Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression

Abstract

We evaluated early disease progression and its impact on overall survival (OS) in previously untreated follicular lymphoma patients in GALLIUM (clinicaltrials.gov identifier: 01332968), and investigated the effect on early disease progression of the two randomization arms: obinutuzumab-based versus rituximab-based immunochemotherapy. Cause-specific Cox regression was used to estimate the effect of treatment on the risk of disease progression or death due to disease progression within 24 months of randomization and to analyze OS in patients with or without disease progression after 24 months. Mortality in both groups was analyzed 6, 12, and 18 months post randomization (median follow up, 41 months). Fewer early disease progression events occurred in obinutuzumab (57 out of 601) versus rituximab (98 out of 601) immunochemotherapy patients, with an average risk reduction of 46.0% (95%CI: 25.0-61.1%; cumulative incidence rate 10.1% vs 17.4%). At a median post-progression follow up of 22.6 months, risk of mortality increased markedly following a progression event [HR of time-varying progression status, 25.5 (95%CI: 16.2-40.3)]. Mortality risk was higher the earlier patients progressed within the first 24 months. Age-adjusted HR for OS after 24 months in surviving patients with disease progression versus those without was 12.2 (95%CI: 5.6-26.5). Post-progression survival was similar by treatment arm. In conclusion, obinutuzumab plus chemotherapy was associated with a marked reduction in the rate of early disease progression events relative to rituximab plus chemotherapy. Early disease progression in patients with follicular lymphoma was associated with poor prognosis, with mortality risk higher after earlier progression. Survival post progression did not seem to be influenced by treatment arm.

Figure 1.

Progression-free survival (PFS) and progressive disease or death due to progressive disease (POD) events in the 24 months after randomization (POD24) by treatment arm. The table below the graph shows the number of PFS and POD events occurring in the 24 months post-randomization, along with the risk of these events. n: number; PD: progressive disease; CI: confidence interval; HR: hazard ratio; G-chemo: obinutuzumab plus chemotherapy; R-chemo: rituximab plus chemotherapy. ^aAll 155 patients had PD. ^bAt 24 months after randomization, deaths from any cause had occurred in 26 (G-chemo) and 38 (R-chemo) patients.

Figure 2.

Overall survival in POD24 patients post-progression by treatment arm. Shaded sections of lines show 95% Hall-Wellner confidence bands for the period during which patients died. G-chemo: obinutuzumab plus chemotherapy; R-chemo: rituximab plus chemotherapy; N: number. POD24: progressive disease or death due to progressive disease events in the 24 months after randomization.

Figure 3.

Landmark overall survival (OS) analysis, comparing patients with progressive disease or death due to progressive disease (POD) before the landmark and patients with noPOD. (A) 6-month, (B) 12-month, (C) 18-month, and (D) 24-month landmarks. The shaded sections of lines show 95% Hall-Wellner confidence bands for the period during which patients died. The table below the graph shows 2-year OS estimates (with 95%CI) at each landmark. N: number; CI: confidence interval; HR: hazard ratio.