The treatment of CLL is really undergoing a transformative period, largely because of these new oral agents. They&rsquo;re really targeted therapies rather than traditional chemotherapy or chemoimmunotherapy. In the last several years, we&rsquo;ve seen an acceleration of the development of these drugs and broader use of them.

In terms of up-front therapy, we&rsquo;ll often break down patients into several groups, perhaps an older patient, a younger patient. Sometimes we also differentiate by fitness, meaning how well they might be able to tolerate a given therapy. One thing to keep in mind is that for CLL, the average patient at diagnosis is over 70, so I guess you&rsquo;d call that older. For that typical patient, in the past, perhaps we might not consider as aggressive a treatment regimen. If patients were less fit, we would choose agents based on those criteria. Those boundaries are blurring a bit now because newer agents, drugs like ibrutinib, are very well tolerated. You could consider giving them to older patients, the patients who are less fit. There is nothing wrong with giving it to a younger patient who is fit either.

Our standard approach, traditionally for treating CLL, whether in the frontline setting or in the relapsed setting, has been chemotherapy or chemoimmunotherapy. Combination therapy has become much more relevant. The immunotherapy aspect is usually an antibody, like rituximab used in combination. For example, we have several very standard regimens: bendamustine and rituximab, and the FCR regimen (fludarabine/cyclophosphamide/rituximab). Those were often our choices. In older patients, single-agent therapy, like chlorambucil alone or maybe chlorambucil plus rituximab, can be used. We&rsquo;ve had another antibody approved for use in CLL, obinutuzumab, and an older drug, ofatumumab. Different choices and how you combine those and how you sequence them is quite variable.

With newer oral agents that are extremely effective and also very well tolerated, we&rsquo;re going to see that all change. Certainly, in the relapsed setting, in patients who&rsquo;ve already had standard chemoimmunotherapy, there&rsquo;s generally no reason not to use a drug like ibrutinib. If you repeat a regimen, a chemoimmunotherapy regimen, or give one that&rsquo;s a little different, you often have fewer patients respond, and that response duration is shorter. You&rsquo;re still going to be facing that issue down the road. Whereas with a drug like ibrutinib, right now we&rsquo;re getting very prolonged responses and we may be able to continue to manage patients for many years with that approach. As we get more data in direct comparison to some of our chemoimmunotherapy regimens, we&rsquo;ll see increasing use of ibrutinib.

Initiation of Up-front Therapy for CLL

The RESONATE-2 trial is a randomized phase III trial for previously untreated patients who needed therapy by our traditional criteria, but had not previously had any treatment for their CLL. It compared a drug, chlorambucil, which has been around a long time, which some would consider standard-of-care in older patients, versus ibrutinib. The trial was limited to older patients, those over 65 years. We often use that cutoff, since the average CLL patient is in their 70s. Therefore, it is very realistic to look at that population. The trial simply asked the question, if one treatment was better than another, with the primary endpoint being progression-free survival, did patients do better for a longer period of time?

There&rsquo;s other secondary endpoints, such as response rate and safety. What this study showed was a very significant difference between the two treatment arms in favor of ibrutinib. Progression-free survival was significantly longer. Even with fairly short follow-up of the study, a median follow-up of about 18 months, there was an overall survival advantage. People lived longer if they received ibrutinib as their initial therapy. From a safety perspective, there was really no difference across the board, certainly no increased safety concerns with the use of ibrutinib. Chlorambucil is a bit more myelosuppressive, so you see more effects on the blood counts. In contrast, with ibrutinib, you usually see very prompt and very sustained improvements in cytopenia, which often are problematic and often are the reason to start therapy in patients with CLL. From the perspective of bringing a better therapy, better in terms of responses, better in terms of tolerability, better in terms of something that&rsquo;s easy for our patients to use, it really kind of met all of those criteria.

In addition, in the study, we had patients between ages 65 and 70, and then we had those 70 and older. Those 70 and older would be an average CLL patient who is starting therapy, and we saw benefit in both groups. There really was no distinction. It also speaks to the fact that it&rsquo;s well tolerated. Often patients who are older have more comorbidities, such as diabetes and hypertension, which didn&rsquo;t impact either the efficacy or the tolerability of the treatment.

