Which Rituximab-based Regimen Works Best in Non-Hodgkin Lymphoma?

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The treatment of non-Hodgkin lymphoma (NHL) patients has been recently informed by several important studies, which were discussed at the Best of ASCO Boston meeting by Michael E. Williams, MD, of the University of Virginia Cancer Center in Charlottesville.

Bendamustine Outperforms R-CHOP in NHL

In a presentation at this year’s ASCO Annual Meeting Plenary Session, German investigators reported that in the phase III Study Group Indolent Lymphomas (StiL) NHL1 trial, the combination of bendamustine (Treanda) plus rituximab (Rituxan), or BR, more than doubled the median progression-free survival vs standard treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and proved more tolerable as well in patients with NHL.1 While B-R has been a recommended treatment option by the National Comprehensive Cancer Network since the initial study data were announced in 2009, many U.S. oncologists have not yet utilized the regimen.

The updated StiL NHL1 results will likely change that, according to Dr. Williams, who was also the invited discussant of the study at the Annual Meeting. “The U.S. Intergroup trials have now adopted B-R as a backbone of the current clinical trials for indolent and mantle cell lymphomas,” he said. “I think this was among the most practice-changing abstracts at ASCO.”

StiL NHL1 Details

The study randomly assigned 549 patients newly diagnosed with stage III or IV indolent or mantle cell NHL to standard R-CHOP or B-R. After a median follow-up of 45 months, median progression-free survival was 69.5 months with B-R vs 31.2 months with R-CHOP, a 42% reduction in the risk of progression (P = .0000148).

Benefit was seen in all subgroups except marginal zone lymphoma, where progression-free survival was comparable between the arms. Overall survival for all patients, however, was similar at 5 years: 80.1% with B-R and 77.8% with R-CHOP. B-R was associated with significantly less toxicity, with only skin toxicity being more common with this regimen.

Dr. Williams pointed out that bendamustine was given at 90 mg/m2 in the study, whereas the FDA-approved dose is 120 mg/m2, a dose he considers too high. He also advocates giving the regimen every 4 weeks for most patients, not every 3, to avoid excessive hematologic toxicity.

“StiL NHL1 establishes B-R as a front-line regimen for indolent B-cell NHL and non–transplant-eligible mantle cell lymphoma patients. It shows equivalent or better responses than R-CHOP and with less toxicity,” Dr. Williams noted.

He acknowledged, however, that caveats include the following: the median progression-free survival of 31 months with R-CHOP appears somewhat short compared with some comparable trials, there are limited data as yet on the ability to collect stem cells after B-R, the detailed results have not been published in a peer-reviewed journal, and confirmatory data are needed.

“B-R is not yet the standard of care,” he concluded, “but we can say that it is an active regimen. The study certainly supports the use of BR as a front-line treatment.”

Value of Maintenance in NHL Subtypes

Eastern Cooperative Oncology Group (ECOG) 4402, the phase III RESORT trial, showed no benefit for maintenance rituximab (given every 3 months) vs retreatment upon progression in follicular lymphoma as presented by the study chair Brad Kahl, MD, at the 2011 ASH Annual Meeting,2 but a planned subgroup analysis showed that nonfollicular patients (n = 137) who responded to rituximab weekly times 4 rituximab induction therapy did fare better on maintenance.3

In the subgroup analysis presented at ASCO by Dr. Williams, a higher rate of response to rituximab induction was observed in patients with follicular lymphoma (70%) than in those with nonfollicular disease (39%, P < .001). By nonfollicular subtype, the responses rate was much higher for marginal zone lymphomas (51%) than for small lymphocytic lymphoma (22%).

At a median follow-up of 4.3 years, the time to treatment failure was 3.74 years for maintenance rituximab vs 1.07 years for retreatment (P = .0002). At 3 years, 100% of the maintenance arm vs 70% of the retreatment arm remained free of the need for cytotoxic therapy, Dr. Williams reported.

“We found that maintenance rituximab performed much better for patients in these subgroups who respond to initial rituximab induction, but not in follicular lymphoma where a retreatment strategy is preferred based upon our data,” Dr. Williams said.

Advanced Follicular Lymphoma

An Italian study comparing three different rituximab-based regimens concluded that R-CHOP and R-FM (rituximab, fludarabine, mitroxantrone) are both superior to R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) in delaying treatment failure.4 RCHOP and R-FM showed similar antilymphoma activity, and R-CHOP and R-CVP were less toxic than R-FM. Therefore, “R-CHOP was associated with the best risk/benefit ratio,” Dr. Williams noted.

Response rates were approximately 90% per arm, but progression-free survival at 3 years was 68% with R-CHOP, 63% with R-FM, and 52% with R-CVP. The efficacy of R-FM was diluted by the much higher rate of grade 3/4 neutropenia, exceeding 30% by the third of six planned cycles, compared with 20% with R-CHOP and 13% with R-CVP. Secondary cancers and progressive disease were also more common with R-FM.

“The take-home message is that R-CHOP is more active than R-CVP, and there is no role for fludarabine-based treatment front-line in this disease. It is stem-cell depleting and may impair the ability to transplant patients, and certainly is more toxic,” Dr. Williams advised.

It remains to be answered whether R-CVP might be equivalent to R-CHOP if it is followed by rituximab maintenance, he added, “and it could be that bendamustine/rituximab may trump all of these regimens.” ■

Disclosure: Dr. Williams has received research funding from Genentech and Cephalon and has served on advisory boards for Genentech.


1. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment in patients with indolent and mantle cell lymphomas: Updated results from the StiL NHL1 study. 2012 ASCO Annual Meeting. Abstract 3. Presented June 3, 2012.

2. Kahl BS, Hong F, Williams ME, et al: Results of Eastern Cooperative Oncology Group Protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden follicular lymphoma. 2011 American Society of Hematology Annual Meeting. Abstract LBA6. Presented December 13, 2011.

3. Williams ME, Hong F, Kahl BS, et al: A subgroup analysis of small lymphocytic and marginal zone lymphomas in the Eastern Cooperative Oncology Group protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab dosing strategies for low tumor burden indolent non-Hodgkin lymphoma. 2012 ASCO Annual Meeting. Abstract 8007. Presented June 2, 2012.

4. Federico M, Luminari S, Dondi A, et al: R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi. 2012 ASCO Annual Meeting. Abstract 8006. Presented June 2, 2012.

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