-
Critical Care (London, England) Nov 2017Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric... (Review)
Review
BACKGROUND
Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions.
METHODS
A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting.
RESULTS
Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis.
CONCLUSIONS
Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.
Topics: Anti-Bacterial Agents; Cefepime; Cephalosporins; Consciousness Disorders; Drug-Related Side Effects and Adverse Reactions; Humans; Neurotoxicity Syndromes; Seizures
PubMed: 29137682
DOI: 10.1186/s13054-017-1856-1 -
The Lancet. Neurology Mar 2014Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children... (Review)
Review
Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children worldwide, and some diagnoses seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence. In 2006, we did a systematic review and identified five industrial chemicals as developmental neurotoxicants: lead, methylmercury, polychlorinated biphenyls, arsenic, and toluene. Since 2006, epidemiological studies have documented six additional developmental neurotoxicants-manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane, tetrachloroethylene, and the polybrominated diphenyl ethers. We postulate that even more neurotoxicants remain undiscovered. To control the pandemic of developmental neurotoxicity, we propose a global prevention strategy. Untested chemicals should not be presumed to be safe to brain development, and chemicals in existing use and all new chemicals must therefore be tested for developmental neurotoxicity. To coordinate these efforts and to accelerate translation of science into prevention, we propose the urgent formation of a new international clearinghouse.
Topics: Animals; Brain; Developmental Disabilities; Environmental Exposure; Humans; Methylmercury Compounds; Neurotoxicity Syndromes; Polychlorinated Biphenyls
PubMed: 24556010
DOI: 10.1016/S1474-4422(13)70278-3 -
Acta Neuropathologica Communications Mar 2023In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified... (Review)
Review
In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, or neuroinflammatory reactive astrocytes. In contrast to typical astrocytes, which promote neuronal survival, support synapses, and maintain blood-brain barrier integrity, these reactive astrocytes downregulate supportive functions and begin to secrete neurotoxic factors, complement components like C3, and chemokines like CXCL10, which may facilitate recruitment of immune cells across the BBB into the CNS. The proportion of pro-inflammatory reactive astrocytes increases with age through associated microglia activation, and these pro-inflammatory reactive astrocytes are particularly abundant in neurodegenerative disorders. As the identification of astrocyte phenotypes progress, their molecular and cellular effects are characterized in a growing array of neuropathologies.
Topics: Humans; Astrocytes; Microglia; Central Nervous System; Blood-Brain Barrier; Chemokines; Neurotoxicity Syndromes
PubMed: 36915214
DOI: 10.1186/s40478-023-01526-9 -
Transplantation and Cellular Therapy Jun 2022Chimeric antigen receptor (CAR) T cell therapy is a novel therapy for patients with relapsed or refractory hematologic malignancies. Most CAR T cell therapy recipients... (Review)
Review
Clinical Presentation, Risk Factors, and Outcomes of Immune Effector Cell-Associated Neurotoxicity Syndrome Following Chimeric Antigen Receptor T Cell Therapy: A Systematic Review.
