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: 10824451
• 负责人: RICHARD Frederick AMBINDER
• 金额: $ 10.44万
• 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/10824451
• 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

项目摘要 南非PLWH（S.A.）的霍奇金淋巴瘤（HL）结局不如HIV（ - ）患者的霍奇淋巴瘤（S.A.） 尽管结果在临床试验中有利。晚期舞台疾病和一致的EBV协会 在PLWH中得到广泛认可。在诊断时，在S.A.中，有些PLWH处于如此差的临床状态 他们没有受到治疗。诊断延迟有助于延迟演示，因为HL诊断需要手术 活检进行确定的病理评估。在这方面，S.A。中的资源和基础设施受到限制。 为了更好地了解PLWH的标准设置中的不同结果，我们提出了一个预期的 S.A.中HIV（+）和HIV（ - ）HL的观察性研究（AIM 1）。性能状态（PS），有机功能，临床 将评估阶段，肿瘤组织学亚型，EBV关联和突变景观 化学疗法方案，对治疗的反应和死亡原因，由最小侵入性确定 同意参与者的尸检。由于结核病（TB）是S.A. PLWH中死亡的主要原因，所以 其中模仿HL，HL患者的症状经常经过经验治疗，并反复测试了TB 进行了弹性活检。高的共感染率与免疫抑制化疗相结合 在治疗过程中导致PLWH的结核病进展，并可能导致最终死亡率。因此，目标1将 还关注结核病的贡献。这项研究的结果将导致更好的理解 PS，器官功能和TB在PLWH中的HL预后以及EBV方面具有的作用 关联和突变特征。 HIV（+）HL中EBV的近均匀关联可能有助于通过非侵入性在PLWH中识别HL 血浆EBV测试可以鉴定需要紧急检查活检的患者。为了探索这种可能性，我们 在发现与HL的PLWH群体中开发诊断算法（AIM 2A）的建议 恶性。 EBV DNA将与其他血浆标记一起评估以提高特异性。最佳 标记的组合将用于开发一种算法，该算法将在高风险的验证队列中进行测试 PLWH（AIM 2B）。将获得基线PS和器官功能，并进行严格的一年随访将确保 淋巴瘤患者的准确分类。在那些被诊断为HL或其他淋巴瘤的人中 器官功能将被重新评估。这些措施下降明显下降的参与者 观点表明他们没有接受标准的化疗，如果诊断性 可以在临床上应用算法。我们注意到，实施分子所需的许多基础设施 S.A.可用技术，并且我们的南非合作者有介绍的记录 TB的软化分子诊断。 1