Therapy-related leukemia following autologous transplantation for lymphoma

淋巴瘤自体移植后治疗相关性白血病

• 批准号: 10456961
• 负责人: SMITA BHATIA
• 金额: $ 40.99万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-02 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456961
• 关键词: Acute Myelocytic Leukemia; Address; Adopted; Adult; Age; Alkylating Agents; Autologous; Autologous Transplantation; Biometry; CD34 gene; Candidate Disease Gene; Cells; Characteristics; Cities; Clinical; Complication; Computational Biology; Coupled; Cytotoxic Chemotherapy; DNA Damage; DNA Repair; Development; Diagnosis; Dose; Dysmyelopoietic Syndromes; Early Diagnosis; Etoposide; Exposure to; Funding; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genomics; Goals; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Hodgkin Disease; Incidence; Informatics; Interdisciplinary Study; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediator of activation protein; Medical Care Team; Medical Genetics; Minnesota; Mitochondria; Molecular Epidemiology; Mutation; Nebraska; Non-Hodgkin' s Lymphoma; Outcome; PPM1D gene; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Stem Cell; Population; Prognosis; Publishing; Radiation; Regulation; Reporting; Research; Risk; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Somatic Mutation; TP53 gene; Testing; Therapeutic; Time; TimeLine; Transplant Recipients; Transplantation; Universities; Validation; Variant; Whole-Body Irradiation; Work; bead chip; case control; chemotherapy; clinical predictors; clinical risk; cohort; conditioning; driver mutation; drug metabolism; evidence base; exome sequencing; genome wide association study; genomic profiles; hematopoietic cell transplantation; high risk; innovation; inter-individual variation; leukemia; mortality; next generation sequencing; non-Hodgkin' s lymphoma patients; peripheral blood; personalized medicine; predictive modeling; response; risk prediction model; stem; therapy development; transplantation therapy

PROJECT SUMMARY Therapy-related myelodysplasia/acute myeloid leukemia (t-MDS/AML) is a lethal complication of autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma NHL). The 10-year cumulative incidence of t-MDS/AML is ~6% to 8%. Post-aHCT t-MDS/AML is associated with older age at aHCT, pre-aHCT exposure to alkylators, etoposide and radiation, peripheral blood stem cell (PBSC) mobilization with etoposide, and conditioning with total body irradiation (TBI). t-MDS/AML is characterized by poor response to conventional chemotherapy, and median survival of <10 months. t-MDS/AML is the leading cause of non-relapse mortality among aHCT recipients for HL/NHL. It is generally believed that hematopoietic stem cells (HSCs) exposed to cytotoxic therapy suffer genomic damage leading to malignant transformation. However, high inter-individual variation in t-MDS/AML risk suggests a potential role for genetic susceptibility. Previous reports (using a candidate gene approach) suggest an association between germline single nucleotide polymorphisms (SNPs) and t-MDS/AML risk. We are conducting a genome-wide association study (GWAS: Illumina® HumanOmni5-Quad BeadChip platform; 303 cases; 606 controls) to identify germline variants associated with t-MDS/AML; top SNPs will contribute to creation of genetic profile. Somatic mutations in leukemia-associated genes DNMT3A, ASXL1, and TET2 seen in peripheral blood in ~10% of older healthy population, are associated with >10-fold increase in risk for subsequent leukemia; targeted next-generation sequencing will be used to identify driver mutations. We observed altered gene expression in PBSC samples from patients who subsequently developed t-MDS/AML when compared with patients who did not. This information was used to develop a 38-gene PBSC classifier in an independent test set; this classifier will also contribute to the genomic profile. The elevated risk of t-MDS/AML after aHCT, coupled with the poor prognosis, present an unmet need for pre-aHCT identification of patients at increased risk for post-aHCT t-MDS/AML to guide use of alternative therapeutic options for HL/NHL management. We hypothesize that a combined clinical and genetic risk prediction model applied prior to aHCT will allow identification of HL/NHL patients at increased risk for post-aHCT t-MDS/AML. The City of Hope cohort with the available PBSC products will serve as the Discovery cohort (n=1,915). aHCT recipients for HL/NHL with PBSC product at the University of Nebraska or University of Minnesota will be utilized as an independent Validation cohort (n=2,036). The two cohorts will be used to develop a prediction model that includes clinical predictors (therapeutic exposures, conditioning, stem cell mobilization and CD34+ cell dose) and genetic factors (SNPs, gene expression profile and clonal somatic mutations) to optimize pre-aHCT identification of HL/NHL patients at highest risk for t-MDS/AML after aHCT. This proposal is innovative in its use of a comprehensive, evidence-based approach to develop a risk prediction model for t-MDS/AML that can be adopted prior to aHCT, allowing for risk-informed personalized treatment.

项目摘要 与治疗相关的骨髓增生/急性髓细胞性白血病（T-MDS/AML）是自体的致命并发症 霍奇金淋巴瘤（HL）和非霍奇金淋巴瘤NHL的造血细胞移植（AHCT）。 T-MDS/AML的10年累积发生率为约6％至8％。 AHCT T-MDS/AML与老年有关 在AHCT上，AHCT暴露于烷基烷基，依托泊苷和辐射，外周血干细胞（PBSC） 用依托泊苷动员和全身照射（TBI）调节。 T-MDS/AML的特征是 对常规化学疗法的反应不佳，中位存活率<10个月。 T-MDS/AML是领导者 HL/NHL的AHCT受体中非释放死亡率的原因。通常认为造血 暴露于细胞毒性疗法的干细胞（HSC）遭受基因组损伤，导致恶性转化。 但是，T-MDS/AML风险的高个体间差异表明遗传敏感性的潜在作用。 先前的报告（使用候选基因方法）表明种系单核苷酸之间存在关联 多态性（SNP）和T-MDS/AML风险。我们正在进行全基因组协会研究（GWAS： Illumina®Hanumomni5-Quad Beadchip平台； 303例； 606个控件）以识别种系变体 与T-MDS/AML相关；顶级SNP将有助于创造遗传特征。体细胞突变 白血病相关的基因DNMT3A，ASXL1和TET2在外周血中观察到约10％的老年人健康 人口与随后的白血病风险增加> 10倍；有针对性的下一代 测序将用于识别驾驶员突变。我们观察到PBSC样品中基因表达的改变 与未进行的患者相比，随后患有T-MDS/AML的患者。这 信息用于在独立的测试集中开发38基因PBSC分类器。这个分类器也将 有助于基因组谱。 AHCT后T-MDS/AML的风险升高，再加上预后不良， 提出了未满足的对AHCT前AHCT T-MDS/AML风险增加的患者的需求 指导使用HL/NHL管理的替代治疗选择。我们假设合并的临床 在AHCT之前应用的遗传风险预测模型将允许在增加的HL/NHL患者中鉴定 AHCT后T-MDS/AML的风险。与可用PBSC产品的Hope City Cohort一起将作为 发现队列（n = 1,915）。 NEBRASKA大学的HL/NHL的AHCT接受者或PBSC产品或 明尼苏达大学将被用作独立验证队列（n = 2,036）。这两个队列将是 用于开发包括临床预测因子的预测模型（治疗性暴露，条件，茎 细胞动员和CD34+细胞剂量）和遗传因素（SNP，基因表达谱和克隆体细胞 突变）以优化AHCT后T-MDS/AML风险最高的HL/NHL患者的AHCT前鉴定。 该建议在使用一种综合，基于证据的方法来制定风险预测方面具有创新性 可以在AHCT之前采用的T-MDS/AML的模型，从而允许风险信息的个性化治疗。