BCL2 Inhibition in Leukemia - Episode 1
Harry Erba, MD, PhD:Welcome to thisTargeted Oncology™ presentation in precision medicine called “BCL2 Inhibition in Leukemia.” I am Dr Harry Erba, a professor of medicine and the director of the Leukemia Program at Duke University in Durham, North Carolina.
BCL2 has been a promising target, and the new clinical experiences with venetoclax bring great promise. Today we will discuss the rationale for and historical experience with targeting BCL2, provide an overview of the venetoclax clinical data, and discuss future directions.
Please join me in welcoming my colleague, Dr Matthew Davids, an assistant professor at Harvard Medical School and a medical oncologist and an associate director for the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts. Welcome, Dr. Davids.
Matthew Davids, MD, MMSc:Thank you, Dr Erba.
Harry Erba, MD, PhD:Let’s begin. Why don’t we start with a discussion of the goals of our therapeutic interventions for patients with CLL [chronic lymphocytic leukemia] and maybe even start with, Do all patients need therapy?
Matthew Davids, MD, MMSc:Often, CLL patients present with stage 0 disease, meaning they just have circulating lymphocytes but no other symptoms or signs of the disease. And actually, we can safely observe these patients, sometimes for many years. The indications for treatment have not changed: they remain advanced-stage disease, which includes cytopenias, anemia, or thrombocytopenia; bulky organ-threatening lymphadenopathy or splenomegaly; or constitutional symptoms that are being driven by disease progression, so-called B symptoms. In the absence of those, we still observe, but patients often do require therapy. And we fortunately have a variety of different treatments we can offer them now.
Harry Erba, MD, PhD:When you start to evaluate a patient with CLL, is there anything besides stage of the disease and symptoms that you look at in determining treatment options and risk stratification?
Matthew Davids, MD, MMSc:To risk stratify CLL patients, we have a number of different factors and tests that we can send, and we find it useful to send these early in the course because it helps really predict how the patient will do over time. The key factors include FISH [fluorescence in situ hybridization] cytogenetic testing, which can identify a high-risk subgroupfor example, deletion 17p, which can have relatively rapid progression of the disease. Other abnormalities, like deletion 11q, are accompanied by certain specific clinical scenarios, like bulky lymph node disease, that are central and often not palpable, for example. And other factors, like trisomy 12 and deletion 13q, all have a typical course in which we know what to expect.
The second factor that’s very important is theIGHVmutation status. This can be either mutated, which is the more indolent or slow-moving CLL, or unmutated, which is a more steadily progressive disease that usually requires therapy within a few years of diagnosis and, at least historically, has a much shorter duration of benefit from chemoimmunotherapy-based approaches. Those are the 2 key factors that we check: FISH andIGHV. But increasingly, we like to send forTP53mutation status as well. We notice that these patients often do poorly just like deletion 17p patients, and it’s helpful to identify them up front, because it helps to predict the course of the disease but also to select therapy.
Harry Erba, MD, PhD:I’ve heard some investigators and clinicians like to check karyotype as well. Is that something you recommend?
Matthew Davids, MD, MMSc:Yes. Typically, we do send karyotype testing. I think we have to be a little careful with that because you need a very experienced lab that’s sending a stimulated karyotype. In CLL, we don’t often see many abnormalities with typical metaphase karyotype. And so if you have a lab that’s experienced with doing karyotype testing and can do the stimulated karyotype, it can be useful, mainly because we’ve noticed that patients, even on the novel agent-based therapies, do tend to have a shorter duration of benefit when they have complex karyotype, particularly if that includes deletion 17p as 1 of the abnormalities.
Harry Erba, MD, PhD:I think a lot of times people wonder about what this mutated form of the immunoglobulin heavy-chain gene is. I find it fascinating. It really tells us something about the biological subsets of lymphocytes that are becoming neoplastic, the pregerminal center versus 1 that’s already been exposed to antigen in the germinal center.
Matthew Davids, MD, MMSc:Right.
Harry Erba, MD, PhD:But you have to clone, you have to PCR [polymerase chain reaction]amplify the variable region and get it sequenced and look for a difference of what, about 2% from the germline sequence?
Matthew Davids, MD, MMSc:That’s right.
Harry Erba, MD, PhD:As I remember, there were some older assays that were felt to correlate with that, likeZAP70,CD38. Are these things that we should still be checking, or do you think we’ve moved on now to immunoglobulin heavy-chain mutational status?
Matthew Davids, MD, MMSc:That’s a great question. We often do still seeCD38andZAP70testing being done in various labs. And 1 of the challenges with these tests is that they are highly variable. Even in a given lab on a given day, you may see variation in the level of expression of these. Even though there is some value if you’re not able to get an IGHV test, we do think theIGHV-mutation status trumps those other factors. If you have access to good testing forIGHV, it’s no longer necessary to getCD38orZAP70testing.
Transcript edited for clarity.