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Annals of Medicine Dec 2022Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study aimed to systematically review the cytopenias following anti-CD19 CAR-T therapy and further analyse the contributing factors.
METHODS
Databases including PubMed, MEDLINE, Embase and Cochrane were systematically searched on 8 May 2022. A random-effect meta-analysis was used to estimate the incidence of cytopenia, and subgroup analyses were applied to explore heterogeneity.
RESULTS
A total of 68 studies involving 2950 patients were included in this study. The overall incidence of all grade anaemia, thrombocytopenia, neutropenia, leukopoenia, lymphocytopenia and febrile neutropenia was 65%, 55%, 78%, 62%, 70% and 27%, respectively, and the corresponding cytopenias of grade 3 or worse were 33%, 31%, 61%, 45%, 46%, and 21%, respectively. Subgroup analysis showed increased incidence of cytopenias in subgroups with lower median age, proportion of males (<65%) and proportion of bridging therapy (<80%) and in the subgroup with a median line of prior therapy ≥3. In terms of disease and therapeutic target, cytopenias were more frequent in ALL patients and in dual-target CAR-T therapies (targeting CD19 in combination with other targets). Furthermore, CAR-T products manufactured by lentiviral vectors and those with the costimulatory domain of CD28 were more likely to cause haematological toxicity. No significant differences were observed in cytopenia between patients treated with CAR-T products with murine and humanized scFv.
CONCLUSION
In conclusion, neutropenia is the most frequent cytopenia after CAR-T therapy, both in all grades or grade ≥3. The incidence of cytopenias following CAR-T therapy is influenced by the age, sex, disease and number of prior therapy lines of the patients, as well as the target and costimulatory domain of CAR-T cells, and viral vectors used for manufacturing.KEY MESSAGESNeutropenia is the most frequent cytopenia after CAR-T therapy.The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy.
Topics: Male; Humans; Mice; Animals; Receptors, Chimeric Antigen; Quality of Life; Antigens, CD19; Anemia; Thrombocytopenia; Neutropenia; Cell- and Tissue-Based Therapy
PubMed: 36382675
DOI: 10.1080/07853890.2022.2136748 -
The Pharmacogenomics Journal Jul 2022Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the... (Meta-Analysis)
Meta-Analysis
Although clozapine is the most effective pharmacotherapy for treatment-resistant schizophrenia, it is under-utilized, and initiation is often delayed. One reason is the occurrence of a potentially fatal adverse reaction, clozapine-induced agranulocytosis (CIA). Identifying genetic variations contributing to CIA would help predict patient risk of developing CIA and personalize treatment. Here, we (1) review existing pharmacogenomic studies of CIA, and (2) conduct meta-analyses to identify targets for clinical implementation. A systematic literature search identified studies that included individuals receiving clozapine who developed CIA and controls who did not. Results showed that individuals carrying the HLA-DRB1*04:02 allele had nearly sixfold (95% CI 2.20-15.80, p = 0.03) higher odds of CIA with a negative predictive value of 99.3%. Previously unreplicated alleles, TNFb5, HLA-B*59:01, TNFb4, and TNFd3 showed significant associations with CIA after multiple-testing corrections. Our findings suggest that a predictive HLA-DRB1*04:02-based pharmacogenomic test may be promising for clinical implementation but requires further investigation.
Topics: Agranulocytosis; Alleles; Antipsychotic Agents; Clozapine; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 35710824
DOI: 10.1038/s41397-022-00281-9 -
Pharmacogenetics and Genomics Aug 2021Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk...
Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe agranulocytosis. We here describe three patients with metamizole-associated agranulocytosis. Patient #1 suffered from agranulocytosis and tonsillitis followed by severe sepsis by Streptococcus pneumoniae and Epstein-Barr virus reactivation. Her dizygotic twin sister (patient #2) also suffered from agranulocytosis after a surgical intervention. Patient #3 initially had a tonsillitis and also developed neutropenia after metamizole intake. For all patients, pharmacogenetic diagnostic for the genes CYP2C9, CYP2C19 and NAT2, which are involved in metamizole metabolism and degradation of toxic metabolites, was initiated. Pharmacogenetic analysis revealed NAT2 slow acetylator phenotype in all three patients. Additionally, patient #2 is an intermediate metabolizer for CYP2C19 and patient #3 is a poor metabolizer for CYP2C9. Impairment of these enzymes causes a reduced degradation of toxic metabolites, for example, 4-methylaminoantipyrine (4-MAA) or 4-aminoantipyrine. The metabolite 4-MAA can complex with hemin, which is an early breakdown product during hemolysis. Hemolysis is often observed during invasive infections or after surgical procedures. It is known that the 4-MAA/hemin complex can induce cytotoxicity in the bone marrow and interrupt granulocyte maturation. In conclusion, metamizole-induced agranulocytosis most likely was a consequence of the underlying genetical predisposition, that is, polymorphisms in the genes NAT2, CYP2C9 and CYP2C19. Hemolysis may have increased the toxicity of metamizole metabolites.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arylamine N-Acetyltransferase; Dipyrone; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Neutropenia
PubMed: 33675325
DOI: 10.1097/FPC.0000000000000432 -
Translational Psychiatry Apr 2021The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions,...
The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm and 1500/mm were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E-06) and agranulocytosis (OR = 10.49, P = 1.83E-06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E-08; agranulocytosis: OR = 16.31, P = 1.39E-06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.
Topics: Antipsychotic Agents; Clozapine; HLA-DQ beta-Chains; Humans; Neutropenia
PubMed: 33846298
DOI: 10.1038/s41398-021-01322-w -
Expert Review of Hematology Jul 2022Febrile neutropenia (FN) is a major dose-limiting toxicity of myelosuppressive chemotherapy, and several patients receiving chemotherapy are at intermediate risk of... (Review)
Review
INTRODUCTION
Febrile neutropenia (FN) is a major dose-limiting toxicity of myelosuppressive chemotherapy, and several patients receiving chemotherapy are at intermediate risk of developing FN. However, the guidelines remain less clear regarding the use of granulocyte colony-stimulating factors (G-CSFs) for this population and insights about real-world prophylaxis patterns and FN outcomes are needed.
AREAS COVERED
This scoping review summarizes the variability in real-world G-CSF prophylaxis treatment patterns, incidence of FN, and associated outcomes among patients receiving chemotherapy at intermediate risk of FN. G-CSF PP use varied across the included studies (N = 23). Overall, there was a trend for reduced FN incidence among patients who received G-CSF PP vs. those who did not. G-CSF PP was also associated with a lower incidence of FN-related dose delays and reductions and fewer hospitalization days. Gaps in the literature of real-world studies exist, particularly around incorporating FN risk factor assessment, patient-reported outcomes, and health economic outcomes.
EXPERT OPINION
Further studies are warranted to determine the impact of G-CSF PP use on clinical, quality of life, and economic outcomes in patients with intermediate FN risk, which could optimize care for this subgroup of patients, resulting in better population-based FN-related outcomes.
Topics: Antineoplastic Combined Chemotherapy Protocols; Febrile Neutropenia; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Quality of Life
PubMed: 35791622
DOI: 10.1080/17474086.2022.2093712 -
British Journal of Clinical Pharmacology May 2022Acute neutropenia induced by antibiotics is a rare side effect of this frequently prescribed class of drugs. We aim to find similarities and differences between reported... (Review)
Review
AIMS
Acute neutropenia induced by antibiotics is a rare side effect of this frequently prescribed class of drugs. We aim to find similarities and differences between reported cases.
METHODS
Through a database search (PubMed, 1968-2020), we identified published case reports and extracted, among other data, patient demographics, duration of treatment with the respective agent, and duration of recovery.
RESULTS
Overall, 83 cases were included. Neutropenia developed after a median (min-max) of 21 (17.5-28.5) days of treatment and was resolved after a median (min-max) of 6 (3.0-8.75) days. Vancomycin and ceftaroline emerged as the two most commonly described antibiotics. In 51.8% of cases, the suspected antibiotic was discontinued; in 37.4% of cases, it was substituted by another agent. Only three case reports mentioned death as a result of neutropenia. The use of granulocyte colony-stimulating growth factors (CSFs) shortened the duration of neutropenia and improved outcome for patients' health.
CONCLUSION
Neutropenia induced by antibiotics remains a rare or rarely reported side effect. Long-term and high-dose treatment regimens expose a higher risk of development. Thus, regular full blood counts are advised during therapy.
Topics: Anti-Bacterial Agents; Drug-Related Side Effects and Adverse Reactions; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia
PubMed: 34897762
DOI: 10.1111/bcp.15170 -
Journal of Psychopharmacology (Oxford,... Apr 2023Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions... (Review)
Review
OBJECTIVES
Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs.
