Dataset Information

A comprehensive analysis of the fatal toxic effects associated with CD19 CAR-T cell therapy.

ABSTRACT: To determine the incidence, spectrum, timing, and clinical features of CD19 Chimeric antigen receptor (CAR-T) cell therapy-associated fatal toxic effects. We initiated a comprehensive analysis. First, we retrospectively queried the real-world data from a World Health Organization (WHO) pharmacovigilance database (Vigilyze). Furthermore, we performed a meta-analysis of published trials of CD19 CAR-T cell therapy. From screening the WHO database, we identified 1200 patients: 499 received Kymriah therapy, and 701 received Yescarta therapy. We compared the adverse reactions of the two drugs. We evaluated all published clinical trials, comprising 19 trials and 890 patients. Our meta-analysis showed that the incidence of fatal toxic effects associated with death was 5.4%. Infections and infestations appeared to present the highest risk of death. The toxic effect specific median time to death was 30, 30, and 68 days for total, cytokine release syndrome (CRS), and nervous system disorders (NSD), respectively. We observed a high mortality rate for some toxic effects and an early onset of death with varied causes, indicating the need for clinicians to pay more attention to the monitoring and treatment of these fatal toxic effects when using CD19 CAR-T cell therapy, especially for infections and infestations.

SUBMITTER: Cai C

PROVIDER: S-EPMC7585129 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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A comprehensive analysis of the fatal toxic effects associated with CD19 CAR-T cell therapy.

Cai Changjing C Tang Diya D Han Ying Y Shen Edward E Abdihamid Omar O Guo Cao C Shen Hong H Zeng Shan S

Aging 20200924 18

To determine the incidence, spectrum, timing, and clinical features of CD19 Chimeric antigen receptor (CAR-T) cell therapy-associated fatal toxic effects. We initiated a comprehensive analysis. First, we retrospectively queried the real-world data from a World Health Organization (WHO) pharmacovigilance database (Vigilyze). Furthermore, we performed a meta-analysis of published trials of CD19 CAR-T cell therapy. From screening the WHO database, we identified 1200 patients: 499 received Kymriah t ...[more]

PMID: 32973124

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Project description:CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-β1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.

Project description:ImportanceImmune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.ObjectiveTo determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.Design, setting, and participantsWe retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally.ExposuresAnti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab).Main outcomes and measuresTiming, spectrum, outcomes, and incidence of ICI-associated toxic effects.ResultsInternationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4).Conclusions and relevanceIn the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

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A comprehensive analysis of the fatal toxic effects associated with CD19 CAR-T cell therapy.

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A comprehensive analysis of the fatal toxic effects associated with CD19 CAR-T cell therapy.

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