Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in a randomised trial of systemic therapy in early-stage follicular lymphoma.

Background: We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies.

Methods: Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT + CVP). From 2006 rituximab was added to IFRT + CVP (IFRT + R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively).

Findings: Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at median follow-up 11.3-years, progression-free survival (PFS) remained superior for IFRT+(R)CVP vs. IFRT (hazard ratio [HR] = 0.60, 95% CI = 0.37-0.98, p = 0.043; 10-year PFS 62% vs. 43%) respectively. Although no significant difference in overall survival was observed (HR = 0.44, 95% CI = 0.16-1.18, p = 0.11, 10-year OS 95% vs. 84%), patients receiving IFRT+(R)CVP experienced fewer composite (histological transformation and death) events (p = 0.045). PFS of IFRT + R-CVP-treated patients compared with all other treatments lacking rituximab (IFRT alone plus IFRT + CVP) was superior (HR = 0.36, 95% CI = 0.13-0.82, p = 0.013). Amongst PET-staged patients, PFS differences between IFRT + R-CVP vs. IFRT were maintained (HR = 0.38, 95% CI = 0.16-0.89, p = 0.027) indicating benefit distinct from stage migration. FL-related mutations and BCL2-translocations were not associated with PFS. However, by multivariate analysis elevated CD8A gene expression in diagnostic biopsy tissue was independently associated with improved PFS (HR = 0.45, 95% CI = 0.26-0.79, p = 0.037), a finding confirmed in both ESFL validation cohorts. CD8A gene expression was raised (p = 0.02) and CD8+ T-cell density higher within follicles in ESFL vs. advanced-stage FL (p = 0.047). Human leucocyte antigen class I specific neoantigens were detected in 43% of patients, suggesting neoantigen-specific CD8+ T-cells have a role in confining the spread of the disease.

Interpretation: Adjuvant R-CVP and elevated intratumoural CD8 expression were independently associated with sustained disease control after radiotherapy in ESFL.

Funding: Cancer Council Victora; National Health and Medical Research Council; Leukaemia Foundation; Mater Foundation.