Case Report: Local Cytokine Release Syndrome in an Acute Lymphoblastic Leukemia Patient After Treatment With Chimeric Antigen Receptor T-Cell Therapy: A Possible Model, Literature Review and Perspective

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.

TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors

“…BB.ζ CAR-T cells exhibit significantly higher levels of cytokine release than B7-H3.TMI.ζ CAR-T cells, it is possible that a localized CRS played a role in this outcome. A similar effect has been reported in the clinic, described as a "local" (49) or "compartmental" (50) CRS. This toxicity could also be magnified by the intratumoral injection of CAR-T cells in this model compared to intravenous administration in our other models.…”

Cervical Edema Extending to the Larynx as Local Cytokine Release Syndrome Following Chimeric Antigen Receptor T-Cell Therapy in a Boy with Refractory Acute Lymphoblastic Leukemia

“…Considering that the cervical mass resolved 1 month after CAR T-cell therapy, the cervical mass was presumed to have first enlarged immediately after CAR T-cell infusion and then shrunk thereafter. In the second case, a patient with refractory Ph-like B-ALL developed cervical edema and dyspnea despite treatment with tocilizumab for persistent fever and low blood pressure as symptoms of systemic CRS [ 5 ]. There are two important points to consider when comparing the present case with these previous cases.…”

“…Therefore, patients with a cervical mass prior to CAR T-cell infusion are considered to be at higher risk for airway obstruction due to CRS. Such local inflammation is considered as “local CRS” and may be distinguished from systemic CRS [ 5 , 6 ]. However, in the second and the present case, the patients had no history of cervical lymphadenopathy or mass during the treatment course, including the initial symptoms at ALL diagnosis.…”

“…Local edema outside the brain or the lungs is a rare symptom of CRS [ 3 , 4 ]. However, a new type of CRS, called “local CRS,” has been recently proposed, which is thought to occur when CAR T cells accumulate and proliferate in the tumor local area and release a large amount of cytokines because they capture and kill tumor cells [ 5 , 6 ]. This case report compares the present case with similar cases reported previously [ 5 , 7 ].…”

Cervical Local Cytokine Release Syndrome Following Chimeric Antigen Receptor T-cell Therapy in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

“…Compared to these prevalent systemic symptoms of CRS, an acute inflammatory phenomenon at specific body regions, named local CRS, is a rare complication. However, data on local CRS is scarce [ 10 - 13 ]. We here present two patients who developed local CRS with significant cervical edema following anti-CD19 CAR-T therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL).…”