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Frontiers in Immunology 2020There has been less volume of literature focusing on the Immune-related Hematological Adverse Drug Events (Hem-irAEs) of Immune Checkpoint Inhibitors (ICPis) in cancer...
There has been less volume of literature focusing on the Immune-related Hematological Adverse Drug Events (Hem-irAEs) of Immune Checkpoint Inhibitors (ICPis) in cancer patients. Furthermore, there has been no consensus about the management of hematological toxicity from immunotherapy in the recently published practice guidelines by the European Society for Medical Oncology (ESMO). We conducted a systematic review of case reports/series to describe the diagnosis and management of potentially rare and unrecognized Hem-irAEs. We searched Medline, OVID, Web of Science for eligible articles. Data were extracted on patient characteristics, Hem-irAEs, and management strategies. We performed quality assessment using the Pierson-5 evaluation scheme and causality assessment using the Naranjo scale. Our search retrieved 49 articles that described 118 cases. The majority of patients had melanoma (57.6%) and lung cancer (26.3%). The most common Hem-irAEs reported with ICPis (such as nivolumab, ipilimumab, and pembrolizumab) were thrombocytopenia, hemolytic and aplastic anemias. Less reported adverse events included agranulocytosis and neutropenia. Steroids were commonly used to treat these adverse events with frequent success. Other used strategies included intravenous immunoglobulins (IVIG), rituximab, and transfusion of blood components. The findings of this review provide more insights into the diagnosis and management of the rarely reported Hem-irAEs of ICPis.
Topics: Antineoplastic Agents, Immunological; Hematologic Diseases; Humans; Immune Checkpoint Inhibitors; Neoplasms
PubMed: 33193289
DOI: 10.3389/fimmu.2020.01354 -
Pediatrics Jan 2022Immune system dysfunction is poorly represented in pediatric organ dysfunction definitions.
CONTEXT
Immune system dysfunction is poorly represented in pediatric organ dysfunction definitions.
OBJECTIVE
To evaluate evidence for criteria that define immune system dysfunction in critically ill children and associations with adverse outcomes and develop consensus criteria for the diagnosis of immune system dysfunction in critically ill children.
DATA SOURCES
We conducted electronic searches of PubMed and Embase from January 1992 to January 2020, using medical subject heading terms and text words to define immune system dysfunction and outcomes of interest.
STUDY SELECTION
Studies of critically ill children with an abnormality in leukocyte numbers or function that is currently measurable in the clinical laboratory in which researchers assessed patient-centered outcomes were included. Studies of adults or premature infants, animal studies, reviews and commentaries, case series (≤10 subjects), and studies not published in English with inability to determine eligibility criteria were excluded.
DATA EXTRACTION
Data were abstracted from eligible studies into a standard data extraction form along with risk of bias assessment by a task force member.
RESULTS
We identified the following criteria for immune system dysfunction: (1) peripheral absolute neutrophil count <500 cells/μL, (2) peripheral absolute lymphocyte count <1000 cells/μL, (3) reduction in CD4+ lymphocyte count or percentage of total lymphocytes below age-specific thresholds, (4) monocyte HLA-DR expression <30%, or (5) reduction in ex vivo whole blood lipopolysaccharide-induced TNFα production capacity below manufacturer-provided thresholds.
LIMITATIONS
Many measures of immune system function are currently limited to the research environment.
CONCLUSIONS
We present consensus criteria for the diagnosis of immune system dysfunction in critically ill children.
Topics: Child; Critical Illness; HLA-DR Antigens; Humans; Immune System; Immune System Diseases; Leukocyte Count; Lymphocyte Count; Lymphopenia; Multiple Organ Failure; Neutropenia; Neutrophils; Severity of Illness Index; Tumor Necrosis Factor-alpha
PubMed: 34970674
DOI: 10.1542/peds.2021-052888N -
The Cochrane Database of Systematic... May 2020Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas.
OBJECTIVES
To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020.
SELECTION CRITERIA
All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo.
DATA COLLECTION AND ANALYSIS
The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies.
MAIN RESULTS
The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable).
AUTHORS' CONCLUSIONS
In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Brain Neoplasms; Cancer Vaccines; Disease Progression; ErbB Receptors; Glioblastoma; Humans; Lymphopenia; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Randomized Controlled Trials as Topic; Thrombocytopenia
PubMed: 32395825
DOI: 10.1002/14651858.CD013238.pub2 -
Supportive Care in Cancer : Official... Nov 2022The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became the standard of care in the... (Meta-Analysis)
Meta-Analysis
Infectious complications of cyclin-dependent kinases 4 and 6 inhibitors in patients with hormone-receptor-positive metastatic breast cancer: a systematic review and meta-analysis.
