Circulating biomarkers of ALK+ anaplastic large cell lymphoma

项目摘要 间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶，由位于5 q35的ALK基因编码。 结构改变，包括易位、拷贝数增加和靶向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、斯皮策样瘤、 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%的儿童 间变性大细胞淋巴瘤（ALCL）是该人群中最常见的成熟T细胞淋巴瘤形式， 染色体畸变t（2;5）（p23;q35）导致组成型活性酪氨酸的表达 激酶NPM-ALK。NPM-ALK阳性淋巴瘤已作为理解ALK介导的 肿瘤发生和靶向治疗的发展，因此NPM-ALK相关研究具有深远的意义 对癌症领域的影响。不幸的是，即使目前的密集结合 化疗后，大约30%的患者在两周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，使用非侵入性方法可以容易地获得的预后生物标志物尚未被发现。 在接受靶向治疗的ALCL患者中明确定义。我们的核心假设是， 使用数字液滴（dd）PCR对循环NPM-ALK转录物进行特异性定量评估， 与ALK自身抗体的血浆水平结合将作为独特的疾病特异性生物标志物， 将提供评估对治疗的反应的机会，并产生预后生物标志物， 可以识别复发风险高的患者。使用来自统一治疗患者的血浆样本 入组一项维布妥昔单抗和克唑替尼的儿童肿瘤组（COG）II期研究， 对于新诊断的ALCL，我们通过以下具体目标来解决我们的假设：1）确定 ddPCR在ALK+ ALCL中用于微小疾病检测和疾病监测的效用，2）确定 抗ALK免疫应答在ALK+ ALCL中的预后效用3）研究 ALK+ ALCL患者中联合ddPCR和对ALK的免疫应答的多变量模型。的 对微小播散性疾病和/或微小残留进行敏感和精确的评估 疾病将在ALK+ ALCL患者的管理中发挥重要作用， 停止治疗和识别有复发/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.