Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in early-stage follicular lymphoma: TROG99.03
Authors: MacManus Michael P. , Seymour John F , Tsang Hennes , Fisher Richard , Keane Colm , Sabdia Muhammed B , Law Soi C , Gunawardana Jay , Nath Karthik , Kazakoff Stephen H , Marques-Piubelli Mario L , Duenas Daniela E , Green Michael R , Roos Daniel , O’Brien Peter , McCann Andrew , Tsang Richard , Davis Sidney , Christie David , Cheah Chan , Amanuel Benhur , Cochrane Tara , Butler Jason , Johnston Anna , Shanavas Mohamed , Li Li , Vajdic Claire , Kridel Robert , Shelton Victoria , Hershenfield Samantha , Baetz Tara , Lebrun David , Johnson Nathalie , Brodtkorb Marianne , Ludvigsen Maja , d’Amore Francesco , Thompson Ella R , Blombery Piers , Gandhi Maher K , Tobin Joshua WD 
Published: August 2024

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 2000-2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. Per 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 andBCL2-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.