Understanding the High-Risk Follicular Lymphoma Population

Sonali Smith, MD

As part of our coverage of the American Society of Hematology or ASH annual conference being held December 3rd to December 6th in San Diego, California, we are speaking with Sonali Smith, MD, an associate professor of medicine and the director of the lymphoma program at the University of Chicago. Dr. Smith takes care of patients with Hodgkin and non-Hodgkin lymphoma and also runs clinical trials. At the ASH meeting, Dr. Smith will give a talk called “Emerging Biology Leading to New Therapies in Follicular Lymphoma.”

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: Could you talk briefly about the current treatment landscape for follicular lymphoma as far as the broad therapy options and a bit on the natural course of the disease on these agents?

Dr. Smith: Thanks so much for having me. So follicular lymphoma is the second most common type of non-Hodgkin lymphoma that we see. There are about 30,000 cases per year. In general, we think of follicular lymphoma as an indolent disease. So it’s slow growing, it’s something that in the majority of people grows quite slowly and it’s something they live with and not die from. However, what we have learned over the last few years is that there is a high-risk population of patients, maybe about 20% of patients who despite appearing to be clinically quite similar to others actually have a very aggressive course and in fact may even progress within several years of their first line of therapy. What we know now is that those patients not only have a more rapid progression, but actually have a much shorter survival.  So in general we think about follicular lymphoma as being a relatively manageable chronic disease, but it’s important to know there is this portion of patients who won’t do as well, and we’re trying to identify who those patients are. 

When we think of therapy, the general approach, when we first meet somebody is to decide whether or not they need treatment. For those patients who do not have any symptoms, even if they have stage III or IV disease, the standard of care is observation, and there are many studies that have shown there is no advantage to early therapy. For those patients who do need treatment, we end up dividing them into those patients who have what we call “high-tumor burden,” where they need chemotherapy plus a monoclonal antibody, or low-tumor burden in which case a monoclonal antibody alone is often sufficient to take care of their symptoms.

Now, when people have progression at some point, we end up thinking about second-line therapy and there’s a number of different options, which I will be covering in this symposium and they range to more chemo-immunotherapy, more monoclonal antibodies, a combination called lenalidomide and rituximab, radioimmunotherapy, or what was FDA-approved several years ago, is a PI3 kinase inhibitor, idelalisib. The challenge, despite the fact that we have all these tools at our disposal, is that nobody knows the best sequence, nobody knows which patients will respond best to which regimen and I think this is where we really need to go back and understand the biology of the disease.

OncoTherapy Network: You mentioned this a little bit when you talked about the high-risk disease patient population. Is that the major unmet need as far as follicular lymphoma? And maybe a bit on how many patients fall into this “unaddressed by current therapy options” category.

Dr. Smith: Right, absolutely. There are several different unmet needs in follicular lymphoma and this group of early progressing patients is one of them. They have been dubbed “progression of disease 24” because in one of the larger studies that has looked at this in a respective registry way is the LymphoCare trial, and what this study did is it looked at patients with follicular lymphoma enrolled on a registry all of whom had been treated with R-CHOP. And they found that those patients who had progressed within 2 years of their R-CHOP chemotherapy had a 5-year survival of less than 50%, which is significantly different than those patients did not progress within the first 2 years. Now, identifying these high-risk patients upfront is an unmet need. Managing these patients once you have identified them is another unmet need, and trying to change that overall survival is a big part of the goal of current therapy. 

Now, there are other unmet needs within follicular lymphoma and that would include patients who have multiple relapsed and refractory disease. So by the time patients no longer have disease that responds to, let’s say, rituximab or an alkylating agent, they now have a very aggressive course where they go from therapy to therapy and eventually either do not survive their disease or have significant toxicity from the treatments that are available. So several different unmet needs. And then if I can editorialize a little bit, I think the overarching unmet need, is that despite the fact many patients do well this remains an incurable disease.

OncoTherapy Network: What are we learning about the molecular make-up of this tumor type or other factors that may lead towards new targets and new therapies?

Dr. Smith: So, we have known for a long time that this is a biologically and clinically heterogeneous disease, but we didn’t really have the tools to say what that biology was. I think what is very exciting is that the picture is coming a little more into focus that follicular lymphoma early molecular events are actually quite common in the general US population. So for example, the 1418 rearrangement, which is the hallmark lesion in follicular lymphoma, can be found in a significant number of patients and probably derives from normal bone marrow B cells. Once these B-cells enter the germinal center they get exposed to a variety of different antigens and there is some type of recycling that occurs and every time this recycling within the germinal center occurs, newer biologic events and mutations occur and eventually some people will develop follicular lymphoma. 

At this ASH meeting there is, within the symposium I’m speaking, the two scientists who precede me are talking about some of these early biologic events. What is interesting is that many of them fall into the category of epigenetic phenomenon.  So in other words, EZH2 mutations and other methyltransferase genes are involved and there is a very strong and early epigenetic signature in addition to what we know about BCL2. The other point we will hear about in this symposium is that there are additional pathways that get used-some of them are NF Kappa B pathways, B-cell receptor signaling, PI3 kinase, and a number of other pathways start to accumulate as the disease progresses.

In addition to these mutations and mutational events that are occurring primarily in the malignant cells, we also know that the microenvironment of follicular lymphoma is critically important both in its biology, prognosis, and pathogenesis. There are a number of agents that potentially target the microenvironment and we will be hearing more about those at ASH as well.

OncoTherapy Network: Thank you so much for joining us today, Dr. Smith.

Dr. Smith: Thank you so much for having me, I really appreciate it.