Maintenance Rituximab Extends Remission in Pretreated Patients with Follicular Lymphoma

Until about eight years ago, the frontline treatment for follicular lymphoma was R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) plus the monoclonal antibody rituximab. At that time, studies such as the PRIMA trial showed that giving maintenance rituximab every two to three months for two years to patients who had responded to R-CHOP would extend their duration of remission.

Then, in the STIL and BRIGHT trials, researchers showed that bendamustine plus rituximab (BR) was at least as good if not better than R-CHOP, and that patients tolerated it better. So BR became the standard frontline treatment for follicular lymphoma with high tumor burden. Many oncologists have extrapolated from the experience with R-CHOP and given patients maintenance rituximab after BR.

No prospective trial, however, has shown whether maintenance rituximab after BR is safe and effective. And oncologists disagree about whether the practice is a good idea for follicular lymphoma patients treated with BR.

“There is still a significant amount of practice variation among oncologists, even those who specialize in lymphoma,” says Brian T. Hill, MD, PhD, Director of the Lymphoid Malignancies Program. “Some people felt really strongly that we didn’t know that maintenance rituximab was safe and effective after BR. Others said the PRIMA study showed that maintenance treatment can extend the duration of remission after R-CHOP and therefore we should just go ahead and do it after BR.”

Improved duration of remission

To help shed additional light on the issue, Dr. Hill and colleagues conducted a retrospective analysis of the outcomes of 640 follicular lymphoma patients across 13 U.S. academic medical centers. The study was published recently in the British Journal of Haematology.

Of these patients, 410 had responses to induction therapy, including 262 with complete remission (CR) and 114 with partial remission (PR). In the entire study cohort, the three-year progression-free survival was 84.2 percent for maintenance rituximab compared with 61.2 percent for no maintenance (P < 0.001)

Improved duration of response (DOR) was seen in patients who achieved PR after four or more cycles of BR and continued with maintenance rituximab compared with no maintenance therapy (80 percent vs 45 percent; P = 0.003). However, this was not true of patients who achieved CR (three-year DOR: 85.9 percent vs 80.2 percent; P = 0.535).

“We found overall that maintenance rituximab does improve the duration of remission after BR,” says Dr. Hill. “But when we looked a little more closely, the benefit seemed to be most pronounced in the people who had a partial remission from their frontline therapy. Those patients who had a complete remission, we really couldn’t really see any benefit to rituximab maintenance.”

Selection bias

The recent GALLIUM trial, which compared BR with bendamustine/obinutuzumab, followed by either rituximab or obinutuzumab maintenance, showed a high rate of fatal adverse events in patients treated with BR and then with rituximab maintenance.

“Many of those deaths were from infectious complications during the maintenance period,” says Dr. Hill. “When we examined at our data, we did not see an increased risk in infectious deaths in the patients who received rituximab maintenance after BR compared to those who had just observation after BR. My suspicion is that the GALLIUM study had some selection bias to older, frailer patients to receive BR as opposed to R-CHOP.”

Future direction

The possibility that maintenance treatment may preferentially benefit patients with suboptimal response to BR and not those in CR is a relatively new concept. Dr. Hill cautioned that “these are retrospective data which can be confounded by unappreciated systemic bias.”

Because the gold-standard — a prospective trial — to test maintenance treatment after BR is unlikely to be performed, however, future study of additional outcomes in other cohorts are needed to validate these findings.