Molecular Subtypes of Splenic Marginal Zone Lymphoma (SMZL) Are Associated with Distinct Pathogenic Mechanisms and Outcomes - Interim Analysis of the IELSG46 Study

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.922-922
• Main Authors: Guidetti, Francesca, Bruscaggin, Alessio, Frigeni, Marco, Spina, Valeria, Terzi di Bergamo, Lodovico, Condoluci, Adalgisa, Forestieri, Gabriela, Bertoni, Francesco, Cascione, Luciano, Mollejo, Manuela, Meignin, Véronique, Traverse-Glehen, Alexandra, Geyer, Julia T, Broccoli, Alessandro, Tucci, Alessandra, Bea, Silvia, Boldorini, Renzo, Tapia, Gustavo, Maiorana, Antonino, Gomes da Silva, Maria, Garcia, Juan F., Hitz, Felicitas, Merli, Michele, Vanini, Giorgio A., Novak, Urban, Piazza, Francesco, Pizzolitto, Stefano, Dietrich, Sascha, Devizzi, Liliana, Ladetto, Marco, Ponzoni, Maurilio, Rambaldi, Alessandro, Corradini, Paolo, Tarella, Corrado, Santambrogio, Elisa, Vitolo, Umberto, Zaja, Francesco, Passamonti, Francesco, Tzankov, Alexandar, Cogliatti, Sergio, Montalban, Carlos, Marasca, Roberto, de Leval, Laurence, Visco, Carlo, Baptista, Maria Joao, Canzonieri, Vincenzo, Matutes, Estella, Facchetti, Fabio, Paulli, Marco, Campo, Elias, Oscier, David, Sabattini, Elena, Zinzani, Pier Luigi, Bhagat, Govind, Pileri, Stefano A., Inghirami, Giorgio, Gaidano, Gianluca, Salles, Gilles, Thieblemont, Catherine, Piris, Miguel A., Cavalli, Franco, Zucca, Emanuele, Arcaini, Luca, Rossi, Davide
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-115958

Introduction. The majority of SMZLs display an indolent course, however the disease is still incurable and a significant proportion of patients (~25-30%) experience poor outcomes surviving 5 years, and for whom tumor material collected before initiation of medical therapy was available. Mutation analysis was performed by CAPP-seq targeted deep next generation sequencing of tumor genomic DNA. A stringent bioinformatic pipeline was applied to suppress the background noise allowing to call variants with a sensitivity of 5x10-2 in FFPE derived DNA. Copy number variations (CNVs) were identified by using the sequencing reads-based GATK4-CNV algorithm. IGHV rearrangements were obtained by using LymphoTrack® IGH FR1 Assay Panel kit. Molecular clusters were identified by an iterative algorithm that maximizes genetic distinctiveness of subgroups by reassigning patients between clusters that are created a priori based on the co-occurrence of genetic lesions. Relative survival, defined as the ratio between actuarial survival observed in the SMZL cohort and expected survival of the general population matched to patients by geographical origin, sex, age and calendar year of diagnosis, was calculated using the Ederer II method. Results. The analysis included 303 patients with a SMZL diagnosis confirmed on spleen histology. The sample size allowed to identify 30% differences in survival for molecular subgroups comprising at least 5% of cases with a statistical power between 80-100%. Median follow-up was 9.2 years. At 10 years, 85% of patients were alive, consistent with the known indolent behavior of this lymphoma. Genes recurrently affected by non-synonymous somatic mutations in >10% of SMZL included KLF2 (24%), NOTCH2 (19%), KMT2D (15%), TNFAIP3 (13%), EP300 and TP53 (10%). Deletion 7q was documented in 25% of cases and IGHV1-2*04 usage in 32%. By cluster analysis, three major molecular subgroups were identified, each of them characterized