When to Initiate Therapy for CLL

Thomas J. Kipps, MD, PhD: There’s a lot of debate on when to start therapy, and I think that obviously having therapy that is orally bioavailable and easy to take has prompted some to question whether we should treat patients earlier. I think it’s very important that we recognize that patients who have chronic lymphocytic leukemia or indolent lymphoma, such as follicular lymphomas, may have a varied clinical core. Some patients may require therapy relatively soon, and some patients may not require therapy for many years.

And so, the question remains, if we put all patients on therapy early before we have the standard indications for therapy, are we going to be overtreating those who may not require therapy for years after their diagnosis? I think this really needs to be established. There are some studies now that are ongoing to try and evaluate what the benefit is of earlier treatment, particularly for patients who have high-risk factors. We have, through the work on the biology of chronic lymphocytic leukemia (CLL), identified certain genetic factors and also phenotypic features that are associated with a tendency to require therapy early versus late. And so, if you are able to assess those features in a patient and find that they have features that would indicate that they would have an early need for therapy, then protocols are being designed to offer them early therapy with some of the targeted therapies versus the traditional “watch-and-wait” until patients develop either disease-related symptoms or clear evidence for disease progression.

I think it’s important that we try to look at these studies because there have been early treatment studies before that have been done, and it’s always true that with the intention to do well by your patients, it doesn’t always translate into a beneficial outcome for our patients. And that’s why it’s very critical that we have clinical trials that can evaluate truly whether this is a benefit to the patient.

We have to understand that even with these targeted therapies—and the fact that they have a very high therapeutic index indicating that they have a very good response potential and fewer side effects than perhaps traditional therapies — there are still effects and complications that we have to contend with when we take these medicines. So, I really feel that a thoughtful approach to this is warranted. But, until we have those data, I would advocate that we still maintain the traditional guidelines for when we start therapy. And those typically are being advocated by the International Workshop of Chronic Lymphocytic Leukemia, which I’m a member of, and we have our new guidelines that are being formulated. They should be out in 2017.

And the real indications for therapy are the same. Namely, when patients have disease-related symptoms that you can clearly peg on to the disease that are affecting quality of life, if they develop clear signs of disease progression that you can document in terms of rising lymphocyte counts or increasing lymph node size over a defined period of time, or if they develop evidence for bone marrow failure, namely the leukemia lymphomas have gone into the marrow and caused problems in making either red cells or platelets, then clearly the indication would be to start therapy at that time. And that would still be the indication for the targeted therapies today.

I will say this, as we look at these genetic changes, we are embarking on studies to look with the new technologies, which involves next generation sequencing, where you can take a small number of cells and apply advanced technologies and sequence all the genes within the cell. And this is allowing us to spot for genetic changes that might occur in the cell over time. One thing that’s clear is that leukemias and lymphomas, and also myeloid leukemias, will have a tendency to potentially evolve over time so that you have a genetic lesion that might crop up in the course of the evolution of the disease. And this is also apparent when you apply therapy. So, you may have a number of subclones, if you will, that carry different genetic changes, and then when you apply therapy, it applies a bottleneck on this. Some of the subclones actually die off, but some of the subclones may be selected. And that selection process allows for you to change the complexity of the disease. That’s why we develop resistance to therapy over time.

I think if we look at the changes that occur over time without therapy and the changes that might occur with treatment, for example, with conventional chemotherapy versus targeted therapies, we’ll also have very good insight into how the clonal evolution occurs with these newer therapies. There has been some work to describe this. Landau had very important work looking at clonal evolution in the context of patients treated with chemotherapy and did have a follow-up study where patients treated with ibrutinib were monitored over time. And the same clonal evolutionary patterns that we saw with conventional chemotherapy were not the same with a treatment with a drug such as ibrutinib.

I think this is providing us with a lot of hope because by identifying the right kind of patient and the right time to treat, we can use these targeted therapies most effectively, and look for those causes of resistance that might be there and to try and develop alternative strategies ahead of time before the patient really gets in trouble with their disease.