COMMENTARY

Advances in Treating Chronic Lymphocytic Leukemia: Toward a Chemotherapy-Free Future

Bruce D. Cheson, MD; Kanti R. Rai, MD

Disclosures

December 15, 2015

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Bruce D. Cheson, MD: Welcome to Medscape Oncology from the 57th annual American Society of Hematology (ASH) meeting in Orlando, Florida. I'm Bruce Cheson, deputy chief of hematology/oncology and head of hematology, Georgetown University Hospital and the Lombardi Comprehensive Cancer Center. I am delighted to be joined today by my dear friend, Dr Kanti Rai, from North Shore-Long Island Jewish Health System, who is chief of the chronic lymphocytic leukemia (CLL) program. Thank you for joining me, Kanti.

Kanti R. Rai, MD: Thank you very much, Bruce. It is a pleasure, as always, to be associated with you in any form.

Dr Cheson: Don't believe a word he says, except when we talk about the abstracts from today. This is a very exciting meeting. We are seeing some data that we have been waiting a long time for in CLL. For the last couple of years, we've been seeing data coming out on these new drugs in relapsed or refractory patients, and now we're seeing activity of drugs in the frontline setting. I think that the RESONATE-2 trial is of particular interest.[1] Tell me what you think about it.

RESONATE-2: Ibrutinib as Frontline Therapy for CLL

Dr Rai: You're right. RESONATE-2 is a very important trial that compared ibrutinib, the Bruton tyrosine kinase (BTK) inhibitor that already has been proven to be very effective in salvaging patients with relapsed or refractory CLL, but now bringing it to the frontline setting and comparing it with chlorambucil. This was a large, international, randomized, multicenter study in which patients either received ibrutinib, in the standard doses for which it has been approved in the relapsed or refractory setting, or chlorambucil in standard doses. What the trial demonstrated, and not at all as a surprise, is that ibrutinib is an extremely effective drug in inducing overall remissions and extending the duration of those remissions in a much more effective manner than the control arm, chlorambucil.

Toxicity wise, ibrutinib did not show any surprising new toxicities other than what we already are familiar with in the relapsed or refractory setting. Therefore, this is an extremely important study. I am hoping that this will bring ibrutinib approval from the regulatory agencies for frontline use because ibrutinib is approved by the US Food and Drug Administration (FDA) for patients with 17p deletion, who have an extremely poor prognosis, and as frontline treatment in patients with 17p deletion. This trial enlarges the frontline scope.

Dr Cheson: Now, let's say that the FDA approves this drug for use in the frontline setting. Should everybody now get it, instead of bendamustine and rituximab (BR), fludarabine and cyclophosphamide with rituximab (FCR), obinutuzumab and chlorambucil, and some of the other regimens already approved? Should we all jump on that bandwagon?

Dr Rai: No. I will be very cautious, naturally. From a statistical and clinical safety point of view, the point has been made. But [we must be cautious until] we have had the luxury of larger sample sizes assuring ourselves that no newer toxicities or any other unforeseen problems emerge. Therefore, I would say that we do have fairly good, effective frontline regimens—for fit patients, we have FCR; for unfit or elderly patients, obinutuzumab plus chlorambucil; and for relatively older and not so fit patients, BR. These regimens are in the comfort zone for frontline use; however, I'm sure that with the passage of time, ibrutinib will also become a very important choice.

Treatment Options After Ibrutinib Failure

Dr Cheson: Let's say that physicians elect to use ibrutinib frontline when it's approved. Ibrutinib gets you partial responses in most patients but not very many complete responses, so patients will eventually progress. The question will be, "If I use ibrutinib upfront, what am I going to do when it fails?" Right now, you give patients BR, FCR, or one of the other regimens, and if those treatments fail, you give them ibrutinib. Ibrutinib moves up front. What have we learned from this meeting about life after ibrutinib?

