Pathophysiology, Prognostic Factors, and Potential Risks That Influence Treatment in CLL

Steven Coutre, MD: We take a number of factors into consideration when [we’re] making a decision about which regimens to use for a patient. And it’s important to individualize things according to that particular patient. We have prognostic factors. Remember, prognostic factors mean they might predict time to treatment; for example, time to initial treatment. But, they’re not predictive. Predictive factors really are factors that influence how patients may respond to a given therapy and therefore may influence what therapy you choose for that patient. So, I think even if you don’t believe in measuring some of the prognostic factors—chromosome abnormalities that we measure by FISH, for example, or the immunoglobulin mutational status—I would advocate obtaining that information when you’ve decided that a patient needs treatment.

Right now, the major issue there, of course, is deletion 17p. Fortunately, maybe 5%, 6% of patients have deletion 17p at presentation. Admittedly, it’s not the majority, but it’s very important to know that because those patients don’t respond to standard chemoimmunotherapy and clearly a drug like ibrutinib would be the treatment of choice. But, I think getting that information at initiation of treatment is still quite helpful, especially later in their course if you’re having to decide on a second-line therapy.

As you know from your own practices, you have a lot of treatment choices for younger patients. Fitness can influence things. That may be a patient you’re not interested in giving FCR (fludarabine, cyclophosphamide, rituximab) to, and I think that’s one of the major reasons why bendamustine and rituximab (BR) has become so popular. So, perhaps that late 50-year-old patient who has significant comorbidities, you might have chosen bendamustine/rituximab. Remember, in the German trial of FCR versus BR, we learned that FCR was superior in terms of progression-free survival, but we also learned that BR was better tolerated; there was less of the infections risk associated with it. I think, historically, this patient would get bendamustine/rituximab; it’s still a reasonable choice. But, of course, we have ibrutinib, and that’s also a very reasonable choice. And I think as we get more data on the use of ibrutinib in this kind of setting, and certainly data from randomized trials, then we’ll learn more about the role of ibrutinib here. In my practice, if it was outside of a clinical trial, I wouldn’t have any hesitation to prescribe ibrutinib. You have that conversation with the patient—here’s the options, here’s the pros and cons—and then really make a joint decision.

Part of the conversation you have with your patient, of course, is the risks and benefits of each of the therapies that you’re discussing. So, let’s use bendamustine and rituximab as an example. It is a time-limited therapy, twice a week, 6 months in a row, with some risk of myelosuppression, some risk of infection. That infection might lead to hospitalization in some cases in order to treat that infection. And there’s the need to come in for the infusions. Most patients respond to some degree, and the expectation would be that that response duration is about 3 years, maybe 3.5 years. Those are the data we have with bendamustine and rituximab up front. Remember, that patient’s still young, so you’re going to be facing another treatment decision in the not-too-distant future.

And then we have ibrutinib, and we know that these patients respond. Virtually every patient is going to respond to the treatment; primary resistance is really virtually unheard of. And most patients are not going to stop the therapy or be unable to derive the benefit because of an adverse event, at least with their initiation of treatment. It is an oral drug, take a pill, you don’t have to come in. The potential drawback for now is, it’s continuous therapy. We don’t have any recommendations at this point as far as how long somebody needs to take treatment. So, that’s a question that patients often ask, and it’s something that we’re addressing in ongoing trials.

We’ve learned a lot more about the biology of hematologic cancers like CLL. And by understanding the mechanisms of what gives these cells a proliferative advantage and anti-apoptotic signal that we see in these cells, we’ve been able to identify signaling pathways and proteins in these pathways that regulate these processes. One example might be Bruton’s tyrosine kinase; that’s a target of ibrutinib. And by targeting these pathways, we can reverse those advantages. So, it’s a completely different way of approaching treatment, very different than traditional chemotherapy and even different than immunotherapy. I think those insights are really changing how we approach treatment in patients with CLL.

We also can identify subgroups of patients. Everyone is talking about precision medicine these days and tailoring therapy; we have a little bit of that in CLL. You can look at specific abnormalities in chromosomes by a very simple test. A FISH (fluorescence in situ hybridization) test from the peripheral blood identifies patients who are at higher risk of progression and, in some cases like with deletion 17p, identifies patients who respond differently to different therapies. And so, those are the kinds of insights that we’re looking for to help us better choose treatments for our patients. And I think that’s where the field is going. Hopefully, we’ll be able to better tailor the choices we have toward specific patient groups.