Long-Term Outcome of Patients with Follicular Lymphoma Is Not Fundamentally Affected By KMT2D, EZH2, and Crebbp Mutational Status

BACKGROUND: Analysis of 2 large datasets from the National LymphoCare Study (NLCS) and the University of Iowa and Mayo Clinic Molecular Epidemiology Resource (MER) identified a group of patients with early progression of follicular lymphoma (FL) as having poor long-term outcome. In patients with FL who received chemoimmunotherapy as first-line treatment, progression of disease (POD) within 2 years of diagnosis was associated with increased risk of death. Understanding the genomic basis of this poor prognosis is important for improving outcome in this high-risk group. We sought to test the hypothesis that there are distinguishing features in the mutational landscape between patients with FL who experience early progression versus those without early POD.

METHODS: We retrospectively identified patients with FL diagnosed at MSKCC who experienced early POD, defined as progression in less than 12 months from diagnosis (FLEP), and those who experienced late POD, defined as no progression within 36 months from diagnosis (FLLP). Genomic DNA was isolated from FFPE tissue specimens and whole exome sequencing (WES) was performed at MSKCC. Patients with FL grade IIIB, mixed histology, or de novo transformation at diagnosis were excluded. The results were analyzed to identify any mutation enrichment in the FLEP cohort versus the FLLP cohort, and whether there were any new gene mutations picked up with WES that are not covered in the HemePACT or clinical IMPACT targeted signaling platforms.

Genes with significant differences or trends in the occurrence of mutations between the FLEP vs FLLP cases were analyzed in a larger cohort of patients with FL by looking at clinical IMPACT data at MSKCC, comparing progression-free survival (PFS) and overall survival (OS) by mutational status. PFS was calculated from date of diagnosis till date of progression after first-line treatment, death, or censored at date of last follow-up. OS was calculated from date of diagnosis till death or censored at date of last follow-up. To validate previous findings by Casulo et al., OS was stratified by those with POD within 2 years of diagnosis and those without POD within 2 years of diagnosis. OS and PFS analyses were performed using the Kaplan-Meier method in SAS 9.4 and log-rank tests were used to compare differences in survival.

RESULTS: Exploratory analysis with WES was performed on 16 FLEP cases and 10 FLLP cases. There were no significant differences in the occurrence of gene mutations between FLEP and FLLP cases in the WES cohort. Only 1 gene, SETD1B, appeared in the WES panel that is not covered in the HemePACT and clinical IMPACT targeted signaling platforms. In the WES data, trends were observed in 3 genes: KMT2D, CREBBP, and EZH2, with a higher occurrence of mutations in FLLP cases compared to FLEP cases.

To examine these trends further, a larger cohort of 295 patients with available clinical IMPACT data were analyzed. Genomic alterations in KMT2D, CREBBP, and EZH2 were identified and PFS and OS were stratified by mutational status (mutated vs unmutated) in these 3 genes. Patient characteristics are shown in Table 1. Median age of diagnosis was 57 years (range 26-92) with a slight male predominance (53%). The median follow-up was 5.1 years (95% CI, 4.5 - 5.7). Initial treatment in this series of 295 patients with FL included monoclonal antibody + chemotherapy (57%), single-agent rituximab (15%), chemotherapy (2%), radiotherapy alone (8%), and other treatments (6%). Thirty-five patients (12%) were never treated. POD within 2 years was associated with less favorable OS (Figure 1), validating previous findings that early POD identifies a high-risk FL population. Mutational status of KMT2D, CREBBP, and EZH2 were not significantly prognostic of PFS or OS.

DISCUSSION: This analysis further describes the mutational landscape in FL. Our results are congruent with previous findings from the NLCS and MER datasets that early POD after initial therapy is prognostic for poor OS in patients with FL. Mutations in KMT2D, CREBBP, and EZH2 are among the most common mutations in FL, and our data suggest that long-term outcome of patients with FL is not fundamentally affected by the presence or absence of these common mutations. Further research involving targeted sequencing and gene-expression profiling is needed to understand the mechanisms behind the prognostic effect of early POD on survival and improve long-term outcome in this high-risk FL group.

Papaemmanuil:Isabl Inc.: Current equity holder in private company, Current holder of stock options in a privately-held company, Other: CEO, Patents & Royalties: Whole genome cancer analysis; TenSixteen Bio: Current equity holder in private company. Zelenetz:Genentech/Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Juno Pharmaceuticals: Consultancy, Honoraria; MBS: Consultancy, Honoraria; Pharmacyclics/Abbvie: Consultancy, Honoraria; Gilead/Kite Pharma: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.