Need for standardization of cytokine profiling in CAR T cell therapy.

With expansion of chimeric antigen receptor (CAR) T cell therapy and broader utilization of anti-cytokine directed therapeutics for toxicity mitigation, the routine assessment of cytokines may enhance understanding of toxicity profiles, guide therapeutic interventions, and facilitate cross-trial comparisons. As specific cytokine elevations can correlate with and provide insights into CAR T cell toxicity, mitigation strategies, and response, we explored the reporting of cytokine detection methods and assessed for the correlation of cytokines to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) across clinical trials. In this analysis, we reviewed 21 clinical trials across 60 manuscripts that featured a US Food and Drug Administration-approved CAR T cell construct or one of its predecessors. We highlight substantial variability and limited reporting of cytokine measurement platforms and panels used across CAR T cell clinical trials. Specifically, across 60 publications, 28 (46.7%) did not report any cytokine data, representing 6 of 21 (28.6%) clinical trials. In the 15 trials reporting cytokine data, at least 4 different platforms were used. Furthermore, correlation of cytokines with ICANS, CRS, and CRS severity was limited. Considering the fundamental role of cytokines in CAR T cell toxicity, our manuscript supports the need to establish standardization of cytokine measurements as a key biomarker essential to improving outcomes of CAR T cell therapy.

Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing.

BACKGROUND AND AIMS: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. METHODS: We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. RESULTS: NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. INTERPRETATION: NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

Neurological complications in oncology and their monitoring and management in clinical practice: a narrative review.

IMPORTANCE: New anti-tumor treatments, such as immune checkpoint inhibitors and CAR T-cell therapy, are associated with an increasing number of neurological issues linked to tumors not arising from nervous system such as neurological and neuropsychological side effects that can significantly impair quality of life in the short or long term. The science of pathomechanisms, therapeutic approaches, and preventive measures is still in its early stages, and the progress is hampered by the lack of studied connection between neurological and oncological disciplines. OBJECTIVES: This work aimed to provide an overview of the questions raised in the field of clinical neuroscience that concern the outcomes of oncological diseases and their treatment. Furthermore, we give an outline of how a collaborative approach between neurology and oncology, with the implementation of neuroscience techniques including up-to-date diagnostics and therapy, can help to improve the quality of oncological patients' lives. EVIDENCE REVIEW: The covered areas of investigation in the evaluated articles primarily encompassed the review of known neurological complications of oncological diseases caused by neurotoxic mechanisms of performed therapies or those linked to concurrent pathological conditions. Similarly, the methods of their diagnostics were assessed. FINDINGS: Our literature review of 65 articles, including clinical trials, cohort studies, reviews, and theoretically based in vitro studies published between 1998 and 2023, outlines the broad spectrum of neurological complications primarily associated with malignant diseases and the anti-tumor therapies employed. Notably, immune-mediated complications, whose incidence is increasing due to the expanding use of new immunotherapies, require early detection and targeted treatment to prevent severe progression. In this context, neurological complications mediated by immune checkpoint inhibitors are often associated with significant impairments and high mortality, necessitating specialist consultation for early detection and differentiation from other phenotypically similar syndromes. Current data on the pathophysiology of these neurological complications are not reliable due to the limited number of studies. Moreover, there is a lack of evidence regarding the appropriate oncological approach in the event of therapy-related complications. Initial study results suggest that the establishment of interdisciplinary treatment interfaces for the management of oncology patients could improve the safety of these therapies and enhance the patients' quality of life. CONCLUSIONS AND RELEVANCE: The accumulated knowledge on neurotoxicity caused by oncological diseases shows that the challenges in diagnosing and managing this condition are expanding in tandem with the growing array of therapies being employed. Therefore, it requires interdisciplinary approach with the introduction of new facilities enabling more personalized patient care.

Metabolomics analysis reveals characteristic metabolites in different levels of oxaliplatin-induced neurotoxicity.