Chimeric antigen receptor (CAR) T cell therapy is a novel therapy for patients with relapsed or refractory hematologic malignancies. Most CAR T cell therapy recipients will experience clinical features of the immune effector cell-associated neurotoxicity syndrome (ICANS), a potentially life-threatening condition. Here we describe the clinical, biological, and radiological findings associated with ICANS in adults with hematologic malignancies treated with CAR T cell therapy, as well as the acute and long-term outcomes of ICANS. A literature search of Ovid Medline, Embase, PubMed, Scopus, Web of Science Core Collection, Cochrane Library, and Google Scholar was conducted from each database's inception through February 1, 2022, using search terms reflecting CAR T cell therapy and ICANS. We included studies that enrolled adults (age ≥18 years) who received CAR T cell therapy as management for hematologic malignancies and reported the clinical presentation, predictors, and/or acute or long-term outcomes of ICANS. Two reviewers independently extracted data following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) reporting guidelines. Quality was assessed using the Joanna Briggs Institute critical appraisal tool for cohort studies. Of the 2928 studies screened, 23 observational studies (10 prospective, 11 retrospective, 1 mixed design, and 1 cross-sectional) with a total of 1666 participants met our eligibility criteria and were included in our review. The most common hematologic malignancies were diffuse large B cell lymphoma, acute lymphocytic leukemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia. ICANS onset was most often associated with the presence and severity of cytokine release syndrome, as well as with C-reactive protein and ferritin levels. Aphasia was the most common ICANS-related symptom reported, although the neurologic manifestations of ICANS were highly variable. Neuroimaging studies (magnetic resonance imaging or computed tomography) were often normal in cases of ICANS; however, electroencephalography often showed generalized background slowing, abnormal rhythmic, and periodic discharge patterns. The pooled mean (± SD) onset of ICANS was 6.4 ± 3.2 days, with a pooled mean duration of 8.3 ± 10.5 days. Two of the 23 studies (9%) reported 5 ICANS-related deaths among 233 participants. A subset of patients experienced persistent neurocognitive complaints at ≥1-year after CAR T cell therapy. The clinical presentation, onset, severity, long-term sequelae, and grading system of ICANS are variable. Future studies should consider using a consensus grading/reporting scale that would permit cross-trial comparisons of the safety profile of various CAR T cell products and enable the development of interventions to mitigate or manage these neurotoxicities. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This systematic review was conducted according to a published protocol (PROSPERO CRD42020207864) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) in systematic review reporting guidelines (Supplementary Table S1) [15,16].
Topics: Adult; Cell- and Tissue-Based Therapy; Cross-Sectional Studies; Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Neurotoxicity Syndromes; Prospective Studies; Receptors, Chimeric Antigen; Retrospective Studies; Risk Factors
PubMed: 35288347
DOI: 10.1016/j.jtct.2022.03.006 -
Addiction (Abingdon, England) Oct 2022There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
There have been few head-to-head clinical trials of pharmacotherapies for alcohol withdrawal (AW). We, therefore, aimed to evaluate the comparative performance of pharmacotherapies for AW.
METHODS
Six databases were searched for randomized clinical trials through November 2021. Trials were included after a blinded review by two independent reviewers. Outcomes included incident seizures, delirium tremens, AW severity scores, adverse events, dropouts, dropouts from adverse events, length of hospital stay, use of additional medications, total benzodiazepine requirements, and death. Effect sizes were pooled using frequentist random-effects network meta-analysis models to generate summary ORs and Cohen's d standardized mean differences (SMDs).
RESULTS
Across the 149 trials, there were 10 692 participants (76% male, median 43.5 years old). AW severity spanned mild (n = 32), moderate (n = 51), and severe (n = 66). Fixed-schedule chlormethiazole (OR, 0.16; 95% CI, 0.04-0.65), fixed-schedule diazepam (OR, 0.16; 95% CI, 0.04-0.59), fixed-schedule lorazepam (OR = 0.19; 95% CI, 0.08-0.45), fixed-schedule chlordiazepoxide (OR = 0.21; 95% CI, 0.08-0.53), and divalproex (OR = 0.22; 95% CI, 0.05-0.86) were superior to placebo at reducing incident AW seizures. However, only fixed-schedule diazepam (OR, 0.19; 95% CI, 0.05-0.76) reduced incident delirium tremens. Oxcarbazepine (d = -3.69; 95% CI, -6.21 to -1.17), carbamazepine (d = -2.76; 95% CI, -4.13 to -1.40), fixed-schedule oxazepam (d = -2.55; 95% CI, -4.26 to -0.83), and γ-hydroxybutyrate (d = -1.80; 95% CI, -3.35 to -0.26) improved endpoint Clinical Institute Withdrawal Assessment for Alcohol-Revised scores over placebo. Promazine and carbamazepine were the only agents significantly associated with greater dropouts because of adverse events. The quality of evidence was downgraded because of the substantial risk of bias, heterogeneity, inconsistency, and imprecision.
