Abstract
Current understanding of the mutation spectrum of relapsed/refractory (RR) tumors is limited. We performed whole exome sequencing (WES) on 47 diffuse large B cell lymphoma (DLBCL) tumors that persisted after R-CHOP treatment, 8 matched to primary biopsies. We compared genomic alterations from the RR cohort against two treatment-naïve DLBCL cohorts (n=112). While the overall number and types of mutations did not differ significantly, we identified frequency changes in DLBCL driver genes. The overall frequency of MYD88 mutant samples increased (12% to 19%), but we noted a decrease in p.L265P (8% to 4%) and increase in p.S219C mutations (2% to 6%). CARD11 p.D230N, PIM1 p.K115N and CD79B p.Y196C mutations were not observed in the RR cohort, although these mutations were prominent in the primary DLBCL samples. We observed an increase in BCL2 mutations (21% to 38% of samples), BCL2 amplifications (3% to 6% of samples) and CREBBP mutations (31% to 42% of samples) in the RR cohort, supported by acquisition of mutations in these genes in relapsed compared to diagnostic biopsies from the same patient. These increases may reflect the genetic characteristics of R-CHOP RR tumors expected to be enriched for during clinical trial enrollment. These findings hold significance for a number of emerging targeted therapies aligned to genetic targets and biomarkers in DLBCL, reinforcing the importance of time-of-treatment biomarker screening during DLBCL therapy selection.
Highlights
Non-Hodgkin’s lymphoma (NHL) is the most prevalent form of lymphoma, comprising an estimated 88% of 80,900 new lymphoma cases in 2015 [1]
40% of diffuse large B cell lymphoma (DLBCL) patients still relapse after initial treatment with the R-CHOP (Rituximabcyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) immunochemotherapy regimen, which is considered the standard of care (SOC) for DLBCL [7]
The majority of these trials incorporated gene expression profiling for the purposes of cell of origin (COO) subtype identification, five trials included mutational analysis of specific genes, but only four trials included an intent to analyze the genomic landscape of DLBCL, including the cohort we analyzed and a recent study reported by Morin et al [9]
Summary
Non-Hodgkin’s lymphoma (NHL) is the most prevalent form of lymphoma, comprising an estimated 88% of 80,900 new lymphoma cases in 2015 [1]. Understanding the landscape is critical for development of novel targeted treatments for DLBCL for which clinical trial success depends on initial studies in patients who have failed SOC therapies. To put this into context, we identified 54 clinical studies of novel therapeutics in relapsed/refractory (RR) DLBCL that were opened during the sample collection period (20102015) for the samples evaluated in this study [8]. The majority of these trials incorporated gene expression profiling for the purposes of cell of origin (COO) subtype identification, five trials included mutational analysis of specific genes, but only four trials included an intent to analyze the genomic landscape of DLBCL, including the cohort we analyzed and a recent study reported by Morin et al [9]
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