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
- Author(s)
- MacManus, MP; Seymour, JF; Tsang, H; Fisher, R; Keane, C; Sabdia, MB; Law, SC; Gunawardana, J; Nath, K; Kazakoff, SH; Marques-Piubelli, ML; Duenas, DE; Green, MR; Roos, D; O'Brien, P; McCann, A; Tsang, R; Davis, S; Christie, D; Cheah, C; Amanuel, B; Cochrane, T; Butler, J; Johnston, A; Shanavas, M; Li, L; Vajdic, C; Kridel, R; Shelton, V; Hershenfield, S; Baetz, T; LeBrun, D; Johnson, N; Brodtkorb, M; Ludvigsen, M; d'Amore, F; Thompson, ER; Blombery, P; Gandhi, MK; Tobin, JWD;
- Journal Title
- eBioMedicine
- Publication Type
- Research article
- Abstract
- 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.
- Publisher
- Elsevier
- Keywords
- Humans; *Lymphoma, Follicular/therapy/metabolism/mortality; *Rituximab/therapeutic use/pharmacology; Male; Female; Middle Aged; Aged; *Neoplasm Staging; Adult; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; CD8-Positive T-Lymphocytes/metabolism/immunology; Treatment Outcome; Cd8; Early-stage follicular lymphoma; Neoantigen. randomized clinical trial; Radiotherapy; Rituximab
- Department(s)
- Radiation Oncology; Haematology; Pathology
- Publisher's Version
- https://doi.org/10.1016/j.ebiom.2024.105468
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-01-07 06:16:13
Last Modified: 2025-01-07 06:21:14