Insights From: Alexey V. Danilov, MD, PhD, Oregon Health & Science University; Carla Casulo, MD, University of Rochester, Wilmot Cancer Institute
Alexey V. Danilov, MD, PhD: When patients present with relapsed/refractory lymphoma, there are several factors to consider. One of them, of course, is how soon after initial therapy relapse has occurred. Patients who relapsed within 24 months of initial therapy have poorer prognosis, compared to patients who relapsed later in their disease. For those patients who relapse late—say 7, 8, 10 years after initial therapy—repeating chemoimmunotherapy is a very viable choice. If they received a CHOP [cyclophosphamide/doxorubicin/vincristine/prednisone]/rituximab combination in the past, one could use bendamustine/rituximab or bendamustine/obinutuzumab. One could potentially even repeat CHOP [cyclophosphamide/doxorubicin/vincristine/prednisone], if those patients don’t have cardiac comorbidities, for example.
In patients who progress within 24 months of initial therapy, the choices become somewhat harder and more limited. Typically, for those patients, you can still use chemoimmunotherapy again. However, one would expect that they may not respond as well, and it may be beneficial to use some of the novel agents. Recently, a combination of lenalidomide/rituximab has been approved in the therapy of relapsed follicular lymphoma based on the results of the AUGMENT clinical trial, where a lenalidomide/rituximab combination demonstrated benefit in progression-free survival over rituximab alone. For patients with high-risk disease who progress early, that could be a good option, as this treatment does not target the same pathway as chemotherapy. This remains an area of unmet medical need, and investigations are ongoing, including cooperative group trials, which try to really zone in on this patient population and determine what the best therapy is for those patients.
Carla Casulo, MD: Whatever you use in the beginning to treat your patient will definitely influence what happens afterward. That’s because some treatments have a lifetime dose limit. For example, if you treat your patient with R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone], then you have 6 cycles of anthracycline, which may be the dose limit for that particular patient, so you wouldn’t repeat R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] if they relapsed at some point in the future. That is a perfect example of how what you begin with influences what you do next. However, bendamustine is a little bit different. There’s no dose limit to bendamustine; however, few I think would repeat bendamustine after 6 cycles because you can develop a lot of cytopenia.
Those are the 2 most commonly used induction regimens for frontline treatment, and they often get repeated second-line, but most often, they don’t. Most often, you would choose to use something different. Right now, we have several FDA-approved treatments for relapsed follicular lymphoma. As I mentioned, lenalidomide and rituximab were just approved by the FDA on May 28th for relapsed follicular lymphoma and marginal zone lymphoma.
Then, we also have 3 different PI3 kinase inhibitors with varying adverse effects that can be used in the relapse setting. You don’t have to necessarily repeat what was used in the beginning. Some patients may even get single-agent rituximab at the time of relapse, because it’s a relatively asymptomatic relapse and much time has elapsed from the beginning of their treatment to when their disease recurred. You don’t necessarily have to worry about repeating the treatment that you used in the beginning.
In general, most patients with follicular lymphoma treated with either R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] or bendamustine have a long duration of response. The vast majority of them will have a very durable disease control.
There’s a recent study that was published some time ago now, maybe a year or so ago, that was an updated analysis of SWOG S0016, which was a very large United States group study looking at CHOP [cyclophosphamide/doxorubicin/vincristine/prednisone] with radioimmunotherapy versus R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone]. That study showed that at 10 years, 80% of patients with follicular lymphoma were still alive. That tells us that it matters what you use in the beginning, but the vast majority of patients will do very well. I think what we need to focus on is finding the patients who are less likely to do well so that you can treat those patients differently.