The 2-drug regimen was "much better tolerated" and, to the surprise of the investigators, the efficacy was not only noninferior, it showed "a clear and statistically significant superiority," said lead researcher Mathias Rummel, MD, PhD, head of hematology at the University Hospital in Giessen, Germany. He was presenting the final results from the phase 3 head-to-head comparator study conducted by the German Study Group for Indolent Lymphomas (StiL) here at the American Society of Hematology 51st Annual Meeting.
"The combination of bendamustine plus rituximab improves progression-free survival and complete remission rates while showing a better tolerability," Dr. Rummel told conference delegates. "These promising results suggest that the combination has the potential to become a new standard first-line treatment option for patients with follicular lymphoma, mantle cell lymphoma, and indolent lymphomas," he said.
Several of the experts in the audience agreed, and congratulated Dr. Rummel on the study.
"These are potentially practice-changing data," said Richard Van Etten, MD, PhD, director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts, and moderator of the press conference at which the results were discussed. "I would like to see a confirmatory study, and I would like to see overall survival results, but I don't think we need to wait for that."
Dr. Rummel countered that it would take a long time to show any effect on overall survival, because this is "an incurable and long, slow disease."
In contrast to aggressive lymphoma, these conditions cannot be cured with chemotherapy; it was for this reason, Dr. Rummel explained, that his team set out to determine whether the efficacy could be maintained with a less toxic regimen.
Patients were randomized to treatment with 2 doses of bendamustine (90 mg/m2) and 1 dose of rituximab (375 mg/m2) every 28 days, or to the standard R-CHOP regimen every 21 days, for a maximum of 6 cycles.
The final results are based on 513 evaluable patients, half of whom had follicular lymphoma (54% and 56% of the 2 treatment groups, respectively); the remainder had mantle cell lymphoma (18% to 19%) and other indolent lymphomas (24% to 27%). All patients were symptomatic, with a large tumor burden, Dr. Rummel said.
The 2-drug combination significantly improved progression-free survival to 54.8 months, compared with 34.8 months with R-CHOP — a gain of 20 months..
The complete remission rate of 40.1% with bendamustine plus rituximab was significantly higher than the 30.8% achieved with R-CHOP. Also highly significant was the difference between the time to next treatment, which is a measure that is free from investigator bias, said Dr. Rummel. He noted that the significance remained when each of the subgroups of lymphoma patients was analyzed separately.
In addition, the 2-drug combination was "much better tolerated." All of the adverse events were significantly less frequent in the bendamustine/rituximab group than in the R-CHOP group.
Adverse Events for Bendamustine/Rituximab vs R-CHOP
| Adverse Event | Bendamustine/Rituximab | R-CHOP |
| Neutropenia (%) | 10.7 | 46.5 |
| Leukocytopenia (%) | 12.1 | 38.2 |
| Alopecia (%) | 15.0 | 62.0 |
| Infectious complications (n) | 95 | 121 |
| Peripheral neuropathy (n) | 18 | 73 |
| Stomatitis (n) | 16 | 47 |
Dr. Rummel noted that there was more use of granulocyte colony-stimulating factor in the R-CHOP group (20%) than in the bendamustine plus rituximab group (4%), but "despite the fact that you support fewer cycles, there was less hematological toxicity and, as a consequence, fewer infections."
The only adverse event that was significantly more common with bendamustine plus rituximab was drug-associated erythematous skin reaction, such as urticaria and rash, which was seen in 42 patients, and in 23 patients in the R-CHOP group (P = .0122).
Bendamustine is an old drug that was used more than 30 years ago in Germany, but it got a new lease on life last year when it was approved (as Treanda, Cephalon) by the US Food and Drug Administration for first-line use in chronic lymphocytic leukemia. However, the dose used for that indication (120 mg/m2 every 3 weeks) is much higher than the dose used in this indolent lymphoma study (90 g/m2 every 4 weeks).
Dr. Rummel reports receiving research funding and honoraria from Roche. Dr. Van Etten has disclosed no relevant financial relationships.
American Society of Hematology (ASH) 51st Annual Meeting: Abstract 405. Presented December 7, 2009.
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