Monitoring disease progression in follicular lymphoma with next-gen sequencing

通过下一代测序监测滤泡性淋巴瘤的疾病进展

• 批准号: 8799864
• 负责人: Christopher S Carlson
• 金额: $ 51.39万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8799864
• 关键词: Acute Lymphocytic Leukemia; Acute leukemia; Adult; Aftercare; American; Antibody Therapy; B-Lymphocytes; BCL2 gene; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Blood; Blood specimen; Bone Marrow; Bone marrow biopsy; Cells; Clinical; Clinical Trials; DNA; DNA Sequence; Data; Detection of Minimal Residual Disease; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Disease remission; Disease-Free Survival; Early Diagnosis; Early Intervention; Early treatment; Elderly; Enrollment; Flow Cytometry; Follicular Lymphoma; Formalin; Frequencies; Guidelines; Health; IGH@ gene cluster; IGL@ gene cluster; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Indolent; Libraries; Light; Lymphoma; Malignant Neoplasms; Malignant lymphoid neoplasm; Marrow; Measurement; Measures; Methods; Monitor; Monoclonal Antibodies; Monoclonal Antibody Therapy; Nested PCR; Non-Hodgkin' s Lymphoma; Outcome; Paraffin Embedding; Patients; Phase II Clinical Trials; Population; Positron-Emission Tomography; Pre-B Acute Lymphoblastic Leukemia; Predictive Value; Progression-Free Survivals; Recurrent disease; Relapse; Residual Neoplasm; Residual Tumors; Risk; Sampling; Southwest Oncology Group; Specimen; Staging; Symptoms; System; T-Cell Receptor; Technology; Testing; Therapeutic; Therapeutic Intervention; Treatment Cost; Tumor Burden; Visit; burden of illness; chemotherapy; complementarity-determining region 3; cost effectiveness; experience; follow-up; high risk; improved; innovation; lymphoid neoplasm; next generation sequencing; novel; novel diagnostics; outcome forecast; peripheral blood; prognostic; prognostic value; public health relevance; research study; screening; tool; tositumomab; tumor

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.

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例患者被诊断。使用靶向单克隆抗体的滤泡性淋巴瘤的创新治疗方法改善了患者的预后，但这些治疗方法价格昂贵。在某种程度上，这些疗法可以靶向疾病正在进展的患者，这将使疗法的成本效益最大化。疾病进展的早期检测对于已经接受治疗以诱导缓解的患者尤其重要，因为当肿瘤负荷较低时，额外的治疗轮次具有最大的影响。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显著地进展，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高度敏感。我们已经开发了用于对来自大群体B细胞的免疫球蛋白基因的体细胞重排互补决定区3（CDR 3）区段进行测序的方法。这些CDR 3序列可用作B细胞克隆群体（如淋巴瘤肿瘤）的生物标志物。在目标1和2中，我们建议应用该技术测量接受滤泡性淋巴瘤化疗的滤泡性淋巴瘤患者骨髓标本中的残留肿瘤负荷，并评估这些数据对无进展生存期的预测价值。我们的方法比PET扫描更敏感，并且应该适用于目前可以通过PCR监测IGH/BCL 2易位的显著超过一半的患者。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进展，那么就有可能使用我们的诊断来优化疾病进展风险增加的患者的单克隆抗体治疗。目标3将我们的分析扩展到从相同患者抽取的外周血样本，希望在比骨髓活检侵入性小得多的生物标本中可以检测到残留疾病。如果我们的方法可以监测血液中的疾病负荷，这将有助于更频繁地监测疾病状态，从而允许比目前可能的更早地干预疾病进展者。所提出的诊断方法有可能显着改善滤泡性淋巴瘤的治疗结果，通过集中治疗干预复发风险最大的患者，同时通过检测复发比目前可能的更早增加治疗的有效性。