Intrathecal chemotherapy for management of steroid-refractory CAR T-cell–associated neurotoxicity syndrome

Abstract

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are major limitations of chimeric antigen receptor (CAR) T-cell therapy. 1 Although tocilizumab, an anti-interleukin-6R (IL-6R) antibody, can ameliorate CRS, it has limited effectiveness in ICANS. 1,2 Systemic high-dose corticosteroids and supportive care are the current mainstay therapies for ICANS. Because infiltration of immune effector cells (IECs) into the central nervous system (CNS) 3 is implicated in ICANS, we administered intrathecal (IT) chemotherapy for steroid-refractory ICANS with rapid resolution of toxicities. We describe the clinical course and outcomes of 2 patients with steroidrefractory ICANS treated with IT chemotherapy. Institutional Review Board submission was deferred per institutional policy for case series that include ,3 patients. A 71-year-old man with chemorefractory diffuse large B-cell lymphoma (DLBCL) received secondgeneration 41BB CD3z anti-CD19 anti-CD20 (LV20.19) bispecific CAR T cells on a phase 1 clinical trial (NCT03019055). On day 15 post-LV20.19 CAR infusion, the patient developed grade 2 CRS that resolved with tocilizumab. On day 17, he developed grade 2 neurotoxicity by Common Terminology Criteria for Adverse Events v5. Treatment with dexamethasone, 10 mg every 6 hours, was initiated. With rapid improvement, his dexamethasone was tapered. Unfortunately, he progressed with grade 3 neurotoxicity on day 113 that was manifested by tremor, mutism, and nonresponsiveness. Lumbar puncture (LP) was performed, and cerebrospinal fluid (CSF) analysis revealed a white blood cell (WBC) count of 18 cells per microliter (Figure 1A), with a predominantly non-CAR CD4 1 T-cell population (Figure 1B). Pulse IV SOLU-MEDROL, 500 mg 3 3 days, was initiated, followed by dexamethasone, 10 mg every 6 hours, without any clinical improvement. Brain magnetic resonance imaging did not reveal any significant intracranial abnormality. An electroencephalogram was negative for seizures, and the patient was diagnosed with steroid-refractory ICANS.

Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline

“…53 e Noting limited experience with other agents and alternate options for persistent or worsening ICANS may include anakinra, siltuximab, ruxolitinib, cyclophosphamide, antithymocyte globulin, or intrathecal hydrocortisone (50 mg) plus methotrexate (12 mg). 46,54 Although the acute toxicities of CAR T-cell therapy, such as CRS and ICANS, are well-defined, less is known about the long-term and late effects facing cancer survivors who receive CAR T-cell therapy, although data are beginning to emerge as survival of these patients increases. Longterm and late effects of CAR T-cell therapy may include cytopenias and infection, as well as B-cell aplasia and hypogammaglobulinemia.…”

Severe Motor Weakness Due to Disturbance in Peripheral Nerves Following Tisagenlecleucel Treatment

“…In our case, steroids, as well as tocilizumab, were completely ineffective, and the symptoms improved after high-dose chemotherapy followed by aPBSCT. Previous reports have shown that CPA, anti-thymocyte globulin, and intrathecal chemotherapy, which directly affect T lymphocytes, are effective in cases of steroid/tocilizumab refractory neurotoxicity (20)(21)(22). CAR and non-CAR T-cells have been reported to infiltrate the cerebrospinal fluid and brain parenchyma, consistent with encephalitis, in a non-human primate model (23).…”

Optimizing the Clinical Impact of CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia: Looking Back While Moving Forward

“…IT chemotherapy has been used for controlling refractory CAR-T-associated ICANS that is non-responsive to steroids (100,101). Shah et al have administered IT chemotherapy to two CAR-T-receiving patients and demonstrated that it can mediate rapid ICANS resolution without any long-term complications (100). This method can also accelerate the recovery process and reduce the complications of systemic long-term corticosteroid administration (100).…”

“…Shah et al have administered IT chemotherapy to two CAR-T-receiving patients and demonstrated that it can mediate rapid ICANS resolution without any long-term complications (100). This method can also accelerate the recovery process and reduce the complications of systemic long-term corticosteroid administration (100). Moreover, Yucebay et al have also reported similar results from a study where IT chemotherapy resulted in the resolution of high-grade neurotoxicity (grade 3-4) of CD19-redirected CAR-T-receiving patients while corticosteroid therapy was inefficient (101).…”