NEJM：全球首個獲批CAR-T療法可長期緩解難治性B細胞ALL

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Tisagenlecleucel使複發性或難治性B細胞ALL獲得長期緩解

Kymriah（Tisagenlecleucel）是一種抗cd19嵌合抗原受體T細胞（CAR-T），選擇性殺滅表面表達CD19的腫瘤細胞。

一期研究結果顯示，60名患複發或難治性的B細胞ALL的兒童及青年人，使用Kymriah治療，獲得了93%的完全緩解率，CAR-T治療的過程中細胞因子釋放綜合征（CRS）及其嚴重神經系統副作用仍不能忽視，此前JACR015和KTE-C19的CAR-T臨床研究均出現腦水腫死亡案例，但長達四年的觀察中也注意到CAR-T持久控制疾病的良好作用。

為了評估CAR-T採樣、運送、集中製備、分發回輸的現實可能性和細胞穩定性，本項2期臨床試驗進一步檢驗了全球供應鏈保障體系提供的CAR-T的療效和安全性。

納入75例患者，其中46例患者曾行同種異體幹細胞移植。「清淋」後予以單次Kymriah輸注，3個月內的總緩解率是81%，6個月和12個月無複發生存率分別為80%和59%，總生存率分別為90%和76%。最常見治療相關副作用為CRS，有37%患者接受託昔珠單抗治療。神經系統不良事件發生率40%，但未出現4級事件或腦水腫。Kymriah血中中位存在時間168天。

Kymriah是全球首個獲批的CAR-T療法，通過全球供應鏈保障體系提供的CAR-T單次輸注可使複發性或難治性青少年B細胞ALL獲得長期緩解。（編譯：北京佑安醫院 高原）

原文鏈接:

http://www.nejm.org/doi/full/10.1056/NEJMoa1709866

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導管消融治療改善心衰合併房顫患者預後

心衰患者常合併心房顫動，其死亡率和發病率高於單純心衰。房顫增加了卒中、心衰加重與死亡的風險，針對房顫的治療可以改善心衰患者的預後，如抗心律失常藥物、導管消融等治療方法。但導管消融作為一種改善預後的手段，其效果尚缺乏大型臨床試驗的有力支持。

一項多中心隨機對照試驗納入363名慢性心衰患者（NYHA II-IV級，左心室射血分數≤35%），給予植入除顫器（ICD或CRT-D）。這些患者合併陣發性或持續性房顫，抗心律失常藥物療效不佳，或有不可接受的副作用，或患者拒服。患者隨機接受導管消融或藥物治療，主要研究終點包括死亡或心衰惡化住院。

中位隨訪37.8月發現：與藥物治療相比，導管消融將主要終點事件發生風險降低了38%（28.5%vs44.6%，P=0.007）；死亡風險降低了47%（13.4%vs25.0%，P=0.01）；心衰惡化住院風險降低了44%（20.7%vs35.9%，P=0.004）；心血管死亡風險降低了51%（11.2%vs22.3%，P=0.009）。

本研究為心衰合併房顫患者的導管消融治療提供了有力支持。（編譯：北京301醫院 韓英傑）

原文鏈接:

http://www.nejm.org/doi/full/10.1056/NEJMoa1707855

原文摘要

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Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Shannon L. Maude, M.D., Ph.D., Theodore W. Laetsch, M.D.,Jochen Buechner, M.D., Ph.D., Susana Rives, M.D., Ph.D., et al.

BackgroundIn a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

MethodsWe conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.

ResultsFor this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.

ConclusionsIn this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects.

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Catheter Ablation for Atrial Fibrillation with Heart Failure

Nassir F. Marrouche, M.D., Johannes Brachmann, M.D., Dietrich Andresen, M.D., Jürgen Siebels, M.D., Lucas Boersma, M.D., et al.

BackgroundMortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment.

MethodsWe randomly assigned patients with symptomatic paroxysmal or persistent atrial fibrillation who did not have a response to antiarrhythmic drugs, had unacceptable side effects, or were unwilling to take these drugs to undergo either catheter ablation (179 patients) or medical therapy (rate or rhythm control) (184 patients) for atrial fibrillation in addition to guidelines-based therapy for heart failure. All the patients had New York Heart Association class II, III, or IV heart failure, a left ventricular ejection fraction of 35% or less, and an implanted defibrillator. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure.

ResultsAfter a median follow-up of 37.8 months, the primary composite end point occurred in significantly fewer patients in the ablation group than in the medical-therapy group (51 patients [28.5%] vs. 82 patients [44.6%]; hazard ratio, 0.62; 95% confidence interval [CI], 0.43 to 0.87; P=0.007). Significantly fewer patients in the ablation group died from any cause (24 [13.4%] vs. 46 [25.0%]; hazard ratio, 0.53; 95% CI, 0.32 to 0.86; P=0.01), were hospitalized for worsening heart failure (37 [20.7%] vs. 66 [35.9%]; hazard ratio, 0.56; 95% CI, 0.37 to 0.83; P=0.004), or died from cardiovascular causes (20 [11.2%] vs. 41 [22.3%]; hazard ratio, 0.49; 95% CI, 0.29 to 0.84; P=0.009).

ConclusionsCatheter ablation for atrial fibrillation in patients with heart failure was associated with a significantly lower rate of a composite end point of death from any cause or hospitalization for worsening heart failure than was medical therapy.

GIF

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