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Journal of Clinical Psychopharmacology Aug 2017Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and... (Review)
Review
PURPOSE/BACKGROUND
Clozapine is associated with hematological abnormalities, notably neutropenia, which may progress to agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce the frequency and duration of clozapine-associated neutropenia. This review aims to explore the use, efficacy, and tolerability of these cytokines in the treatment of clozapine-associated agranulocytosis.
METHODS/PROCEDURES
We conducted a systematic review of published interventional and observational studies, case series, and case reports where G-CSF/GM-CSF was used to treat clozapine-associated agranulocytosis.
FINDINGS/RESULTS
We identified 29 reports (40 patients). The median duration of neutrophil recovery time after stopping clozapine and starting cytokine treatment was 7 days (range, 2-13 days) for those with agranulocytosis (absolute neutrophil count < 0.5 × 10 cells/L). Ninety-four percent (n = 29) had no serious adverse reactions, and no deaths occurred.
IMPLICATIONS/CONCLUSIONS
Our findings indicate that G-CSF/GM-CSF use is well tolerated and suggest that G-CSF can sometimes be safely used to reduce the duration of neutropenia associated with clozapine use. However, the interpretation of this outcome is difficult, given the likely publication bias for positive outcomes in case reports.
Topics: Agranulocytosis; Antipsychotic Agents; Clozapine; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Observational Studies as Topic
PubMed: 28437295
DOI: 10.1097/JCP.0000000000000715 -
British Journal of Clinical Pharmacology Sep 2019Antithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in... (Meta-Analysis)
Meta-Analysis
AIMS
Antithyroid drug (ATD)-induced agranulocytosis is a life-threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD-induced agranulocytosis. To examine the associations between HLA genotypes and ATD-induced agranulocytosis, we conducted a systematic review and meta-analysis of pharmacogenomics studies.
METHODS
We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case-control studies on the associations between HLA genotypes with ATD-induced agranulocytosis. The Newcastle-Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random-effects model meta-analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD-induced agranulocytosis.
RESULTS
We included 5 studies with 142 ATD-induced agranulocytosis cases, 1529 matched ATD-tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD-induced agranulocytosis was associated with HLA-B*27:05 (OR 10.97; 95% CI 0.75-159.99), HLA-B*38:02 (OR 19.85; 95% CI 7.94-49.57) and HLA-DRB1*08:03 (OR 5.29; 95% CI 3.44-8.14). After excluding propylthiouracil, the associations of ATD-induced agranulocytosis with HLA-B*27:05 and HLA-B*38:02 were strengthened (OR being 20.61 (95% CI 5.21-81.58) and 40.59 (95% CI 13.24-124.47), respectively). The associations of ATD-induced agranulocytosis with HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86-14.07), 36.43 (95% CI 12.80-103.70) and 5.42 (95% CI 2.36-12.47), respectively). HLA-B*27:05, HLA-B*38:02, and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.
CONCLUSIONS
HLA-B*27:05, HLA-B*38:02 and HLA-DRB1*08:03 alleles were associated with ATD-induced agranulocytosis, especially in carbimazole/methimazole-induced agranulocytosis.
Topics: Agranulocytosis; Alleles; Antithyroid Agents; Graves Disease; HLA Antigens; Humans
PubMed: 31108563
DOI: 10.1111/bcp.13989 -
Supportive Care in Cancer : Official... Oct 2012Carbapenems represent a broad-spectrum alternative to anti-pseudomonal penicillin (APP) combination or single-agent therapy for the management of pediatric febrile... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Carbapenems represent a broad-spectrum alternative to anti-pseudomonal penicillin (APP) combination or single-agent therapy for the management of pediatric febrile neutropenia (FN). Our primary objective was to describe the risk of treatment failure in children treated with an APP or carbapenem as initial empiric treatment for FN. Our secondary objective was to compare outcomes of APP versus carbapenem therapy in this population.
METHODS
An electronic search of Ovid Medline, EMBASE, and the Cochrane Central Register of Controlled Trials was performed. We limited studies to prospective pediatric trials of FN in which at least one treatment arm consisted of an APP (with or without an aminoglycoside) or a carbapenem.
RESULTS
Of 7,281 articles reviewed, 27 studies comprising 30 treatment regimens were included for meta-analysis. Treatment failure, including antibiotic modification, occurred in 41% (95% confidence interval (CI) 32-50%), 34% (95% CI 27-41%), and 35% (95% CI 24-45%) of patients treated with APP-aminoglycoside, APP monotherapy, and carbapenem monotherapy regimens, respectively. There was no significant difference in treatment failure including antibiotic modification, infection-related mortality, or adverse events when comparing either APP regimen with carbapenem monotherapy. Although a limited number of studies were available, when stratified by FN risk group, no differences were seen in any outcome.
