-
Biomedicine & Pharmacotherapy =... Jun 2023Chemotherapy kills fast-growing cells including gut stem cells. This affects all components of the physical and functional intestinal barrier, i.e., the mucus layer,... (Review)
Review
Chemotherapy kills fast-growing cells including gut stem cells. This affects all components of the physical and functional intestinal barrier, i.e., the mucus layer, epithelium, and immune system. This results in an altered intestinal permeability of toxic compounds (e.g., endotoxins) as well as luminal bacterial translocation into the mucosa and central circulation. However, there is uncertainty regarding the relative contributions of the different barrier components for the development of chemotherapy-induced gut toxicity. This review present an overview of the intestinal mucosal barrier determined with various types of molecular probes and methods, and how they are affected by chemotherapy based on reported rodent and human data. We conclude that there is overwhelming evidence that chemotherapy increases bacterial translocation, and that it affects the mucosal barrier by rendering the mucosa more permeable to large permeability probes. Chemotherapy also seems to impede the intestinal mucus barrier, even though this has been less clearly evaluated from a functional standpoint but certainly plays a role in bacteria translocation. Combined, it is however difficult to outline a clear temporal or succession between the different gastrointestinal events and barrier functions, especially as chemotherapy-induced neutropenia is also involved in intestinal immunological homeostasis and bacterial translocation. A thorough characterization of this would need to include a time dependent development of neutropenia, intestinal permeability, and bacterial translocation, ideally after a range of chemotherapeutics and dosing regimens.
Topics: Humans; Bacterial Translocation; Intestinal Mucosa; Antineoplastic Agents; Permeability; Mucus; Neutropenia
PubMed: 37018992
DOI: 10.1016/j.biopha.2023.114644 -
Journal of Clinical Immunology Jan 2022WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined...
PURPOSE
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published.
METHODS
To summarize current information on HSCT efficacy in disease treatment, seven pediatric patients with WHIM syndrome who underwent allogeneic HSCT were identified in five centers worldwide.
RESULTS
All patients presented early after birth with neutropenia. Two of seven patients exhibited severe disease complications: poorly controlled autoimmunity (arthritis and anemia) in one and progressive myelofibrosis with recurrent infections in the other. The remaining patients received HSCT to correct milder disease symptoms (recurrent respiratory infections, progressing thrombocytopenia) and/or to preclude severe disease course in older age. All seven patients engrafted but one developed graft rejection and died of infectious complications after third HSCT. Three other patients experienced severe viral infections after HSCT (including post-transplant lymphoproliferative disease in one) which completely resolved with therapy. At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism. One patient 1.4 years after HSCT had moderate thrombocytopenia and delayed immune recovery; the others had adequate immune recovery and were free of prior disease symptoms.
CONCLUSION
HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts.
Topics: Child; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Primary Immunodeficiency Diseases; Receptors, CXCR4; Warts
PubMed: 34697698
DOI: 10.1007/s10875-021-01155-8 -
Basic & Clinical Pharmacology &... Feb 2020Despite ongoing debates about its safety, the use of metamizole (dipyrone) is still increasing in many countries. In this study, we analysed spontaneous reports of...
Despite ongoing debates about its safety, the use of metamizole (dipyrone) is still increasing in many countries. In this study, we analysed spontaneous reports of suspected metamizole-associated agranulocytosis recorded in EudraVigilance database from 1985 to 2017 with regard to patient and treatment characteristics as well as fatal vs non-fatal outcomes and compared these findings among countries. A total of 1448 reports from 31 different countries were included (Germany 42.0%; Spain 29.6%; Switzerland 13.1%; other countries 15.3%). Mean age of patients was 53.6 years (63.4% females). Differences among countries were observed, for example with respect to patient age, route of administration and daily doses. Overall, median time between starting metamizole and developing an agranulocytosis was 13 days with 34.7% of cases occurring up to 7 days. This time was much shorter in patients who had already received metamizole before (median: 6 vs 15 days). About 16% of cases ended fatally. Patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes. When adjusting for age and sex in a multivariable logistic regression, methotrexate was associated with an increased risk of fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78). In conclusion, metamizole-associated agranulocytosis is still a life-threatening condition, especially in the elderly and those also receiving methotrexate. As agranulocytosis can develop weeks after last administration and independently of dose and duration of treatment, prescribers and patients should be aware of its signs and symptoms.
Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Age Factors; Aged; Aged, 80 and over; Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Child; Child, Preschool; Databases, Factual; Dipyrone; Female; Humans; Infant; Male; Middle Aged; Pharmacovigilance; Retrospective Studies; Risk Factors; Young Adult
PubMed: 31449718
DOI: 10.1111/bcpt.13310 -
Blood Advances Nov 2023We used a next-generation sequencing platform to characterize microbial cell-free DNA (mcfDNA) in plasma samples from patients undergoing allogeneic hematopoietic stem... (Observational Study)
Observational Study
We used a next-generation sequencing platform to characterize microbial cell-free DNA (mcfDNA) in plasma samples from patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). In this observational study, we sought to characterize plasma mcfDNA in order to explore its potential association with the immunologic complications of transplantation. We compared serially collected patient samples with plasma collected from healthy control subjects. We observed changes in total mcfDNA burden in the plasma after transplantation, which was most striking during the early posttransplant neutropenic phase. This elevation could be attributed to a number of specific bacterial taxa, including Veillonella, Bacteroides, and Prevotella (genus level). For an additional cohort of patients, we compared the data of mcfDNA from plasma with 16s-ribosomal RNA sequencing data from stool samples collected at matched time points. In a number of patients, we confirmed that mcfDNA derived from specific microbial taxa (eg, Enterococcus) could also be observed in the matched stool sample. Quantification of mcfDNA may generate novel insights into mechanisms by which the intestinal microbiome influences systemic cell populations and, thus, has been associated with outcomes for patients with cancer.
