Evolution of Biological Understandings in CLL

Transcript:

Matthew S. Davids, MD: Until the early 2010s, chemoimmunotherapy-based regimens were really the gold standard for all patients with CLL receiving initial therapy, including those patients with high-risk markers, such as deletion 17p. The major innovation over the last several years has been the development of novel agents, which target a variety of different pathways in the CLL cells and work very differently than chemoimmunotherapy. One of the biggest insights in this disease was that targeting the B-cell receptor pathway can be a very effective strategy. This is a key survival pathway for CLL cells in the lymph nodes and in the bone marrow. By disrupting this pathway, these new drugs can actually move CLL cells out of these protected microenvironments and into the bloodstream where they become susceptible to dying through a process called apoptosis. Examples of drugs like this include ibrutinib, which targets Bruton’s tyrosine kinase in the B-cell receptor pathway, and idelalisib, which targets PI3 kinase, the delta isoform, in that same pathway.

Another strategy has been to target the apoptotic machinery of the cell directly, and that’s with the drug venetoclax that targets a protein called BCL2, which is a prosurvival protein that’s really one of the key regulators of apoptosis, or programmed cell death. Venetoclax is also a very highly effective agent that is right now only approved for patients with relapsed CLL who have this high-risk deletion 17p marker, but it is increasingly being worked into different regimens as a combination approach.

FISH testing has been around for quite a while now. The original papers came out around 20 or so years ago and define these different subgroups of patients who are at different risks for progression and, ultimately, poorer survival. One of the older techniques to look at the chromosomes and the cells is actually a karyotype technique, which was not very fruitful in the early days of CLL because we couldn’t identify a lot of the key abnormalities that we need to look for.

In more recent years, there have been new techniques to look at karyotype. For example, there is a CpG stimulation technique that can bring out some of these abnormalities that we weren’t seeing before. One of the things that has evolved in the last few years is looking at the complex karyotype, which involves 3 or more different abnormalities in the chromosomes of the CLL cell. We know now that those patients who have a complex karyotype, particularly those who have deletion 17p as one of those abnormalities, have a particularly poor prognosis, unfortunately, not just to chemoimmunotherapy but even to the newer drugs when used as monotherapies.

I think that the complex karyotype is one of the key innovations that has been discovered over the last few years. I think FISH remains a very important test to define deletion 17p. The other thing that we should be testing for is the mutational status of TP53. This is the key regulator gene that’s on chromosome 17. It can either be deleted, as in deletion 17p, or it can be mutated, where the chromosome is still present. We don’t see that deletion on the FISH test, but we can detect the mutation in about 5% to 10% of patients at the time of diagnosis. This does confer resistance to therapy and has increasingly informed our choice of therapy, because we’ve moved toward a novel agent-based approach and away from chemotherapy for those patients.

In terms of other chromosomal abnormalities that we see in CLL, another common one is deletion 11q, which we think deletes ATM. That’s the main gene on chromosome 11 that we think is responsible for some of the pathophysiology of that abnormality. This is seen in about 20% of CLL patients at time of diagnosis and tends to be associated with bulky internal lymphadenopathy, a need for treatment sooner in the course of the disease, and a less durable response to chemoimmunotherapy-based regimens.

We have some conflicting data about this abnormality in terms of the response to the novel agents. Originally, from some of the ibrutinib studies that were first performed, there was a suggestion that there was less durability of ibrutinib therapy for patients with deletion 11q. But some recent studies actually suggest, in a larger data set, that might not be the case and that patients with deletion 11q can actually have very durable responses to ibrutinib-based therapy.

Michael Choi, MD: Transformation of CLL to a more aggressive lymphoma is a rare but feared complication, or development, of this disease. Many patients will ask about that, even when they first have been diagnosed. Fortunately, it’s a rare event, occurring in between 5% and 10% of patients. At this point, I do not think there’s still a large amount of understanding regarding what factors can predict Richter’s transformation or transformation to large cell lymphoma.

Some studies have looked at germline mutations and genes like BCL2 or CD38. Some studies have found an association between deletion 17p and an unmutated immunoglobulin gene, also with NOTCH1 mutations. But it should be emphasized that there are many patients with those same factors who do not transform. I do not think any one of those, or even multiple risk factors, destine any one patient for transformation.

There has been a lot of good work done to examine samples from patients who have had transformed disease, and I think there’s a better understanding of the genetic changes that occur. It appears that mutations in P53, c-MYC, or loss of CDKN2 account for about half of the cases. NOTCH1 mutations account for about a quarter. The final quarter are a heterogeneous mix of mutations. But hopefully with that information, we can get better at treating these patients and improving their outcomes, too.

Transcript Edited for Clarity