AIM
The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became the standard of care in the treatment of metastatic hormone-positive breast cancer. However, these combinations increased the risk of neutropenia compared with ET alone. While the infection-related mortalities did not seem to be increased, the exact risk of infections with CDK 4/6 inhibitor and ET combinations is relatively understudied. Therefore, we performed a meta-analysis of CDK 4/6 inhibitor clinical trials to assess the infection risk of adding CDK4/6 inhibitors to ET.
MATERIAL AND METHOD
We systemically searched the PubMed database for relevant clinical trials. For each study, all grade and grade 3 or higher infections, upper respiratory tract infections (URTI), urinary tract infections (UTI), pneumonia, and febrile neutropenia rates were recorded whenever available. The hazard ratios (HR) with a 95% confidence interval (CI) of infection risk were calculated via the generic inverse-variance method with a random-effects model.
RESULTS
Nine eligible studies were included in the analyses (MONALEESA-2,3,7, MONARCH-2,3, MONARCH plus, PALOMA-1,2,3). In the meta-analysis of these studies, CDK 4/6 inhibitors plus ET arms were associated with increased all grade infections (HR 1.77, 95% CI 1.56-2.01, p < 0.00001), grade 3 or higher infections, (HR 1.77, 95% CI 1.28-2.43, p = 0.0005), UTIs (HR 1.59, 95% CI 1.19-2.12, p = 0.002), and febrile neutropenia (HR 4.28, 95% CI 1.73-10.62, p = 0.002).
CONCLUSION
In this meta-analysis, we observed that adding CDK4/6 inhibitors to ET significantly increased the risk of all grade, grade 3 or higher infections, and urinary tract infections. We propose that closer follow-up for infections should be considered for metastatic breast cancer patients using CDK 4/6 inhibitors. This may help clinicians to recognize infections earlier which prevents early death from infection.
Topics: Female; Humans; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Febrile Neutropenia; Protein Kinase Inhibitors; Infections
PubMed: 35972646
DOI: 10.1007/s00520-022-07320-y -
Frontiers in Endocrinology 2023The authors aimed to investigate the clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years.
OBJECTIVE
The authors aimed to investigate the clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years.
METHODS
The data of patients with antithyroid drug-induced aplastic anemia were retrieved from PubMed and Wanfang Medical Network databases from 1992 to August 2022. The clinical characteristics, such as age distribution, gender tendency, common symptoms, blood cell count, bone marrow features, treatment strategy, and prognosis, were analyzed.
RESULTS
A total of 17 cases (male:female = 1:16) had been retrieved. Patients' age ranged from 16 to 74 years (median 50 years). Among them, 82.3% (14/17) of the patients were administered methimazole (MMI), and 78.6% of them had MMI ≥30 mg/day. In addition, 88.2% (15/17) of the patients had sore throat and fever, and 47.1% (8/17) of the patients had hemorrhagic symptoms. Aplastic anemia occurred within 6 months after initiation of the antithyroid therapy in 94.1% of the patients. Agranulocytosis (94.1%) was the most common and earliest blood cell change, and 47.1% of the patients experienced progressive platelet decline during the treatment process. The treatments include timely withdrawal of antithyroid drugs, broad-spectrum antibiotics, granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF), glucocorticoids and other immunosuppressive agents, and supportive treatments such as erythrocyte transfusion and platelet transfusion. Moreover, 70.6% of the patients had complete or near-complete remission within 8 days to 6 weeks.
CONCLUSION
Aplastic anemia is a rare and serious adverse reaction of antithyroid drugs, which is more common in women. It usually occurs during early treatment with high-dose antithyroid drugs. Most patients have a good prognosis after timely drug ceasing and appropriate treatment.
Topics: Female; Humans; Male; Adolescent; Young Adult; Adult; Middle Aged; Aged; Antithyroid Agents; Anemia, Aplastic; Methimazole; Bone Marrow; Glucocorticoids
PubMed: 36777352
DOI: 10.3389/fendo.2023.1064723 -
Medicine Dec 2021Granulocyte colony-stimulating factors (G-CSFs) include long-acting ones and short-acting ones. They have been mainly applied in Chinese clinical practice for years to... (Meta-Analysis)
Meta-Analysis
Long-acting versus short-acting granulocyte colony-stimulating factors among cancer patients after chemotherapy in China: A systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Granulocyte colony-stimulating factors (G-CSFs) include long-acting ones and short-acting ones. They have been mainly applied in Chinese clinical practice for years to prevent neutropenia. However, which type of G-CSF is more superior has not been conclusively determined.
