NEW YORK CITY—For patients with follicular lymphoma (FL), some recent randomized controlled trials show that use of maintenance rituximab increases progression-free survival (PFS), both after first-line treatment and in relapsed or refractory disease. There are also trends toward improvement in overall survival in relapsed or refractory FL, despite a higher rate of infection and other complications compared with that for observation.
Although FL is considered an indolent lymphoma, patients typically relapse after therapy and experience disease progression. Most patients present with advanced disease and are not curable with current therapy.
Does maintenance therapy with rituximab delay progression of disease and increase survival in patients with relapsed or refractory FL who respond to induction therapy? That was the main issue debated here at the Lymphoma & Myeloma meeting by two top lymphoma experts.
And despite newer trials showing the promise of maintenance therapy in follicular lymphoma presented by one expert, the other remained adamant about not using it. After hearing both speakers, the majority of the audience said they did favor the use of maintenance rituximab therapy, though.
Most patients with follicular lymphoma should receive rituximab maintenance therapy after induction therapy, said David G. Maloney, MD, PhD, noting that rituximab maintenance has been shown to prevent disease progression in clinical trials. Only a small minority of FL patients relapse during rituximab maintenance, he said: “About 80% of the patients have not relapsed at the time maintenance is discontinued. Benefits are extended several years after completion of maintenance.”
Rituximab maintenance therapy reduced the risk of recurrence by 50% in patients with FL who responded to induction therapy with rituximab plus chemotherapy, according to the results of the Primary Rituximab and Maintenance (PRIMA) phase III study, he said, which compared rituximab maintenance therapy versus observation alone. The PRIMA trial, which included 1,217 patients with untreated FL and high tumor burden, showed no benefit in terms of overall survival, but did show a progression-free survival (PFS) benefit in subgroups.
“I have helped design SWOG trials using PFS as an endpoint. The fact that we are seeing an increase in PFS in rituximab maintenance studies is an important observation,” he said. Other studies also show that maintenance leads to a benefit in time to next lymphoma therapy compared with observation, even though there is no difference in overall survival.
In the PRIMA trial, there was no difference in a quality-of-life assessment between the treatment and observation arms. “Curiously, even though the maintenance group had more infusions, this led to similar quality-of- life measures,” he said.
In addition, the PRIMA trial showed that negative PET scans in FL patients were associated with improvements in PFS. “We don't routinely use PET in FL. This might be something we start doing in the future.”
A meta-analysis conducted prior to the PRIMA trial pooled six maintenance studies in FL. The meta-analysis showed an improvement in the hazard ratio of 0.6 for overall survival in favor of maintenance over observation. “This meta-analysis suggests that there is an overall survival advantage with maintenance rituximab,” he said.
In a further breakdown of frontline versus maintenance after first induction or two or more inductions, the meta-analysis showed a survival advantage in both subsets of patients receiving maintenance therapy. “This suggests maintenance therapy improves survival in FL,” Maloney emphasized.
There are, however, potential downsides to rituximab maintenance, he noted. “Toxicity with infusion-related symptoms is generally mild, and there is slightly greater neutropenia and greater prolonged B-cell depletion, which can lead to some immunodeficiency. This is more common after fludarabine and rituximab regimens. There is a small increase in treatable infections. The PRIMA trial showed a doubling of incidences of infections requiring therapy from three percent for observation to six percent for maintenance.
“Reactivation of viral infections can occur, so be cautious with patients with hepatitis.”
Cost is an issue, but this is tricky to analyze, he said, noting that European studies suggest a cost benefit with maintenance therapy.
In conclusion, he said, “Extended rituximab maintenance has proven clinical benefit following rituximab induction in responding patients in the upfront and relapsed setting, after chemotherapy in those with stable disease or better, and rituximab–chemotherapy in the upfront and relapsed setting. The risks appear to be reasonable.”
