Bendamustine Plus Rituximab “StiL” Better Than R-CHOP for Improving Survival in Indolent Lymphomas

Earlier results from the randomized, phase III StiL trial of patients with indolent lymphomas demonstrated that the combination of bendamustine plus rituximab (BR) led to longer progression-free survival (PFS) than the standard front-line treatment of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). At the 2017 ASCO Annual Meeting, 10-year results from the StiL trial confirmed that BR was associated with better disease control than R-CHOP, with the two-drug combination nearly doubling patients’ time to next treatment (TTNT).

Mathias J. Rummel, MD, PhD, from the Department of Hematology and Oncology at the Justus-Liebig Universität in Giessen, Germany, and colleagues enrolled 420 patients (median age = 62 years; range = 60-69 years) with indolent lymphomas (including mantle cell lymphoma [MCL]) who had not received prior cytotoxic therapy, interferon, or monoclonal antibodies.

Patients were randomized to receive up to six cycles of one of the following:

  • BR: bendamustine 90 mg/m2 on days 1 and 2 and rituximab 375 mg/m2 on day 1 (n=215)
  • R-CHOP: rituximab 375 mg/m2 on day 1, cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 1.4 mg/m² (up to a maximum of 2 mg) on day 1, and prednisone 100 mg on days 1-5 (n=205)

Dr. Rummel presented results from a median follow-up period of 117 months, during which 386 patients responded to treatment (either complete response or partial response), for an overall response rate of 91.9 percent (92.7% in BR; 91.3% in R-CHOP).

BR significantly prolonged the TTNT, which Dr. Rummel and investigators selected as a surrogate for disease control, compared with R-CHOP: median = not reached (NR) versus 56 months (hazard ratio [HR] = 0.55; 95% CI 0.41-0.73; p<0.001).

“Patients with initial treatment of BR needed fewer second-line treatments due to disease progression, compared with R-CHOP,” Dr. Rummel said, noting that 77 patients (36%) in the BR group received salvage therapy, compared with 109 patients (53%) in the R-CHOP group. “In the BR group, 16 patients were re-treated with BR and 27 were treated with R-CHOP.”

More patients in the R-CHOP group than the BR group (11 and 3, respectively) went on to receive hematopoietic cell transplantation as a salvage therapy, “probably reflecting that relapses occurred earlier after R-CHOP,” he added.

Notably, the development of secondary malignancies was similar in the BR (n=37) and R-CHOP (n=40) cohorts, and Dr. Rummel mentioned that this will be a focus of detailed investigation in future analyses of the StiL data.

Rates of 10-year overall survival (OS) were not statistically significantly improved in the BR arm (70.3% vs. 66.3%; HR=0.82; 95% CI 0.59-1.16; p=0.249). “Despite the fact that the patients [treated] with BR had less second-line treatment – or perhaps because of it – they had more or less the same overall survival, with 62 deaths in BR and 71 deaths in R-CHOP,” Dr. Rummel noted.

The majority of deaths were related to relapsed lymphoma (65%; n=86); 35 percent (n=47) died in first remission, and 40 percent of those patients had a secondary malignancy. There were also no statistically significant differences in OS between BR and R-CHOP within different lymphoma subtypes.

Subgroup analysis revealed that lactate dehydrogenase (LDH) levels were “a very strong predictor” for OS; patients with low LDH (≤240) at enrollment had a much longer survival than patients with high LDH (>240): NR vs. 127 months (HR=0.45; 95% CI 0.29-0.61; p<0.0001), regardless of treatment group. However, patients with low LDH who received BR had “borderline significantly” longer OS than those in the R-CHOP group: 80.0 percent versus 72.2 percent (HR=0.61; 95% CI 0.37-1.00; p=0.049). “If the LDH is normal, and the histology is low-grade, I believe that’s a typical low-grade lymphoma, and in that circumstance, BR appears to be a very effective treatment with a good long-term outcome,” Dr. Rummel said.

The study’s findings are potentially limited by the variation in salvage therapies between the two groups.


Reference

Rummel MJ, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study. Abstract #7501. Presented at the 2017 American Society of Clinical Oncology Annual Meeting, June 3, 2017; Chicago, Illinois.

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