Q1. According to the cytokine release syndrome (CRS) of CAR T-cell therapy, which of the following statement is incorrect?

• (A) CRS affects 30%-100% of all patients, with grade 3 CRS reported in 10%-30%.
• (B) CRS is characterized by fever 38C, hemodynamic instability and hypoxemia.
• (C) CAR-T activation leads to effector cytokine release [IFN-γ, TNF-α, IL-2] which can trigger pro-inflammatory cytokine release [IL-1, IL-6, IFN-γ, IL-10 and monocyte chemoattractant protein-1], with increased C-reactive protein and hyperferritinemia.
• (D) CRS management combines symptomatic measures (antipyretics, fluids) with rituximab and corticosteroids.
• (E) The differential diagnosis includes neutropenic sepsis and empiric broad-spectrum i.v. antibiotics should be commenced.

點此顯示正解

(D) CRS management combines symptomatic measures (antipyretics, fluids) with rituximab and corticosteroids.

詳解

Analysis of the Incorrect Statement

Statement (D) is INCORRECT because it lists rituximab as part of CRS management, when the correct agent is tocilizumab. Rituximab is an anti-CD20 monoclonal antibody used to treat B-cell lymphomas and autoimmune conditions, not CRS. In contrast, tocilizumab is an anti-IL-6 receptor monoclonal antibody that is FDA-approved specifically for CAR-T cell-mediated cytokine release syndrome¹²⁴. CRS management combines symptomatic measures (antipyretics, intravenous fluids, oxygen) with tocilizumab as first-line cytokine-directed therapy for grade ≥2 CRS, and corticosteroids (typically dexamethasone 10 mg every 6-12 hours) as second-line therapy for refractory or severe cases¹²⁴[^9].

Why the Other Statements Are Correct

Statement (A) is CORRECT: CRS affects a high proportion of CAR-T recipients, with overall incidence ranging from 30-100% depending on the CAR-T product, disease type, and tumor burden. Severe CRS (grade ≥3) occurs in approximately 10-30% of patients[^11]. The incidence and severity vary by CAR-T construct—CD28-costimulated products (e.g., axicabtagene ciloleucel) tend to have higher rates of severe CRS compared to 4-1BB-costimulated products[^9][10].

Statement (B) is CORRECT: The cardinal clinical features of CRS include fever ≥38°C (required for diagnosis), hypotension/hemodynamic instability, and hypoxia²[^6][7]. The American Society for Transplantation and Cellular Therapy (ASTCT) 2019 consensus criteria define CRS severity based on these parameters, with grading determined by the degree of hypotension (vasopressor requirements) and hypoxia (oxygen supplementation needs)²[^7][9].

Statement (C) is CORRECT: The pathophysiology involves a two-step cytokine cascade. CAR-T cell activation upon tumor recognition triggers release of effector cytokines including IFN-γ, TNF-α, and IL-2. These cytokines activate bystander immune cells, particularly monocytes and macrophages, which amplify the inflammatory response by secreting pro-inflammatory cytokines including IL-6, IL-1, IL-10, and monocyte chemoattractant protein-1[^9][10]. This cascade results in elevated acute-phase reactants, notably C-reactive protein (CRP) and ferritin (hyperferritinemia), which serve as biomarkers for CRS severity[^9][10].

Statement (E) is CORRECT: The differential diagnosis of fever in CAR-T recipients must include neutropenic sepsis and other infections, as these patients are immunocompromised and fever may have multiple etiologies⁴[^9][10]. Empiric broad-spectrum intravenous antibiotics should be initiated while evaluating for CRS, as concomitant infections must be excluded and promptly treated⁴[^9][10]. This is a critical safety principle in CAR-T management.

