adolescent; Child; Young Adult; Aged; Agammaglobulinemia; Genetic Predisposition to Disease
PubMed: 38791420
DOI: 10.3390/ijms25105382 -
International Journal of Molecular... May 2024Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the... (Review)
Review
Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, mutations, and unmutated status of the immunoglobulin heavy-chain variable region () gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in or phospholipase Cγ2 (). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Leukemia, Lymphocytic, Chronic, B-Cell; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Pyrimidines; Pyrazoles; Piperidines; Adenine; Phospholipase C gamma; Antineoplastic Agents; Mutation
PubMed: 38791284
DOI: 10.3390/ijms25105246 -
Journal of Clinical Immunology May 2024Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1...
Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.
Topics: Child, Preschool; Female; Humans; Infant; Male; Alleles; B-Lymphocytes; Immunologic Deficiency Syndromes; Interferon Type I; Mutation; Phenotype
PubMed: 38773012
DOI: 10.1007/s10875-024-01733-6 -
RMD Open May 2024Patients with X linked agammaglobulinemia are susceptible to enterovirus (EV) infections. Similarly, severe EV infections have been described in patients with impaired...
OBJECTIVE
Patients with X linked agammaglobulinemia are susceptible to enterovirus (EV) infections. Similarly, severe EV infections have been described in patients with impaired B-cell response following treatment with anti-CD20 monoclonal antibodies (mAbs), mostly in those treated for haematological malignancies. We aimed to describe severe EV infections in patients receiving anti-CD20 mAbs for immune-mediated inflammatory diseases (IMIDs).
METHODS
Patients were included following a screening of data collected through the routine surveillance of EV infections coordinated by the National Reference Center and a review of the literature. Additionally, neutralising antibodies were assessed in a patient with chronic EV-A71 meningoencephalitis.
RESULTS
Nine original and 17 previously published cases were retrieved. Meningoencephalitis (n=21/26, 81%) associated with EV-positive cerebrospinal fluid (n=20/22, 91%) was the most common manifestation. The mortality rate was high (27%). EV was the only causal agents in all reported cases. Patients received multiple anti-CD20 mAbs infusions (median 8 (5-10)), resulting in complete B-cell depletion and moderate hypogammaglobulinemia (median 4.9 g/L (4.3-6.7)), and had limited concomitant immunosuppressive treatments. Finally, in a patient with EV-A71 meningoencephalitis, a lack of B-cell response to EV was shown.
CONCLUSION
EV infection should be evoked in patients with IMIDs presenting with atypical organ involvement, especially meningoencephalitis. Anti-CD20 mAbs may lead to impaired B-cell response against EV, although an underlying primary immunodeficiency should systematically be discussed.
Topics: Humans; Enterovirus Infections; Male; Female; Antibodies, Monoclonal; Antigens, CD20; Middle Aged; Adult; Meningoencephalitis; Aged; Rituximab; B-Lymphocytes; Agammaglobulinemia; Inflammation
PubMed: 38772678
DOI: 10.1136/rmdopen-2023-004036 -
Frontiers in Immunology 2024This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection....
This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Cryoglobulinemia; Myeloid Differentiation Factor 88; Protein Kinase Inhibitors; Middle Aged; Male; Female; Adenine; Aged; Piperidines; Treatment Outcome
PubMed: 38765016
DOI: 10.3389/fimmu.2024.1390958 -
Internal Medicine (Tokyo, Japan) May 2024X-linked agammaglobulinemia (XLA) is associated with an increased risk of gastrointestinal cancers including gastric cancer (GC). We herein report the case of a...
X-linked agammaglobulinemia (XLA) is associated with an increased risk of gastrointestinal cancers including gastric cancer (GC). We herein report the case of a 30-year-old male patient with XLA who developed GC and extensive atrophic gastritis. He tested positive in the urea breath test, thus indicating the presence of Helicobacter pylori. Distal gastrectomy and chemotherapy were performed without any complications; however, the died two years after this diagnosis. Immunoglobulin deficiency makes these patients susceptible to progressive atrophic gastritis and the associated risk of GC. Therefore, patients with XLA are advised to undergo an evaluation for Helicobacter pylori infection as well as monitoring for GC.
PubMed: 38749732
DOI: 10.2169/internalmedicine.3236-23 -
Frontiers in Immunology 2024Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in...
