Frontline Management of Chronic Lymphocytic Leukemia

EP: 1.Case Overview: A 73-Year-Old Woman With CLL

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EP: 2.Frontline Management of Chronic Lymphocytic Leukemia

EP: 3.Second-Line Treatment Options for Relapsed CLL

EP: 4.Monitoring and Managing Adverse Effects of CLL Therapy

EP: 5.Ongoing Challenges and Unmet Needs in CLL

Jeff Sharman, MD: With regard to this patient’s treatment when she was newly diagnosed, there’s really no doubt that BTK [Bruton tyrosine kinase] inhibitors are her best frontline option. The other frontline option that may be appropriate for some patients with high-risk disease, or other patients interested in fixed duration therapy, is obinutuzumab [Gazyva] and venetoclax [Venclexta] from the CLL-14 study. One of the challenges with obinutuzumab-venetoclax is that those patients with 17pclearly have asignificantly less favorable outcome compared with their peers who lack 17p when treated with obinutuzumab-venetoclax.

It’s a little controversial in the field as to whether that regimen is suitable for frontline treatment in somebody with 17p. Key opinion leaders are divided on the topic. It’s not absolutely right or wrong. You just need to know that patients treated with fixed-duration therapy in 17p aren’t going to have as durable an outcome as patients lacking that mutation. When we think about comorbidities, of course, we see accumulation of important comorbidities in patients in their 70s. Particularly for a patient I’m starting on a BTK inhibitor, I want to think about their cardiac condition. Do they have preexisting hypertension? Do they have a history of atrial fibrillation? Are they on any sort of anticoagulation? Do they have rheumatologic conditions or significant joint pains or arthritis? These are things that can come up during the course of treatment with BTK inhibitors.

Several recent press releases indicate that second-generation BTK inhibitors appear to have fewer cardiac adverse effects. We have not yet seen the data publicly released but anticipate that it should be available with the summer congresses. So, when we’re thinking about picking amongst BTK inhibitors, those sorts of cardiac baseline considerations are important to consider. Does this patient require therapy at the time of diagnosis? If so, why? My answer is yes. This patient has stage IV disease at presentation, and she has 17p. We weren’t given her past history to know how quickly her condition evolved, but it wouldn’t be completely surprising for a patient with adverse molecular characteristics to need therapy relatively soon.

Patients who have developed thrombocytopenia or anemia generally are the patients who need treatment at the time the bone marrow dysfunction shows up. It would be very reasonable to treat. With BTK inhibitors, we absolutely continue treatment until progression. It’s not a fixed-duration therapy. It’s indefinite therapy. I tell my patients, “If you’re taking metformin, or if you’re taking blood pressure medications, think of this like that.” Nonetheless, I do think patients have apprehensions about taking cancer medication indefinitely. We can tell them that it’s not chemotherapy, but there’s still a concern, on their part, that they’re taking a cancer medicine indefinitely.

For sure, BTK inhibitors, as currently designed, continue until they stop working. Whether patients are able to do that is a matter of quite a bit of research. In terms of monitoring a patient with CLL [chronic lymphocytic leukemia], there are a couple of issues. For my patients on BTK inhibitors, once they are through their first month or 2 and we’ve addressed symptoms, I generally follow up with those patients every 3 months or so. Oftentimes that gives us enough of a clue that something may be changing.

Minimal residual disease [MRD] is a topic that people are very interested in. But in the management of BTK inhibitors as well as PI3 kinase inhibitors, minimal residual disease has a very limited role. Minimal residual disease, for the most part, is a question of chemotherapy-immunotherapy or venetoclax therapy. In the coming years, we’ll see combinations of BTK with venetoclax. When that happens, MRD may become appropriate again.

There are different ways to test for minimal residual disease. There’s flow cytometry, and there are molecular diagnostics. For those patients for whom we want to get molecular testing, you oftentimes need to submit a sample before you initiate therapy. So you have to think ahead if you’re going to be testing for minimal residual disease. Flow cytometry doesn’t require a pretreatment sample, but it also can’t get as deep of an evaluation of minimal residual disease. With venetoclax, MRD gives us an estimate of how quickly somebody is likely to return. But with BTK and PI3 kinase inhibitors, you can expect these patients to have detectable disease for the most of the duration of their therapy. And yet it turns off proliferation rather than eradicating the cells to that level of depth. Minimal residual disease doesn’t play a huge roll for the BTK or PI3 kinase inhibitors.

This transcript has been edited for clarity.