Oxaliplatin (L-OHP), a third-generation platinum-based anti-tumor drug, finds widespread application in the first-line treatment of metastatic colorectal cancer. Despite its efficacy, the drug's usage is curtailed by a litany of side effects, with L-OHP-induced peripheral neuropathy (OIPN) being the most debilitating. This condition can be classified into varying degrees of severity. Employing serum metabolomics, a high-sensitivity, high-throughput technique, holds promise as a method to identify biomarkers for clinical assessment and monitoring of OIPN patients across different severity levels. In our study, we analyzed serum metabolites in patients with different OIPN levels using ultra-performance liquid chromatography-high resolution mass spectrometry. By employing statistical analyses and pathway enrichment studies, we aimed to identify potential biomarkers and metabolic pathways. Our findings characterized the serum metabolic profiles of patients with varying OIPN levels. Notably, pathway analysis revealed a significant correlation with lipid metabolism, amino acid metabolism, and energy metabolism. Multivariate statistical analysis and receiver operator characteristic curve evaluation pointed to anhalamine and glycochenodeoxycholic acid as potential biomarkers for OIPN C and A, which suggest that serum metabolomics may serve as a potent tool for exploring the metabolic status of patients suffering from diverse diseases and for discovering novel biomarkers.

Neurotoxicology: a clinical systems-based review.

Neurological disease caused by toxins is widespread but under-recognised. Despite increasing public interest and a growing number of novel potential neurotoxins, diagnosis of neurotoxic disease is often delayed or missed, resulting in poorer patient outcomes. This article discusses neurotoxic syndromes using a systems-based approach, focusing on environmental and occupational agents. We do not discuss recreational drugs, pharmaceutical agents or developmental neurotoxins in detail. We aim to provide neurologists with a working understanding of the scenarios in which a clinical presentation may be due to a neurotoxin and how to approach confirmation of the diagnosis.

Antibiomania: clarithromycin-induced neurotoxicity mimicking autoimmune limbic encephalitis.

We describe a 64-year-old woman with relapsing encephalopathy. She initially presented with 5 days of psychomotor agitation, progressing to mania, psychosis and seizures that mimicked autoimmune limbic encephalitis. During her first hospital admission, extensive investigation failed to establish the underlying cause, and she improved with antiseizure medication alone. After a month at home, she relapsed with identical symptoms, and only then did we recognise that both episodes had been provoked by clarithromycin, prescribed for Helicobacter pylori eradication. Clarithromycin-induced neurotoxicity is rarely reported but likely to be under-recognised. It usually manifests within days of starting treatment, with delirium, mania, psychosis or visual hallucinations, sometimes termed 'antibiomania'. Seizures and status epilepticus appear to be less frequent. A full recovery is expected on stopping the medication.

Biomarkers for Predicting Cytokine Release Syndrome following CD19-Targeted CAR T Cell Therapy.

Chimeric Ag receptor (CAR) T cell therapy has shown astonishing potency in treating a variety of hematological malignancies in recent years. Along with this lifesaving potential comes the life-threatening toxicities of cytokine release syndrome (CRS) and neurotoxicity. This work seeks to consolidate biomarker candidates with the potential to predict the severity of CRS and neurotoxicity in patients receiving CD19-targeted CAR T cell therapy. In this systematic review, 33 clinical trials were evaluated for biomarkers that can predict the severity of posttreatment CRS and neurotoxicity. CRS and neurotoxicity occurred in 73.4 and 37% of the reviewed patients, respectively. Identified biomarker candidates included tumor burden, platelet count, C-reactive protein, ferritin, IFN-γ, IL-2, IL-6, IL-8, IL-10, IL-15, and TGF-ß. Combinatorial algorithms based on cytokine levels and clinical parameters show excellent promise in predicting CAR-T-cell-therapy-associated toxicities, with improved accuracy over the component biomarkers.

Framework to leverage physical therapists for the assessment and treatment of chemotherapy-induced peripheral neurotoxicity (CIPN).

