Targeting apoptosis in high-risk AML and MDS with BCL-2 inhibitor Venetoclax and optimized 10-day Decitabine regimen

使用 BCL-2 抑制剂 Venetoclax 和优化的 10 天地西他滨方案靶向高危 AML 和 MDS 中的细胞凋亡

• 批准号: 10415997
• 负责人: Marina Y Konopleva
• 金额: $ 9.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-17 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415997
• 关键词: Acute Myelocytic Leukemia; Apoptosis; Apoptotic; Aspirate substance; Azacitidine; BCL2 gene; BCL2L1 gene; Bone Marrow; Categories; Cells; Clinical; Combined Modality Therapy; Cytogenetics; Data; Decitabine; Dependence; Disease; Dysmyelopoietic Syndromes; Elderly; Enrollment; Family; Family member; Futility; Future; Goals; Hematologic Neoplasms; Hematology; Institution; Leukemic Cell; MCL1 gene; Mass Spectrum Analysis; Molecular; Molecular Analysis; Monitor; Morphology; Mutate; Mutation; Outcome; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phase II Clinical Trials; Prognosis; Prognostic Marker; Protein Family; Proteins; Protocols documentation; Randomized; Recovery; Refractory; Refractory Disease; Regimen; Relapse; Resistance; Risk; Safety; Sampling; Schedule; Source; Stem cell transplant; Subgroup; Surrogate Endpoint; Survival Rate; TP53 gene; Testing; Therapeutic; Toxic effect; Treatment-related toxicity; Variant; acute myeloid leukemia cell; antileukemic activity; base; clinically significant; cohort; design; exome; exome sequencing; high risk; improved; improved outcome; inhibitor; leukemia; leukemic stem cell; novel; novel strategies; older patient; open label; patient response; peripheral blood; phase 2 study; phase II trial; resistance mechanism; response; small molecule inhibitor; stem cell population

PROJECT SUMMARY The outcomes of elderly patients and relapsed/refractory patients with either acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) remain poor. Venetoclax is a selective BCL-2 inhibitor that recently demonstrated impressive activity when combined with hypomethylating agents decitabine or 5-azacitidine; however, outcomes remained more modest among patients with unfavorable risk cytogenetics or with TP53 mutations. Building on recent findings that increasing the schedule of decitabine from days 1-5 to days 1-10 of 28 day cycles was associated with improved overall responses and survival among patients with unfavorable- risk cytogenetics and TP53 mutations, we hypothesize that concomitant use of venetoclax and 10-day decitabine will improve the response and survival rates, especially in patients with high-risk karyotypes or TP53 mutations. We designed a Phase II trial that will enroll four parallel, open-label cohorts, each with 40 patients consisting of high-risk AML or MDS patients, either with advanced age or with relapsed/refractory disease. The primary objective is to determine the composite overall response rate; secondary objectives include determining disease-free and overall survival, and the impact of high-risk karyotypes on response and survival. In addition, two molecular hypotheses will be tested. First, that clearance of exome-defined founding clone mutations from the peripheral blood provides a consistent and quantified response end-point that circumvents many sources of inter-patient response variability, and that combination venetoclax and decitabine will be associated with increased rate and depth of mutation clearance vs. single-agent decitabine. Determining whether a hypomethylating doublet has improved outcomes vs. single-agent has been challenging for all but large randomized studies, partially due to clinical confounders such as hemodilute aspirates and poor count recovery in older and heavily pre-treated patients. This novel approach to response determination isolates anti-leukemic activity from other factors, thus improving statistical power of the study. Second, we will determine whether responses to combination venetoclax and decitabine correlate with leukemic dependence on BCL-2 activity or on other anti-apoptotic proteins. We will apply dynamic BH3 profiling to determine the dependence of AML blasts on BCL-2, BCL-XL or MCL-1 and correlate these results with response, survival, and mutation patterns. Further, we will apply CyTOF analysis to serial bone marrow samples obtained during therapy and at relapse. We will quantify leukemia stem cell subpopulations and the expression of BCL-2 family proteins within bulk AML cells vs. leukemia stem cells. These data will determine whether combination venetoclax and decitabine leads to elimination of both bulk and leukemia stem cell populations, and whether sensitivity within subpopulations corresponds with intracellular levels of BCL-2 family proteins. Collectively, these studies will evaluate clinical responses and molecular outcomes of a novel combination therapy and will identify prognostic biomarkers and resistance mechanisms.

项目总结