Bruce D. Cheson, MD; Myron S. Czuczman, MD


December 19, 2012

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Bruce D. Cheson, MD: Hello. I am Bruce Cheson, Deputy Chief of Hematology-Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights, coming to you from the 2012 annual meeting of the American Society of Hematology. I am delighted to have with me today my good friend Dr. Myron Czuczman, Professor of Medicine at the State University of New York at Buffalo and Professor of Oncology and Chief of the Lymphoma/Myeloma Section at the Roswell Park Cancer Institute in Buffalo, New York. Welcome, Myron, and thank you for coming.

Myron S. Czuczman, MD: Thank you.

Step Aside, Chemo

Dr. Cheson: This meeting is a world changer. We are going to look upon this meeting as the time when the revolution took place. There is no more chemotherapy; it is gone in the lymphoid malignancies. Chemotherapy is on its way out and is being replaced by many novel compounds. Some of these monoclonal antibodies are directed at antigens on the cell surface. We have the drug lenalidomide with which you have done a lot of work within the microenvironment, but we also have drugs directed at the pathways in the cell. Some of these are downstream from the B-cell receptor which, when activated tonically or non-tonically, go through several different pathways. Myriad exciting drugs are coming along, many of which have been discussed at this meeting, which have the potential to change the whole playing field. Why don't we start with ibrutinib? What is it, and what did you hear about it at this meeting that excited you?

Ibrutinib Goes Mainstream

Dr. Czuczman: Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor, which works downstream from the B-cell receptor. It is quite fascinating, and it may actually be one of the most interesting molecules that we have had added to our arsenal in many years. We are still seeing activity in the indolent lymphomas and chronic lymphocytic leukemia (CLL), but a novel addition will be presented today. There was a 40% response rate with ibrutinib as a single agent in relapsing/refractory patients with diffuse large B-cell lymphoma in particular, the activated B cell (ABC) phenotype.[1]

Dr. Cheson: We have had nothing for that patient population.

Dr. Czuczman: We are working on lenalidomide in a phase 2 trial, and we are going to a phase 3 study, but novel agents are limited and we do not have any US Food and Drug Administration-approved drugs as third-line agents for this population.

Dr. Cheson: What about other diseases, such as mantle cell lymphoma?

Dr. Czuczman: Ibrutinib has excellent activity in mantle cell lymphoma as a single agent, but also we saw some novel combinations. One was bendamustine-rituximab with ibrutinib, which has excellent activity, but eventually we will have to do randomized trials.[2] Bendamustine-rituximab is excellent in low-grade lymphomas and mantle cell lymphoma, so we will have to see how much ibrutinib adds to that. Ibrutinib doesn't have the myelosuppression associated with the novel targeted agents. It will be interesting to see whether we will use ibrutinib concurrently with therapy or use it after standard therapies as a short consolidation to mop up any minimal residual disease.

Dr. Cheson: An important benefit of these drugs is that they are all taken orally. We have been waiting for drugs like this for years. We are getting ready to start an upfront study of rituximab and lenalidomide ("R-squared") with ibrutinib in untreated follicular lymphoma.[3]

This drug has the potential to be a game changer. We have been trying to get rid of chemotherapy in indolent lymphomas and CLL, where this drug is also exquisitely active. Some data on CLL were presented at this meeting.[4] What were the response rates, about 80%?

Idelalisib Significantly Active

Dr. Czuczman: It was quite dramatic. However, no single agent is going to be the cure-all. We are on our way to improving outcomes, but we have to keep in mind that at some point we are going to see resistance, and the activity wears off, so we need to work out the optimal way of using these agents in the future. We are going to be seeing tons of combinations over the next couple of years.

Dr. Cheson: There are obviously some others. There is the PI3 kinase inhibitor idelalisib, formally known as CAL-101 and GS-1101. There were some interesting data on idelalisib at this meeting as well.[5]

Dr. Czuczman: Essentially, the study demonstrated that the oral inhibitor for the PI3 kinase delta isoform has significant activity in the indolent lymphomas and CLL.[5]

Dr. Cheson: But it does not have as much activity in large-cell lymphoma?

Dr. Czuczman: It is too early to judge that, because only a limited number of patients were treated with idelalisib in the early trials. The study did not evaluate whether the patients had the ABC or germinal center B-cell (GCB) phenotype. The ABC phenotype was more likely because of its association with the B-cell receptor being more sensitive, although 1 patient with the GCB phenotype responded to ibrutinib, so some small proportion of patients could still respond.

Dr. Cheson: The disease that seems to be the biggest surprise of all is mantle cell lymphoma. We never had anything with which to treat mantle cell lymphoma, and now anything used to treat mantle cell results in a 75% response rate.

Dr. Czuczman: WhenI started at Roswell, we called it "intermediately differentiated lymphocytic lymphoma," but these patients would respond, so we could use purine analogs. A single agent (rituximab) came along and we started looking at transplantation. It is exciting that we will be using a therapy such as bendamustine-rituximab. Will the results be similar or better than using something like a hyer-CVAD regimen? This is one of the trials that will be ongoing with the intergroup study. We also have these novel agents. What is important is how long these responses will last. It's great that we have good responses or good signals, but how long is the progression-free survival, and will we eventually be able to cure a high percentage of patients with these novel targeted agents?

