Q&A: Modifying and Switching Therapies in CLL

EP: 1.BTK Inhibitors in the Management of CLL

EP: 2.ELEVATE-RR and ALPINE Trials in Relapsed CLL

EP: 3.Role of Fixed-Dose Regimens in CLL

EP: 4.Resistance Mechanisms to BTKi in CLL

EP: 5.Using Noncovalent BTK Inhibitors for the Management of CLL

EP: 6.Choosing the Appropriate Treatment Strategy in CLL

EP: 7.Novel Treatments for the Management of CLL

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EP: 8.Q&A: Modifying and Switching Therapies in CLL

EP: 9.Q&A: Early Treatment of CLL

Nitin Jain, MD: Let’s go to the Q&A section. We have several questions. I’ll take the first question. What are your main criteria for bringing treatment for CLL [chronic lymphocytic leukemia]? For treatment of CLL, there are standard iwCLL [International Workshop on CLL] treatment criteria. The most recent version is from 2018, and it’s about the same as the previous version. There are several criteria in the guidelines. In clinical practice, they include presence of cytopenias, hemoglobin less than 10 or 11 g/dL, platelets less than 100 per mm3, significant lymphadenopathy, hepatosplenomegaly, or significant symptoms attributable to the disease affecting quality of life. Those are the 3 major criteria. There are some other criteria, but those are the main criteria we use in the clinical practice for those new to the practice to decide to start treatment for patients with CLL.

Let me go to Dr Furman for the next question. What’s the maximum duration a patient could be on venetoclax to get undetectable MRD [minimal residual disease]? Would increasing the duration of venetoclax exposure cause resistance?

Richard R. Furman, MD: This is a very interesting question. We’re still gathering these data. The biggest problem is that clinically we can only do MRD to 10-4. There’s the ability to do 10-6 using next-generation sequencing. There’s a lot going on that we’re unable to determine to whether we’re still seeing improvements in levels of disease lower than 10-4. The clinical outcomes would be the gold standard, and those data aren’t being developed. But looking at some of the CLL14 data, the German CLL Group has shown us that it looks as if there are a significant number of people who still have further improvements in their MRD level when you go from 10-4 to 10-6 with ongoing venetoclax, and some people who start showing signs of progression.

By and large, 12 months is the minimum, and 24 months is probably going to be the maximum. We don’t have the clinical data supporting that, but the idea is that if a patient hasn’t achieved undetectable MRD by 12 months, they may go on to derive further benefit. But if it’s that slow to become MRD undetectable, once they become undetectable MRD, there will probably be a short duration to their response. The rapidity of them achieving that undetectable MRD predicts the long-term outcome. I don’t think increasing the duration is necessarily going to be of benefit in the long term, although it will be of benefit in the short term.

With regard to resistance, it’s certainly interesting to hypothesize the difference between someone who develops progression on venetoclax vs someone who develops progression after discontinuing venetoclax, and whether you can reuse the venetoclax. We don’t know the answer to either. Matthew Davids from Dana-Farber Cancer Institute has identified certain changes in the BCL2 family members that might be bred or selected for with continuous venetoclax treatment. But whether that clinically is relevant also still isn’t clear. Our hope is that by discontinuing venetoclax, you’ll be able to use it later on, but this is still something that’s unfounded that we believe and aspire to.

Nitin Jain, MD: Fantastic. I’ll take the next question first. Should a patient doing well on ibrutinib for 2 years consider adding venetoclax to stop treatment after 12 to 15 months? That’s a question that gets asked in the clinic all the time for patients who have been on ibrutinib for a while. Can we stop ibrutinib? What can we do about it? Some of the patients are thinking about it. There are studies looking at it. In our group, we have a venetoclax consolidation study where patients who have been on ibrutinib for at least 1 year and had detectable disease—most patients have detectable disease—can add venetoclax on top of ibrutinib for up to 2 years in that study.

The data, which were reported at ASH [American Society of Hematology Annual Meeting] last weekend and will be updated at this coming ASH meeting, shows that in about 45 patients that we treated, the MRD-negative rate was in the 60% to 70% range. You could potentially stop the therapy at that time. Some patients have stopped the therapy, and some patients have continued ibrutinib because their treating physician didn’t want to stop the therapy. They wanted to continue ibrutinib. Certainly, adding venetoclax to ibrutinib will get you to MRD-negative remission in a majority of patients.

Whether that means you can stop the therapy and have durable PFS [progression-free survival], it’s possible or likely, but we don’t have the long-term data for that. Outside a clinical trial setting, I don’t think this is a strategy, or at least I’m not adopting in clinical practice yet. We have to see how these trials mature. I’m aware of the University of Texas MD Anderson Cancer Center trial, but I’m sure there are other groups also looking into this in some fashion, consolidation strategies on ibrutinib to see how we can come off ibrutinib.

I recently saw a trial designed where CAR [chimeric antigen receptor] T strategies were in the same space as patients who were on ibrutinib for a while. Then we give CAR T and then are obviously able to stop, do the CAR T onetime approach, and then eventually be able to stop ibrutinib as well as most of these patients are getting MRD-negative. That’s an exciting field of research but not something I’m doing in clinical practice on a day-to-day basis. Rick, do you have any suggestions about ibrutinib consolidation with venetoclax? What do you think about that strategy?

Richard R. Furman, MD: One of the things I worry about is if a patient is tolerating a therapy well and responding to it and not having any evidence of toxicity, I’m hard-pressed to want to mess with what’s working. It would be nice to discontinue therapy. It would be nice to say to the patient, “There’s no detectable disease,” and stop therapy. The adage is, “You can’t improve upon on an asymptomatic patient.” Unless we have some idea about the downside to continuing the therapy, I’m always a little cautious to jump in. But with ibrutinib, the risks of hypertension give me a lot of pause. Of course, hypertension is something that could have a huge effect on longevity. That issue is going to be different when you start talking about something like zanubrutinib or acalabrutinib, which don’t have those issues in terms of affecting long-term welfare.

Nitin Jain, MD: There’s a question about headaches with acalabrutinib. Does hypertension contribute to headaches with acalabrutinib? My experience has been that patients come in, and they certainly can get headaches without hypertension. Headache is generally an earlier event. It can start within days of starting acalabrutinib. It’s usually more prevalent during the first month and tends to go away, not necessarily that the patient is having hypertension as well at that time. Most patients are normotensive. I don’t think we truly know what causes headache for patients with acalabrutinib in terms of the mechanism. But drinking caffeine, such as coffee, helps these patients. For most of the patients, the headaches are very low grade. They’re milder events. Some patients can have significant headache where we have to interrupt the drug. Most of the time, the patients are able to resume the drug, sometimes at a lower dose. That’s a somewhat unique adverse effect with acalabrutinib, which I don’t think many of the drugs have.

Richard R. Furman, MD: It’s interesting when you think about it, because it isn’t something that’s obviously BTK [Bruton tyrosine kinase] driven.

Nitin Jain, MD: Yes.

Richard R. Furman, MD: Some people have hypothesized about it being related to calcitonin-related peptide. We now have inhibitors of calcitonin-related peptides as prophylaxis for migraines and treatment of migraines. That might be something down the road, but as you pointed out, the headaches tend to be mild and tend to abate within the first 2 to 4 weeks. It’s truly rare for someone to not be able to remain on acalabrutinib because of the headaches.

Transcript Edited for Clarity