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a highly prevalent, dose-limiting, costly, and tough-to-treat adverse effect of several chemotherapy agents, presenting as sensory and motor dysfunction in the distal extremities. Due to limited effective treatments, CIPN can permanently reduce patient function, independence, and quality of life. One of the most promising interventions for CIPN is physical therapy which includes exercise, stretching, balance, and manual therapy interventions. Currently, there are no physical therapy guidelines for CIPN, thus limiting its uptake and potential effectiveness. METHODS: Utilizing the authors' collective expertise spanning physical therapy, symptom management research, oncology, neurology, and treating patients with CIPN, we propose a comprehensive clinical workflow for physical therapists to assess and treat CIPN. This workflow is based on (1) physical therapy guidelines for treating neurologic symptoms like those of CIPN, (2) results of clinical research on physical therapy and exercise, and (3) physical therapy clinical judgement. RESULTS: We present detailed tables of pertinent physical therapy assessment and treatment methods that can be used in clinical settings. CIPN assessment should include detailed sensory assessment, objective strength assessments of involved extremities, and validated physical performance measures incorporating static and dynamic balance, gait, and functional mobility components. CIPN treatment should involve sensorimotor, strength, balance, and endurance-focused interventions, alongside a home-based exercise prescription that includes aerobic training. We conclude with action items for oncology teams, physical therapists, patients, and researchers to best apply this framework to address CIPN. CONCLUSIONS: Physical therapists are in a unique position to help assess, prevent, and treat CIPN given their training and prevalence, yet there are no physical therapy clinical practice guidelines for CIPN. Our preliminary suggestions for CIPN assessments and treatments can catalyze the development of guidelines to assess and treat CIPN. We urge oncology teams, physical therapists, patients, and researchers to develop, adapt, and disseminate this framework to help alleviate the burden of chemotherapy on patients with cancer.

A perspective on In vitro developmental neurotoxicity test assay results: An expert panel review.

For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial screening, but it is not presently a complete or surrogate approach to determine whether a chemical is a DNT in humans. By itself, the DNT IVB does not have the ability to capture nuances and complexity of the developing nervous system and associated outcomes including behavioral ontogeny, motor activity, sensory function, and learning/memory. Presently, such developmental landmarks cannot be adequately assessed in the DNT IVB or by other NAMs. The expert panel (all who serve as co-authors of this review) recommended that additional data generation and validation is required before the DNT IVB can be considered for application within global regulatory frameworks for decision-making.

Advances in treatments of patients with classical and emergent neurological toxicities of anticancer agents.

The neurotoxicity associated to the anticancer treatments has received a growing body of interest in the recent years. The development of innovating therapies over the last 20years has led to the emergence of new toxicities. Their diagnosis and management can be challenging in the clinical practice and further research is warranted to improve the understanding of their pathogenic mechanisms. Conventional treatments as radiation therapy and chemotherapy are associated to well-known and under exploration emerging central nervous system (CNS) and peripheral nervous system (PNS) toxicities. The identification of the risk factors and a better understanding of their pathogeny through a "bench to bedside and back again" approach, are the first steps towards the development of toxicity mitigation strategies. New imaging techniques and biological explorations are invaluable for their diagnosis. Immunotherapies have changed the cancer treatment paradigm from tumor cell centered to immune modulation towards an efficient anticancer immune response. The use of the immune checkpoints inhibitors (ICI) and CAR-T cells (chimeric antigen receptor) lead to an increase in the incidence of immune-mediated toxicities and new challenges in the neurological patient's management. The neurological ICI related adverse events (n-irAE) are rare but potentially severe and may present with both CNS and PNS involvement. The most frequent and well characterized, from a clinical and biological standpoint, are the PNS phenotypes: myositis and polyradiculoneuropathy, but the knowledge on CNS phenotypes and their treatments is expanding. The n-irAE management requires a good balance between dampening the autoimmune toxicity without impairing the anticancer immunity. The adoptive cell therapies as CAR-T cells, a promising anticancer strategy, trigger cellular activation and massive production of proinflammatory cytokines inducing frequent and sometime severe toxicity known as cytokine release syndrome and immune effector cell-associated neurologic syndrome. Their management requires a close partnership between oncologist-hematologists, neurologists, and intensivists. The oncological patient's management requires a multidisciplinary clinical team (oncologist, neurologist and paramedical) as well as a research team leading towards a better understanding and a better management of the neurological toxicities.

