Experts Share Insight on Ibrutinib's Bright Future in CLL Landscape

Jan A. Burger, MD, PhD

It wasn't that long ago when the chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) was the gold standard for patients with chronic lymphocytic leukemia (CLL).

However, experts in the field say that the explosive FDA approval of the BTK inhibitor ibrutinib (Imbruvica) in February 2014 in the second-line setting—followed with the frontline indication approval in March 2016—has dramatically changed the landscape to one that is much more hopeful for patients.

Ibrutinib has demonstrated its impressive clinical activity as a single agent, and currently is also being explored in combination with other game-changing agents in the paradigm, including the BCL-2 inhibitor venetoclax (Venclexta) to further improve patient outcomes. While there may be some challenge with the novel therapy, experts explain that ibrutinib's future looks bright.

Jan A. Burger, MD, PhD, associate professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and Javier Pinilla-Ibarz, MD, PhD, an associate member of the Malignant Hematology and Immunology Program at H. Lee Moffitt Cancer Center, both shed their expertise on the field of CLL and the transformative role of ibrutinib in interviews withTargeted Oncology.

Javier Pinilla-Ibarz, MD, PhD

TARGETED ONCOLOGY:What was the treatment landscape for CLL like prior to the approval of ibrutinib?

Burger:

It was dominated by chemoimmunotherapy, and the two most used regimens were udarabine, cyclophosphamide, and rituximab, and bendamustine/rituximab [BR].

Pinilla-Ibarz:

The treatment landscape was pretty bad, and was based on chemoimmunotherapy depending on the age of the patient. The classical regimen that we were using [was] FCR and BR in the high- to intermediate-stage patients. The data with chlorambucil came, including a combination of CD20-targeted antibodies plus chlorambucil, and [those were] the options that we had for our patients with CLL. Obviously, in the past, we used different drugs but chemoimmunotherapy was the main kind of regimen. Some people may [have used] single-agent anti-CD20 therapy with rituximab.

TARGETED ONCOLOGY:What is the treatment landscape like for CLL now?

Burger:

The use of chemoimmunotherapy has declined, especially in high-risk patients, and that’s been replaced mostly by kinase inhibitors, including ibrutinib.

Pinilla-Ibarz:

We know that ibrutinib has dramatically changed the current paradigm of CLL. It is true that with certain che- moimmunotherapy in certain populations, the goal was to eradicate minimal residual disease [MRD], as well as prolong the progression-free survival [PFS] of these patients as long as we can because most of them will relapse.

However, a [greater] portion of patients belong to immunoglobulin heavy chain variable regions, which we may recognize as having very long periods of PFS. The introduction of BTK inhibition changed the paradigm because these drugs worked very well. The best example of how we best use this drug was in theTP53-mutant patients, for whom we didn’t have anything—even the single-agent monoclonal antibodies or combination therapies had a very short period of PFS. It was the first signal that these drugs were very powerful and could control high-risk disease.

However, the paradigm is changing and shifting because now we have these drugs—specifically, ibrutinib—that produce very long PFS, improved survival in high risk-patients who can take the drug until disease progression or unacceptable toxicity. But, it is to preserve progression and improve quality of life of all populations. However, eradication of the disease is rarely sustained because we still have MRD—which is well controlled, but [the disease] is there. This is kind of the challenge of the new paradigm.

TARGETED ONCOLOGY:What is the current prognosis for a patient with CLL?

Burger:

It depends on CLL risk factors, but for many patients it’s quite similar to age-matched healthy people. It’s an evolution, because we don’t know, at this time, the precise impact of the new agents on long-term survival.

Pinilla-Ibarz:

All of the data that we present and discuss with a patient is from very old data—most of which is with chemotherapy or chemoimmunotherapy. But we are now changing the disease with BTK inhibitors, for sure. There are new drugs which are going to impact that survival and PFS. The selection of BCR inhibitors is changing as we talk about the natural disease of these patients. At the end, the issue here is that CLL is a very long, prolonged disease. We now know if we give these drugs in the second-line setting, we improve survival. You have to extrapolate the data and put it into perspective, but there is no doubt it is changing the natural history of the disease. [Patients] relapse after 2 to 3 lines of therapy, but previously we had nothing else for our patients. Now, we are prolonging the lives of our patients. In the less aggressive forms of CLL, we still need to see data. Data of the longer follow-up with ibrutinib in the phase I/IIb trial of a small portion of patients with treatment-naïve disease, as well as with classic refractory disease with or without a 17p deletion, is 5 years of follow-up but the frontline trials only have 30 months of median follow-up. We are still awaiting more of the data in the long run.

TARGETED ONCOLOGY:Do you believe that the prognosis has improved over the years?

Burger:

It clearly has improved. Patients with short survival are higher-risk patients who didn’t respond well to chemoimmuno- therapy, and those patients now have a better prognosis with the newer agents.

TARGETED ONCOLOGY:What is your go-to approach for patients who progress on ibrutinib?

Burger:

Clinical trials, and right now, outside of clinical trials, the most established approach would be with the BCL-2 antagonist, venetoclax.

Pinilla-Ibarz:

That is a very good question. Progression off of ibrutinib has been described as a very bad outcome. Progression can happen as a transformation to high-grade lymphoma or in the development of mutations that do not allow ibrutinib to work. Progression is more common in people who previously received multiple therapies; it is way less common in patients who received frontline ibrutinib. It really constitutes the most common reasons for discontinuation for switching therapy. We know there are data with other drugs, such as idelalisib [Zydelig] or with venetoclax. Now, we have tremendous success on getting these patients [other options]. It may be better to use venetoclax based on the high ef- cacy and cytotoxicity of this drug in CLL. We want to have therapies to help the patients when the drugs do not work.

