Frontline Therapy In Follicular Lymphoma - Episode 12
Laurie H. Sehn, MD, MPH: The mainstay of therapy for follicular lymphoma has relied on chemotherapy for quite some time. Historically we were using chemotherapy and chemotherapy combinations by itself.
One of the major steps forward in treatment of patients with follicular lymphoma really was the addition of monoclonal antibodies to chemotherapy. There was a series of trials that showed that no matter what chemotherapy was used, the addition of rituximab actually improved progression-free survival [PFS] and even overall survival. More recently the GALLIUM trial tested obinutuzumab against rituximab as the antibody combined with chemotherapy. What we learned from that trial was that obinutuzumab was associated with a longer progression-free survival. It did not at the time of analysis translate into improvement in overall survival. I think at this point, clinical practice probably reflects individual preferences, although obinutuzumab did have a higher progression-free survival. For the time being I’d say that either rituximab or obinutuzumab combined with a chemotherapy backbone is still considered standard of care.
There’s still a lot of debate over what chemotherapy is the best chemotherapy. I think that there are individual physician preferences, but most people would consider either bendamustine, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], or CVP [cyclophosphamide, vincristine, prednisone] as the primary chemotherapy backbone. In my own clinic we use bendamustine-rituximab, and we also use maintenance rituximab, which has been shown to prolong progression-free survival on the heels of induction therapy as well.
Scott Huntington, MD, MPH, MSc: In recent years there’s been development beyond anti-CD20 agents with rituximab, and we now have obinutuzumab, which has developed and actually shown in randomized fashion to improve the progression-free survival in the first-line setting of follicular lymphoma. That therapy led to about a 4% absolute improvement in PFS at 3 years compared with rituximab, but it does have some potential downsides, including increased infusion-related actions as well as perhaps increased neutropenia and infection. And so it’s really a risk-benefit discussion that you have with patients now that we have the longer-term follow-up with obinutuzumab versus rituximab-based immunochemotherapy.
When you think about the GALLIUM data in that trial compared with obinutuzumab with chemotherapy, compared with rituximab with chemotherapy, we now have longer-term follow-up, 3-plus years, and it shows continued significant statistical benefit of obinutuzumab over rituximab in that setting. But the absolute benefit is about 4%. The overall survival at the most recent update seems to be overlapping as well. When I see a patient I typically discuss the potential for improvement in delaying future progression. But I also mention the potential downsides of obinutuzumab, which has slightly higher adverse events, including things like infusion-related interactions which are more common with obinutuzumab. There may be also additional cytopenias and neutropenia, so it is a balance between efficacy and safety in this patient subset.
Based on the GALLIUM study, we do talk about progression-free survival benefit, and in some patients who have rapidly progressive disease that fit that GALLIUM patient population. I do sometimes consider using obinutuzumab. It’s important to note that in the GALLIUM study most of those patients had a higher-volume disease. The median time from diagnosis to treatment was quite short in that study—about 1½ months, which is not typical in a patient population where patients might have disease being actively being observed for years and years.
If I have a young patient who’s fit, who has a more progressive, early progressive presentation, I certainly consider using obinutuzumab with chemotherapy in the first-line setting. But for the majority of patients, I’m still holding on to the fact that overall survival is somewhere between 2 therapies and that the safety profile seems to be better in the rituximab. And so for most patients I’m using rituximab combined with chemotherapy in the first-line setting.
Laurie H. Sehn, MD, MPH: The GALLIUM trial was 1 of the largest trials that’s ever been done in untreated follicular lymphoma, and it was aimed to test the efficacy of obinutuzumab compared with rituximab against a physician’s choice of chemotherapy backbone. The chemotherapy included either CVP [cyclophosphamide, vincristine, prednisone], CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone], or bendamustine. But what the trial showed was that head-to-head, obinutuzumab led to a much longer progression-free survival than rituximab.
Obinutuzumab combined with chemotherapy—you know it’s a highly effective regimen. We know that compared with rituximab, there’s a slight increase in the rate of infusion-related reactions, but they’re largely easily manageable and generally only occur in the first cycle of administration. There’s also a slightly increased risk of neutropenia, but the overall risk of infection is not particularly different.
Scott Huntington, MD, MPH, MSc: The improvement in progression-free survival in terms of efficacy does come with a cost, a downside of obinutuzumab, and really that is on the safety in terms of adverse effects. With obinutuzumab there is a greater risk of grade A, grade 3 or 4 infusion-related reactions. Compared with rituximab it might be 6% compared with, say, 3%. There are also greater cytopenias. And the cytopenias can actually persist with obinutuzumab, including in the maintenance schedule, where you might have cytopenias, grade 3, neutropenia and 15% or so in patient, which would be higher than what we see with rituximab.
If you’re going to use obinutuzumab, there needs to be a little more closer follow-up in terms of adverse effects, cytopenias, and infection than what you might actually do with rituximab.
Transcript Edited for Clarity