KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study,The Lancet

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KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study
The Lancet ( IF 98.4 ) Pub Date : 2021-06-04 , DOI: 10.1016/s0140-6736(21)01222-8
Bijal D Shah ₁ , Armin Ghobadi ₂ , Olalekan O Oluwole ₃ , Aaron C Logan ₄ , Nicolas Boissel ₅ , Ryan D Cassaday ₆ , Thibaut Leguay ₇ , Michael R Bishop ₈ , Max S Topp ₉ , Dimitrios Tzachanis ₁₀ , Kristen M O'Dwyer ₁₁ , Martha L Arellano ₁₂ , Yi Lin ₁₃ , Maria R Baer ₁₄ , Gary J Schiller ₁₅ , Jae H Park ₁₆ , Marion Subklewe ₁₇ , Mehrdad Abedi ₁₈ , Monique C Minnema ₁₉ , William G Wierda ₂₀ , Daniel J DeAngelo ₂₁ , Patrick Stiff ₂₂ , Deepa Jeyakumar ₂₃ , Chaoling Feng ₂₄ , Jinghui Dong ₂₄ , Tong Shen ₂₄ , Francesca Milletti ₂₄ , John M Rossi ₂₄ , Remus Vezan ₂₄ , Behzad Kharabi Masouleh ₂₄ , Roch Houot ₂₅

Affiliation

Moffitt Cancer Center, Tampa, FL, USA.
Washington University School of Medicine and Siteman Cancer Center, St Louis, MO, USA.
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
Helen Diller Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
Hôpital Saint-Louis, Paris, France.
University of Washington School of Medicine, Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance, Seattle, WA, USA.
Centre Hospitalier Universitaire de Bordeaux, Pessac, France.
The University of Chicago Medicine, Chicago, IL, USA.
Universitätsklinikum Würzburg, Würzburg, Germany.
University of California, San Diego, La Jolla, CA, USA.
Wilmot Cancer Institute of University of Rochester, Rochester, NY, USA.
Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Mayo Clinic, Rochester, MN, USA.
University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ludwig-Maximilians-Universität München, Munich, Germany.
University of California-Davis Medical Center, Sacramento, CA, USA.
University Medical Center Utrecht, Utrecht, Netherlands.
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Dana-Farber Cancer Institute, Boston, MA, USA.
Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.
University of California Irvine Medical Center, Irvine, CA, USA.
Kite, a Gilead Company, Santa Monica, CA, USA.
CHU Rennes, University of Rennes, INSERM U1236, EFS, Rennes, France.

Background

Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies.

Methods

We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0–1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10⁶ CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066.

Findings

Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28–52). At the median follow-up of 16·4 months (13·8–19·6), 39 patients (71%; 95% CI 57–82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7–not estimable), median relapse-free survival was 11·6 months (2·7–15·5), and median overall survival was 18·2 months (15·9–not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients.

Interpretation

KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients.

Funding

Kite, a Gilead Company.

中文翻译：

KTE-X19 治疗复发或难治性成人 B 细胞急性淋巴细胞白血病：单臂、开放标签、多中心 ZUMA-3 研究的 2 期结果

背景

尽管采用新疗法和同种异体干细胞移植 (allo-SCT) 巩固治疗，但复发或难治性 B 前体急性淋巴细胞白血病成年患者的预后仍然较差，这凸显了对更有效疗法的需求。

方法

我们报告了 ZUMA-3 的关键 2 期结果，这是一项国际、多中心、单臂、开放标签研究，评估自体抗 CD19 嵌合抗原受体 (CAR) T 细胞疗法 KTE-X19 在患有复发性或难治性 B 前体急性淋巴细胞白血病的成年患者。在美国、加拿大和欧洲的 25 个地点招募了患者。符合条件的患者年龄为 18 岁或以上，东部肿瘤合作组表现状态为 0-1，且骨髓形态学疾病（>5% 原始细胞）。在白细胞去除术和预处理化疗后，患者接受单次 KTE-X19 输注（每公斤体重 1 × 10 ⁶ CAR T 细胞）。主要终点是通过中央评估得出的总体完全缓解率或完全缓解但血液学恢复不完全的比率。缓解持续时间和无复发生存期、总生存期、微小残留病 (MRD) 阴性率和同种异体 SCT 率作为次要终点进行评估。在治疗人群（所有接受一定剂量 KTE-X19 的患者）中进行了疗效和安全性分析。本研究已在 ClinicalTrials.gov 注册，NCT02614066。

发现

2018年10月1日至2019年10月9日期间，共有71名患者入组并接受了白细胞分离术。 KTE-X19 已成功为 65 名 (92%) 名患者生产，并给 55 名 (77%) 名患者服用。接受治疗的患者的中位年龄为 40 岁（IQR 28-52）。中位随访时间为 16·4 个月 (13·8–19·6)，39 名患者 (71%; 95% CI 57–82, p<0·0001) 获得完全缓解或完全缓解但血液学恢复不完全，31 名 (56%) 患者达到完全缓解。中位缓解持续时间为 12·8 个月（95% CI 8·7 – 不可估计），中位无复发生存期为 11·6 个月（2·7–15·5），中位总生存期为 18·2 个月（15·9——不可估计）。在应答者中，未达到中位总生存期，并且 38 名 (97%) 患者的 MRD 呈阴性。十名 (18%) 患者在 KTE-X19 输注后接受了异基因 SCT 巩固治疗。最常见的 3 级或以上不良事件是贫血（27 [49%] 患者）和发热（20 [36%] 患者）。 14 名（25%）患者出现 3 级或以上感染。发生了两起 5 级 KTE-X19 相关事件（脑疝和感染性休克）。 13 名（24%）名患者发生 3 级或更高级别的细胞因子释放综合征，14 名（25%）名患者发生 3 级或更高级别的神经系统事件。