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.

Keywords: acute lymphoblastic leukemia; chimeric antigen receptor T therapy; local cytokine-release syndrome; possible model; systemic cytokine-release syndrome.

Figure 1

Pictures of the cervical region. (A) At D8, her cervical region was obviously swollen. (B) At D14, her cervical region returned to normal. With consent to publish from the patient.

Figure 2

Clinical data of L-CRS. (A) The temperature profile. (B) levels of cytokine. (C) CAR-T copy number. (D) therapeutic process. FC, fludarabine and cyclophosphamide regimen; IL-6, interleukin-6; CRP, c reactive protein; PCR, polymerase chain reaction; FACS, fluorescence activated cell sorter; NSAIDs, non-steroidal anti-inflammatory drugs; Toc, tocilizumab; Tor, torasemide; Met, methylprednisolone; Dex, dexamethasone; FFP, fresh frozen plasma; BM, bone marrow.

Figure 3

The model of L-CRS for compartmental and systemic malignancies. (A) The model of L-CRS for compartmental malignancies. (1) Malignancy cells restricted; (2) First stage, CAR-T cell local expansion; (3) Second stage, CAR-T cell overflow and inflammatory cytokine surge; (4) Third stage, CAR-T cell redistribution and organ damage; (5) Fourth stage, recovery. (B) The model of L-CRS for systemic malignancies in our case. (1) Malignancy cells diffused. (2) First stage, S-CRS; (3) Second stage, CAR-T cell redistribution and organ damage, possible for L-CRS; (4) Third stage, CRS abatement and recovery, possible for a new cycle of S-CRS; (5) In most case, L-CRS does not happen or just too weak to be identified.