Bendamustine/Rituximab Noninferior to Standard Chemotherapy for Advanced Indolent Non-Hodgkin and Mantle Cell Lymphomas 


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The overall response rate was high in both treatment groups. BR is an important treatment option for previously untreated indolent NHL and MCL.

—Ian W. Flinn, MD, PhD

The combination of bendamustine (Treanda) and rituximab (Rituxan), or BR, was found to be noninferior to commonly used chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) in patients with previously untreated advanced indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL) in the randomized phase III BRIGHT trial reported at the 2012 American Society of Hematology (ASH) Annual Meeting.1 Nevertheless, BR and R-CHOP/R-CVP have distinct toxicity profiles, which should be considered in treatment selection.

Important Option

“The overall response rate was high in both treatment groups. BR is an important treatment option for previously untreated indolent NHL and MCL,” stated lead author Ian W. Flinn, MD, PhD, Director of the Hematologic Malignancies Program at Sarah Cannon Research Institute, Nashville.

“There is no single standard therapy for indolent NHL or MCL,” Dr. Flinn continued. The present study sought to evaluate BR, which is becoming a standard in Germany. The StiL NHL study, reported last year, showed a large difference in progression-free survival in patients with follicular NHL and MCL, favoring BR over R-CHOP (at a median follow-up of 45 months, median progression-free survival was 69.5 months for BR vs 31.2 months for R-CHOP).2 A survey presented at this year’s ASH 2012 meeting showed that BR is replacing R-CHOP in Germany for treatment of indolent lymphoma.3 The BRIGHT study was done to see if the advantage of the StiL trial could be confirmed.

Study Design

BRIGHT used complete response as the primary endpoint, and showed no difference between the two treatment arms. Dr. Flinn said that progression-free survival is a more clinically meaningful endpoint than complete response but explained that BRIGHT was designed for an FDA application and is a supportive trial for existing data with longer endpoints.

“Progression-free survival is probably a better endpoint, but the data for that are immature,” he said. Longer follow-up is needed to show progression-free survival differences between the two arms.

BRIGHT was conducted from April 2009 to June 27, 2012, and randomly assigned 447 patients in a 1:1 ratio to the two treatment arms (224 to BR; 223 to R-CHOP or R-CVP). Investigators could choose either R-CHOP or R-CVP at their discretion, prior to the randomization. Patients received up to six cycles during the randomized phase and could receive another two cycles at the investigator’s discretion. Follow-up was 5 years.

Demographic and disease characteristics were comparable between the two treatment arms. Mean age was about 60 years, 64% had an ECOG performance status of 0, and about 69% had stage IV disease.

Evaluable Patients

Among 213 evaluable patients on BR and 206 on R-CHOP or R-CVP, complete response rates were 31% and 25%, respectively. The complete response ratio of 1.26 met the definition of noninferiority, Dr. Flinn said, “but was not statistically significant for superiority.” Overall response rates were 97% for BR vs 91% for R-CHOP/R-CVP.

Toxicity profiles of the two arms were different. Adverse events of all grades included a higher incidence of nausea/vomiting, pyrexia, chills, drug hypersensitivity reactions, decreased appetite, rash, and pruritus for the BR arm, and a higher incidence of constipation, paresthesia, peripheral neuropathy, and alopecia for R-CHOP/R-CVP arms.

Grade 3 or higher adverse events that were increased in the BR arm included hypersensitivity reactions, opportunistic infection, and respiratory/thoracic disorders. More frequent febrile neutropenia, alopecia, and neuropathy were seen in the chemotherapy arms. Despite the use of growth factor support, patients treated with R-CHOP had a higher incidence of grade 3 or more hematologic adverse events including neutropenia and lymphopenia. More deaths occurred in the BR group (six patients, due to pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) than in the R-CHOP/R-CVP group (one patient, due to sepsis).

“There was a much greater use of growth factors in the R-CHOP arm, so lack of growth factor support could not explain the increased neutropenia observed with R-CHOP,” Dr. Flinn said.

Quality-of-life Study

A substudy of BRIGHT compared quality of life in both arms of the trial, based on patient-reported responses to 30 questions pertaining to symptoms and quality of life.4 Patients were surveyed at baseline and during intervals throughout treatment up to cycle 6. Higher scores on functional scales and global health measures equaled better outcome, while higher scores on symptom scales reflected greater severity of symptoms.

“In this study, patients treated with BR had improved global health status, physical function, social and emotional function, fatigue, dyspnea, and constipation compared with the R-CHOP arm,” stated lead author John M. Burke, MD, a clinician at Rocky Mountain Cancer Centers, Aurora, Colorado. ■

Disclosure: Dr. Flinn reported no potential conflicts of interest. Dr. Burke has served on advisory boards for Alexion, Dendreon, Genomic Health, Seattle Genetics, and Spectrum.

References

1. Flinn I, Van der Jagt R, Kahl B, et al: An open-label, randomized stdy of bendamustine and rituximab compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line treatment of advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma: The Bright study. 2012 ASH Annual Meeting. Abstract 902. Presented December 11, 2012.

2. 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 NHL1study. 2012 ASCO Annual Meeting. Abstract 3. Presented June 3, 2012.

3. Knauf W, Abenhardt, Nusch A, et al: Bendamustine-rituximab replaces R-CHOP as “standard of care” in the treatment of indolent non-Hodgkin lymphoma in German hematology outpatient centres. 2012 ASH Annual Meeting. Abstract 3666. Presented December 10, 2012.

4. Burke J, Van der Jagt R, Kahl B, et al: Differences in quality of life between bendamustine plus rituximab compared with standard first-line treatments in patients with previously untreated advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma. 2012 ASH Annual Meeting. Abstract 155. Presented December 9, 2012.


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Expert Point of View: Martin Dreyling, MD

“The BRIGHT study had a noninferiority design, but I question why BR was not found superior, because the StiL trial showed a huge difference in progression-free survival favoring BR,” said Martin Dreyling, MD, Professor at the University of Munich in Germany. “In BRIGHT, BR achieved higher...


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