METHODS
A systematic literature search was conducted using the PubMed, Embase, Cochrane Library, clinical trials.gov, China National Knowledge Infrastructure, and WAN FANG databases for related studies published till August 2021. Revman 5.3 software was used to assess the effectiveness and safety of these 2 types of G-CSFs in patients undergoing chemotherapy.
RESULTS
Ten studies involving 1916 patients were included in our meta-analysis to compare the effectiveness and safety of long-acting G-CSFs and short-acting G-CSFs. We found that the incidence of febrile neutropenia (relative risk [RR] 0.82; 95% confidence interval [CI] 0.57-1.17), the recovery time of the absolute neutrophil count (mean difference -0.23; 95% CI -0.49 to 0.03), and the fatigue rate (RR 0.82; 95% CI 0.62-1.07) were similar between the long- and the short-acting G-CSFs. However, the long-acting G-CSFs significantly decreased the incidence (RR 0.86; 95% CI 0.76-0.96) and shortened the duration (mean difference -0.19; 95% CI -0.38 to 0.00) of severe (grade ≥3) neutropenia, and decreased the rate of bone and/or muscle pain (RR 0.75; 95% CI 0.58-0.98).
CONCLUSION
Primary prophylaxis with long-acting G-CSFs was more effective and safer than primary prophylaxis with short-acting G-CSFs in Chinese adults undergoing chemotherapy.
Topics: Adult; Granulocyte Colony-Stimulating Factor; Granulocytes; Humans; Neoplasms; Neutropenia; Randomized Controlled Trials as Topic
PubMed: 34941082
DOI: 10.1097/MD.0000000000028218 -
Revista Chilena de Infectologia :... Aug 2021Febrile neutropenia in children with onco-hematological diseases is an important cause of morbidity and mortality and requires early and adequate empirical treatment.... (Meta-Analysis)
Meta-Analysis
[Efficacy and safety of empirical treatment with piperacillin/tazobactan as monotherapy in episodes of neutropenia and fever in children with cancer: systematic review and meta-analysis].
BACKGROUND
Febrile neutropenia in children with onco-hematological diseases is an important cause of morbidity and mortality and requires early and adequate empirical treatment. This systematic review was conducted to evaluate if piperacillin/ tazobactan (PTZ) monotherapy leads to a lower incidence of therapeutic failures than comparators.
METHODS
A literature search was carried out in Embase, and MEDLINE databases using the search terms ('febrile neutropenia' OR hemato oncology OR haemato oncology OR 'immunocompromised host' OR 'immunocompromised patient' OR 'chemotherapy-induced febrile neutropenia') AND (piperacillin OR tazobactam OR 'piperacillin plus tazobactam' OR 'piperacillin/tazobactam' OR 'piperacillin-tazobactam' OR tazocin OR 'piperacillin-tazobactam drug combination')), Efficacy endpoint was treatment failure rate. The safety end-point was absence of any adverse effects (AE).
RESULTS
Eleven studies were included. No heterogeneity was detected ( I 2 0%). The risk of failure was not superior for piperacillin/tazobactan to comparators (Global RR: 0.94; IC95% 0.83 a 1.07). Rates of adverse events were similar among studies. No publication bias was detected (p 0.36).
CONCLUSIONS
This systematic review and meta-analysis showed that treating episodes of febrile neutropenia in oncology pediatric patients, the risk of failure for PTZ was not superior to comparators. Adverse events were similar to the comparators.
Topics: Anti-Bacterial Agents; Child; Drug Therapy, Combination; Humans; Neoplasms; Neutropenia; Penicillanic Acid; Piperacillin
PubMed: 34652393
DOI: 10.4067/S0716-10182021000400488 -
Schizophrenia Research Jun 2024Access to literature on clozapine in Russian language remains strikingly limited. We aimed to identify and translate clinical evidence on clozapine-based treatment... (Review)
Review
OBJECTIVE
Access to literature on clozapine in Russian language remains strikingly limited. We aimed to identify and translate clinical evidence on clozapine-based treatment outcomes.
