Intrathecal Chemotherapy as a Potential Treatment for Steroid-refractory Immune Effector Cell-associated Neurotoxicity Syndrome

Abstract

Background/Aim: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of various B-cell malignancies. However, it can cause serious adverse effects like immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS is attributed to disruption of the blood-brain barrier due to inflammatory cytokines and increased levels of immune effector cells (IECs) in the cerebrospinal fluid (CSF). Corticosteroids and supportive management are the mainstays of ICANS treatment. However, no guidelines exist for the treatment of steroid-refractory ICANS. Some reports have shown favorable outcomes with no long-term complications in patients with steroid-refractory ICANS treated with intrathecal (IT) chemotherapy. Case Report: We describe the outcomes of two patients with steroid-refractory ICANS treated with IT chemotherapy. Both patients had refractory large B-cell lymphoma and were not candidates for autologous transplant. They developed steroid-refractory ICANS after CAR T-cell infusion. IT chemotherapy with 12 mg methotrexate and 50 mg hydrocortisone resulted in prompt neurological improvement in both patients. One of them passed away due to multiple other comorbidities, and the other patient continues to do well without any complications. Conclusion: IT chemotherapy could be considered as a potential approach for the management of steroid-refractory ICANS based on our experience. Prospective studies are needed to validate this approach.Chimeric antigen receptor (CAR) T-cell therapy is a novel therapeutic modality that uses genetically modified T cells to target tumor cells. CAR T-cells get activated after binding to a specific antigen on tumor cells to proliferate, secrete cytokines and kill the targeted cancer cells (1). CD-19 targeting CAR T-cells (tisagenlecleucel/tisa-cel and axicabtagene cilileucel/axi-cel) are approved to treat relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) and large B cell lymphomas (2-3).CAR T-cell therapy has revolutionized the treatment of hematologic malignancies. However, it is associated with adverse events like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). CRS is caused by the systemic release of inflammatory cytokines through activated lymphocytes and myeloid cells, which can result in a clinical syndrome consisting of fever, hypotension, and widespread organ dysfunction (4). ICANS may occur with or without CRS, and onset is variable ranging from days to weeks after cell infusion. Its presentation is diverse, ranging from encephalopathy (most common), focal weakness/numbness to tremors, seizures, and cerebral edema.Management of CRS and ICANS depends on the severity of the toxicity, with supportive care, corticosteroids, and IL-6-directed therapy (tocilizumab) being the mainstay of treatment (5). Tocilizumab was approved by FDA in August 2017 for the treatment of CRS as a first-line pharmacotherapy (6). However, it is unclear if it helps treat ICANS without CRS. Corticosteroids are indicat...

Case report: Rapid resolution of grade IV ICANS after first line intrathecal chemotherapy with methotrexate, cytarabine and dexamethasone

“…Due to the possibility that other cytokines, in addition to IL-1, could be implicated in the pathogenesis of ICANS, as well as the potential advantage of local control of CNS inflammation over systemic CAR-T cell depletion, treatment options such as IT administration of immunosuppressive drugs have been proposed. Clinical cases of IT therapy have been reported in the past (37, 41,42), and recently, small clinical studies have shown favorable outcomes in steroid-refractory ICANS (37) (Table 1). Yucebay F. et al reported a small clinical study investigating the IT administration of methotrexate 15mg, cytarabine 40mg, and hydrocortisone 50mg for the management of steroid-refractory or recurring high-grade ICANS following anti-CD19 CAR-T cell therapy.…”

CAR-T cells neurotoxicity from consolidated practice in hematological malignancies to fledgling experience in CNS tumors: fill the gap

“…Treatment with glucocorticoids in association with supportive management represents the standard of care, despite the possibility that corticosteroids reduce the effectiveness of CAR-T cells remains a critical concern (64)(65)(66)(67).…”

“…A few reports have demonstrated favorable outcome in steroidrefractory ICANS treated with intrathecal methotrexate (12 mg) and hydrocortisone (50 mg) (64,66). Asawa et al reported clinical improvement and rapid resolution of ICANS in two patients treated with intrathecal administration of methotrexate and hydrocortisone, both refractory to previous therapy with dexamethasone and tocilizumab (66).…”

Intrathecal hydrocortisone for treatment of children and young adults with CAR T‐cell immune‐effector cell‐associated neurotoxicity syndrome

“…Current strategies typically employ systemic approaches, which may increase risk of immunosuppression in a highly vulnerable population. Limited case reports have described the use of intrathecal hydrocortisone (IT‐HC) ± chemotherapy for steroid‐refractory ICANS in adults with B‐cell lymphoma, leading to the reversal of ICANS symptoms 14–17 . There are limited data of this approach in pediatric patients with B‐ALL, as our institution is one of the few to incorporate this approach routinely 3,18,19 .…”