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
Year: 2024
Type: article
Study design: Clinical Trial
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.
Source: EBioMedicine
Authors: Michael P. MacManus, John F. Seymour, Hennes Tsang, Richard Fisher, Colm Keane, Muhammed B. Sabdia, Soi C. Law, Jay Gunawardana, Karthik Nath, Stephen H. Kazakoff, Mario L. Marques-Piubelli, Daniela E. Duenas, Michael R. Green, Daniel Roos, Peter O'Brien, Andrew McCann, Richard Tsang, Sidney Davis, David Christie, Chan Cheah, Benhur Amanuel, Tara Cochrane, Jason Butler, Anna Johnston, Mohamed Shanavas, Li Li, Claire Vajdic, Robert Kridel, Victoria Shelton, Samantha Hershenfield, Tara Baetz, David Lebrun, Nathalie Johnson, Marianne Brodtkorb, Maja Ludvigsen, Francesco d’Amore, Ella R. Thompson, Piers Blombery, Maher K. Gandhi, Joshua W.D. Tobin
Institutions: The University of Melbourne, Peter MacCallum Cancer Centre, The University of Queensland, Mater Research, Princess Alexandra Hospital, Memorial Sloan Kettering Cancer Center, QIMR Berghofer Medical Research Institute, The University of Texas MD Anderson Cancer Center, Royal Adelaide Hospital, Auckland City Hospital, Princess Margaret Cancer Centre, The Alfred Hospital, Sir Charles Gairdner Hospital, Pathwest Laboratory Medicine, Gold Coast Hospital, Royal Brisbane and Women's Hospital, Royal Hobart Hospital, Mater Adult Hospital, Ochsner Health System, UNSW Sydney, Kirby Institute, Queen's University, Oslo University Hospital, Aarhus University Hospital
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,000
Award: Cancer Center Support Grant
OpenAlex ID: W4404945177