Recapitulation of Prognostic Mutational Subtyping Utilizing F1H in GOYA and CAVALLI and the Potential to Highlight Benefit of Targeted Therapy in De Novo DLBCL
Introduction: Diffuse large B-cell lymphoma (DLBCL), is a genetically and clinically heterogeneous disease. Building on existing clinical prognostic scores in the era of genomic risk modeling is critical to improve patient (pt) outcomes and inform future trials. With advances in next-generation sequ...
Gespeichert in:
Veröffentlicht in: | Blood 2019-11, Vol.134 (Supplement_1), p.2788-2788 |
---|---|
Hauptverfasser: | , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Introduction: Diffuse large B-cell lymphoma (DLBCL), is a genetically and clinically heterogeneous disease. Building on existing clinical prognostic scores in the era of genomic risk modeling is critical to improve patient (pt) outcomes and inform future trials. With advances in next-generation sequencing, the interrogation of genetic drivers to refine prognostic subgroups over and above histological cell of origin (COO) subtypes has been of keen interest. The application of an unsupervised prognostic clustering approach, non-negative matrix factorization (NMF) algorithm, to whole exome sequence (WES) data has led to identification of six distinct molecular clusters with potential clinical relevance (Chapuy et al. Nature Med, 2018). Here, we applied the NMF clustering approach to targeted exome-sequencing data utilizing the FoundationOne HemeTM panel and analyzed RNA gene expression data from the randomized Phase 3 GOYA and Phase 1b/2 CAVALLI studies in de novo DLBCL.
Methods: Biopsy samples, clinical outcomes (overall survival [OS], progression-free survival [PFS]), and targeted exome-sequencing data were available for 499 pts from the GOYA trial (NCT01287741; ITT=1418; obinutuzumab [G]-CHOP vs rituximab [R]-CHOP) and 106 pts from the CAVALLI trial (NCT02055820; ITT=267, venetoclax+[G/R]-CHOP). The FoundationOne HemeTM panel of 465 genes (F1H, Foundation Medicine Inc. [FMI]) was used to define single nucleotide variants, copy number amplifications, and rearrangements. Clustering methodology was implemented using the R package NMF (Gaujoux and Seoighe, BMC Bioinformatics 2010). All models were adjusted for treatment (where applicable), age, International Prognostic Index (IPI), sex, COO (NanoString), and BCL2 by IHC.
Results: Applying the NMF algorithm, de novo pts in GOYA clustered similarly into four of the six groups recently reported by Chapuy et al.: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations (Fig 1A). The mutation profiles and COO subset distribution were also similar to those previously described. Furthermore, the MYD88/CD79B and BCL2/EZH2 groups remained associated with inferior clinical outcomes (Fig 1B), with observed poor prognosis over the NOTCH2/TNFAIP3 and no mutations groups (OS: hazard ratio [HR], 2.0; 95% CI: 0.97, 3.90; PFS: HR, 1.60; 95% CI: 0.93, 2.80), even when adjusting for known prognostic factors. Application of NMF to pts treated with the BCL2-inhibitor venetoclax in combination with R-CHOP (CAVALLI) yielded only MYD |
---|---|
ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2019-124687 |