CLL Progression With BTK Inhibitor Therapy

At the 2018 Lymphoma & Myeloma congress held in New York, Richard R. Furman, MD, Director CLL Research Center, Weill Cornell Medicine, New York, New York, spoke to Oncology Learning Network about CLL progression after BTK inhibitor therapy along with Richter's transformation.

Transcript

We have some data looking at how different patients fare with long-term, BTK inhibitor therapy. What I think is important to differentiate is that almost everyone will respond. What becomes the important endpoint is in determining who are the patients that are going to progress on BTK inhibitor therapy.

There's really two types of progression. The first are those patients who develop a Richter's transformation. The data suggests that Richter's transformation is going to be the predominant type of progression that occurs between initiation of therapy and maybe the second year of therapy.

Beyond the second year of therapy, CLL progression are those patients who have CLL get treated with a BTK inhibitor and go into a response or have a response and then actually develop progression that still is CLL. The CLL progression traditionally begins to increase in its incidence beyond year two and may plateau by year five, we don't know.

The important thing about these two types of progression relate to it's probably events happening before the initiation of therapy that are going to actually cause the progression.

Since Richter's is happening within the first two years of patients on therapy, my assumption is that the events that are going to lead to that Richter's have already happened, and that really is going to be the biology of the CLL cell that's going to lead to that occurrence.

These patients are developing a Richter's transformation. The Richter's is just growing out while the patient is on BTK inhibitor therapy extensively because we're treating the CLL and we can now see the Richter's transformation.

Regarding the CLL progression, we do have data suggesting that the mutations that are probably responsible for most types of progression on BTK inhibitor therapy occur before the therapy is initiated. Therefore, it's just while the patients are on therapy that the CLL was able to grow.

As it turns out the time it takes for one cell to become clinically apparent is going to between two and five years, depending upon the rate of growth. That's why we see those patients progress during those times.

With regard to trying to identify these patients ahead of time, we do have a lot of means or a lot of predictors for patients who are going to develop a Richter's transformation. These include 17p deletion, complex karyotype, MYC abnormalities, NOTCH 1 mutations, as well as certain stereotyped V genes.

With regard to patients who develop CLL progression, we have some predictors as well, including complex karyotype and 17p deletion.

What I really think the most important message from all of these methods for predicting who are those patients that are going to progress is that the complex karyotype and the 17p deletions are, in essence, just an indicator of the genomic instability.

This genomic instability allows these ongoing mutations to occur, and in essence, enable the changes that will make either the patient develop a Richter's transformation or a CLL progression.