This is a title in sentence case:early intrathecal dexamethasone and methotrexate as an effective approach for immune effector cell-associated neurotoxicity syndrome after CAR-T cell therapies

Abstract Introduction：Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated remarkable success in treating relapsed and refractory B-cell hematological malignancies. Although the application of CAR-T therapy in acute myeloid leukemia (AML) is still restricted, we and other institutions have also demonstrated high complete remission rate of CAR-T targeting C-type lectin-like molecule 1 (CLL1) for relapsed or refractory (R/R) AML. However, CAR-T cell related toxicities such as steroid-refractory and severe immune effector cell-associated neurotoxicity syndrome (ICANS) can be life-threatening. Previous cases have reported potential efficacy of intrathecal corticosteroids alone or in combination with chemotherapy. Whether intrathecal dexamethasone and methotrexate (IDM) is beneficial for the patient with steroid-refractory and severe ICANS remains unclear. Methods: We retrospectively analyzed the clinical data of 13 patients with severe or steroid-refractory ICANS, and evaluated the effect of IDM in the treatment of severe ICANS or steroid-refractory ICANS by analyzing the changes in ICANS grade, ICE score, and laboratory indicators. Grade 3-4 ICANS downgraded to grade 1 and grade 1-2 ICANS recovery to an ICE score of 10 is considered ICANS remission. Results: Among 13 patients, 7 of them were AML, 3 were ALL, 1 was MM, 1 was B cell lymphoma, 1 was blastic plasmacytoid dendritic cell neoplasm, with a median age of 39(11-65) years, female (N=7). The median number of prior lines of therapy was 7(1-16). There were six CAR-T products, including 6 targeting CD19, 3 targeting CLL1, and another four targeting CD7, CD123, BCMA, and CD19-CD22, respectively. Median CAR-T cell infusion dose was 2x106/kg. Median bone marrow blasts before lymphocyte depletion was 33.23%(5.3%4-78.50%) and 9 patients had CNS involvement. 2 patients developed grade 1 CRS and 9 patients developed grade 2 CRS. Among them, 3 patients had grade 1 ICANS, 5 patients had grade 2 ICANS, 3 patients had grade 3 ICANS, and 2 patients had grade 4 ICANS. Median onset time of ICANS after CAR-T was 11(3-20) days. All patients received IDM, 7 patients received their first IDM within 12 hours, 3 patients received first IDM within 12-24 hours, 2 patients received first IDM within 24-48 hours, and 1 patient received first IDM within 48-72 hours. Median duration of intravenous dexamethasone before first IDM was 6(1-7) (days). Median time to ICANS grade 1 or ICE 10 after IDM was 1(1-7) days, with median number of IDM was 1(1-3). ICANS remission rate reached 92.3% (12/13 patients). The median OS and median PFS were 6 months and 4 months, respectively.Conclusion: Our data shows that early administration of IDM is feasible and highly effective in management of severe or steroid-refractory ICANS and improving short-term prognosis, which may create opportunities for subsequent treatments in these patients. Larger sample and multicenter clinical trials are warranted to further validate these findings.