Clinical and molecular determinants of CLL eradication with targeted combination therapy
Inhye Ahn
MDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2028
The genomic architecture of residual CLL and molecular determinants of disease progression after targeted combination therapy are unknown. In a phase 2 study of zanubrutinib and venetoclax in CLL, I will investigate the depth of response and genomic changes using cellular and circulating tumor DNA. Data generated from this proposal will provide foundational evidence to develop genomic markers for non-invasive monitoring of treatment response and precise prediction of outcome.
Despite major advancements in understanding and treating blood cancers, chronic lymphocytic leukemia (CLL) remains an incurable disease. CLL has the ability to survive through many treatment options and drive treatment resistance. My previous work has demonstrated that CLL-associated mutations confer the ability for cancer cells to be resilient. I have observed that these genetic changes frequently emerge in cancer cells that hide in the deep-seated area of the body, such as lymph nodes. The overarching goal of my research is to develop new treatment strategies to eradicate CLL and investigate molecular details underlying CLL growth and progression. The current proposal leverages an ongoing clinical trial testing a novel combination regimen called zanubrutinib plus venetoclax in patients with relapsed or refractory CLL. Through this study, I will accurately quantify residual CLL during treatment and track its growth kinetics after treatment. I will explore how CLL-associated mutations affect some CLL cells to become resilient and survive. Further, I will develop a new method to capture mutations occurring in CLL hiding in the lymph nodes using circulating tumor DNA. Circulating tumor DNA is shed by cancer cells and circulates in the bloodstream, which allows a unique opportunity to investigate the genomic changes in tissue-resident CLL cells. Data generated from this proposal will provide new tools to monitor treatment response and generate insight into designing new treatment options that can quell the ability of blood cancer to develop treatment resistance.