Understanding Richter's Transformation in the targeted therapies era

理解靶向治疗时代里克特的转变

基本信息

批准号：
10261511
负责人：
Rosa Lapalombella
金额：
$ 47.44万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261511
关键词：
Address Aftercare Agammaglobulinaemia tyrosine kinase Allogenic BCL2 gene Biological Assay Biological Markers Bromodomain CRISPR screen Chronic Lymphocytic Leukemia Clinical Clinical Trials Complex Complication Confidence Intervals Data Deletion Mutation Development Diagnosis Disease Disease Progression Enrollment Epigenetic Process Frequencies Future Gene Mutation Genes Genomics Goals Immune Immuno-Chemotherapy Immunologics Institution Karyotype Knowledge Lesion Long-Term Survivors Lymphoma Methods Modeling Morphology Mutation NOTCH1 gene Ohio Outcome Pathway interactions Patients Pharmacodynamics Phase Phase Ib/II Trial Phenotype Prevention Relapse Reporting Resistance Risk Factors Sampling Series TP53 gene Testing Tetraploidy Therapeutic Time Translating Tyrosine Kinase Inhibitor Universities Work c-myc Genes clinically significant cohort driver mutation effective therapy follow-up founder mutation high risk human model in vivo inhibitor/antagonist innovation large cell Diffuse non-Hodgkin&apos s lymphoma mouse model novel novel marker patient subsets pre-clinical prevent stem cells targeted treatment translational clinical trial treatment effect treatment risk tumor

项目摘要

PROJECT SUMMARY The therapeutic approach of CLL has evolved significantly over the past decade from chemoimmunotherapy to targeted therapies including Bruton tyrosine kinase inhibitors (BTKi, ibrutinib and acalabrutinib and venetoclax (that targets BCL2). Whereas a large subset of CLL patients will have a favorable outcome with targeted therapies, select high-risk patients develop disease progression that can often manifest as Richter’s transformation (RT), a rapidly growing aggressive lymphoma with morphologic similarity to diffuse large B-cell lymphoma. As the use of targeted therapies continues to grow, emergence of resistance and progression to RT are of increasing clinical concern. Identifying pre-treatment biomarkers associated with this transformation and strategies to prevent and also treat RT in the era of targeted therapies is therefore of utmost importance. In the era of chemoimmunotherapy, early mutations including NOTCH1, XPO1, TP53, and 2p amplification at time of CLL diagnosis were found to be associated with RT development. Other studies examining RT tumors have identified c-MYC expression/amplification or newly acquired TP53 mutations as additional common lesions. However, since the advent of targeted therapy, there have been no reports examining founder mutations or other features predisposing to RT. As chemoimmunotherapy and targeted therapy have different escape pathways, it is likely that these pre-treatment risk factors will differ. Using a large series of pre-treatment samples for CLL patients enrolled across four ibrutinib clinical trials at The Ohio State University, for which follow up data were available, we have described the presence of near-tetraploidy and complex karyotype prior to the start of ibrutinib treatment to be independent risk factors for discontinuing ibrutinib due to RT supporting our hypothesis of the existence of novel biomarkers of transformation that are yet unidentified. We herein propose to: 1) examine the CLL genomic and epigenetic features of patients who develop RT, validate the importance of select gene alterations on development of Richter’s using mouse models of human CLL, and systematically assay phenotypes involved in CLL to RT using in vivo CRISPR screen methods; 2) perform a three institution phase 1b/2 study of ibrutinib and PLX51107 (target BRD4) in patients with previously treated CLL with high risk of developing RT or RT. At completion of this project we will have a much better understanding of risk factors for RT following targeted therapy, have applied novel mouse models to better inform future trials to prevent/treat this CLL complication. Additionally, we will have completed the very first trial with BRD4 inhibitor PLX51107 combined with ibrutinib in CLL patients at high risk for RT and also in RT. Additionally, we will be poised to launch future trials focused on both preventing and treating RT in patients with CLL.

项目概要 CLL 的治疗方法在过去十年中发生了显着的发展，从化学免疫疗法到靶向治疗，包括 Bruton 酪氨酸激酶抑制剂（BTKi、ibrutinib、acalabrutinib 和 Venetoclax）（针对 BCL2），但大部分 CLL 患者将通过靶向治疗获得良好的结果。治疗中，选择高风险患者会出现疾病进展，通常表现为里氏氏病转化 (RT)，一种快速生长的侵袭性淋巴瘤，其形态与弥漫性大 B 细胞相似随着靶向治疗的使用不断增长，耐药性的出现和放疗的进展。识别与这种转变相关的治疗前生物标志物受到越来越多的临床关注。因此，在靶向治疗时代，预防和治疗放疗的策略至关重要。化学免疫疗法时代，早期突变包括NOTCH1、XPO1、TP53和2p扩增其他检查 RT 肿瘤的研究发现 CLL 诊断与 RT 发展相关。将 c-MYC 表达/扩增或新获得的 TP53 突变确定为其他常见病变。然而，自从靶向治疗出现以来，还没有研究创始人突变或其他由于化学免疫治疗和靶向治疗具有不同的逃避途径，因此容易发生放疗。使用大量 CLL 治疗前样本，这些治疗前风险因素可能会有所不同。患者在俄亥俄州立大学参加了四项依鲁替尼临床试验，其随访数据为可用，我们在开始使用依鲁替尼之前描述了近四倍体和复杂核型的存在治疗是因放疗而停止依鲁替尼的独立危险因素，支持我们的假设尚未确定的新型转化生物标志物的存在我们在此建议：1）检查。进行 RT 的患者的 CLL 基因组和表观遗传学特征，验证了选择基因的重要性使用人类 CLL 小鼠模型对 Richter 发展的改变进行系统分析使用体内 CRISPR 筛选方法进行 CLL 至 RT 中涉及的表型 2) 进行三个机构阶段；伊布替尼和 PLX51107（目标 BRD4）在既往接受过治疗且治疗风险高的 CLL 患者中的 1b/2 研究开发 RT 或 RT 完成该项目后，我们将对风险因素有更好的了解。靶向治疗后的放疗应用了新型小鼠模型，以更好地为未来的预防/治疗试验提供信息此外，我们将完成 BRD4 抑制剂 PLX51107 的首次试验。与伊布替尼联合用于治疗高风险放疗的 CLL 患者以及另外的放疗，我们将做好准备。启动未来的试验，重点是预防和治疗 CLL 患者的 RT。