Final Results of a Randomized Phase 2 Multicenter Study of Two Bortezomib Schedules In Patients with Recurrent or Refractory Follicular Lymphoma. Groupe d'Etude Des Lymphomes De l'Adulte (GELA) Study FL-05
Authors: Ribrag Vincent , Tilly Herve , Casasnovas Olivier , Bosly Andre , Bouabdallah Reda , Delarue Richard , Boue Francois , Bron Dominique , Feugier Pierre , Haioun Corinne , Offner Fritz C , Coiffier Bertrand 
Published: October 2019

Abstract
Abstract 768

Background:
Bortezomib has previously demonstrated activity in indolent lymphomas including follicular lymphoma (FL). However, the optimal schedule, dose and precise activity of bortezomib in FL remain to be investigated.

Aims:
To evaluate the efficacy and tolerability of bortezomib in the treatment of advanced FL, but also using a qualitative comparison of two different dose schedules, based on safety, efficacy and dosing convenience to recommend a dose schedule for further clinical studies.

Methods:
This prospective, randomized, sequential, international, multicenter, 2-arm, non-comparative, open-label, clinical study was conducted from 08–2005 to 09–2008. The eligible subjects (follicular lymphoma grade 1–3, no CNS involvement, in relapse or refractory to previous therapy, ECOG 0–2, Absolute neutrophil count > 1000 cells/mL; Platelets > 50,000 cells/mL, Aspartate transaminase < 3 × ULN; Alanine transaminase < 3 × ULN; Total bilirubin < 2 × ULN; Creatinin level < 150 μmol/L, without known previous HIV serology) were randomized to receive either treatment in a 1:1 ratio. Treatment arm A patients (pts) received 1.5 mg/m2 bortezomib administered biweekly on days 1, 4, 8, and 11 of a 21-day cycle for 8 cycles. Treatment arm B pts received 1.6 mg/m2 bortezomib administered weekly on days 1, 8, 15, and 22 of a 35-day cycle for 6 cycles. Treatment allocation was stratified according to number of prior therapies (1 or 2 versus > 2) and time to progression (TPP) for the last given anti-lymphoma therapy (≤ 12 months versus > 12 months). Responses were assessed using 1999 IWG criteria. An interim analysis was planned after 15 evaluable pts randomized in each treatment arm; if only 5 subjects or fewer respond, the treatment arm was concluded to be ineffective and the treatment arm closed to inclusion; otherwise this treatment arm proceeded to include 50 pts.

Results:
87 pts (51 [59%] men and 36 [41%] women) with median age of 65 years (range:40 to 77) were treated with bortezomib. Prior therapies were >2 in 62% and progression <12 months from last therapy in 49%. 30% previously received HDT with ASCT, and all of them were previously treated with immunotherapy. Arm B was closed to inclusion after interim analysis. After this interim analysis, the 6 patients still on therapy in this arm completed therapy according to arm A. 15/50 pts (32%) in arm A (bortezomib 1.5 mg/m2) and 8/37 pts (23%) in arm B (bortezomib 1.6 mg/m2) achieved a complete, unconfirmed complete or partial response at the end of treatment. Median duration of response was 16 (range 1–45) and 15 (1-39) months and PFS was 6 and 7.5 months for arms A and B, respectively. Most drug-related AEs (all grades, all cycles) were mild. AEs > grade 3 observed in more than 5% of pts were lymphopenia (25% both arms), thrombocytopenia (19% and 25% in arms A and B, respectively) and neutropenia (8% both arms). One pt died of possibly drug-related cardiac failure associated with hyponatremia.

Conclusions:
This study demonstrates tolerability and durable clinical benefit of bortezomib when given at 1.5 mg/m2 biweekly on a 21 days cycle in pts with recurrent or refractory FL. These results suggest recommending this dose schedule for further clinical study.

Disclosures:
Ribrag: LFB: Honoraria, Research Funding; servier: Research Funding; celgene: Research Funding; pfizer: Honoraria; novartis: Honoraria. Tilly:Amgen: Honoraria. Feugier:roche: Consultancy, Honoraria.