ORLANDO, Fla.In patients with relapsed follicular lymphoma (FL), the addition of weekly bortezomib (Vc) to rituximab (R) was associated with statistically significant improvements in progression-free survival (PFS), response rate, and time to next anti-lymphoma treatment, results of a randomized phase 3 trial have found.

The open-label multicenter international study (LYM3001), which compared the efficacy and safety of Vc-R vs R alone in patients with relapsed or refractory, R-naïve, or R-sensitive FL, also demonstrated the Vc-R regimen to have additional—but acceptable—toxicity, Bertrand Coiffier, MD, PhD, Hospices Civils de Lyon, Lyon, France, and colleagues reported.

Patients with grade 1/2 measurable FL who had relapsed or progressed following prior therapy (time to progression [TTP] ≥6 months if prior R-containing therapy), ECOG performance status ≤2, and no peripheral neuropathy grade ≥2 were randomized (1:1) to receive 5-week cycles of Vc-R (Vc 1.6 mg/m2, days 1, 8, 15, 22, cycles 1-5, plus R 375 mg/m2, days 1, 8, 15, 22 in cycle 1 and day 1 only in cycles 2-5) or R alone (same schedule as Vc-R arm), Dr. Coiffier said in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.

In both groups, treatment was administered for 5 cycles or until progression or unacceptable treatment-related toxicity. Randomization was stratified by FL International Prognostic Index (FLIPI) score (0–1 vs 2 vs ≥3), prior R therapy (yes/no), time since last dose of anti-FL therapy (≤1 vs >1 year), and region (US vs EU vs rest of world).

Primary end point was PFS; secondary end points included overall response rate (ORR), complete response (CR) rate, TTP, and safety/tolerability. Response and progression were assessed by independent radiology committee (IRC) using the modified International Workshop Response Criteria. Planned sample size was 670 patients to provide 90% power (α=0.05, 2-sided) to detect a 33% improvement in median PFS with Vc-R vs R (ie, 13.3 vs 10 months).

Between April 2006 and August 2008, 676 patients (intent-to-treat [ITT] population) were enrolled from 164 centers in 29 countries across Europe, the Americas, and Asia. Baseline characteristics were well balanced between the two arms; median age was 57 years (range, 21–84 years), 54% were female, 75% were Caucasian, and 21% were Asian. The majority of patients (93%) had an ECOG performance status of 0 or 1, 51% and 48% had grade 1 and 2 FL, respectively, and 41%, 35%, and 24% had high, intermediate, and low FLIPI score, respectively; 82% had Ann Arbor stage 3 or 4, and 38% had bone marrow involvement at baseline.

Thirty-three percent of patients had received ≥3 prior lines of therapy (range, 1-6+); 44% had received prior treatment with R. The most common prior regimens were cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; 38%), cyclophosphamide, vincristine, prednisone (CVP; 25%), single-agent R (17%), R-CHOP (12%), and R-CVP (11%).

At a median follow-up of 33.9 months, 440 PFS events were observed by IRC in the ITT population, 212 in the Vc-R arm, and 228 in the R arm. Median PFS improved from 334 days (95% CI, 278, 365) with R alone to 389 days (95% CI, 351, 456) with Vc-R; hazard ratio was 0.822 (95% CI, 0.681, 0.991; P=0.039). ORR was 63% with Vc-R vs 49% with R (P<0.001), including 25% and 18% verified CR rates, respectively (P=0.035). Durable response rate (>6 months) was 50% with Vc-R vs 38% with R (P=0.002).

Median time to subsequent anti-lymphoma treatment was significantly improved in the Vc-R vs R arm (700 vs 537 days, P=0.027). Median OS was not reached in either group. Patients received a median 25 weeks of treatment in both the Vc-R and R groups (range, 5-40 Vc-R; range, 5-35, R). Adverse events (AEs) were reported for 95% of Vc-R and 78% of R patients.

Most commonly reported AEs were diarrhea (52% Vc-R, 8% R), nausea (36% Vc-R, 11% R), and pyrexia (36% Vc-R, 11% R). Most AEs were grade 1 or 2. Grade ≥3 AEs were reported in 46% of Vc-R and 21% of R patients; most common grade ≥3 AEs were neutropenia (11% vs 4%) and diarrhea (7% vs 0%). Peripheral sensory neuropathy was reported in 16% of patients in the Vc-R arm vs 1% in the R arm; 3% vs 0% grade ≥3. Serious AEs were reported in 18% of Vc-R and 11% of R patients; only 4% and 1% of patients, respectively, discontinued due to drug-related AEs. There were 9 on-treatment deaths in the Vc-R group and 4 in the R group.

The investigators noted discussion of bortezomib (Vc) use in subtypes of non-Hodgkin’s lymphoma other than mantle-cell lymphoma is considered off-label use.

“The increase in side effects did not affect the feasibility of treatment,” concluded Dr. Coiffier.

Off Label Use: Discussion of bortezomib in NHL subtypes other than mantle cell lymphoma is included.