The Role of Front-Line Bendamustine Plus Rituximab in Indolent NHL and MCL

The Role of Front-Line Bendamustine Plus Rituximab in Indolent NHL and MCL

Dr. Ian Flinn presents Abstract 7500.
The combination of bendamustine plus rituximab (BR) showed no statistical difference in overall survival (OS) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP), or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) in patients with certain types of lymphoma, according to 5- and 10-year follow-up data from two separate studies presented during the Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia Oral Abstract Session on June 3.

BRIGHT Study

The first presentation discussed the long-term follow-up of the BRIGHT study in patients with treatment-naive indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL; Abstract 7500). Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute, noted that the initial study results found BR was noninferior to R-CHOP/R-CVP.

There were 447 patients included in the long-term follow-up, 224 patients in the BR intent-to-treat arm, and 223 patients in the R-CHOP/R-CVP arm. In the BR arm, 43% of patients received rituximab maintenance and in the R-CHOP/R-CVP arm, 45%.

By treatment group, the 5-year progression-free survival (PFS) rate was 65.5% (95% CI [58.5, 71.6]) in the BR arm and 55.8% (95% CI [48.4, 62.5]) in the R-CHOP/R-CVP arm (hazard ratio [HR] 0.61, 95% CI [0.45, 0.85]; p = 0.0025). Similar results favoring BR were found in iNHL: PFS for the BR group was 70.3% (95% CI [62.8, 76.5]) compared with 62.0% (95% CI [54.1, 68.9]) for the R-CHOP/R-CVP group (HR 0.70, 95% CI [0.49, 1.01]; p = 0.0582). Among the patients with MCL, PFS in the BR group was 39.7% (95% CI [22.8, 56.1]) compared with 14.2% (95% CI [37.9, 31.3]) in the R-CHOP/R-CVP group (HR 0.40, 95% CI [0.21, 0.75]; p = 0.0035).

Dr. Mathias J. Rummel presents Abstract 7501.
The 5-year OS was 81.6% (95% CI [75.7, 86.3]) in the BR arm and 85.0% (95% CI [79.2, 89.2]) in the R-CHOP/R-CVP arm (HR 1.1, 95% CI [0.72, 1.84]; p = 0.5461). OS by lymphoma type was similar, with no statistical difference between the treatment arms.

The duration of response also favored the BR group: 65.5% (95% CI [58.3, 71.7]) compared with 56.9% (95% CI [49.3, 63.9]; HR 0.66, 95% CI [0.47, 0.92]; p = 0.0134).

More patients in the BR arm developed a secondary malignancy (19%) than in the R-CHOP/R-CVP arm (11%; p = 0.022).

“There is a significantly greater benefit in BR versus R-CHOP/R-CVP regimen, and a greater benefit in BR versus R-CVP,” Dr. Finn said. “The strongest benefit was seen in the MCL subgroup.”

StiL NHL1 Study

In patients with treatment-naive iNHL or MCL, BR demonstrates a time-to-next-treatment benefit over R-CHOP, Mathias J. Rummel, MD, PhD, of Justus-Liebig Universität in Germany, said (Abstract 7501).

In the original study, which was published in 2013, the median PFS was significantly longer in the BR group than in the R-CHOP group (69.5 months, 95% CI [26.1 to not yet reached] vs. 31.2 months, 95% CI [15.2, 65.7]; HR 0.58, 95% CI [0.44, 0.74]; p < 0.0001).1 BR was better tolerated than R-CHOP as well, and the group concluded that BR should be considered a preferred first-line treatment approach because of increased PFS and fewer toxicities.

In this new analysis, the time-to-next-treatment (used as a surrogate for PFS) with 117 months of follow-up was not yet reached in the BR arm and was 56.0 months in the R-CHOP arm (HR 0.55, 95% CI [0.41, 0.73]; p < 0.0001). There were 77 patients in the BR arm and 109 in the R-CHOP arm who required salvage treatments; the number of patients who underwent autologous peripheral blood stem cell transplantation was much higher in the R-CHOP group compared with the BR group (11 vs. 3, respectively).

Dr. Brad S. Kahl discusses Abstracts 7400 and 7501.
“There was no difference in secondary malignancies,” Dr. Rummel said. OS was not statistically different, although it was numerically different, with 70.3% in the BR group alive after 10 years compared with 66.3% in the R-CHOP group (HR 0.82, 95% CI [0.59, 1.16]; p = 0.27).

Discussion

Data from the initial results of the StiL study suggested a greater benefit with BR compared with R-CHOP, with a “much longer PFS, and less toxicity in the short term,” Discussant Brad S. Kahl, MD, of Washington University School of Medicine, said. The BRIGHT study also demonstrated a prolonged 5-year PFS with BR compared with R-CHOP/R-CVP. However, 5- and 10-year follow-up from the BRIGHT and StiL studies, respectively, showed no difference in OS.

“It’s a bit disconcerting when the results from two studies like these are not completely congruent,” Dr. Kahl said. Other data sets may help explain the disconnect.

For instance, the phase III GALLIUM study showed no difference between BR and R-CHOP, but all patients received maintenance therapy, compared with no maintenance in the StiL study and 45% receiving maintenance in the BRIGHT study.

“I’m speculating, but perhaps maintenance therapy with rituximab improves efficacy after R-CHOP but offers little or no efficacy benefit after BR,” Dr. Kahl said, adding that this is a high-priority question that should be evaluated in the BRIGHT data set and others as they become available.

One can argue for either BR or R-CHOP to be a standard-of-care treatment, he said.

“My own view is that BR is a perfectly reasonable standard for high tumor burden follicular lymphoma,” Dr. Kahl said. “The role for maintenance rituximab is unproven. R-CHOP and maintenance therapy is acceptable to me and may be preferred by some.”

–Michelle Dalton, ELS