Screening to Improve Survival in AL Amyloidosis

提高 AL 淀粉样变性患者生存率的筛查

• 批准号: 10266846
• 负责人: Raymond Luke Comenzo
• 金额: $ 26.94万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266846
• 关键词: 22q11.2; Age; Age-Years; Aspirate substance; Autologous Stem Cell Transplantation; B-Lymphocyte Gene Rearrangement; Biological Assay; Bone Marrow; California; Cells; Cessation of life; Clinical; Cohort Studies; Complementary DNA; Complex; Deposition; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early identification; Exercise; Florida; Functional disorder; Genes; Genetic Screening; Goals; Heart; Hematology; Immunoglobulin Light Chain Genes; Immunoglobulin Variable Region; Individual; Laboratories; Light; Light-Chain Immunoglobulins; Marrow; Massachusetts; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Mononuclear; Multicenter Studies; Multiple Myeloma; Neurologist; New York; North Carolina; Organ; Pathologic; Patient observation; Patient-Focused Outcomes; Patients; Pilot Projects; Plasma Cells; Population; Proteins; Public Health; Quality of life; Rare Diseases; Regimen; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Specialist; Stem cell transplant; Symptoms; Testing; Time; Universities; Work; early screening; effective therapy; heart damage; improved; improved outcome; innovation; next generation sequencing; novel; older patient; patient screening; personalized genomic medicine; pre-clinical; primary amyloidosis of light chain type; renal damage; response; screening; tool; variable region gene

Abstract In systemic light-chain (AL) amyloidosis monoclonal immunoglobulin light-chain proteins from clonal plasma cells cause fatal multiorgan disease. Patient age is a critical factor; among those diagnosed with heart involvement, older age independently predicts for earlier death. Among those who have excellent hematologic responses to initial therapy, patients older than 60 at diagnosis have a median survival of 8 years because of the burden of organ damage while those younger than 60 have 80% survival at 8 years. Patients older than 60 are often too sick at diagnosis to undergo intensive therapy such as autologous stem cell transplant. Diagnosing AL before significant and symptomatic organ dysfunction occurs is an urgent unmet need, especially in individuals older than 60. This can be accomplished by screening patients with smoldering multiple myeloma (SMM) or monoclonal gammopathy of unknown significance (MGUS), many of whom progress annually to AL with organ damage because of delays in diagnosis. Every AL patient has an Ig variable region light-chain gene (IGVL) that encodes the pathologic light-chain protein and can be identified by RT-PCR. The proposed mulitcenter study tests the hypothesis that screening for the λ IGVL germline gene can diagnose AL and the risk of AL in asymptomatic SMM or λ MGUS patients before symptomatic organ damage occurs. Eighty percent of AL cases are due to λ light chains. Nine of the 33 λ IGVL germline genes on chr 22q11.2 cause 90% of the cases of AL λ-type. In the single-center pilot study (NCT02741999), 70% of the λ SMM and λ MGUS patients screened had AL-related λ IGVL genes identified and 10% had undiagnosed AL. In the proposed multicenter study we seek to expand to 6 centers and to develop a CLIA-validated next- generation sequencing test for λ IGVL gene identification by screening the clonal marrow plasma cells of 50 λ SMM or λ MGUS patients. This project will shift the paradigm for λ SMM and λ MGUS patients from watchful waiting for AL and organ damage to screening for early identification of AL and risk of AL, and will save lives by enabling earlier diagnosis before organ damage occurs and by permitting older patients to receive more intensive therapy.

摘要 在系统性轻链（AL）淀粉样变性中，来自克隆血浆的单克隆免疫球蛋白轻链蛋白 细胞导致致命的多器官疾病。患者年龄是一个关键因素;在被诊断患有心脏病的患者中， 参与，年龄较大独立预测早期死亡。在那些有良好血液学的人中， 对初始治疗的反应，诊断时年龄大于60岁的患者的中位生存期为8年， 器官损伤的负担，而60岁以下的患者8年存活率为80%。60岁以上患者 诊断时往往病情过重，无法接受强化治疗，例如自体干细胞移植。 在发生显著的和有症状的器官功能障碍之前诊断AL是一个迫切的未满足的需求， 特别是在60岁以上的人中。这可以通过筛查阴燃患者来实现 多发性骨髓瘤（SMM）或意义不明的单克隆丙种球蛋白病（MGUS），其中许多人 由于诊断延迟，每年进展为AL伴器官损伤。每个AL患者都有IG 可变区轻链基因（IGVL），其编码病理性轻链蛋白，并可通过 RT-PCR法拟议的多中心研究验证了以下假设，即λ IGVL生殖系基因的筛选可以 在有症状的器官损害前诊断AL和无症状SMM或λ MGUS患者中的AL风险 发生。80%的AL病例是由于λ轻链。chr上的33个λ IGVL种系基因中的9个 22q11.2是90%的AL λ型的致病基因。在单中心初步研究（NCT 02741999）中，70%的λ 在筛查的SMM和λ MGUS患者中，发现了AL相关的λ IGVL基因，10%的患者患有未诊断的AL。 拟议的多中心研究，我们寻求扩大到6个中心，并开发CLIA验证的下一个- 通过筛选50 λ克隆骨髓浆细胞进行λ IGVL基因鉴定的代测序试验 SMM或λ MGUS患者。该项目将改变λ SMM和λ MGUS患者的模式， 等待AL和器官损伤筛查，以早期识别AL和AL风险，并将通过以下方式挽救生命： 在器官损伤发生之前进行早期诊断，并允许老年患者接受更多的治疗， 强化治疗