Janis C. Kelly

June 16, 2014

CHICAGO ― Lesser survival seen in elderly men with diffuse large B-cell lymphoma (DLBCL) than in elderly women in response to standard therapy appears to be due to sex-related differences in the clearance rates of rituximab (Rituxan, Genentech/Roche) and could be improved by increasing the dose in older men, investigators reported at the 2014 Annual Meeting of the American Society of Clinical Oncology.

Increasing the rituximab dose from 375 mg/m2 to 500 mg/m2 for elderly men improved both progression-free survival (PFS) and overall survival (OS) to the same levels seen in elderly women with DFBCL when both groups were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14). The new results come from the SEXIE-R-CHOP-14 study, which was inspired by another trial, said lead author Michael Pfreundschuh, MD, director, Department of Internal Medicine, Saarlandes University Hospital, Homburg, Germany.

The earlier RICOVER-60 study (6 vs 8 cycles of CHOP-14) demonstrated that PFS improvement was 15% in elderly men but 22% in elderly women. Subsequent analysis showed that serum trough rituximab levels were about one third higher in elderly women than in elderly men.

"Females have significant decrease in rituximab clearance with age," Dr. Freundschuh said.

The objective of the SEXIE-R-CHOP-14 trial was to investigate whether increasing the dose of rituximab in elderly men with DLBCL on the R-CHOP-14 regimen could compensate for this sex-based difference.

Male patients received 500 mg/m2 instead of 375 mg/m2 in the trial. The researchers randomly assigned 271 patients (aged 61-80 years), of whom 268 are evaluable. A total of 148 men received 500 mg/m2 rituximab, and 120 women received 375 mg/m2 rituximab.

After 3 years, event-free survival was 68% in women and 65% in men (P = NS). Three-year PFS was 68% for women and 74% for men (P = NS). Three-year OS was 72% for women and 80% for men (P = NS), Dr. Pfreundschuh said.

He presented the data from SEXIE-R-CHOP-14 on behalf of the German High Grade Non-Hodgkin-Lymphoma Study Group (DSHNHL).

Multivariable analysis showed that with the higher rituximab dose, male vs female rates of EFS, PFS, and OS all improved.

In their study abstract, the authors wrote, "During the treatment period, the increased rituximab dose in males resulted in slightly higher trough serum levels than in females; however, rituximab levels dropped faster in males resulting in nearly identical serum levels thereafter and a very similar overall rituximab exposure time."

The increased rituximab dose was not associated with increased toxicity.

Dr. Pfreundschuh pointed out that not only elderly men but also younger women and younger men have a significantly faster rituximab clearance than elderly women. As a result, both groups will have lower rituximab serum levels and shorter exposure times than older women.

He also suggested that increasing rituximab dose might also improve outcomes in young male and female patients who have aggressive CD20+ B-cell lymphomas.

The study results also have implications for other aspects of clinical trial design.

"With respect to refractoriness and resistance to rituximab, we should revisit our definition and clarify that this is resistance to or refractory to 375 mg/m2. To compare rituximab with novel anti-CD20 antibodies, bona fide head-to-head comparisons (same dose and schedule) are necessary," Dr. Pfreundschuh said.

The new results should inspire a reevaluation of the use of rituximab, said another expert.

"This study is interesting because, although a number of new agents are being developed, we have rituximab in our hands right now. Further exploring how to use it could be very fruitful for our patients," said Sonali M. Smith, MD, associate professor, Section of Hematology/Oncology, and director, Lymphoma Program, University of Chicago Medical Center, Chicago, Illinois.

She spoke at the Highlights of the Day lymphoma session at ASCO.

According to Dr. Smith, since the 1970s, the standard of care for DLBCL has been CHOP. Despite repeated attempts to improve on CHOP, only the addition of rituximab has improved survival.

"Another avenue that has not been evaluated is to go back to the R-CHOP regimen and ask whether we are using rituximab in the best way possible. The current schedule and dosing for rituximab were empirically derived based on drug availability and the number of patients used in the initial phase 2 trial. There has never been a phase 1 study of rituximab in lymphoma patients," she said.

The study was supported by Roche and Deutsche Krebshilfe. Dr. Pfreundschuh and other authors have disclosed financial ties to Roche and other companies.

J Clin Oncol. 2014;32:5s(suppl). Abstract 8501

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