Trial Suggests New First-line Treatment Option for Slow-growing Lymphomas

Adapted from the NCI Cancer Bulletin.

Results from a phase III clinical trial conducted in Germany suggest that the standard initial treatment for patients with slow developing (or indolent) types of B-cell lymphoma should be changed. The trial's lead investigator, Mathias Rummel, M.D., Ph.D., of the University Hospital in Giessen, Germany, reported that patients treated with a combination of rituximab (Rituxan) and bendamustine (Treanda) lived significantly longer without their disease progressing and were less likely to experience major toxicities than patients treated with the standard first-line treatment, a four-drug chemotherapy regimen plus the monoclonal antibody rituximab called R-CHOP. Patients who received rituximab and bendamustine were also more likely to see a nearly complete disappearance of their disease (complete response) compared with the standard first-line treatment.

The findings were presented December 5, 2009, at the American Society of Hematology annual meeting in New Orleans.

A majority of the 549 patients in the trial had follicular lymphoma; most of the remaining patients had either indolent lymphoma or mantle cell lymphoma. The latter is a more aggressive lymphoma that is also typically treated with the R-CHOP regimen, Dr. Rummel explained. Trial participants had substantial tumor growth, complications from their disease, or a large tumor burden. "So [these were] patients in need of treatment, with defined indications for treatment," he said during a press briefing.

Among the 513 patients who were evaluated, the overall response rate-that is, the percentage of patients who experienced at least some tumor shrinkage following treatment-was very high in both groups, 92.7 percent in the bendamustine plus rituximab arm versus 91.3 percent in the R-CHOP arm.

However, the two-drug regimen offered superior outcomes over R-CHOP. Median progression-free survival was 54.9 months versus 34.8 months, respectively, while the complete response rate was 39.6 percent versus 30 percent. Patients treated with bendamustine plus rituximab also had significantly lower rates of infections and of dangerous drops in white blood cells (WBC), and as a result they were much less likely to require treatment with granulocyte colony-stimulating factor to increase WBC production.

The trial was conducted primarily to see if the two-drug regimen was less toxic and equally as effective as R-CHOP, Dr. Rummel noted. "In the end," he continued, "we…demonstrated a clear statistically significant superiority of the better tolerated regimen."

Although he stressed that it can be important to have confirmatory results from another clinical trial, Richard Van Etten, M.D., Ph.D., director of the Tufts Medical Center Cancer Center, concurred with Dr. Rummel that the findings could alter the standard of care.

Some caution is warranted until longer-term data on toxicity are available, noted Dr. Anas Younes, M.D., a lymphoma researcher at the University of Texas M.D. Anderson Cancer Center, who made his comment in response to a reporter's question via Twitter.

Also, there are no overall survival data yet to report. But because these are slow-developing cancers deemed incurable, that may not matter in terms of defining the standard of care, explained Richard Little, M.D., M.P.H., of NCI's Division of Cancer Treatment and Diagnosis. "It's very difficult in this disease to base standard-of-care decisions on overall survival," he said. "Most of the primary endpoint data that drives standard of care is based on progression-free survival, with significant attention paid to the treatment's toxicity." As a result, many clinicians may now favor the bendamustine-plus-rituximab regimen over R-CHOP in patients who require cytotoxic therapy, he said.

Dr. Rummel also stressed that the dose of bendamustine used in the trial is lower than what is indicated on the drug's label for use in lymphoma patients in the United States. The lower dose is critical in this case, he said, because it helped to avoid unnecessary toxicities without apparently compromising effectiveness.

Several proposals have been submitted to NCI for early stage clinical trials using bendamustine and rituximab in combination with other novel agents in patients with follicular lymphoma, Dr. Little noted, in the hope of further improving efficacy and reducing toxicity.