TARGETED ONCOLOGY:What are the patient characteristics, if any, that make a patient eligible for treatment with ibrutinib?

Burger:

It’s approved for all patients with CLL in all lines of treat- ment, so basically any patient could receive ibrutinib treatment, and it’s then an individualized decision if you want to go that route versus alternatives, and that’s driven by risk factors. If patients have low-risk disease then chemoimmunotherapy remains a viable, and oftentimes a very good option, but those are just younger patients who have low-risk disease features, so those are not that common in standard practice.

Pinilla-Ibarz:

For patient with 17p deletion, ibrutinib is the must-have drug to be used. The [younger] population is able to tolerate FCR...and can benefit from this chemoimmunotherapy, but speci cally with FCR and not BR.

For the rest of the groups, [the use of] ibrutinib is up there. We discuss the prolonged therapy of it and some people may not like being on treatment for life and may go on to BR or even chlorambucil because it’s less time on therapy. However, it is a personal discussion with patients.

TARGETED ONCOLOGY:Are there any characteristics that make patients less likely to receive ibrutinib?

Burger:

Ibrutinib-specific side effects can influence a decision towards not using this drug. For example, patients with a history of atrial brillation, or active and symptomatic atrial fibrillation, may experience recurrence or a worsening of their cardiac symptoms. Similarly, in patients with a recent history of serious bleeding events we may choose alternative therapy.

TARGETED ONCOLOGY:Do you have advice for community oncologists managing patients on ibrutinib?

Burger:

Ibrutinib resistance, if that occurs, then my recommendation would be to transfer these patients to a larger center for available clinical trials and to also consider an allogeneic stem cell transplant consult for transplant-eligible patients.

Besides that, it is initially important to prepare patients for redistribution lymphocytosis, which occurs in many, but not all, patients during the first months on therapy. I explain to my patients why this happens, from mobilizing CLL cells from tissues into the blood, as part of the mechanism of how ibrutinib, and other drugs targeting the B-cell receptor pathway, work. Later, it is a matter of monitoring for durability of responses and side effects. High-risk patients, especially relapsed or refractory patients with 17p deletion, should be comanaged with specialists to monitor for emergence of resistance mutations which are more frequent in such patients. Plus, there might be clinical trial or stem cell transplant options for this particular group of high-risk patients that could be beneficial longer-term.

We are looking forward to seeing combinations with ibrutinib with other drugs—maybe in the future we may be able to discontinue the drug. The [length of time on therapy] may be some of the drawbacks for the drug. However, it is a very important discussion that needs to take place with these patients.

Pinilla-Ibarz:

There is the possibility that some side effects may happen, but we don’t have to be concerned about them. [When on ibrutinib], I see patients once a week in the rst month, then every 2 weeks in the second month. Lymphocytosis is not really a problem at all, but you want to be aware of it and ease the patients. At the end of the day, it is not a formal complication; it is just something to be aware of. It is something that we will encourage patients to get control of. It’s going to be more like personalized experience of management of these patients. There are other side effects to be taken into consideration, such as hypertension, and diarrhea can be seen in the first month.

TARGETED ONCOLOGY:Are there any agents or combination approaches currently in development that you find promising?

Burger:

There are a lot of second-generation kinase inhibitors in development which could further improve on the agents that are already approved—ibrutinib and idelalisib—so that’s interesting. They all have potential but then they have to go through randomized studies first to demonstrate any substantial advantages.

Pinilla-Ibarz:

The combination of venetoclax with obinutuzumab [Gazyva] is a trial that is already close to enrollment and we hope to have some data in the next year by the German CLL Study Group. It is one of the things that is exciting the CLL community. Ibrutinib and venetoclax together is another combination being explored and may bring ibrutinib to a situation where we are using it in combination with other drugs.

There are many things coming up, hopefully in the next year or so. We hopefully will see the launch of chimeric antigen receptor [CAR] T cells for CLL; that is something that we know has very exciting data there. However, it is difficult for many companies to fully launch these trials. As you know there [could be potential] for approvals [of CAR T-cell therapy] in lymphomas, and CLL is going to be on the horizon.

TARGETED ONCOLOGY:What are the ongoing challenges in the field of CLL?

Burger:

One challenge is that prices for all drugs, not just ibrutinib, for all medications in the oncology field, have just skyrocketed. It’s gotten very expensive and now we transfer many patients to a very long treatment—kinase inhibitors or BCL2 antagonists given for long periods of time—which makes the expenses for the healthcare systems very high and that’s certainly a challenge. Then the side effects of the new agents can sometimes be a challenge and need to be addressed.

Pinilla-Ibarz:

In my opinion, one of the challenges that we still have for the future is the restoration of the immune system that is affected in these patients. In the future, any intervention that targets the immune system should try to restore the functionality of the immune system so that those patients may protect themselves better—especially from a secondary cancer. This will be a fundamental part of the future of the treatment of patients with CLL.

TARGETED ONCOLOGY:Where do you see this treatment landscape progressing over the next 5 to 10 years?

Burger:

It’s already changing, moving away from chemotherapy-based treatment for many patients, so I think this trend is going to continue. I think there is also going to be a push for combination treatments, where you get patients into deeper remissions by combining new agents with a goal to discontinue treatment at some point, so that patients don’t have to commit to very long and continuous treatment.

Pinilla-Ibarz: