Lancet Oncol：Crizotinib可用于治疗炎性肌纤维母细胞瘤和间变性大细胞淋巴瘤儿童患者

在数个人类肿瘤中——如间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、非小细胞肺癌和神经母细胞瘤中——会出现ALK基因的易位、扩增或癌基因突变。因此，抑制ALK能成为罹患上述病变的儿童肿瘤患者的有效治疗策略。来自美国宾夕法尼亚大学的Yael P Mossé等为了确定在儿童难治性实体瘤或间变性大细胞淋巴瘤患者中，crizotinib的治疗安全性、在2期临床研究中的推荐剂量、以及crizotinib的抗肿瘤作用而设计了相关研究，他们的研究结果发表在Lancet Oncol 4月最新的在线期刊上。

本研究为开放式标签、1期剂量递增研究，纳入研究的受试者的年龄介于12月至22岁之间，他们所罹患的是可测量或评估的实体瘤或中枢神经系统肿瘤，或间变性大细胞淋巴瘤，并且这些受试者对既往治疗反应不佳、目前对这些受试者还不存在治愈性的治疗方案，符合上述入组标准的受试者被纳入到本研究中。上述受试者每日2次接受Crizotinib治疗。Crizotinib治疗剂量分为6个等级，分别为100 mg/m²、130 mg/m²、165 mg/m²、215 mg/m²、280 mg/m²和365 mg/m²，在研究的第一部分中，研究者对不同剂量的方案进行了相应的评估，此部分研究已经完成。这部分研究的主要终点为——在罹患难治性肿瘤的儿童受试者中，估计他们所能够耐受的最大治疗剂量，以及确定crizotinib治疗所带来的毒性反应和crizotinib的药代动力学特征。此外，如果受试者证实了存在ALK易位、突变或扩增，则进入第二部分研究，如果受试者为神经母细胞瘤，则进入第三部分研究，第二部分和第三部分研究中的受试者所接受的crizotinib剂量比第一部分研究低一个水平。同时，研究者评估了肿瘤组织中ALK基因状态，并应用了定量RT-PCR评估了在间变性大细胞淋巴瘤患者中，NPM-ALK在骨髓样本和血液样本中的融合转录情况。纳入最后分析过程的受试者至少接受了一个治疗剂量的crizotinib，纳入毒性反应分析的受试者为至少完成一个疗程的治疗，或出现过剂量限制性毒性反应。本研究在ClinicalTrials.gov注册，注册号为NCT00939770。

在2009年10月2日至2012年5月31日期间，共有79名受试者被纳入研究。他们的中位年龄为10.1岁（1.1岁至21.4岁），43名受试者被纳入第一部分的剂量递增研究，25名受试者被纳入第二部分的研究，11名受试者被纳入第三部分的研究。针对2期临床研究的患者可耐受的crizotinib推荐剂量为280mg/m²，每日2次应用。在第一个疗程的治疗中，有2名受试者出现4级的中性粒细胞减少症，1名受试者出现4级的肝酶升高。在第一个疗程的治疗中，1名以上的受试者出现3级不良反应事件——2人出现淋巴细胞减少，8人出现中性粒细胞减少。在用药4小时（1-6小时）后既能达到药物的血稳态峰浓度，为630ng/mL。在79名受试者中，有14人对治疗出现应答，其中9人为完全应答，5人为部分应答。如果患者存在ALK畸变，那么可以增强药物的抗肿瘤活性。

本研究结果提示，在具有ALK易位的恶性肿瘤患者中，尤其是间变性大细胞淋巴瘤和炎性肌纤维母细胞瘤的患者中，ALK靶向抑制剂具有抗肿瘤活性，但是其对具有已知ALK癌基因突变的神经母细胞瘤患者的治疗效果还有待进一步研究证实。

与淋巴瘤相关的拓展阅读：

• JNCI：抑制肉碱乙酰基转移酶可预防Myc诱导的淋巴瘤生成
• NEJM：利妥昔单抗方案治疗纵隔B细胞淋巴瘤可避免放疗
• JCO:ABVD标准治疗方案不适用于老年霍奇金淋巴瘤
• Blood：红斑狼疮治疗药不增加淋巴瘤风险
• NEJM：霍奇金淋巴瘤患儿药物短缺不容小觑
• Mol Cell Biol：鉴别淋巴瘤突变的好坏 更多信息请点击：有关淋巴瘤更多资讯

Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study.
BACKGROUND
Various human cancers have ALK gene translocations, amplifications, or oncogenic mutations, such as anaplastic large-cell lymphoma, inflammatory myofibroblastic tumours, non-small-cell lung cancer (NSCLC), and neuroblastoma. Therefore, ALK inhibition could be a useful therapeutic strategy in children. We aimed to determine the safety, recommended phase 2 dose, and antitumour activity of crizotinib in children with refractory solid tumours and anaplastic large-cell lymphoma.
METHODS
In this open-label, phase 1 dose-escalation trial, patients older than 12 months and younger than 22 years with measurable or evaluable solid or CNS tumours, or anaplastic large-cell lymphoma, refractory to therapy and for whom there was no known curative treatment were eligible. Crizotinib was given twice daily without interruption. Six dose levels (100, 130, 165, 215, 280, 365 mg/m2 per dose) were assessed in the dose-finding phase of the study (part A1), which is now completed. The primary endpoint was to estimate the maximum tolerated dose, to define the toxic effects of crizotinib, and to characterise the pharmacokinetics of crizotinib in children with refractory cancer. Additionally, patients with confirmed ALK translocations, mutations, or amplification (part A2 of the study) or neuroblastoma (part A3) could enrol at one dose level lower than was currently given in part A1. We assessed ALK genomic status in tumour tissue and used quantitative RT-PCR to measure NPM-ALK fusion transcript in bone marrow and blood samples of patients with anaplastic large-cell lymphoma. All patients who received at least one dose of crizotinib were evaluable for response; patients completing at least one cycle of therapy or experiencing dose limiting toxicity before that were considered fully evaluable for toxicity. This study is registered with ClinicalTrials.gov, NCT00939770.
FINDINGS
79 patients were enrolled in the study from Oct 2, 2009, to May 31, 2012. The median age was 10·1 years (range 1·1-21·4); 43 patients were included in the dose escalation phase (A1), 25 patients in part A2, and 11 patients in part A3. Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumour responses were documented in 14 of 79 patients (nine complete responses, five partial responses); and the anti-tumour activity was enriched in patients with known activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with neuroblastoma, three of seven with inflammatory myofibroblastic tumour, and one of two with NSCLC).
INTERPRETATION
The findings suggest that a targeted inhibitor of ALK has antitumour activity in childhood malignancies harbouring ALK translocations, particularly anaplastic large-cell lymphoma and inflammatory myofibroblastic tumours, and that further investigation in the subset of neuroblastoma harbouring known ALK oncogenic mutations is warranted.
FUNDING
Pfizer and National Cancer Institute grant to the Children's Oncology Group.