1. Kahl, Brad MD

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The first two oral presentations at the lymphoma session at the 2017 ASCO Annual Meeting provided long-term follow-up data from previously published studies. Mathias Rummel, MD, PhD, Head of the Department for Hematology at the Clinic for Hematology and Medical Oncology, Justus-Liebig University-Hospital, Gie[latin sharp s]en, Germany, presented long-term follow-up data from the StiL trial, which was the first study to suggest that bendamustine plus rituximab (BR) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP) in follicular lymphoma and mantle cell lymphoma (Abstract 7501). The long-term follow-up focused on the patients with follicular lymphoma. After more than 9 years of follow-up, the StiL data continued to show substantial superiority of BR over R-CHOP, with a median progression-free survival (PFS) of 69 months versus 31 months. This difference translated into a significant benefit in terms of time to next treatment, although no difference in overall survival was noted. There also was no difference in risk for secondary malignancies.

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Ian Flinn, MD, PhD, Director, Blood Cancer Research Program, and Principal Investigator, Sarah Cannon Research Institute, presented long-term follow-up data from the BRIGHT study (Abstract 7500). BRIGHT, which was conducted in North America, compared BR with R-CHOP/R-CVP. Whether a patient received R-CHOP or R-CVP was up to the treating physician. BR was superior to R-CHOP/R-CVP for PFS, although when the patients treated with BR were analyzed against just the patients assigned to R-CHOP, the statistical significance of the difference was lost. In addition, with long-term follow-up, significantly more secondary malignancies developed in the patients treated with BR than in those treated with R-CHOP/R-CVP (42 vs. 24). It is always a little disturbing when two randomized trials do not yield congruent results. Why should BR beat R-CHOP so handily in the StiL trial when the two regimens are more or less tied in BRIGHT?


Commentary on the Studies

I was the discussant for these presentations and I hypothesized that maintenance rituximab might have a differential effect. We know from the PRIMA trial that maintenance rituximab substantially prolongs PFS after R-CHOP. Is it possible that the same benefit is not realized after BR? No maintenance was given in the StiL trial, whereas approximately half of the patients in BRIGHT received maintenance. In the GALLIUM trial, presented at the 2016 ASH meeting, all the patients received maintenance, and individual centers could select their chemotherapy backbone. When BR plus maintenance was analyzed versus R-CHOP plus maintenance, no difference in PFS was found. In other words, maintenance pulls up the PFS curve after R-CHOP, but is unable to do the same after BR. Of course, this is all speculation. It's an important issue to sort out, and Flinn assured me that he and his colleagues would further analyze the data from BRIGHT.


There is also the safety issue to consider. The rate of fatal adverse events in GALLIUM was close to 5 percent for the patients who received BR followed by maintenance rituximab, whereas it was 2 percent for the patients who received R-CHOP followed by maintenance. Infections appear to be a significant source of this risk, and it is apparent that bendamustine has a considerably greater effect on T cells than R-CHOP does. Many well-respected lymphoma experts are concerned about this worrisome finding and there is a growing minority who feel bendamustine is unsuitable for frontline use in follicular lymphoma.


My own experience with bendamustine for frontline use in follicular lymphoma (and mantle cell lymphoma) has been largely positive. In E2408, a frontline trial of more than 300 patients with follicular lymphoma in which BR plus rituximab maintenance was used in all arms, Andrew Evens, DO, MSc, Director of the Tufts Cancer Center, Boston, and I noted that the rate of fatal adverse events was 2.8 percent-not the 5 percent seen in GALLIUM. Toward the conclusion of my discussion, I listed the pros for BR and the pros for R-CHOP. The lists were comparable in length. I continue to use BR as front-line therapy. I do acknowledge that BR is more myelosuppressive and immunosuppressive. In favor of BR is the lack of neuropathy, the lack of corticosteroid use, and the lack of alopecia. It is also desirable to withhold the anthracycline in case transformation should occur later in the disease course. In BRIGHT, quality of life was better with BR than with R-CHOP.


It will be very important to continue to collect data on infections and secondary malignancies after BR therapy. This story is sure to evolve as we see more long-term follow-up data from all our trials.


BRAD KAHL, MD, is Professor of Medicine and Director of the Lymphoma Program, Washington University School of Medicine, St. Louis, Mo.

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