Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: A retrospective analysis of a prospective clinical trial and validation in a population-based registry

Alessandro Pastore, Vindi Jurinovic, Robert Kridel, Eva Hoster, Annette M. Staiger, Monika Szczepanowski, Christiane Pott, Nadja Kopp, Mark Murakami, Heike Horn, Ellen Leich, Alden A. Moccia, Anja Mottok, Ashwini Sunkavalli, Paul Van Hummelen, Matthew Ducar, Daisuke Ennishi, Hennady P. Shulha, Christoffer Hother, Joseph M. ConnorsLaurie H. Sehn, Martin Dreyling, Donna Neuberg, Peter Möller, Alfred C. Feller, Martin L. Hansmann, Harald Stein, Andreas Rosenwald, German Ott, Wolfram Klapper, Michael Unterhalt, Wolfgang Hiddemann, Randy D. Gascoyne, David M. Weinstock, Oliver Weigert

Research output: Contribution to journalArticle

201 Citations (Scopus)

Abstract

Background: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. Methods: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). Findings: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (. EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). Interpretation: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Funding: Deutsche Krebshilfe, Terry Fox Research Institute.

Original languageEnglish
Article number153
Pages (from-to)1111-1122
Number of pages12
JournalThe Lancet Oncology
Volume16
Issue number9
DOIs
Publication statusPublished - Sep 1 2015
Externally publishedYes

Fingerprint

Follicular Lymphoma
Registries
Clinical Trials
Mutation
Population
Genes
Survival
Vincristine
Prednisone
Cyclophosphamide
Biopsy
High-Throughput Nucleotide Sequencing
Treatment Failure
DNA Sequence Analysis
Doxorubicin

ASJC Scopus subject areas

  • Oncology

Cite this

Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma : A retrospective analysis of a prospective clinical trial and validation in a population-based registry. / Pastore, Alessandro; Jurinovic, Vindi; Kridel, Robert; Hoster, Eva; Staiger, Annette M.; Szczepanowski, Monika; Pott, Christiane; Kopp, Nadja; Murakami, Mark; Horn, Heike; Leich, Ellen; Moccia, Alden A.; Mottok, Anja; Sunkavalli, Ashwini; Van Hummelen, Paul; Ducar, Matthew; Ennishi, Daisuke; Shulha, Hennady P.; Hother, Christoffer; Connors, Joseph M.; Sehn, Laurie H.; Dreyling, Martin; Neuberg, Donna; Möller, Peter; Feller, Alfred C.; Hansmann, Martin L.; Stein, Harald; Rosenwald, Andreas; Ott, German; Klapper, Wolfram; Unterhalt, Michael; Hiddemann, Wolfgang; Gascoyne, Randy D.; Weinstock, David M.; Weigert, Oliver.

In: The Lancet Oncology, Vol. 16, No. 9, 153, 01.09.2015, p. 1111-1122.

Research output: Contribution to journalArticle

Pastore, A, Jurinovic, V, Kridel, R, Hoster, E, Staiger, AM, Szczepanowski, M, Pott, C, Kopp, N, Murakami, M, Horn, H, Leich, E, Moccia, AA, Mottok, A, Sunkavalli, A, Van Hummelen, P, Ducar, M, Ennishi, D, Shulha, HP, Hother, C, Connors, JM, Sehn, LH, Dreyling, M, Neuberg, D, Möller, P, Feller, AC, Hansmann, ML, Stein, H, Rosenwald, A, Ott, G, Klapper, W, Unterhalt, M, Hiddemann, W, Gascoyne, RD, Weinstock, DM & Weigert, O 2015, 'Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: A retrospective analysis of a prospective clinical trial and validation in a population-based registry', The Lancet Oncology, vol. 16, no. 9, 153, pp. 1111-1122. https://doi.org/10.1016/S1470-2045(15)00169-2
Pastore, Alessandro ; Jurinovic, Vindi ; Kridel, Robert ; Hoster, Eva ; Staiger, Annette M. ; Szczepanowski, Monika ; Pott, Christiane ; Kopp, Nadja ; Murakami, Mark ; Horn, Heike ; Leich, Ellen ; Moccia, Alden A. ; Mottok, Anja ; Sunkavalli, Ashwini ; Van Hummelen, Paul ; Ducar, Matthew ; Ennishi, Daisuke ; Shulha, Hennady P. ; Hother, Christoffer ; Connors, Joseph M. ; Sehn, Laurie H. ; Dreyling, Martin ; Neuberg, Donna ; Möller, Peter ; Feller, Alfred C. ; Hansmann, Martin L. ; Stein, Harald ; Rosenwald, Andreas ; Ott, German ; Klapper, Wolfram ; Unterhalt, Michael ; Hiddemann, Wolfgang ; Gascoyne, Randy D. ; Weinstock, David M. ; Weigert, Oliver. / Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma : A retrospective analysis of a prospective clinical trial and validation in a population-based registry. In: The Lancet Oncology. 2015 ; Vol. 16, No. 9. pp. 1111-1122.
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abstract = "Background: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. Methods: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). Findings: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (. EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28{\%}, 43/151) with 5-year failure-free survival of 38·29{\%} (95{\%} CI 25·31-57·95) versus 77·21{\%} (95{\%} CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95{\%} CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95{\%} CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64{\%} and 78{\%}, respectively, with a C-index of 0·80 (95{\%} CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22{\%}, 24/107) with 5-year failure-free survival of 25·00{\%} (95{\%} CI 12·50-49·99) versus 68·24{\%} (58·84-79·15) in the low-risk group (HR 3·58, 95{\%} CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72{\%} and 68{\%} for negative predictive value, with a C-index of 0·79 (95{\%} CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95{\%} CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95{\%} CI 1·12-3·67). Interpretation: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Funding: Deutsche Krebshilfe, Terry Fox Research Institute.",
author = "Alessandro Pastore and Vindi Jurinovic and Robert Kridel and Eva Hoster and Staiger, {Annette M.} and Monika Szczepanowski and Christiane Pott and Nadja Kopp and Mark Murakami and Heike Horn and Ellen Leich and Moccia, {Alden A.} and Anja Mottok and Ashwini Sunkavalli and {Van Hummelen}, Paul and Matthew Ducar and Daisuke Ennishi and Shulha, {Hennady P.} and Christoffer Hother and Connors, {Joseph M.} and Sehn, {Laurie H.} and Martin Dreyling and Donna Neuberg and Peter M{\"o}ller and Feller, {Alfred C.} and Hansmann, {Martin L.} and Harald Stein and Andreas Rosenwald and German Ott and Wolfram Klapper and Michael Unterhalt and Wolfgang Hiddemann and Gascoyne, {Randy D.} and Weinstock, {David M.} and Oliver Weigert",
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doi = "10.1016/S1470-2045(15)00169-2",
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TY - JOUR

