Bendamustine Superiority in Lymphoma Regimen Confirmed

Mathias J. Rummel, MD, PhD

Bendamustine, developed in the former German Democratic Republic a half-century ago yet unknown in the United States until recent years, should become the preferred chemotherapy standard of care in initial combination regimens for indolent lymphomas and mantle cell lymphoma, a leading researcher said at the American Society of Clinical Oncology (ASCO) annual meeting Saturday.

Mathias J. Rummel, MD, PhD, professor of medicine at the University Hospital Giessen in Germany, presented long-term results from a phase III study that compared a regimen of bendamustine (Treanda) and rituximab (Rituxan) (B-R) with standard R-CHOP therapy in 514 patients with previously untreated indolent non-Hodgkin or mantle cell lymphomas. The R-CHOP regimen consists of rituximab plus the chemotherapy drugs cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine, and prednisone.

At median follow-up of 45 months, median progression-free survival (PFS) was 69.5 months in the B-R group versus 31.2 months for the R-CHOP group (hazard ratio, 0.58, 95% CI, 0.44-0.74; P=.0000148). Moreover, there was no hair loss and a lower incidence of nerve toxicity, infections, and grades 3/4 hematotoxicity with B-R therapy. There was a higher incidence of mild skin reactions with B-R.

“B-R is not only less toxic but also more effective than the most often used front-line treatment approach, R-CHOP, and should therefore be considered as a preferred first-line treatment for patients with these disease entities,” said Rummel.

During the briefing and in an interview, Rummel recounted the remarkable journey of bendamustine from the days when an Iron Curtain indeed separated oncologists in East Germany from their counterparts in West Germany.

Although bendamustine had been successfully used in East Germany for several decades, there was no communication among scientists in the Cold War era, and oncologists in the western part of the country did not learn about bendamustine until after reunification in 1990.

“We were all very skeptical,” Rummel said about the reaction among oncology specialists in the western part of the country. He said studies had not been conducted and peer-reviewed articles had not been published.

Rummel, however, said that they started using the agent, and found it effective. In 2000, Rummel decided to launch a study comparing B-R with R-CHOP. He said his colleagues in the worldwide oncology community thought the study would not succeed because R-CHOP was so well established. Rummel said the study was conducted in Germany because “we believed in it due to our own experience.”

In 2008, the FDA approved Treanda for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of therapy with rituximab alone or in combination.

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Dr. Rummel on Treanda Plus Rituxan in Indolent Lymphoma

The following year, Rummel presented phase II results at the American Society of Hematology annual meeting that were so positive that doctors in the United States and elsewhere began using bendamustine. Now, he said bendamustine is frequently used off-label in earlier settings. “Nobody is waiting until patients become rituximab-refractory,” he said.

Rummel said R-CHOP remains the foremost choice for treating patients with diffuse large B-cell lymphoma, but that “there was always an ongoing debate about whether you need such an aggressive regimen for the treatment of patients with indolent lymphomas.”

In the trial discussed this week at ASCO, the patients were diagnosed with the indolent lymphoma subtypes of follicular, Waldenstrom, marginal zone, and small lymphocytic, as well as with mantle cell lymphoma.

Although bendamustine delivered a markedly higher PFS benefit than R-CHOP, there was no statistically significant improvement in overall survival (OS). The overall response rate was 92.7% in the B-R group (261 patients) versus 91.3% in the R-CHOP group (253 patients). The difference in complete response was 39.8% with B-R versus 30.0% with R-CHOP (P=.021).

Nearly half of those R-CHOP patients whose disease continued to progress were permitted to cross over to B-R. Rummel also noted that the R-CHOP patients who progressed were re-treated more aggressively if they received additional R-CHOP, and that the typically long survival in indolent lymphoma makes OS difficult to assess.

“The primary objective of such a trial in indolent lymphoma is progression-free survival,” Rummel said. “Here we see a huge difference in favor of bendamustine.”

Bruce J. Roth, MD, a professor of medicine in the Division of Oncology at the Washington University School of Medicine in St. Louis, Missouri, who moderated the press briefing where the findings were discussed, said bendamustine has striking clinical characteristics.

“It’s certainly remarkable to have an agent that provides superior efficacy and decreased toxicity at the same time,” Roth said. “A number of US physicians had already switched to this regimen after preliminary data from this trial presented at ASH in 2009, but certainly it’s nice to have the final data and certainly this is likely to become a new standard of care for these individuals.”

Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. J Clin Oncol. 2012;30(suppl; abstr 3).

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