scholarly journals CAR T-Cell Therapy: Adverse Events and Management

2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Sherry Adkins, RN, MSN, ANP-C
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Overview of Adverse Events Associated With Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

2021 ◽  
Author(s):  
Ekaterina Vorozheikina ◽  
Magdalena Ruiz ◽  
Maria Leticia Solari ◽  
Dmitry Ostasevich ◽  
Luis Mendoza
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Clinical Manifestations ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.

Real-world adverse events associated with CAR T-cell therapy among adults age ≥ 65 years

2020 ◽  
Author(s):  
Marjorie E. Zettler ◽  
Bruce A. Feinberg ◽  
Eli G. Phillips Jr ◽  
Andrew J. Klink ◽  
Sonam Mehta ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Real World ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals CD19 and CD30 CAR T-Cell Immunotherapy for High-Risk Classical Hodgkin’s Lymphoma

2021 ◽  
Vol 10 ◽  
Author(s):  
YuanBo Xue ◽  
Xun Lai ◽  
RuiLei Li ◽  
ChunLei Ge ◽  
BaoZhen Zeng ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Adverse Events ◽  
Cell Therapy ◽  
Low Doses ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Severe Adverse Events

BackgroundIn clinical applications of CAR T-cell therapy, life-threatening adverse events including cytokine release syndrome and neurotoxicity can lead to treatment failure. Outcomes of patients treated with anti-CD30 CAR T- cell have been disappointing in relapsing/refractory (r/r) classical Hodgkin’s Lymphoma (cHL).MethodsIn order to understand the applicable population of multiple CAR T-cell therapy, we examined the expression of CD19, CD20, and CD30 by immunohistochemistry (IHC) in 38 paraffin-embedded specimens of cHL. In the past two years, we found only one patient with cHL who is eligible for combined anti-CD19 and CD30 CAR T-cell treatment. This patient’s baseline characteristics were prone to severe adverse events. We treated this patient with low doses and multiple infusions of anti-CD19 and CD30 CAR T-cell.ResultsThe positive expression of CD19+ + CD30+ in Reed-Sternberg (RS) cells is approximately 5.2% (2/38). The patient we treated with combined anti-CD19 and CD30 CAR T-cell did not experience severe adverse events related to CAR T-cell therapy and received long term progression-free survival (PFS).ConclusionFor high risk r/r cHL patients, low doses of CAR T-cell used over different days at different times might be safe and effective. More clinical trials are warranted for CD19 and CD30 CAR T-cell combination therapy.

scholarly journals Immune-related Adverse Events Associated With Checkpoint Inhibition in the Setting of CAR T Cell Therapy: A Case Series

2020 ◽  
Vol 20 (3) ◽  
pp. e118-e123 ◽  
Author(s):  
Swetha Kambhampati ◽  
Lissa Gray ◽  
Bita Fakhri ◽  
Mimi Lo ◽  
Khoan Vu ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Case Series ◽  
Checkpoint Inhibition ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Overview of Adverse Events Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy

2021 ◽  
pp. 11-31
Author(s):  
Ekaterina Vorozheikina ◽  
Magdalena Ruiz ◽  
Leticia Solari ◽  
Dmitry Ostasevich ◽  
Luis Mendoza
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Clinical Manifestations ◽  
Antigen Receptor ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.

scholarly journals Adverse Events Following CAR T-Cell Therapy: A Single Institution Retrospective Analysis of Toxicities Following CAR T-Cell Therapy for Children and Young Adults with Relapsed Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1731-1731
Author(s):  
Sara K. Silbert ◽  
Elizabeth M. Holland ◽  
Seth M. Steinberg ◽  
Lauren Little ◽  
Toni Foley ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Phase I ◽  
Median Number ◽  
Toxicity Profile ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: CAR T-cells have demonstrated remarkable ability to induce complete remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL). This success, however, is tempered by the toxicities associated with CAR T-cell therapy. Much has been published on cytokine release syndrome (CRS), but, to date, a comprehensive profile of specific end organ toxicities secondary to CAR T-cell therapy in the pediatric and young adult population is lacking. Methods: This retrospective, single center study, was performed to characterize the specific adverse events (AEs) experienced by pediatric and young adult patients during the first 30 days following CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events (CTCAE) were collected from all patients with r/r ALL treated on one of three phase I CAR T-cell trials (CD19, CD22, and CD1922) at the Pediatric Oncology Branch of the National Cancer Institute at the National Institutes of Health from 2012-2020. The primary objective was to determine the incidence of all severe AEs, defined as > grade (Gr) 3 AEs, overall and by organ system, attributed to research or disease. Secondary objectives were to stratify severe AEs based on development of CRS and CRS grade (using ASTCT CRS grading criteria). Descriptive statistics were reported along with comparisons of continuous parameters using Mann-Whitney and binomial parameters using Fischer's exact tests. Results: We reviewed AE data from 134 patients with r/r ALL receiving one of 3 unique CAR T-cell constructs (Table). The median age was 15.2 years (Interquartile range (IQR) 9.5-21.2). The median number of prior therapies was 5 (IQR 3-6) and 57% had received a prior hematopoietic stem cell transplant (HSCT). Amongst the 134 patients, a total of 1747 individual > Gr 3 AEs were experienced by 133 patients (99%) during the first 30 days following CAR infusion (Figure 1A). The median number of > Gr 3 AEs per patient was 10 (IQR 4.8-19). Cytopenias (including neutropenia, thrombocytopenia and anemia) comprised the vast majority of total > Gr 3 AEs (n=983, 56.3%). The most common severe (> Gr 3) AEs were thrombocytopenia (n=433, 24.8%), metabolic abnormalities (i.e. electrolyte derangements) (n=333, 19.1%), neutropenia (n=332, 19%), and anemia (n=218, 12.5%). With exclusion of cytopenias, 764 > Gr 3 AEs were experienced by 111 patients (83%), with a median of 4 (IQR 1-8.3) > Gr 3 AEs per patient. One grade 5 pulmonary AE occurred in the setting of acute respiratory distress syndrome (ARDS). Focusing on non-cytopenia AEs (Figure 1B), metabolic AEs made up 43.6% of AEs; hepatic toxicities (n=115, 15%), febrile neutropenia (n=114, 14.9%), and cardiovascular toxicities (n=59, 7.7%) were the next most frequent. Of the 134 patients, 104 (77.6%) developed CRS. All 30 patients without CRS had at least 1 > Gr 3 AE (median 6, IQR 3-11.3). In contrast, the median number of > Gr 3 AEs in those with CRS was 11.5 (IQR, 6-21.5), (p=0.0021). When stratified by CRS Gr 1-2 versus CRS Gr 3-4 (Figure 2), patients with higher-grade CRS also had a higher median number of > Gr 3 AEs per patient (p= 0.0017). Conclusions: Among 134 children and young adults with r/r ALL receiving phase I CAR T-cells, we found a high incidence (99%) of severe AEs, with a per patient median of 10 (IQR 4.8-19) > Gr 3 AEs. While the majority of > Gr 3 AEs were cytopenias, 17 different categories of AEs were experienced. The development and severity of CRS associated with an increase in the median number of severe AEs per patient. As phase I trials of CAR T-cell therapy expand, it is imperative to understand the full toxicity profile of these therapies. While the definition and refined grading of CRS has helped advance the field, there is a gap in knowledge regarding patient specific end-organ toxicities beyond CRS. Our data help establish a foundation for the full toxicity profile experienced by patients enrolling on phase I CAR T-cell trials. With an emerging role for earlier intervention for CRS, we anticipate that the toxicity burden will decrease. Next steps include characterizing the specific toxicities within each AE category, evaluating duration and time to resolution, distinguishing attribution to research versus disease and studying the impact of earlier use of tocilizumab on toxicity profile. Future directions will incorporate assessment of baseline organ function pre-CAR and its impact on development of post CAR severe AEs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Neurological Adverse Events Following CAR-T Cell Therapy: A Real-World Analysis of Adult Patients Treated with Axicabtagene Ciloleucel or Tisagenlecleucel

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1952-1952 ◽  
Author(s):  
Ajeet Gajra ◽  
Marjorie E Zettler ◽  
Eli G Phillips Jr. ◽  
Andrew J Klink ◽  
Jonathan K. Kish ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Real World ◽  
Case Reports ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction: Neurotoxicity is a major adverse event (AE) of CAR-T therapy with diverse presentation. When severe, it can be fatal, and may lead to neurologic sequelae as well as contribute to increased health care utilization, driving up cost of therapy. In clinical trials, the most common neurologic AEs with axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) included encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia and anxiety. Fatal and serious cases of cerebral edema, leukoencephalopathy and/ or seizures have been reported with both agents. In this real-world analysis, we reviewed post-marketing case reports from the FDA Adverse Events Reporting System (FAERS). Database involving axi-cel or tis-cel for large B cell lymphoma (LBCL), with the dual objectives of characterizing the various components of neurotoxicity and assessing the association of neurological (neuro) AEs with demographic and treatment factors as well as with other AEs reported with CAR-T cell therapy use. Methods: The FAERS database contains anonymized reports of product-related AEs, classified using the Medical Dictionary for Regulatory Activities (MedDRA) and categorized as serious or non-serious. The FAERS database was queried for cases involving axi-cel or tis-cel (and their respective trade names) from the FDA approval date for the LBCL indication (October 18, 2017 for axi-cel; May 1, 2018 for tis-cel) through March 31, 2019. Cases were excluded if patient age was unknown or if the case was reported outside the US. Of all patients reported to have neuro AEs, the frequency of various components was collected. The association of neuro AEs with patient age, concomitant AEs and key lab abnormalities were evaluated by Fisher's exact test, using a two-sided α=0.05 to determine statistical significance. Median age in each subgroup was compared using the Mann-Whitney U test. Results: In the 397 case reports identified, the majority of reactions (376, 95%) were classified as serious. Overall, 258 (65%) were reported to have neuro AEs, with "neurotoxicity" reported in 170 cases (66%); encephalopathy including CAR-T cell-related, metabolic and toxic in 92 cases (36%); seizures including status epilepticus, myoclonus and partial seizures in 12 cases (5%); stroke including cerebrovascular accident, hemiparesis, basal ganglia, brain stem, cerebellar and cerebral infarcts, motor dysfunction, facial and cranial nerve paralysis in 13 cases (5%); speech disorders including terms of aphasia, dysarthria, speech and language impairment in 55 cases (21%); amnesia and memory impairment in 18 cases (7%); brain or spinal cord edema and increased intracranial pressure in 6 cases (2%). Peripheral neuropathy was reported in 5 cases (2%). Symptoms of headache, tremors, dizziness and somnolence were reported in 30 (12%), 41 (16%) 3 (1%) and 34 (13%) cases respectively. Confusional state, delirium or agitation were reported in 61 cases (24%). Neuro AEs were associated with use of axi-cel vs. tis-cel (69% vs. 24%, p <0.01) and with age ≥65 years (43% vs. 36% in age <65, p=0.02) but did not impact death or hospitalization (Table). Neuro AEs were associated with cytokine release syndrome (CRS, 67% vs. 49% without, p<0.01) as well as with cardiac AEs including tachycardia (p<0.01). There was an association of psychiatric AEs with neuro AEs though some (delirium, agitation, hallucination) may be considered a part of the neuro AEs. There were no associations of febrile neutropenia, thrombocytopenia, serum ferritin and C-reactive protein with neuro AEs (all p values>0.05). Conclusions: Neuro AEs were common with CAR-T cell therapy in the real world and largely resembled those reported in clinical trials. Neuro AEs were associated with the agent used, age ≥65 as well as the presence of CRS, cardiac and psychiatric AEs but not with any of the laboratory values studied. The limitations of this study include its retrospective nature, potential under-reporting to FAERS and the relatively small number of patients in the tis-cel group due to its later approval and shorter time available for uptake compared to axi-cel. Despite these limitations, our findings can serve to inform clinicians' decision making when treating adult patients with CAR-T cell therapy. Further research is needed to better discern the etiopathology and biomarkers of neuro AEs in CAR-T cell therapy. Disclosures Gajra: Cardinal Health: Employment. Zettler:Cardinal Health: Employment. Phillips Jr.:Cardinal Health: Employment. Klink:Cardinal Health: Employment. Kish:Cardinal Health: Employment. Mehta:Cardinal Health: Employment. Feinberg:Cardinal Health: Employment.

