Optimizing novel agent combination therapy for previously untreated, high risk chronic lymphocytic leukemia

优化针对先前未治疗的高风险慢性淋巴细胞白血病的新药联合疗法

• 批准号: 10705268
• 负责人: MATTHEW S DAVIDS
• 金额: $ 39.54万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705268
• 关键词: Achievement; Agammaglobulinaemia tyrosine kinase; Apoptotic; B lymphoid malignancy; B-Cell Leukemia; BCL2L1 gene; Biological Assay; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Combined Modality Therapy; Data; Dependence; Disease; Elderly; Elements; Family member; Flow Cytometry; Future; Generations; Genes; Genomics; Genotype; Goals; Grant; Head; Heme; In complete remission; Karyotype; Laboratories; Laboratory Study; MCL1 gene; Maps; Mitochondria; Monoclonal Antibody CD20; Multi-Institutional Clinical Trial; Mutation; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Phosphorylation; Phosphotransferases; Population; Principal Investigator; Progression-Free Survivals; Protein Family; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Regimen; Research Personnel; Residual Neoplasm; Resistance; Resistance development; Rest; Risk; Safety; Sampling; Sampling Studies; Somatic Mutation; Subgroup; TP53 gene; Technology; Testing; Therapeutic; Therapy trial; Time; Toxic effect; Triplet Multiple Birth; Tyrosine Kinase Inhibitor; Writing; anti-CD20; chronic lymphocytic leukemia cell; clinical predictors; comorbidity; design; efficacy evaluation; experience; genomic predictors; high risk; individualized medicine; inhibitor; innovation; leukemia treatment; leukemia/lymphoma; next generation sequencing; novel; optimal treatments; personalized decision; predicting response; protein B; resistance mechanism; response; response biomarker; standard of care; survival prediction; targeted agent; therapy duration; tositumomab; treatment duration; treatment response

SUMMARY/ABSTRACT Patients with high-risk TP53 aberrant chronic lymphocytic leukemia (CLL) have a shorter survival than other CLL patients. We previously found that the BTK inhibitor acalabrutinib (A) and the BCL-2 inhibitor venetoclax (V) are highly effective at killing CLL cells ex vivo. We developed AVO, a new time-limited triplet combination regimen combining AV with an anti-CD20 antibody obinutuzumab (O). The AVO clinical trial and correlative laboratory studies on primary samples from this trial comprise the key elements of this project. The first aim of the project is to determine the efficacy of the AVO combination regimen in patients with previously untreated TP53 aberrant CLL. We hypothesize that AVO will be a highly efficacious and well- tolerated novel agent triplet regimen, with individualized therapy duration guided by achievement of undetectable minimal residual disease (uMRD). This hypothesis will be tested through determining the proportion of patients who achieve complete response (CR) with uMRD, as well as characterizing the safety of the regimen, in an investigator-initiated, phase 2, multicenter clinical trial of AVO in patients with previously untreated CLL. The second aim of the project is to assess whether MRD clonal dynamics, pre-treatment mitochondrial priming, or genomic complexity predict clinical response to AVO. We will utilize a next-generation sequencing (NGS) based technology, Adaptive ClonoSEQ, to assess whether MRD clonal dynamics with this assay can more accurately predict survival and guide treatment duration decisions compared with conventional flow cytometry- based MRD. Through functional interrogation of CLL cell mitochondria by BH3 profiling, we hypothesize that patients with higher levels of mitochondrial priming at baseline and/or early on treatment will achieve a higher rate of CR with uMRD on AVO. Genomic predictors of response will also be assessed through stimulated karyotype and mutational profiling with a 95-gene NGS ‘rapid heme panel’ (RHP). The third aim of the project is to elucidate mechanisms of resistance to AVO, including acquired somatic mutations, modulation in mitochondrial priming, alterations in phosphorylation, and kinase activity. We will use RHP to evaluate the pattern of somatic mutations as they develop. We will also evaluate whether CLL cells that are typically dependent on BCL-2 at baseline will develop alternative survival dependencies on other anti- apoptotic proteins at progression. In addition, we will assess whether BCL-2 family protein phosphorylation may represent a functional resistance mechanism, and whether PP2A activators can help reverse this and thereby restore sensitivity. And we will use high-throughput kinase activity mapping (HT-KAM) to identify which kinases are activated in resistant patients to identify new, potentially therapeutically actionable targets. Elucidating resistance mechanisms will inform the design of future novel agent combination therapy trials, with the goal of decreasing the risk of acquired therapy resistance in CLL and eventually other B cell malignancies.