Topics: Humans; Cell-Free Nucleic Acids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Neoplasms; Neutropenia
PubMed: 37399491
DOI: 10.1182/bloodadvances.2023010208 -
Cancer Apr 2023
Topics: Humans; Gastrointestinal Microbiome; Neutropenia
PubMed: 36950861
DOI: 10.1002/cncr.34739 -
BMC Psychiatry Jun 2020Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia... (Review)
Review
Clozapine remains the only drug treatment likely to benefit patients with treatment resistant schizophrenia. Its use is complicated by an increased risk of neutropenia and so there are stringent monitoring requirements and restrictions in those with previous neutropenia from any cause or from clozapine in particular. Despite these difficulties clozapine may yet be used following neutropenia, albeit with caution. Having had involvement with 14 cases of clozapine use in these circumstances we set out our approach to the assessment of risks and benefits, risk mitigation and monitoring with a practical guide.
Topics: Antipsychotic Agents; Clozapine; Humans; Neutropenia; Schizophrenia
PubMed: 32503471
DOI: 10.1186/s12888-020-02592-2 -
The Oncologist Oct 2021In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse... (Review)
Review
In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee-assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22-38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL. IMPLICATIONS FOR PRACTICE: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, in the third-line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.
Topics: Humans; Hydrazines; Lymphoma, Large B-Cell, Diffuse; Multicenter Studies as Topic; Neutropenia; Treatment Outcome; Triazoles
PubMed: 34132444
DOI: 10.1002/onco.13859 -
Critical Reviews in Oncology/hematology Apr 2024Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The... (Review)
Review
Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The filgrastim biosimilar, EP2006, has been available in Europe since 2009, and in the United States since 2015. In this time, preclinical and clinical data used to support the approval of EP2006 have been published. These data established the biosimilarity of EP2006 to reference filgrastim in terms of structure, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Additional real-world evidence studies have also demonstrated equivalent efficacy and safety of EP2006 compared with reference filgrastim, both in the reduction of neutropenia and in stem cell mobilization in clinical practice. This review summarizes these preclinical, clinical, and real-world data, as well as the available cost-effectiveness data, for EP2006 since its approval 15 years ago.
Topics: Humans; United States; Filgrastim; Biosimilar Pharmaceuticals; Double-Blind Method; Neutropenia; Antineoplastic Combined Chemotherapy Protocols; Granulocyte Colony-Stimulating Factor
PubMed: 38401695
DOI: 10.1016/j.critrevonc.2024.104306 -
Supportive Care in Cancer : Official... Nov 2023Recent clinical practice guidelines have recommended ambulatory management of febrile neutropenia in patients with low risk of complications. Although some centers have... (Review)
Review
PURPOSE
Recent clinical practice guidelines have recommended ambulatory management of febrile neutropenia in patients with low risk of complications. Although some centers have begun developing management protocols for these patients, there appears to be a certain reluctance to implement them in clinical practice. Our aim is to evaluate the strengths and weaknesses of this strategy according to available evidence and to propose new lines of research.
METHODS
Systematic review using a triple aim approach (efficacy, cost-effectiveness, and quality of life), drawing from literature in MEDLINE (PubMed), Embase, and Cochrane Library databases. The review includes studies that assess ambulatory management for efficacy, cost-efficiency, and quality of life.
RESULTS
The search yielded 27 articles that met our inclusion criteria.
CONCLUSION
In conclusion, based on current evidence, ambulatory management of febrile neutropenia is safe, more cost-effective than inpatient care, and capable of improving quality of life in oncological patients with this complication. Ambulatory care seems to be an effective alternative to hospitalization in these patients.
Topics: Humans; Adult; Neoplasms; Fever; Quality of Life; Hospitalization; Febrile Neutropenia
PubMed: 37921996
DOI: 10.1007/s00520-023-08065-y -
British Journal of Haematology Sep 2022Inborn errors of immunity (IEI) are inherited monogenic disorders resulting in defective immune response. Non-infectious presentations are increasingly more apparent....
Inborn errors of immunity (IEI) are inherited monogenic disorders resulting in defective immune response. Non-infectious presentations are increasingly more apparent. Widely available, cost-effective early indicators are needed. Peripheral-blood cytopenia may be a presenting laboratory feature or an observed secondary phenomenon. This retrospective review of the South African Primary Immunodeficiency Registry (SAPIDR) aimed to assess the haematological indices at presentation and their association with the International Union of Immunological Societies (IUIS) 2019 IEI classification and mortality. Of 396 patients on the SAPIDR, 66% (n = 257) had available haematological results. Sixty percent were males and 85% under 18 years. A majority (53%) had predominantly antibody deficiency. At presentation, infection was prominent (86%) followed by cytopenia (62%). Neutropenia was associated with IUIS III [odds ratio (OR) 3.65, confidence interval (CI) 1.44-9.25], thrombocytopenia with IUIS II (OR 14.39, CI 2.89-71.57), lymphopenia with IUIS I (OR 12.16, CI 2.75-53.73) and pancytopenia with IUSI I (OR 12.24, CI 3.82-39.05) and IUIS II (OR 5.99, CI 2.80-12.76). Cytopenia showed shorter overall survival (OR 2.81, CI 1.288-4.16). Cytopenias that are severe, persistent, unusual and/or recurrent should prompt further investigation for IEI. The full blood count and leucocyte differential may facilitate earlier identification and serve as an adjunct to definitive molecular classification.
Topics: Adolescent; Anemia; Female; Humans; Lymphopenia; Male; Neutropenia; Pancytopenia; Thrombocytopenia
PubMed: 35791731
DOI: 10.1111/bjh.18337