Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study,The Lancet Oncology

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Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study
The Lancet Oncology ( IF 41.6 ) Pub Date : 2022-07-12 , DOI: 10.1016/s1470-2045(22)00339-4
Alison Sehgal ₁ , Daanish Hoda ₂ , Peter A Riedell ₃ , Nilanjan Ghosh ₄ , Mehdi Hamadani ₅ , Gerhard C Hildebrandt ₆ , John E Godwin ₇ , Patrick M Reagan ₈ , Nina Wagner-Johnston ₉ , James Essell ₁₀ , Rajneesh Nath ₁₁ , Scott R Solomon ₁₂ , Rebecca Champion ₁₃ , Edward Licitra ₁₄ , Suzanne Fanning ₁₅ , Neel Gupta ₁₆ , Ronald Dubowy ₁₇ , Aleco D'Andrea ₁₈ , Lei Wang ₁₇ , Ken Ogasawara ₁₉ , Jerill Thorpe ₁₇ , Leo I Gordon ₂₀

Affiliation

University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, USA.
Intermountain Healthcare, LDS Hospital, Salt Lake City, UT, USA.
Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.
BMT and Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI, USA.
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
Providence Cancer Center, Earle A Chiles Research Institute, Portland, OR, USA.
University of Rochester Medical Center, Rochester, NY, USA.
Department of Oncology, Johns Hopkins Hospital, Baltimore, MD, USA.
Oncology Hematology Care, Cincinnati, OH, USA.
Department of Stem Cell Transplant and Cellular Therapy, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.
Transplant and Cellular Immunotherapy Program, Northside Hospital Cancer Institute, Atlanta, GA, USA.
Hematologic Malignancies Program, Norton Cancer Institute, Louisville, KY, USA.
Astera Cancer Care, East Brunswick, NJ, USA.
Prisma Health, Greenville, SC, USA.
Stanford Cancer Genetics Clinic, Palo Alto, CA, USA.
Bristol Myers Squibb, Seattle, WA, USA.
Celgene, a Bristol-Myers Squibb company, Boudry, Switzerland.
Bristol Myers Squibb, Lawrence Township, NJ, USA.
Northwestern University, Feinberg School of Medicine, Robert H Lurie Comprehensive Cancer Center, Chicago, IL, USA.

Background

Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.

Methods

PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/m² and intravenous cyclophosphamide 300 mg/m² daily for 3 days) followed 2–7 days later by two sequential lisocabtagene maraleucel infusions (equal target doses of CD8⁺ and CD4⁺ CAR⁺ T cells for a total target dose of 100 × 10⁶ CAR⁺ T cells). The primary endpoint was the overall response rate and was assessed in all patients who received lisocabtagene maraleucel and had confirmed PET-positive disease before lisocabtagene maraleucel administration based on an independent review committee according to the Lugano 2014 criteria. Safety was assessed in all patients who received lisocabtagene maraleucel. Patient follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT03483103.

Findings

Between July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70–78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1–18·0). 49 (80% [95% CI 68–89]; p<0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.

Interpretation

These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.

Funding

Juno Therapeutics, a Bristol-Myers Squibb company.

中文翻译：

Lisocabtagene maraleucel 作为成人复发或难治性大 B 细胞淋巴瘤患者的二线治疗，这些患者不适合造血干细胞移植 (PILOT)：一项开放标签的 2 期研究

背景

一线治疗后复发或难治性大 B 细胞淋巴瘤不打算进行造血干细胞移植 (HSCT) 的患者预后不良且治疗选择有限。我们评估了 Lisocabtagene maraleucel 的抗肿瘤活性和安全性，这是一种自体 CD19 定向嵌合抗原受体 (CAR) T 细胞产品，作为成人复发或难治性大 B 细胞淋巴瘤的二线治疗，不适合 HSCT。

方法

PILOT 是一项在美国 18 个临床中心进行的开放标签 2 期试验，包括 18 岁或以上患有复发性或难治性大 B 细胞淋巴瘤和 PET 阳性疾病的成年人，他们接受了含有蒽环类药物和 CD20 靶向药物，他们的医生不打算用于 HSCT，并且至少符合一项预先指定的非预期移植标准。患者接受淋巴耗竭化疗（静脉内氟达拉滨 30 mg/m ²和静脉内环磷酰胺 300 mg/m ²每天 3 天），然后在 2-7 天后连续输注两次利索卡布他根 maraleucel（CD8 ⁺和 CD4 ⁺ CAR ⁺ T的目标剂量相等总目标剂量为 100 × 10的细胞^{6 个}CAR ⁺ T 细胞）。主要终点是总反应率，并根据独立审查委员会根据卢加诺 2014 年标准对所有接受 Lisocabtagene maraleucel 并在 Lisocabtagene maraleucel 给药前确认 PET 阳性疾病的患者进行评估。对所有接受 Lisocabtagene maraleucel 的患者进行了安全性评估。患者随访正在进行中。该研究已在 ClinicalTrials.gov 注册，NCT03483103。

发现

2018 年 7 月 26 日至 2021 年 9 月 24 日（主要分析数据截止），74 名患者接受了白细胞分离术，61 名患者接受了 Lisocabtagene maraleucel（疗效和安全组）；中位年龄为 74 岁（IQR 70-78），24 名（39%）患者为女性，37 名（61%）男性，54 名（89%）患者为白人。61 名患者中有 16 名 (26%) 的东部肿瘤协作组表现状态为 2，33 名 (54%) 患有难治性疾病，13 名 (21%) 在一线治疗 1 年内复发，15 名 (25%) 复发经过12个月的一线治疗。中位研究随访时间为 12·3 个月（IQR 6·1-18·0）。49 (80% [95% CI 68–89]; p<0·0001) 患者有总体反应。最常见的 3 级或更严重的治疗引起的不良事件是中性粒细胞减少症（29 [48%] 患者）、白细胞减少症（13 [21%]）和血小板减少症（12 [20%]）。13 名 (21%) 患者报告了与 Lisocabtagene maraleucel 相关的严重治疗出现的不良事件。没有与治疗相关的死亡。23 名（38%；1 名 3 级）患者发生细胞因子释放综合征，19 名（31%；3 名 3 级）患者发生神经系统事件，无 4 级事件或死亡。