Wearables, sensors, and smart devices for the detection and monitoring of chemotherapy-induced peripheral neurotoxicity: Systematic review and directions for future research.

Chemotherapy-induced peripheral neurotoxicity (CIPN) diagnosis is largely based on patient reported outcomes. Wearables, sensors, and smart devices may potentially provide early detection and monitoring of CIPN. We systematically reviewed data on wearables, sensors, and smart devices to detect and/or monitor signs and symptoms of CIPN. Moreover, we provide directions and recommendations for future studies. A literature search using PubMed/MEDLINE, Web of Science, IEEE Xplore, and CINHAL databases was conducted from database inception until March 2021. The search was further updated in July 2022 to ensure currency of results. A total of 1885 records were title-abstract screened, 33 full texts were assessed, and 16 were included. The retrieved papers were heterogeneous in terms of study design, sample size, CIPN severity, chemotherapy agents, type of wearable/sensor/device applied, parameters of interest, and purpose. Data are promising and provide preliminary evidence on wearables, sensors, and smart devices for CIPN detection and monitoring. There are several issues and knowledge gaps that should be addressed. We propose a framework for future studies.

Prospectively assessing serum neurofilament light chain levels as a biomarker of paclitaxel-induced peripheral neurotoxicity in breast cancer patients.

Our aim was to assess the significance of measuring serum neurofilament light chain (sNfL) levels as a biomarker of paclitaxel-induced peripheral neurotoxicity (PIPN). We longitudinally measured sNfL in breast cancer patients, scheduled to receive the 12-weekly paclitaxel-based regimen. Patients were clinically examined by means of the Total Neuropathy Score-clinical version (TNSc), while sNfL were quantified, using the highly sensitive Simoa technique, before starting chemotherapy (baseline), after 2 (week 2) and 3 (week 3) weekly courses, and at the end of chemotherapy (week 12). Among 59 included patients (mean age: 53.1 ± 11.5 years), 33 (56%) developed grade 0-1 and 26 (44%) grade 2-3 PIPN at week 12. A significant longitudinal increase of sNfL levels from baseline to week-12 was determined, whereas patients with TNSc grade 2-3 PIPN had significantly increased sNfL levels at week 12, compared to those with grade 0-1. receiver-operated characteristics (ROC) analysis defined a value of NfL of >85 pg/mL at week 3 as the best discriminative determination to predict the development of grade 2-3 PIPN at week 12 (sensitivity 46.2%, specificity 84.8%). The logistic binary regression analysis revealed that age > 50 years and the cutoff of >85 pg/mL of sNfL levels at week 3 independently predicted the development of grade 2-3 PIPN at week 12 with a sensitivity of 46%, a specificity of 91%, and a positive and negative predictive values of 75% and 67%, respectively. sNfL levels seem to be a valuable biomarker of neuro-axonal injury in PIPN. An early increase of this biomarker after a 3-weekly chemotherapy course can be a predictive marker of final PIPN severity.

Prognostic value of neutrophil to lymphocyte ratio in the diagnosis of neurotoxicity after glufosinate ammonium poisoning.

