Growth Kinetics May Help Identify Ibrutinib Resistance in CLL Patients

It may be time to rethink what causes treatment resistance in patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib (Imbruvica).

Researchers at Weill Cornell Medicine recently published a study in Nature Communications explaining that the rate at which genetically mutated cancer cells grow may help explain why some CLL patients develop treatment resistance. The findings demonstrate how mutations that arise before treatment begins can influence how the disease responds to therapies. The findings also highlight the possibility of designing regimens that can preempt resistance.

"In the future, this information will allow clinicians to devise a treatment plan adapted to the genetic differences seen among cancer cell populations," said study investigator Dan Avi Landau, MD, who is an assistant professor of medicine and of physiology and biophysics at Weill Cornell Medicine, New York, in a news release. "Once we are able to characterize the spectrum of genetic changes that occur in cancer patients, we will be able to determine what combination of drugs could be used to eradicate the arising resistant cell populations."

Dr. Landau and his colleagues performed mathematical modeling of the growth rates of the sensitive and resistant cells, and discovered that a small cluster of cancer cells survived ibrutinib therapy due to a genetic mutation that was present prior to treatment.  

The team used blood samples from five patients with CLL and performed genetic sequencing of their cancer cell DNA. To assess the presence of genetic abnormalities, researchers took samples before and after treatment with ibrutinib. Until now, resistance to the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib was thought to be solely due to mutations in BTK and its related pathway molecules. Dr. Landau’s team used whole-exome and deep-targeted sequencing, and dissected evolution of ibrutinib resistance in serial samples.

The researchers were able to detect a BTK-C481S mutation or multiple PLCG2 mutations in two of the five samples. The other three patients were found to exhibit an expansion of clones harboring del(8p) with additional driver mutations (EP300, MLL2, and EIF2A). The researchers were able to identify ibrutinib-resistant subclones and estimate subclone size prior to treatment initiation.  

Dr. Landau developed a technique, for which a patent is pending, to calculate growth kinetics of ibrutinib-resistant cancer cells. With the growth kinetics data from each patient's cancer, the team was able to predict exactly when the CLL would reoccur and which resistant cell populations would take over. He explained that being able to calculate cancer growth rates among resistant cells could be essential for cancer treatments in the future.

Many patients eventually develop resistance, but understanding the rate at which resistant cells grow in each individual case could provide insight for better treatments and lead to better patient prognoses.