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Human Psychopharmacology Jul 2020To determine the prevalence, background factors, and progression of and recovery from clozapine-induced agranulocytosis in Japan.
OBJECTIVE
To determine the prevalence, background factors, and progression of and recovery from clozapine-induced agranulocytosis in Japan.
METHODS
Data on treatment-resistant schizophrenia patients registered with the Clozaril Patient Monitoring Service (CPMS) between July 29, 2009 and January 20, 2016 were extracted. Patients with a neutrophil count <500/mm were defined as having agranulocytosis, and those with a leukocyte count <3,000/mm or a neutrophil count <1,500/mm but not meeting the criteria for agranulocytosis were defined as having leukopenia/neutropenia.
RESULTS
Of 3,746 patients, agranulocytosis and leukopenia/neutropenia were observed in 38 (1.0%) and 182 (4.9%) patients, respectively. Age was significantly higher in the agranulocytosis group (p < .001). Decreased leukocyte counts 1 week prior to discontinuation were observed only in the agranulocytosis group. The median number of days to recovery from agranulocytosis and leukopenia/neutropenia was 10 and 4, respectively, with more variation in the latter.
CONCLUSIONS
Although some patients with leukopenia/neutropenia might carry less pathologic significance, the results of this study reconfirmed the importance of regular blood monitoring for preventing agranulocytosis.
Topics: Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Disease Progression; Female; Humans; Japan; Leukocyte Count; Male; Middle Aged; Neutrophils; Prevalence; Schizophrenia
PubMed: 32420645
DOI: 10.1002/hup.2739 -
Pediatric Blood & Cancer Jul 2020
Topics: Anti-Infective Agents; Child; Febrile Neutropenia; Humans; Inpatients; Neoplasms; Outpatients
PubMed: 32383822
DOI: 10.1002/pbc.28342 -
Cells Oct 2022Leukocytes are essential for the function of the immune system and cell-cell interaction in the human body, but hematological diseases as well as chemotherapeutic... (Review)
Review
Leukocytes are essential for the function of the immune system and cell-cell interaction in the human body, but hematological diseases as well as chemotherapeutic treatments due to cancer lead to occasionally or even permanent leukocyte deficiency. Normally, more than 50% of leukocytes are neutrophilic granulocytes, and leukopenia is, therefore, mostly characterized by a decrease in neutrophilic granulocytes. The consequence of neutropenia is increased susceptibility to infection, but also healing disorders are suggestable due to the disturbed cell-cell interaction. While there is no surgical treatment for leucocyte disorders, patients suffering from neutropenia are sometimes in need of surgery for other reasons. Less is known about the morbidity and mortality of this patients, which is why this narrative review critically summarizes the results of recent research in this particular field. The results of this review suggest that neutropenic patients in need of emergency surgery have a higher mortality risk compared to non-neutropenic patients. In contrast, in elective surgery, there was not a clear tendency for a higher mortality risk of neutropenic patients. The role of neutrophilic granulocytes in inflammation and immunity in surgical patients is emphasized by the results, but most of the evaluated studies showed methodological flaws due to small sample sizes or risk of bias. Further research has to evaluate the risk for postoperative complications, particularly of infectious complications such as surgical site infections, in neutropenic patients undergoing elective surgery, and should address the role of neutrophilic function in postoperative morbidity and mortality.
Topics: Humans; Neutropenia; Granulocytes; Morbidity; Leukocytes; Digestive System Surgical Procedures
PubMed: 36291181
DOI: 10.3390/cells11203314 -
Cells Oct 2021Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated... (Review)
Review
Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T-LGL or NK cells. Chronic isolated neutropenia represents the clinical hallmark of the disease, being present in up to 80% of cases. New advances were made in the biological characterization of neutropenia in these patients, in particular mutations and a discrete immunophenotype are now recognized as relevant features. Nevertheless, the etiology of LGLL-related neutropenia is not completely elucidated and several mechanisms, including humoral abnormalities, bone marrow infiltration/substitution and cell-mediated cytotoxicity might cooperate to its pathogenesis. As a consequence of the multifactorial nature of LGLL-related neutropenia, a targeted therapeutic approach for neutropenic patients has not been developed yet; moreover, specific guidelines based on prospective trials are still lacking, thus making the treatment of this disorder a complex and challenging task. Immunosuppressive therapy represents the current, although poorly effective, therapeutic strategy. The recent identification of a STAT3-mediated miR-146b down-regulation in neutropenic T-LGLL patients emphasized the pathogenetic role of STAT3 activation in neutropenia development. Accordingly, JAK/STAT3 axis inhibition and miR-146b restoration might represent tempting strategies and should be prospectively evaluated for the treatment of neutropenic LGLL patients.
Topics: Diagnosis, Differential; Fas Ligand Protein; Humans; Immunophenotyping; Leukemia, Large Granular Lymphocytic; Neutropenia; Prognosis
PubMed: 34685780
DOI: 10.3390/cells10102800 -
Expert Review of Hematology 2023Severe chronic neutropenia, i.e. absolute neutrophil count (ANC) less than 0.5 × 10/L, is a serious health problem because it predisposes patients to recurrent... (Review)
Review
INTRODUCTION
Severe chronic neutropenia, i.e. absolute neutrophil count (ANC) less than 0.5 × 10/L, is a serious health problem because it predisposes patients to recurrent bacterial infections. Management radically changed with the discovery that granulocyte colony-stimulating factor (G-CSF) could be used to effectively treat most patients; therapy required regular subcutaneous injections. In the early days of G-CSF therapy, there were concerns that it might somehow overstimulate the bone marrow and cause myelodysplasia (MDS) or acute myeloid leukemia (AML). Detailed research records from the Severe Chronic Neutropenia International Registry (SCNIR) indicate that this is a relatively low-risk event. The research records suggest that certain patient groups are primarily at risk. Presently, allogeneic hematopoietic stem cell therapy serves as an alternate form of therapy.
AREAS COVERED
Due to these concerns and the desire for an easy-to-take oral alternative, several new treatments are under investigation. These treatments include neutrophil elastase inhibitors, SGLT-2 inhibitors, mavorixafor - an oral CXCR4 inhibitor, gene therapy, and gene editing.
EXPERT OPINION
All of these alternatives to G-CSF are promising. The risks, relative benefits, and costs are yet to be determined.
Topics: Humans; Neutropenia; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 37978893
DOI: 10.1080/17474086.2023.2285987 -
Expert Review of Clinical Immunology Mar 2023Infectious complications, particularly invasive bacterial and fungal infections, are still a major cause of morbidity in pediatric cancer patients and are associated... (Review)
Review
INTRODUCTION
Infectious complications, particularly invasive bacterial and fungal infections, are still a major cause of morbidity in pediatric cancer patients and are associated with significant mortality. Over the last few years, there has been much effort in defining risk groups to tailor antimicrobial therapy, and in establishing pediatric-specific guidelines for antimicrobial strategies.
AREAS COVERED
This review provides a critical overview of defining risk groups for infection, diagnostic work-up, antimicrobial prophylaxis, empirical therapy, and treatment of established infections.
EXPERT OPINION
To date, no generalizable risk prediction model has been established for pediatric cancer patients. There is growing interest in defining the impact of the individual genetic background on infectious complications. New diagnostic tools have been developed over the last few years, but they need to be validated in pediatric cancer patients. International, pediatric-specific guidelines for antimicrobial prophylaxis, empirical therapy, and treatment of established infections have recently been published and will harmonize antimicrobial strategies in the future.
Topics: Child; Humans; Neoplasms; Mycoses; Anti-Bacterial Agents; Risk Factors; Febrile Neutropenia
PubMed: 36635981
DOI: 10.1080/1744666X.2023.2168646 -
Psychological Medicine Mar 2020Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the prevalence of agranulocytosis and related death in clozapine-treated patients.