詳解 · 中文翻譯

不正確陳述的分析

陳述 (D) 不正確，因為它列舉rituximab 作為 CRS 管理的一部分，而正確的代理是 tocilizumab。Rituximab 是用於治療 B 細胞淋巴瘤和自身免疫病症的抗 CD20 單克隆抗體，不用於 CRS。相反，tocilizumab 是抗 IL-6 受體單克隆抗體，FDA 特別批准用於 CAR-T 細胞介導的細胞激素釋放症候群¹²⁴。CRS 管理將症狀治療措施（退燒藥、靜脈補液、氧氣）與 tocilizumab 作為第 ≥2 級 CRS 的一線細胞激素導向治療，以及皮質類固醇（通常為地塞米松 10 mg 每 6-12 小時）作為難治性或嚴重病例的二線治療相結合¹²⁴[^9]。

其他陳述為何正確

陳述 (A) 正確：CRS 影響高比例的 CAR-T 接收者，總體發生率根據 CAR-T 產品、疾病類型和腫瘤負荷從 30-100% 不等。嚴重 CRS（≥3 級）發生在約 10-30% 的患者中[^11]。發生率和嚴重程度因 CAR-T 構造而異——CD28 共刺激產品（如 axicabtagene ciloleucel）傾向於相比 4-1BB 共刺激產品有更高的嚴重 CRS 發生率[^9][10]。

陳述 (B) 正確：CRS 的基本臨床特徵包括 發熱 ≥38°C（診斷所需）、低血壓/血流動力學不穩定和低氧血症²[^6][7]。美國移植和細胞療法學會（ASTCT）2019 共識標準根據這些參數定義 CRS 嚴重程度，分級由低血壓程度（血管升壓劑需求）和低氧血症（氧補充需求）決定²[^7][9]。

陳述 (C) 正確：病理生理涉及兩步細胞激素級聯。CAR-T 細胞在腫瘤識別時的激活導致 效應細胞激素（包括 IFN-γ、TNF-α 和 IL-2）的釋放。這些細胞激素激活旁觀者免疫細胞，特別是單核細胞和巨噬細胞，後者通過分泌 促炎細胞激素（包括 IL-6、IL-1、IL-10 和單核細胞趨化蛋白-1）放大炎症反應[^9][10]。此級聯導致急性期反應物升高，特別是 C 反應蛋白（CRP）和鐵蛋白（高鐵蛋白血症），這些作為 CRS 嚴重程度的生物標誌物[^9][10]。

陳述 (E) 正確：CAR-T 接收者發熱的鑑別診斷必須包括 中性粒細胞減少性敗血症和其他感染，因為這些患者免疫受損，發熱可能有多種病因⁴[^9][10]。應開始實驗性廣譜靜脈抗生素，同時評估 CRS，因為必須排除並迅速治療伴隨感染⁴[^9][10]。這是 CAR-T 管理中的關鍵安全原則。

參考文獻 (AMA)

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1. Brudno JN, Maus MV, Hinrichs CS. CAR T Cells and T-Cell Therapies for Cancer: A Translational Science Review. Jama. 2024;332(22):1924-1935. doi:10.1001/jama.2024.19462. PMID:39495525. ↩↩↩↩

2. Santomasso BD, Nastoupil LJ, Adkins S, et al. Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2021;39(35):3978-3992. doi:10.1200/JCO.21.01992. PMID:34724386. ↩↩↩↩↩↩↩↩

3. Hirayama AV, Turtle CJ. Toxicities of CD19 CAR-T Cell Immunotherapy. American Journal of Hematology. 2019;94(S1):S42-S49. doi:10.1002/ajh.25445. PMID:30784102. ↩

4. Caserta S, Martino EA, Vigna E, et al. T-Cell-Redirecting Immunotherapies in Relapsed/Refractory Mantle Cell Lymphoma: Current Evidence, Sequencing, and Future Directions. European Journal of Haematology. 2026;116(2):129-141. doi:10.1111/ejh.70063. PMID:41207679. ↩↩↩↩↩↩↩↩

5. Westin JR, Kersten MJ, Salles G, et al. Efficacy and Safety of CD19-directed CAR-T Cell Therapies in Patients With Relapsed/Refractory Aggressive B-Cell Lymphomas: Observations From the JULIET, ZUMA-1, and TRANSCEND Trials. American Journal of Hematology. 2021;96(10):1295-1312. doi:10.1002/ajh.26301. PMID:34310745. ↩

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