William Wierda, MD, PhD: Indications for starting treatment haven’t changed recently, so we’re still using those indications that we used for many years, which are aggressive anemia, progressive thrombocytopenia, or disease-related symptoms that we want to go away and that are impacting the patients' quality of life. John Burke, maybe you can help us understand how you think about prognostic factors and how they're useful in terms of selecting first-line therapy. What are the things that you're thinking about when you're assessing the patient and deciding on first-line therapy, in terms of the prognostic factors?

John Burke, MD: I think for the prognostic factors—some of them we’ve already discussed—I go through the CLL-IPI [chronic lymphocytic leukemia International Prognostic Index], of which one of the factors is age. The older the patient, that's an adverse factor. The more advanced the stage, the farther along the disease is. I look at IGHV mutational status, which seems to be the most important as a prognostic factor with chemotherapy. I look for 17pdeletion and other chromosomal abnormalities on the FISH [fluorescence in situ hybridization] panel, and then on the next-generation sequencing panel, I look at the TP53 mutation and other mutations like BIRC3, SF 3B1, and NOTCH1 mutation.

Those are things I look at. There is this formal CLL-IPI score that one can calculate. I confess I don't often actually do the math, but I look at those factors when I'm thinking through the patient and his or her prognosis.

William Wierda, MD, PhD: In terms of thinking about options for first-line therapy, we've had chemoimmunotherapy for many years now. We have BTK [Bruton tyrosine kinase] inhibitor-based therapy. We have BCL2 inhibitor-based therapy. Help me understand a little bit about how you select which treatments you're going to use, because we know and we’ve known for many years that agents work best in the front-line setting. Therefore, the response rates with a BTK inhibitor are going to be higher and the progression-free survival is going to be longer for a BTK inhibitor, for example, when used in the front-line setting compared to the relapsed setting.

Selection and choice of first-line therapy is an important decision to make for patients. We have options, and we have a lot of data to support what our decisions are. We have differing opinions in terms of how to prioritize and how to select front-line therapy. John Burke, we'll start with you, and maybe you could just highlight what are the factors that help you select for a BTK inhibitor versus a BCL2 inhibitor versus chemoimmunotherapy.

John Burke, MD: I would say for most patients, the choice comes down to a BTK inhibitor versus BCL2 inhibitor, venetoclax-obinutuzumab combination. The exception where it becomes even more complicated, I would say, is the younger, fit patient who has favorable risk factors, that is, mutated IGHV and lack of any adverse factors on FISH and lack of a 17p deletion and TP53 aberrancy.

I think the reason is that that group of patients seems to have a particularly good outcome with FCR [fludarabine, cyclophosphamide, rituximab] and chemotherapy. As you and your group have shown, potential for significant percentage of those patients treated with FCR to continue to be disease free well beyond 10 years now, so that's a group that seems to get particular benefit from the FCR regimen. In that group, I think the FCR regimen or something similar to that still comes into play as an option.

For most everyone else, the choice in my mind is probably going to be a BTK inhibitor versus venetoclax-obinutuzumab. How do you choose between those? Honestly, it doesn't have as much to do for me with the disease, the biology, the gene mutation, etc. A lot of it comes down to other factors related to the patient and the patient's preferences. For example, venetoclax-obinutuzumab is a 1-year, fixed-duration therapy. That's a big difference from indefinite therapy with a BTK inhibitor. That factor of the different duration of therapy comes into play in that discussion. Other factors like the presence of underlying cardiac disease, atrial fibrillation, or use of an anticoagulation therapy really is going to knock BTK inhibitors a little bit to the side because of their toxicity profile. That's going to help make the decision. For the patient who doesn't have the obvious contraindication, it comes down for me to patient preference. As Dr Shadman said, it's really a long conversation over a period of many visits, often weeks or months, and sorting out what works for the individual patient. So, that's how I approach it.

William Wierda, MD, PhD: So it is highly individualized, and it sounds like you engage the patient quite a bit in the decision.

John Burke, MD: Absolutely, yes.

Transcript Edited for Clarity