METHODS
We performed a systematic review in PubMed, Embase and scientific indexes from former USSR states searching for articles published in Russian from the database inception till January 2023 and summarized the data in a scoping review (PROSPERO Reg. Number CRD42023386737).
RESULTS
A total of 60 papers were included comprising eight main topic categories: 1) clozapine-related intoxications (n = 20), 2) effectiveness/efficacy and safety of clozapine treatment (n = 14), 3) adverse drug-induced reactions (ADRs) related to clozapine treatment (n = 9), 4) therapeutic drug monitoring for clozapine (n = 5), 5) combination of clozapine and non-pharmacological treatments (n = 4), 6) pharmacoepidemiology of clozapine (n = 3), 7) effects of clozapine on the brain electrical activity (n = 3), and 8) novel clozapine formulations (n = 2). Among clozapine-related intoxications there were reports of criminal poisoning, which was associated with low lethality. Worse outcomes were accompanied by systemic reactions to intoxications. Clinical benefits of hemoadsorption were reported in the management of clozapine-related intoxications. Only half of studies reporting clozapine effectiveness used standardized scales to assess outcomes. Clozapine superiority in treatment-resistant schizophrenia (TRS) was replicated in one trial. No reports of clozapine-related agranulocytosis were identified. Clozapine ranked among most prescribed antipsychotics for TRS and non-TRS.
CONCLUSIONS
As clinical research in former USSR states is advancing to adopt western clinical research standards, comparability and extrapolation of findings is expected to increase, with transfer of older findings to clinical practice being particularly challenging.
Topics: Clozapine; Humans; Antipsychotic Agents; Schizophrenia; Russia
PubMed: 37741739
DOI: 10.1016/j.schres.2023.09.020 -
The Journal of Rheumatology Mar 2023The use of colchicine has been associated with varying degrees of myelosuppression. Despite expanded use in cardiovascular and inflammatory conditions, there remains...
OBJECTIVE
The use of colchicine has been associated with varying degrees of myelosuppression. Despite expanded use in cardiovascular and inflammatory conditions, there remains clinician concern because of potential myelosuppressive side effects. A systematic review was conducted to explore the reported myelosuppressive events of colchicine.
METHODS
A systematic review was conducted using the MeSH terms ("colchicine") AND ("myelosuppression," "bone*," "marrow," "suppression," "aplasia," "leukopenia/leucopenia," "lymphopenia," "neutropenia") on September 1, 2020, and was updated on November 30, 2021. The search was conducted in PubMed, ScienceDirect, Scopus, Embase, and Cochrane Library. The search included references published from 1978 to 2020 and was limited to English-language observational studies (ie, case reports, case series, case control studies, and cohort studies) or trial data.
RESULTS
In total, 3233 articles were screened, with 30 studies of 47 patients with myelosuppression from colchicine identified. Most patients with myelosuppression had comorbidities, including renal impairment (21/47, 44.7%). Out of 47 patients, 15 (31.9%) and 13 (27.7%) were reported to be concurrently taking cytochrome P450 3A4 (CYP3A4) inhibitors and P-glycoprotein (P-gp) efflux transporter inhibitors, respectively. Patients with renal impairment accounted for the majority of overall patients taking these CYP3A4 and P-gp inhibitors (8/15, 53.3%, and 8/13, 61.5%, respectively). Out of 21 patients with renal impairment, 13 had worsening cytopenia during colchicine use. The presentations ranged from moderate anemia (grade 2) to severe thrombocytopenia, neutropenia, and leukopenia (grade 4).
CONCLUSION
Colchicine has few reports of myelosuppression. The majority of patients with myelosuppression had preexisting renal impairment or concomitant CYP3A4 or P-gp inhibitor use. Caution should be taken in this subset of patients with increased monitoring.
Topics: Humans; Colchicine; Cytochrome P-450 CYP3A; Comorbidity; Bone Marrow Diseases; Neutropenia
PubMed: 36319015
DOI: 10.3899/jrheum.220524 -
British Journal of Haematology Jun 2020Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete...
Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.
Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).
Topics: Adult; Age of Onset; Aged, 80 and over; Antimetabolites; Cladribine; Dose-Response Relationship, Drug; Female; France; Histiocytosis, Langerhans-Cell; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Neutropenia; Proportional Hazards Models; Remission Induction; Retrospective Studies; Sepsis; Virus Diseases
PubMed: 32191819
DOI: 10.1111/bjh.16449