摘要/摘要 高危TP53异常慢性淋巴细胞性白血病（CLL）的患者的生存率比其他 CLL患者。我们以前发现BTK抑制剂acarabrutinib（A）和Bcl-2抑制剂Venetoclax （V）在杀死离体的CLL细胞方面非常有效。我们开发了AVO，这是一种新的时限三重组合 将AV与抗CD20抗体Obinutuzumab（O）结合的方案。 AVO临床试验和相关性 该试验中主要样本的实验室研究包括该项目的关键要素。 该项目的第一个目的是确定AVO组合方案的效率 以前未经处理的TP53异常CLL。我们假设AVO将是一个高效且良好的 可耐受的新型药物三重疗法，其个性化治疗持续时间是通过实现的 无法检测到的最小残留疾病（UMRD）。该假设将通过确定 使用UMRD实现完全反应的患者（CR）的比例，并表征 该方案在研究人员发起的第2阶段，AVO的多中心临床试验中 未经处理的CLL。 该项目的第二个目的是评估MRD克隆动力学，治疗前线粒体启动是否是否 或基因组复杂性预测对AVO的临床反应。我们将使用下一代测序（NGS） 基于自适应克罗诺斯的技术，用于评估使用此测定的MRD克隆动力学是否可以更多 与常规流式细胞术相比，准确预测生存和指导治疗持续时间的决策 基于MRD。通过通过BH3分析对CLL细胞线粒体的功能询问，我们假设 基线时线粒体启动和/或治疗时具有较高水平的线粒体启动的患者将获得更高的 AVO上的CR率。基因组反应的基因组预测指标也将通过刺激来评估 带有95基因NGS“快速血红素面板”（RHP）的核型和突变分析。 该项目的第三个目的是阐明对AVO的抵抗机制，包括获得的体细胞 突变，线粒体启动的调节，磷酸化的改变和激酶活性。我们将使用 RHP在形成体细胞突变的情况下评估它们的模式。我们还将评估CLL细胞是否 基线时通常取决于Bcl-2的，将会对其他抗 - 进展时凋亡蛋白。此外，我们将评估Bcl-2家族蛋白磷酸化是否 可能代表一种功能性机制，以及PP2A激活剂是否可以帮助扭转这一点，并且 从而恢复灵敏度。我们将使用高通量激酶活动映射（HT-KAM）来识别哪个 在耐药患者中激活激酶，以鉴定新的，潜在的热可作用靶标。 阐明抗药性机制将为未来的新型代理联合疗法试验的设计提供信息， 降低CLL和其他B细胞恶性肿瘤中获得的治疗耐药性风险的目的。

项目成果

Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.

• DOI: 10.3324/haematol.2023.283245
• 发表时间: 2024-01-01
• 期刊: HAEMATOLOGICA
• 影响因子: 10.1
• 作者: Zhu, Fen;Crombie, Jennifer L.;Ni, Wei;Hoang, Nguyet-Minh;Garg, Swati;Hackett, Liam;Chong, Stephen J. F.;Collins, Mary C.;Rui, Lixin;Griffin, James;Davids, Matthew S.
• 通讯作者: Davids, Matthew S.

Overcoming Resistance in Chronic Lymphocytic Leukemia-Maybe Less Is More?

克服慢性淋巴细胞白血病的耐药性——也许少即是多？

• DOI: 10.1158/1078-0432.ccr-23-2872
• 发表时间: 2024
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Al-Sawaf,Othman;Davids,MatthewS
• 通讯作者: Davids,MatthewS