Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy

Abstract

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.

Timing of Tocilizumab Administration Under the Guidance of IL-6 in CAR-T Therapy for R/R Acute Lymphoblastic Leukemia

“…If we had a sufficient number of ICANS, it would be reasonable to set up a maximum level of IL-6 beyond which measures were demanded to prevent ICNAS after using Tocilizumab. Severe CRS has been demonstrated to be associated with infections ( 28 , 29 ) which may be related to liver secreting acute inflammatory proteins induced by IL-6 and pancytopenia caused by severe CRS ( 28 ). In our study, patients with elevated CRP over 1.83 times were more likely to develop severe infections after receiving Tocilizumab, which suggested that we should pay more attention to the patients’ infection progression after administration of Tocilizumab and intervene as soon as possible.…”

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges

“…Cytopenia is frequently observed during CAR-T cell therapy and lasts for several days to months, including anemia, thrombocytopenia, and leukopenia, and the incidence of cytopenia range from 30% to 100% in clinical trials (2,29,72,79,142,143). It has been demonstrated that cytopenia is associated with severe CRS (144)(145)(146). Under inflammatory conditions, CD40 is significantly up-regulated on granulocytic progenitor/precursor cells which also express low levels of CD40L, and the CD40/CD40L interactions between granulocytic progenitor/precursor cells significantly promote their own apoptosis (147).…”

Allogeneic CD34+ Selected Hematopoietic Stem Cell Boost Following CAR T-cell Therapy in a Patient with Prolonged Cytopenia and Active Infection

“…While LD chemotherapy can play a role, the etiology is likely multifactorial since hematotoxicty has also been observed in patients who did not receive it (5). High grade CRS has been shown to be associated with delayed hematopoietic recovery (3,4). Other studies show that baseline cytopenias (6) and patients who received prior allogeneic transplants, particularly those who received CAR T-cells less than one year following transplant, were at increased risk (7).…”