Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.
Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.
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DOI：
10.1200/jco.19.01892
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发表时间：
2020-02-10
期刊：
影响因子：
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通讯作者：
Porter DL
中科院分区：
文献类型：
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作者：
Frey NV;Shaw PA;Hexner EO;Pequignot E;Gill S;Luger SM;Mangan JK;Loren AW;Perl AE;Maude SL;Grupp SA;Shah NN;Gilmore J;Lacey SF;Melenhorst JJ;Levine BL;June CH;Porter DL
抗CD 19嵌合抗原受体T细胞疗法tisagenlecleucel（CTL 019）在复发或化疗难治性（r/r）B细胞急性淋巴细胞白血病（ALL）儿童中的应答率为81%。细胞因子释放综合征（CRS）是一种危及生命的治疗相关毒性，限制了成人的全部治疗潜力。我们报告了采用优化的CTL 019给药和CRS管理策略治疗r/r ALL成人的结局。成人r/r B细胞ALL患者在2项试验中的1项中接受了CTL 019治疗。患者接受淋巴细胞清除，然后接受CTL 019，作为一次性输注或分次输注，分3天输注（第1天，10%;第2天，30%;第3天，60%），这允许第2天和第3天的剂量因早期CRS而暂停。总计划的CTL 019剂量随着响应于疗效和CRS毒性的适应性方案修改而变化。35名患有r/r ALL的成人在3个给药队列中的1个中接受了CTL 019。低剂量组（n = 9）接受单次或分次给药，毒性可控，完全缓解（CR）率为33%。在高剂量单次输注队列中，6例难治性CRS伴培养阳性脓毒症患者中有3例死亡，3例达到CR。高剂量分次（HDF）队列中的20例患者的CR率为90%，CRS可管理。HDF队列的生存率最高，2年总生存率为73%（95% CI，46%-88%），无事件生存率为49.5%（95% CI，21%-73%）。CTL 019分次给药和患者内剂量调整优化了r/r ALL成人患者的安全性，而不影响疗效。
The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.