Upfront Ibrutinib: RESONATE-2 Trial 

Ibrutinib was approved several years ago for patients with CLL who have had prior treatment. It also was approved for initial treatment if patients had deletion 17p, but that&rsquo;s uncommon at presentation. Because of the RESONATE-2 trial, it very recently received approval for initial treatment of patients with CLL. That really broadens our ability to use the drug in patients as up-front therapy. With an FDA approval, it&rsquo;s much easier to obtain it for a patient, from an insurance perspective. In our practice, where we&rsquo;re largely doing clinical trials, that&rsquo;s not as relevant. For a patient treated in the community, it&rsquo;s all about what they&rsquo;re able to obtain, as well. We&rsquo;ve seen with the approval in the frontline setting, that it&rsquo;s quite easy to access the drug for an appropriate patient. In our treatment algorithm overall, it&rsquo;s really being integrated in the context of a trial or in standard practice for pretty much all patients. It gives you another very good option when you&rsquo;re making that decision about what&rsquo;s most appropriate for that individual patient.

Physicians often ask, &ldquo;What do we do after ibrutinib? What if a patient progresses?&rdquo; Fortunately, that&rsquo;s not been all that common. There are some published data on that, but one has to be very careful about interpreting that data because that study involved heavily pretreated patients who were receiving ibrutinib. In many cases, they had exhausted all prior conventional therapy and had quite advanced disease. That&rsquo;s a very different patient receiving ibrutinib than someone receiving it as initial therapy or even as second-line therapy after an FCR (fludarabine/cyclophosphamide/rituximab) regimen. Those patients didn&rsquo;t do well, and that&rsquo;s not a surprise, because they didn&rsquo;t have other treatment options.

For someone receiving it earlier, I would argue two things. First, we do have other treatment options for them, including newer oral drugs, as well. Second, it&rsquo;s a very different patient population, and the progression is going to be much less common. Also, those patients will respond to subsequent therapies, whether they be traditional chemoimmunotherapy or other novel targeted agents. The idea that you want to hold back your best for later, if you&rsquo;re calling ibrutinib your best, I think you have to move beyond. There&rsquo;s nothing wrong with using your best therapy initially.

Patient Selection for Upfront Ibrutinib

We often treat older patients with ibrutinib. We&rsquo;ve certainly treated them in the context of the trials, and we&rsquo;ve treated those patients with commercially available ibrutinib now that it&rsquo;s approved as frontline therapy. A very typical patient would be one that I saw last week; for example, a 78-year-old woman who I had been following for a number of years who presented initially with an asymptomatic lymphocytosis and over the years has had some increase in her lymphocyte count. She&rsquo;s developed some adenopathy, as well as anemia, and now it&rsquo;s gotten to the point where she&rsquo;s significantly anemic and it&rsquo;s impacting her quality of life. She&rsquo;s symptomatic, so she really meets the standard need for treatment. She made it very clear that she&rsquo;s not interested in losing her hair, and she also didn&rsquo;t like the idea of chemotherapy.

It&rsquo;s a good example of really looking at your individual patient and then deciding what your goal is. What do you want to accomplish when you&rsquo;re choosing a treatment in this particular patient? It&rsquo;s not just a one-size-fits-all. It&rsquo;s not that I treat everyone with this regimen as initial treatment. You always look at your options and then make a decision. For her, it was rather easy. We have an oral therapy that&rsquo;s approved and well tolerated. We know it&rsquo;s going to work, and we use that option. Really reassure the patient that not only are we going to see a response, and she is going to feel better because we&rsquo;re effectively treating the disease, but she&rsquo;s likely to tolerate it very well.

Chronic Lymphocytic Leukemia with Steven Coutre, MD Case 1

Initiation of Up-front Therapy for CLL

Upfront Ibrutinib: RESONATE-2 Trial

Patient Selection for Upfront Ibrutinib

Ibrutinib in Older Patients with Newly-Diagnosed CLL