Bortezomib + Rituximab Shows Benefit in Patients With Relapsed, Rituximab-Naive or -Sensitive Follicular Lymphoma vs Rituximab Alone

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.