Q&A: Early Treatment of CLL

Nitin Jain, MD: We’ll move to some other questions. We have 3 minutes left, but we’ll take some questions on early treatment. It’s an interesting topic, and I’d like to get your thoughts on this as well. This question comes up in our group discussion as well with the leukemia group. If a patient has 17p deletion and high-risk features, and we know they’ll progress early, which may lead to Richter transformation, should we still wait for these patients to meet the iwCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria, or should we consider earlier treatment? This is a question I get asked all the time from patients. I’m curious about your thoughts of early treatment and where you think that field is evolving, especially for high-risk patients, like those with deletion 17p.

Richard R. Furman, MD: We need to revisit watch-and-wait. The watch-and-wait paradigm was developed in the 1970s when we couldn’t prognosticate who was going to need treatment vs who didn’t. We also had lousy treatments that had toxicities. Now that we have very effective treatments that don’t have myelosuppression or bone marrow damage, the bar to starting treatment should be a lot lower. When you have a population of people who have a risk of developing Richter transformation, like those who are 17p deleted or TP53 mutated, patients are going to need treatment. It’s not a matter of if but when. Starting treatment earlier may help diminish the risk of them developing resistance to the BTK [Bruton tyrosine kinase] inhibitor or developing Richter transformation. That’s a very important area to explore and something that could be very advantageous to the patients.

Nitin Jain, MD: This is the second-to-last question we’ll take. Would you let WBC [white blood cell] count in CLL [chronic lymphocytic leukemia] go above 200,000 per mm3 without treatment? It’s a question that comes up often in discussions with a patient if it’s a watch-and-wait approach and they have a gradual worsening of their WBC count over years and they’re approaching 200,000 per mm3, or maybe above 200,000 and are at 250,000 per mm3 but otherwise don’t meet iwCLL treatment criteria. In your practice, do you think about starting treatment? How do you think about those patients? Do you have a cutoff in your mind being used for patients for treatment that you won’t let them go beyond a certain number for white blood cell count?

Richard R. Furman, MD: It’s interesting. Seven years ago, we had a lot of reasons to kick the can down the road. I had a patient whose platelet counts fell 10,000 per mm3 every year, and I watched them go from 150,000 down to 70,000 per mm3. When they hit 70,000 per mm3, ibrutinib was approved, so I was able to start them on ibrutinib without worrying about exposing them to any chemoimmunotherapy. Now that we have these agents, there’s far less reason to delay.

Someone whose white blood cell count is 200,000 per mm3 is likely going to need treatment because of the magnitude of the white blood cell count and the fact that it got there. Treating them and even knocking them back to 10 years earlier would provide them with significant benefit in terms of the fact that you might be keeping their immune system in healthier shape. You might be preventing some of the loss of the T-cell function and residual B-cell development. It might help them in the long term. We don’t have data supporting that, but these are people who are having disease that’s progressing and there might be long-term benefits that we’ll never be able to prove but are real, and we should definitely take advantage of that.

Nitin Jain, MD: This is a very good point, because with patients who are slowly progressing vs patients who are rapidly doubling, that’s an easier argument to make. Sometimes these are patients who are slowly progressing, maybe going up every year from an ALC [absolute lymphocyte count] of 20,000 or 30,000 cells per mcl to approaching 200,000 cells per mcl. I recently saw a patient where it was a much higher value where she was just being watched. The question becomes, “Should we treat them?” It’s an area of research where we need to figure out if there’s a magic number or if we should immediately treat them now that we have much better drugs. There are ongoing randomized studies with the cooperative groups and elsewhere looking at this particular question of early treatment for high-risk patients for therapy.

We’ll take 1 last question for you, Rick. I want to clarify this point for the audience. With the first-line therapy with TP53 mutation still being doublet therapy, what’s your approach to a patient with a TP53 mutation in the first-line setting?

Richard R. Furman, MD: My ideal therapy of choice would be BTK inhibitor plus venetoclax. Overall, the way I look at patients with CLL is that 80% of patients could probably get treated with a single-agent BTK inhibitor and be fine indefinitely. But the 20% are the ones who are going to develop resistance to the BTK inhibitor or Richter’s transformation. Of course, we’re probably not perfect in predicting who’s in which group, so maybe we should just treat everyone with a BTK inhibitor plus venetoclax. But certainly, for a 17p deleted patient, the likelihood of them being in that 20% of bad actors is likely, so those are people in whom I’d definitely want to treat with 2 agents to make sure we take care of any BTK resistance that might be developing and keep them from developing Richter transformation. What would your approach be?

Nitin Jain, MD: I agree. We’re also enrolling patients on clinical trials with doublets or triplets. But outside the clinical trial setting, we have BTK inhibitor long-term—for example, acalabrutinib or zanubrutinib long-term therapy. Or once we have the ibrutinib-venetoclax combination available, that regimen would be quite appropriate, whether you can slap the BTK inhibitor onto acalabrutinib, venetoclax, or something like that, because I worry about the adverse effects from ibrutinib. Now that we have a safer BTK inhibitor available, if we’re able to do the acalabrutinib plus venetoclax for patients in this situation, that would be quite appealing.

We’re coming to the end of our time. I hope you all enjoyed this discussion. We have many more questions in the chat box, but unfortunately, we’re not able to get to them. With this, I’d like to conclude this session. Have a good evening. See you later. Thank you.

Richard R. Furman, MD: Have a good night.

Nitin Jain, MD: Good night.

Transcript Edited for Clarity