Risk Stratification and Outcomes in Follicular Lymphoma


Carla Casulo, MD: There are several prognostic tools that exist for follicular lymphoma. The first one that was developed was the FLIPI system, which was made in the pre-rituximab era from over 2000 patients, retrospectively. The FLIPI system is really an important tool, because it puts together different clinical prognostic factors and groups patients in to different risk profiles depending on the number of factors that they have. That would be low, intermediate, or high risk.

The FLIPI-2 system was made in the rituximab era, and that added 2 other factors that include bone marrow involvement, beta-2 microglobulin, and also the presence of bulky disease. That was an important contribution because it included patients who were treated in the rituximab era and had a different endpoint of progression-free survival.

The m7-FLIPI is the newest iteration of prognostic models in follicular lymphoma and that’s really exciting because it takes the actual FIPI score, but also includes the mutational status of 7 different genes. This was done by the German Low-Grade Lymphoma Study Group. It included the gene mutations, performance status, and the FLIPI score, and all of those together in a multi-varied analysis were better than the FLIPI system at identifying high-risk patients. This is really important because the FLIPI system alone probably overestimates the degree of risk in patients, and over time we need to move to different models that use both clinical and pathologic markers of disease progression.

With regards to gene expression profiling, gene expression profiling is a tool that we have to understand the number of genes that are either upregulated or downregulated in a certain condition. And in follicular lymphoma, the first gene expression profiling attempt was done by Sandeep Dave, and that showed that the tumor microenvironment in follicular lymphoma is really important at influencing survival.

The overexpression of macrophages and dendritic cells actually impacts survival in follicular lymphoma. More recently, we’re learning that you can use paraffin-embedded tissue, just the actual archived sample that your patient’s tumor comes in. We can use that to understand gene expression profiling. And this was recently looked at during the Lugano Meeting, showing that there were 2 different groups of patients that emerged based on their gene expression profiling. While right now it’s still considered a research tool, gene expression profiling I think is rapidly going to be moving into prime time for risk stratification in follicular lymphoma.

Nathan H. Fowler, MD: We know, and we’ve known for a long time, that patients with follicular lymphoma can have very, very different outcomes, even with the same treatment. And so, one of the efforts that has actually been ongoing for the past couple decades is trying to develop scoring systems, or prognostic systems, to try to stratify patients and predict patients who will do well and patients who won’t do well. Unfortunately, most of the systems that we’ve so far developed—things like the FLIPI scoring system and the FLIPI-2 scoring system—are able to predict the outcome of groups of patients, but not individuals within that group.

What that means is that you can take a group of 100 patients, and if a certain percentage of those patients have poor risk factors, the entire group will do poorly. However, certain patients within that group may do greatly. In other words, patients who have a poor risk score can sometimes do very, very well, and patients who have a very good score can sometimes do poorly.

Now traditionally, the scoring systems have been made up by pretreatment clinical factors. For example, the FLIPI scoring system is made of low hemoglobin, LDH, stage, age, and number of nodal sites. Each one of those factors gets 1 point. If patients have 3 or more points, then they’re considered high risk. And if you look at the entire group, they tend to do poorly. But again, as I mentioned, there are many patients within that high-risk group who can do very, very well. What that means to us in practice is that, at least today, we don’t use these scoring systems to determine therapy. Even though patients may have a high-risk FLIPI score, a high risk FLIPI-2 score, or a high risk m7-FLIPI score—which is a scoring system based upon certain mutations that are common in follicular lymphoma—today, we don’t use these to determine treatment. Patients can have very good outcomes regardless of their scoring system.

Transcript Edited for Clarity

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