Interview: Big Changes in CLL Treatment 2012

Big Changes in CLL Treatment   2012

Interview with John Pagel, MD, PhD Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center  Seattle Cancer Care Alliance

By Andrew Schorr, PatientPower


Andrew Schorr: Things are changing in CLL, or chronic lymphocytic leukaemia, and to help us understand all the changes and what it could mean for you is Dr. John Pagel from the Seattle Cancer Care Alliance. Dr. Pagel is a specialist in the treatment of CLL. Dr. Pagel, thank you so much for being with us. Tell us your view of the changes in CLL.

Dr. Pagel: Andrew, honestly, no one could imagine what we are experiencing now in CLL. The drugs we are using in clinical trials and some of the newer drugs are really changing the game for CLL. This is one of the most exciting times you could ever imagine in research for CLL, and these drugs are available through clinical trials for patients now. There are several drugs that are in development that clearly are providing major, profound benefits for patients.

Some of these drugs are pills that you just take daily. One is called ibrutinib (PCI-32765). It’s a drug that targets an enzyme in the B-cell called Bruton’s tyrosine kinase. It’s very well tolerated. You take the pill daily. We see people have their lymph nodes melt away, their white counts go back to normal, and people are maintained on this daily pill for indefinite long periods of time. We have no idea how long those remissions will last, but it’s perhaps turning this disease into something where you don’t need chemotherapy and keeps the disease away for a long, long period of time.

Another drug that’s really exciting that we have in clinical trial besides ibrutinib (PCI-32765) is another pill. It’s called GS-1101 (CAL-101). Some people might know it as CAL-101. It targets another step in that B-cell signalling cascade. This one is called PI3-kinase, and it’s the delta isoform. It’s not important exactly to say what that is, but this is targeted biologic therapy. It’s not chemotherapy. This drug is again a pill, a daily pill, with the same kinds of results, amazing reduction in lymph nodes, ability to the get white counts under control in very, very advanced patients.

Patients that have failed lots of chemotherapies become refractory to antibody-mediated therapies like rituximab, and now they’re getting remissions even in the worst-case biological patients, patients with 17p deletions, 11qs. These are usually more difficult cases after multiple relapses becoming refractory, having complete remissions to these drugs.

Actually, there’s another pill, there’s a third drug that we have in clinical trial that has really provided tremendous benefits to our patients here at the SCCA. It’s called ABT-199 (GDC-0199). It’s another pill. It targets a different biological marker on the B-lymphocyte or the CLL cell. This drug inhibits a protein called Bcl-2, and when you do that it causes the CLL cell to die. And, again, daily pill, amazing. Patients do incredibly well with it. The lymph nodes go away, patients have white counts go back to normal, and, again, in some of the most difficult cases we’ve seen just really outstanding results.

Those are three drugs that are changing the landscape or changing the way we treat patients with CLL. They’re game changers. These are going to be how we treat people for the long-term future, with a daily pill, indefinitely. And it’s going to get away from chemotherapy. The era of FCR (FLU-CY-Rituximab combination chemotherapy), while we will need it occasionally here and there, I think it’s going away.

Those aren’t the only drugs. Those are three oral pills that we have in clinical trial that’s very valuable, but there are other antibody therapies out there that are incredibly exciting. One is called GA-101. It’s kind of the super rituximab. It’s been shown to have outstanding activity in CLL, and in fact that antibody is being combined with some of these oral pills in clinical trials. And there’s another one that’s in development that we have at our center called TRU-016. Different from GA-101 or rituximab (Rituxan) that targets CD20 on the surface of the lymphocyte or the CLL cell. This targets CD37, very, very highly expressed on almost specifically B- lymphocytes, or CLL cells.

You could imagine now even targeting these different pathways and different spots with the pills, these biologic, antibody-like therapies or even now T cell mediated therapies, which we have in clinical trials, and lots of people have been talking about that and thinking about how they could get into a trial like that, something that people might know about called chimeric antigen receptors or CARs. The whole way we treat CLL has dramatically changed, and we’re getting away from chemotherapy, getting away from toxicity, and clearly improving outcomes and likely improving long-term survival.

Andrew Schorr: Over the last few years we’ve begun talking about subtypes of CLL, people with different deletions, some more aggressive, some not. It sounds like now you are developing treatment strategies and have tools for a wide range of these situations so that people can live better and live longer.

Dr. Pagel: I think that’s absolutely right. I think what we’re learning is that there are lots of options even for the patients with the worst biologic disease. I mentioned a drug called ABT-199. The first patient I treated with that has a 17p deletion, or I should say had a 17p deletion and hadn’t had a platelet count over 50,000 in at least two years. She’s now in a complete remission almost a year out from starting that oral, daily pill and also has a normal platelet count. It’s really remarkable, and we’ve seen that many times in patients with bad biologic features.

And I also mentioned that that’s not where it has to stop. There are people that will fail these drugs at some point here and there, and we’ve really done great with those kinds of people, 17p deletions, 11qs, with reduced intensity allogeneic transplants. They’re not for everybody, but for the people who need it, it can in fact be curative in a subset or some degree of patients.

This is a good time from a researcher’s standpoint, from a clinician’s standpoint, to be able to apply these great new approaches to patients. Certainly patients don’t want CLL, but there’s lots of great options for them, and we have a lot of those things in clinical trials. I hope patients will think about that.

Andrew Schorr: Truly exciting news for people with any stage of CLL. Dr. John Pagel, thank you for your devotion to patients and all your work in clinical trials at the Seattle Cancer Care Alliance.

© Seattle Cancer Care Alliance and Andrew Schorr 2012