Dr Rai: Very good question. Fortunately, there is hope for people who have been treated with ibrutinib and need something more or new. An abstract presented by Anthony Mato demonstrated in a multi-institutional study[2] that for patients who have had one of the two currently approved BCR inhibitors, such as ibrutinib as a BTK inhibitor and idelalisib as a BI3 kinase inhibitor, if the patient has failed or become resistant to, for example, ibrutinib, that idelalisib is quite effective in salvaging. Similarly, idelalisib failing patients can be effectively salvaged by ibrutinib. A similar result was obtained by my colleague, Jacqueline Barrientos, in a single-institution study confirming essentially what Dr Mato presented.[3]

So one alternative for patients in whom frontline ibrutinib has failed is idelalisib, but there are other drugs emerging that we might talk about such as the B-cell lymphoma (BCL)-2 inhibitor venetoclax, which has been tested and reported at this ASH meeting in a number of settings, including relapsed or refractory CLL. That is one other likely choice on the horizon because venetoclax has not been presented to the FDA yet, and then you have every reason to test whether FCR, BR, or obinutuzumab may also have some value in this circumstance.

Considering New Drug Combinations for CLL

Dr Cheson: What we are also encountering is a plethora of new drugs and combinations of drugs. I think it's highly unlikely that we're ever going to cure CLL with a single agent. I may be wrong down the line. These drugs get you mostly partial remissions, and patients need to stay on these drugs indefinitely. There are cost issues, clearly. We're seeing lots of studies of drug combinations; how do we decide which two or three drugs to put together?

Dr Rai: I think you make an extremely important point, which is relevant from society's point of view, patients' point of view, and clinical investigators' and clinicians' points of view. However, I will not go into the elephant in the room, which is cost. You and I are not going to be able to solve this because America as a country will have to handle this. This is not just relevant for CLL but for all human malignancies.

Let us say that the most important observation that you just suggested is the potential of combinations. You are absolutely right that idelalisib, ibrutinib, and all other drugs that have come up recently with a great degree of enthusiasm are not cures. They achieve good-quality remissions, and progression-free survival is long, but the bone marrow is not as cleaned out as we have seen with FCR or BR. With the combination of ibrutinib or idelalisib with other things that are preferably not another chemotherapy, there are a number of abstracts in this ASH meeting in which ibrutinib has been combined with BR or with bendamustine. Similarly, idelalisib has been combined with other agents.

We are hoping that if we combine the newer agents that we are comfortable calling "non-classic examples" of chemotherapy—idelalisib and ibrutinib, or ibrutinib and venetoclax, or ibrutinib and obinutuzumab—these combinations make patients more comfortable that they are not getting indiscriminate cytotoxic agents, and therefore they are hopefully protected from adverse myelotoxicity-related side effects. But those regimens have to be tested. We are going in an appropriate manner, step by step. First, identify and get a new activity proven, and then move to combining with other agents.

Dr Cheson: I completely agree with you, but there was an interesting abstract in this meeting combining venetoclax with an anti-CD20 (rituximab), and what was very impressive was not only was the response rate extremely high, but many of those responses were complete remissions, and most of the complete remissions were associated with eradication of minimal residual disease.[4] I think that's getting us a little closer to where we want to go.

Dr Rai: I agree. There was also an abstract presented by Ian Flinn evaluating venetoclax and obinutuzumab, also showing an amazing level of activity.[5] Ibrutinib and obinutuzumab, as you suggested, is an amazing combination, and we have to see more of the patients treated with good, reliable, and solid results.

Dr Cheson: Well, I think what we can draw out of this meeting is that this is a very exciting time, and we really are on the way to a chemotherapy-free future for patients with CLL. Now the drugs that we're testing and looking at, and using in the clinic, do have toxicities. Some of them may be more prominent in the frontline setting, as we're going to see in some abstracts on idelalisib, but now we have second- and third-generation drugs. There's an interesting abstract on ACP-196, with a 93% overall response rate in patients with CLL.[6] I think that we're heading towards a time with more effective therapies and, hopefully, less toxic therapies.

Dr Rai: I agree. I think that the last word has not been written yet, as you suggested with ACP-196, as well as with the other BTK inhibitors in the pipeline. Some of these agents are being presented at this meeting, and some are still in the pipeline. We have an exciting future, but from a patient's point of view, we are not able to say that we have a cure.

Dr Cheson: Thank you. This is Bruce Cheson for Medscape Oncology with my dear friend Kanti Rai, signing off from the ASH meeting in Orlando, Florida.

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