Risk Stratification in Follicular Lymphoma

John M. Burke, MD:The standard approach to risk stratification in follicular lymphoma is to use what’s called the FLIPI score, which stands for Follicular Lymphoma International Prognostic Index. The FLIPI score is a score of 5 clinical points that can be easily assessed for any individual patient with follicular lymphoma. That is an old prognostic indicator, but it still can be used in this day and age to assess the risk for a person with follicular lymphoma for how well they will or will not do in the future.

The other factor of follicular lymphoma that significantly affects prognosis is the grade. Follicular lymphoma is graded based on the number of large versus small cells that are present in the biopsy tissue. Grades 1, 2, and 3A are generally lumped together as what we think of as follicular lymphoma— the more indolent variety of follicular lymphoma. Whereas, grade 3B, which has an increased number of large malignant cells in the biopsy tissue, is generally more aggressive and behaves more along the lines of diffuse large B-cell lymphoma and is treated accordingly.

In modern practice, most physicians still use the FLIPI score as the main way to risk stratify. Another score that has been developed is the FLIPI2 score, which incorporates some other factors, including the bone marrow biopsy and the β-2-microglobulin tumor marker test. I would say that the FLIPI2 score is used less commonly because many times, it is thought that the bone marrow is not absolutely necessary when you’re staging the patient. So it’s probably less common for doctors to actually calculate a FLIPI2 score.

The outcomes for patients with follicular lymphoma can be quite variable. For example, there are some patients with follicular lymphoma who never need treatment at all, and there are other patients who need treatment from the moment they walk in the door. The outcome is somewhat related to stage, but most patients with follicular lymphoma have advanced stage, stage III, or IV disease at the time of presentation. We generally divide those patients with advanced stage into 2 groups, either a high-tumor-burden group or a low-tumor-burden group. In the low-tumor-burden group, we generally advise a watch-and-wait strategy. However, patients with high tumor burden are having symptoms—very large bulky lymph nodes, pleural effusions, or cytopenias for marrow involvement.

I think many patients who present have low tumor burden but advanced-stage disease. For those patients, I like to keep in mind the following statistics that we know from trials: about 50% of those patients will need treatment within the next 3 years, but around 10% to 20% of those patients can still go 10 years and not even need treatment.

That points to the variability of the natural history of the disease that there are patients who can go 10 years or more and still not need treatment. The majority of patients will need treatment, but again, there are also those lucky patients who can go a long time even without needing treatment.

Furthermore, after treatment has begun in patients who do need treatment, there is, of course variability in outcome. We know that patients whose disease relapses within the first 2 years of initiating treatment have a less favorable outcome and a median survival on the order of 5 years. However, patients whose disease does not relapse within the first 2 years of their initiation of treatment have a more favorable outcome and may have a life span that is quite close to that of someone their age who does not have follicular lymphoma. This again, is pointing to quite different variability in outcome for different patients with the disease. Follicular lymphoma is not unique in that way. There’s variability in outcome in virtually every type of cancer and especially the blood cancers that I treat. That’s true of multiple myeloma, diffuse large B-cell lymphoma, and so forth.

In my opinion, risk scores are not so much used to determine the best approach to therapy, but more so used to help patients understand their prognosis and how they’re likely to do. But, in terms of choosing an actual therapy, my choice of a patient’s therapy doesn’t depend as much on their FLIPI score or other risk stratification modality that I’m using. It depends on whether they need treatment based on their clinical presentation. Then I choose the treatment independent of their prognostic score from the start.

About three-quarters of patients who present with follicular lymphoma have advanced-stage disease, that is stage III or IV disease, and not all of them need treatment right away. In fact, many of them don’t. In general, the field has evolved to think of these patients as having either tumor burden or low-tumor-burden disease. In general, we think that the optimal time to initiate therapy is when a patient reaches that high-tumor-burden state. If a patient who walks in the door has a high-tumor- burden state, then that person probably needs treatment. On the other hand, if the patient walking in the door has a low-tumor-burden state, we generally will advise a watch-and-wait strategy until that patient hits the high-tumor-burden state.

What is considered high tumor burden generally involves the degree of cancer in their body and whether that cancer is a threat to their organ function or whether it’s causing them any symptoms. That might include heavy bone marrow involvement causing low blood counts. It might mean that the patient has a pleural effusion that’s causing them to be short of breath or need fluid drained from their lung. That would be an indication to start treatment. It may be that there’s a bulky lymph node that’s starting to press on the ureter and therefore about to lead to some kidney dysfunction. That would be a reason to start treatment.

The GELF [Groupe d'Etude des Lymphomes Folliculaires] criteria from a French group also uses lymph node sizes. GELF node criteria include any lymph node measuring 7 cm or more in size or 3 or more lymph nodes measuring 3 cm or more in size. Some people will use those criteria, as well, as a decision point to initiate therapy.

Transcript edited for clarity.