INTRODUCTION
Non-Hodgkin's lymphoma (NHL) encompasses a diverse group of lymphoma subtypes with a wide range in disease course. Previous studies show that hypogammaglobulinemia in treatment-naïve patients is associated with poorer survival in high grade B-cell non-Hodgkin's lymphomas, though it is not known how this applies across all B-cell lymphoid malignancies.
METHODS
We conducted a retrospective study of immunoglobulin levels and clinical outcomes including survival, hospitalization, and infection rates in patients diagnosed with B-cell non-Hodgkin lymphomas of all grades at our institution.
RESULTS
Two-hundred twenty-three adults (aged = 18 years) with available pre-treatment IgG levels were selected, with hypogammaglobulinemia defined as IgG< 500 mg/mL. For this analysis, we grouped DLBCL (n=90), Primary CNS (n=5), and Burkitt lymphoma (n=1) together as high-grade, while CLL (n=52), mantle cell (n=20), marginal zone (n=25), follicular (n=21), and Waldenstrom macroglobulinemia (n=5) were low-grade. The incidence of hypogammaglobulinemia in our cohort of both high and low-grade lymphoma patients was 13.5% (n=30). Across all NHL subtypes, individuals with baseline IgG< 500 mg/dL showed an increased rate of hospitalization (4.453, CI: 1.955-10.54, p= 0.0005) and higher mortality (3.325, CI: 1.258, 8.491, p= 0.013), yet no association in number of infections when compared with those with IgG=500 mg/dL. There was a higher hospitalization rate (3.237, CI: 1.77-6.051, p=0.0017) in those with high-grade lymphoma with hypogammaglobulinemia when compared with low-grade. There was no statistically significant difference in individuals who were alive after three years in those with baseline IgG<500 mg/dL.
DISCUSSION
Our study is the first to analyze incidence of hypogammaglobulinemia at the time of diagnosis of NHL as a potential biomarker of interest for future outcomes including hospitalization and infection.
Topics: Humans; Retrospective Studies; Female; Male; Middle Aged; Aged; Immunoglobulin G; Lymphoma, Non-Hodgkin; Adult; Aged, 80 and over; Agammaglobulinemia
PubMed: 38745669
DOI: 10.3389/fimmu.2024.1334899 -
Saudi Journal of Kidney Diseases and... Nov 2023In 1952, X-linked agammaglobulinemia (XLA) was discovered as a rare inherited disorder. It markedly compromises the ability of the body to combat infectious...
Membranoproliferative Glomerulonephritis Type I Associated with Intravenous Immunoglobulin Administration Arising in a Child with X-Linked Agammaglobulinemia: A Case Report and a Reappraisal.
In 1952, X-linked agammaglobulinemia (XLA) was discovered as a rare inherited disorder. It markedly compromises the ability of the body to combat infectious microorganisms. Membranoproliferative glomerulonephritis (MPGN) Type I is characterized by subendothelial immune complex deposits. Patients with XLA can rarely develop immune-complex-induced diseases. Here, we report a case of MPGN Type I in a 12-year-old male patient with a past and family history of XLA. The patient presented with fever, productive cough, vomiting, and lower limb edema. Clinical and radiological examinations established a diagnosis of bronchopneumonia. The laboratory findings revealed proteinuria and hematuria, and a renal biopsy was performed. The histological examination of this biopsy revealed mesangial hypercellularity and thickened basement membranes. Immunofluorescence studies showed mesangiocapillary staining for Complement 3 and Immunoglobulin (Ig) G and, to a lesser extent, for IgA, IgM, and Complement 1q. Ultrastructural studies revealed partly thick, double-contoured glomerular basement membranes, glomerular endothelial cells with swollen cell bodies, and podocytes with effaced foot processes. Small subendothelial and mesangial eosinophilic deposits were identified. The diagnosis of MPGN type I was established. The patient was started on prednisolone. To the best of our knowledge, this is a rare case of MPGN Type I in a patient with XLA. The pathogenetic mechanisms underlying the development of MPGN Type I were not apparent in our patient. However, residual humoral immunity may play a role in the development of MPGN.
Topics: Child; Humans; Male; Agammaglobulinemia; Biopsy; Genetic Diseases, X-Linked; Glomerulonephritis, Membranoproliferative; Immunoglobulins, Intravenous; Treatment Outcome
PubMed: 38725215
DOI: 10.4103/sjkdt.sjkdt_133_23