William G. Wierda, MD, PhD: So, let’s move on to treatment. We’ll start the discussion, first, talking about first-line therapy. And maybe, Matt, you can start. The iwCLL guidelines came out. The last version was in 2008 and my understanding is that there’s a new version that’s forthcoming very soon. Maybe you could just briefly review the indications to start treatment, what are we looking for, and which should be the triggers to start treatment?

Matthew S. Davids, MD, MMSc: This is fairly common if you’re familiar with indolent non-Hodgkin’s lymphoma. The criteria are similar but a little bit different in CLL. So, the iwCLL criteria, there’s 3 main groups that I cluster these into. And those include patients who are developing cytopenias that are due to infiltration of the CLL into the bone marrow. There’s different thresholds that we can use. Hemoglobin in the 10 to 11 range is where we start to think about treatment or platelets in the 100 or less range. If patients are developing bulky lymphadenopathy that’s either highly symptomatic or sometimes for cosmetic reasons if it’s in the neck, patients may want treatment. And then the third reason that’s often the most challenging is when patients are having symptoms that are being driven by CLL disease progression. And sometimes, these can be vague constitutional symptoms.

Fatigue is often a common complaint, which may sometimes be related to CLL but may be related to other medical issues. So, if fatigue alone is the presenting complaint, I usually look hard to find another cause if the CLL is not progressing. But in the context of progressive CLL, fatigue, unintentional weight loss, night sweats, and these sorts of things can all be reasons to initiate treatment. More rarely, patients can have autoimmune cytopenias. We try to treat these with steroids or rituximab. But if they’re refractory to those treatments, then sometimes full blown CLL therapy will be required.

William G. Wierda, MD, PhD: How about early treatment? Early treatment for anybody, 17p for example?

Matthew S. Davids, MD, MMSc: So, this has been studied in a number of randomized trials over the years. Most of these have looked at chemotherapy or chemoimmunotherapy-based interventions for higher-risk patients, and these studies have all been negative in terms of an overall survival benefit for early intervention.

Nicole Lamanna, MD: Or not enrolled.

Matthew S. Davids, MD, MMSc: Or not enrolled, that’s true. There’s an interesting ongoing study in Germany now, the CLL12 study, looking at early intervention with ibrutinib, but we don’t have data back from that.

Steven Coutre, MD: Again, high-risk patients.

Matthew S. Davids, MD, MMSc: And high-risk patients. So, I would not advocate early intervention outside of the iwCLL criteria.

Nicole Lamanna, MD: But an important question that hopefully will get answered with the study.

Matthew S. Davids, MD, MMSc: Yes.

Shuo Ma, MD, PhD: One other factor, too, for indication for treatment is the short lymphocyte doubling time. So, when the absolute lymphocyte doubling time is less than 6 months, that could be an indication for treatment, even though it’s kind of a soft criteria.

William G. Wierda, MD, PhD: Any white blood cell count usually it doesn’t happen in isolation. That has been my experience. Is there any white blood cell count at which point patients need to start treatment?

Shuo Ma, MD, PhD: No. So, the absolute lymphocyte count itself is really not an indication to treat. Because CLL patients—the lymphocyte’s different from acute chemotherapy, especially ALL—who have a very high number of white blood cells actually almost never see the leukostasis.

Nicole Lamanna, MD: I think that’s the one thing we do have to caution. So I agree with you. I think that you’re following the doubling time. But I think that they are different. Everybody’s tempo is different and there are some people who may rapidly rise but then plateau for a while and rise again. So, if you want to change the frequency of the visit because they are rapidly doubling, that’s fine because you’re going to try to catch them before they develop cytopenias. We have to caution physicians not to just treat based on the white blood cell count or the doubling because there could be a change of tempo, and it may be OK. You just bring them in sooner to see what’s going on.

Shuo Ma, MD, PhD: Right. And you also have to find out what’s going on with a patient otherwise. For example, I often have patients who had a steroid injection for their arthritis. And then when the next visit comes, their white blood cell count may have had a huge jump. But then you can follow them longer and they go back to their previous baseline. So don’t rush to go into treatment if it’s solely based on white blood cell counts.

Matthew S. Davids, MD, MMSc: One other nuance to that is that if you decide you want to check FISH testing at baseline diagnosis, that’s great. But if a patient goes on observation for a period of time and then has a somewhat sudden change in the rapidity of the lymphocyte doubling time, it’s important to repeat the FISH testing before you start treatment. Because actually, patients can undergo spontaneous clonal evolution to deletion 17p, and you need to know that before you start treatment.