Dr. Cheson: Idelalisib is isoform delta, which is where it comes from, so this agent focuses on the delta isoform, but there are other isoforms which may or may not be important. Some preliminary data are being presented for another drug, IPI-145,[6] which is a delta and gamma isoform inhibitor. They are still in phase 1, but the partial responses and complete responses are great in patients who previously failed a median of 4 regimens. Those are some of the pathways downstream from the B-cell receptor, but there are other important pathways, such as apoptosis. Many of these diseases are characterized by overexpression of B-cell lymphoma protein-2 (Bcl-2). The drug, ABT-263, is no longer being developed and now we have ABT-199. What have you heard about this?

Dr. Czuczman: We heard a presentation[7] earlier today that as a single agent in patients with relapsing/refractory B-cell malignancy, single-agent activity was quite astounding. Objective response rates were in the 80% range for CLL and a very high percentage of patients with various types of lymphoma, including mantle cell. The original attempts to downregulate Bcl-2 with the antisense oligonucleotide oblimersen unfortunately were not successful, but that drug required a long infusion. This new agent is in oral pill form. The entire premise of the balance between pro- and antiapoptotic proteins is fascinating. The other agent, ABT-263, downregulated both Bcl-2 and B-cell lymphoma-extra large (Bcl-xL).[8] Depending on which proteins are downregulated, thrombocytopenia can result. With ABT-199, we are not seeing thrombocytopenia, so we will be able to add this agent without that concern.

Enter the Antibody-Drug Conjugates

Dr. Cheson: Another class of agents is the antibody-drug conjugates. The drug that we all are becoming familiar with is brentuximab vedotin, which is active in Hodgkin lymphoma and anaplastic large cell lymphoma. As we saw at this meeting,[9] it is also active in some other CD-30 positive diseases, T-cell lymphomas, and perhaps even diffuse large B-cell lymphoma. However, that is not the only kid on the block, is it?

Dr. Czuczman: No. I have been working with Genentech on one of their antibody-drug conjugates. The names are letters now; they do not have fancy names yet. They are DCDT298OS, DCDS4501A, and anti-CD79B (the first to be active against CD79B, which is part of the B-cell receptor). The other is the CD22 antibody-drug conjugate. Both have the same drug, the monomethyl auristatin E (the vedotin that is with brentuximab). The 2 targets used for B-cell lymphomas, the 79B and the CD22, are fascinating. When antibodies bind to those sites, they internalize the antibody-antigen complex with a very strong linker type of chemistry which binds the actual drug and it internalizes within the cell. It is like the pizza delivery service to the cell. It is still quite early. Phase 1 trials are completed[10,11] and we are moving into the phase 2 trials, but most of the patients who were tested demonstrated antitumor responses.

Dr. Cheson: There is also a randomized trial opening soon comparing rituximab plus the anti-CD22 antibody-drug conjugate vs rituximab plus the anti-79b antibody-drug conjugate, with a crossover [to receive the other antibody-drug conjugate] for patients who have progressive disease.

Dr. Czuczman: I also was involved in discussing the development of that protocol. It is interesting. The way to look at it is, which door do you knock on to enter the cell? We are still using the same target. The same chemotherapy drug is getting in, but one is coming in through the 79B door and the other is coming in through the CD22. It does not take very much of the vedotin to kill, so it may be that the regimens will be comparable. We could be underestimating the utility of brentuximab vedotin in diffuse large B-cell lymphoma because, just by immunohistochemistry, we aren't measuring CD30. Maybe with a more sensitive assay, we will treat more patients with large cell lymphoma, because I do not believe that there has been any association between the expression of CD30 and its activity. With just a small number of sites, the chemotherapy is so potent that we may actually be using it a lot more in large cell lymphoma than we expected.

Changing Tactics: No More Maximum Tolerated Dose?

Dr. Cheson: We are learning some very interesting things. In John Byrd's presentation[12] on ibrutinib, a question was raised about the patients who have failed idelalisib. He had patients who had failed one agent and responded to the other. When we were developing our clinical trials, 2 things are going on that are quite different than ever before. One is our eligibility criteria. With all of these drugs and studies going on, we had to make sure that we were not bringing in the wrong people who have had some other drug. The second thing is the phase 1 studies. In the past, phase 1 studies get to the maximum tolerated dose. The patients get sick, and then you back off a level. With these targeted therapies, we have to look at the various pathways. Does it hit the target? Does it do what it is supposed to do? Do we really have to increase the dose if we are achieving the appropriate occupancy? Why do we have to keep increasing the dose? This could actually help us provide more personalized therapy and shorten the time of drug development because we no longer have to spend so much time looking for doses. If we can define the target and determine what it does to the target and how much it takes, we can just move on.

Dr. Czuczman: That is very true. Historically, we learned -- and we taught our fellows -- a shotgun effect: hitting patients with chemotherapy drugs that go through their whole system causing a lot of nonspecific toxicity. It is not only exciting for those of us who take care of patients, but the quality of life for our patients in the future is going to be much better.

Dr. Cheson: For years, I had a slide that I showed when giving a talk, which said, "More is not better, different is better" and I think we are finally there. This meeting will be looked upon as the time the world changed. Thank you, Myron, and thank you to the audience for joining us for this edition of Medscape Oncology Insights.


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