METHODS
A literature search in the international (PubMed, PsycINFO, and EMBASE) and Chinese (WanFang, Chinese National Knowledge Infrastructure, and Sinomed) databases was conducted. Prevalence estimates of agranulocytosis and related death in clozapine-treated patients were synthesized with the Comprehensive Meta-Analysis program using the random-effects model.
RESULTS
Thirty-six studies with 260 948 clozapine-treated patients published between 1984 and 2018 were included in the meta-analysis. The overall prevalence of agranulocytosis and death caused by agranulocytosis were 0.4% (95% CI 0.3-0.6%) and 0.05% (95% CI 0.03-0.09%), respectively. The prevalence of agranulocytosis was moderated by sample size, study quality, year of publication, and that of data collection.
CONCLUSIONS
The prevalence of clozapine-associated agranulocytosis is low. Agranulocytosis-related death appears rare.
Topics: Agranulocytosis; Antipsychotic Agents; Cause of Death; Clozapine; Drug-Related Side Effects and Adverse Reactions; Humans; Observational Studies as Topic; Prevalence
PubMed: 30857568
DOI: 10.1017/S0033291719000369 -
The Australian and New Zealand Journal... May 2020
Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; HLA Antigens; Humans; Leukocyte Count
PubMed: 31968985
DOI: 10.1177/0004867419900296 -
Acta Paediatrica (Oslo, Norway : 1992) Nov 2021Congenital neutropenia with autosomal recessive inheritance was first described by the Swedish paediatrician Rolf Kostmann who coined the term 'infantile genetic... (Review)
Review
Congenital neutropenia with autosomal recessive inheritance was first described by the Swedish paediatrician Rolf Kostmann who coined the term 'infantile genetic agranulocytosis'. The condition is now commonly referred to as Kostmann disease. These patients display a maturation arrest of the myelopoiesis in the bone marrow and reduced neutrophil numbers and suffer from recurrent, often life-threatening infections. The molecular mechanism underlying congenital neutropenia has been intensively investigated, and mutations in genes that impinge on programmed cell death have been identified. The present review provides an overview of these studies.
Topics: Congenital Bone Marrow Failure Syndromes; Humans; Mutation; Neutropenia; Syndrome
PubMed: 34160857
DOI: 10.1111/apa.16005 -
Schizophrenia Research Jun 2024After the introduction of clozapine eight Finnish patients died after developing agranulocytosis. Clozapine was withdrawn from the market and only reintroduced with... (Review)
Review
After the introduction of clozapine eight Finnish patients died after developing agranulocytosis. Clozapine was withdrawn from the market and only reintroduced with strict mandatory white blood cell monitoring as long as treatment lasts and thresholds at which clozapine must be discontinued definitively. The fear of agranulocytosis and the need for intensive blood monitoring is the single most important barrier for prescribers and patients alike and leads to underprescription of the only effective and approved medication for treatment-resistant schizophrenia. We summarize evidence that the risk of agranulocytosis is smaller than perceived at the time of reintroduction, is concentrated in the first 18 weeks of treatment, is not greater than with other antipsychotics thereafter and that frequent blood monitoring has not demonstrably decreased the rate of agranulocytosis. Therefore we propose 1) mandatory monitoring of the absolute neutrophil count (ANC) exclusively during the first 18 weeks of clozapine treatment, 2) that thereafter the prescriber and the well-informed patient decide together about further monitoring frequency, 3) that clozapine treatment must be stopped if the ANC falls below 1.0 × 10/L. Continuation of clozapine or a rechallenge are possible if prescriber and patient determine that the benefits outweigh the risks. 4) National registries which control the haematologic monitoring are unnecessary and do not help to reduce clozapine-induced agranulocytosis. They should at least be restricted to the first 18 weeks of clozapine use.
Topics: Clozapine; Humans; Agranulocytosis; Antipsychotic Agents; Leukocyte Count; Drug Monitoring; Schizophrenia
PubMed: 37770377
DOI: 10.1016/j.schres.2023.09.024