Kalakonda Nagesh, Maerevoet Marie, Cavallo Federica, Follows George, Goy Andre, Vermaat Joost S P, Casasnovas Olivier, Hamad Nada, Zijlstra Josée M, Bakhshi Sameer, Bouabdallah Reda, Choquet Sylvain, Gurion Ronit, Hill Brian, Jaeger Ulrich, Sancho Juan Manuel, Schuster Michael, Thieblemont Catherine, De la Cruz Fátima, Egyed Miklos, Mishra Sourav, Offner Fritz, Vassilakopoulos Theodoros P, Warzocha Krzysztof, McCarthy Daniel, Ma Xiwen, Corona Kelly, Saint-Martin Jean-Richard, Chang Hua, Landesman Yosef, Joshi Anita, Wang Hongwei, Shah Jatin, Shacham Sharon, Kauffman Michael, Van Den Neste Eric, Canales Miguel A
University of Liverpool, Liverpool, UK.
Institut Jules Bordet, Brussels, Belgium.
Lancet Haematol. 2020 Jul;7(7):e511-e522. doi: 10.1016/S2352-3026(20)30120-4.
Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit.
SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling).
Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor.
Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting.
Karyopharm Therapeutics Inc.
复发或难治性弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性癌症，中位总生存期不到6个月。我们旨在评估口服核输出选择性抑制剂塞利尼索单药治疗对没有潜在临床获益治疗选择的复发或难治性DLBCL患者的疗效。
SADAL是一项在19个国家59个地点开展的多中心、跨国、开放标签的2b期研究。纳入年龄在18岁及以上、经病理确诊为弥漫性大B细胞淋巴瘤、东部肿瘤协作组体能状态评分为2分或更低、既往接受过2至5线治疗且在自体干细胞移植后病情进展或不适合进行自体干细胞移植的患者。通过免疫组化确定生发中心B细胞或非生发中心B细胞肿瘤亚型以及双表达或三表达状态，通过细胞遗传学确定双打击或三打击状态。患者在每周第1天和第3天口服60mg塞利尼索，直至疾病进展或出现不可接受的毒性。该研究最初设计用于评估每周两次60mg和100mg剂量的塞利尼索；然而，2017年3月29日方案（第7.0版）中停用了100mg剂量，当时观察到60mg剂量具有更好的治疗窗口。主要结局为总缓解率。在按照方案第6.0版接受60mg塞利尼索治疗，或按照方案第7.0版或更高版本入组并接受至少一剂塞利尼索治疗的所有患者中评估主要结局和安全性。该试验已在ClinicalTrials.gov注册，编号为NCT02227251（处于活动状态但未招募）。
2015年10月21日至2019年11月2日期间，267例患者被随机分组，175例分配至60mg组，92例分配至停用的100mg组。60mg组中有48例患者因在方案第6.0版之前入组而被排除；其余127例患者接受了60mg塞利尼索治疗，并纳入主要结局和安全性分析。总缓解率为28%（36/127；95%CI 20.7 - 37.0）；15例（12%）达到完全缓解，21例（17%）达到部分缓解。最常见的3 - 4级不良事件为血小板减少（n = 58）、中性粒细胞减少（n = 31）、贫血（n = 28）、疲劳（n = 14）、低钠血症（n = 10）和恶心（n = 8）。最常见的严重不良事件为发热（n = 9）、肺炎（n = 6）和脓毒症（n = 6）。没有判定与塞利尼索治疗相关的死亡病例。
口服塞利尼索单药治疗在接受过至少两线既往化疗免疫治疗的复发或难治性DLBCL患者中诱导出持久缓解，且不良事件可控。在这种情况下，塞利尼索可被视为一种新的口服非细胞毒性治疗选择。
Karyopharm Therapeutics公司
