Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The lancet oncology, 2015-09, Vol.16 (9), p.1111-1122

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Summary 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.