CONCLUSIONS
Although some pharmacotherapeutic modalities, particularly benzodiazepines, appear to be safe and efficacious for reducing some measures of alcohol withdrawal, methodological issues and a high risk of bias prevent a consistent estimate of their comparative performance.
Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Benzodiazepines; Carbamazepine; Diazepam; Female; Humans; Male; Network Meta-Analysis; Seizures; Substance Withdrawal Syndrome
PubMed: 35194860
DOI: 10.1111/add.15853 -
The Cochrane Database of Systematic... Mar 2019Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD.
OBJECTIVES
To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs).
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information.
SELECTION CRITERIA
Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia.
DATA COLLECTION AND ANALYSIS
We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales.
MAIN RESULTS
Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls.
AUTHORS' CONCLUSIONS
We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.
Topics: Activities of Daily Living; Aged; Aged, 80 and over; Akathisia, Drug-Induced; Alzheimer Disease; Cognition Disorders; Dementia; Dementia, Vascular; Excitatory Amino Acid Antagonists; Humans; Memantine; Randomized Controlled Trials as Topic; Withholding Treatment
PubMed: 30891742
DOI: 10.1002/14651858.CD003154.pub6 -
International Journal of Molecular... Apr 2022Glyphosate, a non-selective systemic biocide with broad-spectrum activity, is the most widely used herbicide in the world. It can persist in the environment for days or... (Review)
Review
Glyphosate, a non-selective systemic biocide with broad-spectrum activity, is the most widely used herbicide in the world. It can persist in the environment for days or months, and its intensive and large-scale use can constitute a major environmental and health problem. In this systematic review, we investigate the current state of our knowledge related to the effects of this pesticide on the nervous system of various animal species and humans. The information provided indicates that exposure to glyphosate or its commercial formulations induces several neurotoxic effects. It has been shown that exposure to this pesticide during the early stages of life can seriously affect normal cell development by deregulating some of the signaling pathways involved in this process, leading to alterations in differentiation, neuronal growth, and myelination. Glyphosate also seems to exert a significant toxic effect on neurotransmission and to induce oxidative stress, neuroinflammation and mitochondrial dysfunction, processes that lead to neuronal death due to autophagy, necrosis, or apoptosis, as well as the appearance of behavioral and motor disorders. The doses of glyphosate that produce these neurotoxic effects vary widely but are lower than the limits set by regulatory agencies. Although there are important discrepancies between the analyzed findings, it is unequivocal that exposure to glyphosate produces important alterations in the structure and function of the nervous system of humans, rodents, fish, and invertebrates.
Topics: Animals; Central Nervous System Depressants; Glycine; Herbicides; Neurotoxicity Syndromes; Glyphosate
PubMed: 35562999
DOI: 10.3390/ijms23094605 -
Neurotoxicology Sep 2022Investigation of the toxicity triggered by chemicals on the human brain has traditionally relied on approaches using rodent in vivo models and in vitro cell models... (Review)
Review
Investigation of the toxicity triggered by chemicals on the human brain has traditionally relied on approaches using rodent in vivo models and in vitro cell models including primary neuronal cultures and cell lines from rodents. The issues of species differences between humans and rodents, the animal ethical concerns and the time and cost required for neurotoxicity studies on in vivo animal models, do limit the use of animal-based models in neurotoxicology. In this context, human cell models appear relevant in elucidating cellular and molecular impacts of neurotoxicants and facilitating prioritization of in vivo testing. The SH-SY5Y human neuroblastoma cell line (ATCC® CRL-2266™) is one of the most used cell lines in neurosciences, either undifferentiated or differentiated into neuron-like cells. This review presents the characteristics of the SH-SY5Y cell line and proposes the results of a systematic review of literature on the use of this in vitro cell model for neurotoxicity research by focusing on organic environmental pollutants including pesticides, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), flame retardants, PFASs, parabens, bisphenols, phthalates, and PAHs. Organic environmental pollutants are widely present in the environment and increasingly known to cause clinical neurotoxic effects during fetal & child development and adulthood. Their effects on cultured SH-SY5Y cells include autophagy, cell death (apoptosis, pyroptosis, necroptosis, or necrosis), increased oxidative stress, mitochondrial dysfunction, disruption of neurotransmitter homeostasis, and alteration of neuritic length. Finally, the inherent advantages and limitations of the SH-SY5Y cell model are discussed in the context of chemical testing.
