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.

Autor:	MacManus MP; Peter MacCallum Cancer Institute, Melbourne, VIC, Australia; University of Melbourne, VIC, Australia. Electronic address: Michael.Macmanus@petermac.org., Seymour JF; Peter MacCallum Cancer Institute, Melbourne, VIC, Australia; University of Melbourne, VIC, Australia., Tsang H; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia., Fisher R; Peter MacCallum Cancer Institute, Melbourne, VIC, Australia., Keane C; Frazer Institute, University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Brisbane, QLD, Australia., Sabdia MB; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia., Law SC; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia., Gunawardana J; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia., Nath K; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kazakoff SH; Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia., Marques-Piubelli ML; MD Anderson Cancer Centre, Houston, TX, USA., Duenas DE; MD Anderson Cancer Centre, Houston, TX, USA., Green MR; MD Anderson Cancer Centre, Houston, TX, USA., Roos D; Royal Adelaide Hospital, Adelaide, SA, Australia., O'Brien P; Genesis Cancer Care, Newcastle, NSW, Australia., McCann A; Auckland City Hospital, Auckland, New Zealand., Tsang R; Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Davis S; The Alfred, Melbourne, VIC, Australia., Christie D; Genesis Cancer Care, Tugun, QLD, Australia., Cheah C; Sir Charles Gairdner Hospital, Perth, WA, Australia., Amanuel B; PathWest Laboratory Medicine WA, Australia., Cochrane T; Gold Coast University Hospital, Gold Coast, QLD, Australia., Butler J; Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia., Johnston A; Royal Hobart Hospital, Hobart, TAS, Australia., Shanavas M; Mater Adult Hospital, Brisbane, QLD, Australia., Li L; Ochsner Health, New Orleans, LA, USA., Vajdic C; UNSW Kirby Institute, Sydney, NSW, Australia., Kridel R; Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Shelton V; Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Hershenfield S; Princess Margaret Cancer Centre, Toronto, Ontario, Canada., Baetz T; Queen's University, Kingston, Ontario, Canada., Lebrun D; Queens Cancer Research Institute, Kingston, Ontario, Canada., Johnson N; McGill Centre for Translational Research in Cancer, Quebec, Canada., Brodtkorb M; Oslo University Hospital, Norway., Ludvigsen M; Aarhus University Hospital, Aarhus, Denmark., d'Amore F; Aarhus University Hospital, Aarhus, Denmark., Thompson ER; Peter MacCallum Cancer Institute, Melbourne, VIC, Australia., Blombery P; Peter MacCallum Cancer Institute, Melbourne, VIC, Australia; University of Melbourne, VIC, Australia., Gandhi MK; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Brisbane, QLD, Australia. Electronic address: m.gandhi@uq.edu.au., Tobin JWD; Mater Research Institute, University of Queensland, Brisbane, QLD, Australia; Princess Alexandra Hospital, Brisbane, QLD, Australia. Electronic address: j.tobin@uq.edu.au.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Dec; Vol. 110, pp. 105468. Date of Electronic Publication: 2024 Dec 03.
DOI:	10.1016/j.ebiom.2024.105468
Abstrakt:	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. Competing Interests: Declaration of interests Amgen (GCSF) and Roche (Rituximab) for the provision of study materials. There are no other relevant conflicts of interest. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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