Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy

Abstract

Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19 B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells. CRS developed in 70% of patients, including 62.5% with grade 1 to 3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4, and 3.8% with grade 5. A majority of cases of grade ≥4 CRS occurred during CAR T-cell dose finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8 central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand factor, which are biomarkers of endothelial activation, were increased during severe CRS and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR T-cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR T-cell therapy.

Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'

“…This precautionary approach was required in the clinical trials of axi-cel, but we have not found this to be necessary in studies using CAR T cell constructs containing a 4-1BB co-stimulatory domain, including tisagenlecleucel, JCAR014, and JCAR017, in both ALL and NHL populations. Fever is typically the presenting symptom of CAR T cell-associated CRS (at least with 4-1BB CAR T cells), with critical illness arising 12-96 h later, if at all [7][8][9][10][11][12] . Patients can therefore be infused with CAR T cells in the outpatient setting and admitted to hospital at the time of fever development.…”

Open access? Widening access to chimeric antigen receptor (CAR) therapy for ALL

“…The mechanism for neurotoxicity is not clearly understood, but in view of the correlation between severity of CRS and of CRES, the latter does appear to be related to systemic inflammation in the setting of rapid early CAR T cell expansion, and particularly with the rapid upstroke of systemic inflammatory cytokines such as IL-6 38 . This has led to the implication of rapid transfer of inflammatory cytokines from the systemic circulation into the CSF as a potential mechanism.…”

“…Investigation of biomarkers of severe CRS in a predominantly paediatric cohort revealed an association between low fibrinogen and grade 4 CRS in paediatric patients 35 . This was explored further in an adult cohort treated at the Fred Hutchinson Cancer Center 38,45 where grade 4 or greater CRS was associated with hypofibrinogenaemia, increased d-dimers and reduced platelets, consistent with disseminated intravascular coagulation.…”

“…However, in general, the predictive value of such biomarker signatures is study-specific and may relate to differences in CAR T cell products or the patient population studied. Severity of CRS has correlated with disease burden, peak of plasma/serum IL-6 30,35,37 , earlier onset of CRS 35,38 and CAR T cell dose 24,25,30,38 in a number of studies. This latter finding has led to adoption of split 39 or risk adapted CAR T cell dosing 25 to mitigate risk of severe CRS.…”

“…The frequency of seizures varies dependent on the CAR design, being more frequent in studies where a CD28-containing CAR was adopted. Symptoms may be of variable severity, however, severe neurotoxicity generally develops in those with more severe CRS 24, 38 and often develops after the peak of CRS manifestations 38 . The symptoms of CRES overlap with those of infective encephalopathy as well as neurological toxicity resulting from methotrexate or fludarabine administration, and these are relevant differentials to consider.…”