Zosia Chustecka

May 26, 2010

May 26, 2010 — Rituximab maintenance therapy halved the risk for relapse in patients with follicular lymphoma who responded to induction therapy with a combination of rituximab and chemotherapy, according to results from the large international Primary Rituximab and Maintenance (PRIMA) trial.

"These findings provide hope for the way we manage this disease," said lead investigator Gilles Salles, MD, from the University of Lyon in France, adding that rituximab maintenance "should be considered a standard of care."

Dr. Salles was speaking at a presscast ahead of the forthcoming American Society of Clinical Oncology (ASCO) 2010 Annual Meeting, where he is due to present the findings on June 5.

"Congratulations on a strikingly positive and truly important study," said George Sledge Jr., MD, president-elect of ASCO.

The results show that lymphoma, like several other cancers, can now be regarded as a chronic disease, with chronic therapy to help keep it in remission, Dr. Sledge explained. "It will be interesting to see if this translates into a survival benefit," he added.

The PRIMA trial was funded by Roche, the manufacturer of rituximab, and the company has already used these data to apply for extended approval in both the United States and Europe for the use of rituximab maintenance in patients with follicular lymphoma.

Rituximab is already approved for maintenance therapy, but in the United States the labeling specifies that approval is only for patients who received induction therapy with cyclophosphamide, vincristine, and prednisone. Approval was based on the results from the E1496 study, which began in 1997; at that time, induction was carried out with chemotherapy alone.

Since then, clinical practice has changed. Induction is now commonly carried out with rituximab in combination with chemotherapy, and the most commonly used regimen is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

When the results from the E1496 study were published last year (J Clin Oncol. 2009;27:1607-1614), the researchers explained that one of the questions not addressed in their trial — which they noted at the time as being important for extrapolating the results to clinical practice — was the issue of rituximab maintenance therapy in patients who had already received rituximab during the induction therapy phase, as reported by Medscape Oncology.

This was the question that PRIMA set out to answer, and it has now established the benefit of rituximab maintenance in patients who were initially treated with the combination.

Significant Benefit on Progression-Free Survival

The trial was conducted in 1217 patients with follicular lymphoma, most of whom (75%) had received induction therapy with rituximab plus CHOP; the remainder received rituximab with other chemotherapy combinations. Patients were then randomized to receive rituximab maintenance (1 dose of 375 mg/m2 intravenously every 8 weeks for 2 years) or to be followed with observation alone.

A significant improvement in progression-free survival was seen in the rituximab group. During the median follow-up of 25 months, disease progression occurred in 18% of patients in the rituximab group and in 34% of patients in the observation group (hazard ratio, 0.50; P < .0001). The benefits were observed regardless of the patients' stage of remission, age, or previous treatment regimen, Dr. Salles reported.

Rituximab maintenance therapy was well tolerated, and there was no impact on quality of life, he reported. The most commonly reported adverse effects were infections (37% in the rituximab group and 22% in the observation group).

Maintenance rituximab significantly improves progression-free survival with "little additional toxicity," and the PRIMA results provide evidence for "a new standard of care in follicular lymphoma," Dr. Salles concluded.

Principal investigator of the E1496 trial, Howard Hochster, MD, professor of medicine at the New York University Cancer Institute in New York City, told Medscape Oncology that "all in all," the PRIMA study confirms the findings from the E1496 study, even though it used a more intensive chemotherapy regimen. There were several other differences between the trials, including the rituximab maintenance administration schedule that was used.

Dr. Hochster said that he agreed with Dr. Salles' concluding comments. "Maintenance rituximab should certainly be considered a standard of care," he said.

But Do Patients Live Longer?

So far, there are no survival data from the PRIMA trial.

In the E1496 trial, which showed a similar benefit on progression-free survival to that seen in the PRIMA trial, the effect of rituximab maintenance on overall survival was of borderline statistical significance (92% in the rituximab group vs 86% in the observation group at 3 years; P = .05). At the time, Dr. Hochster said that "in this group of patients, even 10 years of observation is a little too soon to show survival benefits, but the trend is present." In addition, rituximab maintenance is "reasonably nontoxic" and can improve disease-free survival by several years, he added.

A survival benefit was shown for rituximab maintenance therapy in a meta-analysis published last year of 5 trials involving more than 1000 patients (J Natl Cancer Inst. 2009;101:248-255).

Lead author Liat Vidal, MD, from the Rabin Medical Center in Petah-Tikva, Israel, told Medscape Oncology at that time that this is "the first time, to our knowledge " that the survival benefit has been demonstrated. "Rituximab maintenance should be used for patients with relapsed follicular lymphoma after successful induction treatment," Dr. Vidal continued. Such use is not currently recommended in guidelines, but many physicians are already doing this, she added.

However, some cautionary comments on the meta-analysis results appeared in a report on the National Cancer Institute (NCI) Web site.

This analysis confirms the value of rituximab in extending the lives of patients with follicular lymphoma, according to Wyndham Wilson, MD, head of the Lymphoma Therapeutics Section of the NCI's Center for Cancer Research. However, it does not answer the question of whether patients treated with maintenance rituximab live longer than patients who are treated with rituximab when their disease relapses, he points out.

"We know that patients with follicular lymphoma benefit from treatment with rituximab," writes Dr. Wilson. "But we cannot conclude from this analysis that maintenance therapy is the optimal approach to administering rituximab."

The current standard of care in the United States is to treat patients with follicular lymphoma with rituximab when their disease relapses after initial chemotherapy, Dr. Wilson reports. The findings of this meta-analysis do not justify changing that standard, he concludes.

It will be interesting to hear the discussion that follows the presentation of the PRIMA results at the ASCO meeting, to see if the latest results sway expert opinion on rituximab maintenance therapy in follicular lymphoma.

The PRIMA study was funded by Roche. Dr. Salles reports serving as a consultant or advisor for Roche, receiving honoraria from Roche, and receiving research funding from Genentech. Dr. Hochster reports acting as a consultant for Roche and Genentech, and receiving honoraria and research funding from Genentech.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract 8004. To be presented June 5, 2010.

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