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Maintenance rituximab improves PFS in follicular lymphoma
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ATLANTA — Maintenance rituximab following first-line bendamustine and rituximab significantly improved PFS, with a trend toward improved OS, among patients with follicular lymphoma, according to a retrospective analysis of the BRIGHT trial presented at the ASH Annual Meeting and Exposition.
“There is no signal that OS is negatively influenced by maintenance rituximab [Rituxan; Genentech, Biogen] in responding patients,” Brad S. Kahl, MD, professor of medical oncology at Washington University School of Medicine in St. Louis and a HemOnc Today Editorial Board Member, said during his presentation. “If anything, the data favor maintenance, which I think provides some reassurance regarding the fatal adverse event rate shown in previous studies.”
Some clinicians feared bendamustine-rituximab might be detrimental for patients, following the presentation of the GALLIUM trial during the plenary session of ASH in 2016.
“The fatal adverse events rate in the GALLIUM trial drew attention,” Kahl said. “It was approximately 5% in bendamustine plus rituximab or obinutuzumab [Gazyva, Genentech] arm vs. about 2% in the rituximab or obinutuzumab plus CHOP-containing arm.”
Researchers of the BRIGHT study investigated the safety and efficacy of bendamustine-rituximab vs. rituximab plus CHOP chemotherapy, known as R-CHOP, or R-CVP (rituximab with cyclophosphamide, vincristine and prednisone) among treatment-naive patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma.
Five-year follow-up data from that trial confirmed that duration of response and PFS significantly improved with bendamustine-rituximab. However, OS did not appear statistically different between bendamustine-rituximab vs. R-CHOP or R-CVP.
Kahl and colleagues conducted a retrospective analysis of this study to determine the impact of maintenance rituximab.
The study included 288 patients with follicular lymphoma who received bendamustine-rituximab (n = 144) or R-CHOP or R-CVP (n = 144). Further, 56% of the rituximab-bendamustine group and 58% of the R-CHOP or R-CVP group received rituximab maintenance.
In the bendamustine-rituximab treatment group, patients with B symptoms more commonly received maintenance rituximab (38% vs. 30%), whereas the opposite appeared true in the R-CHOP/R-CVP treatment group (29% vs 43%). In both treatment groups, patients with lactate dehydrogenase greater than 240 U/L and 2-microglobulin greater than 3 mg/L were less likely to receive maintenance rituximab.
In the bendamustine-rituximab group, patients achieving complete response to induction therapy were more likely to not receive rituximab maintenance (40% vs. 22%; P = .0231). In the R-CHOP/R-CVP treatment group, a similar proportion of patients with complete response did and did not receive maintenance rituximab (19% vs. 21%).
Patients who received maintenance rituximab after achieving complete or partial response to bendamustine-rituximab had a significantly better PFS than patients who did not receive maintenance rituximab (HR = 0.5; 95% CI, 0.26-0.94).
Patients who achieved complete or partial response to R-CHOP/R-CVP and received maintenance rituximab had a trend toward better PFS than responding patients who did not receive maintenance (HR = 0.66; 95% CI 0.38-1.16).
OS also tended to be better in patients assigned maintenance rituximab in the bendamustine-rituximab arm (HR = 0.39; 95% CI 0.14-1.05) and in the R-CHOP/R-CVP arm (HR = 0.32; 95% CI, 0.1-1.05).
Researchers noted that, because physician’s discretion determined who received maintenance rituximab, there may be confounding variables in the analysis.
“It’s important to note we cannot comment on toxicities that may have been influenced by maintenance rituximab,” Kahl said. “This study was not designed to provide a full accounting of the risk-benefit ratio. Virtually all of the fatal events were infections that occurred during maintenance or later and raised concerns over whether rituximab maintenance added toxicity without justifying additional efficacy benefits. In fact, it remains unproven whether an efficacy benefit even exists for maintenance rituximab.” – by Chuck Gormley
Reference:
Kahl BS, et al. Abstract 484. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Marcus RE, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosures: Kahl reports consultant roles with Celgene, Genentech, Gilead and Seattle Genetics, and research funding from ADC Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Caron Jacobson, MD
Rituximab maintenance has improved PFS following successful upfront chemoimmunotherapy, but this benefit is specific to R-CHOP and R-CVP chemotherapy regimens. The question as to whether rituximab maintenance will yield a similar improvement in PFS following upfront therapy with bendamustine and rituximab is unanswered. This retrospective analysis of nonrandomized data from the BRIGHT study sheds some light on this question.
The 5-year PFS seen with bendamustine and rituximab, without rituximab maintenance, on the BRIGHT trial is very similar to the PFS reported from the randomized Study Group Indolent Lymphomas (StiL) study of bendamustine and rituximab vs. R-CHOP in indolent non-Hodgkin lymphoma. This makes the statistically significant PFS benefit seen following maintenance rituximab intriguing, especially as there was a higher proportion of patients in a partial, rather than complete, remission in this group compared with the group that was observed.
However, this is a retrospective analysis of nonrandomized data, so there may be important key differences between the observation and maintenance rituximab groups that influence these results. In addition, we do not know how many doses of rituximab maintenance patients were able to receive. For how long were they treated? On what scheduled were they treated? What was the differential toxicity? These are all important questions to consider when determining the feasibility and risk-benefit ratio of rituximab maintenance following induction chemoimmunotherapy with bendamustine and rituximab, especially given the lack of OS benefit seen to date with maintenance rituximab strategies in follicular lymphoma. I find it difficult to explain the trend toward improved OS with rituximab maintenance on this trial with relatively short follow-up. This is a disease with a long, 10- to 20-year, natural history, and so it would be surprising to see a real OS benefit following two highly effective therapies after such a short follow-up period.
For patients who need chemotherapy, rather than rituximab monotherapy, the current standard therapy is bendamustine and rituximab for six cycles, or R-CHOP followed by 2 years of maintenance rituximab. Whether to use rituximab maintenance following a partial or complete response to bendamustine and rituximab is typically a discussion with the patient, rather than a default, with many oncologists recommending against it in the absence of clinical trial data.
This study is intriguing and adds to that discussion, but it is unlikely to change practice. We need the results of randomized studies to change our standards in that way. Unfortunately, the MAINTAIN study from the StiL group, which randomly assigned patients who respond to bendamustine and rituximab to 2 years vs. 4 years of maintenance rituximab, does not contain an observation arm and will not move us further toward an answer to this question.
Reference:
Rummel MJ, et al. Lancet. 2013;doi:10.1016/S0140-6736(12)61763-2.
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