CONCLUSIONS
Our meta-analysis suggests that APP-aminoglycoside, APP monotherapy, and carbapenem monotherapy are all efficacious therapeutic options for the empiric management of pediatric FN.
Topics: Anti-Bacterial Agents; Bacteria; Carbapenems; Child; Child, Preschool; Drug Therapy, Combination; Fever; Humans; Neutropenia; Penicillins; Prospective Studies; Risk Assessment
PubMed: 22138849
DOI: 10.1007/s00520-011-1333-3 -
Seminars in Arthritis and Rheumatism Oct 2015To systematically review the available evidence to evaluate (1) the prevalence and degree of leukopenia, lymphopenia, and neutropenia in patients with systemic lupus... (Review)
Review
OBJECTIVE
To systematically review the available evidence to evaluate (1) the prevalence and degree of leukopenia, lymphopenia, and neutropenia in patients with systemic lupus erythematosus (SLE), (2) whether these conditions carry a major infection risk for patients, and (3) whether a treatment with colony stimulating factors (CSF) can be an effective and safe option in SLE patients with leukopenia.
MATERIAL AND METHODS
MedLine and Embase were searched by including MeSH terms, text words, and subheadings "systemic lupus erythematosus," "leukopenia" (first search), and "colony stimulating factor" (second search). Inclusion and exclusion criteria were a priori defined and two reviewers screened the retrieved articles for selection criteria; data from the included studies were recorded in ad hoc standard forms; the results were synthesized and transported to evidence tables.
RESULTS
A total of 17 articles were included in the systematic literature review: nine articles were retrieved for the first research question and 11 for the second while no articles satisfied the inclusion criteria for the third research question. The prevalence of leukopenia is reported in 22-41.8% of cases and lymphopenia is reported cumulatively from 15% to 82% of the patients while neutropenia is described in 20-40% of the patients. There is no evidence of a significant association between overall reduction of white blood cells and infection occurrence while some studies found a strong association between low lymphocytes/neutrophils count and the risk of major infections. Only case reports and case series have been found to investigate the safety of CSF in SLE patients.
CONCLUSIONS
The results of this systematic literature review are inconclusive for many aspects related to the original research questions and highlight the need for further studies. Indeed, the strength of the evidence is not sufficiently robust to draw specific recommendations on how to balance between the need to treat the patient with SLE with immunosuppressive drugs and the risk of severe infections.
Topics: Comorbidity; Humans; Leukopenia; Lupus Erythematosus, Systemic; Lymphopenia; Neutropenia; Prevalence
PubMed: 26170228
DOI: 10.1016/j.semarthrit.2015.05.009 -
PloS One 2012Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted treatment based on clinical risk stratification. Our previous meta-analysis demonstrated 16 rules had been described and 2 of them subject to validation in more than one study. We aimed to advance our knowledge of evidence on the discriminatory ability and predictive accuracy of such risk stratification clinical decision rules (CDR) for children and young people with cancer by updating our systematic review.
METHODS
The review was conducted in accordance with Centre for Reviews and Dissemination methods, searching multiple electronic databases, using two independent reviewers, formal critical appraisal with QUADAS and meta-analysis with random effects models where appropriate. It was registered with PROSPERO: CRD42011001685.
RESULTS
We found 9 new publications describing a further 7 new CDR, and validations of 7 rules. Six CDR have now been subject to testing across more than two data sets. Most validations demonstrated the rule to be less efficient than when initially proposed; geographical differences appeared to be one explanation for this.
CONCLUSION
The use of clinical decision rules will require local validation before widespread use. Considerable uncertainty remains over the most effective rule to use in each population, and an ongoing individual-patient-data meta-analysis should develop and test a more reliable CDR to improve stratification and optimise therapy. Despite current challenges, we believe it will be possible to define an internationally effective CDR to harmonise the treatment of children with febrile neutropenia.
