Cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life‐threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B‐ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high‐dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti‐leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid‐refractory and even life‐threatening CRS.

中文翻译：

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鲁索替尼在 CAR T 治疗期间减轻类固醇难治性 CRS

细胞因子释放综合征 (CRS) 和免疫效应细胞相关的神经毒性是两种主要的 CAR T 相关毒性。在托珠单抗和类固醇的干预下，许多患者可以从严重的 CRS 中恢复过来。然而，一些患者对类固醇耐药并产生危及生命的后果。鲁索替尼是一种口服 JAKs 抑制剂，是一种很有前途的炎症性疾病药物。在这项初步研究中，我们评估了鲁索替尼在 CRS 中的疗效。在接受 CD19 或 CD22 CAR T 细胞疗法的 14 名 r/r B-ALL 儿童中，4 名患者出现严重（≥ 3 级）CRS，其症状未通过大剂量类固醇缓解，因此接受了鲁索替尼治疗。鲁索替尼治疗后 4 名患者观察到 CRS 症状快速消退。鲁索替尼干预后血清细胞因子显着降低。所有患者在输注后第 30 天达到完全缓解，尽管使用了鲁索替尼，我们仍然可以检测到体内 CAR T 扩增。没有与鲁索替尼相关的明显不良事件。体外试验表明，ruxolitinib 可以抑制 CAR T 扩增和细胞毒性，这表明应仔细考虑使用 ruxolitinib 的时机和剂量，以避免抑制抗白血病反应。我们的结果表明，ruxolitinib 在类固醇难治性甚至危及生命的 CRS 中具有活性且耐受性良好。提示应仔细考虑鲁索替尼的时间和剂量，以避免抑制抗白血病反应。我们的结果表明，ruxolitinib 在类固醇难治性甚至危及生命的 CRS 中具有活性且耐受性良好。提示应仔细考虑鲁索替尼的时间和剂量，以避免抑制抗白血病反应。我们的结果表明，ruxolitinib 在类固醇难治性甚至危及生命的 CRS 中具有活性且耐受性良好。