Updates in Targeted Therapies for B-Cell Malignancies - Episode 1

Ibrutinib's Role as Frontline Therapy in CLL


Ian W. Flinn, MD, PhD: Hello, and thank you for joining us for this OncLive Peer Exchange® titled, “Updates in Targeted Therapies for B-Cell Malignancies.” I’m joined by a group of my colleagues who are renowned experts in B-cell malignancies.

B-cell malignancies represent a diverse group of diseases that form in B-cells. Among the B-cell malignancies are chronic lymphocytic leukemia [CLL], mantle cell lymphoma, and Waldenstrom macroglobulinemia. Today we’ll discuss the diagnosis and treatment approaches for these 3 B-cell malignancies and highlight emerging agents.

I’m Dr Ian Flinn, director of lymphoma research at the Sarah Cannon Research Institute in Nashville, Tennessee.

Participating today on our distinguished panel are:

Dr Matthew Davids, associate director and medical oncologist at the Center for Chronic Lymphocytic Leukemia at the Dana-Farber Cancer Institute in Boston, Massachusetts.

Dr Brad Kahl, professor of medicine and director of the lymphoma program at Washington University School of Medicine in St. Louis, Missouri.

And Dr John Pagel, chief of hematologic malignances and director of stem cell transplantation at the Swedish Cancer Institute in Seattle, Washington.

Thank you so much for joining us. Let’s begin. Matt, I’m going to start with you. I want to first start talking about chronic lymphocytic leukemia and some of the new emerging therapies there. This year at ASH [the American Society of Hematology annual meeting], we saw 3 different presentations on targeted molecules comparing ibrutinib alone or in combination versus various different standard chemotherapies. I think these are really important studies that were presented, and some are now published. Walk us through some of that data and how you think about your approach to chronic lymphocytic leukemia.

Matthew S. Davids, MD, MMSc: CLL therapy has changed quite a bit in the last few years. We’ve had novel agents approved for several years, but it’s really not until this ASH meeting that we saw randomized phase III data comparing ibrutinib to some of the standard chemoimmunotherapy regimens that are widely used. In terms of chemoimmunotherapy, we have several options, so we will often use FCR [fludarabine/cyclophosphamide/rituximab] therapy for the youngest and fittest patients. We’ve used bendamustine and rituximab for older patients and those with comorbidities. Then, for our oldest and frailest patients, we’ve been using chlorambucil with obinutuzumab, which actually has been shown to be superior to chlorambucil with rituximab in the CLL11 study.

At the ASH meeting, we saw comparisons of ibrutinib against all of these different regimens in 3 different studies. Why don’t we go through each one briefly? The first study to mention is the Alliance A041202 study run in the United States, which compared ibrutinib to bendamustine and rituximab. Interestingly, this was a 3-arm study, so it also had an ibrutinib plus rituximab arm. The big picture story with this is, both ibrutinib arms looked superior to bendamustine and rituximab with respect to progression-free survival [PFS], which was the primary endpoint of the study. Interestingly, the rituximab did not add any benefit to the ibrutinib in terms of PFS, and I think another interesting part of this study were the differences based on IGHV mutation status. IGHV can be mutated, which tends to be a more indolent form of CLL, or it can be unmutated, which is a more steadily progressive form.

The benefits of the ibrutinib-based regimens were primarily seen in the unmutated or more aggressive subgroups. The study wasn’t completely powered to look at that, but I think it’s very interesting. We saw a similar PFS and OS [overall survival] in the mutated IGHV groups with chemoimmunotherapy versus ibrutinib, so I think there’s still some room for chemoimmunotherapy in that situation. That was a very important study. It really defined the role of ibrutinib for this large group of CLL patients who might otherwise be getting bendamustine and rituximab.

Now, we have the oldest, frailest patients who get chlorambucil with obinutuzumab, which has been a reasonable regimen. It’s a time-limited 6-month course of therapy. It was compared in the iLLUMINATE study to ibrutinib with obinutuzumab. Again, the ibrutinib arm was superior in terms of progression-free survival. Interestingly, this ibrutinib/obinutuzumab regimen seemed to be particularly active in patients with higher-risk forms of CLL. This study included deletion 17p, unmutated IGHV, and 11q. The PFS for that group looked very strong for the ibrutinib/obinutuzumab regimen. It is designed as a continuous therapy, so that is one consideration as we compare 6 months of chlorambucil/obinutuzumab to continuous ibrutinib with 6 months of combination therapy.

The last study was the ECOG E1912 study, which was presented as a late-breaking abstract at ASH and defined the role of ibrutinib with rituximab compared to FCR [fludarabine/cyclophosphamide/rituximab] in a phase III setting. This was targeted toward younger patients under the age of 70 who were [fludarabine/cyclophosphamide/rituximab] candidates, and again, showed a strong benefit for ibrutinib/rituximab over [fludarabine/cyclophosphamide/rituximab] in terms of PFS. What was surprising to us was that there was also an overall survival benefit starting with the ibrutinib/rituximab strategy. This wasn’t just due to issues with infections from the [fludarabine/cyclophosphamide/rituximab]. There were actually more CLL progression events in the [fludarabine/cyclophosphamide/rituximab]-treated patients early on, so it suggests that ibrutinib is a good option for younger patients, too.

This is the first robust dataset that we’ve had for young patients getting ibrutinib in the frontline setting. Again, the benefits seemed to be greatest for patients with unmutated IGHV. This study excluded deletion 17p patients. For mutated IGHV patients, there was a strong trend toward an improvement in PFS with the ibrutinib regimen, although it wasn’t quite statistically significant. I think it will be interesting to see how that evolves over time. Collectively, these 3 studies have provided very robust evidence that ibrutinib is a great treatment option in the frontline setting for basically all CLL patients.

Ian W. Flinn, MD, PhD: John, do you agree? Is it ibrutinib for all? What do you think about the whole CD20 question with ibrutinib? Is that question dead? The rituximab didn’t really help, but we still don’t know about obinutuzumab. What do you think?

John Pagel, MD, PhD: I think the data here are pretty clear. Matt’s really outlined that well, and the addition of rituximab—not just in these studies, but with other studies, too—ibrutinib has not shown any significant benefit in CLL. Now, the jury is still out with obinutuzumab, and we’ll see about that. Of course, the coming data on upfront acalabrutinib using obinutuzumab as the anti-CD20 antibody will likely give us the answer to that, and whether an anti-CD20 antibody will be relevant in these patients.

Transcript Edited for Clarity