Real-World Analysis of Adverse Events Associated with CAR T-Cell Therapy Among Adults Age ≥65 Years

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1951-1951 ◽  
Author(s):  
Marjorie E Zettler ◽  
Bruce A Feinberg ◽  
Eli G Phillips Jr. ◽  
Andrew J Klink ◽  
Sonam Mehta ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Real World ◽  
Age Group ◽  
T Cell Therapy ◽  
Younger Patients ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) are chimeric antigen receptor (CAR) T-cell therapies that target CD19-expressing B cells. Both therapies have been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL) after at least 2 lines of systemic therapy. The median age at diagnosis of diffuse LBCL is 66 years, with over half the cases occurring in patients over age 65. Patients >65 years have worse survival than younger patients. Despite this predilection for older age, only one quarter of the patients in the pivotal trials supporting approval of the 2 therapies were age 65 or older. An analysis of the safety of axi-cel in the pivotal ZUMA-1 trial showed no significant differences between the age <65 and ≥65 subgroups; however, the small number of older patients included on the original clinical trials due to the constraints of the stringent eligibility criteria limits the generalizability of these findings (Sano et al, Blood 2018 132:96). In this analysis, we reviewed post-approval adverse events (AEs) involving axi-cel or tis-cel for LBCL and compared reactions and outcomes by age utilizing the FDA Adverse Events Reporting System (FAERS) Database, which was created to support FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. Methods: The FAERS database contains anonymized reports of product-related AEs, classified using the Medical Dictionary for Regulatory Activities (MedDRA) and categorized as serious or non-serious. The database was queried for cases involving axi-cel or tis-cel (and their respective trade names) from the FDA approval date for the LBCL indication (October 18, 2017 for axi-cel; May 1, 2018 for tis-cel) through March 31, 2019. Cases were excluded if the age of the patient was unknown. Cases reported outside the US were excluded. Patient characteristics and adverse events were summarized using descriptive statistics. Comparisons of rates of AEs by age group were made using Fisher's exact test; statistical significance was determined at a two-sided α=0.05. Results: A total of 397 cases were retrieved (360 involving axi-cel, 37 involving tis-cel). The median age of the patients involved was 62 years (range 18-81), with 153 (39%) of the patients age 65 or older. The vast majority of reactions (376, 95%) reported to FAERS were classified as serious. Overall, 141 (36%) cases resulted in hospitalization; 33 (8%) cases had an outcome categorized as life-threatening; 46 (12%) cases resulted in death; 6 (2%) resulted in disability. The most common reaction in each age group was cytokine release syndrome (CRS), reported in 64% and 56% of patients <65 and ≥65 groups, respectively (Table). When a composite definition for CRS was utilized by including individual clinical features that comprise CRS, a higher proportion of patients <65 were noted to have CRS (80% vs. 67%, p<0.01). Pyrexia (41% vs. 24%, p<0.01), tachycardia (17% vs. 8%, p=0.01), hospitalization (42% vs. 25%, p<0.01) and elevated ferritin levels (3% vs. 0%, p=0.03) were significantly more common among the younger age group. Patients ≥65 had a significantly higher proportion of cases of neurotoxicity (50% vs. 39%, p=0.04); atrial fibrillation was also reported more frequently in the older age group compared to younger patients (8% vs. 3%, p=0.02). Conclusions: This large-scale post-marketing report of CAR T-cell therapy associated AEs in the real world suggests differences based on age: patients ≥65 had a higher incidence of neurotoxicity and atrial fibrillation while younger patients had increased incidence of some CRS components, especially pyrexia and tachycardia. There was no demonstrable difference in deaths between the 2 groups, but younger patients had higher rates of hospitalization. This report provides real-world evidence for use of CAR T-cell therapy in patients ≥65 and can inform clinical care based on patterns of AEs observed. Potential under-reporting of cases to the FAERS database, the retrospective design of this study and limited data available in the case reports preclude interpretation of causality. Despite these limitations, our findings identified real-world trends in reported signals that complement clinical trial safety data and support further pharmacoepidemiologic study. Disclosures Zettler: Cardinal Health: Employment. Feinberg:Cardinal Health: Employment. Phillips Jr.:Cardinal Health: Employment. Klink:Cardinal Health: Employment. Mehta:Cardinal Health: Employment. Gajra:Cardinal Health: Employment.

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