Ian Flinn, MD: John, I’m going to turn to you. Tell me a little about trying to risk stratify patients. There is a variety of different prognostic indexes, the FLIPI [Follicular Lymphoma International Prognostic Index], the FLIPI2, the m7. They work, but do you use these in a regular basis in patients? Is this only for clinical trials? How do you risk stratify your patients?

John Leonard, MD: Sure. So the IPI, or the International Prognostic Index, has been around for over 25 years, looking at age, performance status, LDH [lactate dehydrogenase], extranodal disease, and stage of disease. That evolved into the Follicular Lymphoma IPI, which has some similarities, some overlap, including LDH, age, but takes into account hemoglobin and number of sites of disease. That’s evolved into the FLIPI2, which also includes beta-2-microglobulin. And then the m7-FLIPI, or the molecular version or modified version of the FLIPI, looks at a couple of different mutations that can be seen in follicular lymphoma and correlates that with outcome. For instance, EZH2, which we’ll come back to later, is a mutation occasionally seen in follicular lymphoma that’s associated with a better prognosis in general with follicular lymphoma.

The net of that is that we have these markers. How we translate them when you’re choosing therapy is not so clear. One could argue that we really shouldn’t risk adapt at all on the basis of these because we have very little randomized data that says that a high-risk patient should be treated differently from a low-risk patient.

That said, clearly a patient who has high-risk features, bulky disease, and more symptoms may be a patient who needs more therapy, needs chemotherapy versus a low tumor burden, and we’re going to get to the GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria as an example, and the tumor burden there. The higher tumor burden patients tend to have higher-risk FLIPI scores and therefore more symptoms, and therefore they may need a chemoimmunotherapy approach versus something like an antibody-alone approach with rituximab.

I think that’s how it primarily influences things. Also, again, you worry a little more about transformation in higher-risk patients. They’re the ones who are going to have the high LDH, so those are people where you’re more prone to give R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] as an example, even if you don’t diagnose transformation, you at least are maybe more concerned about it and lean a little more in that direction in some cases.

Ian Flinn, MD: Pier Luigi, is there a similar approach in Italy to what he’s talking about? Do you use these prognostic indices for changing therapy or not? Or do you just find it helpful for giving sort of long-term information?

Pier Luigi Zinzani, MD, PhD: I think we use it the same way. In particular with the recent advent of the GALLIUM study, we use obinutuzumab in combination with conventional chemotherapy like bendamustine, R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], or CVP [cyclophosphamide, vincristine, prednisone]. In Europe, there was official indication considering the use of obinutuzumab instead of rituximab; in particular, in intermediate high-risk patients, according to the FLIPI score. For his reason, this is an example of how we can use this kind of a prognostic score in terms of differentiating the treatment in the setting of follicular lymphoma.

Ian Flinn, MD: Lori, 1 of the things we haven’t talked about is how you use comorbidities, age, and other things to incorporate into your initial evaluation of patients and how that might change treatment. These are diseases of aging. The incidence of follicular lymphoma is higher in patients who are older, and they’re the patients who are going to have other illnesses. How does that factor in?

Lori A. Leslie, MD: It’s very important to consider the whole patient’s course in chronic illnesses such as follicular lymphoma and how potentially to sequence things, particularly in patients with comorbidities. So maybe an older patient, 80s or 90s, who does meet GELF criteria and otherwise would start treatment, maybe that patient you would watch and wait even longer, do a less intensive therapy because their overall life expectancy independent of the follicular lymphoma is very different from when you’re considering treatments for a patient in their 30s at diagnosis and maybe has a more rapidly progressive course but is not technically meeting criteria to start treatment. That patient’s journey is going to be dramatically different. It’s important to consider age, comorbidities, along with available treatment options in this rapidly changing treatment environment in terms of the timing of when you start things and what you choose and what you plan to do next if that treatment fails.

John Leonard, MD: One thing that comes up more and more that I’m curious about is what other people in the group say is the concern about bendamustine in older patients. I have to say, I’m a little less concerned about that, but I hear people expressing a lot more concern if they have a patient in their late 70s or 80s—not giving a reduced dose of bendamustine but giving something like CVP [cyclophosphamide, vincristine, prednisone] instead if the patient needs chemotherapy. I’m curious what you all think.

Ian Flinn, MD: It’s been awhile since I’ve given CVP [cyclophosphamide, vincristine, prednisone]. I can understand. I haven’t experienced it, and in general I would dose reduce and use bendamustine if I’m using a chemoimmunotherapy.

Pier Luigi Zinzani, MD, PhD: Yeah, the same for me.

John Gribben, MD, DSc: When the obinutuzumab data came out from GALLIUM, that was when we got the signal. Of course, there was bendamustine toxicity in both arms of GALLIUM, but I’m increasingly hearing people say that they would consider using CVP [cyclophosphamide, vincristine, prednisone] with obinutuzumab. Once you’ve started thinking about using CVP [cyclophosphamide, vincristine, prednisone] again, as Lori already said, people are then maybe escalating down. I’m with you: I’m finding bendamustine pretty well tolerated in these patients, and it certainly hasn’t been my experience to see some of the toxicities that were seen in the GALLIUM data. But I’m hearing people who hadn’t used CVP [cyclophosphamide, vincristine, prednisone] for a long time going back to using it on the basis of what came out of GALLIUM.

Lori A. Leslie, MD: On the other end, I have concern long before starting bendamustine in a very young patient. Not necessarily because I think they won’t tolerate it or will have higher infectious risk, but the prolonged lymphopenia, particularly if you’re considering obinutuzumab, combine neutropenia and then moving forward. Maybe that patient eventually needs a cellular therapy and the long-term effect on bone marrow from bendamustine, I think we don’t know as much about in the young follicular lymphoma patient.

Transcript Edited for Clarity