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Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

ABSTRACT: Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations.

SUBMITTER: Burns EA

PROVIDER: S-EPMC8006027 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

Burns Ethan A EA Gentille Cesar C Trachtenberg Barry B Pingali Sai Ravi SR Anand Kartik K

Diseases (Basel, Switzerland) 20210317 1

Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac eve ...[more]

PMID: 33802788

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Project description:BackgroundCytopenia is one of the most common adverse events following the CAR-T cell infusion, affecting the quality of life and potentially leading to life-threatening bleeding and infection. This study aimed to systematically review the cytopenias following anti-CD19 CAR-T therapy and further analyse the contributing factors.MethodsDatabases including PubMed, MEDLINE, Embase and Cochrane were systematically searched on 8 May 2022. A random-effect meta-analysis was used to estimate the incidence of cytopenia, and subgroup analyses were applied to explore heterogeneity.ResultsA total of 68 studies involving 2950 patients were included in this study. The overall incidence of all grade anaemia, thrombocytopenia, neutropenia, leukopoenia, lymphocytopenia and febrile neutropenia was 65%, 55%, 78%, 62%, 70% and 27%, respectively, and the corresponding cytopenias of grade 3 or worse were 33%, 31%, 61%, 45%, 46%, and 21%, respectively. Subgroup analysis showed increased incidence of cytopenias in subgroups with lower median age, proportion of males (<65%) and proportion of bridging therapy (<80%) and in the subgroup with a median line of prior therapy ≥3. In terms of disease and therapeutic target, cytopenias were more frequent in ALL patients and in dual-target CAR-T therapies (targeting CD19 in combination with other targets). Furthermore, CAR-T products manufactured by lentiviral vectors and those with the costimulatory domain of CD28 were more likely to cause haematological toxicity. No significant differences were observed in cytopenia between patients treated with CAR-T products with murine and humanized scFv.ConclusionIn conclusion, neutropenia is the most frequent cytopenia after CAR-T therapy, both in all grades or grade ≥3. The incidence of cytopenias following CAR-T therapy is influenced by the age, sex, disease and number of prior therapy lines of the patients, as well as the target and costimulatory domain of CAR-T cells, and viral vectors used for manufacturing.KEY MESSAGESNeutropenia is the most frequent cytopenia after CAR-T therapy.The clinical characteristics of the patients, the design of CAR-T cells and the protocol of CAR-T treatment can influence the occurrence of cytopenias following the CAR-T therapy.

Project description:BackgroundRecent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary.MethodsWe generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).ResultsData from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49-24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74-18.08 months) and 6.93 months (95% CI, 3.13-10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017-0.601).ConclusionsThe results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy.Trial registrationClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687.

Project description:ObjectiveDespite substantial advances in the treatment of systemic lupus erythematosus (SLE), some patients do not respond to the current state-of-the art therapies. This study assessed the tolerability and efficacy of CD19 chimeric antigen receptor (CAR) T cells in a small series of seriously ill and treatment-resistant patients with SLE.MethodsFive patients with SLE (four female patients and one male patient) with a median age of 22 (range 18-24) years, a median disease duration of 4 (range 1-9) years, and active disease (median Systemic Lupus Erythematosus Disease Activity Index score of 16 [range 8-16]) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use CAR-T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded, and reinfused at a dose of 1 × 106 CAR T cells per kilogram of body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide.ResultsCAR T cells expanded in vivo and led to deep depletion of B cells, improvement of clinical symptoms, and normalization of laboratory parameters, including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to definition of remission in SLE criteria was achieved in all five patients after 3 months, and the median Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (range 2). Drug-free remission was maintained during longer follow-up (median of 8 [range 12] months after CAR-T cell administration) and even after the reappearance of B cells, which was observed after a mean (±SD) of 110 ± 32 days after CAR-T cell treatment. Reappearing B cells were naive and showed non-class-switched B cell receptors. CAR-T cell treatment was well tolerated, with only mild cytokine release syndrome.ConclusionThese data suggest that CD19 CAR-T cell therapy was feasible, tolerable, and effective in this small case series of refractory SLE. Nevertheless, larger placebo-controlled trials are warranted.

Dataset Information

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

Publications

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

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