Study Uncovers Patterns of Mutations in Drug-Resistant CLL 

Written by: Rob Levy

A pair of subversives, the genes BTK and PLCG2 are often mutated in chronic lymphocytic leukemia (CLL) that is resistant to the drug ibrutinib. But how common are these genetic alterations and to what extent do they contribute to ibrutinib resistance? 

The answers will help doctors determine which targeted therapies are most likely to help individual patients if resistance develops. At the 2023 International Workshop on CLL (iwCLL), held in Boston in October, a Dana-Farber scientist and her colleagues won a Best Research Abstract award for a study that fills in some of those answers. 

“Most patients with CLL treated with drugs like ibrutinib that target the protein BTK have long-lasting remissions, but some develop resistance, which allows the disease to progress,” says Inhye Ahn, MD, the first author of the study. “One of the best-known mechanisms of resistance is a mutation, known as C481, in the BTK gene. This produces an altered form of the BTK protein, which prevents ibrutinib and other BTK inhibitors from binding there firmly. 

“We set out to determine the frequency of BTK and PLCG2 mutations in patients with CLL treated with ibrutinib.” 

Inhye Ahn. Photo by Sam Ogden.

Those mutations turned out to be frequent indeed. In analyzing blood samples from 419 patients across six clinical trials, the researchers found that one in five had BTK and/or PLCG2 mutations in their tumor cells. Almost 17% of the patients included in the study had BTK mutations, compared to just over 9% with PLCG2 mutations. Five percent had both. 

Among the many mutations that can crop up in BTK, the one known as C481 was by far the most prevalent, accounting for 93% of all BTK mutations identified. (Mutations are named for the specific portion of the genome where they occur.) By comparison, two other mutations in BTK — L528 and T474 — made up less than 1% of all mutations of the gene. 

Researchers also drew a connection between patients’ treatment history and their likelihood of acquiring BTK or PLCG2 mutations. Those treated with chemotherapy followed by ibrutinib were almost 10 times more likely to have a BTK mutation — and more than twice as likely to have a PLCG2 mutation — than those who received ibrutinib as their initial therapy for CLL. 

The findings have particular bearing on patients initially treated for CLL before 2016, when the U.S. Food and Drug Administration approved ibrutinib as a first-line therapy for the disease. Today, ibrutinib is an initial treatment option for patients with CLL. The study findings help explain why patients first treated with chemotherapy are at higher risk of becoming ibrutinib-resistant than those treated with ibrutinib from the start. 

Knowing the frequency and types of mutations in CLL will help researchers determine which BTK inhibitors – there are several besides ibrutinib — work best against cancers with specific patterns of mutations, Ahn remarks. Research is under way to determine how each of these mutations impacts sensitivity to different targeted therapies. That, in turn, will help doctors prescribe the most effective sequence of such drugs for each patient.