METHODS
MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis.
RESULTS
Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, -value = 0.065). Two administration strategies were identified, "as-needed" and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented.
CONCLUSIONS
Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.
Topics: Humans; Clozapine; Antipsychotic Agents; Neutropenia; Granulocyte Colony-Stimulating Factor
PubMed: 36794520
DOI: 10.1177/02698811231154111 -
Indian Journal of Pediatrics Sep 2022To describe the clinical characteristics of patients with chronic neutropenia.
OBJECTIVES
To describe the clinical characteristics of patients with chronic neutropenia.
METHODS
Data of 36 patients with chronic neutropenia, who were followed up in the authors' clinic between May 2013 and May 2020, were analyzed retrospectively. Patients were diagnosed based on their clinical and laboratory characteristics.
RESULTS
A total of 36 patients (23 females, 13 males) were included in the study. The mean age at diagnosis was 9.85 ± 9.17 mo while the mean follow-up time was 21.83 ± 20.03 mo. The mean absolute neutrophil count (ANC) at admission was 462.5 ± 388.8 cells/mm (median = 375 cells/mm), and the lowest and highest ANC mean was 241.2 ± 262.1 cells/mm (median = 125 cells/mm), and 1362.9 ± 1127.9 cells/mm (median = 925 cells/mm), respectively. Idiopathic neutropenia was found in 28 (77.8%) patients, autoimmune neutropenia in 6 (16.7%) patients, and congenital neutropenia in 2 (5.6%) patients. Neutrophil normalization was observed in 19 (52.8%) of the patients.
CONCLUSIONS
Chronic neutropenia is a heterogeneous picture that presents with different clinical symptoms in childhood. The cause of neutropoenia in children is usually benign and resolves spontaneously but especially in those with severe neutropoenia genetic examination should be performed.
Topics: Child; Female; Hospitalization; Humans; Leukocyte Count; Male; Neutropenia; Neutrophils; Retrospective Studies
PubMed: 35267133
DOI: 10.1007/s12098-022-04104-4 -
Archivos de Bronconeumologia May 2021
Topics: Humans; Neutropenia; Tuberculosis
PubMed: 33876731
DOI: 10.1016/j.arbres.2020.08.021 -
Journal of Korean Medical Science Aug 2021Vaccine safety surveillance is important because it is related to vaccine hesitancy, which affects vaccination rate. To increase confidence in vaccination, the active...
BACKGROUND
Vaccine safety surveillance is important because it is related to vaccine hesitancy, which affects vaccination rate. To increase confidence in vaccination, the active monitoring of vaccine adverse events is important. For effective active surveillance, we developed and verified a machine learning-based active surveillance system using national claim data.
METHODS
We used two databases, one from the Korea Disease Control and Prevention Agency, which contains flu vaccination records for the elderly, and another from the National Health Insurance Service, which contains the claim data of vaccinated people. We developed a case-crossover design based machine learning model to predict the health outcome of interest events (anaphylaxis and agranulocytosis) using a random forest. Feature importance values were evaluated to determine candidate associations with each outcome. We investigated the relationship of the features to each event via a literature review, comparison with the Side Effect Resource, and using the Local Interpretable Model-agnostic Explanation method.
RESULTS
The trained model predicted each health outcome of interest with a high accuracy (approximately 70%). We found literature supporting our results, and most of the important drug-related features were listed in the Side Effect Resource database as inducing the health outcome of interest. For anaphylaxis, flu vaccination ranked high in our feature importance analysis and had a positive association in Local Interpretable Model-Agnostic Explanation analysis. Although the feature importance of vaccination was lower for agranulocytosis, it also had a positive relationship in the Local Interpretable Model-Agnostic Explanation analysis.
CONCLUSION
We developed a machine learning-based active surveillance system for detecting possible factors that can induce adverse events using health claim and vaccination databases. The results of the study demonstrated a potentially useful application of two linked national health record databases. Our model can contribute to the establishment of a system for conducting active surveillance on vaccination.
Topics: Adverse Drug Reaction Reporting Systems; Agranulocytosis; Anaphylaxis; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Machine Learning; Product Surveillance, Postmarketing; Republic of Korea; Vaccination; Vaccines
PubMed: 34402232
DOI: 10.3346/jkms.2021.36.e198