Treatment Selection Strategies for Chronic Lymphocytic Leukemia

Kirollos Hanna, PharmD, BCPS, BCOP: We discussed tons of information. We talked about BCL2 BTK [Bruton tyrosine kinase]. We talked about finite processing times. We talked about the long-term effectiveness of BTK and BTK plus anti-CD20. Obviously, this landscape is getting extremely crowded and the processing algorithms are getting more complicated. Explain to us the treatment selection strategies for a patient with CLL [chronic lymphocytic leukemia].

Anthony Perissinotti, PharmD, BCOP: The unbiased opinion is to throw venetoclax and obinutuzumab in a hat with ibrutinib, acalabrutinib, and zanubrutinib, and choose one. Honestly, it’s the right therapy for the patient – they’re all fantastic options. My preference is to use venetoclax with obinutuzumab. The reason is that you have a fixed duration. You will treat these patients on the front line for only 1 year. According to the LLC14, the majority of your patients 4 years later will still be off treatment. No. 1, patients are going to stop therapy. They will not suffer adverse effects from a therapy they are not following. Number 2 is the cost of therapy. An analysis was published that looked at a variety of regimens: ibrutinib regimen vs FCR [fludarabine, cyclophosphamide, rituximab] vs chlorambucil-obinutuzumab vs venetoclax with obinutuzumab, therefore the CLL14 study. Over a 3 year horizon, you’re looking at about $350,000 for venetoclax-obinutuzumab, which seems like a lot until you look at BTK inhibitors. You are looking at between $500,000 and $600,000 over a 3 year horizon for most patients.

Based on RESONATE-2 data presented at ASH [American Society of Hematology Annual Meeting], about 60% of patients are still on treatment at 7 years. With a 7 year horizon, you are looking at millions of dollars. From a cost perspective, the majority of patients should receive limited venetoclax-obinutuzumab therapy. That being said, the elephant in the room is COVID-19. None of us want to bring our patients to our infusion centers to receive obinutuzumab. Most of us try to avoid an anti-CD20 monoclonal [antibody] because of the vaccine responses, it is therefore very interesting to write a prescription for a BTK inhibitor, to send the patient home and to do virtual visits. That’s the challenge with COVID-19. We switched to using single-agent oral therapy because of this.

Other patients I would consider a BTK inhibitor for are those who have TP53 changes. the [University of Texas] MD Anderson [Cancer Center] presented its data to ASH. It was about 6 years of follow-up, and 60% of patients are progression-free despite a TP53 mutation. This is very similar to RESONATE-2. Essentially your TP53 patients do as well as any other CLL patient if treated with a BTK inhibitor. A TP53 the mutation sways towards a BTK inhibitor for me, as opposed to venetoclax.

So the question is which BTK inhibitor do you choose? We’ve been using ibrutinib for nearly a decade, so we’ve had a lot of personal experience with it. Most of our patients were still using ibrutinib. If there’s a patient we’re worried about who has comorbidities or cardiovascular disease, and we’re worried about long-term complications, if that patient gets A-fib [atrial fibrillation] or hypertension, what will this mean for their long-term results? We are moving towards using our second generation [BTK inhibitors]. As I said, some institutions have discontinued ibrutinib and are continuing because the data supports it. The data confirms that BTK or second generation inhibitors [BTKs] are better tolerated.

What about your center on the front line? Nothing? I don’t want to give my own bias, but this is my interpretation of literature. This is what I seek for patients. Discontinuation of therapy and cost of therapy are 2 of the most important things, from my point of view, [along with] your ability to deal with toxicities. If you’re comfortable preventing or managing toxicities, I don’t think ibrutinib is a bad option. But if you are uncomfortable and only deal with a few [patients with] CLL per year, you should probably upgrade to the second generation [BTKs]. What are your thoughts?

Kirollos Hanna, PharmD, BCPS, BCOP: I completely agree with you, Dr. Perissinotti. It’s really exciting. In CLL, we can almost say that our patients will succumb to advanced age or other comorbidities unrelated to their disease. We have many interesting options. But I am in favor of what you say and rather in favor of a limited duration of treatment. You limit costs, you limit treatment exposure, you limit adverse events [AE] potential. We know from what we’ve learned that these patients can still respond to some of the therapies that we’ve already used in the finite approach rather than telling someone you’re going to be on ibrutinib for 8, 9, 10 years. This poses a challenge.

This brings us into the bucket of some of the challenges we see in the CLL patient population, which will also help us move into the future outlook for CLL. A challenge that we mainly see in CLL is if you have a patient who is doubly exposed and you have exhausted your BTK and BCL2, what now? Are we going to PI3K? Are we going to chemoimmunotherapy? This is where we have some difficulty with PI3Ks. We’ll talk about exciting things to come, but PI3Ks are hard to tolerate, at least the ones we have that have been FDA-approved in LLC or more widely used, and they’ve really fallen out of favor.

We see a lot of adverse events related to the immune system or adverse events that [result from] immunotherapy, something like a pembrolizumab, for example. We see a lot of colitis, a lot of GI [gastrointestinal] involvement, and many other AEs that many patients are unfamiliar with when on BCL2 or BTK. By then they are older, they are more frail, and they have more comorbidities, so chemoimmunotherapy is not a very good option for many of these patients. What are we doing? Are we enrolling them in a clinical trial looking at all the exciting approaches we’ve seen? Is 1 patient more appropriate than another? It becomes very difficult. But in clinical practice, I don’t see many patients for whom I think of third-line treatment. That’s really exciting to say about CLL these days.

Transcript edited for clarity.

Martin E. Berry