Bendamustine and Rituximab Combo Shines in Indolent Lymphoma

Zosia Chustecka

June 10, 2012

June 3, 2012 (Chicago, Illinois) — New long-term results from a German trial of patients with indolent and slow-growing lymphoma confirm that a simpler 2-drug combination can be used in these patients instead of a more aggressive chemotherapy approach.

These updated results should now "be strong enough to change clinical practice," said lead researcher Mathias Rummel, MD, PhD, professor of medicine at Justus-Liebig-University Hospital in Giessen, Germany.

The standard treatment for these more challenging types of lymphoma — which include indolent follicular, Waldenström's, marginal zone, and mantle cell lymphoma in elderly patients — has been the R-CHOP chemotherapy regimen (rituximab [Rituxan, Genentech] plus cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], and prednisone).

There has been an ongoing debate about whether such an aggressive chemotherapy combination is needed for these indolent lymphomas, Dr. Rummel noted.

The updated results from the German Study Group for Indolent Lymphoma (StiL) "clearly show" that the simpler 2-drug combination of bendamustine plus rituximab is more effective and less toxic, Dr. Rummel said.

Speaking before his presentation at the plenary session here at the 2012 Annual Meeting of the American Society of Clinical Oncology, Dr. Rummel told journalists that he expects these new results to change clinical practice, especially in the United States, where the R-CHOP regimen is still widely used.

Decades-Old Drug

Bendamustine was originally developed 50 years ago in East Germany, but there was always some skepticism about using a drug that originated from behind the Iron Curtain, he explained. It was not until reunification in 1989 that physicians in West Germany started to use the drug, Dr. Rummel said; they were impressed when it produced response rates of 90% in a phase 2 trial.

This prompted the StiL group to conduct this phase 3 trial. Previous results from this trial, reported in 2009, suggested that the 2-drug combination led to better outcomes than the R-CHOP regimen. There was some uptake of the 2-drug combination, but it was not universal, Dr. Rummel reported.

He is hopeful that the updated results will convince physicians that the 2-drug combination of bendamustine plus rituximab should be the preferred choice for first-line treatment for indolent lymphoma.

New Standard of Care

This 2-drug combination is likely to become the new standard of care, said Bruce Roth, MD, from the Department of Oncology at the Washington University School of Medicine in St. Louis, Missouri, who moderated the press conference. "It is remarkable to see better efficacy and lower toxicity," he added.

Michael Williams, MD, from the University of Virginia Medical Center in Charlottesville, who was discussant for the abstract at the plenary session, congratulated the German group and said that the data from this trial support the use of bendamustine plus rituximab as a front-line therapy in all the types of lymphoma that were included in this trial, with the exception of marginal-zone lymphoma, for which there was no difference between the 2 treatment approaches. All the other subtypes, including low-risk and high-risk follicular lymphoma, mantle cell lymphoma, and Waldenström's macroglobulinemia, showed a statistically significantly better progression-free survival with bendamustine plus rituximab than with R-CHOP, plus there was less toxicity with the 2-drug combination.

"I expect it to become a preferred and commonly used regimen in these disease," he added.

Dr. Williams added 2 caveats to this: so far there are no data showing an overall survival advantage, and follow-up was just over 4 years, so there is still a need to document long-term toxic effects.

He noted that the National Comprehensive Cancer Network already includes the combination of bendamustine plus rituximab as one of the recommended front-line therapies for indolent lymphoma. He added that there has been increasing use of this combination by physicians in the United States since 2009, when Dr. Rummel presented early results from this trial.

Updated Results

The StiL trial involved 514 patients randomized to receive either bendamustine plus rituximab or the R-CHOP regimen for a maximum of 6 cycles.

The updated results come from a median follow-up of 45 months.

The primary end point of progression-free survival was twice as long with bendamustine plus rituximab as it was with R-CHOP (69.5 vs 31.2 months). "This is highly statistically significant," Dr. Rummel emphasized. The hazard ratio was 0.58.

The overall response rate was similar with bendamustine plus rituximab and R-CHOP (92.7% vs 91.3%), but a complete response was seen in more patients on the 2-drug combination (39.8% vs 30.0%).

Overall survival did not differ between the bendamustine plus rituximab and the R-CHOP groups (43 vs 45 deaths). However, Dr. Rummel told Medscape Medical News that there was considerable crossover in the trial, and 37% of patients who progressed on R-CHOP went on to receive bendamustine plus rituximab.

"Far Better" Toxicity Profile

The toxicity profile of bendamustine plus rituximab was "by far lower," Dr. Rummel said.

Hematologic toxicity was statistically significantly lower; leukocytopenia was seen in 12% of patients on bendamustine plus rituximab and in 38.2% on R-CHOP, and neutropenia was seen in 10.7% and 46.5%, respectively. This led to less use of granulocyte-colony stimulating factor (G-CSF) with the 2-drug combination than with R-CHOP (4% vs 20%).

"Not a single person experienced hair loss" with bendamustine plus rituximab, Dr. Rummel noted, whereas nearly all the patients on R-CHOP lost their hair.

In addition, there was less paresthesia with the 2-drug combination than with R-CHOP (18% vs 73%), and less stomatitis (16% vs 47%).

The only adverse event that was more frequent with bendamustine plus rituximab than with R-CHOP was skin reactions (42% vs 23%), but this was not statistically significant, Dr. Rummel said.

Bendamustine Available Worldwide

Bendamustine is currently available in most countries, although it is labeled for use in patients with lymphoma who are refractory to rituximab, Dr. Rummel explained. Most physicians are using it off-label in first- or second-line therapy, and are not waiting for the patient to become refractory to rituximab before using it, he said.

There is no patent protection for the drug because it was discovered so long ago, he said, but there is a data exclusivity provision that gives protection similar to a patent for the drug. It is marketed as Ribomustin in Germany and as Levact by Munidipharma Pharmaceuticals in a number of European countries, and was launched as Treanda by Cephalon in the United States.

A study analyzing the cost effectiveness of both treatments for indolent and mantle cell lymphoma from the perspective of the American healthcare payer, presented at the meeting in a poster (abstract 6553), concluded that the combination of bendamustine plus rituximab is a cost-effect alternative to R-CHOP.

Dr. Rummel reports receiving honoraria and research funding from Mundipharma and Roche Diagnostics.

2012 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract 3. Presented June 3, 2012.

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