近日，FDA批准诺华CAR-T细胞疗法正式上市，用于治疗复发性或难治性儿童、青少年B-细胞急性淋巴细胞白血病，其商品名为Kymriah（tisagenlecleucel）。 批准日期：2017年8月30日 公司：诺华制药 KYMRIAH（tisagenlecleucel）悬浮液，用于静脉输注 美国最初批准：2017年 警告：CYTOKINE RELEASE SYNDROME和 神经毒性 查看完整的盒装警告的完整处方信息。 接受KYMRIAH的患者发生细胞因子释放综合症（CRS），包括致命或危及生命的反应。不要将KYMRIAH给患有活动性感染或炎症性疾病的患者。用托珠单抗或托珠单抗和皮质类固醇治疗严重或危及生命的CRS。 在使用KYMRIAH治疗后，可能会出现严重或危及生命的神经毒性，包括与CRS同时发生。用KYMRIAH治疗后监测神经事件。根据需要提供支持性护理。 KYMRIAH仅通过名为KYMRIAH REMS的风险评估和缓解策略（REMS）下的受限计划提供。 最近的重大变化 适应症和用法，成人复发或难治性（r/r）弥漫性 大B细胞淋巴瘤（DLBCL）：5/2018 剂量和给药，成人复发或难治性（r/r）弥漫性大B细胞淋巴瘤（DLBCL）的剂量：5/2018 剂量和用法，管理：5/2018 警告和注意事项：5/2018 作用机制 KYMRIAH是CD19指导的遗传修饰的自体T细胞免疫疗法，其涉及用编码嵌合抗原受体（CAR）的转基因重编程患者自身的T细胞，以鉴定和消除表达CD19的恶性和正常细胞。 CAR由鼠单链抗体片段组成，其识别CD19并与来自4-1BB（CD137）和CD3ζ的细胞内信号传导结构域融合。 CD3 zetacomponent对于启动T细胞活化和抗肿瘤活性至关重要，而4-1BB增强了KYMRIAH的扩增和持久性。 在与表达CD19的细胞结合后，CAR传递信号以促进T细胞扩增，活化，靶细胞消除和KYMRIAH细胞的持久性。 适应症和用法 KYMRIAH是一种CD19定向的基因修饰自体T细胞免疫疗法，用于治疗：25岁以下患有B细胞前体急性淋巴细胞白血病（ALL）的患者，其难治性或第二次或晚期复发。 成人患者在两次或多次全身治疗后出现复发或难治性（r/r）大B细胞淋巴瘤，包括未另行说明的弥漫性大B细胞淋巴瘤（DLBCL），高级B细胞淋巴瘤和滤泡性淋巴瘤引起的DLBCL。 使用限制：KYMRIAH不适用于治疗原发性中枢神经系统淋巴瘤患者。 剂量和给药 仅供自体使用。仅限静脉注射。 如果需要，在输注KYMRIAH之前施用淋巴清除方案。 不要使用白细胞过滤器。 在输注前验证患者的身份。 预防用对乙酰氨基酚和H1-抗组胺药。 在输注前确认tocilizumab的可用性。 KYMRIAH的剂量基于嵌合抗原受体（CAR）阳性活T细胞的数量。 小儿和年轻成人B细胞ALL（最多25岁）对于50kg或更小的患者，静脉内给予每kg体重0.2至5.0×106CAR阳性的活T细胞。 对于50kg以上的患者，静脉内施用0.1至2.5×10 8个总CAR阳性活T细胞（非基于重量）。 成人复发或难治性弥漫性大B细胞淋巴瘤静脉注射0.6至6.0×10 8个CAR阳性活T细胞。 剂量形式和强度 小儿和青年成人B细胞ALL（最多25岁）单剂量的KYMRIAH对于50千克或更少的患者，或每千克体重，含有0.2至5.0×106 CAR阳性存活T细胞，或0.1至2.5×108 CAR积极性T患者细胞超过50公斤，悬浮在患者特异性融合袋中静脉注射输液。 成人复发或难治性弥漫性大B细胞淋巴瘤单剂量的KYMRIAH含有0.6至6.0×10 8个CAR阳性活T细胞，其悬浮在一个或多个患者特异性输注袋中用于静脉内输注。 禁忌症 没有。 警告和注意事项 超敏反应：监测输注过程中的超敏反应。 严重感染：监测患者的感染迹象和症状;适当治疗。 延长血细胞减少：患者在输注KYMRIAH后数周可能出现≥3级血细胞减少症。长期中性粒细胞减少与感染风险增加有关。 低丙种球蛋白血症：监测并提供替代疗法直至解决。评估接受治疗的母亲的新生儿的免疫球蛋白水平与KYMRIAH。 继发性恶性肿瘤：如果在使用KYMRIAH治疗后发生继发性恶性肿瘤，请联系诺华制药 公司在1-844-4KYMRIAH。 对驾驶和使用机器的能力的影响：建议患者避免驾驶和从事危险的职业或活动，例如 在接受KYMRIAH后至少8周内操作重型或潜在危险的机器。 不良反应 小儿和青年成人B细胞ALL（最高25岁）：最常见的不良反应（发生率大于20％）是细胞因子释放 综合征，低丙种球蛋白血症，感染 - 病原体未指明，发热，食欲减退，头痛，脑病，低血压，出血性心动过速，心动过速，恶心，腹泻，呕吐，病毒感染性疾病，缺氧，疲劳，急性肾损伤，水肿，咳嗽和谵妄。 成人复发或难治性弥漫性大B细胞淋巴瘤：最常见的不良反应（发生率大于20％）是CRS，感染病原体特异性，发热，腹泻，恶心，疲劳，低血压，水肿和头痛。 包装提供/存储和处理 KYMRIAH作为遗传修饰的自体T细胞的冷冻悬浮液提供在标记为特定接受者的输注袋中。KYMRIAH在液氮杜瓦瓶中直接运送到与输液中心相关的细胞实验室。产品和患者特定标签位于杜瓦瓶内。 全部：NDC 0078-0846-19 DLBCL：NDC 0078-0958-19 收到后确认患者身份。 在温度监测系统中将输液袋存放在液氮（小于或等于-120℃）的气相中。 在设施内运输输液袋时，请使用封闭，防破裂，防漏的容器。 输注前解冻KYMRIAH [见剂量和用法]。 完整说明资料附件： https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad3ba54-dfd3-4cb3-9e2b-c5ef89559189 KYMRIAH(tisagenlecleucel) suspension for intravenous infusion KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Important Safety Information for KYMRIAH® (tisagenlecleucel) WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGICAL TOXICITIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab, or tocilizumab and corticosteroids Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS Warnings and Precautions Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 54 (79%) of the 68 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 33 (49%) of patients. The median time to onset of CRS in KYMRIAH trials was 3 days (range: 1-51), and in only 2 patients was onset after Day 10. The median time to resolution was 8 days (range: 1-36). Of the 54 patients with r/r ALL who had CRS, 27 (50%) received tocilizumab; 7 (13%) patients received 2 doses of tocilizumab, 3 (6%) patients received 3 doses of tocilizumab and 14 (26%) patients received addition of corticosteroids (eg, methylprednisolone). Five deaths occurred within 30 days of KYMRIAH infusion. One patient with r/r ALL died with CRS and progressive leukemia, 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (96%), hypotension (67%), hypoxia (20%), and tachycardia (30%). CRS may be associated with hepatic, renal, and cardiac dysfunction, and coagulopathy. Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden. Ensure that 2 doses of tocilizumab are available on-site prior to KYMRIAH infusion. Monitor patients for signs or symptoms of CRS 2 to 3 times during the first week, then for at least 4 weeks after treatment. Counsel patients to remain within proximity of the health care facility for at least 4 weeks following infusion and seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, immediately evaluate the patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated. Risk factors for severe CRS are high pre-infusion tumor burden (≥50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes. Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 49 (72%) of the 68 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 21% of patients. Among patients who had a neurological toxicity, 88% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days (range: 1-359) from infusion, and the median duration was 6 days for patients with r/r ALL. The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The most common neurological toxicities observed in r/r ALL studies included headache (37%), encephalopathy (34%), delirium (21%), anxiety (13%), sleep disorders (10%), dizziness (6%), tremor (9%), and peripheral neuropathy (4%). Other manifestations included seizures, mutism and aphasia. Monitor patients for neurological events, specifically 2 to 3 times during the first week following KYMRIAH infusion, and exclude other causes for neurological symptoms. Provide supportive care as needed for KYMRIAH-associated neurological events. KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742). Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH. Serious Infections: Infections, including life-threatening or fatal infections, occurred in 95 (55%) of 174 patients after infusion with KYMRIAH in clinical trials. Fifty-eight (33%) patients experienced grade ≥3 infections, including fatal infections in 2 (3%) patients with r/r ALL after KYMRIAH infusion. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately. Febrile neutropenia (≥ grade 3) was also observed in 37% of patients with r/r ALL after KYMRIAH infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before cell collection for manufacturing. Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. In patients with r/r ALL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had ≥ grade 3 neutropenia or thrombocytopenia, respectively. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved. Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia (IgG) can occur in patients with a complete remission after KYMRIAH infusion. Hypogammaglobulinemia was reported in 43% of patients with r/r ALL. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines. The safety of immunization with live viral vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH. Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH. Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. Monitor lifelong for secondary malignancies. If a second malignancy occurs, call 1-844-4KYMRIAH (1-844-459-6742) to obtain instructions on patient samples to collect for testing. Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, including altered mental status or seizures, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. Drug Interactions HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false positive results in patients who have received KYMRIAH. Pregnancy, Lactation, Females and Males of Reproductive Potential No data are available of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. Adverse Reactions The most common adverse reactions (≥20%) in patients with r/r ALL were cytokine release syndrome, hypogammaglobulinemia, infections-pathogen unspecified, pyrexia, decreased appetite, headache, encephalopathy, hypotension, bleeding episodes, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, fatigue, acute kidney injury, edema, cough, and delirium.