Therapy-related leukemia following autologous transplantation for lymphoma

淋巴瘤自体移植后治疗相关性白血病

基本信息

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
项目类别：
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&apos 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&apos s lymphoma patients peripheral blood personalized medicine predictive modeling response risk prediction model stem therapy development transplantation therapy

项目摘要

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.

项目概要治疗相关性骨髓增生异常/急性髓系白血病（t-MDS/AML）是自体骨髓移植的致命并发症造血细胞移植（aHCT）治疗霍奇金淋巴瘤（HL）和非霍奇金淋巴瘤（NHL）。 aHCT 后 t-MDS/AML 的 10 年累积发病率约为 6% 至 8%，与年龄较大相关。在 aHCT 时、aHCT 前暴露于烷化剂、依托泊苷和辐射、外周血干细胞 (PBSC) 依托泊苷动员和全身照射 (TBI) 的特点是 t-MDS/AML。对常规化疗的反应较差，t-MDS/AML 的中位生存期<10 个月。 HL/NHL aHCT 受者非复发死亡的原因一般认为是造血系统。接受细胞毒性治疗的干细胞（HSC）会遭受基因组损伤，导致恶性转化。然而，t-MDS/AML 风险的个体间差异较大表明遗传易感性具有潜在作用。之前的报告（使用候选基因方法）表明种系单核苷酸之间存在关联我们正在开展全基因组关联研究 (GWAS)。 Illumina® HumanOmni5-Quad BeadChip 平台；303 例对照），用于识别种系变异与 t-MDS/AML 相关；顶级 SNP 将有助于创建体细胞突变。约 10% 的健康老年人外周血中发现白血病相关基因 DNMT3A、ASXL1 和 TET2 人群，与随后的下一代白血病风险增加 10 倍以上相关；我们将使用测序来识别驱动突变，并观察 PBSC 样本中的基因表达。随后发展为 t-MDS/AML 的患者与未发展为 t-MDS/AML 的患者进行了比较。信息用于在独立测试集中开发 38 基因 PBSC 分类器；该分类器还将导致 aHCT 后 t-MDS/AML 风险升高，加上预后不良，对 aHCT 前识别 aHCT 后 t-MDS/AML 风险增加的患者的需求尚未得到满足指导 HL/NHL 管理的替代治疗方案的使用。 aHCT 之前应用的遗传风险预测模型将允许在增加的情况下识别 HL/NHL 患者具有可用 PBSC 产品的 City of Hope 队列将作为 aHCT 后 t-MDS/AML 的风险。发现队列（n=1,915）使用内布拉斯加大学的 PBSC 产品进行 HL/NHL 的 aHCT 接受者或明尼苏达大学将被用作独立的验证队列（n=2,036）。用于开发预测模型，其中包括临床预测因素（治疗暴露、调节、干细胞细胞动员和 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 后对 t-MDS/AML 风险最高的 HL/NHL 患者进行 aHCT 识别。该提案的创新之处在于它使用了全面的、基于证据的方法来制定风险预测 t-MDS/AML 模型可在 aHCT 之前采用，从而实现风险告知的个性化治疗。