Neurotoxicity related to glufosinate ammonium is known to occur after a latent period of 4-60 hr following ingestion of this herbicide. However, neurotoxicity is difficult to predict in the emergency department (ED) and only a few parameters are known to be useful to indicate development of neurotoxicity. Determination of a systemic inflammation parameter such as the neutrophil to lymphocyte ratio (NLR), is a rapid and simple method which was found to be a prognostic marker in various clinical conditions such as sepsis, cardiac disorders, stroke, and cancer. Therefore, the aim of this study was to determine whether the NLR might predict neurotoxicity and be used at ED to detect neurotoxicity induced following glufosinate ammonium poisoning in admitted patients. This retrospective observational study collected data from consecutive patients diagnosed with acute glufosinate ammonium poisoning between January 2005 and December 2020. The primary outcome was development of neurotoxicity following acute glufosinate ammonium poisoning. Out of the 72 patients selected 44 patients (61.1%) exhibited neurotoxic symptoms. Neurotoxicity appeared with an approximate latent period of 12 hr. The NLR was significantly higher in the group displaying neurotoxicity. Multivariable analysis showed that the NLR was significant in predicting neurotoxicity. The NLR was independently associated with neurotoxicity initiated by glufosinate ammonium. Therefore, the use of the NLR might help clinically to readily and rapidly predict development of neurotoxicity associated with glufosinate ammonium at the ED.

Ertapenem-induced neurotoxicity in an end-stage renal disease patient on intermittent haemodialysis: a case report.

BACKGROUND: Carbapenem-induced neurotoxicity is an unusual side effect, with seizure being the most commonly reported symptom. Among the carbapenems, imipenem-cilastin is classically associated with the most severe neurotoxicity side effects. Carbapenem is mainly excreted by the kidney and its half-life is significantly increased in patients with chronic kidney disease (CKD). Therefore, dose adjustment is necessary in such patients. Ertapenem-associated neurotoxicity is increasingly being reported in CKD patients, but rarely seen in patients with recommended dose adjustment. CASE PRESENTATION: We report a case of a 56-year-old male patient with chronic kidney disease 5 on dialysis(CKD 5D). The patient presented with a history of fever, chills and rigours during a session of haemodialysis (HD). He was diagnosed with Enterobacter cloacae catheter-related blood stream infection and was started on ertapenem. After 13 days of ertapenem, he experienced an acute confusional state and progressed to having auditory and visual hallucinations. His blood investigations and imaging results revealed no other alternative diagnosis. Hence a diagnosis of ertapenem-induced neurotoxicity was made. He had complete resolution of symptoms after 10 days' discontinuation of ertapenem. CONCLUSION: Our case draws attention to the risk of potentially serious toxicity of the central nervous system in HD patients who receive the current recommended dose of ertapenem. It also highlights that renal dosing in CKD 5D patients' needs to be clinically studied to ensure antibiotic safety.

Integration of toxicodynamic and toxicokinetic new approach methods into a weight-of-evidence analysis for pesticide developmental neurotoxicity assessment: A case-study with DL- and L-glufosinate.

DL-glufosinate ammonium (DL-GLF) is a registered herbicide for which a guideline Developmental Neurotoxicity (DNT) study has been conducted. Offspring effects included altered brain morphometrics, decreased body weight, and increased motor activity. Guideline DNT studies are not available for its enriched isomers L-GLF acid and L-GLF ammonium; conducting one would be time consuming, resource-intensive, and possibly redundant given the existing DL-GLF DNT. To support deciding whether to request a guideline DNT study for the L-GLF isomers, DL-GLF and the L-GLF isomers were screened using in vitro assays for network formation and neurite outgrowth. DL-GLF and L-GLF isomers were without effects in both assays. DL-GLF and L-GLF (1-100 µM) isomers increased mean firing rate of mature networks to 120-140% of baseline. In vitro toxicokinetic assessments were used to derive administered equivalent doses (AEDs) for the in vitro testing concentrations. The AED for L-GLF was ∼3X higher than the NOAEL from the DL-GLF DNT indicating that the available guideline study would be protective of potential DNT due to L-GLF exposure. Based in part on the results of these in vitro studies, EPA is not requiring L-GLF isomer guideline DNT studies, thereby providing a case study for a useful application of DNT screening assays.

De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

[Evaluation of the implementation of Diagnostic Criteria of Occupational Acute Neurotoxic Diseases Caused by Chemicals (GBZ 76-2002)].

