A Randomized Trial Of Rituximab Vs Observation Following Autologous Stem Cell Transplantation (ASCT) For Relapsed Or Refractory CD20-Positive B Cell Lymphoma: Final Results Of NCIC CTG LY.12

NCIC CTG LY.12 was an international randomized trial evaluating two treatment strategies for patients (pts) with aggressive lymphoma relapsing after or with progressive disease following primary therapy. The first randomization demonstrated that gemcitabine, dexamethasone, cisplatin (GDP) was non-inferior to and significantly less toxic than dexamethasone, cytarabine, cisplatin (DHAP) as salvage therapy (ASH 2012). Here we report the results of the second randomization, testing the ability of the CD20 antibody rituximab (R) administered post-ASCT to improve event-free survival (EFS) compared to no further therapy.

Pts with CD20-positive aggressive lymphoma who underwent ASCT after GDP or DHAP who had recovered from ASCT-related toxicities and who remained clinically progression-free within 3-5 weeks post-transplant were stratified by centre, salvage regimen received, response to salvage therapy (CR vs PR/SD) and prior treatment with R, and were randomized using a minimization algorithm to receive R 375 mg/m²every 2 months for 6 doses, or observation. Response assessment by CT scanning was required at 3,7,13 and 25 mos post-ASCT or as needed to evaluate possible disease recurrence. The primary endpoint of the second randomization was 2 year EFS; to detect an improvement by 15% (from 50 to 65%, hazard ratio 0.62) required 142 events, with a 2-sided α 0.05 and power 0.80. Because of the low event rate over the last year and a projected time of many years to reach the protocol specified event rate, the Data Safety Monitoring Committee approved a request for study closure and analysis, with 118 events recorded.

230 patients were randomized to R maintenance (115) or observation (115). Baseline patients and disease characteristics were well balanced between treatment arms: median age was 53 yrs, 28% were age >65 and 40% were female; 52% received GDP and 48% DHAP; 55% had an IPI score of 2 or more at relapse/progression, and 17% had transformed (TR) from previous indolent lymphoma. Response to salvage pre-ASCT: CR 24%, PR 58%; 70% had received R with chemotherapy prior to study enrolment, and 69% received R with protocol salvage treatment. All analyses are by intention to treat (ITT). To date, there have been 118 EFS events (R 53, observation 65). After a median follow-up of 63 months, 2 year EFS was 64% for pts treated with maintenance R vs 51% for those on observation (HR 0.74, 95% CI 0.48-1.14, p= 0.11); there was no difference in overall survival (OS) at 4 years (R 69%, observation 68%, p=0.64). Grade 3-4 neutropenia was reported in 36% of pts on R maintenance vs 25% during observation; and Gr 3-4 thrombocytopenia in 11% and 16%, respectively. Febrile neutropenia occurred in 10 pts (9%) on R maintenance and 2 pts (2%) on observation. Two year EFS was similar in subsets defined by stratification variables at randomization: GDP salvage therapy: R 57.0% vs observation 45.9% (HR 0.84, 95% CI 0.52-1.36), DHAP: R 70.0% vs observation 57.1% (HR 0.68, 0.39-1.18); response to salvage CR/CRu: R 69.0% vs 52.9% (HR 0.71, 0.32-1.6), PR: R 64.5% vs observation 57.4% (HR 0.90, 0.55-1.46); R use with prior treatment: R 53.7% vs observation 42.0% (HR 0.81, 0.54-1.22); no prior R: R 83.3% vs observation 70.6% (HR 0.64, 0.29-1.38). In multivariable analysis, only age >60 was significantly associated with EFS; ECOG performance status, treatment arm, stage and extra-nodal disease were not significant.

This evaluation of rituximab maintenance treatment every 2 mos for one year after ASCT for aggressive lymphoma failed to meet the study endpoint of improved EFS, compared to observation.

Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Kuruvilla:Roche Canada Seattle Genetics, Janssen, Celgene, Lundbeck, Karyopharm: Honoraria. Kouroukis:Roche: Honoraria. Federico:MedImmune: Research Funding. Meyer:Lilly: Consultancy; Celgene: Consultancy.