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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

基本信息

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
项目类别：
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

项目摘要

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/文摘

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
作者：
Al-Sawaf,Othman;Davids,MatthewS
通讯作者：
Davids,MatthewS