Scott Huntington, MD, MPH, MSc: When a new patient presents with follicular lymphoma in the first-line setting, the most important thing is to stage them. Patients typically are presenting with advanced-stage disease, but about 20% of patients with follicular lymphoma will have early stage disease, and that disease is treated differently. We may have options including definitive radiation, so when a patient presents, the first step is really staging a follicular lymphoma patient.

Once you have a patient who is advanced stage and you’re not able to offer them radiation, the next step is to assess the disease burden in the fitness of the patient. Fitness might be comorbidities, and age plays a factor in some respect. But assessing the fitness of a patient is important in stratifying risk factors.

The next step is to assess the disease burden of follicular lymphoma. Patients can have indolent slow-growing and low-volume disease, which would not require urgent therapy, and those patients are best managed initially with surveillance. If patients typically present later on in their course with more bulky disease, that would be an indication to start treatment. And that may also come with anemias, and it may come with B-symptoms, and that would be a treatment indication.

Historically, we’ve been using the FLIPI [follicular lymphoma international prognostic index] score to assess the risk factors and long-term prognosis of patients with follicular lymphoma. In recent years the molecular mutation burden has been recognized as a potential solution to improving our prognostication and predictive value of these tools. The m7-FLIPI was developed in a cohort of patients treated with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] and then validated subsequently in a cohort of patients treated with R-CVP [rituximab, cyclophosphamide, vincristine, prednisone]. And in that study, they found that 7 genes are frequently mutated, can help the FLIPI predict a low- versus high-risk disease. In this year’s ASH [American Society of Hematology Annual Meeting & Exposition], there were additional studies [looking] at how well m7-FLIPI is predicting patient outcome with newer therapies, either chemotherapy alone or with bendamustine-based therapy, and the m7-FLIPI has not been shown to predict as well as in R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. And so currently m7-FLIPI is more of a continued process in using clinical trials, and I think there’s plenty of additional work to improve on a prognostic and predictive value in risk factors for follicular lymphoma.

Laurie H. Sehn, MD, MPH: The analysis of the m7-FLIPI in the GALLIUM trial is actually quite interesting. It was intended to be a validation of m7-FLIPI to demonstrate that it has utility and prognosticating outcome in patients with follicular lymphoma. It’s interesting in that it did validate the m7-FLIPI in patients receiving R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] and R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. Interestingly, it was not prognostic in patients receiving a bendamustine-based chemotherapy.

I think we’re in desperate need to find biomarkers that are predictive of outcome in patients with follicular lymphoma, and the m7-FLIPI shows some promise. Just as we’d suspected, biomarkers likely need to be put in context of the therapy being given. And definitely seeing the results of this trial and broken down by homogenously treated patients, I think, is quite informative: the m7-FLIPI clearly has value in the right context.

It’s interesting that EZH2 was confirmed as a prognostic marker within the data of the GALLIUM trial, particularly within patients receiving CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or CVP [cyclophosphamide, vincristine, prednisone]. For the patients treated with CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or CVP [cyclophosphamide, vincristine, prednisone], those with an EZH2 mutation actually had a better outcome and longer progression-free survival, but that wasn’t seen in patients receiving bendamustine. In fact, there’s evidence that we might be able to use it as a predictive marker because patients with EZH2 mutations actually seemed to preferentially benefit from CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or CVP [cyclophosphamide, vincristine, prednisone], and the contrary was true for patients without the mutation, with wild-type EZH2, where they seemed to have preferential benefit from bendamustine.

Scott Huntington, MD, MPH, MSc: There’s considerable heterogenous in follicular lymphoma patients. About 80% of patients will do very well with standard immunochemotherapy. The remaining 20% unfortunately have early progression within 24 months. We’ve identified that as a poor prognostic and long-term predictor of poor outcomes. Unfortunately, our current tools of risk stratifying patients are unable to identify patients at greatest risk for early progression. But it is certainly an active research question, in which we really need to predict and identify those patients at greatest risk and ideally identify therapies that improve outcomes in that highest-risk population.

There have been a number of studies recently that are trying to identify the patients at greatest risk for early progression. The m7-FLIPI in patients treated with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] does seem to have some prognostic ability to identify a high-risk population. About 20% of patients have a high m7-FLIPI score, and in those patients only 25% are without progression at 5 years. But that was a group treated with R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. In all-comers, we unfortunately don’t have the predictive tool right now to identify those patients at greatest risk. There was an abstract presented at this year’s ASH looking at the T-cell component in the intrafollicular region of follicular lymphoma. And there was a signal that perhaps looking at CD4 staining may be able to improve upon FLIPI, but that work needs to be evaluated going forward.

Transcript Edited for Clarity