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：
10664976
负责人：
Rosa Lapalombella
金额：
$ 46.49万
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/10664976
关键词：
Address Aftercare Agammaglobulinaemia tyrosine kinase Allogenic BCL2 gene Biological Assay Biological Markers Bromodomains and extra-terminal domain inhibitor CRISPR screen Chronic Lymphocytic Leukemia Clinical Clinical Trials Complex Complication Confidence Intervals Data Development Diagnosis Disease Disease Progression 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 Stem cell transplant TP53 gene Testing Tetraploidy Therapeutic Time Translating Translational trial 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 inhibitor therapy innovation large cell Diffuse non-Hodgkin&apos s lymphoma mouse model novel novel marker participant enrollment patient subsets pre-clinical prevent targeted treatment 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.

项目摘要在过去的十年中，CLL的治疗方法从化学免疫疗法到靶向疗法，包括布鲁顿酪氨酸激酶激酶抑制剂（BTKI，ibrutinib和acalabrutinib和venetoclax （靶向Bcl2）。疗法，选择的高风险患者发展为Richter的疾病进展转化（RT），一种快速生长的侵略性侵袭性淋巴瘤，具有形态学相似性，可扩散大B细胞淋巴瘤随着靶向疗法的使用而持续增长在临床上越来越多。因此，在Tarap Tarapies中的RT策略至关重要化学免疫疗法的时代，早期突变包括Notch1，XPO1，TP53和2P扩增。发现CLL诊断与RT发育有关。鉴定出C-YC Express/扩增/扩增或新获得的TP53 MUTER其他常见病变。霍弗（Howver），由于有针对性疗法的出现，尚无报道检查创始人叛变或其他作为化学免疫疗法和tARAPY的特征这些预处理风险因素可能会使用大量的CLL预处理样本而有所不同。在俄亥俄州立大学进行了四项伊布鲁替尼凝固试验的患者，后续数据是可用时，我们描述了在ibrutinib开始之前的近四倍体和comprex karyotype 由于RT支持我们的假设 AET核心的新型生物标志物的存在。发展RT的患者的CLL基因组和表观遗传特征，验证精选的重要性使用人类CLL的鼠标模型和系统性测定法对Richter的开发变化使用体内CRISPR屏幕方法涉及的表型； 2 Ibrutinib和PLX51107（靶BRD4）的1B/2研究对CLLY的患者的高风险高。开发RT或RT。靶向治疗后的RT，已应用新颖的小鼠模型将试验骗给此CLL汇编。在RT中，与RT高风险的CLL患者相结合。 Launkh将来的试验侧重于预防和治疗CLL患者的RT。