Topics: Adult; Animals; Cell Line, Tumor; Cell Survival; Child; Environmental Pollutants; Flame Retardants; Fluorocarbons; Humans; Neuroblastoma; Neurotoxicity Syndromes; Parabens; Pesticides; Polychlorinated Dibenzodioxins
PubMed: 35914637
DOI: 10.1016/j.neuro.2022.07.008 -
Journal of Neurology Dec 2019The primary aim of this systematic review was to establish the prevalence, character, and risk factors of peripheral neuropathy amongst chronic alcohol abusers and to... (Meta-Analysis)
Meta-Analysis
The primary aim of this systematic review was to establish the prevalence, character, and risk factors of peripheral neuropathy amongst chronic alcohol abusers and to identify the most appropriate management strategies. In this review, possible pathogenetic mechanisms are also discussed. A systematic, computer-based search was conducted using the PubMed database. Data regarding the above parameters were extracted. 87 articles were included in this review, 29 case-control studies, 52 prospective/retrospective cohort studies and 2 randomised control trials, 1 cross sectional study, and 3 population-based studies. The prevalence of peripheral neuropathy amongst chronic alcohol abusers is 46.3% (CI 35.7- 57.3%) when confirmed via nerve conduction studies. Alcohol-related peripheral neuropathy generally presents as a progressive, predominantly sensory axonal length-dependent neuropathy. The most important risk factor for alcohol-related peripheral neuropathy is the total lifetime dose of ethanol, although other risk factors have been identified including genetic, male gender, and type of alcohol consumed. At present, it is unclear what the pathogenetic mechanisms for the development of neuropathy amongst those who chronically abuse alcohol are, and therefore, it is unknown whether it is attributed to the direct toxic effects of ethanol or another currently unidentified factor. There is presently sparse data to support a particular management strategy in alcohol-related peripheral neuropathy, but the limited data available appears to support the use of vitamin supplementation, particularly of B-vitamin regimens inclusive of thiamine.
Topics: Alcoholic Neuropathy; Humans; Peripheral Nervous System Diseases
PubMed: 30467601
DOI: 10.1007/s00415-018-9123-1 -
Journal of Hematology & Oncology Dec 2020B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic... (Meta-Analysis)
Meta-Analysis
BACKGROUND
B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes.
METHODS
We performed a database search using the terms "BCMA," "CAR," and "multiple myeloma" for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332).
RESULTS
Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0-88.2); 10.5% (6.8-16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3-26.7; I = 45%) versus 2.8% (1.3-6.1; I = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5-85.9); complete responses (CR) were observed in 44.8% (35.3-54.6). A pooled CR rate of 71.9% (62.8-79.6; I = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5-41.1; I = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4-17.4) months, which compared favorably to the expected PFS of 1.9 (1.5-3.7) months (HR 0.14; p < 0.0001).
CONCLUSIONS
Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.
Topics: B-Cell Maturation Antigen; Cytokine Release Syndrome; Humans; Immunotherapy, Adoptive; Multiple Myeloma; Neurotoxicity Syndromes; Progression-Free Survival; Receptors, Chimeric Antigen; Treatment Outcome
PubMed: 33272302
DOI: 10.1186/s13045-020-01001-1