A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization
Authors: Lopez-Guillermo Armando , Canales Miguel A. , Dlouhy Ivan , Briones Javier , Caballero Dolores , Sancho Juan Manuel , Vilchez Santiago Mercadal , Moraleda Jose María , Terol María José , Salar Antonio , Palomera Luis , Gardella Santiago , Jarque Isidro , Ferrer Secundino , Bargay Joan , Lopez Andres , Panizo Carlos , Muntanola Anna , Montalban Carlos , Conde Eulogio , Hernandez Miguel , Soler Alfons , Marin Julian , Marco Jose García , Deben Guillermo , Tomas José Francisco 
Published: October 2019

Abstract

Patients with FL can have long time of survival, but disease progression typically occurs 3-5 years after initial treatment. Consolidation with Z after initial therapy has shown to improve progression-free survival (PFS) mainly in the pre-R era, whereas maintenance with R also has demonstrated a substantial benefit in terms of PFS in patients treated with immunochemotherapy. In this setting, the Spanish intergroup PETHEMA/GELTAMO/GELCAB started a randomized phase 2 trial in order to compare the use of consolidation with Z vs. R maintenance in patients with FL responding to R-CHOP. From June 2008 to July 2010, 146 patients (66M/80F; median age, 55 years) were enrolled from 25 Spanish institutions in the randomized phase 2 trial ZAR2007 (ClinicalTrials.gov, number NCT00662948). Main inclusion criteria were: FL grade 1, 2 or 3a, age 18-75 years, stages II-IV and need of treatment according to modified GELF criteria. Patients with FL grade 3b or transformed to DLBCL were excluded. In addition, patients with platelet count <150x109/L or bone marrow infiltration>25% before randomization were also excluded. Main end-point of the trial was PFS from randomization. The distribution according to the FLIPI score was as follows: low-risk 14%, intermediate 47%, and high 39%. After R-CHOP, 124 patients in CR (n=56), CR[u] (13) or PR (55) were randomized 1:1 (stratified by response) to arm A (90Y ibritumomab tiuxetan 0.4 mCi/kg IV; total dose of 90Y was capped at 32 mCi) vs. arm B (1 infusion of R 375 mg/m2 every 8 weeks for 2 years). Sixty three (51%) patients were assigned to arm A (Z) and 61 (49%) to arm B (R). Twenty two patients were not randomized due to response <PR, low neutrophil or platelets counts or patient decision. After a median follow-up of 37 months from randomization (range, 26 to 56), 31 patients eventually progressed/relapsed with a 36-month PFS of 64% (95% confidence interval [CI] 52-76) for patients in arm A (consolidation with Z) (22 events) and 86% (95% CI 77-95) for patients in the R maintenance (9 events) (p=0.01; HR=0.38, 95%CI 0.17-0.83) as shown in the figure. The number of patients in PR after R-CHOP who reached CR during maintenance were 14 of 28 (50%) and 12 of 26 (46%) for arms A and B, respectively. Two patients developed transformation to DLBCL at 8 (arm A) and 39 months (arm B) after randomization. During the maintenance period, patients receiving Z showed grade 3-4 neutropenia in 6 of 63 cases and grade 3-4 thrombocytopenia in 5 of 63, whereas these figures were 1 of 61 and 0 of 61 (p=0.05) for patients in arm B, respectively. No unexpected late toxicities have been reported. Five patients have died during the follow-up due to the progression of lymphoma in all cases, with no differences between the arms (36-month OS, 98% vs. 95% for arms A and B, respectively). In conclusion, in patients with FL in response after R-CHOP, maintenance with R was superior to consolidation with Z in terms of PFS, with no differences in OS with the current follow-up.

Disclosures:
Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees. Briones:F. Hoffmann-La Roche: Honoraria.