Topics: Child; Decision Making; Fever; Humans; Neoplasms; Neutropenia; Quality Control; Risk Assessment
PubMed: 22693615
DOI: 10.1371/journal.pone.0038300 -
Cancer Chemotherapy and Pharmacology Jul 2017Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side... (Meta-Analysis)
Meta-Analysis Review
Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side effect of irinotecan, and UDP glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A1*6 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A1*6 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A1*6 polymorphisms was found. Patients with recessive models (GA + AA vs. GG) of UGT1A1*6 showed an increased risk (OR 2.03, 95% CI 1.54-2.68; RD = 0.11, P < 0.001). Specifically, the heterozygous variant of UGT1A1*6 showed an increased risk (OR 1.83, 95% CI 1.36-2.46; RD = 0.09, P < 0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83-4.75; RD = 0.18, P < 0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A1*6 (China: GA + AA vs. GG, OR 1.83, 95% CI 1.28-2.59; RD = 0.08, P = 0.001; Japan: GA + AA vs. GG, OR 2.39, 95% CI 1.45-3.92; RD = 0.15, P = 0.001). In conclusion, in this meta-analysis, the UGT1A1*6 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment.
Topics: Antineoplastic Agents, Phytogenic; Asian People; Camptothecin; Dose-Response Relationship, Drug; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Neutropenia; Polymorphism, Genetic; Risk Factors
PubMed: 28585035
DOI: 10.1007/s00280-017-3344-3 -
The Journal of Clinical Psychiatry Jul 2016To evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures... (Review)
Review
OBJECTIVE
To evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures designed to avoid clozapine-induced agranulocytosis.
DATA SOURCES
A structured MEDLINE search with no language limitation was performed from database inception until March 31, 2015, using the terms clozapine and benign ethnic neutropenia. Retrieved articles were cross-checked for additional relevant studies.
STUDY SELECTION
Included in the study were articles that reported on the prevalence, etiology, and complications of benign ethnic neutropenia and the hematologic outcome of clozapine treatment in patients with this condition.
DATA EXTRACTION
Study results that documented the epidemiology, pathobiology, and clozapine utilization in persons of African, Arabian, and Mediterranean descent with a neutrophil count in the 1,000-1,800/mm³ range.
RESULTS
The search identified 342 publications. Forty-two articles described the epidemiology, pathobiology, and management of benign ethnic neutropenia. Of these, 12 articles described patients with benign ethnic neutropenia whose neutrophil count decreased during treatment with clozapine. Persons with benign ethnic neutropenia do not have signs of impaired phagocytosis, and the frequency, severity, and outcome of their infections are similar to those observed in the general population. These features suggest that a neutrophil count > 1,000/mm³ is safe for initiating and/or resuming clozapine therapy.
CONCLUSIONS
The presence of benign ethnic neutropenia should not prevent treatment with clozapine. Patients with benign ethnic neutropenia who develop a clozapine-induced decrease in the neutrophil count, but have no evidence of infection or impaired phagocytosis, may resume clozapine as soon as they have > 1,000 neutrophils/mm³.
Topics: Agranulocytosis; Clozapine; Contraindications; Ethnicity; Humans; Leukocyte Count; Neutropenia; Neutrophils
PubMed: 27464332
DOI: 10.4088/JCP.15r10085 -
Journal of Clinical Pharmacy and... Oct 2016Metamizole was withdrawn from the market in the United States and several European countries following reports of fatal agranulocytosis among users, but is still... (Review)
Review
WHAT IS KNOWN AND OBJECTIVE
Metamizole was withdrawn from the market in the United States and several European countries following reports of fatal agranulocytosis among users, but is still available in many countries in Europe, South America and Asia. Over the past several decades, a number of epidemiologic studies have been conducted to quantify the risk of agranulocytosis and other adverse effects associated with metamizole and other non-narcotic analgesics. The objective of this study was to perform a systematic review of the safety of metamizole.
METHODS
Epidemiologic studies published between 1 January 1980 and 15 December 2014 were identified through systematic searches of PubMed and Google Scholar; the reference sections of selected articles were also reviewed to identify potentially relevant studies. Studies included in this review focused on the safety of metamizole, that is on outcomes such as haematologic abnormalities, gastrointestinal bleeding, anaphylaxis and hepatotoxicity. Two study investigators independently reviewed the abstracts and articles to determine relevant studies according to prespecified criteria.
RESULTS AND DISCUSSION
A total of 22 articles met the criteria for evaluation. The majority of studies that evaluated agranulocytosis indicated an increased risk associated with metamizole, with relative risk (RR) estimates ranging from 1·5 (95% CI, 0·8-2·7) to 40·2 (95% CI, 14·7-113·3). Findings of three case-control studies do not suggest an association between metamizole and aplastic anaemia. Of the five case-control studies that evaluated the risk of upper gastrointestinal bleeding, four found a statistically significant increased risk associated with metamizole (RR estimates ranging from 1·4 to 2·7). There is insufficient evidence to determine whether metamizole increases the risk of other outcomes (e.g. hepatic effects, anaphylaxis, congenital anomalies). Few studies evaluated the effects of dose, route of administration or duration of therapy.