T1 - Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma

T2 - A retrospective analysis of a prospective clinical trial and validation in a population-based registry

AU - Pastore, Alessandro

AU - Jurinovic, Vindi

AU - Kridel, Robert

AU - Hoster, Eva

AU - Staiger, Annette M.

AU - Szczepanowski, Monika

AU - Pott, Christiane

AU - Kopp, Nadja

AU - Murakami, Mark

AU - Horn, Heike

AU - Leich, Ellen

AU - Moccia, Alden A.

AU - Mottok, Anja

AU - Sunkavalli, Ashwini

AU - Van Hummelen, Paul

AU - Ducar, Matthew

AU - Ennishi, Daisuke

AU - Shulha, Hennady P.

AU - Hother, Christoffer

AU - Connors, Joseph M.

AU - Sehn, Laurie H.

AU - Dreyling, Martin

AU - Neuberg, Donna

AU - Möller, Peter

AU - Feller, Alfred C.

AU - Hansmann, Martin L.

AU - Stein, Harald

AU - Rosenwald, Andreas

AU - Ott, German

AU - Klapper, Wolfram

AU - Unterhalt, Michael

AU - Hiddemann, Wolfgang

AU - Gascoyne, Randy D.

AU - Weinstock, David M.

AU - Weigert, Oliver

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. Methods: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). Findings: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (. EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). Interpretation: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Funding: Deutsche Krebshilfe, Terry Fox Research Institute.

AB - Background: Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model. Methods: We did DNA deep sequencing to retrospectively analyse the mutation status of 74 genes in 151 follicular lymphoma biopsy specimens that were obtained from patients within 1 year before beginning immunochemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These patients were recruited between May 4, 2000, and Oct 20, 2010, as part of a phase 3 trial (GLSG2000). Eligible patients had symptomatic, advanced stage follicular lymphoma and were previously untreated. The primary endpoints were failure-free survival (defined as less than a partial remission at the end of induction, relapse, progression, or death) and overall survival calculated from date of treatment initiation. Median follow-up was 7·7 years (IQR 5·5-9·3). Mutations and clinical factors were incorporated into a risk model for failure-free survival using multivariable L1-penalised Cox regression. We validated the risk model in an independent population-based cohort of 107 patients with symptomatic follicular lymphoma considered ineligible for curative irradiation. Pretreatment biopsies were taken between Feb 24, 2004, and Nov 24, 2009, within 1 year before beginning first-line immunochemotherapy consisting of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Median follow-up was 6·7 years (IQR 5·7-7·6). Findings: We established a clinicogenetic risk model (termed m7-FLIPI) that included the mutation status of seven genes (. EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the Follicular Lymphoma International Prognostic Index (FLIPI), and Eastern Cooperative Oncology Group (ECOG) performance status. In the training cohort, m7-FLIPI defined a high-risk group (28%, 43/151) with 5-year failure-free survival of 38·29% (95% CI 25·31-57·95) versus 77·21% (95% CI 69·21-86·14) for the low-risk group (hazard ratio [HR] 4·14, 95% CI 2·47-6·93; p<0·0001; bootstrap-corrected HR 2·02), and outperformed a prognostic model of only gene mutations (HR 3·76, 95% CI 2·10-6·74; p<0·0001; bootstrap-corrected HR 1·57). The positive predictive value and negative predictive value for 5-year failure-free survival were 64% and 78%, respectively, with a C-index of 0·80 (95% CI 0·71-0·89). In the validation cohort, m7-FLIPI again defined a high-risk group (22%, 24/107) with 5-year failure-free survival of 25·00% (95% CI 12·50-49·99) versus 68·24% (58·84-79·15) in the low-risk group (HR 3·58, 95% CI 2·00-6·42; p<0.0001). The positive predictive value for 5-year failure-free survival was 72% and 68% for negative predictive value, with a C-index of 0·79 (95% CI 0·69-0·89). In the validation cohort, risk stratification by m7-FLIPI outperformed FLIPI alone (HR 2·18, 95% CI 1·21-3·92), and FLIPI combined with ECOG performance status (HR 2·03, 95% CI 1·12-3·67). Interpretation: Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure. Funding: Deutsche Krebshilfe, Terry Fox Research Institute.

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