Circulating biomarkers of ALK+ anaplastic large cell lymphoma

项目摘要 间变性淋巴瘤激酶(ALK)是由位于5q35的ALK基因编码的一种受体酪氨酸激酶。 结构改变，包括易位、拷贝数增加和针对ALK的激活突变 发生在许多类型的人类癌症中，包括肺癌、非霍奇金淋巴瘤、Spitzoid 黑素细胞病变、神经母细胞瘤和炎性肌纤维母细胞瘤。超过80%的儿科医生 间变性大细胞淋巴瘤(ALCL)是该人群中最常见的成熟T细胞淋巴瘤， 染色体突变t(2；5)(p23；q35)导致结构性活性酪氨酸的表达 激酶NPM-ALK。NPM-ALK阳性淋巴瘤已成为理解ALK介导的模型 肿瘤的发生和靶向治疗的发展，因此NPM-ALK的相关研究具有深远的意义 对一般癌症领域的影响。不幸的是，即使目前的密集程度加在一起 化疗，大约30%的患者在两年内经历疾病进展或复发 多年的治疗。然而，导致ALCL复发的临床或遗传因素尚不清楚。 此外，可以使用非侵入性方法容易获得的预后生物标志物还没有被 明确定义为ALCL中接受靶向治疗的患者。我们的中心假设是敏感和 应用数字液滴(Dd)聚合酶链式反应(Dd)技术检测慢性粒细胞白血病患者循环NPM-ALK转录本的特异性 与血浆ALK自身抗体水平相结合，将作为独特的疾病特异性生物标志物 将提供一个评估治疗反应的机会，并导致预后生物标志物 可能识别出复发风险较高的患者。使用统一治疗的患者的血浆样本 参加儿童肿瘤学小组(COG)关于布妥昔单抗、维多丁和克里佐替尼的第二阶段研究， 新诊断的ALCL，我们通过以下具体目标解决我们的假设：1)确定 DdPCR在ALK+ALCL最小疾病检测和疾病监测中的应用，2)确定 抗ALK免疫反应在ALK+AlCl3中的预后价值 联合ddPCR与ALK+ALCL患者免疫应答的多因素模型。这个 制定对最小播散性疾病和/或最小残留的敏感和精确评估 疾病将在ALK+ALCL患者的管理中发挥重要作用，并有助于决策 停止治疗并确定有复发/进展风险的患者。

Project Summary Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the ALK gene located on 5q35. Structural alterations including translocations, copy number gains and activating mutations targeting ALK occur in many types of human cancer, including lung cancer, non- Hodgkin lymphomas, Spitzoid melanocytic lesions, neuroblastoma and inflammatory myofibroblastic tumor. In over 80% of pediatric anaplastic large cell lymphoma (ALCL), the most common form of mature T cell lymphoma in this population, the chromosomal aberration t(2;5)(p23;q35) results in the expression of the constitutively active tyrosine kinase NPM-ALK. NPM-ALK positive lymphoma has served as a model for understanding ALK-mediated oncogenesis and development of targeted therapies, thus NPM-ALK related studies carry profound implications for the cancer field in general. Unfortunately, even with current intensive combined chemotherapy, approximately 30% of patients experiences disease progression or recurrence within two years of treatment. However, clinical or genetic factors that cause ALCL relapse are not known. Furthermore, prognostic biomarkers that can be easily obtained using non-invasive methods have not been clearly defined in patients receiving targeted therapies in ALCL. Our central hypothesis is that sensitive and specific quantitative assessment of circulating NPM-ALK transcript using digital droplet (dd)PCR in conjunction with plasma levels of ALK auto- antibody will serve as unique disease-specific biomarkers that will provide an opportunity for assessment of response to therapy and lead to prognostic biomarkers that may identify patients with high risk for relapse. Using plasma samples from uniformly treated patients enrolled in a Children's Oncology Group (COG) Phase II study of Brentuximab Vedotin and Crizotinib with newly diagnosed ALCL, we address our hypothesis through the following specific aims: 1) Determine the utility of ddPCR for minimal disease detection and disease monitoring in ALK+ ALCL, 2) Determine the prognostic utility of anti-ALK immune response in ALK+ ALCL 3) Investigate the prognostic significance of a multivariate model combining ddPCR and immune response to ALK in patients with ALK+ ALCL. The development of sensitive and precise assessment of minimal disseminated disease and/or minimal residual disease will play an important role in management of patients with ALK+ ALCL and facilitate decisions about discontinuation of treatment and identifying patients at risk of relapse/progression.