Greater Survival and Response Rates with Bendamustine-Rituximab than Fludarabine-Rituximab in Patients with Non-Hodgkin Lymphoma and Mantle Cell Lymphoma

The combination of bendamustine and rituximab (BR) resulted in superior overall response rates (ORR) and complete response (CR) rates, as well as progression-free survival (PFS) and overall survival (OS), compared with the combination of fludarabine plus rituximab (FR) in patients with relapsed, indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The randomized, open-label, phase III study, by Prof. Matthias Rummel, from the Department of Hematology and Oncology at the Justus-Lieig Universität in Giessen, Germany, and colleagues, included 219 patients from 55 centers in Germany enrolled between October 8, 2003, and August 5, 2010.

“At the time of the design and development, no standard treatment approach had been established for relapsed patients with indolent lymphomas or MCL who were ineligible for stem cell transplant,” the authors wrote, “making treatment decisions somewhat subjective.” As patients who relapse are typically older and have comorbidities, tolerable treatments that provide durable remissions and prolonged survival are needed, they added.

The median patient age of the study population was 67 years (range = 59-74 years), with approximately one-third of patients older than 70 years, “suggesting that our patient population is representative of that typically noted in clinical practice,” the authors wrote. The median number of prior treatments was one, with most patients having received cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP)-based chemotherapy.

All patients had stage 2 to 4 disease, a World Health Organization performance status of 0 to 2, and one of the following CD20-positive lymphoma entities confirmed by a histology report:

  • Follicular lymphoma (grade 1 and 2)
  • Lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)
  • Small lymphocytic lymphoma (SLL)
  • Nodular and generalized marginal zone lymphoma
  • MCL

Patients were excluded from the study if they were refractory to regimens that included rituximab, bendamustine, or purine analogue drugs or had significant comorbidities.

Patients were randomized to receive rituximab (375 mg/m2 on day 1 of each cycle) with either bendamustine (90 mg/m2 administered as a 30-minute infusion on days 1 and 2; n=114) or fludarabine (25 mg/m2 on days 1-3; n=105).

PFS (the study’s primary endpoint) was assessed via clinical assessment every three months and computed tomography scan and sonographic examination every six months until relapse.

After a median follow-up of 96 months, the median PFS was significantly higher in the BR-treated cohort, compared with the FR-treated cohort: 34.2 months (95% CI 23.5-52.7) versus 11.7 months (95% CI 0.38-0.72; p<0.0001).

Patients in the BR cohort also had longer median OS: 109.7 months (95% CI 50.2-not reached) versus 49.1 months (95% CI 36.2-59) in the FR group (hazard ratio [HR] = 0.64; 95% CI 0.45-0.91; p=0.012).

Overall and complete responses were significantly higher with the bendamustine combination, as well. See TABLE for an additional comparison of response rates between treatment groups.

Prof. Rummel and colleagues also stratified patients based on histologic subtypes, finding that patients with follicular lymphoma who received BR experienced the greatest increase in PFS compared with FR treatment:

  • Follicular lymphoma: HR = 0.56 (95% CI 0.34-0.87)
  • MCL: HR=0.45 (95% CI 0.22-0.76)
  • SLL sub-entities: HR=0.28 (95% CI 0.07-0.62)

The authors noted no differences in adverse events (AEs) between the BR and FR treatment groups. The most common AEs in both cohorts were infections (11 in the BR group and 8 in the FR group) and myelosuppression (3 and 2).

The study protocol was amended in 2006, after the European Medicines Agency approved rituximab maintenance therapy for patients with relapsed FL, to allow administration of rituximab maintenance therapy for patients who had responded to BR or FR treatment.

“Our study showed a survival benefit of one chemo-immunotherapy regimen over another, and suggests that the use of rituximab maintenance potentially further improves outcomes in the relapsed setting,” Prof. Rummel told ASH Clinical News. “The combination of BR was once more confirmed to be an effective and well-tolerated treatment regimen.”

Of the 152 patients who responded to either BR or FR, 44 patients received rituximab maintenance with BR (n=25) or FR (n=19) and 108 patients did not (BR, n=69; FR, n=39). Median PFS was longer among the 44 patients who had received maintenance rituximab therapy, compared with those who did not: 72.1 months (95% CI 54.1 – not reached) versus 30.4 months (95% CI 24.7-36.5), for an HR of 0.52 (95% CI 0.37-0.86; p=0.01).

Similarly, median OS was significantly increased in patients who received maintenance rituximab therapy: not reached (95% CI 93.6 – not reached) versus 69.7 months (95% CI 49.4 – not reached), for an HR of 0.52 (95% CI 0.34-0.92; p=0.03).

However, in this subgroup analysis, the authors observed no statistically significant difference in PFS between those originally treated with BR (72.1 months; 95% CI 52.7-not reached) and FR (93.6 months; 95% CI 45-not reached; HR=1.02; 95% CI 0.42-2.50; p=0.96).

The authors noted that the post-hoc design of this analysis was a limitation of the study. Since the study began in 2003 and patients had received their first treatment prior to enrollment, fewer than half (42%; n=91) had previously received rituximab, Prof. Rummel and co-authors explained. “Because most patients now receive rituximab-based chemotherapy in the first-line setting, results might not be fully generalizable to these patients,” they wrote. “Results from the subset of patients given rituximab maintenance must be interpreted with caution, given that this was a post-hoc analysis, included a small sample size, and patients were not randomly assigned between groups.” Other study limitations include investigators not being blinded to treatments patients received, and assessing the relative contribution of rituximab maintenance to study results.


Reference

Rummel M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016;17:57-66.

TABLE. Responses to Treatment in Each Cohort
  Bendamustine Plus Rituximab Fludarabine Plus Rituximab p value
Overall response 94(82%) 54(51%) <0.0001
Complete response 46(40%) 18(17%) 0.0002
Partial response 48(42%) 36(34%) 0.2345
Stable disease 7(6%) 16(15%) 0.0282
Progressive disease 8(7%) 30(29%) <0.0001
Not evaluable 5
(4%)
5(5%) 0.8941

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