Overcoming BTK Inhibitor Resistance in Chronic Lymphocytic Leukemia

Jennifer Woyach

MD

The Ohio State University

Project Term: April 1, 2021 - March 21, 2026

Project Summary

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the United States, and is not curable with current therapies. Targeted therapies, including the BTK inhibitor ibrutinib have significantly improved the care of patients with CLL. Most people who are treated with ibrutinib have longer remissions than with other therapies. However, over time, many patients develop resistance to ibrutinib. Most patients who develop resistance and relapse on ibrutinib do so by developing mutations in BTK, and these mutations are often detectable many months prior to the development of clinical relapse. The only drug that is effective in patients who relapse on ibrutinib is the BCL2 inhibitor venetoclax. Even this medication only works for a short time in this setting. Therefore, new approaches to ibrutinib-resistance are needed. Also, it would be helpful to be better able to identify which patients are at high risk of relapsing on ibrutinib, so these patients can be closely monitored. I will try to improve upon the success of ibrutinib by addressing issues of drug resistance. We have samples from patients treated with ibrutinib or with the second generation BTK inhibitor acalabrutinib. I will determine if gene expression patterns and/or certain mutations present at the start of treatment can predict which patients are most likely to have short or long remission durations. The goal of these studies is to identify high-risk patients who should be preferentially treated on clinical trials with novel therapeutic approaches. The second part of the project will focus on patients who develop mutations in BTK while on ibrutinib, but who have not yet clinically progressed. We will perform a clinical trial of patients on ibrutinib with BTK mutations where we will add venetoclax to see if the combination can eliminate resistant disease. The third part of this project will focus on patients who have CLL that is relapsed after ibrutinib or acalabrutinib. I will complete a first in human clinical trial of a reversible BTK inhibitor, ARQ 531, along with correlative laboratory studies. We have performed the laboratory work associated with this agent and shown that it is effective in patient samples that are resistant to ibrutinib, including those with BTK mutations. This project in entirety will expand our knowledge of the biology of relapse on ibrutinib and acalabrutinib, and will test two novel strategies of therapy for patients who have or will relapse on ibrutinib. I expect that this will lead to future studies to define the best care for patients with CLL.