SAN DIEGO – Stretching out the delivery of rituximab significantly improved overall and event-free survival among older patients with poor-prognosis diffuse large B-cell lymphoma, German investigators reported.
Patients older than 60 years who had diffuse large B-cell lymphoma (DLBCL) were treated with the CHOP regimen and rituximab (Rituxan) on days 4 and 1 before CHOP and at increasing intervals thereafter, in the SMARTE-R-CHOP-14 trial.
Those with poor-prognosis disease had an overall survival rate of 80% at 37 months, compared with 67% for similar patients treated with CHOP and biweekly rituximab in an earlier trial (P = .034), reported Dr. Michael Pfreundschuh on behalf of his colleagues in the German High-Grade Non-Hodgkin's Lymphoma Study Group.
Event-free survival rates among poor-prognosis patients (defined as those with an International Prognostic Index [IPI] score higher than 2) were also significantly higher with the extended rituximab–dosing schedule, dubbed SMARTE-R-CHOP-14, at 67% vs. 54% for patients who received biweekly rituximab in the previous RICOVER-60 trial (P = .030).
"SMARTE-R-CHOP 14 has achieved by far the best results reported to date for elderly patients with poor prognosis," said Dr. Pfreundschuh of Saarland University in Homburg, Germany, at the annual meeting of the American Society of Hematology (ASH).
Giving rituximab every 3 weeks after 2 pre-CHOP doses maintains serum levels of rituximab over a longer period than when it is given every other week, he said.
Patients with good- or moderate-prognosis disease (defined as an IPI of 1 or 2) also had numerically better event-free and overall survival rates, compared with patients treated with biweekly rituximab, he noted, but the differences were not significant.
Although CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) given every 14 days (CHOP-14) had been shown to be superior to CHOP given every 21 days (CHOP-21), the same could not be said when rituximab was added (R-CHOP-14 vs. R-CHOP-21). Presentations at ASH in 2009 and at the American Society of Clinical Oncology annual meeting in 2011 suggested that biweekly rituximab dosing was suboptimal, Dr. Freundschuh said.
In the SMARTE-R-CHOP-14 study, Dr. Pfreundschuh and colleagues treated 190 patients with DLBCL with six cycles of CHOP-14. combined with eight cycles of rituximab 375 mg/m2. The first three rituximab cycles were given in a dose-dense fashion on days 1 and 4 before CHOP, followed by infusions on days 10, 29, 57, 99, 155, and 239. Patients also received prophylaxis against infections with levofloxacin, acyclovir, and cotrimoxazole. One patient did not give informed consent for the trial, and was not included in the final analysis.
In the RICOVER-60 trial that was used for comparison, patients received six cycles of CHOP plus rituximab given on days 1, 15, 29, 43, 57, 71, 85, and 99. The baseline characteristics of patients were similar between the trials, except that significantly more patients in SMARTE-R-CHOP-14 had high-risk disease (P = .015).
Complete response rates overall were not significantly different (85% in SMARTE-R and 78% in RICOVER-60). Among patients with IPI scores less than 2, the respective rates were 90% and 84%, also not significantly different. Among patients with an IPI greater than 2, however, the complete response rate in SMARTE-R-CHOP-14 was 81%, compared with 68% in RICOVER-60 (P = .035).
Overall survival did not differ significantly between the trials, at 84% in SMARTE-R and 78% in RICOVER. When patients stratified by risk were considered, there were no between-trial differences for low-risk patients.
Overall event-free survival was 71% at 37 months’ median follow-up in SMARTE-R, and 66% at 34 months in RICOVER; this difference was not significant, nor was the difference between the trials among patients with low-risk disease.
"The pharmacokinetics of eight biweekly applications of rituximab are adequate for elderly patients with good prognosis, meaning patients with IP1 1 or 2, or low tumor burden diffuse large B-cell lymphoma, but not for higher tumor loads," Dr. Pfreundschuh said.
The investigators are exploring the SMARTE-R treatment strategy in a prospective trial, labeled "OPTIMAL Greater Than 60."
The trial was supported by Deutsche Krebshilfe and Roche. Dr. Pfreundschuh disclosed serving on a Roche board of directors or advisory committee, and receiving research funding from that company and from Amgen.