New Targeted Therapies for CLL

Jennifer R. Brown, MD, PhD

There have been many new drugs approved by the US Food and Drug Administration (FDA) for chronic lymphocytic leukemia (CLL), a blood and bone marrow disease that increases the number of B lymphocytes in patients. Almost 16,000 people in the United States are diagnosed with CLL annually, and about 4,600 will die of the disease in 2014, according to the National Cancer Institute. Today, we are speaking with Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute and professor at Harvard University. Dr. Brown treats patients with CLL and has been part of clinical trials for new agents that have been approved for CLL.

 -Interviewed by Anna Azvolinsky 

Cancer Network:Dr. Brown, could you review the new targeted therapies for CLL approved by the FDA in the last few years?

Dr. Brown: Sure. There are two new antibody-type drugs, as well as two new targeted, or small-molecule, drugs. The latest approval was last November and that was for an antibody drug called obinutuzumab, or Gazyva, in combination with chlorambucil for upfront therapy. This represents, more or less, the third-generation version of antibodies that target a protein called CD20, which is on the surface of B cells and B-cell malignancies. The first-generation antibody, Rituxan (rituximab), is well known as an excellent drug for treating CLL and other lymphomas. The second-generation antibody, ofatumumab, or Arzerra, was approved for relapsed patients a couple of years ago-but received a new indication for an upfront therapy in April. The newest version, Gazyva, is engineered to better effectively target the immune system to kill the cells and also results in more direct cell killing than the other antibodies. The clinical trial of that drug shows that it improved overall survival when you add it to chlorambucil. Ofatumumab, the second-generation version of the antibody, has a slightly different way of killing the CLL cells.

We also have two new targeted kinase inhibitors that represent a new class of drugs for CLL therapy and are very exciting. The first is ibrutinib, which targets a protein called BTK. That received an accelerated approval in February of this year and a full approval in July as a single agent in relapsed CLL, as well as for a particular subtype called 17p deletion, for upfront therapy. The other targeted agent is called idelalisib and that was approved in July-a full approval-in combination with rituximab for relapsed patients who have medical problems that make them not candidates for chemotherapy. The combination of all of these drugs has really transformed the CLL treatment landscape.

Cancer Network:Four of the agents you mentioned received a breakthrough designation by the FDA during their development. What were the treatment options prior to the availability of these newer agents that are still standard-of-care therapies being used in CLL?

Dr. Brown: The older treatment options include various chemotherapies. The oral agent chlorambucil has been around for decades; IV therapies include fludarabine and bendamustine, which was relatively recently approved. We’ve had the first-generation antibody, the anti-CD20 rituximab, as well as ofatumumab, for some time for relapsed patients. The more aggressive or refractory diseases are really where we have less effective therapies. We often used high-dose steroid regimens or an antibody called alemtuzumab, which is anti-CD52. The main issue was that a chemotherapy plus an antibody would be used for initial therapy and would usually be pretty effective, but over time, sensitivity to that therapy would go away, so you could use it once or twice but by the time you got to the third or fourth time it wouldn’t work and there wouldn’t be too many options left. These newer drugs seem to work longer and they also work in people in whom chemotherapy no longer works. We are still using chemotherapy, especially for initial therapy, but that is really changing for older patients and those with other medical problems. For younger, fit patients, it will take a little bit longer to change because the chemotherapy has been more effective in that group, so there is a higher bar to change the paradigm, but that is likely to change over the next couple of years as well.

Cancer Network:What should clinicians consider when deciding on the best first- and second-line therapy for their patients with CLL?

Dr. Brown: I think that everyone is pretty aware that who the patient is, is a huge clinical factor, in terms of what other comorbidities they have, how old they are, their general health, and the goals of therapy. We often don’t treat people for awhile, so you have to consider the state of the disease. If people don’t need treatment because the disease is not bothering them, then you can wait. But when treatment is needed, it’s also important to consider the features of the disease because CLL is biologically very variable. There are some people who have a very indolent, slow-moving CLL for whom the disease is really not going to threaten them in a major way, and even the older treatments would control it for an extended period. And then there are other CLLs that can be much more aggressive. Adapting the therapy to how risky the CLL is in the context of who the patient is, is really what we need to do.

Cancer Network:Are there any other issues in CLL or any novel therapies that are still in development that you would like to highlight?

Dr. Brown: There are a whole series of further targeted therapies that are coming along behind ibrutinib and idelalisib. There are second-generation BTK inhibitors following on ibrutinib. There are other versions of PI3 kinase inhibitors coming behind idelalisib. One of those is actually in registration trials now and that is IPI-145. There is also a different class of targeted drugs, which I should highlight, and they are very exciting right now. This class inhibits a protein called BCL-2, a protein that keeps the CLL cells alive inappropriately, when we would like them to die in response to chemotherapy. This drug is called ABT-199 and it has been profoundly effective in clinical trials. It also is currently in registration trials. We hope that it gets approved in the next couple of years. Between combining this class of drugs with our BTK and PI3 kinase inhibitors with the new antibodies, this should really markedly reduce the need for chemotherapy in CLL.

Cancer Network:Thank you so much for joining us today, Dr. Brown.

Dr. Brown: My pleasure.