WHAT IS NEW AND CONCLUSION
Published studies reported differences in the magnitude of risk of adverse outcomes associated with metamizole use and often had small sample sizes and a number of other limitations that may have biased the results. Further research is needed to better quantify the potential risks associated with metamizole compared to other non-narcotic analgesics.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Dipyrone; Epidemiologic Studies; Europe; Humans; Safety; United States
PubMed: 27422768
DOI: 10.1111/jcpt.12422 -
Multiple Sclerosis and Related Disorders Dec 2022Neutropenia is an infrequent complication of treatment with CD20 depleting agents and may require the administration of granulocyte-colony stimulating factors (G-CSF),...
BACKGROUND
Neutropenia is an infrequent complication of treatment with CD20 depleting agents and may require the administration of granulocyte-colony stimulating factors (G-CSF), which have been associated with an increased relapse risk in patients with multiple sclerosis (PwMS). The management of this side effect is still matter of debate.
METHODS
Aim of this study is to evaluate the clinical features and the management of neutropenia occurring in anti-CD20 treated PwMS through a single-center case series and a systematic review of the literature, performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
RESULTS
A total of 19 patients were included (3 from our clinical experience, 16 from the systematic review). Median age was 38 years-old (25-69) and nearly 70% were female, most of these patients had already received a median of 3 (0-4) previous treatments. Neutropenia occurred in 11 patients treated with ocrelizumab and 8 with rituximab, after a median of 2 (1-7) infusions and 9.5 (1-42) months from the first infusion. Most of these patients had late-onset neutropenia, that occurred after a median time of 90 days (2-156). About 70% of patients were symptomatic and most were treated with G-CSF or antibiotics. No relapses after G-CSF were reported. In those who did not suspend anti-CD20 (68.8%), neutropenia reoccurred in 18.2% of cases. Finally, switching between rituximab and ocrelizumab seem not to affect the occurrence of neutropenia.
CONCLUSION
Our data provides practical evidence regarding the occurrence and the management of neutropenia during treatment with anti-CD20 in PwMS.
Topics: Adult; Female; Humans; Male; Granulocyte Colony-Stimulating Factor; Multiple Sclerosis; Neutropenia; Retrospective Studies; Rituximab
PubMed: 35994977
DOI: 10.1016/j.msard.2022.104090 -
Journal of Clinical Oncology : Official... Jun 2016To describe treatment failure and mortality rates with different antibiotic regimens and different management strategies for empirical treatment of fever and neutropenia... (Review)
Review
Strategies for Empiric Management of Pediatric Fever and Neutropenia in Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: A Systematic Review of Randomized Trials.
PURPOSE
To describe treatment failure and mortality rates with different antibiotic regimens and different management strategies for empirical treatment of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients.
METHODS
We conducted a systematic review and performed searches of MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials. Studies were included if pediatric patients had cancer or were HSCT recipients and the intervention was related to the management of FN. Strategies synthesized were monotherapy versus aminoglycoside-containing combination therapy; antipseudomonal penicillin monotherapy versus fourth-generation cephalosporin monotherapy; inpatient versus outpatient management; oral versus intravenous antibiotics; and addition of colony-stimulating factors.
RESULTS
Of 11,469 citations screened, 68 studies randomly assigning 7,265 episodes were included. When compared with monotherapy, aminoglycoside-containing combination therapy did not decrease treatment failures (risk ratio, 1.13; 95% CI, 0.92 to 1.38; P = 0.23), and no difference in mortality was observed. Antipseudomonal penicillin and fourth-generation cephalosporin monotherapy were associated with similar failure and mortality rates. Outpatient management and oral antibiotics were safe in low-risk FN with no infection-related mortality observed in any patient and no significant differences in outcomes compared with inpatient management and intravenous therapy. Therapeutic colony-stimulating factors were associated with a 1.42-day reduction in hospitalization (95% CI, 0.62 to 2.22 days; P < .001).
CONCLUSION
There were a moderate number of pediatric randomized trials of FN management. Monotherapy for high-risk FN and outpatient and oral management for low-risk FN are effective strategies. These findings will provide the basis for guideline recommendations in pediatric FN.
Topics: Anti-Bacterial Agents; Child; Febrile Neutropenia; Hematopoietic Stem Cell Transplantation; Humans; Neoplasms; Randomized Controlled Trials as Topic
PubMed: 27022114
DOI: 10.1200/JCO.2015.65.8591