Objective: To investigate the implementation of Diagnostic Criteria of Occupational Acute Neurotoxic Diseases Caused by Chemicals (GBZ 76-2002) for accumulating basis of standard revision. Methods: In February 2020, 85 experts in occupational diseases and neurology from 39 medical and health institutions were selected as the respondents. The modified Delphi method was used to establish the standard evaluation index system and special group was organized for discussing the pre-survey and completing the questionnaire survey. Questionnaire survey was performed to investigate the grasp of the standards, application and modification suggestions of respondents. Results: The respondents' mastery of standard-related knowledge mainly came from work experience (84.7%, 72/85) , standard learning (81.2%, 69/85) and training (75.3%, 64/85) . Among the institutions in which the respondents worked, 98.8% (84/85) could carry out CT examinations, 96.5% (82/85) could carry out nerve conduction velocity and electromyography examinations, 89.4% (76/85) could carry out EEG examinations, 80% (68/85) could carry out evoked potential examinations and 72.9% (62/85) could carry out MRI examinations. Among the toxicants diagnosed as occupational acute toxic myelopathy, 10.6% (9/85) were organic phosphorus and 9.4% (8/85) were asphyxiating gas; Among the toxicants diagnosed as delayed peripheral neuropathy, pesticides accounted for 25.9% (22/85) and asphyxiating gases accounted for 12.9% (11/85) . 85.9% (73/85) of the respondents believed that the basis for the classification of acute toxic encephalopathy needed to supplement objective evidence; 80.0% (68/85) of the respondents thought that the diagnosis and classification of peripheral neuropathy should be refined according to the abnormal indexes of neuroelectromyography. Conclusion: The applicability of the criteria needs to be improved because the current criteria has a long application cycle without enough objective investigation bases in classification criteria index.

Valproate-Associated Hyperammonaemic Encephalopathy.

We present the case of a 55 year old who presented multiple times with altered conscious levels. He was often treated as being post-ictal, when in fact, he had Sodium Valproate induced hyperammonaemic encephalopathy. Sodium Valproate can frequently increase ammonia levels, and in some patient lead to hyperammonaemic encephalopathy.

Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T cells.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell-mediated neurotoxicity warrants evaluation in prospective clinical trials.

The preferences of women with ovarian cancer for oral versus intravenous recurrence regimens.

OBJECTIVE: To assess preferences of women with ovarian cancer regarding features of available anti-cancer regimens for platinum-resistant, biomarker-positive disease, with an emphasis on oral PARP inhibitor and standard intravenous (IV) chemotherapy regimens. METHODS: A discrete-choice-experiment preferences survey was designed, tested, and administered to women with ovarian cancer, with 11 pairs of treatment profiles defined using seven attributes (levels/ranges): regimen (oral daily, IV weekly, IV monthly); probability of progression-free (PFS) at 6 months (40%-60%); probability of PFS at 2 years (10%-20%); nausea (none, moderate); peripheral neuropathy (none, mild, moderate); memory problems (none, mild); and total out-of-pocket cost ($0 to $10,000). RESULTS: Of 123 participants, 38% had experienced recurrence, 25% were currently receiving chemotherapy, and 18% were currently taking a PARP inhibitor. Given attributes and levels, the relative importance weights (sum 100) were: 2-year PFS, 28; cost, 27; 6-month PFS, 19; neuropathy,14; memory problems, nausea, and regimen, all ≤5. To accept moderate neuropathy, participants required a 49% (versus 40%) chance of PFS at 6 months or 14% (versus 10%) chance at 2 years. Given a 3-way choice where PFS and cost were equal, 49% preferred a monthly IV regimen causing mild memory problems, 47% preferred an oral regimen causing moderate nausea, and 4% preferred a weekly IV regimen causing mild memory and mild neuropathy. CONCLUSIONS: These findings challenge the assumption that oral anti-cancer therapies are universally preferred by patients and demonstrate that there is no "one size fits all" regimen that is preferable to women with ovarian cancer when considering recurrence treatment regimens.