Mechanism and Frontline Use of BTK Inhibitors in CLL

Dr. Brian Hill: Hello, and welcome to this OncLive program entitled Updates on Chronic Lymphocytic Leukemia from ICML 2023 and beyond. My name is Dr. Brian Hill. I'm the director of the Lymphoid Malignancies Program at the Cleveland Clinic Taussig Cancer Institute. I'm joined today by Dr. Paul Ghia. Dr. Ghia, would you like to introduce yourself?

Dr. Paul Ghia: Yes. Thank you. I'm Paul Ghia. I'm professor of Medical Oncology in Milano at Università Vita-Salute San Raffaele, where I'm the director of the CLL program.

Dr. Brian Hill: Very good. So we're going to talk today about updates in CLL and Dr. Ghia, maybe you can just start us off by talking about some of the mechanisms of action of the known BTK inhibitors that are out there.

Dr. Paul Ghia: Yes. The BTK inhibitors have been really the revolution in CLL because they are targeting one of the major mechanism involved in the pathogenesis of the disease. So, in contrast to many other diseases, the BTK is not mutated in patient with CLL, but still is activated due to the signals that the chemic cells receive from the B cell receptor, from the antigen. So they receive a probably almost physiological stimulus through the B-cell receptor through the immunoglobulin. And then the signal is delivered inside the cells, activated the cells inducing proliferation, inducing the survival of the cells, and that is all going through BTK. So that's the reason why by blocking BTK through small molecules, it has been so relevant in changing really the outcome of our patient.

Dr. Brian Hill: What is the mechanism of action of BTK inhibitors and the rationale and the treatment of CLL?

Dr. Paul Ghia: Inhibition of BTK is really revolutionized the treatment of patient with CLL because BTK has shown to be a major target in CLL because it is a major player in the pathogenesis of CLL. And in particular, BTK is on the signaling pathway downstream, the B cell receptor, the immunoglobulin through which the leukemic cells receive signals, from outside, from the antigen, very likely almost physiological antigenic stimulation. The signal goes through BTK and induces proliferation of the cells, the survival of the cells, activation of the cells, which makes them leukemic. So BTK is not mutated, it's really activated through exogenous stimuli. And therefore, by inhibiting that molecule, BTK, then we can induce indeed a response in the leukemic cells. And that translates in the wonderful outcome that we see nowadays with BTK inhibitors.

Dr. Brian Hill: Very good.

Dr. Paul Ghia: And so now talking about BTK inhibitors, what can you tell me about covalent BTK inhibitors? How do you choose them in the frontline therapy for CLL?

Dr. Brian Hill: Yes. So for frontline treatment of CLL has really been revolutionized over the past five to 10 years by the introduction of BTK inhibitors in particular, when compared to Chemoimmunotherapy we have two US trials and other trials from the UK that have shown in head-to-head studies that continuous therapy with oral BTK inhibitors, covalent BTK inhibitors that we improve outcomes and have less toxicity in general compared to chemotherapy regimens such as FCR or bendamustine rituximab. There are alternatives to continuous therapy with BTK inhibitors. We also now have access to venetoclax, which is given in combination with obinutuzumab in a time limited therapy. And we have data from the Derma trials that show now that these are superior to chemoimmunotherapy as well. And in particular, one differentiating factor is that these are what we call time limited therapy. So venetoclax obinutuzumab is typically given for a total of 12 months.

Dr. Paul Ghia: Yes, indeed. So now, novel therapies are definitely the first choice for our patient. How do you select them? What are the factors that you take into your decision?

Dr. Brian Hill: Sure. Yes. So if the decision is made to use a BTK inhibitor, there are three in the US that are FDA approved for frontline treatment. So we have ibrutinib, which in order of approval was the first, followed by acalabrutinib and most recently zanubrutinib. What we'll talk about today is some of the more recent data showing some of the comparative trials and head-to-head studies of what we call second generation or newer covalent BTK inhibitors. And so generally the preference in 2023, I would say, if the decision is made to use a BTK inhibitor, we have data now with acalabrutinib, robust long-term data as well as Zanubrutinib that show very favorable safety profiles and high levels of efficacy.