Hodgkin Lymphoma in PLWH in South Africa: TB, EBV, and Tumor Molecular Markers

南非 PLWH 霍奇金淋巴瘤：TB、EBV 和肿瘤分子标记

• 批准号: 10613422
• 负责人: RICHARD Frederick AMBINDER
• 金额: $ 84.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613422
• 关键词: AIDS-Related Lymphoma; Address; Algorithms; Autopsy; Biological Assay; Biopsy; Cause of Death; Cessation of life; Characteristics; Chemotherapy-Oncologic Procedure; Chromosomes; Classification; Clinical; Clinical Trials; Consent; Control Groups; Country; Coupled; DNA; Deterioration; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disparity; Enlargement of lymph nodes; Enrollment; Ensure; Epstein Barr Virus associated tumor; Epstein-Barr Virus-Related Lymphoma; Evaluation; Excision biopsy; Fine needle aspiration biopsy; General Population; HIV; HIV Infections; Histologic; Hodgkin Disease; Hospitals; Human Herpesvirus 4; Immunoglobulins; Inferior; Infrastructure; Knowledge; Laboratories; Lymphoma; Malignant Neoplasms; Measures; Methylation; Modernization; Molecular; Mutation; Newly Diagnosed; Observational Study; Odds Ratio; Operative Surgical Procedures; Organ; Outcome; Participant; Pathologic; Patient Triage; Patients; Pattern; Performance; Performance Status; Persons; Plasma; Population Study; Predictive Value; Prognosis; Progression-Free Survivals; Reporting; Resources; Risk Factors; Role; Somatic Mutation; South Africa; South African; Specificity; Specimen; Symptoms; Techniques; Testing; Time; Tuberculosis; Tumor Markers; Validation; antiretroviral therapy; cancer care; chemotherapy; co-infection; cohort; cost; diagnostic algorithm; diagnostic strategy; experience; follow-up; high risk; improved; infection rate; information gathering; minimally invasive; molecular diagnostics; molecular marker; mortality; novel diagnostics; outcome disparities; programs; prospective; response; standard of care; treatment response; tuberculosis diagnostics; tuberculosis treatment; tumor; tumor progression

PROJECT SUMMARY Hodgkin lymphoma (HL) outcomes in PLWH in South Africa (S.A.) are inferior to those in HIV(-) patients, although outcomes compare favorably in clinical trials. Advanced stage disease and consistent EBV-association are well recognized in PLWH. In S.A., at the time of diagnosis, some PLWH are in such poor clinical condition that they are not treated. Diagnostic delays contribute to late presentations, as HL diagnoses require surgical biopsies for a definitive pathologic evaluation. Resources and infrastructure in S.A. are limited in this regard. To better understand disparate outcomes in PLWH in standard-of-care settings, we propose a prospective observational study of HIV(+) and HIV(-) HL in S.A. (Aim 1). Performance status (PS), organ function, clinical stage, tumor histological subtype, EBV association, and mutational landscape will all be assessed, as will chemotherapy regimen, response to treatment, and cause of death, as determined by a minimally invasive autopsy in consenting participants. Since tuberculosis (TB) is the leading cause of death in PLWH in S.A., the symptoms of which mimic HL, HL patients are often empirically treated and repeatedly tested for TB before excisional biopsies are pursued. A high co-infection rate coupled with immunosuppressive chemotherapy may lead to TB progression in PLWH during therapy, and may contribute to ultimate mortality. Therefore, Aim 1 will also have a major focus on the contributions of TB. The results of this study will lead to a better understanding of the roles that PS, organ function and TB have in HL prognosis in PLWH, as well as aspects of the EBV association and the mutational features. The near uniform association of EBV in HIV(+) HL may aid in the recognition of HL in PLWH via a non-invasive plasma EBV test that can identify patients needing urgent excisional biopsy. To explore this possibility, we propose to develop a diagnostic algorithm (Aim 2A) in a discovery cohort of PLWH with HL and without malignancy. EBV DNA will be assessed along with additional plasma markers to increase specificity. The optimal combination of markers will be used to develop an algorithm that will be tested in a validation cohort of high risk PLWH (Aim 2B). Baseline PS and organ function will be obtained, and a rigorous yearlong follow-up will ensure accurate classification of persons with lymphoma. In those who are diagnosed with HL or other lymphoma, PS and organ function will be re-assessed. Participants who experience a marked decline in these measures, to the point that they do not receive standard chemotherapy, will be considered potential “lives saved” if the diagnostic algorithm could be applied clinically. We note that much of the infrastructure needed to implement the molecular techniques is available in S.A., and that our South African collaborators have a track record of introducing sophisticated molecular diagnostics for TB to the entire country. 1

项目概要 南非 (S.A.) PLWH 中霍奇金淋巴瘤 (HL) 的预后低于 HIV(-) 患者的预后， 尽管在临床试验中结果比较有利，并且与 EBV 相关性一致。 在南澳，一些 PLWH 在诊断时临床状况很差。 诊断延迟会导致晚期就诊，因为 HL 诊断需要手术。 用于明确病理学评估的活检在这方面南澳的资源和基础设施有限。 为了更好地了解 PLWH 在标准护理环境中的不同结果，我们提出了一项前瞻性研究 S.A. 中 HIV(+) 和 HIV(-) HL 的观察性研究（目标 1）、体能状态 (PS)、器官功能、临床。 分期、肿瘤组织学亚型、EBV 关联和突变情况都将被评估， 化疗方案、治疗反应和死亡原因，由微创方法确定 由于结核病 (TB) 是南澳州 PLWH 死亡的主要原因，因此 其症状与 HL 相似，HL 患者通常会在之前接受经验性治疗并反复进行结核病检测 可能会进行切除活检，同时进行免疫抑制化疗。 导致 PLWH 在治疗期间结核病进展，并可能导致最终死亡率，因此，目标 1 将导致。 也主要关注结核病的贡献。这项研究的结果将有助于更好地理解。 PS、器官功能和 TB 在 PLWH HL 预后中的作用，以及 EBV 的各个方面 关联和突变特征。 HIV(+) HL 中 EBV 几乎一致的关联可能有助于通过非侵入性方法识别 PLWH 中的 HL 血浆 EBV 检测可以识别需要紧急切除活检的患者。为了探索这种可能性，我们进行了研究。 建议在患有 HL 和不患有 HL 的 PLWH 发现队列中开发一种诊断算法（目标 2A） EBV DNA 将与其他血浆标记物一起进行评估，以提高最佳特异性。 标记组合将用于开发一种算法，该算法将在高风险验证队列中进行测试 将获得 PLWH（目标 2B）基线 PS 和器官功能，并确保严格的一年随访。 淋巴瘤患者的准确分类 对于被诊断患有 HL 或其他淋巴瘤的患者，PS。 和器官功能将重新评估在这些措施中出现明显下降的参与者。 指出他们没有接受标准化疗，如果诊断结果正确，将被视为潜在的“挽救生命” 我们注意到，实现该分子所需的大部分基础设施都可以应用于临床。 技术在南非可用，并且我们的南非合作者有引进的记录 为全国提供先进的结核病分子诊断服务。 1