Monitoring disease progression in follicular lymphoma with next-gen sequencing

描述(由申请人提供)：滤泡性淋巴瘤是第二常见的非霍奇金淋巴瘤，在美国每年约有14,000名患者确诊。使用靶向单抗的滤泡性淋巴瘤的创新治疗方法改善了患者的预后，但这些治疗方法很昂贵。在某种程度上，这些疗法可以针对疾病进展的患者，这将使治疗的成本效益最大化。对于接受治疗以诱导缓解的患者来说，及早发现疾病进展尤其重要，因为当肿瘤负担较低时，额外的几轮治疗具有最大的影响。不幸的是，监测低水平疾病的诊断方法没有像滤泡性淋巴瘤的治疗那样取得显著进展，因此需要开发广泛适用于滤泡性淋巴瘤患者的诊断工具，并且在检测残留疾病方面具有高度的敏感性。我们已经开发了从大量B细胞中对免疫球蛋白基因的体细胞重排互补决定区3(CDR3)片段进行测序的方法。这些CDR3序列可以作为B细胞克隆性群体的生物标志物，例如淋巴瘤肿瘤。在目标1和2中，我们建议应用这项技术来测量滤泡性淋巴瘤患者接受化疗的骨髓样本中的残留肿瘤负荷，并评估这些数据对无进展生存的预测价值。我们的方法比正电子发射计算机断层扫描更敏感，而且应该适用于目前可以通过聚合酶链式反应监测IgH/BCL2易位的一半以上的患者。如果我们的诊断方法可以在分析的临床试验中检测到疾病进展之前预测疾病的进展，那么使用我们的诊断方法来优化针对疾病进展风险增加的患者的单抗治疗是可能的。目的3将我们的分析扩展到来自同一患者的外周血样本，希望在比骨髓活检侵入性小得多的生物标本中检测到残留疾病。如果我们的方法可以监测血液中的疾病负担，这将有助于更频繁地监测疾病状态，从而允许对疾病进展者进行比目前可能的更早的干预。建议的诊断方法有可能显著改善滤泡性淋巴瘤的治疗结果，将治疗干预集中在复发风险最高的患者上，同时通过比目前可能的更早发现复发来提高治疗效果。

DESCRIPTION (provided by applicant): Follicular Lymphoma is the second most common Non-Hodgkin Lymphoma, with roughly 14,000 patients diagnosed annually in the US. Innovative treatments for follicular lymphoma using targeted monoclonal antibodies have improved the prognosis for patients, but these treatments are expensive. To the extent that these therapies can be targeted to patients in whom the disease is progressing, it will maximize the cost- effectiveness of the therapy. Early detection of disease progression is especially important in patients who have undergone therapy to induce remission, as additional rounds of therapy have the greatest impact when tumor burden is low. Unfortunately, diagnostic methods to monitor low level disease have not progressed as dramatically as treatments for follicular lymphoma, so there is a need to develop diagnostic tools that are broadly applicable to follicular lymphoma patients, and highly sensitive in detecting residual disease. We have developed methods for sequencing the somatically rearranged complementarity determining region 3 (CDR3) segments of immunoglobulin genes from large populations of B-cells. These CDR3 sequences can be used as biomarkers for clonal populations of B-cells, such as lymphoma tumors. In Aim 1 and 2, we propose to apply this technology to measure residual tumor burden in bone marrow specimens from follicular lymphoma patients undergoing chemotherapy for follicular lymphoma, and to assess the predictive value of these data for progression free survival. Our methods are more sensitive than PET scans, and should be applicable to significantly more than the half of patients who can currently be monitored by PCR of the IGH/BCL2 translocation. If our diagnostic methods can predict disease progression before it was detected in the clinical trials analyzed, then it might be possible to use our diagnostic to optimize monoclonal antibody therapies for patients who are at increased risk of disease progression. Aim 3 extends our analysis to peripheral blood samples drawn from the same patients, in the hope that residual disease might be detected in biospecimens that are much less invasive than bone marrow biopsies. If our methods can monitor disease burden in blood, this would facilitate much more frequent monitoring of disease state, and thereby allow for significantly earlier intervention in disease progressors than is currently possible. The proposed diagnostic methods have the potential to significantly improve therapeutic outcomes for follicular lymphoma, by focusing therapeutic intervention on patients at greatest risk of relapse, while increasing the effectivenes of treatment by detecting relapse earlier than is presently possible.