William G. Wierda, MD, PhD: So frontline therapies become more complicated because there’s a lot more options. There are different approaches that people can take, that physicians can take, and patients also are developing their own opinions about what they want and how they want to be managed. So I think we’re going to have some relatively diverse opinions in the next discussion. I think maybe we’ll start with something that probably we’ll all agree on, and that is how to manage a previously untreated patient who has 17p deletion. I think there’s less controversy in that topic. Maybe, Dr. Ma, you can comment on how one would manage a patient with 17p deletion who needs to be treated.

Shuo Ma, MD, PhD: We know from historical data from chemoimmunotherapy that patients with 17p deletion really don’t do very well, and they either don’t respond or if they respond, they have a very short duration response. But with the new development of the BTK inhibitor, currently we have ibrutinib available, so that has definitely shown that even patients with symptom 17p deletion can equally benefit from the ibrutinib therapy. So, nowadays, I think probably most of us would agree that for a patient with 17p deletion, it’s better to avoid immunochemotherapy because not only does it not help, it actually may induce more genetic changes, which may make the disease more aggressive. Instead, those patients would be most suitable for novel kinase inhibitor therapy such as ibrutinib.

William G. Wierda, MD, PhD: Is age an important feature when you’re thinking about that patient with 17p that you’re going to start on a PTK inhibitor or…?

Shuo Ma, MD, PhD: Age will be something, yes. Whenever we start any treatment, we have to look at a patient as a whole: their age, their comorbidities. For chemoimmunotherapy, age is a huge factor. But for kinase inhibitors, age itself is really not an important factor. It’s more the comorbidities and there are other medications that will determine whether there’s any contraindication or increased risk for taking ibrutinib.

William G. Wierda, MD, PhD: So, in terms of the non-17p deletion, maybe we can start with you, Steven. You can comment on what are the features and characteristics that you consider when you’re considering first-line therapy for a patient. What’s important and how do you use that information in your approach?

Steven Coutre, MD: Again, to emphasize, if you haven’t tested for prognostic reasons, this is the time to test mutation status, repeat the FISH. And in many circumstances, particularly as Matt mentioned, it’s sudden change. So, that’s really important because now we’re talking about predictive factors in some cases. And then, of course, the fitness of the patient, however you want to measure that. I think we all can tell after a few minutes talking to our patients whether they tolerate a chemoimmunotherapy regimen. And then, I think a really, really important point is, what’s your goal? What is your goal in that individual patients?

If you’re starting therapy because somebody is 78 and they’ve got bulky neck and head neuropathy, they may tell you, “I don’t want to lose my hair,” and that’s their main goal. And that’s very different than how you might approach somebody who’s 68 who has got cytopenias and bulky disease. So, take all that information, decide what you want to achieve because it’s not one-size-fits-all.

But I think one really important issue is mutation status. It’s clear, repeatedly, that chemoimmunotherapy regimens do not give prolonged benefit in the unmutated patient. And of all the tests that we do, that’s the one that probably is done least often. You can see a lot more FISH testing, which is great. So, that’s really, really important. The kinase inhibitors work equally as well whether you’re mutated or unmutated in contrast to chemoimmunotherapy. If you’re looking at a young patient, let’s say, that’s really important because you might consider chemoimmunotherapy in a fit patient or at least have that conversation with them if they’re mutated. Whereas if they’re unmutated, perhaps, right now we have ibrutinib commercially available. And in the older patients, for tolerability reasons, you might easily just choose ibrutinib. But again, we have obinutuzumab if you want to use an antibody to shrink lymph nodes in an elderly person, that’s your goal. And some people may still want to give bendamustine and rituximab in select patients. So, it sort of depends. But at least we have information to allow us to make choices.

William G. Wierda, MD, PhD: So, repeating FISH and mutation status, those are the 2 lab tests that are most useful in directed therapy and not considering the patient’s age and comorbidities.

Matthew S. Davids, MD, MMSc: IGVH mutations, just to be clear.

Steven Coutre, MD: Yes.

Matthew S. Davids, MD, MMSc: IGVH mutation status.

Steven Coutre, MD: Readily available tests.

Nicole Lamanna, MD: Agreed.

Transcript Edited for Clarity