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Rituximab maintenance for indolent lymphoma prolongs PFS, not OS
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Maintenance rituximab prolonged PFS for patients with low-grade lymphoma, according to the long-term follow-up results of a randomized phase 3 study.
However, rituximab (Rituxan; Genentech, Biogen) maintenance therapy did not influence OS.
“Although the significant impact of rituximab in general is undisputed, and combined immunochemotherapy is the standard of care, the role of maintenance rituximab therapy after induction is less well defined,” Stefan K. Barta, MD, MD, MRCP, transplant specialist and assistant professor in the department of hematology/oncology at Fox Chase Cancer Center, and colleagues wrote.
Barta and colleagues evaluated the survival benefit of rituximab maintenance therapy in a long-term follow-up of the E1496 study. The study included 387 patients with indolent lymphoma who received induction chemotherapy with cyclophosphamide, vincristine and prednisone. Researchers randomly assigned patients with stable disease or better to undergo observation (n = 153; 56% men; median age, 56 years; range, 32-86 years) or four weekly doses of 375 mg/m2 rituximab every 6 weeks for 2 years (n = 158; 54% male; median age, 58 years; range, 26-84).
PFS served the primary endpoint for the maintenance portion of the study. Secondary endpoints included OS, response rate and safety.
Earlier results showed that after a median follow-up of 3.7 years, patients who received maintenance rituximab experienced a 60% reduction in risk for progression or death compared with patients in the observation group. Further, there appeared to be a trend toward improved OS (one-sided log-rank, P = .05).
Median follow-up for this analysis was 11.5 years.
Patients in the rituximab arm experienced longer median PFS compared with patients in the observation arm (4.8 years vs. 1.3 years; HR = 0.49; 95% CI, 0.37-0.64).
However, 10-year OS did not differ between the rituximab and observation arms (67% vs. 59%; median OS, 13.5 years vs. not reached).
In a multivariate analysis, longer PFS was associated with receiving rituximab maintenance (HR = 0.47; 95% CI, 0.36-0.61) and achieving minimal residual disease (HR = 0.71; 95% CI, 0.54-0.94). Factors associated with longer OS included low initial tumor burden (P = .03), minimal residual disease (P = .01), a low Follicular Lymphoma International Prognostic Index score (P = .003), follicular histology (P = .002) and female sex (P = .003).
Secondary primary cancers occurred in fewer patients who underwent rituximab maintenance (25 cancers in 20 patients) than observation (38 cancers in 35 patients; P = .03).
“First-line maintenance rituximab for indolent lymphomas after chemotherapy ... results in a substantial and sustained PFS improvement with an acceptable safety profile, regardless of the initial tumor burden or the response to induction therapy,” Barta and colleagues wrote. “Nonetheless, even after a median follow-up of 11.5 years, there was no benefit for OS as the curves came back together after 10 years. This suggests a prolonged effect of maintenance rituximab on remission but eventual salvage with subsequent therapy.”
Maintenance rituximab should be an optional intervention to manage indolent lymphoma because of the lack of OS impact, the researchers wrote. – by Nick Andrews
Disclosure: Barta reports grants and personal fees from Celgene, Merck, Pharmacyclics and Seattle Genetics. Please see the full study for a list of all other researchers' relevant financial disclosures.
Perspective
Back to TopNathan H. Fowler
Over the past several years, we have witnessed a major improvement in the expected OS of patients with newly diagnosed follicular lymphoma. Much of this success can be attributed to the integration of monoclonal antibodies that target CD20 into standard therapy. Combining rituximab (Rituxan; Genentech, Biogen) with various chemotherapy backbones, as well as the use of rituximab as maintenance therapy, has resulted in an impressive prolongation of PFS in multiple clinical studies.
Barta and colleagues published the long-term follow-up of the E1496 study. Researchers randomly assigned patients to receive 2 years of rituximab maintenance vs. observation following induction with cyclophosphamide, vincristine and prednisone. As expected, the use of maintenance therapy resulted in a prolongation of PFS compared with observation alone. Similar findings have been reported from several randomized studies comparing observation vs. rituximab maintenance after induction with chemotherapy with or without rituximab.
Interestingly, although a significant benefit in PFS was noted, long-term follow-up did not demonstrate a benefit in 10-year OS with a maintenance approach. A lack of survival benefit has also been noted in several other randomized studies comparing maintenance rituximab vs. observation and highlights the fact that many patients may have similar benefit with a retreatment approach. It is important to note that only 64% of patients enrolled in the study had high tumor burden, and trial patients were not required to have symptomatic disease. Whether a survival benefit would emerge in a larger experience with high tumor–burden patients is unknown. In addition, several patients were allowed to crossover to maintenance rituximab after 50% of events occurred in the trial, further diluting the potential to observe a survival benefit between arms.
Prolongation of remission remains an important endpoint in clinical trials for lymphoma, and is the benchmark by which most studies are currently compared. How these primary endpoints will evolve in the modern era where multiple salvage options are effective, patients can be retreated, and an OS benefit is increasingly difficult to demonstrate, remains to be seen. For now, the use and recommendation of maintenance rituximab following effective induction therapy should be individualized and include a discussion about the cost, toxicity and convenience of a maintenance approach compared with observation.
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