Comprehensive Genomic Profiling of Mature B-Cell Lymphomas/Leukemias: Foundation One Heme Reveals Actionable Alterations and Biomarkers

Introduction: Molecular profiling of mature B-cell lymphomas and leukemias informs diagnosis, prognosis, and therapy. For example, WHO and NCCN guidelines designate specific genomic alterations, such as TP53 mutations in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), as essential for risk stratification. Gene rearrangements, including those involving IRF4, CCND1, BCL2, BCL6, and MYC, also have diagnostic and prognostic significance for B-cell neoplasms. We analyzed the genomic landscape of a large cohort of mature B-cell lymphomas/leukemias tested on the FoundationOne Heme (F1H) assay platform, highlighting the clinical utility of CGP in patient management. Methods: F1H is a hybrid-capture next-generation sequencing (NGS) assay that analyzes all classes of genomic alterations in DNA (exons from 406 genes, select introns from 31 genes) and rearrangements in RNA (265 genes) from fresh blood, bone marrow, or formalin-fixed paraffin-embedded (FFPE) tumor samples. Samples with diagnoses of CLL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or MCL undergoing F1H testing between 12/2013 and 9/2023 were included in the study. Diagnoses were assigned by board-certified hematopathologists with molecular expertise who reviewed the submitted test requisition forms, hematopathology reports, and accompanying H&E or Wright Giemsa-stained slides. Results: In all, 3,692 unique samples were identified, including 1,188 CLL, 1,374 DLBCL, 624 FL, and 506 MCL cases. The median age was 61 years (range, 3 to >89) and 63% of the patients were male. Sixty-four percent were submitted as FFPE tissue, 26% as peripheral blood, and 10% as bone marrow aspirates. Most samples harbored pathogenic genomic alterations with diagnostic, prognostic, or therapeutic importance. Base substitution or indel variants were detected in TP53 (28% of cases), KMT2D (25%), CREBBP (14%), EZH2 (8%), MYD88 (8%), TNFRSF14 (8%), ATM (8%), NOTCH1 (7%), ARID1A (6%), B2M (6%), TNFAIP3 (6%), PIM1 (4%), CD79B (3%), BTK (2%, 97% of which were C481X ibrutinib resistance mutations in cases of CLL), MEF2B (2%), BCL2 (1%), and PLCG2 (1%). Amplifications of MYC and CD274 were both detected in 1% of cases. Overall, 57% of cases harbored a gene rearrangement, including IGH::BCL2 (24%), IGH::CCND1 (12%), IGH::BCL6 (4%), and IGH::MYC (3%), with 13% of rearrangements detectable by RNA sequencing only. One hundred twenty and 63 unique rearrangement partners were detected for IGH and BCL6, respectively. Overall, 75% of FLs harbored a canonical IGH::BCL2 rearrangement and 86% of MCLs harbored a canonical IGH::CCND1 rearrangement. Conclusions: This analysis of 3,692 samples demonstrated that the F1H assay platform reliably detects a broad landscape of genomic alterations across a range of mature B-cell lymphoma/leukemia subtypes. By detecting all classes of genomic alterations in a single sequencing reaction, F1H provides an important advantage over single-gene and small-panel molecular tests in an era when the diagnosis, prognosis, and treatment of hematological malignancies increasingly rely on assessing the presence, as well as the absence, of numerous genomic alterations.