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

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

doi:10.1016/j.ebiom.2024.105468

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

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 CheahBenhur 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^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin - Blodsygdomme

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Artikelnummer	105468
Tidsskrift	EBioMedicine
Vol/bind	110
DOI	https://doi.org/10.1016/j.ebiom.2024.105468
Status	Udgivet - dec. 2024

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10.1016/j.ebiom.2024.105468Licens: CC BY-NC

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MacManus, M. P., Seymour, J. F., Tsang, H., Fisher, R., Keane, C., Sabdia, M. B., Law, S. C., Gunawardana, J., Nath, K., Kazakoff, S. H., Marques-Piubelli, M. L., Duenas, D. E., Green, M. R., Roos, D., O'Brien, P., McCann, A., Tsang, R., Davis, S., Christie, D., ... Tobin, J. W. D. (2024). 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. EBioMedicine, 110, Artikel 105468. https://doi.org/10.1016/j.ebiom.2024.105468

@article{fc81e0842e7d4f5186b1ff2996763333,

title = "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",

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.",

keywords = "CD8, Early-stage follicular lymphoma, Neoantigen. randomized clinical trial, Radiotherapy, Rituximab",

author = "MacManus, {Michael P.} and Seymour, {John F.} and Hennes Tsang and Richard Fisher and Colm Keane and Sabdia, {Muhammed B.} and Law, {Soi C.} and Jay Gunawardana and Karthik Nath and Kazakoff, {Stephen H.} and Marques-Piubelli, {Mario L.} and Duenas, {Daniela E.} and Green, {Michael R.} and Daniel Roos and Peter O'Brien and Andrew McCann and Richard Tsang and Sidney Davis and David Christie and Chan Cheah and Benhur Amanuel and Tara Cochrane and Jason Butler and Anna Johnston and Mohamed Shanavas and Li Li and Claire Vajdic and Robert Kridel and Victoria Shelton and Samantha Hershenfield and Tara Baetz and David Lebrun and Nathalie Johnson and Marianne Brodtkorb and Maja Ludvigsen and Francesco d'Amore and Thompson, {Ella R.} and Piers Blombery and Gandhi, {Maher K.} and Tobin, {Joshua W.D.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = dec,

doi = "10.1016/j.ebiom.2024.105468",

language = "English",

volume = "110",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

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 2024, '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', EBioMedicine, bind 110, 105468. https://doi.org/10.1016/j.ebiom.2024.105468

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. / MacManus, Michael P.; Seymour, John F.; Tsang, Hennes et al.
I: EBioMedicine, Bind 110, 105468, 12.2024.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - 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

AU - MacManus, Michael P.

AU - Seymour, John F.

AU - Tsang, Hennes

AU - Fisher, Richard

AU - Keane, Colm

AU - Sabdia, Muhammed B.

AU - Law, Soi C.

AU - Gunawardana, Jay

AU - Nath, Karthik

AU - Kazakoff, Stephen H.

AU - Marques-Piubelli, Mario L.

AU - Duenas, Daniela E.

AU - Green, Michael R.

AU - Roos, Daniel

AU - O'Brien, Peter

AU - McCann, Andrew

AU - Tsang, Richard

AU - Davis, Sidney

AU - Christie, David

AU - Cheah, Chan

AU - Amanuel, Benhur

AU - Cochrane, Tara

AU - Butler, Jason

AU - Johnston, Anna

AU - Shanavas, Mohamed

AU - Li, Li

AU - Vajdic, Claire

AU - Kridel, Robert

AU - Shelton, Victoria

AU - Hershenfield, Samantha

AU - Baetz, Tara

AU - Lebrun, David

AU - Johnson, Nathalie

AU - Brodtkorb, Marianne

AU - Ludvigsen, Maja

AU - d'Amore, Francesco

AU - Thompson, Ella R.

AU - Blombery, Piers

AU - Gandhi, Maher K.

AU - Tobin, Joshua W.D.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

KW - CD8

KW - Early-stage follicular lymphoma

KW - Neoantigen. randomized clinical trial

KW - Radiotherapy

KW - Rituximab

UR - http://www.scopus.com/inward/record.url?scp=85210707749&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2024.105468

DO - 10.1016/j.ebiom.2024.105468

M3 - Journal article

C2 - 39631145

AN - SCOPUS:85210707749

SN - 2352-3964

VL - 110

JO - EBioMedicine

JF - EBioMedicine

M1 - 105468

ER -

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

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