ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Abstract

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment of patients up to age 25 years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell-and bispecific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

A review of chimeric antigen receptor T-cells in lymphoma

“…High levels of Granzyme B, which has previously been linked to neuronal injury, as well as IL-12 and IL-15 correlate with more severe ICANS [26]. While imaging is mostly unrevealing, computerized tomography and magnetic resonance imaging of patients with ICANS has been observed to demonstrate abnormalities in the splenium similar to presentations with mild encephalopathy with reversible splenial lesion syndrome [22]. ICANS has been described in most clinical trials with use of CAR-T and ranges in severity from mild and self-limited to lethal.…”

“…Despite these features, CRP it is not currently included in CRS grading criteria as elevations may lag behind clinical symptoms of CRS and thus delay provider intervention. Despite this limitation, routine measurement of CRP remains encouraged as ongoing data collection may shape future guidelines for CRS activity [22]. Multiple CRS grading systems have been used and amended through time in an attempt to better compare results across clinical trials as well as to provide standardized guidelines for when to initiate practitioner intervention [20,22].…”

“…Despite this limitation, routine measurement of CRP remains encouraged as ongoing data collection may shape future guidelines for CRS activity [22]. Multiple CRS grading systems have been used and amended through time in an attempt to better compare results across clinical trials as well as to provide standardized guidelines for when to initiate practitioner intervention [20,22]. The Common Terminology Criteria for Adverse Events version 3 (CTCAEv3) and later fell short of being able to accurately define and stratify CRS seen with CAR-T due to lack of objective measurements as well as inclusion of criteria not applicable to CAR-T such as including the response to infusion interruption [23].…”

“…Supportive care is indicated for all grades of CRS while uses of immunomodulatory therapies like Tocolizumab ± Corticosteroids are the mainstay of CRS grade 2 and higher [21,22,24]. It is recommended that CRS grading be performed at least twice daily with additional assessment after any status change.…”

“…The Immune effector cell-associated encephalopathy core (ICE) has been developed by the ASTCT for ICANS grading. This score uses assessment of orientation, naming, ability to follow commands, writing, and attention to propose specific and objective discrimination of ICANS severity and administration of treatment [22]. Tocilizumab has poor CNS penetration so corticosteroids such as methylprednisolone administered at 2 mg/kg/day with rapid weaning or dexamethasone 0.5 mg/ kg at a maximum 10 mg are the preferred interventions for life threatening central nervous system manifestations of CAR-T toxicity [5,24].…”