Bruce D. Cheson, said that before rituximab maintenance can be accepted in follicular lymphoma, clinicians need to know the optimal maintenance regimen or duration, the effect on overall survival, the impact on subsequent therapy, its role relative to retreatment, and the long-term toxicities.
He noted that maintenance schedules vary widely, from doses every two to six months to being based on drug blood levels.
A handful of recent clinical trials show no overall survival advantage for rituximab maintenance, he continued. In some studies, progression-free survival is initially significantly higher with maintenance, but “with longer follow-up, the PFS and overall survival curves are getting closer together. Survival is no longer as significant as it once was.”
He had a different interpretation of the meta-analysis mentioned by Dr. Maloney, saying it shows that rituximab maintenance therapy does not consistently improve overall survival versus observation.
Cheson pointed out that the meta-analysis showed an “astounding” increase in infections with rituximab maintenance, with toxicity reduced in the control arm compared with the treatment arm. “In randomized controlled trials, the neutropenia and infection rates are twice as high with maintenance therapy. In other studies, the hospitalization rate is higher as well,” he said.
Delayed complications of rituximab maintenance include late cytopenias, prolonged reduction in serum immunoglobulins, infections, reactivation of hepatitis B and C, and interstitial pneumonitis. “The worst is progressive multifocal leukoencephalopathy, which develops in the setting of rituximab and is a uniformly fatal complication,” he said.
In the CORAL trial, 396 patients with relapsed or refractory diffuse large B-cell lymphoma were randomized to receive rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) or rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) followed by autologous stem cell transplant. Both regimens produced a similar response rate of 63%, but the R-DHAP regimen was slightly more toxic. Patients who relapsed from rituximab-containing regimens did worse than those who did not.
Event-free survival (EFS) based on prognostic factors found two negative predictive factors. One was failure from diagnosis in less than 12 months. “The strongest negative predictor of outcome following stem cell transplantation was prior rituximab therapy,” he said, adding that the CORAL trial also suggests impaired response to subsequent therapy with rituximab.
Gender may also be a predictive factor. Observations have been made in German trials and the PRIMA trial that men who have maintenance rituximab do worse than women do. An investment in pharmacokinetics of men and women is needed to evaluate this factor, he said.
“Rituximab maintenance is expensive, cumbersome, increases toxicities, shows no survival benefit, may impair response to subsequent therapy, and induces rituximab resistance. We have to use rituximab appropriately. If we induce rituximab resistance and the patient relapses, we have lost one of our most important therapeutic tools.”
He suggested considering other drugs for maintenance, such as lenalidomide. For upfront therapy of FL he said he prefers to use a combination of bendamustine and rituximab, which “appears to be more effective than R-CHOP. We need to work on the front end. If we had better induction, we wouldn't need maintenance.”
Before each presentation, and again after both presentations, the audience was asked: Should all FL patients receive maintenance rituximab?” The audience appeared to respond positively to Maloney's argument, with a majority (59%) voting in favor of maintenance rituximab after the presentation, an increase from the pre–presentation survey (41%).
During the discussion, when Cheson was asked whether he uses rituximab maintenance, he said flatly: “In the last year I have not given any FL patient rituximab maintenance. I only use it for marginal zone patients who need therapy.”
Maloney pointed out that “the CORAL trial is often misinterpreted—If we look at the effect of prior rituximab, more patients were cured and therefore will not relapse or need to go to transplantation.”
Cheson again pointed out that the preliminary data for follow-up no longer show a difference in favor of rituximab maintenance.
The meeting's Chair, Morton Coleman, MD, commented: “My objection to rituximab maintenance is that 40% of patients have one or two infections. The biggest problem I encounter is chronic sinusitis, which will not clear with antibiotics. Then I have to give gamma globulin monthly, which is enormously expensive. I'm not so sure it is a totally innocuous approach to therapy.”
Maloney noted that he routinely checks immunoglobulin levels on all patients on rituximab maintenance.