Intrathecal Chemotherapy: An Alternative Treatment Strategy to Prolonged Corticosteroids for Severe CAR T Associated Neurotoxicity

Yucebay, Filiz; Maakaron, Joseph; Grana, Allison; Jaglowski, Samantha; Roddy, Julianna

doi:10.1016/j.bbmt.2019.12.390

Cited by 10 publications

(7 citation statements)

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“…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). However, both of these studies suggest that this method requires detailed evaluations in future clinical trials (100, 101).…”

Section: Intrathecal (It) Chemotherapymentioning

confidence: 80%

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

Kozani

Rahbarizadeh

2021

Front. Immunol.

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Chimeric antigen receptor T-cell (CAR-T) therapy has been successful in creating extraordinary clinical outcomes in the treatment of hematologic malignancies including relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). With several FDA approvals, CAR-T therapy is recognized as an alternative treatment option for particular patients with certain conditions of B-ALL, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, or multiple myeloma. However, CAR-T therapy for B-ALL can be surrounded by challenges such as various adverse events including the life-threatening cytokine release syndrome (CRS) and neurotoxicity, B-cell aplasia-associated hypogammaglobulinemia and agammaglobulinemia, and the alloreactivity of allogeneic CAR-Ts. Furthermore, recent advances such as improvements in media design, the reduction of ex vivo culturing duration, and other phenotype-determining factors can still create room for a more effective CAR-T therapy in R/R B-ALL. Herein, we review preclinical and clinical strategies with a focus on novel studies aiming to address the mentioned hurdles and stepping further towards a milestone in CAR-T therapy of B-ALL.

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Section: Intrathecal (It) Chemotherapymentioning

confidence: 80%

“…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).…”

Section: Intrathecal (It) Chemotherapymentioning

confidence: 99%

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

Kozani

Rahbarizadeh

2021

Front. Immunol.

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“…The median duration of steroid treatment in these patients was 11 days. Two patients out of the seven did not respond (9). Another report of two patients with chemo-refractory DLBCL who received anti CD-19 CAR T-therapy demonstrated rapid and sustained response in both patients after treatment with IT chemotherapy for steroidrefractory ICANS (8).…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2022

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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...

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“…The median time to IT chemotherapy from onset of neurotoxicity was 11 days, which could contribute to the late resolution of ICANS (37). A recent retrospective study has highlighted the superior efficacy of early IT hydrocortisone administration for steroid-refractory high-grade ICANS compared to late IT hydrocortisone or systemic corticosteroid therapy (36). In this study, the first group of 7 patients with steroid-refractory ICANS received IT hydrocortisone within the first 5 days after high-grade ICANS development.…”

Section: Discussionmentioning

confidence: 97%

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

Katsin,

Shman,

Migas

et al. 2024

Front. Immunol.

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Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS.

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Intrathecal Chemotherapy: An Alternative Treatment Strategy to Prolonged Corticosteroids for Severe CAR T Associated Neurotoxicity

Cited by 10 publications

References 0 publications

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

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

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

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

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