The Evolving Landscape of Therapy for Follicular Lymphoma - Episode 4
Anas Younes, MD: The choice of a frontline regimen is determined by the performance status and the comorbidities of the patient. So, in general, the majority of patients with lymphomas would be physically fit and would tolerate chemotherapy. And then, you have 2 choices. Widely used regimens for these patients are the R-CHOP regimen and the R-bendamustine regimen. The only time when I can choose one over the other is when you do a PET scan and find a lesion that may be transformed, whether by biopsy or just by high SUV. That will sway me to use R-CHOP over R-bendamustine. If there’s no evidence of transformation, I’ll use R-bendamustine. For the elderly patients who have comorbidities, the only thing we have for now is basically rituximab as a single agent. In the future, we’ll probably be adding a few other non-chemotherapy-based regimens to the rituximab backbone to hopefully achieve good responses, but without much toxicity.
Bruce Cheson, MD: Given that follicular lymphoma is generally considered an incurable disease— although, I believe some patients are curable, but the majority aren’t—we need to find new approaches for these patients and, in particular, newer and more effective drugs. Anti-CD20s have become the mainstay of treatment for follicular and low-grade lymphomas, and no matter what chemotherapy regimen you combine them with, they prolong not only progression-free survival but also, in general, overall survival. So, there has been a hunt for newer and better anti-CD20s. We’ve been through a dozen of these over the last few years, none of which have really panned out until obinutuzumab, which is a next-generation anti-CD20 that has a greater cytotoxicity than does rituximab in preclinical models, including in combination with bendamustine. It doesn’t have much complement dependent cytotoxicity, but it has greater ADCC (antibody-dependent cell-mediated cytotoxicity) and greater cell kill in in vivo models and in patients. So, as a result, there has been considerable interest in bringing obinutuzumab into the therapeutic arena, not only as a single agent but also in combinations with a variety of other therapies. This has led to a number of phase II and, subsequently, phase III trials looking at the role of obinutuzumab in the management of patients with follicular and low-grade lymphoma.
The GALLIUM study was a very large randomized phase III trial in which patients with follicular low-grade lymphoma were randomized to 1 of 3 chemotherapy regimens—CHOP, CVP, or bendamustine—with rituximab as the anti-CD20 or obinutuzumab. The results of the study were very interesting and quite controversial. Obinutuzumab was the better partner in that it prolonged progression-free survival, which was the primary endpoint of the study. However, there was no survival advantage, and there was greater toxicity in the obinutuzumab regimens. In particular, with bendamustine, there was a surprising increase in toxicities and fatalities, including infections, which we had never seen before in any other bendamustine/anti-CD20 regimen study.
Now, how is this regimen going to change our approach to follicular lymphoma? I think it’s not clear at this point in time, because we’re going to have to weigh things. How important is progression-free survival? Well, progression-free survival is important if it is unaccompanied by toxicity. And in this case, there was greater toxicity of all sorts. So, whether or not physicians will adopt this regimen is not clear. Now, bendamustine/rituximab has become the most common frontline regimen in the United States. Will physicians be willing to drop the rituximab and substitute obinutuzumab based on this study? I think this remains to be seen. Are they willing to take a little progression-free survival with no survival and increased toxicity and change how they approach these patients? I’m not sure, and time will tell whether or not that is really going to happen.
Transcript Edited for Clarity